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CN1810795A - Benzopyran compound and its prepn and use - Google Patents

Benzopyran compound and its prepn and use Download PDF

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Publication number
CN1810795A
CN1810795A CNA2006100243422A CN200610024342A CN1810795A CN 1810795 A CN1810795 A CN 1810795A CN A2006100243422 A CNA2006100243422 A CN A2006100243422A CN 200610024342 A CN200610024342 A CN 200610024342A CN 1810795 A CN1810795 A CN 1810795A
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Prior art keywords
oxo
chromene
methyl ester
methyl
oxazole
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杨玉社
余娟红
嵇汝运
陈凯先
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Shanghai Institute of Materia Medica of CAS
Nanjing Changao Pharmaceutical Science and Technology Co Ltd
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Shanghai Institute of Materia Medica of CAS
Nanjing Changao Pharmaceutical Science and Technology Co Ltd
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Priority to CNA2006100243422A priority Critical patent/CN1810795A/en
Priority to PCT/CN2006/000661 priority patent/WO2007098644A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/20—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 hydrogenated in the hetero ring

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Abstract

The present invention provides benzopyran compound as shown and its pharmaceutically acceptable inorganic and organic salts. The present invention also provides the preparation process of the compounds and medicine composite including the compounds as the active matter for treating type-II diabetes and its complications.

Description

The benzopyran compounds that one class is new, Preparation Method And The Use
Technical field
The present invention relates to pharmaceutical chemistry and endocrine therapy and learn the field, be specifically related to the synthetic of benzopyran compounds and the purposes in the anti-type ii diabetes medicine of preparation thereof.
Background technology
Diabetes (diabetes) are because Regular Insulin (insulin) hyposecretion or insulin resistant (insulin resistance), cause carbohydrate, fat and protein metabolism unusual, and be one group of clinical syndrome of main performance with the chronic hyperglycemia.Think that now insulin resistant (peripheral tissues such as fatty tissue descend to insulin sensitivity for skeletal muscle, liver) is the major cause of diabetes B morbidity.The hyperglycemia that continues can cause the generation of many complication, as retina, kidney, neural system, cardiovascular complication, especially cardiovascular complication is the deadly major cause of morbidity [Shinkai, H.Exp.Opin.Ther.Patents.2000,10:596] of diabetic subject.
Studies show that, insulin resistant is the main pathogenic factor of diabetes, therefore the development euglycemic agent that improves insulin resistance has become an important research direction of prevention and treatment diabetes (Exp.Opin.Ther.Patents 2000,10 (5): 623; WO 0073252).First thiazolidinediones euglycemic agent troglitazone went on the market in 1997, the similar medicine U-721017E and the rosiglitazone of this medicine and listing afterwards, can both control patient's blood sugar well clinically, but such medicine has all shown hepatotoxicity [Henry in various degree after listing, R.R.Endocrinol.Metab.Clin.North Am.1997,26,553], wherein troglitazone is withdrawn from market because of liver toxicity is big.Because the toxicity of this compounds is under a cloud relevant with the thiazolidinedione ring in its structure, so non-thiazolidinediones euglycemic agent synthetic and develop a main direction that becomes anti-type ii diabetes drug research gradually (US 6414002; Current Medicinal Chemistry 2003,10:267).
Summary of the invention
An object of the present invention is to provide acceptable inorganic or organic salt on novel benzopyrans compounds with insulin-sensitizing activity and the pharmacology thereof, this compound can be avoided above-mentioned defective of the prior art effectively.
Another object of the present invention provides the preparation method of this compounds.
A further object of the present invention provides a kind of pharmaceutical composition, this pharmaceutical composition comprises at least a compound of the present invention as effective constituent, wherein can Individual existence as the compound of effective constituent or in conjunction with acceptable vehicle or carrier at least a pharmacology.This pharmaceutical composition can be used for treating type ii diabetes and complication thereof.
Below the present invention is carried out specific description.
The invention provides and have as shown in the formula accepting inorganic or organic salt on the benzopyrans compounds of (I) structure and the pharmacology thereof:
Figure A20061002434200091
Wherein, be singly-bound or two key between 3 and 4 carbon; N=2 or 3; X is CH 2, O or S; When being singly-bound for 3,4, the configuration of 4 carbon atoms can be R type or S type or raceme;
R 1For hydrogen atom, contain substituent or do not contain the straight or branched alkyl of substituent C1-C6; Or other alkyl that is fit to;
R 2For containing substituent or not containing the straight or branched alkyl of substituent C1-C6; Or other alkyl that is fit to; Or
Aromatic group or aromatic heterocycle group;
R 3, R 4, R 5And R 6For halogen, hydroxyl, nitro, amino, trifluoromethyl, contain substituent or do not contain the straight or branched alkyl of substituting group C1-C6; Or other alkyl that is fit to; Contain substituent or do not contain the straight or branched alkoxyl group of substituting group C1-C6; Or other alkoxyl group that is fit to; Contain substituent or do not contain the substituting group phenyl; Contain substituent or do not contain the aromatic group or the aromatic heterocycle group of substituent phenoxy group.
The straight or branched alkyl of C1-C6 is a methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl, the 1-methyl butyl, the 2-methyl-propyl, hexyl, isohexyl, the 1-methyl amyl, the 2-methyl amyl, the 3-methyl amyl, the 2-methyl butyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 3-dimethylbutyl, 3, the 3-dimethylbutyl, the 1-ethyl-butyl, the 2-ethyl-butyl, 1,1,2-trimethylammonium propyl group, 1,2,2-trimethylammonium propyl group, 1-ethyl-1-methyl-propyl or 1-ethyl-2-methyl-propyl.In these groups, being preferably carbonatomss such as methyl, ethyl, propyl group, sec.-propyl, butyl is the individual alkyl of 1-4, and more preferably methyl, ethyl or propyl group most preferably are with methyl or ethyl.
Aromatic group is represented aromatic hydrocarbyl, is preferably the aryl of 6-14 carbon atom, is in particular phenyl, tolyl, xylyl, xenyl, naphthyl, indenyl, anthryl or phenanthryl, wherein is preferably phenyl or naphthyl, most preferably is phenyl.
Described aromatic heterocycle group represents to contain 1-4 heteroatomic five yuan or six membered heteroaryl that is selected from Sauerstoffatom, nitrogen-atoms or sulphur atom, is in particular furyl, thienyl, pyrryl, imidazolyl, thiazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazolyl, tetrazyl etc.In these groups, be preferably thienyl, furyl, oxazolyl, isoxazolyl or thiazolyl, more preferably thienyl, oxazolyl Huo isoxazolyl.
Described substituting group be selected from comprise halogen atom, the alkyl identical, alkoxyl group, acyloxy with above-mentioned definition ,-OH ,-NH 2, NO 2One or more groups among the ,-NHAc.
In the compound of formula of the present invention (I) expression, representative example is as follows:
1) 7-[2-(5-methyl-2-xenyl-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
2) 7-[2-(5-methyl-2-(3-aminomethyl phenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
3) 7-[2-(5-methyl-2-(4-aminomethyl phenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
4) 7-[2-(5-methyl-2-(4-tert-butyl-phenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
5) 7-[2-(5-methyl-2-(4-p-methoxy-phenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
6) 7-[2-(5-methyl-2-(3-p-methoxy-phenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
7) 7-[2-(5-methyl-2-(4-chloro-phenyl-)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
8) 7-[2-(5-methyl-2-(3-fluorophenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
9) 7-[2-(5-methyl-2-(4-fluorophenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
10) 7-[2-(5-methyl-2-(3-trifluoromethyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
11) 7-[2-(5-methyl-2-(4-benzyloxy phenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
12) 7-[2-(5-methyl-2-(4-hydroxy phenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
13) 7-[2-(5-methyl-2-(3-nitrophenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
14) 7-[2-(4-mesyloxy phenyl) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
15) 7-[2-(5-methyl-2-xenyl-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester;
16) 7-[2-(5-methyl-2-(3-aminomethyl phenyl)-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester;
17) 7-[2-(5-methyl-2-(4-aminomethyl phenyl)-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester;
18) 7-[2-(5-methyl-2-(4-tert-butyl-phenyl)-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester;
19) 7-[2-(5-methyl-2-(4-p-methoxy-phenyl)-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester;
20) 7-[2-(5-methyl-2-(3-p-methoxy-phenyl)-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester;
21) 7-[2-(5-methyl-2-(3-fluorophenyl)-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester;
22) 7-[2-(5-methyl-2-(4-fluorophenyl)-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester;
23) 7-[2-(5-methyl-2-(3-trifluoromethyl)-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester;
24) 7-[2-(4-methylsulfonic acid base phenyl) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester;
25) 7-[2-(2-oxo-5,6,7,8-tetralyl) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
26) 7-[2-(2-oxo xenyl) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
27) 7-[2-(2-oxo xenyl)-oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester;
28) 7-[2-(4-phenoxy group phenoxy group) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
29) 7-[3-(4-phenoxy group phenoxy group) propoxy-]-2-oxo-2H-1-chromene-3-carboxylate methyl ester.
The method for preparing the benzopyrans compounds shown in the formula of the present invention (I) can be undertaken by following three kinds of flow processs respectively:
Flow process I
Figure A20061002434200141
Illustration: a. yellow soda ash, substituted aroma isoxazolecarboxylic acid; B. acetic anhydride, pyridine; C. phosphorus oxychloride, N, dinethylformamide; D.i) Lithium Aluminium Hydride, tetrahydrofuran (THF); Ii) four triphenyl phosphorus Palladous chlorides; Iii) 2N sodium hydroxide, methyl alcohol; Iv) diisobutyl aluminium hydride, tetrahydrofuran (THF); E. borine, tetrahydrofuran (THF); F. triphenyl phosphorus, diethylazodicarboxylate or diisopropyl azo-2-carboxylic acid; G.H2/Pd-C
The preparation method of flow process I specifies as follows:
(1) 2,4-Dihydroxy benzaldehyde and propanedioic acid methyl esters react 7-hydroxyl-3-tonka bean camphor carboxylate methyl ester.
(2) press reference [Alexander, G.G.; Dawn.A.B.J.Org.Chem.2003,68,2623] and the preparation method of [WO 0218355] report, prepare corresponding 2-(5-methyl-2-aryl-4-oxazole) ethanol.
(3) the corresponding alcohol that obtains in 7-hydroxyl-3-tonka bean camphor carboxylate methyl ester and the step (2) carries out Mitsunobu prepared in reaction compound 1～11,13.The solvent that Mitsunobu reaction is adopted is anhydrous inert solvents such as anhydrous tetrahydro furan, anhydrous dioxane, dry-out benzene, anhydrous diethyl ether, chloroform, methylene dichloride, temperature of reaction-10～100 ℃, and the reaction times is 0～3 day.The mixed solvent recrystallization that thick product is formed by suitable proportion with methyl alcohol, ethanol, Virahol, ethyl acetate, chloroform, methylene dichloride or its two or more components.The condition of answering of rising in rebellion most is in the anhydrous tetrahydro furan, room temperature reaction 0.1～24 hour, thick product recrystallizing methanol.
(4) compound 1～6,8～10 under suitable condition catalytic hydrogenation reduction obtain compound 15～23.The catalyzer of catalytic hydrogenation can be selected 10% or 5% palladium carbon or other catalyzer that contains palladium for use, or Raney-Ni, or other contains the catalyzer of palladium or nickel, and preferred catalyzer is 10% palladium carbon.Solvent can be selected low alkyl alcohol such as methyl alcohol, ethanol, Virahol etc. for use, also can select other solvents such as acetate or water for use, and best is methyl alcohol.Reaction times all can from 0.1 hour to no longer inhaling hydrogen.Temperature of reaction from room temperature to 40 ℃ all can, room temperature preferably.Reaction pressure from normal pressure to tens normal atmosphere all can, best condition is a normal pressure.The mixed solvent recrystallization that recrystallization solvent is formed by suitable proportion with ethanol, methyl alcohol, Virahol, acetone, ethyl acetate, chloroform, methylene dichloride, benzene, toluene, normal hexane, normal heptane or its two or more components, the preferred recrystallization solvent of each compound is seen embodiment.
(5) compound 11 under suitable condition the catalytic hydrogenation debenzylation obtain compound 12.The catalyzer of catalytic hydrogenation can be selected 10% or 5% palladium carbon or other catalyzer that contains palladium for use, and preferred catalyzer is 5% palladium carbon.Solvent can be selected low alkyl alcohol such as methyl alcohol, ethanol, Virahol etc. for use, and best is methyl alcohol.Reaction times is 12 hours, and pressure remains on normal pressure.
Flow process II
Illustration: a. methylsulfonyl chloride, triethylamine, methylene dichloride; B. Lithium Aluminium Hydride, tetrahydrofuran (THF); C. triphenyl phosphorus, diethylazodicarboxylate or diisopropyl azo-2-carboxylic acid; D.H 2/ Pd-C
The preparation method of flow process II specifies as follows:
(1) method of reference literature [J.Chem.Soc.Perkin Trans.11980,31-42] makes 2-(4-methanesulfonates) phenylethyl alcohol
(2) 7-hydroxyl-3-tonka bean camphor carboxylate methyl ester and 2-(4-methanesulfonates) phenylethyl alcohol carry out Mitsunobu react compound 14.The solvent that Mitsunobu reaction is adopted is anhydrous inert solvents such as anhydrous tetrahydro furan, anhydrous dioxane, dry-out benzene, anhydrous diethyl ether, chloroform, methylene dichloride, temperature of reaction-10～100 ℃, and the reaction times is 0～3 day.The mixed solvent recrystallization that thick product is formed by suitable proportion with methyl alcohol, ethanol, Virahol, ethyl acetate, chloroform, methylene dichloride or its two or more components.Optimum reaction conditions is in the anhydrous tetrahydro furan, room temperature reaction 0.1～24 hour, thick product recrystallizing methanol.
(4) compound 14 under suitable condition catalytic hydrogenation reduction obtain compound 24.The catalyzer of catalytic hydrogenation can be selected 10% or 5% palladium carbon or other catalyzer that contains palladium for use, or Raney-Ni, or other contains the catalyzer of palladium or nickel, and preferred catalyzer is 10% palladium carbon.Solvent can be selected the mixed solvent of methylene dichloride and low alkyl alcohol such as methyl alcohol, ethanol, Virahol etc. for use, and best is the mixed solvent of methyl alcohol in methylene dichloride.Reaction times all can from 0.1 hour to no longer inhaling hydrogen.Temperature of reaction from room temperature to 40 ℃ all can, room temperature preferably.Reaction pressure from normal pressure to tens normal atmosphere all can, best condition is a normal pressure.
The embodiment of flow process III is described as follows:
Illustration: a. sodium hydroxide, acetone; B. cesium carbonate, N, dinethylformamide; C.H 2/ Pd-C
The preparation method of flow process III specifies as follows:
(1) to contain substituting group or do not contain substituent phenol be starting raw material with various, and with glycol dibromide or 1, the 3-dibromopropane reacts under alkaline condition and makes the aromatic hydrocarbon that aromatic hydrocarbon that bromine oxethyl replaces or bromine propoxy-replace.The solvent that reacts used can be acetone, N, and dinethylformamide, methyl-sulphoxide or acetonitrile wherein are preferably acetone.The alkali of using in the reaction can be salt of wormwood, yellow soda ash, cesium carbonate, sodium hydroxide or potassium hydroxide, is preferably sodium hydroxide.
(2) 7-hydroxyl-3-tonka bean camphor carboxylate methyl ester and bromine oxethyl contain substituting group or do not contain substituent aromatic hydrocarbon or the bromine propoxy-contains substituting group or do not contain the condensation under alkaline condition of substituent aromatic hydrocarbon and obtains compound 25,26,28,29.The solvent that reacts used can be acetone, N, and dinethylformamide, methyl-sulphoxide or acetonitrile wherein are preferably N, dinethylformamide.The alkali of using in the reaction can be salt of wormwood, yellow soda ash, cesium carbonate, sodium hydroxide or potassium hydroxide, is preferably cesium carbonate.
(3) with compound 26 under suitable condition catalytic reduction obtain compound 27.The catalyzer of catalytic hydrogenation can be selected 10% or 5% palladium carbon or other catalyzer that contains palladium for use, or Raney-Ni, or other contains the catalyzer of palladium or nickel, and preferred catalyzer is 10% palladium carbon.Solvent can be selected low alkyl alcohol such as methyl alcohol, ethanol, Virahol etc. for use, also can select other solvents such as acetate or water for use, and best is methyl alcohol.Reaction times all can from 0.1 hour to no longer inhaling hydrogen.Temperature of reaction from room temperature to 40 ℃ all can, room temperature preferably.Reaction pressure from normal pressure to tens normal atmosphere all can, best condition is a normal pressure.
Those skilled in the art can make acceptable inorganic or organic salt on the pharmacology with compound of the present invention by the method for knowing in the prior art.Subsalt such as sodium salt, sylvite, calcium salt etc.
Table 1 representative compounds structural formula and relevant pharmacological datum
Figure A20061002434200181
Figure A20061002434200191
Figure A20061002434200201
A.3T3-L1 cellular fat content increases by 30% pairing compound concentration than DMSO control group.
Wherein rosiglitazone proposes as correlated prior art, compound 25 to 29 its structures wherein and above compound 1 to 24 closely similar, therefore it will be appreciated by those skilled in the art that it should have similar character.Have similar or stronger insulin-sensitizing activity by the compound of the present invention as can be seen of the data in the table 1 than positive control rosiglitazone, therefore have similar or more excellent curative effect with respect to rosiglitazone.
Acceptable salt has the function of the formation of control diabetes B blood glucose level in patients and inhibition complication on the present invention's benzopyrans compounds required for protection and the pharmacology thereof.
Acceptable salt has the insulin-sensitizing activity similar or stronger than thiazolidine dione compounds rosiglitazone on the present invention's benzopyrans compounds required for protection and the pharmacology thereof, so these compounds can be used for preparing the medicine of novel therapeutic diabetes and complication thereof.
Acceptable salt can be made into various preparations on compound of the present invention and the pharmacology thereof, wherein comprises on The compounds of this invention in the safety, significant quantity scope or its pharmacology acceptable vehicle or carrier on the acceptable salt and pharmacology.Wherein " safety, significant quantity " refers to: the amount of compound is enough to obviously improve the state of an illness, and is unlikely to produce severe side effect.The safety of compound, significant quantity are determined according to particular cases such as age of treatment target, the state of an illness, the courses of treatment.
" acceptable carrier on the pharmacology " refers to: one or more consistency solids or liquid filler or gelatinous mass, they are suitable for the people uses, and enough purity and enough low toxicity must be arranged." consistency " referred to herein as each component energy and compound of the present invention and blending mutually between them in the composition, and the drug effect of not obvious reduction compound.Acceptable carrier part example has Mierocrystalline cellulose and derivative thereof (as Xylo-Mucine on the pharmacology, ethyl cellulose sodium, cellulose ethanoate etc.), gelatin, talcum, solid lubricant is (as stearic acid, Magnesium Stearate), calcium sulfate, vegetables oil is (as soya-bean oil, sesame oil, peanut oil, the olive wet goods), polyvalent alcohol is (as propylene glycol, glycerine, N.F,USP MANNITOL, sorbyl alcohol etc.), emulsifying agent (as tween ), wetting agent (as sodium lauryl sulphate), tinting material, seasonings, stablizer, antioxidant, sanitas, apirogen water etc.
Embodiment
The present invention is further elaborated below in conjunction with embodiment, but these embodiment never are any limitation of the invention.Among all embodiment, fusing point is measured with MEL-TEMP fusing point instrument, and thermometer is not proofreaied and correct; 1H-NMR Varian Mercury 400 nuclear magnetic resonance analyser records, chemical shift is represented with δ (ppm); Separate with the unaccounted 200-300 order that is of silica gel.
Embodiment 1:7-[2-(5-methyl-2-xenyl-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester (compound 1)
2-[5-methyl-2-(4-xenyl)-4-oxazole] ethanol [Alexande r, G.G.; Dawn.A.B.J.Org.Chem.2003,68,2623] 0.09g (0.32mmol), 7-hydroxyl-3-tonka bean camphor carboxylate methyl ester 0.07g (0.32mmol) is dissolved in the 15ml anhydrous tetrahydro furan, add triphenylphosphine 0.11g (0.42mmol), 0 ℃ drips diethylazodicarboxylate 0.08ml (0.53mmol) down.Stirring at room 24 hours.Remove solvent under reduced pressure, residue is separated out white solid in methyl alcohol.The gained solid is got target compound 0.08g with recrystallizing methanol, yield: 51.6%.M.P.159.0-160.0℃。
1HNMR(CDCl 3)：δ＝2.40(s，3H)，3.04(t，J＝6.3Hz，2H)，3.94(s，3H)，4.36(t，J＝6.6Hz，2H)，6.88(m，2H)，7.37(m，5H)，7.60(m，4H)，8.04(dd，J＝8.41Hz，J＝6.92Hz，1H)，8.54(s，1H)。
Embodiment 2:7-[2-(5-methyl-2-(4-xenyl)-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester (compound 15)
Compound 1 0.07g (0.14mmol) is dissolved in 10ml methyl alcohol: in the mixed solvent of dioxane=1: 3, add 20mg 10% Pd-C, mixing, normal pressure stir logical hydrogen till stop to inhale hydrogen.Filtering Pd-C removes solvent under reduced pressure, and residue is separated out solid in methyl alcohol, and suction filtration gets product 0.06g, yield: 85.4%.M.P.122.5-123.0℃。
1HNMR(CDCl 3)：δ＝2.40(s，3H)，3.03(t，J＝6.3Hz，2H)，3.29(dd，J＝15.8Hz，J＝6.05Hz，1H)，3.54(dd，J＝15.9Hz，J＝8.66Hz，1H)，3.93(m，4H)，4.35(t，J＝6.7Hz，2H)，6.86(m，2H)，7.02(d，J＝8.65Hz，1H)，7.37(m，5H)，7.59(m，4H)。
Embodiment 3:7-[2-(5-methyl-2-(3-aminomethyl phenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester (compound 2)
2-[5-methyl-2-(3-aminomethyl phenyl)-4-oxazole] ethanol 0.40g (1.84mmol) [Alexander, G.G.; Dawn.A.B.J.Org.Chem.2003,68,2623], 7-hydroxyl-3-tonka bean camphor carboxylate methyl ester 0.41g (1.84mmol) is dissolved in the 60ml anhydrous tetrahydro furan, add triphenylphosphine 0.63g (2.40mmol), 0 ℃ drips diethylazodicarboxylate 0.08ml (3.11mmol) down.Stirring at room 24 hours.Remove solvent under reduced pressure, residue is separated out white solid in methyl alcohol.The gained solid is got target compound 0.45g with recrystallizing methanol, yield: 58.3%.M.P.134.0-134.5℃。
1HNMR(CDCl 3)：δ＝2.40(s，3H)，2.38(s，3H)，3.02(t，J＝6.59Hz，2H)，3.93(s，3H)，4.34(t，J＝6.59Hz，2H)，6.83(d，J＝2.33Hz，1H)，6.88(dd，J＝8.66Hz，J＝2.34Hz，1H)，7.22(dd，J＝7.70Hz，J＝0.69Hz，1H)，7.32(t，J＝7.69Hz，1H)，7.48(d，J＝8.79Hz，1H)，7.76(d，J＝7.69Hz，1H)，7.81(d，J＝0.55Hz，1H)，8.53(s，1H)。
Embodiment 4:7-[2-(5-methyl-2-(3-aminomethyl phenyl)-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester (compound 16)
Compound 3 is a raw material, to be similar to the method preparation of compound 2, yield: 94.5%.M.P.129.0-130.0℃。
1HNMR(CDCl 3)：δ＝2.37(s，3H)，2.40(s，3H)，2.97(t，J＝6.6Hz，2H)，3.09(dd，J＝15.8Hz，J＝6.05Hz，1H)，3.34(dd，J＝15.9Hz，J＝8.66Hz，1H)，3.74(m，4H)，4.21(t，J＝6.73Hz，2H)，6.23(d，J＝2.34Hz，1H)，6.67(dd，J＝8.24Hz，J＝2.47Hz，1H)，7.08(d，J＝8.24Hz，1H)，7.22(d，J＝7.55Hz，1H)，7.32(m，1H)，7.77(d，J＝7.69Hz，1H)，7.82(s，1H)。
Embodiment 5:7-[2-(5-methyl-2-(4-aminomethyl phenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester (compound 3)
2-[5-methyl-2-(4-aminomethyl phenyl)-4-oxazole] ethanol [Alexander, G.G.; Dawn.A.B.J.Org.Chem.2003,68,2623] 0.30g (1.38mmol), 7-hydroxyl-3-tonka bean camphor carboxylate methyl ester 0.30g (1.38mmol) is dissolved in the 40ml anhydrous tetrahydro furan, add triphenylphosphine 0.46g (1.76mmol), 0 ℃ drips diisopropyl azo-2-carboxylic acid 0.35ml (1.78mmol) down.Stirring at room 24 hours.Remove solvent under reduced pressure, residue is separated out white solid in methyl alcohol.The gained solid is got target compound 0.22g with recrystallizing methanol, yield: 38.0%.M.P.166.0-163.0℃。
1HNMR(CDCl 3)：δ＝2.38(s，3H)，2.39(s，3H)，3.02(t，J＝6.55Hz，2H)，3.93(s，3H)，4.34(t，J＝6.55Hz，2H)，6.83(d，J＝2.35Hz，1H)，6.88(dd，J＝8.73Hz，J＝2.35Hz，1H)，7.24(d，J＝8.39Hz，2H)，7.48(d，J＝9.06Hz，1H)，7.86(d，J＝8.39Hz，2H)，8.53(s，1H)。
Embodiment 6:7-[2-(5-methyl-2-(4-aminomethyl phenyl)-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester (compound 17)
Compound 5 is a raw material, to be similar to the method preparation of compound 2, yield: 87.1%.M.P.136.5-137.5℃。
1HNMR(CDCl 3)：δ＝2.36(s，3H)，2.39(s，3H)，2.97(t，J＝6.6Hz，2H)，3.09(dd，J＝15.9Hz，J＝6.04Hz，1H)，3.34(dd，J＝15.79Hz，J＝8.65Hz，1H)，3.73(m，4H)，4.21(t，J＝6.59Hz，2H)，6.63(d，J＝2.33Hz，1H)，6.67(dd，J＝8.24Hz，J＝2.47Hz，1H)，7.07(d，J＝8.38Hz，1H)，7.23(d，J＝7.97Hz，2H)，7.86(d，J＝8.24Hz，2H)。
Embodiment 7:7-[2-(5-methyl-2-(4-tert-butyl-phenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester (compound 4)
7.1 2-[5-methyl-2-(4-tert-butyl-phenyl)-4-oxazole] the alcoholic acid preparation
24.96g (147mmol) L-aspartic acid methyl ester hydrochloride is dissolved in the 100ml water, is cooled to 5 ℃, be added dropwise to 31.2g (294mmol) yellow soda ash in the solution of 150ml water with ice bath.Stirred 10 minutes, 0 ℃ slowly is added dropwise to the solution that 28.9g (147mmol) 4-tert.-butylbenzene formyl chloride is dissolved in 35.0ml acetone.All the other class of operation are similar to experiment 3.1, get crude product 2-(4-tert.-butylbenzene methane amide)-4-methoxyl group-4-ketobutyric acid 20.23g at last.
Crude product 2-(4-tert.-butylbenzene methane amide)-4-methoxyl group-4-ketobutyric acid 6.3g (20.5mmol) is dissolved in the 20.8ml pyridine, adds aceticanhydride 12.5ml, and 90 ℃ were reacted 2 hours.Remove pyridine and aceticanhydride under reduced pressure, residue adds ethyl acetate 60ml, with 10.0ml 10% hydrochloric acid soln washing organic phase, and again with the 20ml washing, the washing of 20ml saturated common salt, anhydrous magnesium sulfate drying.Remove solvent under reduced pressure, residue is with sherwood oil: ethyl acetate=8: 1 is an eluent, and silica gel column chromatography is got white solid 3-(4-tert.-butylbenzene methyl nitrosourea)-4-oxopentanoie acid methyl esters 4.20g, yield: 67.1%.
3-(4-tert.-butylbenzene methyl nitrosourea)-4-oxopentanoie acid methyl esters 1.11g (3.64mmol) is dissolved in 8ml N, dinethylformamide, room temperature drips phosphorus oxychloride 1.01ml, and 90 ℃ were reacted 0.5 hour.Reaction solution is poured in the trash ice, after treating ice-out, with 3 * 15ml extracted with diethyl ether, merge organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying, with sherwood oil: ethyl acetate=8: 1 is an eluent, and silica gel column chromatography is got white solid 2-[5-methyl 2-(4-tert-butyl-phenyl)-4-oxazole] methyl acetate 0.75g.Yield: 72.1%.
With 2-[5-methyl 2-(4-tert-butyl-phenyl)-4-oxazole] methyl acetate 0.75g (2.61mmol) is dissolved in the 10ml anhydrous tetrahydro furan, and 0 ℃ is added drop-wise in the anhydrous tetrahydrofuran solution that 20ml is suspended with the 0.16g Lithium Aluminium Hydride.Dripped complete stirring at room 0.5 hour, slowly add 0.15ml (2eq) water, stir after 45 minutes, drip 1.11g (1eq) 15% sodium hydroxide solution, continue to stir 1 hour, suction filtration is removed insolubles, removes solvent under reduced pressure and gets product 2-[5-methyl-2-(the 4-tertiary butyl) phenyl-4-oxazole] ethanol 0.67g.Yield: 100%.
1HNMR(CDCl 3)：δ＝1.32(s，9H)，2.40(s，3H)，2.96(t，J＝5.96Hz，2H)，3.92(t，J＝5.96Hz，2H)，7.38(d，J＝8.38，2H)，7.94(d，J＝8.38，2H)。(7.2:7-[2-5-methyl-2-(4-tert-butyl-phenyl)-4-oxazole) oxyethyl group]-preparation of 2-oxo-2H-1-chromene-3-carboxylate methyl ester
2-[5-methyl-2-(4-tert-butyl-phenyl)-4-oxazole] ethanol 0.37g (1.44mmol), 7-hydroxyl-3-tonka bean camphor carboxylate methyl ester 0.32g (1.44mmol) is dissolved in the 60ml anhydrous tetrahydro furan, add triphenylphosphine 0.49g (1.87mmol), 0 ℃ drips diethylazodicarboxylate 0.37ml (2.45mmol) down.Stirring at room 24 hours.Remove solvent under reduced pressure, residue is separated out white solid in methyl alcohol.The gained solid is got target compound 0.45g with recrystallizing methanol, yield: 61.6%.M.P.168.0-169.0℃。
1HNMR(CDCl 3)：δ＝1.34(s，9H)，2.38(s，3H)，3.02(t，J＝6.55Hz，2H)，3.93(s，3H)，4.34(t，J＝6.88Hz，2H)，6.83(d，J＝2.18Hz，1H)，6.88(dd，J＝8.73Hz，J＝2.35Hz，1H)，7.90(d，J＝8.38，2H)，8.53(s，1H)。
Embodiment 8:7-[2-(5-methyl-2-(4-tert-butyl-phenyl)-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester (compound 18)
Compound 70.11g (0.24mmol) is dissolved in methyl alcohol: in the mixed solvent of methylene dichloride=6: 1, add 10% Pd-C 20mg, mixing, the logical hydrogen of normal pressure is till stop to inhale hydrogen, filtering Pd-C, with sherwood oil: ethyl acetate=5: 1 is an eluent, and silica gel column chromatography is got product 0.09g, yield: 81.5%.M.P.101.5-102.0℃。
1HNMR(CDCl 3)：δ＝1.33(s，9H)，2.17(s，3H)，2.97(t，J＝6.74Hz，2H)，3.11(dd，J＝15.6Hz，J＝6.70Hz，1H)，3.32(dd，J＝15.7Hz，J＝8.59Hz，1H)，3.74(m，4H)，4.21(t，J＝6.73Hz，2H)，6.62(d，J＝2.34Hz，1H)，6.66(dd，J＝8.38Hz，J＝2.48Hz，1H)，7.07(d，J＝8.25Hz，1H)，7.44(dd，J＝6.74Hz，J＝2.06Hz，2H)，7.89(dd，J＝6.73Hz，J＝1.92Hz，2H)。
Embodiment 9:7-[2-(5-methyl-2-(4-p-methoxy-phenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester (compound 5)
2-[5-methyl-2-(4-p-methoxy-phenyl)-4-oxazole] ethanol [Alexander, G.G.; Dawn.A.B.J.Org.Chem.2003,68,2623] 0.55g (2.36mmol), 7-hydroxyl-3-tonka bean camphor carboxylate methyl ester 0.52g (2.36mmol) is dissolved in the 40ml anhydrous tetrahydro furan, add triphenylphosphine 0.80g (3.05mmol), 0 ℃ drips diisopropyl azo-2-carboxylic acid 0.60ml (3.05mmol) down.Stirring at room 24 hours.Remove solvent under reduced pressure, residue is separated out white solid in methyl alcohol.The gained solid is got target compound 0.56g with recrystallizing methanol, yield: 54.5%.M.P.161.0-162.0℃。
1HNMR(CDCl 3)：δ＝2.37(s，3H)，3.01(t，J＝6.74Hz，2H)，3.85(s，3H)，3.93(s，3H)，4.34(t，J＝6.74Hz，2H)，6.83(d，J＝2.25Hz，1H)，6.88(dd，J＝8.60Hz，J＝2.34Hz，1H)，6.94(m，2H)，7.48(d，J＝8.69Hz，1H)，7.91(m，2H)，8.53(s，1H)。
Embodiment 10:7-[2-(5-methyl-2-(4-p-methoxy-phenyl)-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester (compound 19)
Compound 9 is a raw material, to be similar to the method preparation of compound 2, yield: 92.4%.M.P.132.0-133.0℃。
1HNMR(CDCl 3)：δ＝2.35(s，3H)，2.95(t，J＝6.72Hz，2H)，3.09(dd，J＝15.61Hz，J＝5.87Hz，1H)，3.36(dd，J＝15.94Hz，J＝8.56Hz，1H)，3.74(m，4H)，3.85(s，3H)，4.21(t，J＝6.72Hz，2H)，6.63(d，J＝2.52Hz，1H)，6.67(dd，J＝8.39Hz，J＝2.52Hz，1H)，6.94(m，2H)，7.07(d，J＝8.23Hz，1H)，7.91(m，2H)。
Embodiment 11:7-[2-(5-methyl-2-(3-p-methoxy-phenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester (compound 6)
2-[5-methyl-2-(3-p-methoxy-phenyl)-4-oxazole] ethanol [Alexander, G.G.; Dawn.A.B.J.Org.Chem.2003,68,2623] 0.43g (1.85mmol), 7-hydroxyl-3-tonka bean camphor carboxylate methyl ester 0.33g (1.85mmol) is dissolved in the 40ml anhydrous tetrahydro furan, add triphenylphosphine 0.63g (2.40mmol), 0 ℃ drips diisopropyl azo-2-carboxylic acid 0.48ml (2.40mmol) down.Stirring at room 24 hours.Remove solvent under reduced pressure, residue is separated out white solid in methyl alcohol.The gained solid is got target compound 0.56g with recrystallizing methanol, yield: 70.0%.M.P.142.0-143.0℃。
1HNMR(CDCl 3)：δ＝2.39(s，3H)，3.02(t，J＝6.59Hz，2H)，3.89(s，3H)，3.93(s，3H)，4.34(t，J＝6.60Hz，2H)，6.84(d，J＝2.33Hz，1H)，6.88(dd，J＝8.65Hz，J＝2.47Hz，1H)，6.96(m，1H)，7.34(t，J＝8.11Hz，1H)，7.48(s，1H)，7.50(d，J＝2.74Hz，1H)，7.56(m，1H)，8.53(s，1H)。
Embodiment 12:7-[2-(5-methyl-2-(3-p-methoxy-phenyl)-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester (compound 20)
Compound 11 is a raw material, to be similar to the method preparation of compound 2, yield: 89.6%.M.P.88.0-89.0℃。
1HNMR(CDCl 3)：δ＝2.37(s，3H)，2.97(t，J＝6.46Hz，2H)，3.09(dd，J＝15.8Hz，J＝6.04Hz，1H)，3.34(dd，J＝15.79Hz，J＝8.2Hz，1H)，3.74(m，4H)，3.87(s，3H)，4.22(t，J＝6.59Hz，2H)，6.63(d，J＝2.34Hz，1H)，6.67(dd，J＝8.37Hz，J＝2.47Hz，1H)，6.96(dd，J＝7.96Hz，J＝2.06Hz，1H)，7.08(d，J＝8.53Hz，1H)，7.33(m，1H)，7.50(s，1H)，7.57(d，J＝7.7Hz，1H)。
Embodiment 13:7-[2-(5-methyl-2-(4-chloro-phenyl-)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester (compound 7)
13.1 2-[5-methyl-2-(4-chloro-phenyl-)-4-oxazole] the alcoholic acid preparation
12.7g (75mmol) L-aspartic acid methyl ester hydrochloride is dissolved in 80ml water, is cooled to 5 ℃, be added dropwise to 15.9g (150mmol) yellow soda ash in the solution of 78ml water with ice bath.Stirred 10 minutes, 0 ℃ slowly is added dropwise to the solution that 9.64g (56.5mmol) 4-chloro-benzoyl chloride is dissolved in 40ml acetone.All the other class of operation be similar to the experiment 3.1, at last thick product 2-(4-chlorobenzamide)-4-methoxyl group-4-ketobutyric acid 20.1g.
Thick product 2-(4-chlorobenzamide)-4-methoxyl group-4-ketobutyric acid 20.1g (78.0mmol) is dissolved in the 71.4ml pyridine, adds aceticanhydride 44.1ml, 90 ℃ were reacted 2 hours.Remove unnecessary pyridine and aceticanhydride under reduced pressure, residue adds ethyl acetate 150ml, with 30ml 10% hydrochloric acid soln washing organic phase, and again with the 40ml washing, the washing of 240ml saturated common salt, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, get crude product 3-(4-chlorophenylmethyl acid amides)-4-oxopentanoie acid methyl esters 21.49g.
3-(4-chlorophenylmethyl acid amides)-4-oxopentanoie acid methyl esters 21.49g is dissolved in 150ml N, dinethylformamide, room temperature drips phosphorus oxychloride 17.2ml, and 90 ℃ were reacted 0.5 hour.Reaction solution is poured in the trash ice, after treating ice-out, with 3 * 80ml extracted with diethyl ether, merge organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying, with sherwood oil: ethyl acetate=4: 1 is an eluent, and silica gel column chromatography is got white solid 2-[5-methyl 2-(4-chloro-phenyl-)-4-oxazole] methyl acetate 3.85g.Three step yields: 19.33%.
With 2-[5-methyl 2-(4-chloro-phenyl-)-4-oxazole] methyl acetate 1.0g (3.8mmol) is dissolved in the 20ml dry toluene, and cryosel is bathed and is chilled to-15 ℃, and the Ar protection drips DIBAH (20%weight) 7.16ml down, the control rate of addition, temperature is not more than-10 ℃ in making.Dripping Bi Tongwen stirred 1 hour, 0 ℃ with the DIBALH that it is unnecessary that the 10ml shrend is gone out, stirred 20 minutes, and told water, organic phase is more respectively with 15ml water, the washing of 15ml saturated common salt once, anhydrous magnesium sulfate drying removes solvent under reduced pressure, with methylene dichloride and sherwood oil recrystallization, get product 2-[5-methyl-2-(4-chloro-phenyl-)-4-oxazole] ethanol 0.78g, yield: 87.2%.
1HNMR(CDCl 3)：δ＝2.34(s，3H)，2.73(t，J＝5.90Hz，2H)，3.92(t，J＝5.90Hz，2H)，7.41(m，2H)，7.92(m，2H)。
13.2 7-[2-(5-methyl-2-(4-chloro-phenyl-)-4-oxazole) oxyethyl group]-preparation of 2-oxo-2H-1-chromene-3-carboxylate methyl ester
2-[5-methyl-2-(4-chloro-phenyl-)-4-oxazole] ethanol 0.45g (1.90mmol), 7-hydroxyl-3-tonka bean camphor carboxylate methyl ester 0.42g (1.9mmol) is dissolved in the 40ml anhydrous tetrahydro furan, add triphenylphosphine 0.60g (2.29mmol), 0 ℃ drips diisopropyl azo-2-carboxylic acid 0.48ml (2.29mmol) down.Stirring at room 24 hours.Remove solvent under reduced pressure, residue is separated out white solid in methyl alcohol.The gained solid is got target compound 0.60g with recrystallizing methanol, yield: 74.4%.M.P.142-142.5℃。
1HNMR(CDCl 3)：δ＝2.46(s，3H)，3.02(t，J＝6.3Hz，2H)，3.93(s，3H)，4.35(t，J＝6.3Hz，2H)，6.83(d，J＝2.19Hz，1H)，6.88(dd，J＝8.5Hz，J＝2.35Hz，1H)，7.41(m，2H)，7.49(d，J＝8.65Hz，1H)，7.92(m，2H)，8.52(s，1H)。
Embodiment 14:7-[2-(5-methyl-2-(3-fluorophenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester (compound 8)
14.1 2-[5-methyl-2-(3-fluorophenyl)-4-oxazole] the alcoholic acid preparation
16.7g (98.3mmol) L-aspartic acid methyl ester hydrochloride is dissolved in 100ml water, is cooled to 5 ℃, be added dropwise to 20.84g (197mmol) yellow soda ash in the solution of 90ml water with ice bath.Stirred 10 minutes, 0 ℃ slowly is added dropwise to the solution that 15.59g (98.3mmol) 4-fluorobenzoyl chloride is dissolved in 40ml acetone.All the other class of operation are similar to experiment 3.1, at last must product 2-(3-fluorobenzamide)-4-methoxyl group-4-ketobutyric acid 20.35g.
Thick product 2-(3-fluorobenzamide)-4-methoxyl group-4-ketobutyric acid 20.35g is dissolved in the 78ml pyridine, adds aceticanhydride 47.6ml, 90 ℃ were reacted 2 hours.Remove unnecessary pyridine and aceticanhydride under reduced pressure, residue adds ethyl acetate 180ml, with 30ml 10% hydrochloric acid soln washing organic phase, and again with the 60ml washing, the washing of 60ml saturated common salt, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, get thick product 3-(3-fluorobenzene methyl nitrosourea)-4-oxopentanoie acid methyl esters 21.63g.
3-(3-fluorobenzene methyl nitrosourea)-4-oxopentanoie acid methyl esters 21.63g is dissolved in 78ml N, dinethylformamide, room temperature drips phosphorus oxychloride 23.0ml, and 90 ℃ were reacted 0.5 hour.Reaction solution is poured in the trash ice, after treating ice-out, with 3 * 60ml extracted with diethyl ether, merge organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying, with sherwood oil: ethyl acetate=4: 1 is an eluent, and silica gel column chromatography is got white solid 2-[5-methyl 2-(3-fluorophenyl)-4-oxazole] methyl acetate 2.18g.Three step yields: 8.93%.
With 2.18g 2-[5-methyl 2-(3-fluorophenyl)-4-oxazole] methyl acetate is dissolved in the 50ml anhydrous tetrahydro furan, and 0 ℃ is added drop-wise in the anhydrous tetrahydrofuran solution that 80ml is suspended with the 0.44g Lithium Aluminium Hydride.Dripped complete stirring at room 0.5 hour, slowly add 0.32ml (2eq) water, stir after 45 minutes, drip 3.10g (1eq) 15% sodium hydroxide solution, continue to stir 1 hour, suction filtration is removed insolubles, removes solvent under reduced pressure and gets product 2-[5-methyl-2-(3-fluorine) phenyl-4-oxazole] ethanol 1.87g, yield: 96.6%.
1HNMR(CDCl 3)：δ＝2.33(s，3H)，2.72(t，J＝5.76Hz，2H)，3.92(t，J＝5.76Hz，2H)，7.16(m，1H)，7.39(m，1H)，7.65(m，1H)，7.75(d，J＝7.24Hz，1H)。
(14.2:7-[2-5-methyl-2-(3-fluorophenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester
2-[5-methyl-2-(3-fluorophenyl)-4-oxazole] ethanol 0.28g (1.30mmol), 7-hydroxyl-3-tonka bean camphor carboxylate methyl ester 0.50g (1.30mmol) is dissolved in the 40ml anhydrous tetrahydro furan, add triphenylphosphine 0.40g (1.56mmol), 0 ℃ drips diisopropyl azo-2-carboxylic acid 0.30ml (1.56mmol) down.Stirring at room 24 hours.Remove solvent under reduced pressure, residue is separated out white solid in methyl alcohol.The gained solid is got target compound 0.42g with recrystallizing methanol, yield: 78.4%.M.P.179.5-180.0℃。
1HNMR(CDCl 3)：δ＝2.39(s，3H)，3.02(t，J＝6.33Hz，2H)，3.93(s，3H)，4.34(t，J＝6.33Hz，2H)，6.83(d，J＝2.2Hz，1H)，6.88(dd，J＝8.66Hz，J＝2.34Hz，1H)，7.11(m，1H)，7.39(m，1H)，7.49(d，J＝8.66Hz，1H)，7.67(m，1H)，7.77(d，J＝7.7Hz，1H)，8.53(s，1H)。
Embodiment 15:7-[2-(5-methyl-2-(3-fluorophenyl)-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester (compound 21)
Compound 14 is a raw material, to be similar to the method preparation of compound 2, yield: 90.2%.M.P.124.0-124.5℃。
1HNMR(CDCl 3)：δ＝2.38(s，3H)，2.97(t，J＝5.87Hz，2H)，3.10(dd，J＝15.65Hz，J＝8.41Hz，1H)，3.34(dd，J＝15.65Hz，J＝8.41Hz，1H)，3.74(m，4H)，4.22(t，J＝5.87Hz，2H)，6.63(d，J＝2.15Hz，1H)，7.10(m，2H)，7.40(dd，J＝13.89Hz，J＝7.83Hz，1H)，7.67(d，J＝9.59Hz，1H)，7.77(d，J＝7.63Hz，1H)。
Embodiment 16:7-[2-(5-methyl-2-(4-fluorophenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester (compound 9)
16.1 2-[5-methyl-2-(4-fluorophenyl)-4-oxazole] the alcoholic acid preparation
9.11g (57.5mmol) L-aspartic acid methyl ester hydrochloride is dissolved in 40ml water, is cooled to 5 ℃, be added dropwise to 12.2g (115mmol) yellow soda ash in the solution of 60ml water with ice bath.Stirred 10 minutes, 0 ℃ slowly is added dropwise to the solution that 9.11g (57.5mmol) 4-fluorobenzoyl chloride is dissolved in 20ml acetone.All the other class of operation be similar to the experiment 3.1, at last thick product 2-(4-fluorobenzamide)-4-methoxyl group-4-ketobutyric acid 10.68g.
Thick product 2-(4-fluorobenzamide)-4-methoxyl group-4-ketobutyric acid 10.68g is dissolved in the 41ml pyridine, adds aceticanhydride 25ml, 90 ℃ were reacted 2 hours.Remove unnecessary pyridine and aceticanhydride under reduced pressure, residue adds ethyl acetate 100ml, with 20ml 10% hydrochloric acid soln washing organic phase, again with 25ml * 2 washings, the washing of 25ml saturated common salt, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, with sherwood oil: ethyl acetate=5: 1 is an eluent, and silica gel column chromatography is got 3-(4-fluorobenzene methyl nitrosourea)-4-oxopentanoie acid methyl esters 4.13g.Two step yields: 26.9%
3-(4-fluorobenzene methyl nitrosourea)-4-oxopentanoie acid methyl esters 4.13g (15.5mmol) is dissolved in 40mlN, dinethylformamide, room temperature drips phosphorus oxychloride 4.40ml, and 90 ℃ were reacted 0.5 hour.Reaction solution is poured in the trash ice, after treating ice-out, with 3 * 50ml ethyl acetate extraction, merge organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying, with sherwood oil: ethyl acetate=8: 1 is an eluent, and silica gel column chromatography is got white solid 2-[5-methyl 2-(4-fluorophenyl)-4-oxazole] methyl acetate 2.31g.Yield: 60.0%.
With 2-[5-methyl 2-(4-fluorophenyl)-4-oxazole] methyl acetate 2.31g (9.3mmol) is dissolved in the 50ml anhydrous tetrahydro furan, and 0 ℃ is added drop-wise in the anhydrous tetrahydrofuran solution that 80ml is suspended with the 0.49g Lithium Aluminium Hydride.Dripped complete stirring at room 0.5 hour, slowly add 0.46ml (2eq) water, stir after 45 minutes, drip 3.44g (1eq) 15% sodium hydroxide solution, continue to stir 1 hour, suction filtration is removed insolubles, removes solvent under reduced pressure and gets product 2-[5-methyl-2-(4-fluorophenyl)-4-oxazole] ethanol 2.00g, yield: 97.6%.
1HNMR(CDCl 3)：δ＝2.37(s，3H)，2.70(t，J＝5.87Hz，2H)，3.90(t，J＝5.87Hz，2H)，7.08(m，2H)，7.94(m，2H)。
(16.2:7-[2-5-methyl-2-(4-fluorophenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester
2-[5-methyl-2-(4-fluorophenyl)-4-oxazole] ethanol 0.28g (1.30mmol), 7-hydroxyl-3-tonka bean camphor carboxylate methyl ester 0.50g (1.30mmol) is dissolved in the 40ml anhydrous tetrahydro furan, add triphenylphosphine 0.40g (1.56mmol), 0 ℃ drips diisopropyl azo-2-carboxylic acid 0.30ml (1.56mmol) down.Stirring at room 24 hours.Remove solvent under reduced pressure, residue is separated out white solid in methyl alcohol.The gained solid is got target compound 0.40g with recrystallizing methanol, yield: 74.7%.M.P.168.5-169.0℃。
1HNMR(CDCl 3)：δ＝2.38(s，3H)，3.02(t，J＝6.74Hz，2H)，3.93(s，3H)，4.34(t，J＝6.74Hz，2H)，6.83(d，J＝2.33Hz，1H)，6.88(dd，J＝8.66Hz，J＝2.48Hz，1H)，7.11(m，2H)，7.49(d，J＝8.67Hz，1H)，7.96(m，2H)，8.53(s，1H)。
Embodiment 17:7-[2-(5-methyl-2-(4-fluorophenyl)-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester (compound 22)
Compound 16 is a raw material, to be similar to the method preparation of compound 2, yield: 89.9%.M.P.149.0-150.0℃。
1HNMR(CDCl 3)：δ＝2.36(s，3H)，2.96(t，J＝6.59Hz，2H)，3.09(dd，J＝15.8Hz，J＝6.05Hz，1H)，2.34(dd，J＝15.93Hz，J＝8.52Hz，1H)，3.74(m，4H)，4.21(t，J＝6.59Hz，2H)，6.62(d，J＝2.48Hz，1H)，6.67(dd，J＝8.52Hz，J＝2.61Hz，1H)，7.10(m，3H)，7.96(m，2H)。
Embodiment 18:7-[2-(5-methyl-2-(3-trifluoromethyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester (compound 10)
2-[5-methyl-2-(3-trifluoromethyl)-4-oxazole] ethanol [WO 0116120] 0.53g (2.0mmol), 7-hydroxyl-3-tonka bean camphor carboxylate methyl ester 0.43g (2.0mmol) is dissolved in the 40ml anhydrous tetrahydro furan, add triphenylphosphine 0.56g (2.2mmol), 0 ℃ drips diisopropyl azo-2-carboxylic acid 0.42ml (2.2mmol) down.Stirring at room 24 hours.Remove solvent under reduced pressure, residue is separated out white solid in methyl alcohol.The gained solid is got target compound 0.59g with recrystallizing methanol, yield: 63.8%.M.P.187.5-188.0℃。
1HNMR(CDCl 3)：δ＝2.41(s，3H)，3.04(t，J＝6.19Hz，2H)，3.93(s，3H)，4.34(t，J＝6.19Hz，2H)，6.83(d，J＝2.06Hz，1H)，6.89(dd，J＝8.8Hz，J＝2.62Hz，1H)，7.50(d，J＝8.8Hz，1H)，7.57(t，J＝7.98Hz，1H)，7.66(d，J＝7.15Hz，1H)，8.16(d，J＝8.12Hz，1H)，8.24(s，1H)，8.54(s，1H)。
Embodiment 19:7-[2-(5-methyl-2-(3-trifluoromethyl)-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester (compound 23)
Compound 18 is a raw material, to be similar to the method preparation of compound 2, yield: 85.0%.M.P.118.5-119.0℃。
1HNMR(CDCl 3)：δ＝2.40(s，3H)，2.98(t，J＝6.74Hz，2H)，3.10(dd，J＝15.67Hz，J＝5.91Hz，1H)，3.34(dd，J＝15.81Hz，J＝8.66Hz，1H)，3.75(m，4H)，4.22(t，J＝6.46Hz，2H)，6.63(d，J＝2.47Hz，1H)，6.67(dd，J＝8.24Hz，J＝2.33Hz，1H)，7.08(d，J＝8.52Hz，1H)，7.57(d，J＝7.69Hz，1H)，7.66(d，J＝7.84Hz，1H)，8.16(d，J＝7.84Hz，1H)，8.24(s，1H)。
Embodiment 20:7-[2-(5-methyl-2-(4-benzyloxy phenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester (compound 11)
2-[5-methyl-2-(4-benzyloxy phenyl)-4-oxazole] ethanol [WO 0116120] 0.62g (2.00mmol), 7-hydroxyl-3-tonka bean camphor carboxylate methyl ester 0.44g (2.00mmol) is dissolved in the 40ml anhydrous tetrahydro furan, add triphenylphosphine 0.63g (2.4mmol), 0 ℃ drips diisopropyl azo-2-carboxylic acid 0.48ml (2.4mmol) down.Stirring at room 24 hours.Remove solvent under reduced pressure, residue is separated out white solid in methyl alcohol.The gained solid is got target compound 0.70g with recrystallizing methanol, yield: 68.4%.M.P.226.0-226.5℃。
1HNMR(CDCl 3)：δ＝2.36(s，3H)，3.01(t，J＝6.61Hz，2H)，3.93(s，3H)，4.33(t，J＝6.38Hz，2H)，5.11(s，2H)，6.83(d，J＝2.13，1H)，6.88(dd，J＝8.75Hz，J＝2.35Hz，1H)，7.02(d，J＝8.69Hz，2H)，7.42(m，6H)，7.91(d，J＝8.97Hz，2H)，8.53(s，1H)。
Embodiment 21:7-[2-(5-methyl-2-(4-hydroxy phenyl)-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--2H-1-chromene-3-carboxylate methyl ester (compound 12)
Compound 200.1g (0.39mmol) is dissolved in the 25ml ethyl acetate: in the mixed solvent of dioxane=1: 1, add 10%Pd-C 50mg, the logical hydrogen of normal pressure 12 hours, filtering Pd-C, remove solvent under reduced pressure, residue is separated out solid 0.09g in ethyl acetate, yield: 56.3%.M.P.229.5-230.0℃。
1HNMR(CDCl 3)：δ＝2.30(s，3H)，2.92(t，J＝6.45Hz，2H)，3.78(s，3H)，4.34(t，J＝6.46Hz，2H)，6.83(d.J＝6.85Hz，2H)，6.99(d，J＝8.61Hz，1H)，7.05(s，1H)，7.71(d，J＝8.81Hz，1H)，7.82(d，J＝8.81Hz，1H)，8.74(s，1H)，9.96(s，1H)。
Embodiment 22:7-[2-(5-methyl-2-(3-nitrophenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester (compound 13)
22.1 2-[5-methyl-2-(3-nitrophenyl)-4-oxazole] the alcoholic acid preparation
17.08g (108mmol) L-aspartic acid methyl ester hydrochloride is dissolved in 66ml water, is cooled to 5 ℃, be added dropwise to 22.9g (216mmol) yellow soda ash in the solution of 60ml water with ice bath.Stirred 10 minutes, 0 ℃ slowly is added dropwise to the solution that 18.71g (101mmol) 3-nitrobenzoyl chloride is dissolved in 40ml acetone.All the other class of operation are similar to experiment 3.1, at last must product 2-(3-nitrobenzamide)-4-methoxyl group-4-ketobutyric acid 31.1g.
Thick product 2-(3-nitrobenzamide)-4-methoxyl group-4-ketobutyric acid 31.1g is dissolved in the 106ml pyridine, adds aceticanhydride 65.6ml, 90 ℃ were reacted 2 hours.Remove unnecessary pyridine and aceticanhydride under reduced pressure, residue adds ethyl acetate 150ml, with 40ml 10% hydrochloric acid soln washing organic phase, again with 40ml * 2 washings, the washing of 40ml saturated common salt, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, with sherwood oil: ethyl acetate=5: 1,3.5: 1, be eluent at 1: 1, gradient elution, silica gel column chromatography are got 3-(3-oil of mirbane methyl acid amides)-4-oxopentanoie acid methyl esters 6.25g.Two step yields: 23.3%.
3-(3-oil of mirbane methyl acid amides)-4-oxopentanoie acid methyl esters 6.25g (21.2mmol) is dissolved in 55ml N, dinethylformamide, room temperature drips phosphorus oxychloride 6.01ml, and 90 ℃ were reacted 0.5 hour.Reaction solution is poured in the trash ice, after treating ice-out, with 3 * 40ml ethyl acetate extraction, merge organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying, with sherwood oil: ethyl acetate=6: 1 is an eluent, and silica gel column chromatography is got white solid 2-[5-methyl 2-(3-nitrophenyl)-4-oxazole] methyl acetate 4.27g.Yield: 72.78%.
With 2-[5-methyl 2-(3-nitrophenyl)-4-oxazole] methyl acetate 3.46g (12.5mmol) is dissolved in the 60ml methyl alcohol, adds 6.5ml 2N sodium hydroxide solution, back flow reaction 5 hours.Remove solvent under reduced pressure, add water 30ml, with 10%HCl conditioned reaction liquid PH=3, with 3 * 25ml ethyl acetate extraction, washing, the saturated common salt washing, anhydrous magnesium sulfate drying removes solvent under reduced pressure and gets solid 3.28g.The hydrolysis products therefrom is dissolved in the 40ml anhydrous tetrahydro furan, and under the Ar protection, 0 ℃ drips 1N borine tetrahydrofuran solution 26.4ml.Drip to finish with text response half an hour, slowly drip saturated sodium carbonate solution 40ml, remove tetrahydrofuran (THF) under reduced pressure, with 3 * 25ml ethyl acetate extraction, washing, the saturated common salt washing, anhydrous magnesium sulfate drying removes solvent under reduced pressure and gets solid 2-[5-methyl-2-(3-nitrophenyl)-4-oxazole] ethanol 2.85g.Yield: 91.7%.
1HNMR(CDCl 3)：δ＝2.40(s，3H)，2.97(t，J＝6.55Hz，2H)，4.36(t，J＝6.55Hz，2H)，7.63(t，J＝8.1Hz，1H)，8.28(m，2H)，8.80(m，1H)。
(22.2:7-[2-5-methyl-2-(3-nitrophenyl)-4-oxazole) oxyethyl group]-preparation of 2-oxo-2H-1-chromene-3-carboxylate methyl ester
2-[5-methyl-2-(3-nitrophenyl)-4-oxazole] ethanol 0.28g (1.13mmol), 7-hydroxyl-3-tonka bean camphor carboxylate methyl ester 0.25g (1.13mmol) is dissolved in the 40ml anhydrous tetrahydro furan, add triphenylphosphine 0.35g (1.36mmol), 0 ℃ drips diisopropyl azo-2-carboxylic acid 0.27ml (1.36mmol) down.Stirring at room 24 hours.Remove solvent under reduced pressure, residue is separated out white solid in methyl alcohol.The gained solid is got target compound 0.29g with recrystallizing methanol, yield: 57.1%.M.P.189.5-190.0℃。
1HNMR(CDCl 3)：δ＝2.43(s，3H)，3.04(t，J＝6.45Hz，2H)，3.93(s，3H)，4.36(t，J＝6.45Hz，2H)，6.83(d，J＝2.19Hz，1H)，6.88(dd，J＝8.66Hz，J＝2.48Hz，1H)，7.49(d，J＝8.65Hz，1H)，7.63(t，J＝8.1Hz，1H)，8.28(m，2H)，8.53(s，1H)，8.80(m，1H)。
Embodiment 23:7-[2-(4-mesyloxy phenyl) oxyethyl group]-preparation (compound 14) of 2-oxo-2H-1-chromene-3-carboxylate methyl ester
[J.Chem.Soc.Perkin.Trans.1 1980 for ethanol with 2-(4-methylsulfonic acid phenyl), 31] 0.3g (1.8mmol), 7-hydroxyl-3-tonka bean camphor carboxylate methyl ester 0.36g (1.8mmol), be dissolved in the 40ml anhydrous tetrahydro furan, add triphenylphosphine 0.62g (2.37mmol), 0 ℃ drips ethyl azodicaboxylate 0.37ml (2.37mmol) down.Stirring at room 24 hours.Remove solvent under reduced pressure, residue is separated out white solid in methyl alcohol.The gained solid is got target compound 0.35g with recrystallizing methanol, yield: 60.3%.M.P.157.5-158.0℃。
1HNMR(CDCl 3)：δ＝3.15(t，J＝7.83Hz，5H)，3.94(s，3H)，4.26(t，J＝6.59Hz，2H)，6.79(d，J＝2.34Hz，1H)，6.87(dd，J＝8.79Hz，J＝2.48Hz，1H)，7.26(d，J＝8.10Hz，2H)，7.34(d，J＝8.79Hz，2H)，8.55(s，1H)。
Embodiment 24:7-[2-(4-methylsulfonic acid phenyl) oxyethyl group]-3, the preparation (compound 24) of 4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester
Compound 23 47mg (0.12mmol) are dissolved in 40ml methyl alcohol: in the mixed solvent of methylene dichloride=2: 1, add 10% Pd-C 41mg, the logical hydrogen of normal pressure is to no longer inhaling till the hydrogen, filtering Pd-C, remove solvent under reduced pressure, residue is with ethyl acetate: sherwood oil=3: 2 is an eluent, and silica gel column chromatography is got product 30mg, yield: 63.5%.M.P.120.0-121.0℃。
1HNMR(CDCl 3)：δ＝3.11(m，6H)，3.35(q，J＝15.66Hz，J＝8.52Hz，1H)，4.14(t，J＝6.6Hz，2H)，6.63(m，2H)，7.09(d，J＝8.51Hz，1H)，7.25(m，3H)，7.32(d，J＝8.51Hz，2H)。
Embodiment 25:7-[2-(2-oxo-5,6,7,8-tetralyl) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester (compound 25)
5,6,7,8-tetralol 0.74g (5mmol) is dissolved in the analytically pure acetone of 20ml, adds 2N sodium hydroxide 2.8ml (1.1eq), reflux 2 hours, equality of temperature drips glycol dibromide 2.6ml (6eq), continues reaction 12 hours, remove solvent acetone under reduced pressure, add water, transfer pH value to neutral with 10%HCl, with 2 * 15ml extracted with diethyl ether, merge organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying, remove solvent under reduced pressure, residue is with sherwood oil: ethyl acetate=20: 1 is an eluent, and silica gel column chromatography is got 6-(2-bromine oxethyl)-1,2,3,4-tetralol 0.51g, yield: 40%.
1HNMR(CDCl 3)：δ＝1.74(m，4H)，2.79(m，4H)，3.72(t，J＝2.86Hz，2H)，4.44(t，J＝2.86Hz，2H)，6.44(dd，J＝2.35Hz，J＝8.61Hz，1H)，6.52(d，J＝2.35Hz，1H)，6.90(d，J＝8.22Hz，1H)。
7-hydroxyl-3-tonka bean camphor carboxylate methyl ester 0.36g (1.6mmol) is dissolved in 20ml analytical pure DMF, add cesium carbonate 0.64g (1.2eq), be heated to 65 ℃ of reactions 2 hours, equality of temperature drips 10m1 and is dissolved with 6-(2-bromine oxethyl)-1,2,3, the DMF solution of 4-tetralol 0.46g (1.8mmol), continue reaction 15 hours, add water 40ml,, merge organic phase with 3 * 30ml ethyl acetate extraction, washing, the saturated common salt washing, anhydrous sodium sulfate drying removes solvent under reduced pressure, residue is with sherwood oil: ethyl acetate=4: 1 is an eluent, and silica gel column chromatography is got target compound 0.3g.Yield: 36.3%.
1HNMR(CDCl 3)：δ＝1.77(m，4H)，2.72(m，4H)，3.94(s，3H)，4.33(t，J＝2.74Hz，2H)，4.39(t，J＝2.72Hz，2H)，6.66(d，J＝2.55Hz，1H)，6.71(d，J＝2.55Hz，1H)，6.88(d，J＝2.35Hz，1H)，6.95(dd，J＝2.35Hz，J＝8.61Hz，1H)，6.99(d，J＝8.22Hz，1H)，7.52(d，J＝8.80Hz，1H)，8.55(s，1H)。
Embodiment 26:7-[2-(2-oxo xenyl) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester (compound 26)
7-hydroxyl-3-tonka bean camphor carboxylate methyl ester 0.11g (0.5mmol) is dissolved in 20ml analytical pure DMF, add cesium carbonate 0.19g (1.2eq), be heated to 65 ℃ of reactions 2 hours, equality of temperature Dropwise 5 ml is dissolved with 4-(2-bromine oxethyl) biphenyl [Pharm.Pharmacol.Commun.1999,491,5] the DMF solution of 0.15g (0.55mmol) continues reaction 15 hours, adds water 40ml, with 3 * 30ml ethyl acetate extraction, merge organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying, remove solvent under reduced pressure, residue is with sherwood oil: ethyl acetate=3: 1 is an eluent, and silica gel column chromatography is got target compound 0.11g.Yield: 52.9%.
1HNMR(CDCl 3)：δ＝3.94(s，3H)，4.36(q，J＝3.3Hz，2H)，4.42(q，J＝3.3Hz，2H)，6.88(d，J＝2.38Hz，1H)，6.94(m，7H)，7.06(m，1H)，7.31(m，2H)，7.53(d，J＝8.8Hz，1H)，8.55(s，1H)。
Embodiment 27:7-[2-(2-oxo xenyl)-oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester (compound 27)
Compound 2650mg (0.12mmol) is dissolved in tetrahydrofuran (THF): in the mixed solvent of methyl alcohol=10: 1, add 10%Pd-C 5mg, the logical hydrogen of normal pressure is to no longer inhaling till the hydrogen, filtering Pd-C, remove solvent under reduced pressure, residue is with ethyl acetate: sherwood oil=6: 1 is an eluent, and silica gel column chromatography is got product 45mg, yield: 85.6%.
1HNMR(CDCl 3)：δ＝3.12(dd，J＝6.07Hz，J＝15.85Hz，1H)，3.37(dd，J＝8.61Hz，J＝16.05，1H)，3.77(m，4H)，4.30(s，3H)，6.69(d，J＝2.54Hz，1H)，6.74(dd，J＝2.54Hz，J＝8.41Hz，1H)，6.95(m，7H)，7.05(m，1H)，7.12(d，J＝8.41Hz，1H)，7.32(m，2H)。
Embodiment 28:7-[2-(4-phenoxy group phenoxy group) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester (compound 28)
7-hydroxyl-3-tonka bean camphor carboxylate methyl ester 0.11g (0.5mmol) is dissolved in 20ml analytical pure DMF, add cesium carbonate 0.19g (1.2eq), be heated to 65 ℃ of reactions 2 hours, equality of temperature Dropwise 5 ml is dissolved with 1-(2-bromine oxethyl)-4-phenoxy group benzene [Pharm.Pharmacol.Commun.1999,491,5] the DMF solution of 0.11g (0.55mmol) continues reaction 15 hours, adds water 40ml, with 2 * 15ml ethyl acetate extraction, merge organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying, remove solvent under reduced pressure, residue is with sherwood oil: ethyl acetate=3: 1 is an eluent, and silica gel column chromatography is got target compound 0.10g.Yield: 37.0%.
1HNMR(CDCl 3)：δ＝3.80(s，3H)，4.39(q，J＝2.15Hz，2H)，4.49(q，J＝2.15Hz，2H)，7.06(d，J＝8.8Hz，2H)，7.12(d，J＝2.35Hz，1H)，7.31(m，1H)，7.42(m，3H)，7.61(d，J＝8.41Hz，4H)，7.86(d，J＝8.8Hz，1H)，8.75(s，1H)。
Embodiment 29:7-[3-(4-phenoxy group phenoxy group) propoxy-]-2-oxo-2H-1-chromene-3-carboxylate methyl ester (compound 29)
7-hydroxyl-3-tonka bean camphor carboxylate methyl ester 0.18g (0.8mmol) is dissolved in 20ml analytical pure DMF, add cesium carbonate 0.32g (1.2eq), be heated to 65 ℃ of reactions 2 hours, equality of temperature Dropwise 5 ml is dissolved with 1-(3-bromine propoxy-)-4-phenoxy group benzene [Bioorg.Med.Chem.Lett.2005,15,51] the DMF solution of 0.28g (0.9mmol) continues reaction 15 hours, add water 40ml, with 2 * 15ml ethyl acetate extraction, merge organic phase, washing, the saturated common salt washing, anhydrous sodium sulfate drying removes solvent under reduced pressure, and residue is with sherwood oil: ethyl acetate=3: 1 is an eluent, silica gel column chromatography is got target compound 0.12g, is yellow solid.Yield: 37.0%.
1HNMR(CDCl 3)：δ＝2.31(m，2H)，3.94(s，3H)，4.15(t，J＝5.87Hz，2H)，4.27(t，J＝6.07Hz，2H)，6.85(d，J＝2.35Hz，1H)，6.95(m.7H)，7.02(m，1H)，7.29(m，2H)，7.52(d，J＝8.61Hz，1H)，8.55(s，1H)
Embodiment 30: biological activity determination
Adipocyte broke up to adipocyte before euglycemic agent can impel, and was index with the differentiation situation of cell, can filter out euglycemic agent specifically.Reference method [KletzeinBF.Mol.Pharm.1991,41,393], with adipocyte model before the 3T3-L1, with the index of triglyceride growing amount in the cell, formula of the present invention (I) compound is carried out the insulin-sensitizing activity evaluation as the reacting cells differentiation.
The 3T3-L1 cell cultures went down to posterity once in the DMEM that contains 10%NBS (new-born calf serum) (Dulbecco ' smodified Eagle ' s medium) nutrient solution in per 3 days.With cell transfer in 24 well culture plates, cover with back 0.5mmol/L IBMX (the fast quinoline of isobutyl-p-dimethylamino-azo-benzene, isobutylmethylxanthine) and 1 μ mol/L DEX (dexamethasone, dexamethasone) and 1.0 μ mol/L Regular Insulin handled 48 hours, what add various dose simultaneously is subjected to the reagent thing, continues to be cultured to experiment and finishes.Collecting cell with triglyceride and the protein content in the colorimetric method for determining cell, calculates after the administration increasing amount of triglyceride in the cell.
ED30 measures: each testing compound is provided with 5 dosage, is respectively 0.001,0.01,0.1,1.0 and 10 μ M, and blank and positive control are set simultaneously.Positive controls is a rosiglitazone, and the blank group is the nutrient solution that contains 0.1%DMSO.Increased value according to triglyceride level in the cell behind the various dose drug effect and protein content ratio, calculate the ED30 (3T3-L1 cellular fat content increases by 30% pairing compound concentration than DMSO control group) of testing compound, all experiments all repeat more than 3 times at least.
Embodiment 31: the preparation method who comprises the oral tablet of compound of the present invention
Compound 1-100 weight part of the present invention
Cellulose ethanoate 1-1000 weight part
Gelatin 1-50 weight part
Magnesium Stearate is an amount of
Additives such as compound of the present invention and cellulose ethanoate are mixed, use gelatin as tamanori, wet granulation, vacuum-drying.Add an amount of Magnesium Stearate and mix compressing tablet.
Embodiment 32: the capsular preparation method who comprises compound of the present invention
Compound 1-100 weight part of the present invention
Ethyl cellulose sodium 1-1000 weight part
Gelatin 1-50 weight part
Glycerine is an amount of
Stearic acid is an amount of
Additives such as this patent compound and ethyl cellulose sodium and glycerine are mixed, make wetting agent with glycerine, wet granulation, vacuum-drying.Add an amount of stearic acid and mix, make hard capsule.
The possibility of utilizing on the industry
Acceptable inorganic or organic salt on benzopyrans compounds of the present invention and the pharmacology thereof It is excellent that the preparation method has that reaction condition gentleness, abundant raw material are easy to get, operation and post processing are simple etc. Point, and toxicity of compound of the present invention is very low, has overcome the shortcoming that prior art exists. Available Medicine in the anti-type ii diabetes of preparation and complication thereof.

Claims (9)

1, a class is by acceptable inorganic or organic salt on benzopyrans compounds shown in the following formula (I) and the pharmacology thereof:
Wherein, be singly-bound or two key between 3 and 4 carbon; N=2 or 3; X is CH 2, O or S, when being singly-bound for 3,4, the configuration of 4 carbon atoms can be R type or S type or raceme;
R 1For hydrogen atom, contain substituent or do not contain the straight or branched alkyl of substituent C1-C6; Or other alkyl that is fit to;
R 2For containing substituent or not containing the straight or branched alkyl of substituent C1-C6; Or other alkyl that is fit to; Or
Aromatic group or aromatic heterocycle group;
R 3, R 4, R 5And R 6For halogen, hydroxyl, nitro, amino, trifluoromethyl, contain substituent or do not contain the straight or branched alkyl of substituting group C1-C6; Or other alkyl that is fit to; Contain substituent or do not contain the straight or branched alkoxyl group of substituting group C1-C6; Or other alkoxyl group that is fit to; Contain substituent or do not contain the substituting group phenyl; Contain substituent or do not contain the aromatic group or the aromatic heterocycle group of substituent phenoxy group.
2, compound according to claim 1, it is characterized in that, the straight or branched alkyl of described C1-C6 is a methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl, the 1-methyl butyl, the 2-methyl-propyl, hexyl, isohexyl, the 1-methyl amyl, the 2-methyl amyl, the 3-methyl amyl, the 2-methyl butyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 3-dimethylbutyl, 3, the 3-dimethylbutyl, the 1-ethyl-butyl, the 2-ethyl-butyl, 1,1,2-trimethylammonium propyl group, 1,2,2-trimethylammonium propyl group, 1-ethyl-1-methyl-propyl or 1-ethyl-2-methyl-propyl.
According to the compound of claim 1, it is characterized in that 3, described aromatic group is phenyl, tolyl, xylyl, xenyl, naphthyl, indenyl, anthryl or phenanthryl; Described aromatic heterocycle group is furyl, thienyl, pyrryl, imidazolyl, thiazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazolyl or tetrazyl.
4, according to the compound of claim 1, it is characterized in that, described substituting group be selected from comprise halogen atom, as the alkyl, alkoxyl group, acyloxy of definition in the claim 2 ,-OH ,-NH 2, NO 2One or more groups among the ,-NHAc.
According to the compound of claim 1, it is characterized in that 5, described compound is selected from following compound:
1) 7-[2-(5-methyl-2-xenyl-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
2) 7-[2-(5-methyl-2-(3-aminomethyl phenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
3) 7-[2-(5-methyl-2-(4-aminomethyl phenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
4) 7-[2-(5-methyl-2-(4-tert-butyl-phenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
5) 7-[2-(5-methyl-2-(4-p-methoxy-phenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
6) 7-[2-(5-methyl-2-(3-p-methoxy-phenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
7) 7-[2-(5-methyl-2-(4-chloro-phenyl-)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
8) 7-[2-(5-methyl-2-(3-fluorophenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
9) 7-[2-(5-methyl-2-(4-fluorophenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
10) 7-[2-(5-methyl-2-(3-trifluoromethyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
11) 7-[2-(5-methyl-2-(4-benzyloxy phenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
12) 7-[2-(5-methyl-2-(4-hydroxy phenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
13) 7-[2-(5-methyl-2-(3-nitrophenyl)-4-oxazole) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
14) 7-[2-(4-mesyloxy phenyl) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
15) 7-[2-(5-methyl-2-xenyl-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester;
16) 7-[2-(5-methyl-2-(3-aminomethyl phenyl)-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester;
17) 7-[2-(5-methyl-2-(4-aminomethyl phenyl)-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester;
18) 7-[2-(5-methyl-2-(4-tert-butyl-phenyl)-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester;
19) 7-[2-(5-methyl-2-(4-p-methoxy-phenyl)-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester;
20) 7-[2-(5-methyl-2-(3-p-methoxy-phenyl)-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester;
21) 7-[2-(5-methyl-2-(3-fluorophenyl)-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester;
22) 7-[2-(5-methyl-2-(4-fluorophenyl)-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester;
23) 7-[2-(5-methyl-2-(3-trifluoromethyl)-4-oxazole) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester;
24) 7-[2-(4-methylsulfonic acid base phenyl) oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester;
25) 7-[2-(2-oxo-5,6,7,8-tetralyl) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
26) 7-[2-(2-oxo xenyl) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
27) 7-[2-(2-oxo xenyl)-oxyethyl group]-3,4-dihydro-2-oxo--4H-1-chromene-3-carboxylate methyl ester;
28) 7-[2-(4-phenoxy group phenoxy group) oxyethyl group]-2-oxo-2H-1-chromene-3-carboxylate methyl ester;
29) 7-[3-(4-phenoxy group phenoxy group) propoxy-]-2-oxo-2H-1-chromene-3-carboxylate methyl ester.
6, a kind of method for preparing the compound of claim 1 may further comprise the steps:
1) 2,4-Dihydroxy benzaldehyde and propanedioic acid methyl esters react 7-hydroxyl-3-tonka bean camphor carboxylate methyl ester;
2) be that starting raw material prepares 2-(5-methyl-2-aryl-4-oxazole) ethanol or is that starting raw material prepares 2-(4-mesyloxy phenyl) ethanol or 2-(4-methanesulfonates) phenylethyl alcohol with the p-hydroxyphenylaceticacid so that various substituent Benzoyl chlorides to be arranged on aspartic acid methyl ester hydrochloride and the phenyl ring, identical in the substituent definition of wherein said Benzoyl chloride and the claim 4;
3) correspondent alcohol of preparation carries out the Mitsunobu reaction 7-hydroxyl-3-tonka bean camphor carboxylate methyl ester and step 2);
4) compound for catalysis reduction or the hydrogenation debenzylation in step 3), obtaining.
7, a kind of method for preparing the compound of claim 1 may further comprise the steps:
1) be starting raw material to contain substituting group or not contain substituent phenol, with 1,2-ethylene dibromide or 1,3-dibromopropane react under alkaline condition and make bromine oxethyl and contain substituting group or do not contain substituent aromatic hydrocarbon or the bromine propoxy-contains substituting group or do not contain substituent aromatic hydrocarbon;
2) 7-hydroxyl-3-tonka bean camphor carboxylate methyl ester and bromine oxethyl contain substituting group or do not contain substituent aromatic hydrocarbon or the bromine propoxy-contains substituting group or do not contain the condensation under alkaline condition of substituent aromatic hydrocarbon;
3) with step 2) in the compound for catalysis reduction that obtains.
8, a kind of pharmaceutical composition comprises the compound as at least a claim 1 to 5 of effective constituent, and described compound can be in conjunction with acceptable vehicle or carrier at least a pharmacology.
9, pharmaceutical composition according to Claim 8 is characterized in that this pharmaceutical composition is used for the treatment of type ii diabetes and complication thereof.
CNA2006100243422A 2006-03-03 2006-03-03 Benzopyran compound and its prepn and use Pending CN1810795A (en)

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