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Synthetic method of (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride

The technology of a hydroxycaproamide and a synthesis method is applied in the preparation of carboxylic acid amides, chemical instruments and methods, preparation of organic compounds, etc., and can solve the problems of chirality in molecular structure, complex synthesis method, and high economic cost, and achieve raw materials. Easy to obtain, simple to operate, and the effect of short synthesis cycle

Inactive Publication Date: 2013-09-11
上海步越化工科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] (3S)-3-Amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride is the key intermediate of telaprevir, a new anti-hepatitis C drug. Due to its complex molecular structure and chirality, Synthetic methods are generally more complex
[0004] The above methods have their own advantages, but all have the defects of many synthetic steps and high economic cost. Therefore, it is necessary to explore new (3S)-3-amino-N-cyclopropyl-2-hydroxyhexylbenzene with few steps and low cost. Synthetic route of amide hydrochloride

Method used

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  • Synthetic method of (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride
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  • Synthetic method of (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0032] Example 1 , Synthesis of (3S)-3-(benzyl((S)-1-phenylethyl)amino)-2-hydroxyl-4-hexenoic acid tert-butyl ester

[0033] Add n-butyllithium (68.7mL×1.6M, 0.11mol) dropwise into a solution of (S)-N-benzyl-1-phenethylamine (23.2g, 0.11mol) in tetrahydrofuran (300mL) and control the external temperature at - 50~-78°C. Then, a solution of tert-butyl sorbate (16.8g, 0.1mol) in tetrahydrofuran (100mL) was added to the reaction solution, and reacted at -50~-78°C for two hours, and then camphorsulfonazine (25.2g, 0.11mol), and reacted at -50~-78°C for one hour, naturally warmed to room temperature around 25°C overnight, added saturated ammonium chloride (300mL) to quench the reaction, and extracted with methyl tert-butyl ether (500mL) , and washed with saturated brine (300mL), the organic phase was concentrated to dryness under reduced pressure to obtain (3S)-3-(benzyl((S)-1-phenylethyl)amino)-2-hydroxy-4-hexenoic acid Tert-butyl ester (24.1g), yield 61%.

Embodiment 2

[0034] Example 2 , Synthesis of (3S)-3-(benzyl((S)-1-phenylethyl)amino)-2-hydroxyl-4-hexenoic acid

[0035] (3S)-3-(Benzyl((S)-1-phenylethyl)amino)-2-hydroxy-4-hexenoic acid tert-butyl ester (24.1 g, 61 mmol) was added to 98% formic acid (60 mL) , stirred at 20-30°C for 12 hours, the reaction solution was concentrated to dryness under reduced pressure, methyl tert-butyl ether (100mL) was added, and the precipitated product was filtered to obtain (3S)-3-(benzyl((S)-1-benzene Ethyl)amino)-2-hydroxy-4-hexenoic acid (19.7g), yield 96%.

Embodiment 3

[0036] Example 3 , Synthesis of (3S)-3-(benzyl((S)-1-phenylethyl)amino)-N-cyclopropyl-2-hydroxyl-4-hexenamide

[0037] (3S)-3-(benzyl((S)-1-phenylethyl)amino)-2-hydroxy-4-hexenoic acid (19.7g, 58mmol), N-hydroxysuccinimide (13.3g , 116mmol) into dimethylformamide (100mL), stirred at 20-30°C for 0.5 hour, added 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC. HCl) condensing agent (22.2g, 116mmol), stirred at 20-30°C for 1 hour, added cyclopropylamine (6.6g, 116mmol), stirred at 20-30°C for 12 hours, added water (200mL) and ethyl acetate (300mL ), the organic layer was washed once with saturated sodium bicarbonate (200mL), concentrated to dryness, added methyl tert-butyl ether (100mL), and the precipitated product was filtered to obtain (3S)-3-(benzyl((S)-1-benzene Ethyl)amino)-N-cyclopropyl-2-hydroxy-4-hexenamide (18.9g), yield 86%.

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Abstract

The invention provides a synthetic method of an intermediate (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride of an anti-hepatitis C new drug Telaprevir. The method comprises the following steps: carrying out (S)-N-benzyl-1-phenylethylamine addition and camphorsulfonyloxaziridine oxidation of a cheap raw material t-butyl sorbate to obtain chiral amine, carrying out t-butyl deprotection, carrying out condensation with cyclopropylamine to obtain amide, and carrying out hydrogenation reduction benzyl-deprotection to form hydrochloride in order to obtain (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride. The method has the advantages of less reaction steps, short synthetic period and strong applicability.

Description

technical field [0001] The invention belongs to the field of chemical medicines, and in particular relates to a synthetic method of an intermediate (3S)-3-amino-N-cyclopropyl-2-hydroxycaproylamide hydrochloride of an anti-hepatitis C new drug telaprevir. Background technique [0002] (3S)-3-Amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride is the key intermediate of telaprevir, a new anti-hepatitis C drug. Due to its complex molecular structure and chirality, Synthetic methods are generally more complex. [0003] WO0218369A2, WO2007022459A2, US20070237818, US20100063252, etc. have reported the preparation method of (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide and its hydrochloride, and their synthetic routes are as follows Figure 1 ~ Figure 4 shown. Method 1: Using Boc-protected L-norvaline as the starting material, synthesize (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide as shown in formula (2) through 7 steps of reaction ( figure 1 ). Method 2: Using the inter...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/04C07C231/14C07C229/22C07C227/14
Inventor 周盛峰冯志勇陈龙杨凯华
Owner 上海步越化工科技有限公司
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