Preparation of pregabalin and related compounds

A technology of compounds and hydrates, applied in the field of γ-amino acids with binding affinity, can solve problems such as increased capital costs, difficulties in preparing bisphosphine ligands, and increased costs

Active Publication Date: 2011-06-22
厄普约翰美国1有限责任公司
View PDF16 Cites 8 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The process discussed in U.S. Patent Application No. 2003 / 0212290A1 represents a commercially viable process for the preparation of pregabalin, but for various reasons, further improvements may be required
For example, it is often difficult to prepare bisphosphine ligands, including the proprietary ligand (R,R)-Me-DUPHOS, because they have 2 chiral centers, which increases their cost
Moreover, asymmetric hydrogenation requires the use of H 2 special equipment, which increases the capital cost

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation of pregabalin and related compounds
  • Preparation of pregabalin and related compounds
  • Preparation of pregabalin and related compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0210] Example 1. Generation of (3S)-3-cyano by enzymatic hydrolysis of (R / S)-3-cyano-2-ethoxycarbonyl-5-methyl-hexanoic acid ethyl ester (Formula 20) -2-Ethoxycarbonyl-5-methyl-hexanoic acid (Formula 21), for enzyme screening

[0211]

[0212] Enzyme screening was carried out using a screening kit comprising individual enzymes placed in separate wells of a 96-well plate previously prepared according to D. Yazbeck et al., Synth. Catal. 345: 524-32 (2003). Prepared by the method described. Each well has a void volume of 0.3ml (shallow well plate). One well of the 96-well plate contains only phosphate buffer (10 μL, 0.1M, pH 7.2), the other well contains only ACN (10 μL), and the remaining Each well contained one of the 94 enzymes listed in Table 2 (10 μL, 100 mg / mL). Before use, remove the screening kit from -80°C storage and allow the enzyme to thaw at room temperature for approximately 5 minutes. Using a multichannel pipette, potassium phosphate buffer (85 μL, 0.1 M, pH...

Embodiment 2

[0216] Example 2. Enzymatic resolution of (R / S)-3-cyano-2-ethoxycarbonyl-5-methyl-hexanoic acid ethyl ester (Formula 20) to generate (3S)-3-cyano- 2-Ethoxycarbonyl-5-methyl-hexanoic acid potassium salt (Formula 23) and (R)-3-cyano-2-ethoxycarbonyl-5-methyl-hexanoic acid ethyl ester (Formula 22)

[0217]

[0218] A reactor (392 L) equipped with overhead stirring was loaded with potassium phosphate buffer (292.2 L, 10 mM, pH 8.0) and 100L, EX type (3.9L). The mixture was stirred at 800 RPM for 1 min and KOH (2M) was added to adjust the pH to 8.0. Add (R / S)-3-cyano-2-ethoxycarbonyl-5-methyl-hexanoic acid ethyl ester (formula 20, 100kg), and during the hydrolysis, titrate the obtained with NaOH aqueous solution (50%) The mixture was maintained at pH 8.0. by HPLC (C 18 Column, 4.6mm x 150mm, detection at 200nm), monitors the extent of the reaction. After reaching about 40-45% conversion (eg, after about 24 h), the reaction mixture was transferred to a separatory funnel. T...

Embodiment 3

[0219] Example 3. Enzymatic resolution of (R / S)-3-cyano-2-ethoxycarbonyl-5-methyl-hexanoic acid ethyl ester (Formula 20) to generate (3S)-3-cyano- 2-Ethoxycarbonyl-5-methyl-hexanoic acid potassium salt (Formula 23) and (R)-3-cyano-2-ethoxycarbonyl-5-methyl-hexanoic acid ethyl ester (Formula 22)

[0220] A reactor (3.92 L) equipped with overhead stirring was loaded with calcium acetate buffer (1.47 L, 100 mM, pH 7.0) and (R / S)-3-cyano-2-ethoxycarbonyl-5-methyl- Ethyl hexanoate (Formula 20, 1 kg). The mixture was stirred at 1100 RPM for 5 minutes and KOH (5M) was added to adjust the pH to 7.0. join in 100 L, type EX (75 mL), during the hydrolysis, the resulting mixture was titrated with KOH (5M), maintaining pH 7.0. by HPLC (C 18 Column, 4.6mm x 150mm, detection at 200nm), monitors the extent of the reaction. After reaching about 42% to 45% conversion (eg, after about 20-25 h), the reaction mixture was transferred to a separatory funnel. The aqueous mixture was extracted ...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

Materials and methods for preparing (S)-(+)-3-aminomethyl-5-methyl-hexanoic acid and structurally related compounds via enzymatic kinetic resolution are disclosed.

Description

[0001] This application is a divisional application of the patent application with the application number 200580020494.9, the application date is June 9, 2005, and the invention title is "Pregabalin and Related Compounds". technical field [0002] The present invention relates to methods and materials for the preparation of enantiomerically-enriched γ-amino acids by enzymatic kinetic resolution, especially for the preparation of 2 Binding affinity of delta calcium channel subunits for gamma-amino acids, including pregabalin and related compounds. Background technique [0003] Pregabalin, (S)-(+)-3-aminomethyl-5-methyl-hexanoic acid, is associated with the endogenous inhibitory neurotransmitter gamma-aminobutyric acid (GABA), which is involved in cranial nerve Modulation of metaactivity. Pregabalin exhibits anti-seizure activity as discussed in U.S. Patent No. 5,563,175 to R.B. Silverman et al., and is believed to be useful in the treatment of, among other conditions, pain, ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): C12P13/04C12P41/00A61K31/198A61P25/08C07C227/18C07C227/22C07C229/08
CPCC12P13/002C12P7/42C07C229/24C12P13/02C07C227/06C07C227/22C12P13/001C07D207/277C07C227/20C07C255/19A61P25/08C07C229/08C07C227/12C07C253/30
Inventor S·胡C·A·马丁尼兹J·陶W·E·塔利P·G·T·凯勒尔Y·R·杜蒙德
Owner 厄普约翰美国1有限责任公司
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap