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Processes and intermediates for preparing steric compounds

a technology of steric compounds and intermediates, which is applied in the preparation of carboxylic compounds, peptides, organic chemistry, etc., can solve the problems of progressively worsening liver inflammation and no broadly effective treatment for the debilitating progression of chronic hcv

Inactive Publication Date: 2007-10-18
VERTEX PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent is about processes and intermediates for making a specific chemical compound called alpha-amino beta-hydroxy acid. This compound is important for making a protease inhibitor. The process involves oxidizing an unsaturated amide or ester to form the corresponding epoxide, and then using a specific aminating reagent to create the alpha-hydroxy, beta-amino acid. The resulting compound has a high level of purity and can be used to make the protease inhibitor. This patent is useful for those working on the development of this important chemical compound.

Problems solved by technology

Infection by hepatitis C virus (“HCV”) is a compelling human medical problem.
Prolonged chronic infection can result in recurrent and progressively worsening liver inflammation, which often leads to more severe disease states such as cirrhosis and hepatocellular carcinoma.
Unfortunately, there are no broadly effective treatments for the debilitating progression of chronic HCV.

Method used

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  • Processes and intermediates for preparing steric compounds
  • Processes and intermediates for preparing steric compounds
  • Processes and intermediates for preparing steric compounds

Examples

Experimental program
Comparison scheme
Effect test

example 1

3-Propyloxirane-2-carboxylic acid

[0115]

[0116] A flask equipped with an overhead stirrer, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with trans-2-hexenoic acid (69.8 g, 611 mmol), water (420 mL) and acetone (420 mL). Sodium bicarbonate (NaHCO3, 224 g, 2.66 mol) was then added portion-wise keeping the reaction temperature at 25±5° C. Once all of the sodium bicarbonate had been added, a solution of OXONE® (454 g, 738 mmol) in 4×10−4 M ethylenediaminetetraacetic acid disodium salt dehydrate (Na2EDTA; 1.32 L) was charged to the addition funnel and added over 90 minutes keeping the reaction temperature at 25±5° C. and the pH between 9.5 and 7.5. The reaction mixture was then allowed to stir for 16 h, after which time no (E)-hex-2-enoic acid was observed by HPLC analysis. The mixture was cooled to 0±5° C., acidified to pH 2 with 6 N HCl (515 mL, 2.8 mol) and extracted with ethyl acetate (EtOAc; 3×250 mL). The combined organic phases were dried over...

example 2

N-cyclopropyl-3-propyloxirane-2-carboxamide

[0118]

[0119] A flask equipped with an overhead stirrer, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with the acid of Example 1 (20.0 g, 154 mmol), and isopropyl acetate (IPAc; 200 mL) then cooled to 0±5° C. 4-Methylmorpholine (NMM, 154 mL, 17 mL) was charged to the addition funnel then added maintaining the temperature at 0±5° C. Once addition was complete the addition funnel washed with IPAc (10 mL) and then charged with isobutyl chloroformate (IBCF, 137 mmol, 19.5 mL) which was added keeping the temperature at 0±5° C. The reaction mixture was stirred at 0±5° C. for 90 min after which time a solution of cyclopropylamine (154 mmol, 10.7) in IPAc (80 mL) was added keeping the temperature at 0±5° C. Upon completion of addition the reaction was warmed to 25±5° C. and allowed to stir for 18 h. Sodium hydroxide (231 mL, 1.0 N) was added and the biphasic mixture stirred vigorously for 30 min, then the laye...

example 3

Alternate preparation of N-cyclopropyl-3-propyloxirane-2-carboxamide

[0121]

[0122] A flask equipped with a stir bar, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with the acid of Example 1 (5.0 g, 38 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI; 8.1 g, 42 mmol), 1-hydroxybenzotriazole hydrate (HOBt; 5.7 g, 42 mmol) and N,N-dimethylformamide (DMF; 50 mL) then cooled to 0±5° C. The addition funnel was charged with NMM (5.9 mL, 54 mmol) which was then added to the reaction mixture maintaining the temperature at 0±5° C. The mixture was stirred for 30 minutes then cyclopropylamine (2.9 mL, 42 mmol) was added and the reaction allowed to warm to 25±5° C. over 16 hours. Hydrochloric acid (50 mL, 1.0 N) and IPAc (50 mL) were added and then the mixture stirred for an additional 30 minutes. The contents were transferred to separatory funnel, the layers separated then the organic layer washed sequentially with HCl (50 mL, 1.0 N)...

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PUM

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Abstract

This invention relates to processes and intermediates for the preparation of an alpha-amino beta-hydroxy acid of Formula 1 wherein the variables R1, R′1 and R2 are defined herein and the compound of Formula 1 has an enantiomeric excess (ee) of 55% or greater.

Description

CROSS-REFERENCE [0001] This application claims the benefits of U.S. Provisional Application Ser. No. 60 / 782,976, filed Mar. 16, 2006, and U.S. Provisional Application Ser. No. 60 / 844,771, filed Sep. 15, 2006.FIELD OF THE INVENTION [0002] This invention relates to processes and intermediates for the preparation of protease inhibitors, in particular, serine protease inhibitors. BACKGROUND OF THE INVENTION [0003] Infection by hepatitis C virus (“HCV”) is a compelling human medical problem. HCV is recognized as the causative agent for most cases of non-A, non-B hepatitis, with an estimated human sero-prevalence of 3% globally [A. Alberti et al., “Natural History of Hepatitis C,” J. Hepatology, 31, (Suppl. 1), pp. 17-24 (1999)]. Nearly four million individuals may be infected in the United States alone. [M. J. Alter et al., “The Epidemiology of Viral Hepatitis in the United States, Gastroenterol. Clin. North Am., 23, pp. 437-455 (1994); M. J. Alter “Hepatitis C Virus Infection in the Uni...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07J9/00C07D303/36
CPCC07B2200/05C07J75/00C07C59/255C07C231/12C07C231/20C07C237/04C07C247/04C07C2101/02C07D209/52C07D301/14C07D303/48C07D401/14C07D403/12C07D403/14C07D498/10C07K5/0202C07K7/02C07B2200/07C07J9/005C07C247/06C07C51/412C07C2601/02A61P31/12
Inventor TANOURY, GERALD J.CHEN, MINZHANGJUNG, YOUNG CHUNFORSLUND, RAYMOND E.
Owner VERTEX PHARMA INC
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