CN113214255B - Synthesis method of 2, 6-diazaspiro [3.5] nonane-6-tert-butyl formate and salt thereof - Google Patents
Synthesis method of 2, 6-diazaspiro [3.5] nonane-6-tert-butyl formate and salt thereof Download PDFInfo
- Publication number
- CN113214255B CN113214255B CN202110434953.9A CN202110434953A CN113214255B CN 113214255 B CN113214255 B CN 113214255B CN 202110434953 A CN202110434953 A CN 202110434953A CN 113214255 B CN113214255 B CN 113214255B
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- reaction solvent
- solvent
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 150000003839 salts Chemical class 0.000 title claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 title abstract description 5
- 238000001308 synthesis method Methods 0.000 title description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 26
- 229940125782 compound 2 Drugs 0.000 claims abstract description 17
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 16
- 229940125904 compound 1 Drugs 0.000 claims abstract description 15
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 13
- 229940126214 compound 3 Drugs 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- 239000003513 alkali Substances 0.000 claims abstract description 9
- 229940125898 compound 5 Drugs 0.000 claims abstract description 9
- 125000006239 protecting group Chemical group 0.000 claims abstract description 6
- 230000009471 action Effects 0.000 claims abstract description 5
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims abstract description 4
- 238000006467 substitution reaction Methods 0.000 claims abstract description 4
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical group [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- KQPABIHNWDOPIY-UHFFFAOYSA-N tert-butyl 2,6-diazaspiro[3.5]nonane-6-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNC1 KQPABIHNWDOPIY-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 4
- -1 lithium aluminum hydride Chemical group 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 3
- 230000003321 amplification Effects 0.000 abstract description 2
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 2
- 230000035484 reaction time Effects 0.000 description 17
- 239000000243 solution Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 238000004809 thin layer chromatography Methods 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000007858 starting material Substances 0.000 description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- 125000001033 ether group Chemical group 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- IXMOEAHDRKNAAG-UHFFFAOYSA-N 1-benzhydrylazetidine-3-carbonitrile Chemical compound C1C(C#N)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 IXMOEAHDRKNAAG-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application discloses a method for synthesizing 2, 6-diazaspiro [3.5] nonane-6-tert-butyl formate, which comprises the following steps: the first step, the compound 1 is subjected to substitution reaction with 1-bromo-3-chloropropane under the action of inert atmosphere, a first reaction solvent and alkali to obtain a compound 2; step two, the compound 2 is reduced by a reducing agent in an inert atmosphere and a second reaction solvent, and then automatically undergoes intramolecular cyclization reaction to obtain a compound 3; thirdly, the compound 3 is subjected to Boc protecting group lifting in a third reaction solvent to obtain a compound 4; fourth, the compound 4 is hydrogenated to remove the protecting group, and the compound 5 is obtained. The method has the advantages of easily obtained raw materials, convenient operation, safe reaction, easy control, suitability for amplification, short route, higher overall yield, suitability for industrial production and the like.
Description
Technical Field
The application relates to the field of chemical synthesis methods, in particular to a synthesis method of 2, 6-diazaspiro [3.5] nonane-6-tert-butyl formate and salts thereof.
Background
The compound tert-butyl 2, 6-diazaspiro [3.5] nonane-6-carboxylate (CAS: 885272-17-3) and related derivatives have wide application in pharmaceutical chemistry and organic synthesis. At present, the synthesis method of the 2, 6-diazaspiro [3.5] nonane-6-carboxylic acid tert-butyl ester is rarely reported in the literature.
Therefore, a synthetic method which has the advantages of easily available raw materials, convenient operation, easy control of reaction and proper overall yield and is suitable for industrial production needs to be developed.
Disclosure of Invention
The application aims to solve the technical problem of providing a method for synthesizing 2, 6-diazaspiro [3.5] nonane-6-tert-butyl formate or a salt thereof, which has the advantages of easily available raw materials, convenient operation, safe reaction, easy control, suitability for amplification, short route, higher overall yield, suitability for industrial production and the like.
In order to solve the technical problems, the application provides the following technical scheme:
a method for synthesizing 2, 6-diazaspiro [3.5] nonane-6-carboxylic acid tert-butyl ester, which comprises the following steps:
the first step, the compound 1 is subjected to substitution reaction with 1-bromo-3-chloropropane under the action of inert atmosphere, a first reaction solvent and alkali to obtain a compound 2;
step two, the compound 2 is reduced by a reducing agent in an inert atmosphere and a second reaction solvent, and then automatically undergoes intramolecular cyclization reaction to obtain a compound 3;
thirdly, the compound 3 is subjected to Boc protecting group lifting in a third reaction solvent to obtain a compound 4;
step four, the compound 4 is catalyzed and hydrogenated to remove the protecting group, and the compound 5, namely the 2, 6-diazaspiro [3.5] nonane-6-carboxylic acid tert-butyl ester is obtained;
the reaction formula is as follows:
wherein,,
the first reaction solvent is selected from any one or more of anhydrous tetrahydrofuran, methyl tertiary butyl ether, N-dimethylformamide or toluene;
the base is selected from lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, or sodium hydride;
the second reaction solvent is selected from any one or more of anhydrous tetrahydrofuran, methyl tertiary butyl ether or toluene;
the reducing agent is selected from lithium aluminum hydride;
the third reaction solvent is selected from any one or more of methanol, ethanol, isopropanol, tertiary butanol, methylene dichloride, ethyl acetate, tetrahydrofuran, methyl tertiary butyl ether, toluene or N, N-dimethylformamide;
the catalyst for catalytic hydrogenation is a palladium catalyst;
the fourth reaction solvent is selected from any one or more of methanol, ethanol, tetrahydrofuran or toluene.
Specifically, the synthesis method further comprises the following steps:
and fifthly, mixing the compound 5 obtained in the fourth step with acid in an organic solvent, stirring for reaction, and separating out salt of the compound 5.
Specifically, in the first step, the hydrogen protons of carbon atoms where cyano groups are located are removed from the compound 1 at the temperature of-80 ℃ to 0 ℃ under the action of alkali, then 1-bromo-3-chloropropane is dropwise added at the temperature of-20 ℃ to 10 ℃, and then the reaction is stirred at the temperature of-10 ℃ to 25 ℃.
Preferably, the base is lithium diisopropylamide. Lithium diisopropylamide may be prepared from diisopropylamine and n-butyllithium, then compound 1 is added.
Specifically, in the first step, 1-bromo-3-chloropropane is added dropwise while stirring for reaction.
Specifically, in the first step, the feeding mole ratio of the compound 1 to the alkali to the 1-bromo-3-chloropropane is 1: (1-3): (1-10); preferably, the feeding mole ratio of the compound 1, the alkali and the 1-bromo-3-chloropropane is 1: (1.05-2): (1.05-5); more preferably, the molar ratio of the compound 1, the alkali and the 1-bromo-3-chloropropane is 1: (1.1-1.5): (1.1-2).
Preferably, in the first step, when the compound 1 is reacted with a base, the reaction temperature is-80 ℃ to-20 ℃; more preferably, the reaction temperature is from-80℃to-50 ℃.
Specifically, in the first step, the reaction time of the compound 1 and the alkali is 30-90 min; preferably, the reaction time is 45 min-75 min; more preferably, the reaction time is 60 minutes.
Preferably, in the first step, when 1-bromo-3-chloropropane is added dropwise, the reaction temperature is controlled to be between-10 ℃ and 5 ℃; more preferably, the reaction temperature is from 0℃to 5 ℃.
Preferably, in the first step, after the 1-bromo-3-chloropropane is completely added, the reaction temperature is controlled to be 0-25 ℃; more preferably, the reaction temperature is 10℃to 25 ℃.
Specifically, in the first step, after adding 1-bromo-3-chloropropane, the reaction time is 1-24 hours; preferably, the reaction time is 2 to 20 hours; more preferably, the reaction time is from 4 to 16 hours. The reaction time can be monitored by TLC.
Preferably, the first reaction solvent is selected from anhydrous tetrahydrofuran.
Specifically, in the second step, a reducing agent is added into the solution of the second reaction solvent of the compound 2, the reaction temperature is controlled to be-20 ℃ to 5 ℃, and the reaction is stirred.
Specifically, in the second step, the feeding molar ratio of the compound 2 to the reducing agent is 1: (1-5); preferably, the molar ratio of compound 2 to reducing agent is 1: (1.1-3); more preferably, the molar ratio of compound 2 to reducing agent is 1: (1.1-1.5).
Specifically, in the second step, the reaction temperature is-10-5 ℃; more preferably, the reaction temperature is from 0℃to 5 ℃.
Specifically, in the second step, the reaction time is 1-12 h; preferably, the reaction time is 2 to 8 hours; more preferably, the reaction time is 2 to 4 hours. The reaction time can be monitored by TLC.
Preferably, the second reaction solvent is anhydrous tetrahydrofuran.
Specifically, in the third step, boc is added 2 O is added into the solution of the third reaction solvent of the compound 3, and the reaction is stirred at 10-35 ℃.
Specifically, in the third step, compound 3 and Boc 2 The feeding mole ratio of O is 1: (1-5); preferably, the molar ratio of compound 2 to reducing agent is 1: (1.1-3); more preferably, the molar ratio of compound 2 to reducing agent is 1: (1.2-2).
Preferably, in the third step, the reaction temperature is 20 ℃ to 30 ℃.
Specifically, in the third step, the reaction time is 1-12 h; preferably, the reaction time is 2 to 6 hours. The reaction time can be monitored by TLC.
Preferably, the third reaction solvent is methanol or ethanol.
Specifically, in the fourth step, the compound 4 is subjected to catalytic hydrogenation reaction under the hydrogen pressure of 20-100 psi and the temperature of 20-50 ℃.
Preferably, in the fourth step, acetic acid is added to the reaction system for activation reaction.
Specifically, the palladium catalyst is 2% -10% palladium carbon; preferably, the palladium catalyst is 5% palladium on carbon.
Preferably, the palladium catalyst is used in an amount of 5 to 20% of the mass of the compound 4; more preferably, the palladium catalyst is used in an amount of 5 to 10% by mass of the compound 4.
Specifically, in the fourth step, the reaction time is 1-24 hours; preferably, the reaction time is from 4 to 20 hours. The reaction time can be monitored by TLC.
Preferably, the fourth reaction solvent is methanol or ethanol.
Specifically, in the fifth step, the acid is selected from hydrogen chloride, hydrogen bromide, acetic acid, maleic acid, citric acid, or fumaric acid; the organic solvent is selected from methanol, ethanol, methylene dichloride, ethyl acetate, methyl tertiary butyl ether or tetrahydrofuran. Preferably, in the fifth step, the acid and the organic solvent are hydrochloric acid methanol solution.
In the present application, the inert atmosphere means that the reaction is performed under the protection of nitrogen or inert gas (such as helium, argon, etc.).
Chinese paraphrasing, partially abbreviated in this application: TLC, thin layer chromatography; boc 2 O is di-tert-butyl dicarbonate.
The beneficial effects of the application include:
1) The application adopts the raw materials of 1-benzhydryl-3-cyano azetidine and 1-bromo-3-chloropropane which are cheap and easy to obtain to prepare the target product, thus saving the cost of raw materials.
2) The application has reasonable reaction process design, obtains the 2, 6-diazaspiro [3.5] nonane-6-carboxylic acid tert-butyl ester through four-step reaction synthesis, and has short synthetic route and higher yield.
3) In the second step, the cyano reduction reaction and the intramolecular cyclization reaction are completed through one-step reaction, and the reaction design is ingenious.
Detailed Description
The following description of the present application will be made clearly and fully, and it is apparent that the embodiments described are some, but not all, of the embodiments of the present application. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application.
Example 1
The first step: diisopropylamine (183 g,1.81 mol) was added dropwise to an n-heptane solution of n-butyllithium (605 ml,2.5M,1.51 mol) at-50℃and stirred at-50℃for 0.5 h. A solution of Compound 1 (250 g,1.01 mol) in tetrahydrofuran (1000 mL) was added dropwise, and 1-bromo-3-chloropropane (189 g,1.20 mol) was added dropwise to the mixture, and the reaction was resumed at room temperature for 16 hours. TLC (petroleum ether/ethyl acetate=5/1) showed complete reaction, the reaction solution was washed with water (500 mL) and saturated brine (500 mL), and the organic phase was separated, dried over anhydrous sodium sulfate and concentrated to give compound 2 (200 g, 61%) as a white solid.
And a second step of: a solution of Compound 2 (162 g,0.498 mol) in tetrahydrofuran (1000 mL) was added dropwise to lithium aluminum hydride (23 g,0.606 mol) in tetrahydrofuran (1500 mL) at-50℃and the mixture was stirred for 16hrs after returning to room temperature. TLC (petroleum ether/ethyl acetate=4/1) monitored the completion of the starting material reaction. The reaction was quenched by the addition of aqueous sodium hydroxide (23 g, 15%). Filtration, filter cake in ethanol (1000 mL) after soaking, combined filtrate concentrated to obtain compound 3 (128 g) crude product.
And a third step of: boc was added to a solution of Compound 3 (100 g) in methanol (305 mL) at room temperature 2 O (79.27 g), stirred at room temperature for 2 hours. TLC (dichloromethane/methanol=10/1) monitored the completion of the starting material reaction. The reaction solution was concentrated and purified by column chromatography (silica, petroleum ether/ethyl acetate=100/1-50/1) to give compound 4 (97 g, 72.7%) as a white solid.
Fourth step, at N 2 To a solution of Compound 4 (80 g,0.203 mol) in ethanol (700 mL) was added a solution of palladium on carbon (10 g) and acetic acid (36 g) in ethanol (100 mL) under protection, and H was replaced 2 Heating to 50 ℃, at H 2 (50 psi) for 16 hours. TLC (Petroleum ether/ethyl acetate)=6/1) the completion of the reaction of the starting materials was monitored. The reaction solution was cooled, filtered, concentrated, added with 10% aqueous hydrochloric acid (150 mL), extracted with methyl tertiary ether (50 ml×3), the aqueous phase was separated, ph=10 was adjusted, the organic phase was dried over anhydrous sodium sulfate, and most of the solvent was removed by concentration to give compound 5. Then, diluted HCl/EtOAc (0.4M diluted with methyl tertiary ether) was added directly, the solid was stirred out, filtered and dried to give the hydrochloride salt of compound 5 (40 g,75% yield) as a white solid.
Example two
The first step: sodium hydride (2.42 g,60%,60.41 mmol) was added to a solution of compound 1 (10 g,40.27 mmol) in tetrahydrofuran (100 mL) at 0deg.C and stirred at 0deg.C for 0.5 h. 1-bromo-3-chloropropane (7.61 g,48.32 mmol) was added dropwise and the reaction was resumed at room temperature for 16 hours. TLC (petroleum ether/ethyl acetate=5/1) showed that a small amount of starting material remained, the reaction mixture was quenched with saturated ammonium chloride (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was separated, dried over anhydrous sodium sulfate and concentrated to give compound 2 (10 g) as a white solid.
Example III
And a third step of: boc was added to a solution of Compound 3 (10 g) in ethyl acetate (50 mL) at room temperature 2 O (7.9 g), stirring at room temperature for 16 hours. TLC (dichloromethane/methanol=10/1) monitored the completion of the starting material reaction. The reaction solution was concentrated and purified by column chromatography (silica, petroleum ether/ethyl acetate=100/1-50/1) to give compound 4 (9 g, 67.1%) as a white solid.
In summary, the above embodiments are only preferred embodiments of the present application, and are not intended to limit the scope of the present application, but any modifications, equivalent substitutions, improvements, etc. within the spirit and principle of the present application should be included in the scope of the present application.
Claims (11)
1. A method for synthesizing 2, 6-diazaspiro [3.5] nonane-6-carboxylic acid tert-butyl ester, which is characterized by comprising the following steps:
the first step, the compound 1 is subjected to substitution reaction with 1-bromo-3-chloropropane under the action of inert atmosphere, a first reaction solvent and alkali to obtain a compound 2;
step two, the compound 2 is reduced by a reducing agent in an inert atmosphere and a second reaction solvent, and then automatically undergoes intramolecular cyclization reaction to obtain a compound 3;
thirdly, the compound 3 is subjected to Boc protecting group lifting in a third reaction solvent to obtain a compound 4;
step four, the compound 4 is subjected to catalytic hydrogenation in a fourth reaction solvent to remove a protecting group, so as to obtain a compound 5;
the reaction formula is as follows:
wherein,,
the first reaction solvent is selected from any one or more of anhydrous tetrahydrofuran, methyl tertiary butyl ether, N-dimethylformamide or toluene;
the base is selected from lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, or sodium hydride;
the second reaction solvent is selected from any one or more of anhydrous tetrahydrofuran, methyl tertiary butyl ether, N-dimethylformamide or toluene;
the reducing agent is selected from lithium aluminum hydride;
the third reaction solvent is selected from any one or more of methanol, ethanol, isopropanol, tertiary butanol, methylene dichloride, ethyl acetate, tetrahydrofuran, methyl tertiary butyl ether, toluene or N, N-dimethylformamide;
the catalyst for catalytic hydrogenation is a palladium catalyst;
the fourth reaction solvent is selected from any one or more of methanol, ethanol, tetrahydrofuran or toluene.
2. The method as recited in claim 1, further comprising:
and fifthly, mixing the compound 5 obtained in the fourth step with an organic solvent of acid to obtain a salt of the compound 5.
3. The method according to claim 1 or 2, wherein in the first step, the hydrogen proton of the carbon atom where the cyano group is located is removed from the compound 1 at-80 ℃ to 0 ℃ under the action of alkali, 1-bromo-3-chloropropane is added dropwise at-20 ℃ to 10 ℃, and then the reaction is stirred at-10 ℃ to 25 ℃.
4. A process according to claim 3, wherein in the first step, the molar ratio of the compound 1, the base and the 1-bromo-3-chloropropane is 1: (1-3): (1-10).
5. A process according to claim 3, wherein in the first step, the reaction temperature is-80 ℃ to-20 ℃ when compound 1 is reacted with a base.
6. The method according to claim 1 or 2, wherein in the second step, a reducing agent is added to the solution of the second reaction solvent of the compound 2, the reaction temperature is controlled to-20 ℃ to 5 ℃, and the reaction is stirred.
7. The method of claim 6, wherein in the second step, the molar ratio of compound 2 to reducing agent is 1: (1-5).
8. The method according to claim 1 or 2, wherein in the third step, boc is added 2 O is added into the solution of the third reaction solvent of the compound 3, and the reaction is stirred at 10-35 ℃.
9. The method of claim 8, wherein in the third step, compound 3 is reacted with Boc 2 The feeding mole ratio of O is 1: (1-5).
10. The process according to claim 1 or 2, wherein in the fourth step, compound 4 is catalytically hydrogenated at a hydrogen pressure of 20 to 100psi and a temperature of 20 to 50 ℃.
11. The method of claim 2, wherein in the fifth step, the acid is selected from hydrogen chloride, hydrogen bromide, acetic acid, maleic acid, citric acid, or fumaric acid; the organic solvent is selected from methanol, ethanol, methylene dichloride, ethyl acetate, methyl tertiary butyl ether or tetrahydrofuran.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110434953.9A CN113214255B (en) | 2021-04-22 | 2021-04-22 | Synthesis method of 2, 6-diazaspiro [3.5] nonane-6-tert-butyl formate and salt thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110434953.9A CN113214255B (en) | 2021-04-22 | 2021-04-22 | Synthesis method of 2, 6-diazaspiro [3.5] nonane-6-tert-butyl formate and salt thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113214255A CN113214255A (en) | 2021-08-06 |
| CN113214255B true CN113214255B (en) | 2023-09-29 |
Family
ID=77088387
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110434953.9A Active CN113214255B (en) | 2021-04-22 | 2021-04-22 | Synthesis method of 2, 6-diazaspiro [3.5] nonane-6-tert-butyl formate and salt thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113214255B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101081851A (en) * | 2006-05-30 | 2007-12-05 | 上海药明康德新药开发有限公司 | Preparation method of alpha-aza toroid drug template |
| CN102791715A (en) * | 2009-12-31 | 2012-11-21 | 西班牙国家癌症研究中心 | Tricyclic compounds for use as kinase inhibitors |
| CN108456208A (en) * | 2017-02-22 | 2018-08-28 | 广州市恒诺康医药科技有限公司 | Aza toroid compound and its preparation method and application |
| CN111620869A (en) * | 2020-05-20 | 2020-09-04 | 上海合全药物研发有限公司 | Synthesis method of tert-butyl-1, 7-diazaspiro [3.5] nonane-1-formylester |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2727914A1 (en) * | 2008-06-19 | 2009-12-23 | Banyu Pharmaceutical Co., Ltd. | Spirodiamine-diaryl ketoxime derivative technical field |
-
2021
- 2021-04-22 CN CN202110434953.9A patent/CN113214255B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101081851A (en) * | 2006-05-30 | 2007-12-05 | 上海药明康德新药开发有限公司 | Preparation method of alpha-aza toroid drug template |
| CN102791715A (en) * | 2009-12-31 | 2012-11-21 | 西班牙国家癌症研究中心 | Tricyclic compounds for use as kinase inhibitors |
| CN108456208A (en) * | 2017-02-22 | 2018-08-28 | 广州市恒诺康医药科技有限公司 | Aza toroid compound and its preparation method and application |
| CN111620869A (en) * | 2020-05-20 | 2020-09-04 | 上海合全药物研发有限公司 | Synthesis method of tert-butyl-1, 7-diazaspiro [3.5] nonane-1-formylester |
Non-Patent Citations (2)
| Title |
|---|
| David Orain等.Synthesis of Orthogonally Protected 2,6-Diazaspiro[3.5]nonane and 2,6-Diazaspiro[3.4]octane Analogues as Versatile Building Blocks in Medicinal Chemistry.Synlett.2015,第26卷1815-1818. * |
| 李永等.7- 苄基- 1，7- 二氮螺［4．4］壬烷- 1- 羧酸叔丁酯的合成.化学试剂.2018,第40卷(第1期),93-96. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113214255A (en) | 2021-08-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2018260728B2 (en) | Process for the preparation of deuterated ethanol from D2 | |
| EA002499B1 (en) | Process for preparing a protected 4-aminomethyl-pyrrolidin-3-one and process for producing 3-aminomethyl-4-methoxyiminopyrrolidine hydroxychloride | |
| KR100691735B1 (en) | New process for preparing 4-aminomethyl-3-alkoxyiminopyrrolidine methanesulphonate | |
| CN113214255B (en) | Synthesis method of 2, 6-diazaspiro [3.5] nonane-6-tert-butyl formate and salt thereof | |
| JP2008515952A (en) | Method for synthesizing 4- (3-sulfonylphenyl) -piperidine | |
| CN111533745A (en) | Process for preparing tert-butyl-3- (aminomethyl) dihydro-5H-triazolodiazepine-8 (9H) -carboxylic acid ester | |
| CN111892599B (en) | Synthesis method of 2,5-diazabicyclo [2.2.2] octane-2-tert-butyl carboxylate | |
| CN116396298A (en) | Intermediate XII of CDK bond-1 and preparation method of CDK bond-1 | |
| CN111548356B (en) | Process for preparing tert-butyl-1, 8-dioxa-4, 11-diazaspiro [5.6] dodecane-11-carboxylic acid ester | |
| US5099067A (en) | Use of ammonium formate as a hydrogen transfer reagent for reduction of chiral nitro compounds with retention of configuration | |
| CN113200997B (en) | Synthesis method of 2, 5-dioxa-8-azaspiro [3.5] nonane and salt thereof | |
| CN113214290B (en) | Synthesis method of 2, 5-dioxa-8-azaspiro [3.5] nonane and salt thereof | |
| CA1037047A (en) | 2-hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-t-butylaminoethyl)pyridine preparation and intermediate compounds | |
| KR101299720B1 (en) | A novel process for preparing 3-amino-5-fluoro-4-dialkoxypetanoic acid ester | |
| CN113214291B (en) | Synthesis method of octahydro-4A, 8-epoxy pyrido [4,3-C ] azepine-6 (5H) -tert-butyl formate | |
| CN113149891B (en) | Preparation method of 2-amino-2- (1-methyl-4-piperidinyl) ethanol | |
| CN110545912A (en) | Method for preparing deuterated ethanol from D2O | |
| CN113121537A (en) | Synthesis method of 2, 8-diazaspiro [4.5] decane-8-tert-butyl formate | |
| CN113234085A (en) | Synthesis method of 2-oxa-6-azaspiro [3.4] octane-8-yl tert-butyl carbamate | |
| CN113387883A (en) | Catalytic synthesis method of 8-substituted quinoline compound | |
| JPS6251946B2 (en) | ||
| KR100574343B1 (en) | Process for preparation of chiral 4-hydroxy-2-piperidinone | |
| CN113816955A (en) | RET kinase inhibitor intermediate and preparation method thereof | |
| CN115521238A (en) | Preparation method of N-methyl-2- (2-chloroethyl) pyrrolidine | |
| CN117510416A (en) | Preparation method of (2R, 5S) -4-Boc-2, 5-dimethylpiperazine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20211215 Address after: 214029 No. 8, Xinrui Road, Xinwu District, Wuxi City, Jiangsu Province Applicant after: WUXI HEQUAN MEDICINE Co.,Ltd. Applicant after: WUXI APPTEC (TIANJIN) CO.,LTD. Address before: 214028 No. 8 Xinrui Road, Xinwu District, Wuxi City, Jiangsu Province Applicant before: WUXI HEQUAN MEDICINE Co.,Ltd. |
|
| TA01 | Transfer of patent application right | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |