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CN105037367A - Amino six-membered ring derivative and application thereof in medicines - Google Patents

Amino six-membered ring derivative and application thereof in medicines Download PDF

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Publication number
CN105037367A
CN105037367A CN201510185339.8A CN201510185339A CN105037367A CN 105037367 A CN105037367 A CN 105037367A CN 201510185339 A CN201510185339 A CN 201510185339A CN 105037367 A CN105037367 A CN 105037367A
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alkyl
group
amino
alkoxyl group
hydroxyl
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Inventor
范江
陈清平
江伟
郑苏欣
叶飞
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Sichuan Haisco Pharmaceutical Co Ltd
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Sichuan Haisco Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention relates to an amino six-membered ring derivative and an application thereof in medicines, and in particular, the invention relates to an amino six-membered ring derivative represented as the general formula (I), or a stereisomer thereof, a pharmaceutically-acceptable salt thereof, a pre-drug thereof, a drug composition comprising the derivative, and the application in a medicine of preparing a dipeptidyl peptidase IV (DPP-IV) inhibitor, wherein the substituent groups in the general formula (I) are defined as same as that in the specification.

Description

Amino six-ring analog derivative and in application pharmaceutically
Technical field
The present invention relates to a kind of amino six-ring analog derivative and application thereof, relate to amino six-ring analog derivative shown in general formula (I) or its available medicinal salt or its steric isomer and the pharmaceutical composition containing this derivative or its available medicinal salt or its steric isomer specifically, and its as therapeutical agent particularly as the purposes of DPP IV (DPP-IV) inhibitor.
Background technology
Diabetes are worldwide great medical care problems, and according to IDF (IDF) statistics, within 2013, global diabetic subject's number has reached 3.82 hundred million, and global medical cost reaches 5,480 hundred million dollars, account for 11% of global medical expenditure.Expect 2035, the global medical cost relevant to diabetes will reach 6,273 hundred million dollars.Regular Insulin is hormone required when being energy by sucrose, starch and other food conversions, and diabetes are normally owing to can not secreting from body or suitably utilizing Regular Insulin to cause.Diabetes are divided into type i diabetes (or insulin-dependent diabetes mellitus, IDDM) and type II diabetes (or non insulin dependent diabetes, NIDDM) usually.Modal diabetes type is type II diabetes, and worldwide, type II diabetes accounts for 90% of all diabetes.Due to modern times unsound mode of life, as tempered the reasons such as minimizing and full diet, the sickness rate of type II diabetes is in the trend increased gradually.Huge market potential has attracted a large amount of drugmakers and research centre to develop new anti-diabetic target spot and medicine.
The medicine being used for the treatment of type II diabetes listing of current approved mainly contains Regular Insulin and analogue, sulfonylurea, biguanides, thiazolidinediones (TZDs), alpha-glucosidase inhibitor, dextrin analogue, gut incretin hormones analogue, depeptidyl peptidase inhibitors (DPP-IV) etc.But the glycolated hemoglobin (HbA1c) that these antidiabetic drugs of patient's long-term taking still can not reach expection reduces index, and these antidiabetic drugs all have side effect, as hypoglycemia, body weight increase and cardiovascular risk etc.These side effects have increased the weight of the burden of diabetic subject.Therefore, in the urgent need to there is novel antidiabetic drug that is efficient, few side effects for type II diabetes exploitation.
DPP IV (DipeptidylPeptidase, DPP-IV, EC3.4.14.5) is a serine protease, holds penultimate hydrolyzing N end dipeptides from the polypeptide N containing L-PROLINE and ALANINE.Although the function of DPP-IV is not fully elucidated, it is considered to the major physiological regulatory factor that some regulates polypeptide, neuropeptide, circulating hormone and chemokine.Although as multiple-effect enzyme, DPP-IV has many substrates, and that the most known is secretin, and it comprises glucagon-like-peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP).Secretin is taking in nutraceutical several minutes internal secretion and the enteron aisle hormone of the nutraceutical disposal of promotion absorption.The effect of GLP-1 with GIP to β cell is identical, β cell function can be improved, comprise the insulin secretion of promotion dependence on the glucose, inducing beta cell propagation, strengthen Anti-G value (DiabetesandVascularDiseaseResearch20063:159).
Different from GIP, GLP-1 is still and promotes insulin secretion in type II diabetes, therefore, improves the means (PharmacolRev60:470 – 512,2008) that GLP-1 is a kind of promising treatment type II diabetes.GLP-1 is used can obviously to reduce blood sugar (Lancet in patients with NIDDM, 2002,359:824-830), but GLP-1 can be hydrolyzed and inactivation rapidly in vivo as the substrate of DPP-IV, therefore develops DPP-IV inhibitor and has very important significance to treatment diabetes.
At present, the research of DPP-IV inhibitor achieves larger progress, comprise sitagliptin, BMS-477118, Egelieting DPP-IV inhibitor ratified listing.The most outstanding feature of DPP-IV inhibitor is, due to incretin only secretion after body feed, DPP-IV inhibitor not easily increases insulin level unsuitable time, produces the side effect hypoglycemia that many antidiabetic drugs are common.Recent clinical data shows, and suppresses DPP-IV that insulin secretion can be made to increase, reduces blood sugar concentration and improve pancreas islet beta cell function (Diabetes, 1998,47:1253-1258).The side effect of common DPP-IV inhibitor has respiratory tract infection, has a sore throat, suffers from diarrhoea, cold like symptoms, headache and dizzy etc.But totally there is good security and tolerance, also do not find that the patient used has serious body weight to increase or potential to lose weight and the symptom such as oedema at present.
The sickness rate of diabetes (mainly type II diabetes), in the world in increasing trend year by year, becomes after cardiovascular disorder and tumour, the Non Communicable Diseases (NCD) of the 3rd threat health of people and life.The treatment of diabetes brings white elephant to family and society.Therefore, being badly in need of the better DPP-IV of the more renewals of exploitation suppresses medicine to meet the needs of extensive patients clinical application.
At present, the document about DPP-IV inhibitor correlative study is reported in succession:
(1) US2007232676 discloses the compound of following structure as DPP-IV inhibitor, wherein:
Ar is selected from and is selected from halogen, hydroxyl, C by 1-5 1-6the phenyl that the substituting groups such as alkyl replace;
V is selected from deng group, and R 3a, R 3bbe selected from independently selected from hydrogen, by the C of 1-5 fluorine atom replacement 1-4alkyl; R 2be selected from the groups such as hydrogen, hydroxyl, halogen, carboxyl; R 8be selected from hydrogen ,-(CH 2) pthe groups such as-phenyl, but without methyl sulphonyl; Do not think that specifically describing in this patent is a part of the present invention.
(2) US20100120863 discloses the compound of following structure as DPP IV (DPP-IV) inhibitor, in the purposes for the treatment of, prevention type ii diabetes, wherein:
Ar is selected from the group such as hydrogen, alkyl;
V is selected from deng, and R 3a, R 3bbe selected from independently selected from hydrogen, by the C of 1-5 fluorine atom replacement 1-4alkyl; R 2be selected from the groups such as hydrogen, hydroxyl, halogen, carboxyl; R 8be selected from-S (O) 2-C 1-6cycloalkyl ,-S (O) 2-C 1-6the groups such as alkyl; Do not think that specifically describing in this patent is a part of the present invention.
(3) compound that CN102272136 discloses following structure has DPP-IV inhibitor effect, as the purposes preventing and/or treating medicine of diabetes, wherein:
Ar is optionally by the phenyl of the group replacements such as 1-5 independent selected from halo, cyano group, hydroxyl;
V is selected from deng group, and R 2be selected from the groups such as hydrogen, cyano group, halogen, alkyl, carbonyl; R 3a, R 3bbe selected from hydrogen or optionally by C that 1-5 fluorine atom replaces 1-4alkyl; R 8be selected from ,-SO 2-C 1-6the groups such as alkyl; Do not think that specifically describing in this patent is a part of the present invention.
(4) compound that WO2007097931 discloses the following structure of DPP-IV inhibitor is used for the treatment of diabetes, wherein:
Ar is selected from substituted or unsubstituted phenyl, and when replacing, phenyl is selected from halogen, hydroxyl, C by 1-3 1-6the replacements such as alkyl;
V is selected from deng group, and R2 is selected from hydrogen, hydroxyl, halogen etc.; R 3a, R 3bthe C be selected from hydrogen, being replaced by 1-5 fluorine atom 1-4alkyl; Do not think that specifically describing in this patent is a part of the present invention.
WO2011103256, WO2008060488, WO2007087231, WO2011037793, WO2011028455, WO2009025784 etc. are also had also to disclose relevant DPP-IV inhibitor compound for treating diabetes.
Summary of the invention
The object of the invention is to introduce a class novel DPP-IV inhibitors, specifically there is the compound shown in general formula (I), show after deliberation, the compound of this class formation has good DPP IV (DPP-IV) inhibit activities and selectivity, has the prospect being used for the treatment of or alleviating type ii diabetes and similar disease.
The present invention relates to the amino six-ring analog derivative shown in a kind of general formula (I) or its steric isomer, pharmacy acceptable salt or prodrug:
Wherein:
W is selected from
X is selected from-O-,-S (=O) n-,-NH or-CH 2-, preferably-O-;
R 1be selected from F, Cl, Br, I, hydroxyl, cyano group, C 1-8alkyl-OH, C 1-8alkyl-C 1-8alkoxyl group, C 3-8cycloalkyl, C 3-8cycloalkyl-C 1-8alkoxyl group, C 1-8alkoxyl group ,-(CH 2) m-C (=O)-R 3,-(CH 2) m-C (=O)-OR 3,-(CH 2) m-NR 4r 5,-(CH 2) m-C (=O)-NR 4r 5,-(CH 2) m-O-C (=O)-NR 4r 5,-(CH 2) m-S (=O) n-R 6,-(CH 2) m-NR 7c (=O)-NR 4r 5,-(CH 2) m-NR 7c (=O)-R 3or-(CH 2) m-NR 7c (=O)-OR 3, wherein said CH 2, alkyl, cycloalkyl or alkoxyl group be optionally selected from F, Cl, Br, I ,-CH by 0 to 5 further 2f ,-CHF 2,-CF 3, cyano group, nitro, isocyano-, hydroxyl, aldehyde radical, carboxyl, C 1-8alkyl or C 1-8the substituting group of alkoxyl group replaced; R 1preferred F, Cl, Br, I, hydroxyl, cyano group, C 1-4alkyl-OH, C 1-4alkyl-C 1-4alkoxyl group, C 3-6cycloalkyl, C 3-6cycloalkyl-C 1-4alkoxyl group, C 1-4alkoxyl group ,-(CH 2) m-C (=O)-R 3or-(CH 2) m-C (=O)-NR 4r 5, wherein said CH 2, alkyl, cycloalkyl or alkoxyl group be optionally selected from F, Cl, Br, I ,-CH by 0 to 3 further 2f ,-CHF 2,-CF 3, hydroxyl, C 1-2alkyl or C 1-2the substituting group of alkoxyl group replaced;
R 2, R 2 ', R 2 ", R 2 " 'and R 2 " "be selected from H, F, Cl, Br, I, cyano group, hydroxyl, C independently of one another 1-8alkyl or C 1-8alkoxyl group, described alkyl or alkoxyl group optional further replace by the substituting group of 0 to 5 F, Cl, Br, I, cyano group, amino or hydroxyl; R 2, R 2 ', R 2 ", R 2 " 'and R 2 " "respective independence preferred H, F, Cl, Br, I, C 1-2alkyl or C 1-2alkoxyl group;
R 3be selected from H, amino, hydroxyl, C 1-8alkyl, C 1-8alkoxyl group, C 3-8cycloalkyl or 3 to 8 yuan of heterocyclic radicals, described heterocyclic radical contains 1 to 5 and is selected from N, O or S (=O) natom or group; R 3preferred H, hydroxyl, C 1-4alkyl or C 1-4alkoxyl group;
R 4, R 5and R 7be selected from H, C independently of one another 1-8alkyl, C 6-14aryl, 6 to 14 yuan of heteroaryls ,-(CH 2) m-C 3-8heterocyclic radical or-(CH 2) m-C 3-8cycloalkyl, wherein said alkyl, aryl, heteroaryl, heterocyclic radical or cycloalkyl are optionally replaced by the substituting group of 0 to 5 F, Cl, Br, I, hydroxyl, cyano group, amino or nitro further; R 4and R 5preferred H or C independently of one another 1-4alkyl, wherein said alkyl is optionally replaced by the substituting group of 0 to 3 F, Cl, Br, I or hydroxyl further;
As selection, R 4and R 5form 3 to 8 yuan of heterocyclic radicals together with the nitrogen-atoms that they connect, described heterocyclic radical contains 1 to 3 and is selected from N, O or S (=O) natom or group, wherein heterocyclyl is replaced by the substituting group of 0 to 3 F, Cl, Br, I, hydroxyl, cyano group, amino or nitro further;
R 6be selected from H, C 1-8alkyl, C 3-8cycloalkyl or 3 to 8 yuan of heterocyclic radicals, described heterocyclic radical contains 1 to 5 and is selected from N, O or S (=O) natom or group;
R 8be selected from H, cyano group, C 1-8alkyl ,-(CH 2) m-S (=O) n-C 1-8alkyl ,-(CH 2) m-S (=O) n-C 3-8cycloalkyl ,-(CH 2) m-S (=O) n-(3 to 8 yuan of heterocyclic radicals) ,-(CH 2) m-S (=O) n-(6 to 14 yuan of heteroaryls) ,-(CH 2) m-S (=O) n-C 6-14aryl ,-(CH 2) m-C (=O)-OH ,-(CH 2) m-C (=O)-C 1-8alkyl ,-(CH 2) m-C (=O)-C 3-8cycloalkyl ,-(CH 2) m-C (=O)-(6 to 14 yuan of heteroaryls) ,-(CH 2) m-C (=O)-C 6-14aryl ,-(CH 2) m-C (=O)-O-C 1-8alkyl ,-(CH 2) m-C (=O)-O-C 3-8cycloalkyl ,-(CH 2) m-C (=O)-O-(6 to 14 yuan of heteroaryls) ,-(CH 2) m-C (=O)-O-C 6-14aryl ,-(CH 2) m-C (=O)-NH 2,-(CH 2) m-C (=O)-NH-C 1-8alkyl ,-(CH 2) m-C (=O)-NH-C 3-8cycloalkyl ,-(CH 2) m-C (=O)-NH-C 6-14aryl or-(CH 2) m-C (=O)-NH-(6 to 14 yuan of heteroaryls), wherein said CH 2, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl be optional further by 0 to 5 F, Cl, Br, I ,-CH 2f ,-CHF 2,-CF 3, hydroxyl, C 1-8alkyl, C 1-8alkoxyl group, C 3-8the substituting group of cycloalkyl or 3 to 8 yuan of heterocyclic radicals replaced; Described heterocyclic radical contains 1 to 5 and is selected from N, O or S (=O) natom or group; R 8preferred H ,-(CH 2) m-S (=O) n-C 1-4alkyl ,-(CH 2) m-S (=O) n-C 3-8cycloalkyl or-(CH 2) m-S (=O) n-(3 to 8 yuan of heterocyclic radicals), wherein said CH 2or alkyl is optional further by 0 to 3 F, Cl, Br, I ,-CH 2f ,-CHF 2,-CF 3or the substituting group of hydroxyl replaced;
R 9be selected from-S (=O) 2-(3 to 12 yuan of heterocyclic radicals) ,-S (=O) 2-C 1-8alkyl-C 1-4alkoxyl group or-C 1-4alkyl-S (=O) 2-C 1-4alkyl, described heterocyclic radical, alkoxyl group, alkyl are optionally further by 0 to 5 F, Cl, Br, I ,-CH 2f ,-CHF 2,-CF 3, hydroxyl, amino, cyano group, C 1-8alkyl or C 1-8the substituting group of alkoxyl group replaced, and heterocyclic radical contains 1 to 5 and is selected from N, O or S (=O) natom or group;
N is selected from 0,1 or 2;
M is selected from 0,1,2,3 or 4.
Preferred version of the present invention, comprises amino six-ring analog derivative or its steric isomer, pharmacy acceptable salt or prodrug shown in general formula (I), wherein:
W is selected from
X is selected from-O-;
R 1be selected from F, Cl, Br, I, hydroxyl, cyano group, C 1-4alkyl-OH, C 1-4alkyl-C 1-4alkoxyl group, C 3-6cycloalkyl, C 3-6cycloalkyl-C 1-4alkoxyl group, C 1-4alkoxyl group ,-(CH 2) m-C (=O)-R 3or-(CH 2) m-C (=O)-NR 4r 5, wherein said CH 2, alkyl, cycloalkyl or alkoxyl group be optionally selected from F, Cl, Br, I ,-CH by 0 to 3 further 2f ,-CHF 2,-CF 3, hydroxyl, C 1-2alkyl or C 1-2the substituting group of alkoxyl group replaced;
R 2, R 2', R 2 ", R 2 " 'and R 2 " "be selected from H, F, Cl, Br, I, C independently of one another 1-2alkyl or C 1-2alkoxyl group, preferred H or F;
R 3be selected from H, hydroxyl, C 1-4alkyl or C 1-4alkoxyl group, preferred hydroxyl or C 1-4alkoxyl group;
R 4and R 5be selected from H or C independently of one another 1-4alkyl, wherein said alkyl is optionally replaced by the substituting group of 0 to 3 F, Cl, Br, I or hydroxyl further;
As selection, R 4and R 5form 3 to 6 yuan of heterocyclic radicals together with the nitrogen-atoms that they connect, described heterocyclic radical contains 1 to 2 and is selected from N, O or S (=O) natom or group, wherein heterocyclyl is replaced by the substituting group of 0 to 3 F, Cl, Br, I, hydroxyl or amino further;
R 8be selected from H ,-(CH 2) m-S (=O) n-C 1-4alkyl ,-(CH 2) m-S (=O) n-C 3-8cycloalkyl or-(CH 2) m-S (=O) n-(3 to 8 yuan of heterocyclic radicals), preferred H ,-(CH 2) m-S (=O) n-C 1-4alkyl, wherein said CH 2or alkyl is optional further by 0 to 3 F, Cl, Br, I ,-CH 2f ,-CHF 2,-CF 3or the substituting group of hydroxyl replaced;
R 9be selected from-S (=O) 2-(3 to 8 yuan of heterocyclic radicals) ,-S (=O) 2-C 1-4alkyl-C 1-4alkoxyl group or-C 1-4alkyl-S (=O) 2-C 1-4alkyl, described heterocyclic radical, alkoxyl group, alkyl are optionally further by 0 to 3 F, Cl, Br, I ,-CH 2f ,-CHF 2,-CF 3, hydroxyl or amino substituting group replaced, heterocyclic radical contains 1 to 3 and is selected from N, O or S (=O) natom or group;
N is selected from 0,1 or 2;
M is selected from 0,1 or 2.
Preferred version of the present invention, comprises amino six-ring analog derivative or its steric isomer, pharmacy acceptable salt or prodrug shown in general formula (I), wherein:
R 1be selected from C 1-4alkyl-OH, C 1-4alkyl-C 1-4alkoxyl group, C 3-6cycloalkyl, C 3-6cycloalkyl-C 1-4alkoxyl group ,-(CH 2) m-C (=O)-R 3or-(CH 2) m-C (=O)-NR 4r 5, wherein said CH 2, alkyl, cycloalkyl or alkoxyl group be optionally selected from F, Cl, Br ,-CH by 0 to 3 further 2f ,-CHF 2,-CF 3or the substituting group of hydroxyl replaced; R 1preferably -C (=O)-OH ,-C (=O)-OCH 3,-C (=O)-OCH 2cH 3,-C (=O)-NH 2,-C (=O)-NHCH 3or-C (=O)-N (CH 3) 2, further preferably -C (=O)-OH ,-C (=O)-OCH 3,-C (=O)-OCH 2cH 3,-C (=O)-NH 2,-C (=O)-NHCH 3or-C (=O)-N (CH 3) 2; Further preferably -C (=O)-OCH 3or-C (=O)-NH 2;
R 2, R 2', R 2 ", R 2 " 'and R 2 " "be selected from H, F, Cl, Br, I, C independently of one another 1-2alkyl or C 1-2alkoxyl group; R 2, R 2', R 2 ", R 2 " 'and R 2 " "preferred from H or F independently of one another; Further, R 2and R 2 " 'preferred H, R 2 "preferred H or F, R 2'and R 2 " "preferred F;
R 3be selected from hydroxyl or C 1-4alkoxyl group;
R 4and R 5be selected from H or C independently of one another 1-4alkyl;
R 8be selected from H or-(CH 2) m-S (=O) n-C 1-4alkyl, wherein said CH 2or alkyl is optional further by 0 to 3 F, Cl, Br, I ,-CH 2f ,-CHF 2,-CF 3or the substituting group of hydroxyl replaced; R 8preferred H or
R 9be selected from-S (=O) 2-(3 to 8 yuan of heterocyclic radicals) ,-S (=O) 2-C 1-4alkyl-C 1-4alkoxyl group or-C 1-4alkyl-S (=O) 2-C 1-4alkyl, described heterocyclic radical, alkoxyl group, alkyl are optionally further by 0 to 3 F, Cl, Br, I ,-CH 2f ,-CHF 2,-CF 3, hydroxyl or amino substituting group replaced, heterocyclic radical contains 1 to 3 and is selected from N, O or S (=O) natom or group; R 9preferably-CH 2-S (=O) 2-CH 3, r 9preferred-CH further 2-S (=O) 2-CH 3,
N is selected from 0,1 or 2, and preferably 0 or 2;
M is selected from 0,1 or 2, and preferably 0 or 1.
Preferred version of the present invention, comprises amino six-ring analog derivative or its steric isomer, pharmacy acceptable salt or prodrug shown in general formula (I), wherein:
R 1be selected from -C (=O)-OH ,-C (=O)-OCH 3,-C (=O)-OCH 2cH 3,-C (=O)-NH 2,-C (=O)-NHCH 3or-C (=O)-N (CH 3) 2, preferably -C (=O)-OH ,-C (=O)-OCH 3,-C (=O)-OCH 2cH 3,-C (=O)-NH 2,-C (=O)-NHCH 3or-C (=O)-N (CH 3) 2, further preferably -C (=O)-OCH 3or-C (=O)-NH 2;
R 2, R 2 ', R 2 ", R 2 " 'and R 2 " "be selected from H or F independently of one another; Further, R 2and R 2 " 'preferred H, R 2 "preferred H or F, R 2 'and R 2 " "preferred F;
R 8be selected from H or-S (=O) n-C 1-4alkyl, wherein said alkyl optional further replace by the substituting group of 0 to 3 F, Cl or Br; R 8preferred H or
R 9be selected from-S (=O) 2-(3 to 6 yuan of heterocyclic radicals) ,-S (=O) 2-C 1-4alkyl-C 1-4alkoxyl group or-C 1-4alkyl-S (=O) 2-C 1-4alkyl, described heterocyclic radical, alkoxyl group or alkyl are optional further by 0 to 3 F, Cl, Br ,-CH 2f ,-CHF 2,-CF 3, hydroxyl or amino substituting group replaced, heterocyclic radical contains 1 to 3 and is selected from N, O or S (=O) natom or group;
R 9preferably-CH 2-S (=O) 2-CH 3,
R 9preferred-CH further 2-S (=O) 2-CH 3,
N is selected from 0,1 or 2.
Preferred version of the present invention, comprises amino six-ring analog derivative or its steric isomer, pharmacy acceptable salt or prodrug shown in general formula (I), wherein:
R 1be selected from -C (=O)-OH ,-C (=O)-OCH 3,-C (=O)-OCH 2cH 3,-C (=O)-NH 2,-C (=O)-NHCH 3or-C (=O)-N (CH 3) 2; Preferably -C (=O)-OCH 3or-C (=O)-NH 2;
R 2and R 2 " 'be selected from H, R 2 "be selected from H or F, R 2'and R 2 " "be selected from F;
R 8be selected from H or
R 9be selected from-CH 2-S (=O) 2-CH 3, preferably-CH 2-S (=O) 2-CH 3,
Preferred version of the present invention, the present invention relates to compound and is selected from, but be not limited to:
The invention still further relates to compound or its steric isomer shown in general formula (I), hydrate, solvate, pharmacy acceptable salt or prodrug, wherein said salt includes but not limited to sodium salt, sylvite, calcium salt, magnesium salts, barium salt, ammonium salt, front three amine salt, triethylamine salt, pyridinium salt, picoline salt, 2,6-lutidine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, dicyclohexyl ammonium salt, hydrochloride, hydrobromate, vitriol, nitrate, phosphoric acid salt, formate, trifluoroacetate, acetate, maleate, tartrate, Citrate trianion, succinate, mandelate, fumarate, malonate, malate, 2 hydroxy propanoic acid salt, oxalate, oxyacetate, salicylate, glucuronate, galacturonic hydrochlorate, citrate, aspartate, glutaminate, benzoate, cinnamate, tosilate, benzene sulfonate, mesylate, esilate, fluoroform sulphonate or their combination.
The invention still further relates to a kind of pharmaceutical composition, described composition comprises: the amino six-ring analog derivative shown in the general formula according to any one of claim 1 ~ 7 (I) of effective dose or its steric isomer, pharmacy acceptable salt or prodrug, or comprises one or more other treatment agent further; And pharmaceutically acceptable carrier or vehicle.
The invention still further relates to a kind of pharmaceutical composition, wherein said other treatment agent comprises:
(a) DPP-IV inhibitor or pharmacy acceptable salt, and/or
(b) SGLT-2 inhibitor or pharmacy acceptable salt, and/or
(c) biguanides, thiazolidinediones, sulfonylurea, arrange how class, alpha-glucosidase inhibitor or glucagon-like peptide-1 analogs, or its pharmacy acceptable salt or prodrug.
The composition that the present invention relates to, wherein said SGLT-2 inhibitor is selected from that Da Gelie is clean, Kan Gelie is clean, A Gelie is clean, En Palie is clean, Yi Palie is clean, Tuo Fulie is clean, Lu Silie is clean, Rui Gelie is clean, She Gelie is clean or relies on row clean; DPP-IV inhibitor be selected from BI 1356, sitagliptin, Vildagliptin, Egelieting, BMS-477118, Na Lieting, carmegliptin, melogliptin, dutogliptin, for Ge Lieting, gigue row spit of fland or bent Ge Lieting; Biguanides therapeutical agent is selected from N1,N1-Dimethylbiguanide or phenformin; Thiazolidinediones therapeutical agent is selected from ciglitazone, pioglitazone, rosiglitazone, troglitazone, Fa Gelie ketone or darglitazone, sulfonylurea treatment agent is selected from glimepiride, tolbutamide, glibornuride, Glyburide, gliquidone, Glipizide or gliclazide, arrange how class therapeutical agent is selected from nateglinide, repaglinide or mitiglinide, alpha-glucosidase inhibitor is selected from acarbose, voglibose or miglitol, and glucagon-like peptide-1 analogs is selected from Exenatide or Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37].
The invention still further relates to the compound described in general formula (I) or its steric isomer, pharmacy acceptable salt and composition thereof or its prodrug are preparing the application in dipeptidyl peptidase-iv inhibitor, wherein said dipeptidyl peptidase-iv inhibitor is for the preparation of the medicine for the treatment of metabolic disease, wherein said metabolic disease is selected from diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, the level of the rising of lipid acid or glycerine, hyperlipidaemia, obesity, hypertriglyceridemia, X syndromes, diabetic complication, atherosclerosis or hypertension.Preferably, described diabetes are type ii diabetes.
Unless there are contrary statement, the term used in the specification and in the claims has following implication.
Carbon, hydrogen, oxygen, sulphur, nitrogen or halogen involved in group of the present invention and compound include their isotropic substance, and in group of the present invention and compound involved carbon, hydrogen, oxygen, sulphur, nitrogen or halogen optional further substitute by the isotropic substance of their correspondences one or more, wherein the isotropic substance of carbon comprises 12c, 13c and 14c, the isotropic substance of hydrogen comprises protium (H), deuterium (D is also called heavy hydrogen), tritium (T is also called tritium), and the isotropic substance of oxygen comprises 16o, 17o and 18o, the isotropic substance of sulphur comprises 32s, 33s, 34s and 36s, the isotropic substance of nitrogen comprises 14n and 15n, the isotropic substance of fluorine 19f, the isotropic substance of chlorine comprises 35cl and 37cl, the isotropic substance of bromine comprises 79br and 81br.
" alkyl " refers to the representative examples of saturated aliphatic hydrocarbyl group of straight chain and side chain, main chain comprises 1 to 20 carbon atom, be preferably 1 to 12 carbon atom, more preferably 1 to 8 carbon atom, be more preferably 1 to 6 carbon atom, the preferably straight chain of 1 to 4 carbon atom and branched group, most preferably 1 to 2 carbon atom further again.The example of alkyl includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, 2-amyl group, 3-amyl group, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl isophthalic acid-butyl, 2-methyl-1-butene base, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-amyl group, 3-methyl-2-amyl group, 4-methyl-2-amyl group, 3-methyl-3-amyl group, 2-methyl-3-amyl group, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,2-dimethyl amyl group, 2,3-dimethyl amyl group, 2,4-dimethyl amyl group, 3,3-dimethyl amyl group, 2-ethyl pentyl group, 3-ethyl pentyl group, n-octyl, 2,2-dimethylhexanyl, 2,3-dimethylhexanyl, 2,4-dimethylhexanyl, 2,5-dimethylhexanyl, 3,3-dimethylhexanyl, 4,4-dimethylhexanyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethyl pentyl group, 2-methyl-3-ethyl pentyl group, n-nonyl, 2-methyl-2-ethylhexyl and positive decyl etc.Alkyl can be replacement or unsubstituted, when substituted, substituting group can be substituted on any spendable tie point, and substituting group is preferably 1 to 5 and is selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxyl group, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano-, aryl, heteroaryl, heterocyclic radical, bridged ring base, volution base cyclic group, hydroxyalkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylicesters ,-(CH 2) m-C (=O)-R a,-O-(CH 2) m-C (=O)-R a,-(CH 2) m-C (=O)-NR br c,-(CH 2) ms (=O) nr a,-(CH 2) m-thiazolinyl-R a, OR dor-(CH 2) m-alkynyl-R a(wherein m, n are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR br c, wherein R bwith R cindependently be selected from and comprise H, hydroxyl, amino, carbonyl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, alkylsulfonyl, trifyl, as selection, R bwith R cfive or six-ring alkyl or heterocyclic radical can be formed.R awith R dindependently be selected from aryl, heteroaryl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, carbonyl, ester group, bridged ring base, volution base cyclic group separately.
" alkoxyl group " refers to-O-alkyl, and wherein alkyl is as hereinbefore definition.Alkoxyl group can be replacement or unsubstituted, and alkoxyl group embodiment includes but not limited to methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, sec-butoxy, n-pentyloxy and positive hexyloxy etc.When substituted, substituting group is preferably 1 to 5 and is selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxyl group, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano-, aryl, heteroaryl, heterocyclic radical, bridged ring base, volution base cyclic group, hydroxyalkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylicesters ,-(CH 2) m-C (=O)-R a,-O-(CH 2) m-C (=O)-R a,-(CH 2) m-C (=O)-NR br c,-(CH 2) ms (=O) nr a,-(CH 2) m-thiazolinyl-R a, OR dor-(CH 2) m-alkynyl-R a(wherein m, n are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR br c, wherein R bwith R cindependently be selected from and comprise H, hydroxyl, amino, carbonyl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, alkylsulfonyl, trifyl, as selection, R bwith R cfive or six-ring alkyl or heterocyclic radical R can be formed awith R drespective be independently selected from aryl, heteroaryl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, carbonyl, ester group, bridged ring base, volution base or and cyclic group.
" alkoxyalkyl " refers to the alkyl be connected with alkoxyl group.Alkoxyalkyl can be replacement or unsubstituted, its non-limiting example comprises, methoxymethyl, methoxy ethyl, ethoxyl methyl, ethoxyethyl group, propoxy methyl, Among, 2-propoxy methyl, butoxypropyl, t-butoxy ethyl, pentyloxy ethyl, hexyloxyehtyl, ring propoxy methyl, ring Among, ring propoxypropyl and cyclohexyloxy methyl; When substituted, substituting group is preferably 1 to 5 and is selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxyl group, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano-, aryl, heteroaryl, heterocyclic radical, bridged ring base, volution base cyclic group, hydroxyalkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylicesters ,-(CH 2) m-C (=O)-R a,-O-(CH 2) m-C (=O)-R a,-(CH 2) m-C (=O)-NR br c,-(CH 2) ms (=O) nr a,-(CH 2) m-thiazolinyl-R a, OR dor-(CH 2) m-alkynyl-R a(wherein m, n are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR br c, wherein R bwith R cindependently be selected from and comprise H, hydroxyl, amino, carbonyl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, alkylsulfonyl, trifyl, as selection, R bwith R cfive or six-ring alkyl or heterocyclic radical can be formed.R awith R drespective be independently selected from aryl, heteroaryl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, carbonyl, ester group, bridged ring base, volution base or and cyclic group.
" thiazolinyl " refers at least containing the alkyl as hereinbefore definition of a carbon-to-carbon double bond composition, preferably containing 2 to 20 carbon atoms, preferred 2 to 12 carbon atoms further, more preferably have 2 to 8 carbon atoms on main chain, and thiazolinyl can be to replace or unsubstituted.Non-limiting example comprises vinyl, allyl group, 1-propenyl, 2-propenyl, 1-butylene base, crotyl, 3-butenyl, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl isophthalic acid-butenyl, 2-methyl-1-butene thiazolinyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentene thiazolinyl, 2-methyl-1-pentene thiazolinyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonene base, 3-nonene base, 1-decene base, 4-decene base, 1, 3-divinyl, 1, 3-pentadiene, 1, 4-pentadiene, 1, 4-hexadiene, 3-hendecene base, 4-laurylene base and 4, 8, 12-14 carbon trialkenyl etc.When substituted, substituting group is 1 to 5 and is selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxyl group, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano-, aryl, heteroaryl, heterocyclic radical, bridged ring base, volution base cyclic group, hydroxyalkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylicesters ,-(CH 2) m-C (=O)-R a,-O-(CH 2) m-C (=O)-R a,-(CH 2) m-C (=O)-NR br c,-(CH 2) ms (=O) nr a,-(CH 2) m-thiazolinyl-R a, OR dor-(CH 2) m-alkynyl-R a(wherein m, n are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR br c, wherein R bwith R cindependently be selected from and comprise H, hydroxyl, amino, carbonyl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, alkylsulfonyl, trifyl, as selection, R bwith R cfive or six-ring alkyl or heterocyclic radical can be formed.R awith R drespective be independently selected from aryl, heteroaryl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, carbonyl, ester group, bridged ring base, volution base or and cyclic group.
" alkynyl " refers to the alkyl as hereinbefore definition comprising at least one carbon-to-carbon triple bond composition, and preferably containing 2 to 20 carbon atoms, preferred 2 to 8 carbon atoms further, more preferably have the alkynyl of 2 to 4 carbon atoms on main chain.Alkynyl can be replacement or unsubstituted.Non-limiting example comprises ethynyl, 1-proyl, 2-propynyl, butynyl, 2-butyne base, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butyne base, 2-hexin base, 3-hexin base, 2-heptyne base, 3-heptyne base, 4-heptyne base, 3-octyne base, 3-n-heptylacetylene base, 4-decynyl, 3-undecyne base and 4-dodecyne base etc.; When substituted, substituting group is preferably one or more following group, independently selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxyl group, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano-, aryl, heteroaryl, heterocyclic radical, bridged ring base, volution base cyclic group, hydroxyalkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylicesters ,-(CH 2) m-C (=O)-R a,-O-(CH 2) m-C (=O)-R a,-(CH 2) m-C (=O)-NR br c,-(CH 2) ms (=O) nr a,-(CH 2) m-thiazolinyl-R a, OR dor-(CH 2) m-alkynyl-R a(wherein m, n are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR br c, wherein R bwith R cindependently be selected from and comprise H, hydroxyl, amino, carbonyl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, alkylsulfonyl, trifyl, as selection, R bwith R cfive or six-ring alkyl or heterocyclic radical can be formed.R awith R drespective be independently selected from aryl, heteroaryl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, carbonyl, ester group, bridged ring base, volution base or and cyclic group.
" amino " refers to-NH 2it can be replacement or unsubstituted, when substituted, substituting group is preferably less than 1 to 3 group, independently selected from alkyl, cycloalkyl, haloalkyl, mercaptan, hydroxyl, sulfydryl, amino, cyano group, isocyano-, aryl, heteroaryl, heterocyclic radical, bridged ring base, volution base cyclic group, hydroxyalkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylicesters ,-(CH 2) m-C (=O)-R a,-O-(CH 2) m-C (=O)-R a,-(CH 2) m-C (=O)-NR br c,-(CH 2) ms (=O) nr a,-(CH 2) m-thiazolinyl-R a, OR dor-(CH 2) m-alkynyl-R a(wherein m, n are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR br c, wherein R bwith R cindependently be selected from and comprise H, hydroxyl, amino, carbonyl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, alkylsulfonyl, trifyl, as selection, R bwith R cfive or six-ring alkyl or heterocyclic radical can be formed.R awith R drespective be independently selected from aryl, heteroaryl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, carbonyl, ester group, bridged ring base, volution base or and cyclic group.
" alkylthio " refers to-S-alkyl or-S-(not being substituted cycloalkyl), and non-limiting example comprises methylthio group, ethylmercapto group, rosickyite base and butylthio etc.
" acyl group " or " carbonyl " refers to-C (=O)-R agroup, wherein R aas defined above.
" aldehyde " refers to-C (=O)-H.
" halogen " refers to fluorine, chlorine, bromine, iodine.
" hydroxyl " refers to-OH.
" cyano group " refers to-C ≡ N.
" isocyano-" refers to-N ≡ C.
" nitro " refers to-NO 2.
" carboxylic acid " refers to-C (=O)-OH.
" carboxylicesters " refers to-C (=O)-O-R d, R dbe selected from alkyl, cycloalkyl or heterocyclic radical.
" haloalkyl " refers to the alkyl as hereinbefore definition of halogen substiuted, non-limiting example comprises a methyl fluoride, difluoromethyl, trifluoromethyl, a brooethyl, two brooethyls, trisbromomethyl, 1-fluoro ethyl-2-base, 2-fluoro ethyl-2-base, 1,1-bis-fluoro ethyl-2-base, 1,2-bis-fluoro ethyl-2-base, 1,1,1-fluoro ethyl-2-base, 1-bromotrifluoromethane-2-base, 2-bromotrifluoromethane-2-base and 1,1,1-three bromomethyl-2-base etc.
" sulfydryl " refers to-SH.
" mercaptan " refers to that the hydrocarbon that the one or more hydrogen atoms in alkyl are replaced by sulfydryl, non-limiting example comprise thiomethyl alcohol, sulfur alcohol, 1,2-bis-mercaptan.
" sulfonyl " or " thiocarbonyl " refers to-C (=S)-R agroup, wherein R aas defined above.
" hydroxyalkyl " refers to that alkyl is optionally substituted with one or more hydroxyl replacement, and preferably replaced by 1,2 or 3 hydroxyl, alkyl is preferably low alkyl group.Non-limiting example comprises methylol, 2-hydroxyethyl, 1-hydroxyethyl, 1,2-dihydroxypropyl, 1,3-dihydroxypropyl and 2,3-dihydroxypropyl etc.
" cycloalkyl " refers to saturated or undersaturated monocyclic cycloalkyl, it can be replacement or unsubstituted, ring carbon atom comprises 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, preferred 3 to 8 carbon atoms further, non-limiting example comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,5-cyclooctadiene base, 1，4-cyclohexadiene base and cycloheptatriene base etc.When substituted, substituting group is 1 to 5 and is selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxyl group, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano-, aryl, heteroaryl, heterocyclic radical, bridged ring base, volution base cyclic group, hydroxyalkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylicesters ,-(CH 2) m-C (=O)-R a,-O-(CH 2) m-C (=O)-R a,-(CH 2) m-C (=O)-NR br c,-(CH 2) ms (=O) nr a,-(CH 2) m-thiazolinyl-R a, OR dor-(CH 2) m-alkynyl-R a(wherein m, n are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR br c, wherein R bwith R cindependently be selected from and comprise H, hydroxyl, amino, carbonyl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, alkylsulfonyl, trifyl, as selection, R bwith R cfive or six-ring alkyl or heterocyclic radical can be formed.R awith R drespective be independently selected from aryl, heteroaryl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, carbonyl, ester group, bridged ring base, volution base or and cyclic group.
" heterocyclic radical " refers to replacement or unsubstituted saturated or unsaturated and be at least selected from the heteroatomic aromatic nucleus of N, O or S, non-aromatic ring containing 1 to 5, aromatic nucleus, non-aromatic ring can be the monocycles of 3 to 10 yuan, the volution of 4 to 20 yuan ring or bridged ring, N, S that in heterocyclic ring, selectivity replaces can be oxidized to various oxidation state.Preferably 3 to 12 yuan of heterocycles.Non-limiting example comprises oxirane base, oxetanylmethoxy, oxocyclopentyl, oxacyclohexyl, oxacyclohexyl, oxa-ring octyl group, ethylenimine base, azelidinyl, nitrogen heterocyclic amyl group, piperidyl, aziridinyl, 1, 3 dioxy cyclopentyl, 1, 4-dioxy cyclopentyl, 1, 3-dioxy cyclopentyl, 1, 3-dioxocyclohex base, 1, 3-bis-sulphur cyclohexyl, azepine base, morpholinyl, piperazinyl, pyridyl, furyl, thienyl, pyrryl, pyranyl, N-alkyl pyrryl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, piperidyl, thio-morpholinyl, dihydropyrane, thiadiazolyl group, oxazolyl, oxadiazolyl, pyrazolyl, 1, 4-Dioxin base, or deng.When substituted, substituting group is 1 to 5 and is selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxyl group, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano-, aryl, heteroaryl, heterocyclic radical, bridged ring base, volution base cyclic group, hydroxyalkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylicesters ,-(CH 2) m-C (=O)-R a,-O-(CH 2) m-C (=O)-R a,-(CH 2) m-C (=O)-NR br c,-(CH 2) ms (=O) nr a,-(CH 2) m-thiazolinyl-R a, OR dor-(CH 2) m-alkynyl-R a(wherein m, n are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR br c, wherein R bwith R cindependently be selected from and comprise H, hydroxyl, amino, carbonyl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, alkylsulfonyl, trifyl, as selection, R bwith R cfive or six-ring alkyl or heterocyclic radical can be formed.R awith R drespective be independently selected from aryl, heteroaryl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, carbonyl, ester group, bridged ring base, volution base or and cyclic group.
" volution " refers to 5 to the 20 yuan of polycyclic moiety sharing a carbon atom (title spiro atom) between replacement or unsubstituted monocycle, and it can comprise 0 to 5 double bond, and can be selected from N, O or S (=O) containing 0 to 5 nheteroatoms.Be preferably 6 to 14 yuan, more preferably 6 to 12 yuan, more select 6 to 10 yuan, its non-limiting example comprises .When substituted, substituting group is 1 to 5 and is selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxyl group, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano-, aryl, heteroaryl, heterocyclic radical, bridged ring base, volution base cyclic group, hydroxyalkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylicesters ,-(CH 2) m-C (=O)-R a,-O-(CH 2) m-C (=O)-R a,-(CH 2) m-C (=O)-NR br c,-(CH 2) ms (=O) nr a,-(CH 2) m-thiazolinyl-R a, OR dor-(CH 2) m-alkynyl-R a(wherein m, n are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR br c, wherein R bwith R cindependently be selected from and comprise H, hydroxyl, amino, carbonyl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, alkylsulfonyl, trifyl, as selection, R bwith R cfive or six-ring alkyl or heterocyclic radical can be formed.R awith R drespective be independently selected from aryl, heteroaryl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, carbonyl, ester group, bridged ring base, volution base or and cyclic group.
" and ring " refers to that each ring in system and other rings in system share the polycyclic moiety of a pair carbon atom adjoined, wherein one or more rings can contain 0 or multiple double bond, and can be replace or do not replace, and each ring in member ring systems can be selected from N, S (=O) containing 0 to 5 nor the heteroatoms of O.Be preferably 5 to 20 yuan, more preferably 5 to 14 yuan, more select 5 to 12 yuan, more preferably 5 to 10 yuan further.Non-limiting example comprises when substituted, substituting group is 1 to 5 and is selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxyl group, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano-, aryl, heteroaryl, heterocyclic radical, bridged ring base, volution base cyclic group, hydroxyalkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylicesters ,-(CH 2) m-C (=O)-R a,-O-(CH 2) m-C (=O)-R a,-(CH 2) m-C (=O)-NR br c,-(CH 2) ms (=O) nr a,-(CH 2) m-thiazolinyl-R a, OR dor-(CH 2) m-alkynyl-R a(wherein m, n are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR br c, wherein R bwith R cindependently be selected from and comprise H, hydroxyl, amino, carbonyl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, alkylsulfonyl, trifyl, as selection, R bwith R cfive or six-ring alkyl or heterocyclic radical can be formed.R awith R drespective be independently selected from aryl, heteroaryl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, carbonyl, ester group, bridged ring base, volution base or and cyclic group.
" bridged ring " refers to the polycyclic moiety of any two carbon atoms directly do not connected, and can contain 0 or multiple double bond, and can be replacement or unsubstituted, and any ring in member ring systems can be selected from N, S (=O) containing 0 to 5 nor O heteroatoms or group (wherein n is 1,1,2).Annular atoms comprises 5 to 20 atoms, is preferably 5 to 14 atoms, preferably 5 to 12 further, at preferably 5 to 10 further.Non-limiting example comprises and diamantane.When substituted, substituting group is 1 to 5 and is selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxyl group, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano-, aryl, heteroaryl, heterocyclic radical, bridged ring base, volution base cyclic group, hydroxyalkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylicesters ,-(CH 2) m-C (=O)-R a,-O-(CH 2) m-C (=O)-R a,-(CH 2) m-C (=O)-NR br c,-(CH 2) ms (=O) nr a,-(CH 2) m-thiazolinyl-R a, OR dor-(CH 2) m-alkynyl-R a(wherein m, n are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR br c, wherein R bwith R cindependently be selected from and comprise H, hydroxyl, amino, carbonyl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, alkylsulfonyl, trifyl, as selection, R bwith R cfive or six-ring alkyl or heterocyclic radical can be formed.R awith R drespective be independently selected from aryl, heteroaryl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, carbonyl, ester group, bridged ring base, volution base or and cyclic group.
" benzyl " refers to-CH 2-phenyl, described phenyl is that replace or unsubstituted, and its non-limiting example comprises-CH 2-phenyl ,-CH 2-p-methylphenyl etc.
" aryl " refers to replacement or unsubstituted 6 to 14 yuan of cyclic aromatic groups, comprises mono-cyclic aromatic base and polycyclic aromatic base.Preferably 6 to 14 yuan of aromatic nucleus, further preferred 6 to 10 yuan of aromatic nucleus, its limiting examples comprises phenyl, naphthyl, anthryl and phenanthryl etc.Described aryl rings can condense on heteroaryl, heterocyclic radical or cycloalkyl ring, and the ring wherein linked together with precursor structure is aryl rings, and non-limiting example comprises:
When substituted, substituting group is 1 to 5 and is selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxyl group, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano-, aryl, heteroaryl, heterocyclic radical, bridged ring base, volution base cyclic group, hydroxyalkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylicesters ,-(CH 2) m-C (=O)-R a,-O-(CH 2) m-C (=O)-R a,-(CH 2) m-C (=O)-NR br c,-(CH 2) ms (=O) nr a,-(CH 2) m-thiazolinyl-R a, OR dor-(CH 2) m-alkynyl-R a(wherein m, n are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR br c, wherein R bwith R cindependently be selected from and comprise H, hydroxyl, amino, carbonyl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, alkylsulfonyl, trifyl, as selection, R bwith R cfive or six-ring alkyl or heterocyclic radical can be formed.R awith R dindependently be selected from aryl, heteroaryl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, carbonyl, ester group, bridged ring base, volution base cyclic group separately.
" heteroaryl " refers to substituted or unsubstituted 5 to 14 yuan of aromatic nucleus, and is selected from N, O or S (=O) containing 1 to 5 nheteroatoms or group, preferably 5 to 10 yuan of assorted aromatic nucleus, preferably 5 to 6 yuan further.The non-limiting example of heteroaryl includes but not limited to that pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkyl pyrryl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, piperidyl, morpholine, thiomorpholine, 1,3-dithiane, benzoglyoxaline, piperazine sting base, benzoglyoxaline, benzo pyridine, pyrrolopyridine etc.Described heteroaryl ring can condense on aryl, heterocyclic radical or cycloalkyl ring, and the ring wherein linked together with precursor structure is heteroaryl ring, and non-limiting example comprises
When substituted, substituting group is 1 to 5 and is selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxyl group, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano-, aryl, heteroaryl, heterocyclic radical, bridged ring base, volution base cyclic group, hydroxyalkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylicesters ,-(CH 2) m-C (=O)-R a,-O-(CH 2) m-C (=O)-R a,-(CH 2) m-C (=O)-NR br c,-(CH 2) ms (=O) nr a,-(CH 2) m-thiazolinyl-R a, OR dor-(CH 2) m-alkynyl-R a(wherein m, n are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR br c, wherein R bwith R cindependently be selected from and comprise H, hydroxyl, amino, carbonyl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, alkylsulfonyl, trifyl, as selection, R bwith R cfive or six-ring alkyl or heterocyclic radical can be formed.R awith R dindependently be selected from aryl, heteroaryl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, carbonyl, ester group, bridged ring base, volution base cyclic group separately.
" artyl sulfo " refers to-S-aryl as defined herein or-S-heteroaryl.Artyl sulfo example includes but not limited to thiophenyl, pyridinylthio, furyl sulfenyl, thienyl sulfenyl, pyrimidine-based sulfur-base etc.
" silylation " refer to one or more hydrogen atoms in silicomethane by alkyl replace the group that formed, embodiment include but not limited to trimethyl silicon based, triethyl is silica-based, t-Butyldimethylsilyl and tert-butyl diphenyl silica-based etc.
Term " singly-bound " refers to chemical single bond, and such as " being a singly-bound between A and B " represents to there is chemical single bond, that is: an A-B between A and B.
" optionally " or " optionally " refer to subsequently described event or environment can but need not beard and hair raw, this explanation comprises the occasion that this event or environment occur or do not occur.As: " optionally by alkyl that F replaces " refer to alkyl can but must do not replaced by F, illustrate and comprise situation that alkyl replaced by F and alkyl not by situation that F replaces.
" pharmacy acceptable salt " or " its pharmacy acceptable salt " refers to the biological effectiveness and characteristic that keep free acid or free alkali, and described free acid by with nontoxic mineral alkali or organic bases, or described free acid those salt by obtaining with nontoxic mineral acid or organic acid reaction, comprise an alkali metal salt, as sodium salt, sylvite, lithium salts etc., alkaline earth salt, as calcium salt, magnesium salts etc., other metal-salts, as molysite, mantoquita, cobalt salt etc., organic alkali salt, as ammonium salt, triethylamine salt, pyridinium salt, picoline salt, 2, 6-lutidine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, ethylenediamine salt, guanidinesalt, sec.-propyl amine salt, trismethylamine salt, tripropyl amine salt, triethanolamine salt, diethanolamine salt, ethanolamine salt, dimethyl ethanol amine salt, dicyclohexyl amine salt, coffee alkali salt, procaine salt, choline salt, beet alkali salt, Penicillin G benethamine salt, glucose amine salt, N-METHYL-ALPHA-L-GLUCOSAMINE salt, cocoa alkali salt, tromethamine salt, purine salt, piperazine salt, alkylbenzyldimethylasaltsum saltsum, piperidinium salt, N-ethylpiperidine salt, tetramethyl-amine salt, dibenzyl amine salt and phenylglycine alkyl ester salt etc., halogen acid salt, as hydrofluoride, hydrochloride, hydriodate, hydrobromate etc., inorganic acid salt, as nitrate, vitriol, perchlorate, phosphoric acid salt etc., lower alkyl sulfonate, as mesylate, fluoroform sulphonate, esilate etc., arylsulphonate, as benzene sulfonate, tosilate etc., organic acid salt, as formate, fumarate, formate, trifluoroacetate, furoate, gluconate, glutaminate, glycollate, isethionate, lactic acid salt, maleate, malate, mandelate, mucus hydrochlorate, embonate, pantothenate, stearate, succinate, sulfanilate, tartrate, malonate, 2 hydroxy propanoic acid salt, Citrate trianion, salicylate, oxalate, oxyacetate, glucuronate, galacturonic hydrochlorate, citrate, lysine salt, arginic acid salt, aspartate, cinnamate etc.
" pharmaceutical composition " represent compound described in one or more texts or its physiology/pharmacy acceptable salt or prodrug combination or/and use clinically be used for the treatment of, the medicine of prevent diabetes or/and SGLT-2 inhibitor is or/and the mixture of DPP-IV inhibitor and other moietys, wherein other component comprises physiology/pharmaceutically acceptable carrier and vehicle.What use clinically is used for the treatment of, the medicine of prevent diabetes comprises biguanides, thiazolidinedione, sulfonylurea, row how, alpha-glucosidase inhibitor, GLP-1 analogue or its pharmacy acceptable salt, such as N1,N1-Dimethylbiguanide, phenformin, ciglitazone (Ciglitazone), pioglitazone (Pioglitazone), rosiglitazone (Rosiglitazone), troglitazone (Troglitazone), Fa Gelie ketone (Farglitazar), darglitazone (Darglitazoan), glimepiride (Glimepiride), tolbutamide (Tolglybutamide), glibornuride (Glibornuride), Glyburide (Glibenclamide), gliquidone (Gliquidone), Glipizide (glipizide), gliclazide (gliclazipe), nateglinide (Nateglinide), repaglinide (Repaglinide), mitiglinide (mitiglinide), acarbose (Acarbose), voglibose (Voglibose), miglitol (Miglitol), Exenatide (Exenatide) or Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] (Liraglutide), SGLT-2 inhibitor is Da Gelie clean (Dapagliflozin) such as, Kan Gelie clean (Canagliflozin), En Palie clean (Empagliflozin), Yi Palie clean (Ipragliflozin), Tuo Fulie clean (Tofogliflozin), Lu Silie clean (Luseogliflozin), Rui Gelie clean (Remogliflozin), She Gelie clean (Sergliflozin) or support row clean (Ertugliflozin), DPP-IV inhibitor is BI 1356 (Linagliptin) such as, sitagliptin (Sitagliptin), Vildagliptin (Vildagliptin), Egelieting (Alogliptin), BMS-477118 (Saxagliptin), ground Na Lieting (Denagliptin), carmegliptin (Carmegliptin), melogliptin (Melogliptin), dutogliptin (Dutogliptin), for Ge Lieting (Teneligliptin), gigue row spit of fland (Gemigliptin) or bent Ge Lieting (Trelagliptin).The object of pharmaceutical composition is the administration promoting compound on organism body.
" carrier " refers to and can not produce obvious stimulation to organism and can not eliminate the biological activity of given compound and the carrier of characteristic or thinner.
" vehicle " refers to and joins in pharmaceutical composition to depend on the inert substance of compound administration further.The example of vehicle includes but not limited to calcium carbonate, calcium phosphate, various sugar and dissimilar starch, derivatived cellulose (comprising Microcrystalline Cellulose), gelatin, vegetables oil, polyethylene glycols, thinner, granulating agent, lubricant, tackiness agent, disintegrating agent etc.
" prodrug " is referred to and in physiological conditions or can be converted into the compound with bioactive the compounds of this invention by solvolysis.Prodrug of the present invention is prepared by the phenolic group group be modified in this compound, and this modification can operation routinely or be removed in vivo, and obtains parent compound.When prodrug of the present invention is bestowed mammalian subject, prodrug is formed free hydroxyl respectively by isolating.The phenolic hydroxyl group that the example of prodrug includes, but are not limited to the compounds of this invention becomes sodium salt derivative with phosphoric acid.
Some compound as herein described can exist as tautomer, along with the transfer of one or more double bond, has different hydrogen tie points.Such as keto-enol tautomerism body.Single tautomer and composition thereof is all included in the scope of the compounds of this invention.Tautomer within the scope of the compounds of this invention includes but not limited to:
Compound described herein can contain one or more asymmetric center, and can exist with racemoid, racemic mixture, single enantiomer, non-enantiomer mixture and single diastereomer thus.
Some compound described herein contains double bond, except as otherwise noted, comprises E and Z geometry structure body.
" X syndromes " refers to the illness of metabolic syndrome, disease and illness.Detailed description is shown in JohannssonJ.Clin.Endocrinol.Metab., 1997,82,727-734.
" effective dose " has guided the amount of the compound of tissue, system or subject physiologic or medical science translation, this amount is sought, is included in and is enough to prevent one or more symptoms of subject illness or illness to occur with it when curee uses or makes it alleviate amount to compound to a certain degree.
" solvate " refers to the compounds of this invention or its salt, and they also comprise with the stoichiometry of non-covalent intermolecular forces combination or non-stoichiometric solvent.When solvent is water, then it is hydrate.
" IC 50" refer to half-inhibition concentration, refer to the concentration reaching maximum suppression effect one half.
The synthetic method of the compounds of this invention
In order to complete object of the present invention, the compounds of this invention can be prepared by following scheme and obtain:
Scheme one:
Intermediate compound I-A and I-B obtains intermediate compound I-C by reductive amination conditioned response, and intermediate compound I-C obtains general formula (I) compound by removing amino protecting group again.
Scheme two:
Intermediate compound I-D and intermediate compound I-E obtains intermediate compound I-C by condensation reaction, and intermediate compound I-C obtains general formula (I) compound by deaminizating protecting group.
Scheme three:
Intermediate compound I-F and intermediate compound I-G obtains intermediate compound I-C by condensation reaction, and intermediate compound I-C again deaminizating protecting group prepares general formula (I) compound.
Prepared by intermediate compound I-A referenced patent WO2010056708, US2007232676 document, its method is described below:
Wherein, R 1, R 2, R 2 ', R 2 ", R 2 " ', R 2 " "with W as hereinbefore defined, R 8abe selected from C 1-8alkyl, C 3-8cycloalkyl, 3 to 8 yuan of heterocyclic radicals, 6 to 14 yuan of heteroaryls or C 6-14aryl, R 9abe selected from 3 to 12 yuan of heterocyclic radicals or C 1-8alkyl-C 1-4alkoxyl group, P is amino protecting group, such as tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or 9-fluorenylmethoxycarbonyl groups (Fmoc), and V is halogen, preferred chlorine, and L is selected from halogen, preferred bromine.
Embodiment
Describe the beneficial effect of implementation process of the present invention and generation below by way of specific embodiment in detail, be intended to help reader to understand essence of the present invention and feature better, not as can the restriction of practical range to this case.
The structure of compound is determined by nucleus magnetic resonance (NMR) and/or mass spectrum (MS).
The mensuration of NMR is with (BrukerADVANCEIII400) nuclear magnetic resonance spectrometer, and measuring solvent is deuterated dimethyl sulfoxide (DMSO-d 6), deuterochloroform (CDCl 3), deuterated methanol (CD 3oD), tetramethylsilane (TMS) is inside designated as.The mensuration of MS uses (Agilent6120B (ESI)).
The mensuration of HPLC uses Agilent 1260DAD high pressure liquid chromatograph (ZorbaxSB-C18100x4.6mm).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate, the specification that the silica-gel plate that tlc (TLC) uses adopts is 0.15mm ~ 0.20mm, and the specification that thin-layer chromatography separation and purification product adopts is 0.4mm ~ 0.5mm.
Column chromatography generally uses Yantai Huanghai Sea silica gel 200 ~ 300 order silica gel to be carrier.
Without specified otherwise, triethylamine, methyl tertiary butyl ether, hydrazine hydrate, Tetrabutyl amonium bromide, thionyl chloride, imidazoles, sodium hydride, triphenyl phosphorus, trifluoroacetic acid are bought in Chengdu Ke Long chemical reagent factory; Two dimethyl dicarbonate butyl esters, N, N'-dicarbapentaborane diimidazole, DMF dimethylacetal, N, O-dimethyl hydroxylamine hydrochloride, cis-4-hydroxy-d-proline hydrochloride are bought in Ace spy (Chengdu) medical science company limited; Cesium carbonate, lithium borohydride, TERT-BUTYL DIMETHYL CHLORO SILANE, N-hydroxysuccinimide, two (trimethyl silicon based) sodium amide, diphenylmethylene glycine ethyl ester, trans-L-1,2-oxyproline are bought in the resistance to Jilin Chemical of peace; Wearing this Martin buys in the smooth Science and Technology Co., Ltd. of upper Haitai; Methyl triflate, 2,5-difluoro bromobenzenes are bought in Shanghai De Mo Pharmaceutical Technology Co., Ltd; 2-iodopropane is bought in Shanghai Bepharm Science & Technology Co., Ltd.; Isopropylmagnesium chloride/lithium chloride tetrahydrofuran solution is bought in lark prestige Science and Technology Ltd.; Propargyl benzene sulfonate, tetrabutyl ammonium fluoride, three (acetoxyl group) sodium borohydride, tetrabutyl phosphofluoric acid amine are bought in this Reagent Company of Adama; Two (triphenylphosphine) ruthenium chloride (II) of cyclopentadienyl is bought in ACROSorgainics; Borane dimethylsulf iotade is bought in splendid scientific and technological (Shanghai) Co., Ltd. of chemistry far away; Tetrahydrofuran (THF)-3-alkylsulfonyl chlorine is bought in Nanjing Kang Manlin chemical industry Industrial Co., Ltd.; Sodium peroxoborate is bought in Tianjin recovery fine chemistry industry institute; Chlorine { [amino-1, the 2-diphenyl-ethyl of (1R, 2R)-(-)-2-] (penta fluoro benzene sulphonyl) is amino } (Paracymene) ruthenium (II) is bought in Stremchemical; Methyl iodide, Methanesulfonyl chloride are bought in medicine company limited-liability company of traditional Chinese medicines group.
Nitrogen atmosphere refers to that reaction flask connects the nitrogen balloon of an about 1L volume.
Nitrogen atmosphere refers to that reaction flask connects the hydrogen balloon of an about 2L volume.
Hydrogenation vacuumizes usually, is filled with hydrogen, repeatable operation 3 times.
Without specified otherwise in embodiment, solution refers to the aqueous solution.
Without specified otherwise in embodiment, the temperature of reaction is room temperature.
Without specified otherwise in embodiment, eluent ratio is volume ratio.
Bn: benzyl; Et: ethyl; Ac: ethanoyl; Me: methyl; Boc: tertbutyloxycarbonyl; Ph: phenyl; COOH: carboxyl; OMe: methoxyl group; OTBS: dimethyl tertiary butyl silicon ether; SO 3h: sulfonic group; Ms: methyl sulphonyl.
Intermediate 1: the tertiary butyl ((2R, 3S)-2-(2,5-difluorophenyl)-5-carbonyl tetrahydrochysene-2H-pyrans-3-base) carbamate (intermediate 1)
tert-butyl((2R,3S)-2-(2,5-difluorophenyl)-5-oxotetrahydro-2H-pyran-3-yl)carbamate
The first step: 2-amino-4-alkynes Valeric acid ethylester (1B)
ethyl2-aminopent-4-ynoate
Under room temperature, by diphenylmethylene glycine ethyl ester 1A (50g, 0.187mol) be dissolved in methyl tertiary butyl ether (300mL), propargyl benzene sulfonate (44g, 0.224mol), Tetrabutyl amonium bromide (6.1g, 0.019mol) are added in reaction solution, be warming up to 50 DEG C, add cesium carbonate (121.8g, 0.374mol), react at 50 DEG C of temperature and spend the night.By reacting liquid filtering, with methyl tertiary butyl ether (40mL × 2) washing leaching cake, merge organic phase, concentrated by rotary evaporation, to half volume, adds hydrochloric acid soln (3mol/L, 100mL), stirred at ambient temperature 1 hour, stratification, aqueous phase methyl tertiary butyl ether (70mL × 2) extracts, collect aqueous phase, obtain 1B.
Second step: 2-((tertbutyloxycarbonyl) is amino)-4-alkynes valeric acid (1C)
2-((tert-butoxycarbonyl)amino)pent-4-ynoicacid
By water-soluble for sodium hydroxide (33.7g, 0.842mol) (100mL), dropwise drop in the reaction solution of 1B (26.4g, 0.187mol), stirred at ambient temperature 2 hours.Two dimethyl dicarbonate butyl esters (45g, 0.206mol) are dissolved in methyl tertiary butyl ether (125mL), drop in reaction solution, stirred at ambient temperature 4 hours.Stratification, aqueous phase methyl tertiary butyl ether (80mL × 2) washs, the hydrochloric acid soln adjust ph to 3 of aqueous phase 3mol/L, with methyl tertiary butyl ether (100mL × 2) extraction, merges organic phase, saturated sodium-chloride water solution (30mL × 2) washs, add anhydrous magnesium sulfate drying in organic phase, filter, be spin-dried for, obtain yellow oily liquid 1C (33g, productive rate 83%).
MSm/z(ESI):212.0[M-1]。
3rd step: the tertiary butyl (1-(methoxyl group (methyl) is amino)-1-carbonyl amyl group-4-alkynes-2-base) carbamate (1D)
tert-butyl(1-(methoxy(methyl)amino)-1-oxopent-4-yn-2-yl)carbamate
Be dissolved in by 1C (33g, 0.155mol) in DMF (200mL), control temperature is less than 10 DEG C, adds in reaction solution by N, N'-carbonyl dimidazoles (32.58g, 0.201mol), reacts 1 hour at 0 DEG C.N, O-dimethyl hydroxylamine hydrochloride (19.6g, 0.186mol) is added in reaction solution, stirred overnight at room temperature.Dropwise add water (150mL), stir 1 hour, extract by ethyl acetate (100mL × 2), merge organic phase, by saturated sodium bicarbonate solution (60mL × 3), saturated nacl aqueous solution (60mL × 3) washing organic phase, in organic phase, add anhydrous magnesium sulfate drying.Filter, filtrate is concentrated, uses column chromatography (petrol ether/ethyl acetate (v/v)=10:1), obtain white solid 1D (35g, productive rate 88.2%).
MSm/z(ESI):156.9[M+1]。
4th step: the tertiary butyl (1-(2,5-difluorophenyl)-1-carbonyl amyl group-4-alkynes-2-base) carbamate (1E)
tert-butyl(1-(2,5-difluorophenyl)-1-oxopent-4-yn-2-yl)carbamate
Under nitrogen protection; by 2; 5-difluoro bromobenzene (15.05g; 78mmol) be dissolved in dry toluene (50mL); cryosel bath is cooled to less than-10 DEG C; dropwise add isopropylmagnesium chloride/lithium chloride tetrahydrofuran solution (66mL, 1.3mol/L), remain on about-10 DEG C and stir 1 hour.1D (10g, 39mmol) is dissolved in dry tetrahydrofuran (100mL), dropwise drops in reaction solution, keep temperature-10 DEG C, finish, react 4 hours under room temperature.Cool the temperature to about-10 DEG C, dropwise add saturated ammonium chloride solution (40mL), stir 10 minutes, with hydrochloric acid soln adjust ph to 5 ~ 6 of 3mol/L, stratification, aqueous phase methyl tertiary butyl ether (50mL × 2) extracts, merge organic phase, with saturated nacl aqueous solution (30mL × 2) washing, in organic phase, add anhydrous sodium sulfate drying, filter, concentrated, column chromatography for separation (petrol ether/ethyl acetate (v/v)=50:1-8:1), obtains faint yellow solid 1E (10.1g, productive rate 83.5%).
MSm/z(ESI):210.1[M+1]。
5th step: the tertiary butyl ((1R, 2S)-1-(2,5-difluorophenyl)-1-Hydroxy pentyl-4-alkynes-2-base) carbamate (1F)
tert-butyl((1R,2S)-1-(2,5-difluorophenyl)-1-hydroxypent-4-yn-2-yl)carbamate
By 1E (16.07g, 52mmol) be dissolved in tetrahydrofuran (THF) (100mL), add triethylene diamine (17.39g, 155mmol) with [(R, R)-N-(2-amino-1,2-Diphenethyl) pentafluorobenzenesulfonamide] chlorination (Paracymene) ruthenium (II) (i.e. RuCl (p-cymene) (R, R)-FSDPEN) (0.37g, 0.52mmol), dropwise add formic acid (14.27g, 310mmol), finish, spend the night in 40 DEG C of reactions.Revolve and evaporate tetrahydrofuran (THF) in reaction solution and formic acid, add water (60mL), hydrochloric acid (3mol/L, 10mL), extract with methyl tertiary butyl ether (90mL × 3), merge organic phase, saturated sodium bicarbonate solution (35mL × 2) washs, anhydrous magnesium sulfate drying is added in organic phase, filter, concentrated, column chromatography for separation (petrol ether/ethyl acetate (v/v)=60:1-10:1), obtains faint yellow jelly 1F (15.37g, productive rate 95%).
MSm/z(ESI):334.2[M+23]。
6th step: the tertiary butyl ((2R, 3S)-2-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrans-3-base) carbamate (1G)
tert-butyl((2R,3S)-2-(2,5-difluorophenyl)-3,4-dihydro-2H-pyran-3-yl)carbamate
By 1F (15.37g, 49.4mmol) be dissolved in N under heating condition, dinethylformamide (75mL), add tetrabutyl ammonium hexafluorophosphate (2.49g, 6.42mmol), N-hydroxysuccinimide (2.84g, 24.75mmol), triphenylphosphine (0.86g, 3.26mmol), sodium bicarbonate (2.16g, 25.69mmol), nitrogen replacement three times, vacuumize 15 minutes, add two (triphenylphosphine) ruthenium chloride (the II) (i.e. CpRuCl (PPh of cyclopentadienyl 3) 2) (1.79g, 2.47mmol), nitrogen replacement three times, and vacuumize 15 minutes, under nitrogen protection, be warming up to 85 DEG C of reactions and spend the night.Water (300mL), methyl tertiary butyl ether (200mL) is added in reaction solution, by filtered through silica gel, filtrate stratification, aqueous phase methyl tertiary butyl ether (90mL × 2) extracts, merge organic phase, wash with saturated sodium bicarbonate solution (60mL × 2), anhydrous sodium sulfate drying is added in organic phase, filtering and concentrating, column chromatography for separation (petrol ether/ethyl acetate (v/v)=80:1-30:1), obtain pale yellow powder solid 1G (8.9g, productive rate 57.9%).
MSm/z(ESI):256.2[M+1]。
7th step: the tertiary butyl ((2R, 3S)-2-(2,5-difluorophenyl)-5-hydroxy tetrahydro-2H-pyrans-3-base) carbamate (1H)
tert-butyl((2R,3S)-2-(2,5-difluorophenyl)-5-hydroxytetrahydro-2H-pyran-3-yl)carbamate
By 1G (8.9g, 28.6mmol) be dissolved in dry methyl tertiary butyl ether (90mL), add dry toluene (9mL), temperature is down to-10 DEG C, dropwise add borane dimethylsulf iotade tetrahydrofuran solution (2mol/L, 35.9mL), react 3.5 hours at 0 DEG C.Slowly add water (4mL), dropwise add sodium hydroxide solution (1mol/L, 89mL), stir 15 minutes, add Sodium peroxoborate (13.2g, 85.8mmol), stirred overnight at room temperature in batches.Stratification, aqueous phase methyl tertiary butyl ether (50mL × 2) extracts, merge organic phase, saturated nacl aqueous solution (20mL × 2) washs, organic phase anhydrous sodium sulfate drying, filter, concentrated, add toluene (50mL), be heated to 90 DEG C of dissolvings, normal hexane (200mL) is dropped in reaction solution, separates out white solid, filter, normal hexane (30mL × 2) washing leaching cake, concentrated except desolventizing, obtain white solid powder 1H (7.9g, productive rate 84%).
MSm/z(ESI):274.1[M+1]。
8th step: the tertiary butyl ((2R, 3S)-2-(2,5-difluorophenyl)-5-carbonyl tetrahydrochysene-2H-pyrans-3-base) carbamate (intermediate 1)
tert-butyl((2R,3S)-2-(2,5-difluorophenyl)-5-oxotetrahydro-2H-pyran-3-yl)carbamate
1H (11.53g, 35.03mmol) is dissolved in methylene dichloride (130mL), is cooled to 0 DEG C, this Martin's oxygenant (29.72g, 70.06mmol) will be worn and add in reaction solution in batches, and naturally rise to room temperature reaction 4 hours.Be cooled to 0 DEG C, saturated sodium bicarbonate solution (60mL) is dropped in reaction solution, stir 20 minutes, filter, filtrate stratification, aqueous phase methyl tertiary butyl ether (60mL × 3) extracts, merge organic phase, wash with saturated sodium bicarbonate solution (30mL × 2), anhydrous sodium sulfate drying is added, filtering and concentrating, column chromatography for separation (petrol ether/ethyl acetate (v/v)=10:1-4:1) in organic phase, obtain White crystal powder intermediate 1 (10.85g, productive rate 94.7%).
MSm/z(ESI):272.0[M+1]；
1HNMR(400MHz,DMSO-d 6):δ7.29-7.13(m,4H),4.77-4.75(d,2H),4.22-4.12(d,2H),4.08-4.02(m,1H),2.75-2.70(m,2H),1.23(s,9H)。
Intermediate 2:(S)-5-tertiary butyl 4-ethyl 1-(methyl sulphonyl)-4,6-pyrrolin also [3,4-c] pyrazoles-4,5 (1H)-dicarboxylic ester (intermediate 2)
(S)-5-tert-butyl4-ethyl1-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-4,5(1H)-dicarboxylate
The first step: (2S, 4R)-ethyl 4-hydroxypyrrole alkyl-2-carboxylate hydrochloride (2B)
(2S,4R)-ethyl4-hydroxypyrrolidine-2-carboxylatehydrochloride
Under room temperature, trans-4-hydroxy-l-proline 2A (10.0g, 76.3mmol) is dissolved in dehydrated alcohol (100mL), be cooled to 0 DEG C, add thionyl chloride (10.3g, 86.2mmol), finish and be warming up to 78 DEG C, back flow reaction 8 hours.Reaction solution is down to-20 DEG C, separates out white solid, add methyl tertiary butyl ether (15mL), continue stirring 30 minutes.Filter, filter cake methyl tertiary butyl ether (30mL × 2) washing, drains, obtains white solid 2B (13.4g, productive rate 90%).
MSm/z(ESI):160.1[M+1]。
Second step: (2S, 4R)-1-tertiary butyl 2-ethyl 4-hydroxypyrrole alkyl-1,2-dicarboxylic ester (2C)
(2S,4R)-1-tert-butyl2-ethyl4-hydroxypyrrolidine-1,2-dicarboxylate
Under room temperature, 2B (13.4g, 68.5mmol) is dissolved in 1, in the mixing solutions of 4-dioxane (50mL) and water (50mL), be cooled to 0 DEG C, add triethylamine (17.3g, 0.171mmol), finish, stir 10 minutes.Methylene dichloride (50mL) solution of tert-Butyl dicarbonate (13.4g, 68.5mmol) is added drop-wise in reaction solution, room temperature reaction 20 hours.Add water in reaction solution (100mL), extract with methylene dichloride (100mL × 4).Merge organic phase, wash with the saturated common salt aqueous solution (50mL × 1).Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume, obtains light yellow liquid 2C (18g, productive rate 100%).
MSm/z(ESI):160.1[M+1]。
3rd step: (S)-1-tertiary butyl 2-ethyl 4-carbonyl pyrrolidine alkyl-1,2-dicarboxylic ester (2D)
(S)-1-tert-butyl2-ethyl4-oxopyrrolidine-1,2-dicarboxylate
Under room temperature, 2C (12.0g, 46.3mmol) is dissolved in methylene dichloride (100mL), adds in batches and wear this Martin (39.3g, 92.3mmol), finish, room temperature reaction 4 hours.Be cooled to 0 DEG C, sodium hydrogen carbonate solution (50mL) is added drop-wise in reaction solution, separate out white solid.By reacting liquid filtering, filter cake methyl tertiary butyl ether (50mL × 3) washs.Filtrate, with methyl tertiary butyl ether (30mL × 2) extraction, merges organic phase, and saturated sodium bicarbonate solution (30mL × 3) washs.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume, obtains light yellow liquid 2D (12g, productive rate 100%).
4th step: (S, E)-1-tertiary butyl 2-ethyl 3-((dimethylamino) methene)-4-carbonyl pyrrolidine alkyl-1,2-dicarboxylic ester (2E)
(S,E)-1-tert-butyl2-ethyl3-((dimethylamino)methylene)-4-oxopyrrolidine-1,2-dicarboxylate
Under room temperature, 2D (12.0g, 46.3mmol) is dissolved in DMF (60mL), adds DMF dimethylacetal (8.34g, 69.96mmol), in 105 DEG C of reactions 3 hours.Be down to room temperature, add water (100mL), ethyl acetate (80mL × 4) extracts.Merge organic phase, use water (80mL × 2), the saturated common salt aqueous solution (50mL × 1) to wash successively.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Column chromatography purification (methylene chloride/methanol (v/v)=100:1-80:1), obtains brown liquid 2E (7.0g, productive rate 48.1%).
Five, six steps: (S)-5-tertiary butyl 4-N-ethyl pyrrole N-also [3,4-c] pyrazoles-4,5-(2H, 4H, 6H) dicarboxylic ester (2G)
(S)-5-tert-butyl4-ethylpyrrolo[3,4-c]pyrazole-4,5(2H,4H,6H)-dicarboxylate
Under room temperature, 2E (7.0g, 22.4mmol) is dissolved in dehydrated alcohol (30mL), adds hydrazine hydrate (1.68g, 33.63mmol, wt=80%), finish, in room temperature reaction 3 hours.Add water (150mL), with ethyl acetate (60mL × 3) extraction, merge organic phase, with the saturated common salt aqueous solution (50mL × 1) washing, anhydrous magnesium sulfate drying, filters, filtrate reduced in volume is obtained compound 2F crude product.Compound 2F crude product is dissolved in methylene dichloride (60mL).Be cooled to 0 DEG C, anhydrous methanol (10mL) solution of tosic acid (1.0g, 5.26mmol) be added drop-wise in reaction solution, finish, in 0 DEG C of reaction 1 hour.Be added drop-wise in reaction solution by sodium hydrogen carbonate solution (20mL), regulate pH to 8, methylene dichloride (30mL × 3) extracts, merge organic phase, the saturated common salt aqueous solution (50mL × 1) washs, anhydrous magnesium sulfate drying, filter, by filtrate reduced in volume.Column chromatography purification (ethyl acetate/petroleum ether (v/v)=1:4-1:2), obtains brown liquid 2G (3.0g, productive rate 46.7%).
7th step: (S)-5-tertiary butyl 4-ethyl 1-(methyl sulphonyl)-4,6-pyrrolin is [3,4-c] pyrazoles-4,5 (1H)-dicarboxylic ester (intermediate 2) also
(S)-5-tert-butyl4-ethyl1-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-4,5(1H)-dicarboxylate
Under room temperature, 2G (0.2g, 0.72mmol) is dissolved in methylene dichloride (5mL), is cooled to 0 DEG C, add triethylamine (0.101g, 0.1mmol), finish stirring 10 minutes.Drip Methanesulfonyl chloride (0.107g, 0.94mmol) in reaction solution, room temperature continues reaction 16 hours.In reaction solution, add water (10mL), methyl tertiary butyl ether (20mL × 4) extracts.Merge organic phase, the saturated common salt aqueous solution (50mL × 1) washs, anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Obtain light yellow solid intermediate 2 (0.20g, productive rate 100%).
MSm/z(ESI):360.1[M+1]。
Intermediate 3:(R)-5-tertiary butyl 4-methyl 1-(methyl sulphonyl)-4,6-pyrrolin also [3,4-c] pyrazoles-4,5 (1H)-dicarboxylic ester (intermediate 3)
(R)-5-tert-butyl4-methyl1-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-4,5(1H)-dicarboxylate
The first step: (2R, 4R)-methyl 4-hydroxypyrrole alkyl-2-carboxylate hydrochloride (3B)
(2R,4R)-methyl4-hydroxypyrrolidine-2-carboxylatehydrochloride
Under room temperature, by cis-4-hydroxy-d-proline hydrochloride 3A (12.8g, 76.38mmol) be dissolved in anhydrous methanol (120mL), be cooled to 0 DEG C, add thionyl chloride (10.27g, 86.31mmol), be warming up to 75 DEG C, reflux 4.5 hours, be down to room temperature reaction and spend the night.Concentrated revolving desolventizes to obtain white solid 3B (13.83g, productive rate 100%).
Second step: (2R, 4R)-1-tertiary butyl 2-methyl 4-hydroxypyrrole alkyl-1,2-dicarboxylic ester (3C)
(2R,4R)-1-tert-butyl2-methyl4-hydroxypyrrolidine-1,2-dicarboxylate
Under room temperature, 3B (13.83g, 76.38mmol) is dissolved in 1, in the mixed solvent of 4-dioxane (50mL) and water (20mL), be cooled to 0 DEG C, add triethylamine (19.32g, 190.95mmol), stirring is finished 10 minutes.Be added drop-wise in reaction solution by methylene dichloride (20mL) solution of tert-Butyl dicarbonate (21.67g, 99.29mmol), room temperature reaction spends the night.In reaction solution, add water (50mL), extract with methylene dichloride (50mL × 3).Merge organic phase, with hydrochloric acid soln (1mol/L, 20mL × 2) and the saturated common salt aqueous solution (40mL × 2) washing.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume, obtains light yellow liquid 3C (17.49g, productive rate 93.4%).
3rd step: (R)-1-tertiary butyl 2-methyl 4-carbonyl pyrrolidine alkyl-1,2-dicarboxylic ester (3D)
(R)-1-tert-butyl2-methyl4-oxopyrrolidine-1,2-dicarboxylate
Under room temperature, be dissolved in by 3C (14.92g, 60.87mmol) in methylene dichloride (100mL), add in batches and wear this Martin (51.63mg, 121.73mmol), stirred at ambient temperature reacts 4 hours.Be cooled to 0 DEG C, sodium hydrogen carbonate solution be added drop-wise in reaction solution and produce to no longer including bubble, separate out white solid.By reacting liquid filtering, filter cake methyl tertiary butyl ether (50mL × 3) washing, filtrate extracts with methyl tertiary butyl ether (30mL × 2).Merge organic phase, saturated nacl aqueous solution (50mL × 2) washs, anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume, obtains light yellow liquid 3D (10.3g, productive rate 59.8%).
MSm/z(ESI):243.6[M+1]。
4th step: (R, E)-1-tertiary butyl 2-methyl 3-((dimethylamino) methene 4-carbonyl pyrrolidine alkyl-1,2-dicarboxylic ester (3E)
(R,E)-1-tert-butyl2-methyl3-((dimethylamino)methylene)-4-oxopyrrolidine-1,2-dicarboxylate
Under room temperature, be dissolved in by 3D (2.0g, 8.23mmol) in DMF (20mL), add DMF dimethylacetal (1.47g, 12.34mmol), 100 DEG C are reacted 3 hours.Be down to room temperature, add water (50mL) in reaction solution, ethyl acetate (40mL × 3) extracts.Merge organic phase, use water (30mL × 2), saturated sodium bicarbonate solution (30mL × 2), the saturated common salt aqueous solution (30mL × 2) to wash successively.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Column chromatography purification (methylene chloride/methanol (v/v)=100:1-80:1), obtains dark red liquid 3E (1.47g, productive rate 60%).
5th step: (R)-5-tertiary butyl 4-methyl 4,6-pyrrolin also [3,4-c] pyrazoles-4,5 (2H)-dicarboxylic ester (3F)
(R)-5-tert-butyl4-methyl4,6-dihydropyrrolo[3,4-c]pyrazole-4,5(2H)-dicarboxylate
Under room temperature, be dissolved in by 3E (5.65g, 18.95mmol) in dehydrated alcohol (50mL), add hydrazine hydrate (1.14g, 22.74mmol, wt=80%), stirred at ambient temperature reacts 2 hours.In reaction solution, add water (100mL), extract with methylene dichloride (50mL × 5).Merge organic phase, with the saturated common salt aqueous solution (50mL × 1) washing, anhydrous magnesium sulfate drying, filters, filtrate reduced in volume is obtained residue.Residue is dissolved in methylene dichloride (50mL), is cooled to 0 DEG C, is added drop-wise in reaction solution by anhydrous methanol (3mL) solution of tosic acid (0.54g, 2.84mmol), stirring reaction 3 hours at 0 DEG C.Regulate reaction solution pH to 8 with sodium hydrogen carbonate solution, extract with methylene dichloride (50mL × 2).Merge organic phase, the saturated common salt aqueous solution (50mL × 2) washs, anhydrous sodium sulfate drying, filters, by filtrate reduced in volume.Column chromatography purification (ethyl acetate/petroleum ether (v/v)=1:4-1:2), obtains yellow oil 3F (2.46g, productive rate 48.6%).
6th step: (R)-5-tertiary butyl 4-methyl 1-(methyl sulphonyl)-4,6-pyrrolin is [3,4-c] pyrazoles-4,5 (1H)-dicarboxylic ester (intermediate 3) also
(R)-5-tert-butyl4-methyl1-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-4,5(1H)-dicarboxylate
Under room temperature, 3F (2.37g, 8.87mmol) is dissolved in tetrahydrofuran (THF) (25mL), is cooled to 0 DEG C, add triethylamine (1.35g, 13.31mmol), stir 45 minutes.Methanesulfonyl chloride (1.52g, 13.31mmol) is added drop-wise in reaction solution, stirring reaction 1 hour at 0 DEG C.In reaction solution, add water (50mL), ethyl acetate (50mL × 3) extracts, and merges organic phase, uses water (50mL × 2), the saturated common salt aqueous solution (50mL × 1) to wash successively.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Column chromatography (ethyl acetate/petroleum ether (v/v)=1:10-1:4), obtains light yellow solid intermediate 3 (2.7g, productive rate 88.2%).
MSm/z(ESI):290.2[M+1]。
Intermediate 4:(S)-tertiary butyl 4-(methoxymethyl)-4,6-pyrrolin also [3,4-c] pyrazoles-5 (2H)-carboxylicesters (intermediate 4)
(S)-tert-butyl4-(methoxymethyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate
The first step: (2S, 4R)-methyl 4-hydroxypyrrole alkyl-2-carboxylate hydrochloride (4A)
(2S,4R)-methyl4-hydroxypyrrolidine-2-carboxylate
Under room temperature, trans-4-hydroxy-l-proline 2A (20.0g, 152.6mmol) is dissolved in anhydrous methanol (200mL), be cooled to 0 DEG C, add thionyl chloride (20.6g, 172.4mmol), be warming up to 64 DEG C, back flow reaction 8 hours.Reaction solution is down to-20 DEG C, separates out white solid, add methyl tertiary butyl ether (50mL), continue stirring reaction 30 minutes.Filter, filter cake methyl tertiary butyl ether (50mL × 2) washing, drains, obtains white solid 4A (28g, productive rate 100%).
Second step: (2S, 4R)-1-tertiary butyl 2-methyl 4-hydroxypyrrole alkyl-1,2-dicarboxylic ester (4B)
(2S,4R)-1-tert-butyl2-methyl4-hydroxypyrrolidine-1,2-dicarboxylate
Under room temperature, 4A (27.7g, 152.6mmol) is dissolved in methylene dichloride (150mL), is cooled to 0 DEG C, add triethylamine (38.6g, 381.5mmol), stir 10 minutes.Be added drop-wise in reaction solution by methylene dichloride (50mL) solution of tert-Butyl dicarbonate (39.9g, 183.1mmol), stirred at ambient temperature reacts 12 hours.Organic phase uses hydrochloric acid (0.5mol/L, 150mL × 1), sodium hydrogen carbonate solution (100mL × 1), the saturated common salt aqueous solution (100mL × 1) to wash successively.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume, obtains light yellow liquid 4B (28.0g, productive rate 100%).
MSm/z(ESI):146.2[M+1]。
3rd step: (2S, 4R)-1-tertiary butyl 2-methyl 4-((t-Butyldimethylsilyl) oxygen base) pyrrolidyl-1,2-dicarboxylic ester (4C)
(2S,4R)-1-tert-butyl2-methyl4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate
Under room temperature, by 4B (10.0g, 40.77mmol) be dissolved in N, in dinethylformamide (40mL), be cooled to 0 DEG C, by imidazoles (3.03g, 44.44mmol) and TERT-BUTYL DIMETHYL CHLORO SILANE (12.78g, 84.80mmol) be added in reaction solution, room temperature reaction 2 hours.Poured into by reaction solution in frozen water (60mL), methyl tertiary butyl ether (40mL × 3) extracts.Organic phase uses hydrochloric acid (1mol/L, 30mL × 1), sodium hydrogen carbonate solution (30mL × 1), the saturated common salt aqueous solution (30mL × 1) to wash successively.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume, obtains light yellow liquid 4C (14.7g, productive rate 100%).
MSm/z(ESI):260.3[M+1]。
4th step: (2S, 4R)-tertiary butyl 4-((t-Butyldimethylsilyl) oxygen base)-2-(methylol) pyrrolidyl-1-carboxylicesters (4D)
(2S,4R)-tert-butyl4-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate
Under room temperature, 4C (14.7g, 40.77mmol) is dissolved in tetrahydrofuran (THF) (100mL), is cooled to 0 DEG C.Add lithium borohydride (2.15g, 99.07mmol) in batches, naturally rise to room temperature reaction 12 hours.Be cooled to 0 DEG C, add ammonium chloride solution (10mL), regulate reacting liquid pH value to 7 with hydrochloric acid (1mol/L, 20mL).With ethyl acetate (40mL × 3) extraction, merge organic phase, use sodium hydrogen carbonate solution (25mL × 1), the saturated common salt aqueous solution (25mL × 1) to wash successively.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume, obtains colourless liquid 4D (13.7g, productive rate 100%).
MSm/z(ESI):276.2[M+1]。
5th step: (2S, 4R)-tertiary butyl 4-((t-Butyldimethylsilyl) oxygen base)-2-(methoxymethyl) pyrrolidyl-1-carboxylicesters (4E)
(2S,4R)-tert-butyl4-((tert-butyldimethylsilyl)oxy)-2-(methoxymethyl)pyrrolidine-1-carboxylate
Under room temperature, 4D (13.26g, 40.0mmol) is dissolved in DMF (80mL), is cooled to 0 DEG C, add sodium hydride (6.40g, 160.0mmol) in batches, stirring reaction 0.5 hour at 0 DEG C.Methyl iodide (12.38g, 87.20mmol) is added drop-wise in reaction solution, at room temperature stirring reaction 12 hours.Be cooled to 0 DEG C, in reaction solution, add ammonium chloride solution (50mL) and water (50mL).With methyl tertiary butyl ether (80mL × 4) extraction, merge organic phase, use water (50mL × 1), the saturated common salt aqueous solution (50mL × 1) to wash successively.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume, obtains light yellow liquid 4E (6.4g, productive rate 46.4%).
MSm/z(ESI):298.4[M+1]。
6th step: (2S, 4R)-tertiary butyl 4-hydroxyl-2-(methoxymethyl) pyrrolidyl-1-carboxylicesters (4F)
(2S,4R)-tert-butyl4-hydroxy-2-(methoxymethyl)pyrrolidine-1-carboxylate
Under room temperature, 4E (6.2g, 17.94mmol) is dissolved in tetrahydrofuran (THF) (60mL), adds tetrabutyl ammonium fluoride (9.38g, 35.88mmol), room temperature reaction 2 hours.In reaction solution, add water (60mL), extract by ethyl acetate (50mL × 4).Merge organic phase, wash with the saturated common salt aqueous solution (40mL × 1).Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume, obtains light yellow liquid 4F (5.0g, productive rate 100%).
MSm/z(ESI):176.3[M+1]。
7th step: (S)-tertiary butyl 2-(methoxymethyl)-4-carbonyl pyrrolidine alkyl-1-carboxylicesters (4G)
(S)-tert-butyl2-(methoxymethyl)-4-oxopyrrolidine-1-carboxylate
Under room temperature, be dissolved in by 4F (5.5g, 23.78mmol) in methylene dichloride (30mL), add in batches and wear this Martin's oxygenant (20.2g, 47.56mmol), stirred at ambient temperature reacts 16 hours.Be cooled to 0 DEG C, add sodium hydrogen carbonate solution (30mL), separate out white solid, diatomite filtration, filter cake methyl tertiary butyl ether (30mL × 2) washs, filtrate, with methyl tertiary butyl ether (40mL × 2) extraction, merges organic phase, uses sodium hydrogen carbonate solution (30mL × 1), the saturated common salt aqueous solution (30mL × 1) to wash successively.Anhydrous magnesium sulfate drying, filters, concentrating under reduced pressure.Column chromatography purification (ethyl acetate/petroleum ether (v/v)=1:30-1:10), obtains brown liquid 4G (1.0g, productive rate 18.3%).
MSm/z(ESI):130.2[M+1]。
8th step: (S, E)-tertiary butyl 3-((dimethylamino) methylene radical)-2-(methoxymethyl)-4-carbonyl pyrrolidine alkyl-1-carboxylicesters (4H)
(S,E)-tert-butyl3-((dimethylamino)methylene)-2-(methoxymethyl)-4-oxopyrrolidine-1-carboxylate
Under room temperature, 4G (1.0g, 4.36mmol) is dissolved in DMF (10mL), adds DMF dimethylacetal (0.78g, 6.54mmol), stirring reaction 2 hours at 100 DEG C.Reaction solution is cooled to 20 DEG C, adds water (60mL), extract by ethyl acetate (40mL × 3).Merge organic phase, the saturated common salt aqueous solution (30mL × 1) washs, anhydrous magnesium sulfate drying, filters, filtrate reduced in volume is obtained brown liquid 4H (1.3g, productive rate 100%).
MSm/z(ESI):285.3[M+1]。
9th step: (S)-tertiary butyl 4-(methoxymethyl)-4,6-pyrrolin is [3,4-c] pyrazoles-5 (2H)-carboxylicesters (intermediate 4) also
(S)-tert-butyl4-(methoxymethyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate
4H (12.4g, 4.36mmol) is dissolved in toluene (6mL), adds hydrazine hydrate (0.26g, 5.23mmol, wt=80%), stirring reaction 2 hours at 35 DEG C.In reaction solution, add water (30mL), merge organic phase, anhydrous magnesium sulfate drying with methylene dichloride (40mL × 3) extraction, filter, by filtrate reduced in volume.Concentrating residues thing (1.3g) is dissolved in methylene dichloride (20mL), be cooled to 0 DEG C, anhydrous methanol (10mL) solution of tosic acid (0.83g, 4.36mmol) is added drop-wise in reaction solution, stirring reaction 1 hour at 0 DEG C.Regulate reacting liquid pH value to 8 with sodium hydrogen carbonate solution, with methylene dichloride (40mL × 4) extraction, merge organic phase, the saturated common salt aqueous solution (30mL × 1) washs.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Column chromatography purification (ethyl acetate/petroleum ether (v/v)=1:4-1:1), obtains brown liquid intermediate 4 (0.45g, productive rate 40.9%).
MSm/z(ESI):254.3[M+1]。
Intermediate 5:(R)-4-(methoxymethyl)-2,4,5,6-Pyrrolidine also [3,4-c] pyrazoles benzene sulfonate (intermediate 5)
(R)-4-(methoxymethyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolebenzenesulfonate
The first step: (2R, 4R)-1-tertiary butyl 2-methyl 4-((t-Butyldimethylsilyl) oxygen base) pyrrolidyl-1,2-dicarboxylic ester (5A)
(2R,4R)-1-tert-butyl2-methyl4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate
Under room temperature, by 3C (49.05g, 0.2mol) be dissolved in N, in dinethylformamide (300mL), be cooled to 0 DEG C, by imidazoles (14.8g, 0.22mol) and TERT-BUTYL DIMETHYL CHLORO SILANE (62.7g, 0.42mmol) be added in reaction solution, stirred at ambient temperature reacts 4 hours.Reaction solution is poured in frozen water (400mL), extract with methyl tertiary butyl ether (200mL × 3).Organic phase uses hydrochloric acid (1mol/L, 300mL × 1), sodium hydrogen carbonate solution (300mL × 1), the saturated common salt aqueous solution (300mL × 2) to wash successively.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume, obtains light yellow liquid 5A (72g, productive rate 100%).
Second step: (2R, 4R)-tertiary butyl 4-((t-Butyldimethylsilyl) oxygen base)-2-(methylol) pyrrolidyl-1-carboxylicesters (5B)
(2R,4R)-tert-butyl4-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate
Under room temperature, 5A (71.9g, 0.2mol) is dissolved in tetrahydrofuran (THF) (300mL), is cooled to 0 DEG C, add lithium borohydride (10.6g, 0.49mol) in batches, naturally rise to room temperature reaction 16 hours.Reaction solution is cooled to 0 DEG C, adds ammonium chloride solution (100mL), by hydrochloric acid (3mol/L, 30mL) adjust ph to 7.With ethyl acetate (40mL × 3) extraction, merge organic phase, use sodium hydrogen carbonate solution (150mL × 1), the saturated common salt aqueous solution (150mL × 2) to wash successively.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume, obtains colourless liquid 5B (67.0g, productive rate 100%).
3rd step: (2R, 4R)-tertiary butyl 4-((t-Butyldimethylsilyl) oxygen base)-2-(methoxymethyl) pyrrolidyl-1-carboxylicesters (5C)
(2R,4R)-tert-butyl4-((tert-butyldimethylsilyl)oxy)-2-(methoxymethyl)pyrrolidine-1-carboxylate
Under room temperature, 5B (33.1g, 100.0mmol) is dissolved in DMF (300mL), is cooled to 0 DEG C, add sodium hydride (16.0g, 40.0mmol) in batches, keep 0 DEG C to react 0.5 hour.Be added drop-wise in reaction solution by Methyl triflate (24.62g, 150.0mmol), stirred at ambient temperature reacts 4 hours.Reaction solution is cooled to 0 DEG C, adds ammonium chloride solution (100mL) and water (400mL).With methyl tertiary butyl ether (300mL × 3) extraction, merge organic phase, use water (200mL × 2), the saturated common salt aqueous solution (300mL × 1) to wash successively.Anhydrous magnesium sulfate drying, filters, filtrate reduced in volume is obtained light yellow liquid 5C (24.0g, productive rate 69.6%).
4th step: (2R, 4R)-tertiary butyl 4-methylol-2-(methoxymethyl) pyrrolidyl-1-carboxylicesters (5D)
(2R,4R)-tert-butyl4-hydroxy-2-(methoxymethyl)pyrrolidine-1-carboxylate
Under room temperature, be dissolved in by 5C (23.0g, 66.56mmol) in tetrahydrofuran (THF) (200mL), add tetrabutyl ammonium fluoride (34.8g, 0.13mol), stirred at ambient temperature reacts 5 hours.Add water (400mL), extract by ethyl acetate (100mL × 3).Merge organic phase, wash with the saturated common salt aqueous solution (100mL × 1).Anhydrous magnesium sulfate drying, filters, filtrate reduced in volume is obtained yellow liquid 5D (7.0g, productive rate 50%).
5th step: (R)-tertiary butyl 2-(methoxymethyl)-4-carbonyl pyrrolidine alkyl-1-carboxylicesters (5E)
(R)-tert-butyl2-(methoxymethyl)-4-oxopyrrolidine-1-carboxylate
Under room temperature, be dissolved in by 5D (7.0g, 30.0mmol) in methylene dichloride (70mL), add in batches and wear this Martin's oxygenant (25.7g, 60.0mmol), stirred at ambient temperature reacts 16 hours.Be cooled to 0 DEG C, add sodium hydrogen carbonate solution (200mL), separate out white solid, diatomite filtration, filter cake methyl tertiary butyl ether (30mL × 2) washs, filtrate, with methyl tertiary butyl ether (100mL × 3) extraction, merges organic phase, uses sodium hydrogen carbonate solution (200mL × 3), the saturated common salt aqueous solution (300mL × 1) to wash successively.Anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure, obtains yellow liquid 5E (6.07g, productive rate 100%).
6th step: (R, E)-tertiary butyl 3-((dimethylamino) methene)-2-(methoxymethyl)-4-carbonyl pyrrolidine alkyl-1-carboxylicesters (5F)
(R,E)-tert-butyl3-((dimethylamino)methylene)-2-(methoxymethyl)-4-oxopyrrolidine-1-carboxylate
Under room temperature, 5E (6.87g, 30.0mmol) is dissolved in DMF (60mL), adds DMF dimethylacetal (4.29g, 36.0mmol), 100 DEG C of stirring reactions 2 hours.Reaction solution concentrating under reduced pressure is obtained brown liquid 5F (7.0g, productive rate 100%).
MSm/z(ESI):285.2[M+1]。
Seven, eight steps: (R)-tertiary butyl 4-(methoxymethyl)-pyrrolidyl [3,4-c] pyrazoles-5 (2H, 4H, 6H)-carboxylicesters (5H)
(R)-tert-butyl4-(methoxymethyl)pyrrolo[3,4-c]pyrazole-5(2H,4H,6H)-carboxylate
Under room temperature, 5F (6.8g, 23.9mmol) is dissolved in toluene (30mL), adds hydrazine hydrate (1.43g, 28.69mmol, wt=80%), 35 DEG C of reactions 2 hours.In reaction solution, add water (30mL), with methylene dichloride (150mL) extraction, merge organic phase, anhydrous magnesium sulfate drying, filter, filtrate reduced in volume is obtained 5G.5G is dissolved in methylene dichloride (30mL), is cooled to 0 DEG C, add anhydrous methanol (10mL) solution of tosic acid (0.45g, 2.39mmol), keep 0 DEG C to react 1 hour.Regulate reacting liquid pH value to 8 with sodium hydrogen carbonate solution, extract with methylene dichloride (40mL × 3).Merge organic phase, with the saturated common salt aqueous solution (30mL × 1) washing, anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Column chromatography purification (ethyl acetate/petroleum ether (v/v)=1:5-1:2), obtains brown liquid 5H (1.0g, productive rate 16.5%).
9th step: (R)-4-(methoxymethyl)-2,4,5,6-Pyrrolidine is [3,4-c] pyrazoles benzene sulfonate (intermediate 5) also
(R)-4-(methoxymethyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolebenzenesulfonate
Under room temperature, 5H (1.0g, 3.95mmol) is dissolved in anhydrous methanol (30mL), adds Phenylsulfonic acid (0.88g, 4.74mmol), heating reflux reaction 48 hours.Reaction solution concentrating under reduced pressure is obtained yellow solid intermediate 5 (0.23g, productive rate 75.2%).
MSm/z(ESI):154.3[M+1]。
Intermediate 6: the tertiary butyl ((2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(pyrrolo-[3,4-c] pyrazoles-5 (2H, 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-base) carbamate (intermediate 6)
tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate
The first step: (E)-tertiary butyl 3-((dimethylamino) methene)-4-carbonyl pyrrolidine alkyl-1-carboxylicesters (6B)
(E)-tert-butyl3-((dimethylamino)methylene)-4-oxopyrrolidine-1-carboxylate
Under room temperature, by N-tertbutyloxycarbonyl-3-pyrrolidone 6A (12.0g, 46.3mmol) be dissolved in N, in dinethylformamide (60mL), add N, dinethylformamide dimethylacetal (8.34g, 69.96mmol), stirring reaction 3 hours at 105 DEG C of temperature.Reaction system is down to room temperature, adds water (100mL), extracts by ethyl acetate (80mL × 4).Merge organic phase, use water (80mL × 2) successively, the saturated common salt aqueous solution (50mL × 1) washs.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Column chromatography purification (methylene chloride/methanol (v/v)=100:1-70:1), obtains brown liquid 6B (7.0g, productive rate 48.1%).
Second step: the tertiary butyl 4,6-pyrrolin is [3,4-c] pyrazoles-5 (2H)-carboxylicesters (6C) also
Tert-butyl4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate
Under room temperature, be dissolved in by 6B (12.3g, 51mmol) in toluene (80mL), add hydrazine hydrate (3.05g, 61mmol), stirred at ambient temperature reacts 21 hours.Distillation remove portion solvent, solid is separated out, and filters, with a small amount of ethyl acetate washing leaching cake, by mother liquor evaporate to dryness again, filters and use ethyl acetate washing leaching cake.Filter cake is dissolved in methylene dichloride (70mL), tosic acid (0.95g, 5mmol) is added in reaction solution, continue stirring reaction under room temperature 4 hours.Regulate reacting liquid pH value to 8 with sodium hydrogen carbonate solution, extract with methylene dichloride (50mL × 3).Merge organic phase, wash with the saturated common salt aqueous solution (40mL × 2), anhydrous magnesium sulfate drying, filter, by filtrate reduced in volume, column chromatography purification (ethyl acetate/petroleum ether (v/v)=1:4-1:1), obtains faint yellow solid 6C (5.5g, productive rate 51.6%).
MSm/z(ESI):210.1[M+1]。
3rd step: 2,4,5,6-Pyrrolidine is [3,4-c] pyrazoles benzene sulfonate (6D) also
2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolebenzenesulfonate
6C (0.5g, 2.4mmol) methyl alcohol (2mL) is dissolved, adds Phenylsulfonic acid (0.67g, 3.6mmol), be warming up to 70 DEG C of reactions 16 hours.Add ethyl acetate washing oily matter to produce to solid, filter, use ethyl acetate (10mL × 2), normal hexane (10mL × 1) washing leaching cake successively, light yellow crystal is had to separate out, vacuum-drying, obtains 6D (0.83g, productive rate 100%).
MSm/z(ESI):110.2[M+1]。
4th step: the tertiary butyl ((2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(pyrrolo-[3,4-c] pyrazoles-5 (2H, 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-base) carbamate (intermediate 6)
tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate
Under room temperature, 6D (0.64g, 2.4mmol) is dissolved in N,N-DIMETHYLACETAMIDE (6.5mL), adds intermediate 1 (0.71g, 2.18mmol).Be cooled to-10 DEG C, three (acetoxyl group) sodium borohydride (0.60g, 2.84mmol) are joined in reaction solution, naturally rise to stirring at room temperature and react 18 hours.In reaction solution, drip water (100mL), separate out solid, filter, filter cake uses water (20mL × 3), normal hexane (30mL × 2) to wash successively.Drain, filter cake methylene dichloride (20mL) is dissolved, add anhydrous magnesium sulfate drying, filtering and concentrating, column chromatography [(methylene chloride/methanol (v/v)=40:1-20:1), add a small amount of ammoniacal liquor], obtain yellow solid intermediate 6 (0.67g, productive rate 72.8%).
MSm/z(ESI):421.2[M+1]。
Embodiment 1
(S)-ethyl 5-((3R; 5S; 6R)-5-amino-6-(2; 5-difluorophenyl)-tetrahydrochysene-2H-pyrans-3-base)-1-(methyl sulphonyl)-1; 4; 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-carboxylicesters (compound 1) also
(S)-ethyl5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)-tetrahydro-2H-pyran-3-yl)-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylate
The first step: (S)-ethyl 1-(methyl sulphonyl)-Isosorbide-5-Nitrae, 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-carboxylicesters (1a) also
(S)-ethyl1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylate
Under room temperature, be dissolved in by intermediate 2 (0.3g, 0.84mmol) in methylene dichloride (1mL), be cooled to 0 DEG C, add trifluoroacetic acid (3mL), 0 DEG C of stirring reaction 2 hours, by reaction solution concentrating under reduced pressure.Column chromatography purification [(methylene chloride/methanol (v/v)=40:1-20:1), adds a small amount of ammoniacal liquor], obtains off-white color solid 1a (0.22g, productive rate 100%).
MSm/z(ESI):260.1[M+1]。
Second step: (S)-ethyl 5-((3R; 5S; 6R)-5-(tertbutyloxycarbonyl)-6-(2; 5-difluorophenyl)-tetrahydrochysene-2H-pyrans-3-base)-1-(methyl sulphonyl)-1; 4; 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-carboxylicesters (1b) also
(S)-ethyl5-((3R,5S,6R)-5-(tert-butoxycarbonyl)-6-(2,5-difluorophenyl)-tetrahydro-2H-pyran-3-yl)-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylate
Under room temperature, 1a (0.2g, 0.72mmol) is dissolved in N,N-DIMETHYLACETAMIDE (5mL), adds intermediate 1 (0.229g, 0.7mmol), Phenylsulfonic acid (0.155g, 0.84mmol), stirring at room temperature 1 hour.Join in reaction solution by three (acetoxyl group) sodium borohydride (0.192g, 0.91mmol), stirring at room temperature reacts 16 hours.Be cooled to 0 DEG C, add water (20mL), ammoniacal liquor (2mL) successively, separate out white solid.By reacting liquid filtering, filter cake uses water (5mL × 3), sherwood oil (10mL × 1) to wash successively, suction filtration, dry, obtains light yellow solid 1b (0.20g, productive rate 100%).
MSm/z(ESI):571.2[M+1]。
3rd step: (S)-ethyl 5-((3R; 5S; 6R)-5-amino-6-(2; 5-difluorophenyl)-tetrahydrochysene-2H-pyrans-3-base)-1-(methyl sulphonyl)-1; 4; 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-carboxylicesters (compound 1) also
(S)-ethyl5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)-tetrahydro-2H-pyran-3-yl)-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylate
Under room temperature, be dissolved in by 1b (0.18g, 0.32mmol) in methylene dichloride (2mL), be cooled to 0 DEG C, add trifluoroacetic acid (6mL), stirring reaction 2 hours at 0 DEG C, by reaction solution concentrating under reduced pressure.Be added drop-wise in reaction solution by sodium hydrogen carbonate solution (20mL), regulate pH to be 8.0, methylene dichloride (30mL × 3) extracts, merge organic phase, with the saturated common salt aqueous solution (50mL × 1) washing, anhydrous magnesium sulfate drying, filter, by filtrate reduced in volume.Residue thin layer prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1), obtains off-white color solid chemical compound 1 (0.06g, productive rate 100%).
1HNMR(400MHz,CD 3OD):δ7.67(s,1H),7.23-7.20(m,1H),7.19-7.14(m,2H),4.35-4.13(m,7H),3.47-3.31(m,5H),3.05-3.00(m,1H),1.66(q,1H),1.28(t,3H)；
MSm/z(ESI):471.1[M+1]。
Embodiment 2
(S)-5-((3R; 5S; 6R)-5-amino-6-(2; 5-difluorophenyl)-tetrahydrochysene-2H-pyrans-3-base)-1-(methyl sulphonyl)-1; 4; 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-base also) methyl alcohol (compound 2)
((S)-5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)-tetrahydro-2H-pyran-3-yl)-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl)methanol
The first step: (S)-tertiary butyl 4-(methylol) 1-(methyl sulphonyl) pyrrolo-[3,4-c] pyrazoles-4,5-(1H, 4H, 6H)-carboxylicesters (2a)
(S)-tert-butyl4-(hydroxymethyl)-1-(methylsulfonyl)pyrrolo[3,4-c]pyrazole-5(1H,4H,6H)-carboxylate
Under room temperature, intermediate 2 (1.4g, 3.9mmol) is dissolved in tetrahydrofuran (THF) (15mL), is cooled to 0 DEG C, adds lithium borohydride (0.206g, 9.48mmol), naturally rises to room temperature reaction 5 hours.Reaction solution is cooled to 0 DEG C, adds saturated ammonium chloride solution (20mL), ethyl acetate (30mL × 3) extracts, and merges organic phase, washs with the saturated common salt aqueous solution (30mL × 1).Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Column chromatography purification (petrol ether/ethyl acetate (v/v)=5:1-1:1), obtains off-white color solid 2a (0.54g, productive rate 43.5%).
MSm/z(ESI):262.0[M+1]。
Second step: (S)-(1-(methyl sulphonyl)-Isosorbide-5-Nitrae, 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-base also) methyl alcohol (2b)
(S)-(1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl)methanol
Under room temperature, 2a (0.52g, 1.64mmol) is dissolved in methylene dichloride (2mL), is cooled to 0 DEG C, add trifluoroacetic acid (4mL), in 0 DEG C of reaction 2 hours, by reaction solution concentrating under reduced pressure.Column chromatography purification [(methylene chloride/methanol (v/v)=40:1-20:1), adds a small amount of ammoniacal liquor], obtains off-white color solid 2b (0.20g, productive rate 56.1%).
MSm/z(ESI):218.1[M+1]。
3rd step: the tertiary butyl (2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5 ((S)-4 (methylol)-1-(methyl sulphonyl) pyrrolo-es [3; 4-c] pyrazoles-5 (1H; 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-base) carbamate (2c)
tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-((S)-4-(hydroxymethyl)-1-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate
Under room temperature, 2b (0.2g, 0.92mmol) is dissolved in N,N-DIMETHYLACETAMIDE (4mL), adds intermediate 1 (0.275g, 0.84mmol) and Phenylsulfonic acid (0.187g, 1.01mmol), stirring at room temperature 2 hours.Join in reaction solution by three (acetoxyl group) sodium borohydride (0.231g, 1.09mmol), room temperature continues reaction 16 hours.Be cooled to 0 DEG C, add water (15mL), ammoniacal liquor (1mL) successively, separate out white solid.By reacting liquid filtering, filter cake use water (5mL × 2) washs, and drains, by filtration cakes torrefaction, obtains off-white color solid 2c (0.22g, productive rate 49.5%).
MSm/z(ESI):529.2[M+1]。
4th step: ((S)-5-((3R; 5S; 6R)-5-amino-6-(2; 5-difluorophenyl)-tetrahydrochysene-2H-pyrans-3-base)-1-(methyl sulphonyl)-1; 4; 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-base also) methyl alcohol (compound 2)
((S)-5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)-tetrahydro-2H-pyran-3-yl)-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl)methanol
Under room temperature, 2c (0.21g, 0.39mmol) is dissolved in methylene dichloride (2mL), is cooled to 0 DEG C, add trifluoroacetic acid (4mL), stirring reaction 2 hours at 0 DEG C.By reaction solution concentrating under reduced pressure.Sodium hydrogen carbonate solution (20mL) is added drop-wise in reaction solution, regulates PH to be 8.0, extract with methylene dichloride (30mL × 3).Merge organic phase, the saturated common salt aqueous solution (20mL × 1) washs, anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Residue thin layer prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1), obtains off-white color solid chemical compound 2 (0.05g, productive rate 29.4%).
1HNMR(400MHz,CD 3OD):δ7.65(s,1H),7.22-7.17(m,1H),7.16-7.12(m,2H),4.22-4.14(m,1H),4.13(m,3H),4.11(m,1H),3.75-3.72(m,1H),3.47(m,2H),3.34(s,3H),2.95-2.91(m,1H),2.32-2.28(m,1H),1.68(q,1H)；
MSm/z(ESI):429.1[M+1]。
Embodiment 3
(R)-methyl 5-((3R, 5S, 6R)-5-amino-6-(2; 5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-base)-1-(methyl sulphonyl)-Isosorbide-5-Nitrae, 5; 6-Pyrrolidine is [3,4-c] pyrazoles-4-carboxylicesters (compound 3) also
(R)-methyl5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylate
The first step: (R)-methyl 1-(methyl sulphonyl)-Isosorbide-5-Nitrae, 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-carboxylicesters (3a) also
(R)-methyl1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylate
Under room temperature, intermediate 3 (1g, 2.90mmol) is dissolved in methylene dichloride (15mL), is cooled to 0 DEG C, add trifluoroacetic acid (5mL), react 7.5 hours at 0 DEG C.By reaction solution concentrating under reduced pressure, add methylene dichloride (20mL), methyl alcohol (1mL) and 5 ammoniacal liquor and mix sample, column chromatography purification [(methylene chloride/methanol (v/v)=40:1-20:1), add a small amount of ammoniacal liquor], obtain yellow oil 3a (0.69g, productive rate 97.2%).
MSm/z(ESI):246.3[M+1]。
Second step: (R)-methyl 5-((3R; 5S; 6R)-5-((tertbutyloxycarbonyl) is amino)-6-(2; 5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-base)-1-(methyl sulphonyl)-1; 4; 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-carboxylicesters (3b) also
(R)-methyl5-((3R,5S,6R)-5-((tert-butoxycarbonyl)amino)-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylate
Under room temperature, 3a (1.24g, 5.06mmol) is dissolved in N,N-DIMETHYLACETAMIDE (15mL), add intermediate 1 (1.50g, 4.60mmol), Phenylsulfonic acid (1.02g, 5.52mmol), finish be cooled to-10 DEG C stir 30 minutes.Join in reaction solution by three (acetoxyl group) sodium borohydride (1.27g, 5.99mmol), stirred at ambient temperature reacts 1 hour.Reaction solution is cooled to 0 DEG C, adds water (80mL), separate out solid.Filter, filter cake methylene dichloride dissolves, and adds anhydrous sodium sulfate drying.Filter, concentrated, column chromatography (methylene chloride/methanol (v/v)=100:1-80:1), obtains off-white color solid 3b (0.87g, productive rate 34%).
MSm/z(ESI):557.3[M+1]。
3rd step: (R)-methyl 5-((3R; 5S; 6R)-5-amino-6-(2; 5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-base)-1-(methyl sulphonyl)-1; 4; 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-carboxylicesters (compound 3) also
(R)-methyl5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylate
Under room temperature, be dissolved in by 3b (0.79g, 1.42mmol) in methylene dichloride (10mL), be cooled to 0 DEG C, add trifluoroacetic acid (5mL), stirring reaction 2 hours at 0 DEG C, is warming up to room temperature reaction 1 hour.By reaction solution concentrating under reduced pressure except desolventizing, add methylene dichloride (25mL), regulate reaction solution pH to 8 with sodium hydrogen carbonate solution, methylene dichloride (20mL × 3) extracts.Merge organic phase, with water (20mL × 3) washing, anhydrous sodium sulfate drying, filters, by filtrate reduced in volume.Residue thin layer prepares plate separation and purification, obtains faint yellow solid compound 3 (0.5g, productive rate 76.9%).
1HNMR(400MHz,CD 3OD):δ7.56(s,1H),7.10–6.69(m,3H),4.80(s,1H),4.28-4.19(m,1H),4.13-4.09(m,1H),4.08-4.04(m,2H),3.70-3.69(s,3H),3.34-3.32(s,3H),2.84-2.77(m,1H),2.26–2.21(m,1H),1.54(q,1H)；
MSm/z(ESI):457.0[M+1]。
Embodiment 4
((R)-5-((3R; 5S; 6R)-5-amino-6-(2; 5-difluorophenyl)-tetrahydrochysene-2H-pyrans-3-base)-1-(methyl sulphonyl)-1; 4; 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-base also) methyl alcohol (compound 4)
((R)-5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)-tetrahydro-2H-pyran-3-yl)-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl)methanol
The first step: (R)-tertiary butyl 4-(methylol)-1-(methyl sulphonyl)-4,6-pyrrolin also [3,4-c] pyrazoles-5 (1H)-carboxylicesters (4a)
(R)-tert-butyl4-(hydroxymethyl)-1-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate
Under room temperature, be dissolved in by intermediate 3 (2.0g, 5.78mmol) in tetrahydrofuran (THF) (40mL), be cooled to 0 DEG C, add lithium borohydride (0.19g, 8.69mmol), 0 DEG C to room temperature reaction 4 hours.Reaction solution is cooled to 0 DEG C, adds saturated ammonium chloride solution (20mL), ethyl acetate (30mL × 3) extracts, and merges organic phase, and the saturated common salt aqueous solution (30mL × 1) washs.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Column chromatography purification (petrol ether/ethyl acetate (v/v)=5:1-1:1), obtains off-white color solid 4a (0.7g, productive rate 40%).
MSm/z(ESI):262.1[M+1]。
Second step: (R)-(1-(methyl sulphonyl)-Isosorbide-5-Nitrae, 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-base also) methyl alcohol (4b)
(R)-(1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl)methanol
Under room temperature, 4a (0.68g, 2.14mmol) is dissolved in methylene dichloride (8mL), is cooled to 0 DEG C, add trifluoroacetic acid (4mL), stirring reaction 2 hours at 0 DEG C.By reaction solution concentrating under reduced pressure, column chromatography purification [(methylene chloride/methanol (v/v)=40:1-20:1), adds a small amount of ammoniacal liquor], obtains off-white color solid 4b (0.32g, productive rate 68.8%).
MSm/z(ESI):218.1[M+1]。
3rd step: the tertiary butyl ((2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5 ((R)-4 (methylol)-1-(methyl sulphonyl) pyrrolo-es [3; 4-c] pyrazoles-5 (1H; 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-base) carbamate (4c)
tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-((R)-4-(hydroxymethyl)-1-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate
Under room temperature, 4b (0.31g, 1.41mmol) is dissolved in N,N-DIMETHYLACETAMIDE (5mL), add intermediate 1 (0.44g, 1.34mmol), Phenylsulfonic acid (0.28g, 1.55mmol), finish in stirred at ambient temperature 1.5 hours.Three (acetoxyl group) sodium borohydride (0.37g, 1.74mmol) are joined in reaction solution, at room temperature continues reaction 16 hours.Reaction solution is cooled to 0 DEG C, adds water (10mL), ammoniacal liquor (2mL) successively, separate out white solid, filter, filter cake uses water (5mL × 2), sherwood oil (10mL × 2) to wash successively.Drain, by filtration cakes torrefaction, obtain off-white color solid 4c (0.22g, productive rate 30%).
MSm/z(ESI):529.1[M+1]。
4th step: ((R)-5-((3R; 5S; 6R)-5-amino-6-(2; 5-difluorophenyl)-tetrahydrochysene-2H-pyrans-3-base)-1-(methyl sulphonyl)-1; 4; 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-base also) methyl alcohol (compound 4)
((R)-5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)-tetrahydro-2H-pyran-3-yl)-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl)methanol
Under room temperature, 4c (0.22g, 0.42mmol) is dissolved in methylene dichloride (4mL), is cooled to 0 DEG C, add trifluoroacetic acid (4mL), in 0 DEG C of reaction 2 hours.By reaction solution concentrating under reduced pressure, add methylene dichloride (40mL), regulate reacting liquid pH value to 8 with sodium hydrogen carbonate solution, methylene dichloride (40mL × 3) extracts.Merge organic phase, anhydrous magnesium sulfate drying, filter, by filtrate reduced in volume.Residue thin layer prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1), obtains off-white color solid chemical compound 4 (0.02g, productive rate 11.2%).
1HNMR(400MHz,CD 3OD):δ7.65(s,1H),7.22-7.17(m,1H),7.17-7.16(m,2H),4.22-4.14(m,1H),4.13(m,3H),4.11(m,1H),3.75-3.72(m,1H),3.47(m,2H),3.34(s,3H),2.95-2.91(m,1H),2.32-2.28(m,1H),1.68(q,1H)；
MSm/z(ESI):429.3[M+1]。
Embodiment 5
((R)-ethyl 5-((3R; 5S; 6R)-5-amino-6-(2; 5-difluorophenyl)-tetrahydrochysene-2H-pyrans-3-base)-1-(methyl sulphonyl)-1; 4; 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-carboxylicesters (compound 5) also
((R)-ethyl5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)-tetrahydro-2H-pyran-3-yl)-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylate
The first step: (R)-5-(tertbutyloxycarbonyl)-Isosorbide-5-Nitrae, 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-carboxylic acid (5a) also
(R)-5-(tert-butoxycarbonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylicacid
Under room temperature, by 3F (1.3g, 4.86mmol) be dissolved in methyl alcohol (20mL) with the admixture solvent of tetrahydrofuran (THF) (10mL), be cooled to 0 DEG C, drip lithium hydroxide (0.41g, 9.72mmol) and the mixed solution of water (5mL), stirring is finished 10 minutes.Room temperature reaction 12 hours, by hydrochloric acid (3mol/L, 5mL) adjust ph to 7, by reaction solution concentrating under reduced pressure.Add water (15mL), be cooled to 0 DEG C, by hydrochloric acid (3mol/L, 5mL) adjust ph to 1-2, ethyl acetate (30mL × 3) extracts.Merge organic phase, the saturated common salt aqueous solution (20mL × 1) washs.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume, obtains light yellow solid 5a (1.2g, productive rate 100%).
Second step: (R)-ethyl Isosorbide-5-Nitrae, 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-carboxylate hydrochloride (5b) also
(R)-ethyl1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylatehydrochloride
Under room temperature, 5a (0.6g, 2.37mmol) is dissolved in dehydrated alcohol (20mL), is cooled to 0 DEG C, add thionyl chloride (0.34g, 2.384mmol), in room temperature reaction 4 hours.By reaction solution concentrating under reduced pressure, obtain off-white color solid 5b (0.52g, productive rate 100%).
MSm/z(ESI):182.1[M+1]。
3rd step: (R)-5-tertiary butyl 4-ethyl 3-pyrrolo-[3,4-c] pyrazoles-4,5-(1H, 4H, 6H) dicarboxylic ester (5c)
(R)-5-tert-butyl4-ethylpyrrolo[3,4-c]pyrazole-4,5(1H,4H,6H)-dicarboxylate
Under room temperature, 5b (0.52g, 2.37mmol) is dissolved in the mixed solvent of dehydrated alcohol (10mL) and methylene dichloride (30mL), be cooled to 0 DEG C, add triethylamine (0.59g, 5.93mmol), stir 10 minutes at 0 DEG C.Tert-Butyl dicarbonate (0.62g, 2.84mmol) is joined in reaction solution, room temperature reaction 16 hours.In reaction solution, add methylene dichloride (50mL), use hydrochloric acid (1mol/L, 30mL × 2), sodium hydrogen carbonate solution (30mL × 2), saturated nacl aqueous solution (30mL × 2) to wash successively.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume, obtains shallow rice-pudding look solid 5c (0.66g, productive rate 100%).
4th step: (R)-ethyl Isosorbide-5-Nitrae, 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-carboxylicesters benzene sulfonate (5d) also
(R)-ethyl1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylatebenzenesulfonate
Under room temperature, 5c (0.66g, 2.37mmol) is dissolved in dehydrated alcohol (15mL), adds Phenylsulfonic acid (0.53g, 2.84mmol), heating reflux reaction 16 hours.By reaction solution concentrating under reduced pressure, obtain class brown solid 5d (0.80g, productive rate 100%).
MSm/z(ESI):167.1[M+1]。
5th step: (R)-ethyl 5-((3R, 5S, 6R)-5-(tertbutyloxycarbonyl)-6-(2,5-difluorophenyl)-tetrahydrochysene-2H-pyrans-3-base)-Isosorbide-5-Nitrae, 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-carboxylicesters (5e) also
(R)-ethyl5-((3R,5S,6R)-5-(tert-butoxycarbonyl)-6-(2,5-difluorophenyl)-tetrahydro-2H-pyran-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylate
Under room temperature, 5d (0.80g, 2.2mmol) is dissolved in N,N-DIMETHYLACETAMIDE (5mL), adds intermediate 1 (0.65g, 2.0mmol), stirring at room temperature 1 hour.Three (acetoxyl group) sodium borohydride (0.59g, 2.8mmol) are joined in reaction solution, continues reaction under room temperature 16 hours.Reaction solution is cooled to 0 DEG C, adds water (20mL), ammoniacal liquor (2mL) successively, separate out white solid, filter, filter cake uses water (10mL × 2), sherwood oil (10mL × 1) to wash successively.Drain, filter cake methylene dichloride (60mL) is dissolved, anhydrous magnesium sulfate drying, filter, by filtrate reduced in volume, obtain light yellow solid 5e (0.98g, productive rate 40.3%).
MSm/z(ESI):493.2[M+1]。
6th step: (R)-ethyl 5-((3R; 5S; 6R)-5-(tertbutyloxycarbonyl)-6-(2; 5-difluorophenyl)-tetrahydrochysene-2H-pyrans-3-base)-1-(methyl sulphonyl)-1; 4; 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-carboxylicesters (5f) also
(R)-ethyl5-((3R,5S,6R)-5-(tert-butoxycarbonyl)-6-(2,5-difluorophenyl)-tetrahydro-2H-pyran-3-yl)-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylate
Under room temperature, 5e (0.98g, 2.0mmol) is dissolved in tetrahydrofuran (THF) (30mL), is cooled to 0 DEG C, add triethylamine (0.28g, 2.8mmol), stir 5 minutes.Be added drop-wise in reaction solution by Methanesulfonyl chloride (0.31g, 2.6mmol), stirred at ambient temperature reacts 16 hours.Add water in reaction solution (30mL), with ethyl acetate (30mL × 2) extraction, merge organic phase, the saturated common salt aqueous solution (20mL × 1) washs.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume, obtains light yellow solid 5f (0.30g, productive rate 30%).
MSm/z(ESI):571.2[M+1]。
7th step: ((R)-ethyl 5-((3R; 5S; 6R)-5-amino-6-(2; 5-difluorophenyl)-tetrahydrochysene-2H-pyrans-3-base)-1-(methyl sulphonyl)-1; 4; 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-carboxylicesters (compound 5) also
((R)-ethyl5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)-tetrahydro-2H-pyran-3-yl)-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylate
Under room temperature, 5f (0.3g, 0.53mmol) is dissolved in methylene dichloride (4mL), is cooled to 0 DEG C, add trifluoroacetic acid (4mL), stirring reaction 2 hours at 0 DEG C.By reaction solution concentrating under reduced pressure, regulate the pH value to 8 of reaction solution with sodium hydrogen carbonate solution, extract with methylene dichloride (30mL × 2).Merge organic phase, wash with the saturated common salt aqueous solution (30mL × 1).Anhydrous magnesium sulfate drying, filter, by filtrate reduced in volume, residue thin layer prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1), obtains off-white color solid chemical compound 5 (0.07g, productive rate 28.3%).
1HNMR(400MHz,CD 3OD):δ7.65(s,1H),7.19-7.06(m,3H),4.86-4.85(m,1H),4.29-4.14(m,6H),3.42-3.39(m,4H),2.95-2.89(m,1H),2.36-2.32(m,1H),1.62(q,1H),1.33(t,1H)；
MSm/z(ESI):471.3[M+1]。
Embodiment 6
(R)-5-((3R, 5S, 6R)-5-amino-6-(2; 5-difluorophenyl)-tetrahydrochysene-2H-pyrans-3-base)-1-(methyl sulphonyl)-Isosorbide-5-Nitrae, 5; 6-Pyrrolidine is [3,4-c] pyrazole-4-carboxamide (compound 6) also
(R)-5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxamide
The first step: (R)-tertiary butyl 4-formamyl-4,6-pyrrolin also [3,4-c] pyrazoles-5 (1H)-carboxylicesters (6a)
(R)-tert-butyl4-carbamoyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate
Under room temperature, 3F (1.5g, 5.61mmol) is dissolved in methanolic ammonia solution (30mL, 2mol/L), room temperature reaction 48 hours, by filtrate reduced in volume, obtains light yellow solid 6a (1.0g, productive rate 70.4%).
MSm/z(ESI):253.3[M+1]。
Second step: (R)-tertiary butyl 4-formamyl-1-(methyl sulphonyl)-4,6-pyrrolin also [3,4-c] pyrazoles 5-(1H)-carboxylicesters (6b)
(R)-tert-butyl4-carbamoyl-1-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate
Under room temperature, 6a (1.0g, 3.97mmol) is dissolved in methylene dichloride (5mL), is cooled to 0 DEG C, add triethylamine (0.51g, 5.56mmol), stir 5 minutes.Methanesulfonyl chloride (0.58g, 5.16mmol) is added drop-wise in reaction solution, room temperature reaction 48 hours.In reaction solution, add water (30mL), ethyl acetate (30mL × 3) extracts.Merge organic phase, the saturated common salt aqueous solution (20mL × 1) washs.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Column chromatography purification (methylene chloride/methanol (v/v)=100:1-50:1), obtains light yellow solid 6b (0.80g, productive rate 61.6%).
MSm/z(ESI):353.2[M+23]。
3rd step: (R)-1-(methyl sulphonyl)-Isosorbide-5-Nitrae, 5,6-Pyrrolidine is [3,4-c] pyrazole-4-carboxamide (6c) also
(R)-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxamide
Under room temperature, be dissolved in by 6b (0.80g, 2.42mmol) in methylene dichloride (4mL), be cooled to 0 DEG C, add trifluoroacetic acid (4mL), 0 DEG C is reacted 2 hours.By reaction solution concentrating under reduced pressure, column chromatography purification [(methylene chloride/methanol (v/v)=40:1-20:1), adds a small amount of ammoniacal liquor], obtains light yellow solid 6c (0.30g, productive rate 53.9%).
MSm/z(ESI):231.2[M+1]。
4th step: the tertiary butyl (2R; 3S; 5R)-5-((R)-4-formamyl-1-(methyl sulphonyl) pyrrolo-[3; 4-c] pyrazoles-5 (1H; 4H; 6H)-Ji)-2-(2,5-difluorophenyl)-tetrahydrochysene-2H-pyrans-3-base) carbamate (6d)
tert-butyl((2R,3S,5R)-5-((R)-4-carbamoyl-1-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate
Under room temperature, 6c (0.30g, 1.30mmol) is dissolved in N,N-DIMETHYLACETAMIDE (6mL), adds intermediate 1 (0.43g, 1.30mmol), Phenylsulfonic acid (0.26g, 1.43mmol), stirring at room temperature 1 hour.Three (acetoxyl group) sodium borohydride (0.38g, 1.82mmol) are joined in reaction solution, room temperature reaction 16 hours.Be cooled to 0 DEG C, add water (20mL), ammoniacal liquor (4mL) successively, separate out white solid.By reacting liquid filtering, filter cake uses water (5mL × 1), sherwood oil (10mL × 2) to wash successively.Drain, by filtration cakes torrefaction, obtain shallow white solid 6d (0.18g, productive rate 26%).
MSm/z(ESI):542.3[M+1]。
5th step: (R)-5-((3R; 5S; 6R)-5-amino-6-(2; 5-difluorophenyl)-tetrahydrochysene-2H-pyrans-3-base)-1-(methyl sulphonyl)-1; 4; 5,6-Pyrrolidine is [3,4-c] pyrazole-4-carboxamide (compound 6) also
(R)-5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxamide
Under room temperature, be dissolved in by 6d (0.16g, 0.31mmol) in methylene dichloride (8mL), be cooled to 0 DEG C, add trifluoroacetic acid (6mL), 0 DEG C is reacted 2 hours.By reaction solution concentrating under reduced pressure, regulate reacting liquid pH value to be 8 with sodium hydrogen carbonate solution, with methylene dichloride (40mL × 4) extraction, merge organic phase, the saturated common salt aqueous solution (20mL × 1) washs.Anhydrous magnesium sulfate drying, filter, by filtrate reduced in volume, residue thin layer prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1), obtains off-white color solid chemical compound 6 (0.102g, productive rate 72.2%).
1HNMR(400MHz,CD 3OD):δ7.54(s,1H),7.11-6.97(m,3H),4.21(m,1H),4.13-4.12(m,1H),4.11-4.09(m,3H),3.21(m,1H),3.13(s,3H),3.09(m,1H),2.82(m,1H),2.26(m,1H),1.57(q,1H)；
MSm/z(ESI):442.2[M+1]。
Embodiment 7
(R)-5-((3R; 5S; 6R)-5-amino-6-(2; 5-difluorophenyl)-tetrahydrochysene-2H-pyrans-3-base)-N-methyl isophthalic acid-(methyl sulphonyl)-1; 4; 5,6-Pyrrolidine is [3,4-c] pyrazole-4-carboxamide (compound 7) also
(R)-5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N-methyl-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxamide
The first step: (R)-tertiary butyl 4-(methylcarbamoyl)-4,6 pyrrolin also [3,4-c] pyrazoles-5 (1H)-carboxylicesters (7a)
(R)-tert-butyl4-(methylcarbamoyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate
Under room temperature, be dissolved in by 3F (1.0g, 3.74mmol) in methylamine methanol solution (30mL, 2mol/L), stirred at ambient temperature reacts 24 hours.By reaction solution concentrating under reduced pressure, obtain light yellow solid 7a (1.0g, productive rate 100%).
MSm/z(ESI):267.1[M+1]。
Second step: (R)-tertiary butyl 4-(methylcarbamoyl)-1-(methyl sulphonyl)-4,6-pyrrolin also [3,4-c] pyrazoles-5 (1H)-carboxylicesters (7b)
(R)-tert-butyl4-(methylcarbamoyl)-1-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate
Under room temperature, 7a (0.53g, 2.0mmol) is dissolved in methylene dichloride (30mL), is cooled to 0 DEG C, add triethylamine (0.28g, 2.8mmol), stir 10 minutes.Be added drop-wise in reaction solution by Methanesulfonyl chloride (0.3g, 2.6mmol), stirred at ambient temperature reacts 16 hours.Add ethyl acetate (30mL), merge organic phase, wash with the saturated common salt aqueous solution (30mL × 1).Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Column chromatography purification [(methylene chloride/methanol (v/v)=40:1-20:1), adds a small amount of ammoniacal liquor], obtains light yellow solid 7b (0.30g produces 43.6%).
MSm/z(ESI):345.1[M+1]。
3rd step: (R)-N-methyl isophthalic acid-(methyl sulphonyl)-Isosorbide-5-Nitrae, 5,6-Pyrrolidine is [3,4-c] pyrazole-3-formamide (7c) also
(R)-N-methyl-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxamide
Under room temperature, 7b (0.30g, 0.87mmol) is dissolved in methylene dichloride (2mL), is cooled to 0 DEG C, add trifluoroacetic acid (2mL), stirring reaction 3 hours at 0 DEG C.By reaction solution concentrating under reduced pressure, column chromatography purification (methylene chloride/methanol (v/v)=100:1-60:1), obtains light yellow solid 7c (0.47g, productive rate 100%).
MSm/z(ESI):245.1[M+1]。
4th step: the tertiary butyl ((2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5-((R)-4-(methylcarbamoyl)-1-(methyl sulphonyl)-pyrrolo-[3; 4-c] pyrazoles-5 (1H; 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-base) carbamate (7d)
tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-((R)-4-(methylcarbamoyl)-1-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate
Under room temperature, 7c (0.31g, 1.41mmol) is dissolved in N,N-DIMETHYLACETAMIDE (5mL), adds intermediate 1 (0.44g, 1.34mmol), Phenylsulfonic acid (0.28g, 1.55mmol), stirring at room temperature 1.5 hours.Join in reaction solution by three (acetoxyl group) sodium borohydride (0.37g, 1.74mmol), stirring at room temperature reacts 16 hours.Be cooled to 0 DEG C, add water (10mL), ammoniacal liquor (2mL) successively, separate out white solid.By reacting liquid filtering, filter cake uses water (5mL × 2), sherwood oil (10mL × 2) to wash successively.Drain, by filtration cakes torrefaction, obtain off-white color solid 7d (0.22g, productive rate 30%).
MSm/z(ESI):556.1[M+1]。
5th step: (R)-5-((3R; 5S; 6R)-5-amino-6-(2; 5-difluorophenyl)-tetrahydrochysene-2H-pyrans-3-base)-N-methyl isophthalic acid-(methyl sulphonyl)-1; 4; 5,6-Pyrrolidine is [3,4-c] pyrazole-4-carboxamide (compound 7) also
(R)-5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N-methyl-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxamide
Under room temperature, be dissolved in by 7d (0.22g, 0.42mmol) in methylene dichloride (4mL), be cooled to 0 DEG C, add trifluoroacetic acid (4mL), 0 DEG C is reacted 2 hours.By reaction solution concentrating under reduced pressure, add methylene dichloride (40mL), regulate the pH value to 8 of reaction solution with sodium hydrogen carbonate solution, methylene dichloride (40mL × 3) extracts.Merge organic phase, anhydrous magnesium sulfate drying, filter, by filtrate reduced in volume, residue thin layer prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1), obtains off-white color solid chemical compound 7 (0.02g, productive rate 11.2%).
1HNMR(400MHz,CD 3OD):δ7.52(s,1H),7.06-7.02(m,3H),4.55(m,1H),4.36(dd,1H),4.23(m,1H),4.10(m,2H),3.21(m,4H),3.12(m,1H),3.05(m,1H),2.85(m,1H),2.68(s,1H),2.22(m,1H),1.51(q,1H)；
MSm/z(ESI):456.3[M+1]。
Embodiment 8
(S)-5-((3R, 5S, 6R)-5-amino-6-(2; 5-difluorophenyl)-tetrahydrochysene-2H-pyrans-3-base)-1-(methyl sulphonyl)-Isosorbide-5-Nitrae, 5; 6-Pyrrolidine is [3,4-c] pyrazole-4-carboxamide (compound 8) also
(S)-5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)-tetrahydro-2H-pyran-3-yl)-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxamide
The first step: (S)-5-tertbutyloxycarbonyl-Isosorbide-5-Nitrae, 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-carboxylic acid (8a) also
(S)-5-(tert-butoxycarbonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylicacid
Under room temperature, by 2G (2.4g, 8.54mmol) be dissolved in the mixing solutions of methyl alcohol (40mL) and tetrahydrofuran (THF) (10mL), be cooled to 0 DEG C, drip lithium hydroxide (0.72g, 17.08mmol) and the mixed solution of water (20mL), stir 10 minutes, stirred at ambient temperature reacts 12 hours, with hydrochloric acid (3mol/L, 20mL) adjust ph to 7, by reaction solution concentrating under reduced pressure.Adding water (25mL), be cooled to 0 DEG C, is 1-2 by hydrochloric acid (3mol/L, 20mL) adjust ph, and ethyl acetate (30mL × 4) extracts.Merge organic phase, the saturated common salt aqueous solution (20mL × 1) washs, anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume, obtains light yellow solid 8a (1.80g, productive rate 83.3%).
Second step: (S)-tertiary butyl 4-formamyl pyrrolo-[3,4-c] pyrazoles-5 (1H, 4H, 6H)-carboxylicesters (8b)
(S)-tert-butyl4-carbamoylpyrrolo[3,4-c]pyrazole-5(1H,4H,6H)-carboxylate
Under room temperature, 8a (1.6g, 6.32mmol) is dissolved in tetrahydrofuran (THF) (30mL), add tetramethyl-urea phosphofluoric acid ester (4.81g successively, 12.64mmol), diisopropylethylamine (4.08g, 31.6mmol), room temperature reaction 1 hour.Add ammoniacal liquor (6.65g, 20.0mmol), room temperature reaction 12 hours.By reacting liquid filtering, filter cake methyl tertiary butyl ether (30mL × 4) washs, merging filtrate, anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure, column chromatography purification (ethyl acetate/petroleum ether (v/v)=1:1-4:1), obtain light yellow solid 8b (1.2g, productive rate 75%).
MSm/z(ESI):253.1[M+1]。
3rd step: (S)-tertiary butyl 4-formamyl-1-(methyl sulphonyl) pyrrolo-[3,4-c] pyrazoles 5-(1H, 4H, 6H)-carboxylicesters (8c)
(S)-tert-butyl4-carbamoyl-1-(methylsulfonyl)pyrrolo[3,4-c]pyrazole-5(1H,4H,6H)-carboxylate
Under room temperature, by 8b (0.3g, 1.19mmol) be dissolved in methylene dichloride (5mL), be cooled to 0 DEG C, add triethylamine (0.17g, 1.67mmol), stir 5 minutes, Methanesulfonyl chloride (0.18g, 1.55mmol) is added drop-wise in reaction solution, room temperature reaction 16 hours.In reaction solution, add water (30mL), ethyl acetate (30mL × 3) extracts.Merge organic phase, the saturated common salt aqueous solution (520mL × 1) washs.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume, obtains light yellow solid 8c (0.33g, productive rate 83.9%).
4th step: (S)-1-(methyl sulphonyl)-Isosorbide-5-Nitrae, 5,6-Pyrrolidine is [3,4-c] pyrazole-4-carboxamide (8d) also
(S)-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxamide
Under room temperature, 8c (0.3g, 0.91mmol) is dissolved in methylene dichloride (2mL), is cooled to 0 DEG C, add trifluoroacetic acid (4mL), stirring reaction 2 hours at 0 DEG C.By reaction solution concentrating under reduced pressure, residue column chromatography purification [(methylene chloride/methanol (v/v)=40:1-20:1), adds a small amount of ammoniacal liquor], obtains off-white color solid 8d (0.15g, productive rate 78%).
MSm/z(ESI):231.1[M+1]。
5th step: the tertiary butyl (2R; 3S; 5R)-5-((S)-4-formamyl-1-(methyl sulphonyl) pyrrolo-[3; 4-c] pyrazoles-5 (1H; 4H; 6H)-Ji)-2-(2,5-difluorophenyl)-tetrahydrochysene-2H-pyrans-3-aminocarbamic acid ester (8e)
tert-butyl(2R,3S,5R)-5-((S)-4-carbamoyl-1-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)-tetrahydro-2H-pyran-3-ylcarbamate
Under room temperature, 8d (0.14g, 0.61mmol) is dissolved in N,N-DIMETHYLACETAMIDE (5mL), adds intermediate 1 (0.18g, 0.56mmol) and Phenylsulfonic acid (0.12g, 0.67mmol), stirring at room temperature 1 hour.Three (acetoxyl group) sodium borohydride (0.15g, 0.73mmol) are joined in reaction solution, room temperature reaction 16 hours.Be cooled to 0 DEG C, add water (20mL), ammoniacal liquor (5mL) successively, separate out white solid.By reacting liquid filtering, filter cake uses water (5mL × 1), sherwood oil (10mL × 2) to wash successively.Drain, by filtration cakes torrefaction, obtain shallow white solid 8e (0.10g, productive rate 30%).
MSm/z(ESI):542.2[M+1]。
6th step: (S)-5-((3R; 5S; 6R)-5-amino-6-(2; 5-difluorophenyl)-tetrahydrochysene-2H-pyrans-3-base)-1-(methyl sulphonyl)-1; 4; 5,6-Pyrrolidine is [3,4-c] pyrazole-4-carboxamide (compound 8) also
(S)-5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)-tetrahydro-2H-pyran-3-yl)-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxamide
Under room temperature, be dissolved in by 8e (0.10g, 0.19mmol) in methylene dichloride (2mL), be cooled to 0 DEG C, add trifluoroacetic acid (4mL), stirring reaction 2 hours at 0 DEG C, by reaction solution concentrating under reduced pressure.Regulate reacting liquid pH value to 8 with sodium hydrogen carbonate solution, methylene dichloride (30mL × 3) extracts.Merge organic phase, the saturated common salt aqueous solution (20mL × 1) washs.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Residue thin layer prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1), obtains off-white color solid chemical compound 8 (0.04g, productive rate 56%).
1HNMR(400MHz,CD 3OD):δ7.63(s,1H),7.21-7.08(m,3H),4.58(m,1H),4.41-4.29(m,1H),4.23-4.14(m,2H),4.11(m,1H),3.31(t,1H),3.30(s,3H),3.24(m,1H),2.94(m,1H),2.38-2.35(m,1H),1.66(q,1H)；
MSm/z(ESI):442.2[M+1]。
Embodiment 9
(S)-methyl 5-((3R; 5S; 6R)-5-amino-6-(2; 5-difluorophenyl)-tetrahydrochysene-2H-pyrans-3-base)-1-(methyl sulphonyl)-1; 4; 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-carboxylicesters (compound 9) also
(S)-methyl5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)-tetrahydro-2H-pyran-3-yl)-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylate
The first step: (S)-methyl Isosorbide-5-Nitrae, 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-carboxylate hydrochloride (9a) also
(S)-methyl1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylatehydrochloride
Under room temperature, 8a (1.27g, 5.0mmol) is dissolved in anhydrous methanol (15mL), is cooled to 0 DEG C, add thionyl chloride (0.71g, 6.0mmol), react 4 hours under room temperature.Reaction solution concentrating under reduced pressure is obtained yellow-brown solid 9a (0.84g, productive rate 100%).
MSm/z(ESI):168.1[M+1]。
Second step: (S)-5-tertiary butyl 4-methylpyrrole also [3,4-c] pyrazoles-4,5 (1H, 4H, 6H) dicarboxylic ester (9b)
(S)-5-tert-butyl4-methylpyrrolo[3,4-c]pyrazole-4,5(1H,4H,6H)-dicarboxylate
Under room temperature, 9a (0.83g, 5.0mmol) is dissolved in methylene dichloride (30mL).Be cooled to 0 DEG C, add triethylamine (1.26g, 12.5mmol), stir 10 minutes at 0 DEG C.Join in reaction solution by tert-Butyl dicarbonate (1.31g, 6.0mmol), stirred at ambient temperature reacts 3 hours.Add methylene dichloride (40mL), use hydrochloric acid (1mol/L, 30mL × 1), sodium hydrogen carbonate solution (30mL × 2), saturated sodium-chloride (40mL × 1) to wash successively.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume, obtains shallow rice-pudding look solid 9b (1.0g, productive rate 80%).
3rd step: (S)-methyl Isosorbide-5-Nitrae, 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-carboxylicesters benzene sulfonate (9c) also
(S)-methyl2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylatebenzenesulfonicacid
Under room temperature, 9b (1.0g, 3.74mmol) is dissolved in anhydrous methanol (15mL), adds Phenylsulfonic acid (0.83g, 4.45mmol), reflux stirring reaction 16 hours.By reaction solution concentrating under reduced pressure, obtain class brown solid 9c (1.22g, productive rate 100%).
MSm/z(ESI):168.1[M+1]。
4th step: (S)-methyl 5-((3R, 5S, 6R)-5-(tertbutyloxycarbonyl) is amino)-6-(2,5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-base)-1,4,5,6-Pyrrolidine is [3,4-c] pyrazoles-4-carboxylicesters (9d) also
(S)-methyl5-((3R,5S,6R)-5-((tert-butoxycarbonyl)amino)-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylate
Under room temperature, 9c (0.40g, 1.23mmol) is dissolved in N,N-DIMETHYLACETAMIDE (5mL), adds intermediate 1 (0.33g, 1.0mmol), stirring at room temperature 1 hour.Three (acetoxyl group) sodium borohydride (028g, 1.3mmol) are joined in reaction solution, room temperature reaction 16 hours.Reaction solution is cooled to 0 DEG C, adds water (20mL), ammoniacal liquor (2mL) successively, separate out white solid.By reacting liquid filtering, filter cake uses water (10mL × 2), sherwood oil (10mL × 1) to wash successively.Drain, filter cake methylene dichloride (50mL) is dissolved, anhydrous magnesium sulfate drying, filter, by filtrate reduced in volume, obtain light yellow solid 9d (0.22g, productive rate 45.9%).
MSm/z(ESI):479.1[M+1]。
5th step: (S)-methyl 5-((3R; 5S; 6R)-5-(tertbutyloxycarbonyl)-6-(2; 5-difluorophenyl)-tetrahydrochysene-2H-pyrans-3-base)-1-(methyl sulphonyl)-1; 4; 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-carboxylicesters (9e) also
(S)-methyl5-((3R,5S,6R)-5-(tert-butoxycarbonyl)-6-(2,5-difluorophenyl)-tetrahydro-2H-pyran-3-yl)-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylate
Under room temperature, 9d (0.22g, 0.44mmol) is dissolved in tetrahydrofuran (THF) (10mL), is cooled to 0 DEG C, add triethylamine (0.06g, 0.57mmol), stir 5 minutes.Methanesulfonyl chloride (0.06g, 0.53mmol) is added drop-wise in reaction solution, room temperature reaction 4 hours.Add methylene dichloride (50mL), use sodium hydrogen carbonate solution (30mL × 2), the saturated common salt aqueous solution (30mL × 1) to wash successively.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume, obtains light yellow solid 9e (0.23g, productive rate 94.3%).
6th step: (S)-methyl 5-((3R; 5S; 6R)-5-amino-6-(2; 5-difluorophenyl)-tetrahydrochysene-2H-pyrans-3-base)-1-(methyl sulphonyl)-1; 4; 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-carboxylicesters (compound 9) also
(S)-methyl5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)-tetrahydro-2H-pyran-3-yl)-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylate
Under room temperature, 9e (0.23g, 0.41mmol) is dissolved in methylene dichloride (4mL), is cooled to 0 DEG C, add trifluoroacetic acid (4mL), stirring reaction 2 hours at 0 DEG C.By reaction solution concentrating under reduced pressure, drip sodium hydrogen carbonate solution and regulate reacting liquid pH value to 8, extract with methylene dichloride (30mL × 3).Merge organic phase, the saturated common salt aqueous solution (15mL × 1) washs.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Residue thin layer prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1), obtains off-white color solid chemical compound 9 (0.04g, productive rate 21.2%).
1HNMR(400MHz,CD 3OD):δ7.56(s,1H),7.05-6.97(m,3H),4.78-4.77(m,1H),4.12-4.01(m,4H),3.70(s,3H),3.35-3.23(m,4H),2.80-2.77(m,1H),2.25-2.21(m,1H),1.53(q,3H)；
MSm/z(ESI):457.3[M+1]。
Embodiment 10
(2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-((S) 4-(methoxymethyl) pyrrolo-[3,4-c] pyrazoles-5 (1H, 4H, 6H)-Ji)-tetrahydrochysene-2H-pyrans-3-amine (compound 10)
(2R,3S,5R)-2-(2,5-difluorophenyl)-5-((S)-4-(methoxymethyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)-tetrahydro-2H-pyran-3-amine
The first step: (S)-4-(methoxymethyl)-2,4,5,6-Pyrrolidine also [3,4-c] pyrazoles benzene sulfonate (10a)
(S)-4-(methoxymethyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolebenzenesulfonate
Under room temperature, intermediate 4 (0.506g, 20.0mmol) is dissolved in Iso Butyl Acetate (10mL), adds Phenylsulfonic acid (0.37g, 20.0mmol) and finish, heating reflux reaction 12 hours.By reaction solution concentrating under reduced pressure.Obtain off-white color solid 10a (0.62g, productive rate 100%).
Second step: the tertiary butyl (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-((S)-4-(methoxymethyl) pyrrolo-[3,4-c] pyrazoles-5 (1H, 4H, 6H)-Ji)-tetrahydrochysene-2H-pyrans-3-base) carbamate (10b)
tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-((S)-4-(methoxymethyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate
Under room temperature, 10a (0.2g, 0.72mmol) is dissolved in N,N-DIMETHYLACETAMIDE (4mL), adds intermediate 1 (0.523g, 1.6mmol), stirred at ambient temperature 1 hour.Three (acetoxyl group) sodium borohydride (0.423g, 2.0mmol) are joined in reaction solution, continues reaction under room temperature 16 hours.Reaction solution is cooled to 0 DEG C, add water (25mL), ammoniacal liquor (0.5mL) successively, separate out white solid, filter, filter cake uses water (10mL × 2), sherwood oil (10mL × 1) to wash successively, drain, filter cake methylene dichloride (60mL) is dissolved, anhydrous magnesium sulfate drying, filter, by filtrate reduced in volume, obtain light yellow solid 10b (0.3g, productive rate 40.3%).
MSm/z(ESI):465.3[M+1]。
3rd step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-((S) 4-(methoxymethyl) pyrrolo-[3,4-c] pyrazoles-5 (1H, 4H, 6H)-Ji)-tetrahydrochysene-2H-pyrans-3-amine (compound 10)
(2R,3S,5R)-2-(2,5-difluorophenyl)-5-((S)-4-(methoxymethyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)-tetrahydro-2H-pyran-3-amine
Under room temperature, 10b (0.3g, 0.65mmol) is dissolved in methylene dichloride (2mL), is cooled to 0 DEG C, add trifluoroacetic acid (4mL), stirring reaction 2 hours at 0 DEG C.By reaction solution concentrating under reduced pressure, regulate reacting liquid pH value to 8 with sodium hydrogen carbonate solution, methylene dichloride (30mL × 4) extracts.Merge organic phase, the saturated common salt aqueous solution (25mL × 1) washs.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Residue thin layer prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1), obtains off-white color solid chemical compound 10 (0.03g, productive rate 12.6%).
1HNMR(400MHz,CD 3OD):δ7.36(s,1H),7.14-7.11(m,1H),7.11-7.06(m,2H),4.34-4.32(m,2H),4.30-4.28(m,1H),4.10(m,2H),3.57(m,1H),3.48(m,2H),3.34(s,3H),2.89-2.86(m,1H),2.33-2.30(m,1H),1.68(q,1H)；
MSm/z(ESI):365.2[M+1]。
Embodiment 11
(2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5 ((S)-4-(methoxymethyl)-2-(methyl sulphonyl) pyrrolo-es [3; 4-c] pyrazoles-5 (2H; 4H, 6H)-Ji)-tetrahydrochysene-2H-pyrans-3-amine (compound 11)
(2R,3S,5R)-2-(2,5-difluorophenyl)-5-((S)-4-(methoxymethyl)-2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-tetrahydro-2H-pyran-3-amine
The first step: (S)-tertiary butyl 4-(methoxymethyl)-2-(methyl sulphonyl) pyrrolo-[3,4-c] pyrazoles-5-(2H, 4H, 6H)-carboxylicesters (11a)
(S)-tert-butyl4-(methoxymethyl)-2-(methylsulfonyl)pyrrolo[3,4-c]pyrazole-5(2H,4H,6H)-carboxylate
(S)-tertiary butyl 4-(methoxymethyl)-1-(methyl sulphonyl) pyrrolo-[3,4-c] pyrazoles-5-(1H, 4H, 6H)-carboxylicesters (12a)
(S)-tert-butyl4-(methoxymethyl)-1-(methylsulfonyl)pyrrolo[3,4-c]pyrazole-5(1H,4H,6H)-carboxylate
Under room temperature, intermediate 4 (2.2g, 8.69mmol) is dissolved in tetrahydrofuran (THF) (30mL), is cooled to 0 DEG C, add sodium hydride (0.417g, 10.43mmol) in batches, stir 30 minutes.Methanesulfonyl chloride (1.39g, 12.17mmol) is added drop-wise in reaction solution, keeps 0 DEG C to react 5 hours.Add ammonium chloride solution (30mL), with methyl tertiary butyl ether (40mL × 3) extraction, merge organic phase, wash with the saturated common salt aqueous solution (25mL × 1).Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Column chromatography purification (ethyl acetate/petroleum ether (v/v)=1:6-1:4), obtains colourless viscous liquid 11a (0.88g, productive rate 30.5%) and 12a (0.68g, productive rate 23.6%).
Compound 11a: 1hNMR (400MHz, CD 3oD): δ 7.95-7.94 (s, 1H), 4.97 (s, 1H), 4.57-4.54 (d, 1H), 4.43-4.36 (m, 1H), 3.80-3.77 (m, 1H), 3.38-3.35 (m, 1H), 3.33-3.31 (m, 3H), 3.26 (s, 3H), 1.52 (s, 9H);
MSm/z(ESI):332.2[M+1]；
Compound 12a: 1hNMR (400MHz, CD 3oD): δ 7.68-7.67 (s, 1H), 4.93-4.90 (s, 1H), 4.68 (d, 1H), 4.56-4.51 (m, 1H), 3.84-3.79 (m, 1H), 3.56-3.52 (m, 1H), 3.42 (s, 3H), 3.35-3.30 (m, 3H), 1.51 (s, 9H);
MSm/z(ESI):332.2[M+1]。
Second step: (S)-4-(methoxymethyl)-2-(methyl sulphonyl)-2,4,5,6-Pyrrolidine also [3,4-c] pyrazoles (11b)
(S)-4-(methoxymethyl)-2-(methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole
Under room temperature, 11a (0.88g, 2.66mmol) is dissolved in methylene dichloride (4mL), is cooled to 0 DEG C, add trifluoroacetic acid (8mL), keep 0 DEG C to react 2 hours.By reaction solution concentrating under reduced pressure.Column chromatography purification [(methylene chloride/methanol (v/v)=40:1-20:1), adds a small amount of ammoniacal liquor], obtains khaki color solid 11b (0.63g, productive rate 100%).
MSm/z(ESI):232.1[M+1]。
3rd step: the tertiary butyl (2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5 ((S)-4-(methoxymethyl)-2-(methyl sulphonyl) pyrrolo-es [3; 4-c] pyrazoles-5 (2H; 4H, 6H)-Ji)-tetrahydrochysene-2H-pyrans-3-aminocarbamic acid ester (11c)
tert-butyl(2R,3S,5R)-2-(2,5-difluorophenyl)-5-((S)-4-(methoxymethyl)-2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-tetrahydro-2H-pyran-3-ylcarbamate
Under room temperature, be dissolved in by 11b (0.3g, 1.3mmol) in N,N-DIMETHYLACETAMIDE (4mL), add intermediate 1 (0.34g, 1.04mmol), Phenylsulfonic acid (0.265g, 1.43mmol), stirring at room temperature reacts 1 hour.Join in reaction solution by three (acetoxyl group) sodium borohydride (0.33g, 1.56mmol), stirred at ambient temperature reacts 16 hours.Reaction solution is cooled to 0 DEG C, adds water (20mL), ammoniacal liquor (1mL) successively, separate out white solid, filter, filter cake uses water (10mL × 2), sherwood oil (10mL × 1) to wash successively.Drain, filter cake methylene dichloride (50mL) is dissolved, anhydrous magnesium sulfate drying, filter, by filtrate reduced in volume, obtain khaki color solid 11c (0.20g, productive rate 28.4%).
MSm/z(ESI):543.3[M+1]。
4th step: (2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5-((S)-4-(methoxymethyl)-2-(methyl sulphonyl) pyrrolo-[3; 4-c] pyrazoles-5 (2H; 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-amine (compound 11)
(2R,3S,5R)-2-(2,5-difluorophenyl)-5-((S)-4-(methoxymethyl)-2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine
Under room temperature, 11c (0.2g, 0.37mmol) is dissolved in methylene dichloride (2mL), is cooled to 0 DEG C, add trifluoroacetic acid (4mL), keep 0 DEG C to react 2 hours.By reaction solution concentrating under reduced pressure, regulate reacting liquid pH value to 8 with sodium hydrogen carbonate solution, extract with methylene dichloride (30mL × 4).Merge organic phase, the saturated common salt aqueous solution (25mL × 1) washs, anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Residue thin layer prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1), obtains off-white color solid chemical compound 11 (0.04g, productive rate 24.4%).
1HNMR(400MHz,CD 3OD):δ7.86(s,1H),7.24-7.23(m,1H),7.22-7.16(m,2H),4.33-4.32(m,2H),4.11-3.97(m,2H),3.64-3.42(m,3H),3.39(m,6H),3.05-3.02(m,1H),2.36-2.33(m,1H),1.73(q,1H)；
MSm/z(ESI):443.2[M+1]。
Embodiment 12
(2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5 ((S)-4-(methoxymethyl)-1-(methyl sulphonyl) pyrrolo-es [3; 4-c] pyrazoles-5 (1H; 4H, 6H)-Ji)-tetrahydrochysene-2H-pyrans-3-amine (compound 12)
(2R,3S,5R)-2-(2,5-difluorophenyl)-5-((S)-4-(methoxymethyl)-1-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)-tetrahydro-2H-pyran-3-amine
The first step: (S)-4-(methoxymethyl)-1-(methyl sulphonyl)-Isosorbide-5-Nitrae, 5,6-Pyrrolidine is [3,4-c] pyrazoles (12b) also
(S)-4-(methoxymethyl)-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole
Under room temperature, 12a (0.68g, 2.07mmol) is dissolved in methylene dichloride (3mL), is cooled to 0 DEG C, add trifluoroacetic acid (6mL), keep 0 DEG C to react 3 hours.By reaction solution concentrating under reduced pressure, residue column chromatography purification [(methylene chloride/methanol (v/v)=40:1-20:1), adds a small amount of ammoniacal liquor], obtains khaki color solid 12b (0.47g, productive rate 100%).
MSm/z(ESI):232.1[M+1]。
Second step: the tertiary butyl (2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5 ((S)-4-(methoxymethyl)-1-(methyl sulphonyl) pyrrolo-es [3; 4-c] pyrazoles-5 (1H; 4H, 6H)-Ji)-tetrahydrochysene-2H-pyrans-3-aminocarbamic acid ester (12c)
tert-butyl(2R,3S,5R)-2-(2,5-difluorophenyl)-5-((S)-4-(methoxymethyl)-1-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)-tetrahydro-2H-pyran-3-ylcarbamate
Under room temperature, 12b (0.28g, 1.2mmol) is dissolved in N,N-DIMETHYLACETAMIDE (4mL), adds intermediate 1 (0.39g, 1.2mmol) and Phenylsulfonic acid (0.22g, 1.2mmol), stirred at ambient temperature 1 hour.Three (acetoxyl group) sodium borohydride (0.33g, 1.4mmol) are joined in reaction solution, continues reaction under room temperature 16 hours.Be cooled to 0 DEG C, add water (30mL), ammoniacal liquor (1mL) successively, separate out white solid, filter, filter cake use water (10mL × 2) washs, and drains.Filter cake methylene dichloride (150mL) is dissolved, anhydrous magnesium sulfate drying, filter, by filtrate reduced in volume, obtain khaki color solid 12c (0.30g, productive rate 46.0%).
MSm/z(ESI):543.3[M+1]。
3rd step: (2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5 ((S)-4-(methoxymethyl)-1-(methyl sulphonyl) pyrrolo-es [3; 4-c] pyrazoles-5 (1H; 4H, 6H)-Ji)-tetrahydrochysene-2H-pyrans-3-amine (compound 12)
(2R,3S,5R)-2-(2,5-difluorophenyl)-5-((S)-4-(methoxymethyl)-1-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)-tetrahydro-2H-pyran-3-amine
Under room temperature, 12c (0.3g, 0.55mmol) is dissolved in methylene dichloride (3mL), is cooled to 0 DEG C, add trifluoroacetic acid (6mL), keep 0 DEG C to react 2 hours.By reaction solution concentrating under reduced pressure, regulate reacting liquid pH value to 8 with sodium hydrogen carbonate solution, extract with methylene dichloride (30mL × 3).Merge organic phase, wash with the saturated common salt aqueous solution (30mL × 1).Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Residue thin layer prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1), obtains light yellow solid Compound 12 (0.04g, productive rate 16.3%).
1HNMR(400MHz,CD 3OD):δ7.51(s,1H),7.04-7.02(m,1H),7.02-6.99(m,2H),4.24-4.20(m,2H),4.10(m,2H),3.99-3.02(m,1H),3.30(m,1H),3.21(m,7H),2.83-2.80(m,1H),2.22-2.19(m,1H),1.57(q,1H)；
MSm/z(ESI):443.2[M+1]。
Embodiment 13
(2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-((R) 4-(methoxymethyl) pyrrolo-[3,4-c] pyrazoles-5 (1H, 4H, 6H)-Ji)-tetrahydrochysene-2H-pyrans-3-amine (compound 13)
(2R,3S,5R)-2-(2,5-difluorophenyl)-5-((R)-4-(methoxymethyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)-tetrahydro-2H-pyran-3-amine
(2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5-((R) 4-(methoxymethyl)-1-(methyl sulphonyl) pyrrolo-[3; 4-c] pyrazoles-5 (1H; 4H, 6H)-Ji)-tetrahydrochysene-2H-pyrans-3-amine (compound 14)
(2R,3S,5R)-2-(2,5-difluorophenyl)-5-((R)-4-(methoxymethyl)-1-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)-tetrahydro-2H-pyran-3-amine
The first step: the tertiary butyl (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-((R)-4-(methoxymethyl) pyrrolo-[3,4-c] pyrazoles-5 (1H, 4H, 6H)-Ji)-tetrahydrochysene-2H-pyrans-3-aminocarbamic acid ester (13a)
tert-butyl(2R,3S,5R)-2-(2,5-difluorophenyl)-5-((R)-4-(methoxymethyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)-tetrahydro-2H-pyran-3-ylcarbamate
Under room temperature, intermediate 5 (0.23g, 1.5mmol) is dissolved in N,N-DIMETHYLACETAMIDE (6mL), adds intermediate 1 (0.49g, 1.5mmol) and Phenylsulfonic acid (0.31g, 1.6mmol), stirred at ambient temperature 60 minutes.Three (acetoxyl group) sodium borohydride (0.45g, 2.1mmol) are joined in reaction solution, continues reaction under room temperature 16 hours.Reaction solution is cooled to 0 DEG C, adds water (20mL), ammoniacal liquor (5.0mL) successively, separate out white solid, filter, filter cake uses water (10mL × 2), sherwood oil (10mL × 1) to wash successively.Drain, filter cake ethyl acetate (120mL) is dissolved, anhydrous magnesium sulfate drying, filter, by filtrate reduced in volume, column chromatography purification [(methylene chloride/methanol (v/v)=40:1-20:1), adds a small amount of ammoniacal liquor], obtain light yellow solid 13a (0.23g, productive rate 33%).
MSm/z(ESI):465.4[M+1]。
Second step: the tertiary butyl (2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5-((R) 4-(methoxymethyl)-1-(methyl sulphonyl) pyrrolo-[3; 4-c] pyrazoles-5 (1H; 4H, 6H)-Ji)-tetrahydrochysene-2H-pyrans-3-aminocarbamic acid ester (13b)
tert-butyl(2R,3S,5R)-2-(2,5-difluorophenyl)-5-((R)-4-(methoxymethyl)-1-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)-tetrahydro-2H-pyran-3-ylcarbamate
Under room temperature, 13a (0.23g, 0.5mmol) is dissolved in methylene dichloride (30mL), is cooled to 0 DEG C, add triethylamine (0.07g, 0.69mmol) and stir 5 minutes.Be added drop-wise in reaction solution by Methanesulfonyl chloride (0.74g, 0.64mmol), stirred at ambient temperature reacts 2 hours.Wash with the saturated common salt aqueous solution (10mL × 1).Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume, obtains light yellow solid 13b (0.25g, productive rate 93.3%).
MSm/z(ESI):543.3[M+1]。
3rd step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-((R) 4-(methoxymethyl) pyrrolo-[3,4-c] pyrazoles-5 (1H, 4H, 6H)-Ji)-tetrahydrochysene-2H-pyrans-3-amine (compound 13)
(2R,3S,5R)-2-(2,5-difluorophenyl)-5-((R)-4-(methoxymethyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)-tetrahydro-2H-pyran-3-amine
(2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5-((R) 4-(methoxymethyl)-1-(methyl sulphonyl) pyrrolo-[3; 4-c] pyrazoles-5 (1H; 4H, 6H)-Ji)-tetrahydrochysene-2H-pyrans-3-amine (compound 14)
(2R,3S,5R)-2-(2,5-difluorophenyl)-5-((R)-4-(methoxymethyl)-1-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)-tetrahydro-2H-pyran-3-amine
Under room temperature, 13b (0.25g, 0.46mmol) is dissolved in methylene dichloride (4mL), is cooled to 0 DEG C, add trifluoroacetic acid (4mL), keep 0 DEG C to react 2 hours.By reaction solution concentrating under reduced pressure, regulate reaction solution adjust ph to 8 with sodium hydrogen carbonate solution, extract with methylene dichloride (30mL × 4).Merge organic phase, the saturated common salt aqueous solution (25mL × 1) washs.Anhydrous magnesium sulfate drying, filter, by filtrate reduced in volume, residue thin layer prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1), obtain off-white color solid chemical compound 13 (0.025g, productive rate 12%) and compound 14 (0.101g, productive rate 49%).
Compound 13: 1hNMR (400MHz, CD 3oD): δ 7.26 (s, 1H), 7.16-7.01 (m, 3H), 4.27-4.22 (m, 2H), 4.08-4.00 (m, 2H), 3.89-3.86 (m, 1H), 3.29-3.22 (m, 2H), 3.21 (m, 4H), 2.96-2.94 (m, 1H), 2.33-2.55 (s, 3H), 1.64 (q, 1H);
MSm/z(ESI):365.4[M+1]；
Compound 14: 1hNMR (400MHz, CD 3oD): δ 7.50 (s, 1H), 7.04-6.96 (m, 3H), 4.25-4.20 (m, 3H), 4.10-4.03 (m, 2H), 3.40 (m, 1H), 3.30 (t, 1H), 3.20 (m, 6H), 3.17-3.14 (s, 1H), 2.84-2.81 (m, 1H), 2.27-2.24 (m, 1H), 1.55 (q, 1H);
MSm/z(ESI):443.3[M+1]。
Embodiment 14
(R)-5-((3R, 5S, 6R)-5-amino-6-(2; 5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-base)-1-(methyl sulphonyl)-Isosorbide-5-Nitrae, 5; 6-Pyrrolidine is [3,4-c] pyrazoles-4-formic acid (compound 15) also
(R)-5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylicacid
The first step: (2R, 4R)-1-(tertbutyloxycarbonyl)-4-hydroxyl pyrrolidine-2-formic acid (15a)
(2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylicacid
Under room temperature, by 3A (9.0g, 53.70mmol) be dissolved in tetrahydrofuran (THF) (90mL), drip sodium hydroxide (4.73g, water (41mL) solution 118.14mmol), be added in reaction solution by tert-Butyl dicarbonate (17.58g, 80.55mmol), stirred at ambient temperature reaction is spent the night.Add sodium hydroxide (2.15g, 53.70mmol), tert-Butyl dicarbonate (9.38g, 42.96mmol), continue stirring under room temperature 5 hours.Underpressure distillation removing tetrahydrofuran (THF), with ethyl acetate (50mL × 2) extracting impurities.The hydrochloric acid soln adjust ph to 3 of aqueous phase 3mol/L, with ethyl acetate (50mL × 3) extraction, merges organic phase, with anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume, obtains colourless liquid 15a (8.7g, productive rate 70.1%).
Second step: (2R, 4R)-2-benzyl 1-tertiary butyl 4-hydroxyl pyrrolidine-1,2-dicarboxylic ester (15b)
(2R,4R)-2-benzyl1-tert-butyl4-hydroxypyrrolidine-1,2-dicarboxylate
Under room temperature, by 15a (8.6g, 37.21mmol) be dissolved in methyl alcohol (80mL), be cooled to 0 DEG C, water (42mL) solution of cesium carbonate (6.06g, 18.61mmol) is dropped in reaction solution, stirs 30 minutes, concentrating under reduced pressure, except desolventizing, obtains white solid.Residue DMF (68mL) dissolves, and adds benzyl bromine (6.36g, 37.21mmol), and stirred at ambient temperature reaction is spent the night.Underpressure distillation removes most of solvent, adds water (100mL), extracts by ethyl acetate (100mL × 3).Merge organic phase, use water (100mL × 1), salt brine solution of being satiated with food (100mL × 2) to wash successively.Anhydrous sodium sulfate drying, filters, by filtrate reduced in volume, obtains light yellow liquid 15b (11.95g, productive rate 100%).
MSm/z(ESI):220.2[M+1]。
3rd step: (R)-2-benzyl 1-tertiary butyl 4-carbonyl pyrrolidine alkane-1,2-dicarboxylic ester (15c)
(R)-2-benzyl1-tert-butyl4-oxopyrrolidine-1,2-dicarboxylate
Under room temperature, be dissolved in by 15b (13.17g, 41.01mmol) in methylene dichloride (100mL), add in batches and wear this Martin's oxygenant (34.79g, 82.01mmol), stirred at ambient temperature reaction is spent the night.In reaction solution, add water (0.81g, 45.11mmol), continue stirring under room temperature 6 hours.Be added drop-wise to by sodium hydrogen carbonate solution in reaction solution and produce to no longer including bubble, separate out white solid, filter, filtrate extracts with methylene dichloride (50mL × 2).Merge organic phase, use saturated sodium bicarbonate (80mL × 2), saturated nacl aqueous solution (80mL × 2) to wash successively.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Column chromatography (ethyl acetate/petroleum ether (v/v)=1:25-1:6), obtains yellow liquid, 15c (4g, productive rate 30.6%).
4th step: (R, E)-2-benzyl 1-tertiary butyl 3-((dimethylamino) methene)-4-carbonyl pyrrolidine alkane-1,2-dicarboxylic ester (15d)
(R,E)-2-benzyl1-tert-butyl3-((dimethylamino)methylene)-4-oxopyrrolidine-1,2-dicarboxylate
Under room temperature, 15c (3.94g, 12.35mmol) is dissolved in DMF (30mL), adds DMF dimethylacetal (2.21g, 18.52mmol), stirring reaction 3.5 hours at 100 DEG C.Reaction solution is down to room temperature, adds ethyl acetate (50mL), mixture is poured into (100mL) in saturated nacl aqueous solution, stratification.Organic phase is saturated sodium bicarbonate solution (100mL × 1), the saturated common salt aqueous solution (100mL × 3) washing successively.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Column chromatography purification (methylene chloride/methanol (v/v)=40:1), obtains dark red oil 15d (3.5g, productive rate 75.8%).
MSm/z(ESI):375.4[M+1]。
5th step: (the R)-4-benzyl 5-tertiary butyl 4,6-pyrrolin also [3,4-c] pyrazoles-4,5 (2H)-dicarboxylic ester (15e)
(R)-4-benzyl5-tert-butyl4,6-dihydropyrrolo[3,4-c]pyrazole-4,5(2H)-dicarboxylate
Under room temperature, be dissolved in by 15d (3.5g, 9.35mmol) in anhydrous methanol (20mL), add hydrazine hydrate (0.56g, 11.22mmol), stirred at ambient temperature reacts 3 hours.Add water (150mL), with methylene dichloride (50mL × 4) extraction, merge organic phase, the saturated common salt aqueous solution (50mL × 1) washs.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Concentrating residues thing is dissolved in methylene dichloride (30mL), is added drop-wise in reaction solution, continues anhydrous methanol (2mL) solution of tosic acid (0.18g, 0.96mmol) stirring reaction and spend the night under room temperature.Add 5 ammoniacal liquor, column chromatography purification (methylene chloride/methanol (v/v)=60:1-30:1), obtains orange colloidal solid, 15e (1.0g, productive rate 45.7%).
MSm/z(ESI):344.3[M+1]。
6th step: (R)-4-benzyl 5-tertiary butyl 1-(methyl sulphonyl)-4,6-pyrrolin also [3,4-c] pyrazoles-4,5 (1H)-dicarboxylic ester (15f)
(R)-4-benzyl5-tert-butyl1-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-4,5(1H)-dicarboxylate
Under room temperature, by 15e (0.2g, 0.582mmol) be dissolved in methylene dichloride (6mL), add triethylamine (0.08g, 0.757mmol), be cooled to 0 DEG C, by Methanesulfonyl chloride (0.08g, 0.698mmol) be added drop-wise in reaction solution, keep 0 DEG C to react 5 hours.Add methylene dichloride (20mL), wash with saturated nacl aqueous solution (30mL × 3).Anhydrous sodium sulfate drying, filters, by filtrate reduced in volume.Column chromatography (methylene chloride/methanol (v/v)=100:1-80:1), obtains light yellow solid, 15f (0.24g, productive rate 100%).
MSm/z(ESI):444.3[M+23]。
7th step: (R)-benzyl 1-(methyl sulphonyl)-Isosorbide-5-Nitrae, 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-carboxylicesters (15g) also
(R)-benzyl1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylate
Under room temperature, be dissolved in by 15f (0.24g, 0.582mmol) in methylene dichloride (6mL), add trifluoroacetic acid (1.5mL), stirred at ambient temperature reacts 3 hours.By reaction solution concentrating under reduced pressure, add methylene dichloride (20mL), methyl alcohol (1mL) and 5 ammoniacal liquor, column chromatography purification (methylene chloride/methanol (v/v)=100:1-70:1), obtains yellow solid 15g (0.1g, productive rate 52.6%).
MSm/z(ESI):322.2[M+1]。
8th step: (R)-benzyl 5-((3R; 5S; 6R)-5-((tertbutyloxycarbonyl) is amino)-6-(2; 5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-base)-1-(methyl sulphonyl)-1; 4; 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-carboxylicesters (15h) also
(R)-benzyl5-((3R,5S,6R)-5-((tert-butoxycarbonyl)amino)-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylate
Under room temperature, 15g (1.24g, 5.06mmol) is dissolved in N,N-DIMETHYLACETAMIDE (10mL), adds intermediate 1 (0.25g, 0.778mmol) and Phenylsulfonic acid (0.17g, 0.934mmol), stir 30 minutes.Be cooled to 0 DEG C, three (acetoxyl group) sodium borohydride (0.21g, 1.011mmol) joined in reaction solution, naturally rises to room temperature reaction and spend the night.Reaction solution is cooled to 0 DEG C, add water (100mL), separate out solid, filter, filter cake methylene dichloride dissolves, add anhydrous sodium sulfate drying, filter, concentrated, residue thin-layer chromatography (methylene chloride/methanol (v/v)=20:1) separation and purification, obtain off-white color solid 15h (0.1g, productive rate 20.4%).
MSm/z(ESI):633.3[M+1]。
9th step: (R)-benzyl 5-((3R; 5S; 6R)-5-amino-6-(2; 5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-base)-1-(methyl sulphonyl)-1; 4; 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-carboxylicesters (15i) also
(R)-benzyl5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylate
Under room temperature, 15h (0.1g, 0.158mmol) is dissolved in methylene dichloride (6mL), is cooled to 0 DEG C, adds trifluoroacetic acid (1.5mL), rises to room temperature reaction 4 hours.By reaction solution concentrating under reduced pressure, residue thin layer preparative separation is purified [(methylene chloride/methanol (v/v)=10:1), adds a small amount of ammoniacal liquor], obtains yellow solid 15i (30mg, productive rate 35.7%).
MSm/z(ESI):533.3[M+1]。
Tenth step: (R)-5-((3R; 5S; 6R)-5-amino-6-(2; 5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-base)-1-(methyl sulphonyl)-1; 4; 5,6-Pyrrolidine is [3,4-c] pyrazoles-4-carboxylic acid (compound 15) also
(R)-5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylicacid
Under room temperature, be dissolved in by 15i (30mg, 0.056mmol) in methyl alcohol (6mL), add palladium carbon (14mg, moisture 50%), with hydrogen exchange 3 times, under a hydrogen atmosphere, stirred at ambient temperature reaction is spent the night.By reacting liquid filtering, by filtrate reduced in volume, thin-layer chromatography (methylene chloride/methanol (v/v)=5:1) separation and purification, obtains yellow solid compound 15 (15mg, productive rate 60%).
MSm/z(ESI):443.2[M+1]。
Embodiment 15
(2R, 3S, 5R)-2-(2; 5-difluorophenyl)-5-(2-oxa-ring fourth-3-base alkylsulfonyl) pyrrolo-[3; 4-c] pyrazoles)-5-(2H, 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-amine (compound 16)
(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(oxetan-3-ylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine
The first step: oxa-ring fourth-3-ylmethyl sulphonate (16b)
oxetan-3-ylmethanesulfonate
Under room temperature, oxa-ring fourth-3-alcohol 16a (10.0g, 135.0mmol) is dissolved in methylene dichloride (300mL), is cooled to 0 DEG C, add triethylamine (20.4g, 202.0mmol), stir 20 minutes.Methanesulfonyl chloride (20.08g, 176.0mmol) is added drop-wise in reaction solution, in room temperature reaction 12 hours.By reacting liquid filtering, filter cake methylene dichloride (100mL × 2) washing, merges organic phase, uses water (200mL × 1), the saturated common salt aqueous solution (200mL × 1) to wash successively.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume, obtains light yellow solid 16b (15.6g, productive rate 75.7%).
Second step: sulphur-oxa-ring fourth-3-base thioacetate (16c)
S-oxetan-3-ylethanethioate
Under room temperature, 16b (11.0g, 2.0mmol) is dissolved in DMF (70mL), adds thioacetic acid potassium (0.28g, 2.8mmol), stir 10 minutes.Be heated to 65 DEG C of stirring reactions 16 hours.In reaction solution, add water (200mL), with methyl tertiary butyl ether (150mL × 4) extraction, merge organic phase, use water (100mL × 2), the saturated common salt aqueous solution (100mL × 2) to wash successively.Anhydrous magnesium sulfate drying, filters, and by filtrate reduced in volume, obtains light yellow liquid 16c (8.56g produces 100%).
3rd step: trimethylene oxide-3-alkylsulfonyl chlorine (16d)
oxetane-3-sulfonylchloride
Under room temperature, 16c (9.56g, 72.29mmol) is dissolved in methylene dichloride (20mL) and water (30mL), is cooled to 0 DEG C, add glacial acetic acid (1mL), pass into chlorine in 0 DEG C of stirring reaction 3 hours.Reaction solution methylene dichloride (30mL × 3) extraction, merges organic phase, uses water (30mL × 1), the saturated common salt aqueous solution (30mL × 1) to wash successively.Anhydrous magnesium sulfate drying, filter, by filtrate reduced in volume, column chromatography purification (ethyl acetate/petroleum ether (v/v)=1:25-1:15), obtains light yellow liquid 16d (3.8g, productive rate 33.6%).
4th step: tertiary butyl 2-(trimethylene oxide-3-alkylsulfonyl)-4,6-pyrrolin also [3,4-c] pyrazoles-5 (2H) carboxylicesters (16e)
tert-butyl2-(oxetan-3-ylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate
Under room temperature, 6C (0.418g, 2.0mmol) is dissolved in DMF (5mL), is cooled to-15 DEG C, add two (trimethyl silicon based) sodium amide (1.5mL, 2.0mmol) and stir 30 minutes.Trimethylene oxide-3-alkylsulfonyl chlorine 16d (0.43g, 2.6mmol) is added drop-wise in reaction solution, naturally rises to stirring at room temperature and react 16 hours.Reaction system is cooled to 0 DEG C, adds water (10mL), filter, filter cake uses water (5mL × 2), sherwood oil (5mL × 2) to wash successively.Filter cake column chromatography purification (ethyl acetate/petroleum ether (v/v)=1:8-1:4) separation and purification, obtains white solid 16e (0.30g, productive rate 45.6%).
MSm/z(ESI):352.3[M+23]。
5th step: 2-(oxa-ring fourth-3-alkylsulfonyl)-2,4,5,6-Pyrrolidines also [3,4-c] pyrazoles (16f)
2-(oxetan-3-ylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole
Under room temperature, 16e (0.28g, 0.85mmol) is dissolved in methylene dichloride (4mL), is cooled to 0 DEG C, add trifluoroacetic acid (4mL), in 0 DEG C of stirring reaction 3 hours.By reaction solution concentrating under reduced pressure, column chromatography purification [(methylene chloride/methanol (v/v)=40:1-20:1), adds a small amount of ammoniacal liquor], obtains light yellow solid 16f (0.15g, productive rate 76.9%).
6th step: the tertiary butyl ((2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5-(2-oxa-ring fourth-3-base alkylsulfonyl) pyrrolo-[3; 4-c] pyrazoles)-5-(2H; 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-base) carbamate (16g)
tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(oxetan-3-ylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate
Under room temperature, 16f (0.15g, 0.65mmol) is dissolved in N,N-DIMETHYLACETAMIDE (5mL), adds intermediate 1 (0.21g, 0.65mmol) and Phenylsulfonic acid (0.15g, 0.85mmol), stirred at ambient temperature 1 hour.Three (acetoxyl group) sodium borohydride (0.19g, 0.91mmol) are joined in reaction solution, in room temperature reaction 16 hours.Reaction system is cooled to 0 DEG C, adds water (10mL), ammoniacal liquor (1mL) successively, separate out white solid, filter, filter cake uses water (5mL × 2), sherwood oil (10mL × 2) to wash successively.Drain, by filtration cakes torrefaction, column chromatography purification (methylene chloride/methanol (v/v)=100:1-80:1), obtains off-white color solid 16g (0.14g, productive rate 39.9%).
MSm/z(ESI):541.3[M+1]。
7th step: (2R, 3S, 5R)-2-(2; 5-difluorophenyl)-5-(2-oxa-ring fourth-3-base alkylsulfonyl) pyrrolo-[3; 4-c] pyrazoles)-5-(2H, 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-amine (compound 16)
(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(oxetan-3-ylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine
Under room temperature, 16g (0.14g, 0.26mmol) is dissolved in methylene dichloride (4mL), is cooled to 0 DEG C, add trifluoroacetic acid (4mL), react 2 hours at 0 DEG C.By reaction solution concentrating under reduced pressure, add methylene dichloride (30mL), regulate reacting liquid pH value to 8 with sodium hydrogen carbonate solution, extract with methylene dichloride (30mL × 3).Merge organic phase, anhydrous magnesium sulfate drying, filter, by filtrate reduced in volume.Residue thin layer prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1), obtains compound as white solid 16 (0.06g, productive rate 52.6%).
1HNMR(400MHz,CD 3OD):δ7.98(s,1H),7.28-7.14(m,3H),4.97-4.92(m,5H),4.32-4.30(m,2H),3.95(s,4H),3.11(m,1H),3.00(m,1H),2.56-2.51(m,1H),1.62(t,1H)；
MSm/z(ESI):441.3[M+1]。
Embodiment 16
(2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5-(2-(((R)-tetrahydrofuran (THF)-3-base) alkylsulfonyl) pyrrolo-[3; 4-c] pyrazoles-5 (2H; 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-amine (compound 17)
(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(((R)-tetrahydrofuran-3-yl)sulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine
The first step: (S)-tetrahydrofuran (THF)-3-ylmethyl sulphonate (17b)
(S)-tetrahydrofuran-3-ylmethanesulfonate
Under room temperature, (S)-tetrahydrofuran (THF)-3-alcohol 17a (7.05g, 80.0mmol) is dissolved in methylene dichloride (80mL), is cooled to 0 DEG C, add triethylamine (10.5g, 104.0mmol), stir 10 minutes.Be added drop-wise in reaction solution by Methanesulfonyl chloride (10.94g, 96.0mmol), stirred at ambient temperature reacts 4 hours.By reacting liquid filtering, filter cake methylene dichloride (30mL × 3) washing, merges organic phase, uses water (30mL × 2), the saturated common salt aqueous solution (30mL × 2) to wash successively.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume, obtains light yellow liquid 17b (10.2g, productive rate 100%).
Second step: (R)-sulphur-(tetrahydrofuran (THF)-3-base) thioacetate (17c)
(R)-S-(tetrahydrofuran-3-yl)ethanethioate
Under room temperature, 17b (10.0g, 60.17mmol) is dissolved in DMF (100mL), adds thioacetic acid potassium (10.3g, 90.25mmol), stir 10 minutes.Be heated to 65 DEG C of stirring reactions 16 hours.Water (400mL) is added to reaction system, extract with methyl tertiary butyl ether (150mL × 3), merge organic phase, water (100mL × 2), the saturated common salt aqueous solution (100mL × 2) is used to wash successively, anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume, obtain light yellow liquid 17c (6.2g produces 70.5%).
3rd step: (R)-tetrahydrofuran (THF)-3-alkylsulfonyl chlorine (17d)
(R)-tetrahydrofuran-3-sulfonylchloride
Under room temperature, 17c (6.0g, 40.0mmol) is dissolved in the mixing solutions of methylene dichloride (50mL) and water (50mL), be cooled to 0 DEG C, add glacial acetic acid (1mL), pass into chlorine, stirring reaction 3 hours at 0 DEG C of temperature.Reaction solution methylene dichloride (40mL × 3) extraction, merges organic phase, uses water (30mL × 1), the saturated common salt aqueous solution (30mL × 1) to wash successively.Anhydrous magnesium sulfate drying, filter, by filtrate reduced in volume, column chromatography purification (ethyl acetate/petroleum ether (v/v)=1:25-1:15), obtains light yellow liquid 17d (1.6g, productive rate 22.9%).
4th step: the tertiary butyl ((2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5-(2-(((R)-tetrahydrofuran (THF)-3-base) alkylsulfonyl) pyrrolo-[3; 4-c] pyrazoles-5 (2H; 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-base) carbamate (17e)
tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(((R)-tetrahydrofuran-3-yl)sulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate
The tertiary butyl ((2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5-(1-(((R)-tetrahydrofuran (THF)-3-base) alkylsulfonyl) pyrrolo-[3; 4-c] pyrazoles-5 (1H; 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-base) carbamate (18a)
tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-(((R)-tetrahydrofuran-3-yl)sulfonyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate
Under room temperature, intermediate 6 (0.6g, 1.43mmol) is dissolved in N, in dinethylformamide (6mL), be cooled to-15 DEG C, add two (trimethyl silicon based) sodium amide (1.18mL, 2.36mmol), stir 30 minutes.17d (0.39g, 2.29mmol) is added drop-wise in reaction solution, naturally rises to room temperature reaction 16 hours.Reaction solution is cooled to-15 DEG C, adds water (12mL), separate out yellow solid, filter, filter cake uses water (5mL × 2), sherwood oil (5mL × 2) to wash successively.Filter cake thin plate chromatography is separated (methylene chloride/methanol (v/v)=20:1), obtains light yellow solid 17e (0.16g, productive rate 20.2%) and 18a (0.17g produces 21.5%).
MSm/z(ESI):555.3[M+1]。
5th step: (2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5-(2-(((R)-tetrahydrofuran (THF)-3-base) alkylsulfonyl) pyrrolo-[3; 4-c] pyrazoles-5 (2H; 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-amine (compound 17)
(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(((R)-tetrahydrofuran-3-yl)sulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine
Under room temperature, 17e (0.16g, 0.30mmol) is dissolved in methylene dichloride (3mL), is cooled to 0 DEG C, add trifluoroacetic acid (3mL), stirring reaction 3 hours at 0 DEG C.By reaction solution concentrating under reduced pressure, add methylene dichloride (30mL) and dissolve, regulate reacting liquid pH value to 8 with sodium hydrogen carbonate solution, extract with methylene dichloride (30mL × 3).Merge organic phase, anhydrous magnesium sulfate drying, filter, by filtrate reduced in volume.Residue thin layer is prepared plate separation and purification (methylene chloride/methanol (v/v)=10:1) column chromatography purification and is obtained light yellow solid Compound 17 (0.08g, productive rate 58.8%).
1HNMR(400MHz,CD 3OD):δ7.90(s,1H),7.21-7.08(m,3H),4.30-4.17(m,4H),3.93-3.80(m,7H),3.30(t,1H),3.09-3.06(m,1H),2.93(m,1H),2.36-2.36(m,1H),2.29-2.28(m,1H),2.26-2.24(m,1H),1.56(q,1H)；
MSm/z(ESI):455.3[M+1]。
Embodiment 17
(2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5-(1-(((R)-tetrahydrofuran (THF)-3-base) alkylsulfonyl) pyrrolo-[3; 4-c] pyrazoles)-5-(1H; 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-amine (compound 18)
(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-(((R)-tetrahydrofuran-3-yl)sulfonyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine
Under room temperature, 18a (0.17g, 0.31mmol) is dissolved in methylene dichloride (5mL), is cooled to 0 DEG C, add trifluoroacetic acid (5mL), stirring reaction 2 hours at 0 DEG C.By reaction solution concentrating under reduced pressure, add methylene dichloride (30mL) and dissolve, drip sodium hydrogen carbonate solution and regulate reacting liquid pH value to 8, extract with methylene dichloride (30mL × 3).Merge organic phase, anhydrous magnesium sulfate drying, filter, by filtrate reduced in volume.Residue thin layer prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1), obtains off-white color solid chemical compound 18 (0.11g, productive rate 78.6%).
1HNMR(400MHz,CD 3OD):δ7.66(s,1H),7.21-7.08(m,3H),4.39(m,1H),4.25-4.14(m,5H),3.90-3.83(m,4H),3.75-3.72(m,1H),3.32(t,1H),2.92(m,1H),2.88(m,1H),2.37-2.29(m,1H),1.54(q,1H)；
MSm/z(ESI):455.3[M+1]。
Embodiment 18
(2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5-(2-(((S)-tetrahydrofuran (THF)-3-base) alkylsulfonyl) pyrrolo-[3; 4-c] pyrazoles-5 (2H; 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-amine (compound 19)
(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(((S)-tetrahydrofuran-3-yl)sulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine
The first step: (R)-tetrahydrofuran (THF)-3-ylmethyl sulphonate (19b)
(R)-tetrahydrofuran-3-ylmethanesulfonate
Under room temperature, (R)-tetrahydrofuran (THF)-3-alcohol 19a (7.05g, 80.0mmol) is dissolved in methylene dichloride (80mL), is cooled to 0 DEG C, add triethylamine (10.5g, 104.0mmol), stir 10 minutes.Methanesulfonyl chloride (10.94g, 96.0mmol) is added drop-wise in reaction solution, reacts 4 hours in stirred at ambient temperature.By reacting liquid filtering, filter cake methylene dichloride (30mL × 3) washing, merges organic phase, uses water (30mL × 2), the saturated common salt aqueous solution (30mL × 2) to wash successively.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume, obtains light yellow liquid 19b (10.2g, productive rate 100%).
Second step: (S)-sulphur-(tetrahydrofuran (THF)-3-base) thioacetate (19c)
(S)-S-(tetrahydrofuran-3-yl)ethanethioate
Under room temperature, 19b (10.0g, 60.17mmol) is dissolved in DMF (100mL), adds thioacetic acid potassium (10.3g, 90.25mmol) and stir 10 minutes.Mixture is heated to 65 DEG C of reactions 16 hours.Add water (400mL) to reaction system, with methyl tertiary butyl ether (150mL × 3) extraction, merge organic phase, use water (100mL × 2), the saturated common salt aqueous solution (100mL × 2) to wash successively.Anhydrous magnesium sulfate drying, filters, and by filtrate reduced in volume, obtains light yellow liquid 19c (6.2g produces 70.5%).
3rd step: (S)-tetrahydrofuran (THF)-3-alkylsulfonyl chlorine (19d)
(S)-tetrahydrofuran-3-sulfonylchloride
Under room temperature, 19c (10.0g, 69.0mmol) is dissolved in the admixture solvent of methylene dichloride (50mL) and water (50mL), be cooled to 0 DEG C, add glacial acetic acid (1.5mL), pass into chlorine, stirring reaction 3 hours at 0 DEG C.Reaction solution methylene dichloride (40mL × 3) extraction, merges organic phase, uses water (30mL × 1), the saturated common salt aqueous solution (30mL × 1) to wash successively.Anhydrous magnesium sulfate drying, filter, by filtrate reduced in volume, column chromatography purification (ethyl acetate/petroleum ether (v/v)=1:25-1:15), obtains light yellow liquid 19d (6.0g, productive rate 53.6%).
4th step: the tertiary butyl ((2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5-(2-(((S)-tetrahydrofuran (THF)-3-base) alkylsulfonyl) pyrrolo-[3; 4-c] pyrazoles-5 (2H; 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-base) carbamate (19e)
tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(((S)-tetrahydrofuran-3-yl)sulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate
The tertiary butyl ((2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5-(1-(((S)-tetrahydrofuran (THF)-3-base) alkylsulfonyl) pyrrolo-[3; 4-c] pyrazoles-5 (1H; 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-base) carbamate (20a)
tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-(((S)-tetrahydrofuran-3-yl)sulfonyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate
Under room temperature, intermediate 6 (0.6g, 1.43mmol) is dissolved in N, in dinethylformamide (6mL), be cooled to-15 DEG C, add two (trimethyl silicon based) sodium amide (1.18mL, 2.36mmol), stir 30 minutes.19d (0.39g, 2.29mmol) is added drop-wise in reaction solution, naturally rises to room temperature reaction 16 hours.Reaction system is cooled to-15 DEG C, adds water (12mL), separate out yellow solid, filter, filter cake uses water (5mL × 2), sherwood oil (5mL × 2) to wash successively.Filter cake, with the separation and purification of thin plate chromatography (methylene chloride/methanol (v/v)=20:1), obtains light yellow solid 19e (0.12g, productive rate 15.2%) and 20a (0.16g, productive rate 20.2%).
MSm/z(ESI):555.3[M+1]。
5th step: (2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5-(2-(((S)-tetrahydrofuran (THF)-3-base) alkylsulfonyl) pyrrolo-[3; 4-c] pyrazoles-5 (2H; 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-amine (compound 19)
(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(((S)-tetrahydrofuran-3-yl)sulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine
Under room temperature, 19e (0.11g, 0.19mmol) is dissolved in methylene dichloride (4mL), is cooled to 0 DEG C, add trifluoroacetic acid (4mL), stirring reaction 3 hours at 0 DEG C.By reaction solution concentrating under reduced pressure, add methylene dichloride (30mL) and dissolve, regulate reacting liquid pH value to 8 with sodium hydrogen carbonate solution, extract with methylene dichloride (30mL × 4).Merge organic phase, anhydrous magnesium sulfate drying, filter, by filtrate reduced in volume.Residue thin layer is prepared plate separation and purification (methylene chloride/methanol (v/v)=10:1) column chromatography purification and is obtained light yellow solid Compound 19 (0.08g, productive rate 58.8%). 1HNMR(400MHz,CD 3OD):δ7.90(s,1H),7.21-7.08(m,3H),4.30-4.17(m,4H),3.93-3.80(m,7H),3.31(t,1H),3.06(m,1H),2.93-2.91(m,1H),2.48-2.45(m,1H),2.29-2.28(m,1H),2.26-2.24(m,1H),1.56(q,1H)；
MSm/z(ESI):455.3[M+1]。
Embodiment 19
(2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5-(1-(((S)-tetrahydrofuran (THF)-3-base) alkylsulfonyl) pyrrolo-[3; 4-c] pyrazoles)-5-(1H; 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-amine (compound 20)
(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-(((S)-tetrahydrofuran-3-yl)sulfonyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine
Under room temperature, 20a (0.17g, 0.31mmol) is dissolved in methylene dichloride (4mL), is cooled to 0 DEG C, add trifluoroacetic acid (4mL), stirring reaction 2 hours at 0 DEG C.By reaction solution concentrating under reduced pressure, add methylene dichloride (30mL), regulate reacting liquid pH value to 8 with sodium hydrogen carbonate solution, extract with methylene dichloride (30mL × 4).Merge organic phase, anhydrous magnesium sulfate drying, filter, by filtrate reduced in volume.Residue thin layer prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1), obtains light yellow solid Compound 20 (0.11g, productive rate 78.6%).
1HNMR(400MHz,CD 3OD):δ7.66(s,1H),7.21-7.09(m,3H),4.28(m,1H),4.24-4.14(m,4H),3.90-3.82(m,4H),3.75-3.72(m,1H),3.31(t,1H),3.10(m,1H),2.93(m,1H),2.43-2.29(m,1H),1.52(q,1H)；
MSm/z(ESI):455.3[M+1]。
Embodiment 20
(2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5-(2-((tetrahydrochysene-2H-pyrans-4-base) alkylsulfonyl) pyrrolo-[3; 4-c] pyrazoles-5 (2H; 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-amine (compound 21)
(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-((tetrahydro-2H-pyran-4-yl)sulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine
The first step: the tertiary butyl ((2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5-(2-((tetrahydrochysene-2H-pyrans-4-base) alkylsulfonyl) pyrrolo-[3; 4-c] pyrazoles-5 (2H; 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-base) carbamate (21a)
tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-((tetrahydro-2H-pyran-4-yl)sulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate
Under room temperature, intermediate 6 (0.21g, 0.5mmol) is dissolved in N, in dinethylformamide (5mL), be cooled to-15 DEG C, add two (trimethyl silicon based) sodium amide (0.4mL, 0.8mmol), stirring is finished 30 minutes.Tetrahydrofuran (THF)-3-alkylsulfonyl chlorine (0.12g, 0.65mmol) is added drop-wise in reaction solution, naturally rises to room temperature reaction 16 hours.Be cooled to-15 DEG C, add water (6mL) in reaction system, separate out yellow solid, filter, filter cake uses water (4mL × 2), sherwood oil (5mL × 2) to wash successively.Filter cake thin plate chromatography is separated (methylene chloride/methanol (v/v)=20:1), obtains light yellow solid 21a (0.12g, productive rate 42.3%)
MSm/z(ESI):555.3[M+1]。
Second step: (2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5-(2-((tetrahydrochysene-2H-pyrans-4-base) alkylsulfonyl) pyrrolo-[3; 4-c] pyrazoles-5 (2H; 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-amine (compound 21)
(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-((tetrahydro-2H-pyran-4-yl)sulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine
Under room temperature, 21a (0.12g, 0.21mmol) is dissolved in methylene dichloride (5mL), is cooled to 0 DEG C, add trifluoroacetic acid (5mL) stirring reaction 3 hours at 0 DEG C.By reaction solution concentrating under reduced pressure, add methylene dichloride (40mL) and dissolve, regulate reacting liquid pH value to 8 with sodium hydrogen carbonate solution.With methylene dichloride (30mL × 4) extraction, merge organic phase, anhydrous magnesium sulfate drying, filter, by filtrate reduced in volume.Residue thin layer prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1), obtains light yellow solid Compound 21 (0.08g, productive rate 80.9%).
1HNMR(400MHz,CD 3OD):δ7.79(s,1H),7.14-7.00(m,3H),4.25-4.17(m,2H),3.820(m,2H),3.72(m,3H),3.68(m,1H),3.26(m,3H),3.01-2.92(m,1H),2.43-2.39(m,1H),1.70-1.66(m,4H),1.43(q,1H)；
MSm/z(ESI):455.3[M+1]。
Embodiment 21
(2R, 3S)-2-(2,5-difluorophenyl)-5-(2-((methyl sulfoxide) methyl) pyrrolo-[3,4-c] pyrazoles-5 (2H, 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-amine (compound 22)
(2R,3S)-2-(2,5-difluorophenyl)-5-(2-((methylsulfonyl)methyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine
The first step: tertiary butyl 2-((methylthio group) methyl)-4,6-pyrrolin also [3,4-c] pyrazoles-5-(2H)-carboxylicesters (22a)
tert-butyl2-((methylthio)methyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate
Under room temperature, 6C (1.00g, 4.78mmol) is dissolved in tetrahydrofuran (THF) (50mL), is cooled to 0 DEG C, add sodium hydride (0.228g, 5.74mmol) in batches, react 30 minutes.Slowly in reaction system, drip chloromethyl methylsulfide (0.601g, 6.21mmol), react 4 hours at keeping 0 DEG C.Reaction solution is down to 0 DEG C, drips saturated sodium bicarbonate aqueous solution and produce to reaction solution bubble-free.With methyl tertiary butyl ether (60mL × 3) extraction, merge organic phase, wash with the saturated common salt aqueous solution (30mL × 1), anhydrous sodium sulfate drying, filters, filtrate decompression is distilled, obtain yellow oily liquid 22a (0.869g, productive rate 67.4%).
MSm/z(ESI):270.2[M+1]。
Second step: tertiary butyl 2-((methyl sulphonyl) methyl)-4,6-pyrrolin also [3,4-c] pyrazoles-5 (2H)-carboxylicesters (22b)
tert-butyl2-((methylsulfonyl)methyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate
Under room temperature, 22a (0.669g, 3.15mmol), ammonium persulfate-sodium bisulfate (5.81g, 9.45mmol) are dissolved in methyl alcohol (30mL) with the mixing solutions of water (0.3mL), and stirred at ambient temperature reacts 12 hours.Filtering reacting liquid, removing insolubles, filtrate reduced in volume is except desolventizing, and column chromatography purification (petrol ether/ethyl acetate (v/v)=10:1-3:1), obtains white solid 22b (0.305g, productive rate 36.9%).
MSm/z(ESI):302.2[M+1]。
3rd step: 2-((methyl sulphonyl) methyl)-2,4,5,6-Pyrrolidines also [3,4-c] pyrazoles benzene sulfonate (22c)
2-((methylsulfonyl)methyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolebenzenesulfonate
Under room temperature, 22b (0.050g, 0.170mmol) and Phenylsulfonic acid (0.050g, 0.260mmol) are dissolved in methyl alcohol (3mL), back flow reaction 12 hours at 68 DEG C.By reaction solution concentrating under reduced pressure, obtain 22c (0.270g, productive rate 100%).
MSm/z(ESI):202.2[M+1]。
4th step: the tertiary butyl ((2R; 3S)-2-(2; 5-difluorophenyl)-5-(2-((methyl sulphonyl) methyl) pyrrolo-[3; 4-c] pyrazoles [3; 4-c] pyrazoles-5 (2H; 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-base) carbamate (22d)
Tert-butyl((2R,3S)-2-(2,5-difluorophenyl)-5-(2-((methylsulfonyl)methyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate
Under room temperature, 22c (0.270g, 0.720mmol) is dissolved in N,N-DIMETHYLACETAMIDE (5mL), adds intermediate 1 (0.170g, 0.540mmol), stirring at room temperature 1 hour.Three (acetoxyl group) sodium borohydride (0.192g, 0.910mmol) are joined in reaction solution, reacts 16 hours in stirred at ambient temperature.Reaction system is cooled to 0 DEG C, adds water (10mL) successively, ammoniacal liquor (1mL) regulates pH to 8, separate out white solid.By reacting liquid filtering, filter cake uses water (5mL × 3), sherwood oil (10mL × 1) to wash successively.Drain, by filtration cakes torrefaction, obtain shallow white solid 22d (0.220g, productive rate 79.7%).
MSm/z(ESI):513.3[M+1]。
5th step: (2R; 3S)-2-(2; 5-difluorophenyl)-5-(2-((methyl sulphonyl) methyl) pyrrolo-[3; 4-c] pyrazoles-5 (2H; 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-amine (compound 22)
(2R,3S)-2-(2,5-difluorophenyl)-5-(2-((methylsulfonyl)methyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine
Under room temperature, 22d (0.220g, 0.430mmol) is dissolved in methylene dichloride (2mL), is cooled to 0 DEG C, add trifluoroacetic acid (1mL), in 0 DEG C of reaction 2 hours.By reaction solution concentrating under reduced pressure, regulate reacting liquid pH value to 8 with sodium hydrogen carbonate solution, extract with methylene dichloride (30mL × 3).Merge organic phase, wash with the saturated common salt aqueous solution (50mL × 1).Anhydrous magnesium sulfate drying, filter, by filtrate reduced in volume, thin layer prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1), obtains compound as white solid 22 (0.106g, productive rate 59.9%).
MSm/z(ESI):413.0[M+1]；
1HNMR(400MHz,CDCl 3):δ7.53(s,1H),7.23-7.06(m,3H),7.54-7.52(d,2H),4.30-4.25(m,2H),3.92-3.86(m,4H),3.43-3.38(t,1H),3.11-3.02(m,1H),2.94(s,3H),2.90-2.88(m,1H),2.50-2.46(m,1H),1.58-1.46(q,1H)。
Bioassay
1, the external enzyme activity determination of DPP-IV
The DPP-IV vitro enzyme of the zymetology reaction assay the compounds of this invention of recombinant human DPP-IV and H-Ala-Pro-AFC is utilized to live.Damping fluid, testing sample working fluid, DPP-IV enzyme diluent and AFC substrate dilution is prepared according to DPP-IVFluorescentActivityAssayKit (BPSBioscience).
Prepare 96 orifice plates, every hole first adds 80 μ L damping fluids, adds 5 μ LDPP-AFC-substrates afterwards.Treat test sample working fluid, every hole 5 μ L adding different concns, blank group adds 5 μ L damping fluids.Finally in test group contrast, add 10 μ LDPP-IV enzymes, in blank group, add 10 μ L damping fluids.With Origin7.5 software, statistical analysis is carried out to data, obtain the IC of each test compounds 50value, the results are shown in Table 1.
Table 1DPP-IV vitro enzyme measurement result alive
Sequence number Compound number IC 50(nM)
3 Compound 3 2.79
4 Compound 6 2.17
7 Compound 14 8.70
8 Compound 16 3.47
9 Compound 17 3.61
10 Compound 18 3.80
11 Compound 19 2.66
12 Compound 21 4.06
13 Compound 22 5.68
Conclusion: the compounds of this invention has the inhibit activities of obvious DPP-IV enzyme.
2, oral glucose tolerance test
Oral glucose tolerance test (OGTT) is utilized to evaluate the hypoglycemic effect of the compounds of this invention in mouse.The animal used is SPF level ICR mouse, surrounding age, male and female half and half, purchased from Beijing Vital River Experimental Animals Technology Co., Ltd., and animal productiong conformity certification number: SCXK (capital) 2012-001.First feeding high lipid food one week, then continuous abdominal injection STZ solution (50mg/kg) 4 days.According to the basal plasma glucose value grouping after fasting, often organize 10.Test-compound becomes the suspension of 1mg/ml with 5%DMSO-5%solutol-90% normal saline.Gastric infusion, dosage is 10mg/kg.Blank group gives 5%DMSO-5%solutol-90% physiological saline.The D/W (1g/kg) of 10% is given after administration 15min, and 0,15,30,45,60,120min time use the steady bold and unconstrained Instrument for Measuring Blood Sugar of Johnson & Johnson to measure the blood glucose value of each mouse, under calculating drug-time curve, area (AUC) reduces ratio.Experimental result is in table 2.
Table 2 Mouse oral glucose tolerance test evaluation result
Sequence number Compound number AUC reduces ratio (%)
1 Compound 1 20.0
2 Compound 2 23.9
3 Compound 3 19.7
Conclusion: the compounds of this invention has good hypoglycemic effect, obviously can reduce blood sugar after the administration of mouse single oral.

Claims (10)

1. the amino six-ring analog derivative shown in general formula (I) or its steric isomer, pharmacy acceptable salt or prodrug:
Wherein:
W is selected from
X is selected from-O-,-S (=O) n-,-NH or-CH 2-;
R 1be selected from F, Cl, Br, I, hydroxyl, cyano group, C 1-8alkyl-OH, C 1-8alkyl-C 1-8alkoxyl group, C 3-8cycloalkyl, C 3-8cycloalkyl-C 1-8alkoxyl group, C 1-8alkoxyl group ,-(CH 2) m-C (=O)-R 3,-(CH 2) m-C (=O)-OR 3,-(CH 2) m-NR 4r 5,-(CH 2) m-C (=O)-NR 4r 5,-(CH 2) m-O-C (=O)-NR 4r 5,-(CH 2) m-S (=O) n-R 6,-(CH 2) m-NR 7c (=O)-NR 4r 5,-(CH 2) m-NR 7c (=O)-R 3or-(CH 2) m-NR 7c (=O)-OR 3, wherein said CH 2, alkyl, cycloalkyl or alkoxyl group be optionally selected from F, Cl, Br, I ,-CH by 0 to 5 further 2f ,-CHF 2,-CF 3, cyano group, nitro, isocyano-, hydroxyl, aldehyde radical, carboxyl, C 1-8alkyl or C 1-8the substituting group of alkoxyl group replaced;
R 2, R 2', R 2 ", R 2 " 'and R 2 " "be selected from H, F, Cl, Br, I, cyano group, hydroxyl, C independently of one another 1-8alkyl or C 1-8alkoxyl group, described alkyl or alkoxyl group optional further replace by the substituting group of 0 to 5 F, Cl, Br, I, cyano group, amino or hydroxyl;
R 3independently selected from H, amino, hydroxyl, C 1-8alkyl, C 1-8alkoxyl group, C 3-8cycloalkyl or 3 to 8 yuan of heterocyclic radicals, described heterocyclic radical contains 1 to 5 and is selected from N, O or S (=O) natom or group;
R 4, R 5and R 7be selected from H, C independently of one another 1-8alkyl, C 6-14aryl, 6 to 14 yuan of heteroaryls ,-(CH 2) m-C 3-8heterocyclic radical or-(CH 2) m-C 3-8cycloalkyl, wherein said alkyl, aryl, heteroaryl, heterocyclic radical or cycloalkyl are optionally replaced by the substituting group of 0 to 5 F, Cl, Br, I, hydroxyl, cyano group, amino or nitro further;
As selection, R 4and R 5form 3 to 8 yuan of heterocyclic radicals together with the nitrogen-atoms that they connect, described heterocyclic radical contains 1 to 3 and is selected from N, O or S (=O) natom or group, wherein heterocyclyl is replaced by the substituting group of 0 to 3 F, Cl, Br, I, hydroxyl, cyano group, amino or nitro further;
R 6be selected from H, C 1-8alkyl, C 3-8cycloalkyl or 3 to 8 yuan of heterocyclic radicals, described heterocyclic radical contains 1 to 5 and is selected from N, O or S (=O) natom or group;
R 8be selected from H, cyano group, C 1-8alkyl ,-(CH 2) m-S (=O) n-C 1-8alkyl ,-(CH 2) m-S (=O) n-C 3-8cycloalkyl ,-(CH 2) m-S (=O) n-(3 to 8 yuan of heterocyclic radicals) ,-(CH 2) m-S (=O) n-(6 to 14 yuan of heteroaryls) ,-(CH 2) m-S (=O) n-C 6-14aryl ,-(CH 2) m-C (=O)-OH ,-(CH 2) m-C (=O)-C 1-8alkyl ,-(CH 2) m-C (=O)-C 3-8cycloalkyl ,-(CH 2) m-C (=O)-(6 to 14 yuan of heteroaryls) ,-(CH 2) m-C (=O)-C 6-14aryl ,-(CH 2) m-C (=O)-O-C 1-8alkyl ,-(CH 2) m-C (=O)-O-C 3-8cycloalkyl ,-(CH 2) m-C (=O)-O-(6 to 14 yuan of heteroaryls) ,-(CH 2) m-C (=O)-O-C 6-14aryl ,-(CH 2) m-C (=O)-NH 2,-(CH 2) m-C (=O)-NH-C 1-8alkyl ,-(CH 2) m-C (=O)-NH-C 3-8cycloalkyl ,-(CH 2) m-C (=O)-NH-C 6-14aryl or-(CH 2) m-C (=O)-NH-(6 to 14 yuan of heteroaryls), wherein said CH 2, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl be optional further by 0 to 5 F, Cl, Br, I ,-CH 2f ,-CHF 2,-CF 3, hydroxyl, C 1-8alkyl, C 1-8alkoxyl group, C 3-8the substituting group of cycloalkyl or 3 to 8 yuan of heterocyclic radicals replaced; Described heterocyclic radical contains 1 to 5 and is selected from N, O or S (=O) natom or group;
R 9be selected from-S (=O) n-(3 to 12 yuan of heterocyclic radicals) ,-S (=O) 2-C 1-8alkyl-C 1-4alkoxyl group or-C 1-4alkyl-S (=O) 2-C 1-4alkyl, described heterocyclic radical, alkoxyl group, alkyl are optionally further by 0 to 5 F, Cl, Br, I ,-CH 2f ,-CHF 2,-CF 3, hydroxyl, amino, cyano group, C 1-8alkyl or C 1-8the substituting group of alkoxyl group replaced, and heterocyclic radical contains 1 to 5 and is selected from N, O or S (=O) natom or group;
N is selected from 0,1 or 2;
M is selected from 0,1,2,3 or 4.
2. the amino six-ring analog derivative according to claim 1 shown in general formula (I) or its steric isomer, pharmacy acceptable salt or prodrug, wherein:
W is selected from
X is selected from-O-;
R 1be selected from F, Cl, Br, I, hydroxyl, cyano group, C 1-4alkyl-OH, C 1-4alkyl-C 1-4alkoxyl group, C 3-6cycloalkyl, C 3-6cycloalkyl-C 1-4alkoxyl group, C 1-4alkoxyl group ,-(CH 2) m-C (=O)-R 3or-(CH 2) m-C (=O)-NR 4r 5, wherein said CH 2, alkyl, cycloalkyl or alkoxyl group be optionally selected from F, Cl, Br, I ,-CH by 0 to 3 further 2f ,-CHF 2,-CF 3, hydroxyl, C 1-2alkyl or C 1-2the substituting group of alkoxyl group replaced;
R 2, R 2 ', R 2 ", R 2 " 'and R 2 " "be selected from H, F, Cl, Br, I, C independently of one another 1-2alkyl or C 1-2alkoxyl group;
R 3independently selected from H, hydroxyl, C 1-4alkyl or C 1-4alkoxyl group;
R 4and R 5be selected from H or C independently of one another 1-4alkyl, wherein said alkyl is optionally replaced by the substituting group of 0 to 3 F, Cl, Br, I or hydroxyl further;
As selection, R 4and R 5form 3 to 6 yuan of heterocyclic radicals together with the nitrogen-atoms that they connect, described heterocyclic radical contains 1 to 2 and is selected from N, O or S (=O) natom or group, wherein heterocyclyl is replaced by the substituting group of 0 to 3 F, Cl, Br, I, hydroxyl or amino further;
R 8be selected from H ,-(CH 2) m-S (=O) n-C 1-4alkyl ,-(CH 2) m-S (=O) n-C 3-8cycloalkyl or-(CH 2) m-S (=O) n-(3 to 8 yuan of heterocyclic radicals), wherein said CH 2or alkyl is optional further by 0 to 3 F, Cl, Br, I ,-CH 2f ,-CHF 2,-CF 3or the substituting group of hydroxyl replaced;
R 9be selected from-S (=O) 2-(3 to 8 yuan of heterocyclic radicals) ,-S (=O) 2-C 1-4alkyl-C 1-4alkoxyl group or-C 1-4alkyl-S (=O) 2-C 1-4alkyl, described heterocyclic radical, alkoxyl group or alkyl are optional further by 0 to 3 F, Cl, Br, I ,-CH 2f ,-CHF 2,-CF 3, hydroxyl or amino substituting group replaced, heterocyclic radical contains 1 to 3 and is selected from N, O or S (=O) natom or group;
N is selected from 0,1 or 2;
M is selected from 0,1 or 2.
3. the amino six-ring analog derivative according to claim 2 shown in general formula (I) or its steric isomer, pharmacy acceptable salt or prodrug, wherein:
R 1be selected from C 1-4alkyl-OH, C 1-4alkyl-C 1-4alkoxyl group, C 3-6cycloalkyl, C 3-6cycloalkyl-C 1-4alkoxyl group ,-(CH 2) m-C (=O)-R 3or-(CH 2) m-C (=O)-NR 4r 5, wherein said CH 2, alkyl, cycloalkyl or alkoxyl group be optionally selected from F, Cl, Br ,-CH by 0 to 3 further 2f ,-CHF 2,-CF 3or the substituting group of hydroxyl replaced;
R 2, R 2', R 2 ", R 2 " 'and R 2 " "be selected from H, F, Cl, Br, I, C independently of one another 1-2alkyl or C 1-2alkoxyl group;
R 3be selected from hydroxyl or C 1-4alkoxyl group;
R 4and R 5be selected from H or C independently of one another 1-4alkyl;
R 8be selected from H or-(CH 2) m-S (=O) n-C 1-4alkyl, wherein said CH 2or alkyl is optional further by 0 to 3 F, Cl, Br, I ,-CH 2f ,-CHF 2,-CF 3or the substituting group of hydroxyl replaced;
R 9be selected from-S (=O) 2-(3 to 8 yuan of heterocyclic radicals) ,-S (=O) 2-C 1-4alkyl-C 1-4alkoxyl group or-C 1-4alkyl-S (=O) 2-C 1-4alkyl, described heterocyclic radical, alkoxyl group, alkyl are optionally further by 0 to 3 F, Cl, Br, I ,-CH 2f ,-CHF 2,-CF 3, hydroxyl or amino substituting group replaced, heterocyclic radical contains 1 to 3 and is selected from N, O or S (=O) natom or group;
N is selected from 0,1 or 2;
M is selected from 0,1 or 2.
4. the amino six-ring analog derivative according to claim 3 shown in general formula (I) or its steric isomer, pharmacy acceptable salt or prodrug, wherein:
R 1be selected from -C (=O)-OH ,-C (=O)-OCH 3,-C (=O)-OCH 2cH 3,-C (=O)-NH 2,-C (=O)-NHCH 3or-C (=O)-N (CH 3) 2;
R 2, R 2', R 2 ", R 2 " 'and R 2 " "be selected from H or F independently of one another;
R 8be selected from H or-S (=O) n-C 1- 4alkyl, wherein said alkyl optional further replace by the substituting group of 0 to 3 F, Cl or Br;
R 9be selected from-S (=O) 2-(3 to 6 yuan of heterocyclic radicals) ,-S (=O) 2-C 1-4alkyl-C 1-4alkoxyl group or-C 1-4alkyl-S (=O) 2-C 1-4alkyl, described heterocyclic radical, alkoxyl group or alkyl are optional further by 0 to 3 F, Cl, Br ,-CH 2f ,-CHF 2,-CF 3, hydroxyl or amino substituting group replaced, heterocyclic radical contains 1 to 3 and is selected from N, O or S (=O) natom or group;
N is selected from 0,1 or 2.
5. the amino six-ring analog derivative according to claim 4 shown in general formula (I) or its steric isomer, pharmacy acceptable salt or prodrug, wherein:
R 1be selected from -C (=O)-OH ,-C (=O)-OCH 3,-C (=O)-OCH 2cH 3,-C (=O)-NH 2,-C (=O)-NHCH 3or-C (=O)-N (CH 3) 2;
R 2and R 2 " 'be selected from H, R 2 "be selected from H or F, R 2'and R 2 " "be selected from F;
R 8be selected from H or
R 9be selected from-CH 2-S (=O) 2-CH 3,
6. the amino six-ring analog derivative according to the general formula (I) of Claims 1 to 5 described in any one or its steric isomer, pharmacy acceptable salt or prodrug, wherein this amino six-ring analog derivative is selected from:
7. the amino six-ring analog derivative according to any one of claim 1 ~ 6 shown in general formula (I) or its steric isomer, pharmacy acceptable salt or prodrug, wherein said salt is selected from sodium salt, sylvite, calcium salt, magnesium salts, barium salt, ammonium salt, front three amine salt, triethylamine salt, pyridinium salt, picoline salt, 2,6-lutidine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, dicyclohexyl ammonium salt, hydrochloride, hydrobromate, vitriol, nitrate, phosphoric acid salt, formate, trifluoroacetate, acetate, maleate, tartrate, Citrate trianion, succinate, mandelate, fumarate, malonate, malate, 2 hydroxy propanoic acid salt, oxalate, oxyacetate, salicylate, glucuronate, galacturonic hydrochlorate, citrate, aspartate, glutaminate, benzoate, cinnamate, tosilate, benzene sulfonate, mesylate, esilate, fluoroform sulphonate or their combination.
8. a pharmaceutical composition, described composition comprises: the amino six-ring analog derivative shown in the general formula according to any one of claim 1 ~ 7 (I) of effective dose or its steric isomer, pharmacy acceptable salt or prodrug, or comprises one or more other treatment agent and pharmaceutically acceptable carrier or vehicle further;
Preferably, wherein said other treatment agent comprises:
(a) DPP-IV inhibitor or pharmacy acceptable salt, and/or
(b) SGLT-2 inhibitor or pharmacy acceptable salt, and/or
(c) biguanides, thiazolidinediones, sulfonylurea, arrange how class, alpha-glucosidase inhibitor or glucagon-like peptide-1 analogs, or its pharmacy acceptable salt or prodrug;
More preferably, wherein said SGLT-2 inhibitor is selected from that Da Gelie is clean, Kan Gelie is clean, A Gelie is clean, En Palie is clean, Yi Palie is clean, Tuo Fulie is clean, Lu Silie is clean, Rui Gelie is clean, She Gelie is clean or relies on row clean; DPP-IV inhibitor be selected from BI 1356, sitagliptin, Vildagliptin, Egelieting, BMS-477118, Na Lieting, carmegliptin, melogliptin, dutogliptin, for Ge Lieting, gigue row spit of fland or bent Ge Lieting; Biguanides therapeutical agent is selected from N1,N1-Dimethylbiguanide or phenformin; Thiazolidinediones therapeutical agent is selected from ciglitazone, pioglitazone, rosiglitazone, troglitazone, Fa Gelie ketone or darglitazone, sulfonylurea treatment agent is selected from glimepiride, tolbutamide, glibornuride, Glyburide, gliquidone, Glipizide or gliclazide, arrange how class therapeutical agent is selected from nateglinide, repaglinide or mitiglinide, alpha-glucosidase inhibitor is selected from acarbose, voglibose or miglitol, and glucagon-like peptide-1 analogs is selected from Exenatide or Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37].
9. the amino six-ring analog derivative shown in general formula according to any one of claim 1 ~ 7 (I) or its steric isomer, pharmacy acceptable salt or prodrug or the pharmaceutical composition described in claim 8 are preparing the application in dipeptidyl peptidase-iv inhibitor.
10. according to the application described in claim 9, wherein said dipeptidyl peptidase-iv inhibitor is for the preparation of the medicine for the treatment of metabolic disease, and wherein said metabolic disease comprises the level of the rising of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, lipid acid or glycerine, hyperlipidaemia, obesity, hypertriglyceridemia, X syndromes, diabetic complication, atherosclerosis or hypertension; Preferably, described diabetes are type ii diabetes.
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CN105085528A (en) * 2014-05-15 2015-11-25 成都贝斯凯瑞生物科技有限公司 Aminotetrahydropyran derivative as dipeptidyl peptidase-IV inhibitor
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US12128035B2 (en) 2021-03-19 2024-10-29 Novo Nordisk Health Care Ag Activating pyruvate kinase R

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