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Method for the stereoselective synthesis of cyclic amino acids

A technology of cycloalkyl and cyanoacetate, applied in the direction of asymmetric synthesis, organic chemical methods, chemical instruments and methods, etc., can solve problems such as difficult to find stereoisomers

Inactive Publication Date: 2005-04-20
WARNER LAMBERT CO LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it is often difficult to find a way to prepare the beneficial stereoisomer with little or no other inactive or deleterious stereoisomer

Method used

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  • Method for the stereoselective synthesis of cyclic amino acids
  • Method for the stereoselective synthesis of cyclic amino acids
  • Method for the stereoselective synthesis of cyclic amino acids

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0602]

[0603] (i) NCCH 2 CO 2 Et, NH 4 OAc, AcOH, toluene, reflux;

[0604] (ii) PhCH 2 MgCl, THF, -78°C;

[0605] (iii) KOH, ethylene glycol, 160°C;

[0606] (iv) (S)-(-)-α-methylbenzylamine, EtOAc, 0 °C;

[0607] (v) HCl(aq);

[0608] (vi)(PhO) 2 P(O)N 3 ,Et 3 N, toluene, reflux;

[0609] (vii) MeOH, toluene, reflux;

[0610] (viii)RuCl 3 , NaIO 4 , CCl 4 , MeCN, H 2 O;

[0611] (ix) 6N HCl, 1,4-dioxane.

[0612] (E and Z)-cyano-((R)-3-methyl-1,1-cyclopentylene)-ethyl acetate

[0613] (R)-(+)-3-Methylcyclopentanone (5g, 51.0mmol), ethyl cyanoacetate (5.42mL, 51.0mmol), ammonium acetate (0.4g, 5.1mmol) and glacial acetic acid (0.58 mL, 10.2 mmol) was refluxed in toluene (30 mL) using a Dean-Stark trap. After 6 hours, the mixture was cooled and diluted with ethyl acetate (100 mL), washed with water (3 x 80 mL) and brine then dried (MgSO 4 ). The solvent was evaporated under reduced pressure. The residue was chromatographed (silica gel, heptane / ethyl...

Embodiment 2

[0653]

[0654]

[0655] (i)(CH 3 ) 3 SiCHN 2 , MeOH, toluene;

[0656] (ii) RuCl 3 , NaIO 4 , CCl 4 , MeCN, H 2 O;

[0657] (iii) (PhO) 2 P(O)N 3 ,Et 3 N, toluene, reflux;

[0658] (iv) MeOH, toluene, reflux;

[0659] (v) 6N HCl, 1,4-dioxane.

[0660] ((1S,3R)-1-Benzyl-3-methyl-cyclopentyl)-acetic acid methyl ester

[0661] Trimethylsilyldiazomethane (31.5mL of 2M hexane solution, 63mmol) was added dropwise to the stirred ((1S,3R)-1-benzyl-3-methyl- Cyclopentyl)-acetic acid (10 g, 43 mmol) in toluene (80 mL) and methanol (20 mL) and the mixture was then warmed to room temperature. The mixture was stirred for 1 hour and then the solvent was evaporated under reduced pressure. The residue was added to ethyl acetate (50 mL), washed with saturated sodium bicarbonate solution, dilute hydrochloric acid, dried (MgSO 4 ) and the solvent was evaporated in vacuo to give 10.6 g (100%) of ((1S,3R)-1-benzyl-3-methyl-cyclopentyl)-acetic acid methyl ester;

[0662] R...

Embodiment 3

[0684]

[0685]

[0686] (i)a) Oxalyl chloride, DMF, CH 2 Cl 2 ; b) t-BuOH, (i-Pr) 2 Net, CH 2 Cl 2 ;

[0687] (ii) RuCl 3 , NaIO 4 , CCl 4 , MeCN, H 2 O;

[0688] (iii)(CH 3 ) 3 SiCHN 2 , MeOH, toluene;

[0689] (iv) CF 3 CO 2 H, CH 2 Cl 2 ;

[0690] (v)(PhO) 2 P(O)N 3 ,Et 3 N, toluene, reflux;

[0691] (vi) MeOH, toluene, reflux;

[0692] (vii) 6N HCl, 1,4-dioxane.

[0693] ((1S,3R)-1-Benzyl-3-methyl-cyclopentyl)-tert-butyl acetate

[0694] Oxalyl chloride (4.14 mL, 47 mmol) was added dropwise to a stirred solution of ((1S,3R)-1-benzyl-3-methyl-cyclopentyl)-acetic acid (10 g, 43 mmol) under argon atmosphere at room temperature. in dichloromethane solution. The reaction mixture was cooled to 5°C, dimethylformamide (1 mL) was carefully added, the mixture was allowed to warm to room temperature and stirring was continued for 2 hours. The solvent was evaporated in vacuo and the residue was diluted with dichloromethane (60 mL). To the reaction m...

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Abstract

The present invention relates to a method for stereospecifically synthesizing 3-substituted 5-membered ring isomers of formula (A). The final product is useful in the treatment of epilepsy, syncope, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, neuropathological disorders, gastrointestinal disorders such as irritable bowel syndrome (IBS), Medications for inflammation especially arthritis, sleep disorders, PMS, and hot flashes. The present invention provides a method for stereoselectively synthesizing gabapentin (Neurontin) analogues of formulas (I), (II), (III) and (IV) and pharmaceutically acceptable salts thereof, wherein R is C1-C10 alkyl Or C3-C10 cycloalkyl.

Description

Background of the invention [0001] Compounds of the formula [0002] [0003] where R 1 is hydrogen or lower alkyl, and n is 4, 5 or 6. The disclosed uses are: protection against convulsions induced by thiosemicarbazide; protection against convulsions of pentylenetetrazol; encephalopathy, epilepsy, syncope, hypokinesia and cranial trauma; and improvement of brain function. The compound can be used in elderly patients. The aforementioned patents are incorporated herein by reference. [0004] U.S. Application Serial No. 09 / 485,382 filed February 8, 2000 discloses a compound of formula I or a pharmaceutically acceptable salt thereof [0005] [0006] Wherein R is hydrogen or lower alkyl; R 1 to R 8 independently selected from hydrogen, straight or branched chain alkyl of 1 to 6 carbon atoms, phenyl, benzyl, fluorine, chlorine, bromine, hydroxyl, hydroxymethyl, amino, aminomethyl, trifluoromethyl 、-CO 2 H, -CO 2 R 15 、-CH 2 CO 2 H, -CH 2 CO 2 R 15 , -OR 15 , ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/20C07B53/00C07B57/00C07B61/00C07C51/08C07C51/347C07C51/353C07C51/377C07C51/41C07C51/43C07C53/134C07C57/46C07C69/608C07C69/616C07C227/32C07C227/34C07C229/28C07C255/31C07C255/41C07C265/08C07C271/12
CPCC07B2200/07C07C51/08C07C51/412C07C51/43C07C69/608C07C69/616C07C227/32C07C229/28C07C255/31C07C255/41C07C265/08C07C271/12C07C2601/08A61P25/00A61P25/08C07C57/46
Inventor J·S·布莱恩斯D·C·布莱克莫尔S·C·威廉姆斯
Owner WARNER LAMBERT CO LLC
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