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Stereoselective synthesis of cyclic amino acids

A kind of cycloalkyl, cyanoacetate technology, applied in Summary of the invention
In the field of 000, it is possible to solve problems such as being difficult to find stereoisomers

Inactive Publication Date: 2003-04-02
WARNER-LAMBERT CO
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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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  • Stereoselective synthesis of cyclic amino acids

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0363] Example 1 (i) NCCH 2 CO 2 Et, NH 4 OAc, AcOH, toluene, reflux; (ii) PhCH 2 MgCl, THF, -78°C; (iii) KOH, ethylene glycol, 160°C; (iv) (S)-(-)-α-methylbenzylamine, EtOAc, 0°C; (v) HCl(aq ); (vi) (PhO) 2 P(O)N 3 ,Et 3 N, toluene, reflux; (vii) MeOH, toluene, reflux; (viii) RuCl 3 , NaIO 4 , CCl 4 , MeCN, H 2 O; (ix) 6N HCl, 1,4-dioxane. (E and Z)-cyano-((R)-3-methyl-1,1-cyclopentylene)-ethyl acetate

[0364](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 acetate, 9:1) to give 8.87 g (90%) of (E and Z)-cyano-((R)-3-methy...

Embodiment 2

[0372] Example 2 (i)(CH 3 ) 3 SiCHN 2 , MeOH, toluene; (ii) RuCl 3 , NaIO 4 , CCl 4 , MeCN, H 2 O; (iii) (PhO) 2 P(O)N 3 ,Et 3 N, toluene, reflux; (iv) MeOH, toluene, reflux; (v) 6N HCl, 1,4-dioxane. ((1S,3R)-1-Benzyl-3-methyl-cyclopentyl)-acetic acid methyl ester

[0373] 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 distilled off in vacuo to give 10.6 g (100%) of ((1S,3R)-1-benzyl-3-methyl-cyclopentyl)-methyl acetate; Rf (heptane-ethyl acetate, 9: 1) 0.40; IR film (cm ...

Embodiment 3

[0378] Example 3 (i)a) Oxalyl chloride, DMF, CH 2 Cl 2 ; b) t-BuOH, (i-Pr) 2 Net, CH 2 Cl 2 ; (ii) RuCl 3 , NaIO 4 , CCl 4 , MeCN, H 2 O; (iii) (CH 3 ) 3 SiCHN 2 , MeOH, toluene; (iv) CF 3 CO 2 H, CH 2 Cl 2 ;(v)(PhO) 2 P(O)N 3,Et 3 N, toluene, reflux; (vi) MeOH, toluene, reflux; (vii) 6N HCl, 1,4-dioxane. ((1S,3R)-1-Benzyl-3-methyl-cyclopentyl)-tert-butyl acetate

[0379] 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 mixture was carefully added 1,1-dimethylethanol (15 mL) foll...

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Abstract

The instant invention is a route to stereospecific 3-substituted 5-membered ring isomers of Formula (A). The final products are useful as agents in the treatment of epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, neuropathological disorders, gastrointestinal disorders such as irritable bowel syndrome (IBS), inflammation especially arthritis, sleep disorders, premenstrual syndrome, and hot flashes. The invention provides novel routes to synthesize stereoselectively analogs of gabapentin (Neurontin3) of Formulas (I), (II), (III) and (IV) wherein R is C1-C10 alkyl or C3-C10 cycloalkyl and pharmaceutically acceptable salts thereof.

Description

Background of the invention [0001] Compounds of the formula 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. [0002] U.S. Application Serial No. 09 / 485,382 filed February 8, 2000 discloses a compound of formula I or a pharmaceutically acceptable salt thereof Wherein R is hydrogen or lower alkyl; R 1 to R 8 independently selected from hydrogen, linear or branched alkyl groups 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 , where R 15 is straight or branched chain...

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
CPCC07C51/412C07C229/28C07C51/43C07B2200/07C07C271/12C07C2101/08C07C227/32C07C69/616C07C51/08C07C265/08C07C255/31C07C255/41C07C69/608C07C2601/08A61P25/00A61P25/08C07C57/46
Inventor J·S·布莱恩斯D·C·布莱克莫尔S·C·威廉姆斯
Owner WARNER-LAMBERT CO
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