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Preparing process of optically active long chain N-Boc-amino acid with end olefinic bond

An optically active and amino acid technology, applied in the field of amino acid preparation, to achieve the effects of cheap and easy-to-obtain raw materials, shorten the synthesis process, and reduce costs

Inactive Publication Date: 2007-06-27
上海药明康德新药开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0029] The technical problem to be solved in the present invention is: avoiding the use of expensive chiral catalysts or resolution reagents in the preparation process of long-chain chiral α-amino acids with terminal ethylenic bonds; shortening the route of the existing synthesis process and increasing the yield High efficiency and low cost; provide a method for preparing optically active long-chain-N-Boc-amino acids with terminal ethylenic bonds

Method used

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  • Preparing process of optically active long chain N-Boc-amino acid with end olefinic bond
  • Preparing process of optically active long chain N-Boc-amino acid with end olefinic bond
  • Preparing process of optically active long chain N-Boc-amino acid with end olefinic bond

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] 1. Synthesis of 2-Boc-amino-4-pentenoic acid

[0040] Step 1: Synthesis of O-TBS-2-Boc-amino-4-pentenol

[0041] CuBrSMe 2 (214mg, 1.04mmol) was suspended in anhydrous THF (28mL), cooled to -78°C with a dry ice-acetone bath, and the Grignard reagent solution of vinyl bromide (4.2mL, 1M, 4.2mmol) was added dropwise. , stirred for 3hr. Then the aziridine derivative (1g, 3.48mmol) in anhydrous Et 2 O (11 mL) solution was added dropwise and stirring was continued for 2 hr. After rising to 20°C, stirring was continued for 3 hr. After the reaction was detected by TLC, the reaction was performed with saturated NaHCO 3 The aqueous solution was quenched, the organic phase was separated, and the aqueous phase was extracted with EtOAc (2*30mL), the organic phases were combined, dried, filtered, and concentrated to obtain a crude product, which was then separated by column chromatography to obtain pure O-TBS-2-Boc-amino -4-pentenol (0.90 g, yield 82%). 1 HNMR (CD 3 Cl, ...

Embodiment 2

[0047] 2. Synthesis of 2-Boc-amino-5-hexenoic acid

[0048] The first step: the synthesis of O-TBS-2-Boc-amino-5-hexenol

[0049] CuBrSMe 2 (107mg, 0.522mmol) was suspended in anhydrous THF (28mL), cooled to -78°C with a dry ice-acetone bath, and the Grignard reagent solution of 3-bromopropene (4.2mL, 1M, 4.2mmol) was added dropwise, and When finished, stir for 1.5 hr. Then the aziridine derivative (1g, 3.48mmol) in anhydrous Et 2 O (11 mL) solution was added dropwise and stirring was continued for 1.5 hr. After the reaction was detected by TLC, the reaction was performed with saturated NaHCO 3 The aqueous solution was quenched, the organic phase was separated, and the aqueous phase was extracted with `EtOAc (2*30mL), the organic phases were combined, dried, filtered, and concentrated to obtain a crude product, which was then separated by column chromatography to obtain the product O-TBS-2-Boc-amino -5-Hexenol (1.03 g, yield 90%). 1 HNMR (CDCl 3 , 400MH z ): δ=0.05...

Embodiment 3

[0055] 3. Synthesis of 2-Boc-amino-7-octenoic acid

[0056] Step 1: Synthesis of O-TBS-2-Boc-amino-7-octenol

[0057] CuBrSMe 2 (214mg, 1.04mmol) was suspended in anhydrous THF (35mL), cooled to -78°C with a dry ice-acetone bath, and the Grignard reagent solution of 5-bromopentene (4.2mL, 1M, 4.2mmol) was added dropwise, and After the addition was complete, stir for 1.5 hr. Then the aziridine derivative (1g, 3.48mmol) in anhydrous Et 2 O (11 mL) solution was added dropwise and stirring was continued for 1.5 hr. After the reaction was detected by TLC, the reaction was performed with saturated NaHCO 3 The aqueous solution was quenched, the organic phase was separated, and the aqueous phase was extracted with EtOAc (2*30mL), the organic phases were combined, dried, filtered, and concentrated to obtain a crude product, which was then separated by column chromatography to obtain the product O-TBS-2-Boc-amino- 7-octenol (1.11 g, 89% yield). 1 HNMR (CDCl 3 , 400MH z ): δ=...

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Abstract

The present invention relates to preparation process of optically active long chain N-Boc-amino acid with end olefinic bond, and the preparation process is superior to available process, which has long path, low yield and expensive chiral reagent. The preparation process includes attacking metylene radical of azirane derivative selectively with olefin halide Grignard reagent with end olefinic bond and opening ring to obtain beta-amino alcohol with protecting group, eliminating protecting hydroxyl group to obtain beta-amino alcohol, and oxidizing to obtain optically active long chain N-Boc-amino acid with end olefinic bond. The present invention is used in preparing anti-HCV medicine BILN2061.

Description

Technical field: [0001] The present invention relates to a method for preparing amino acid, in particular to a method for preparing an optically active long-chain-N-Boc-amino acid with terminal ethylenic bond. Background technique: [0002] Hepatitis C is a disease with a polyheterogeneous course that can lead to chronic hepatitis, cirrhosis, and liver cancer. Since the medical community discovered the hepatitis C virus in 1989, 170 million people worldwide have been infected. [0003] In recent years, BILN2061, an anti-HCV drug developed by Boehringer Ingelheim in Germany, can block the function of HCV NS3 enzyme. Patients with hepatitis C were given placebo or liquid medicine containing BILN 2061, twice a day for a total of 2 days. As a result, after taking BILN 2061, the level of hepatitis C virus in the patient's body decreased by more than 100 times. However, it takes 12 weeks for the previous combination therapy of interferon and ribavirin to achieve a similar effec...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/12C07C229/30A61P31/12
CPCY02P20/55
Inventor 缪伟张治柳马汝建陈曙辉李革
Owner 上海药明康德新药开发有限公司
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