Preparation method of carfilzomib intermediate and intermediate chemical compounds of carfilzomib

A technology of carfilzomib and compounds, which is applied in the preparation of organic compounds, cyanide reaction preparation, chemical instruments and methods, etc., can solve problems such as industrialization difficulties, and achieve the effects of good yield, cost reduction, and mild reaction conditions

Inactive Publication Date: 2016-01-06
湖南华腾制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method uses a chiral complex of metal manganese as a catalyst to induce asymmetric epoxidation to increase the selectivity to 7:1, but because the chiral complex is not commercialized, the industrialization of this method is still difficult

Method used

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  • Preparation method of carfilzomib intermediate and intermediate chemical compounds of carfilzomib
  • Preparation method of carfilzomib intermediate and intermediate chemical compounds of carfilzomib
  • Preparation method of carfilzomib intermediate and intermediate chemical compounds of carfilzomib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] (1) Preparation of N,N-dibenzyl-L-leucine

[0056]

[0057] L-leucine (262g, 2mol) and benzyl bromide (697g, 4.1mol) were added to N,N-dimethylformamide (3000ml), then anhydrous potassium carbonate (552g, 4mol) was added, heated Reflux, react for 9 hours, TLC detects that the raw material spots disappear, concentrate to remove most of N,N-dimethylformamide, add water and ethyl acetate, extract, separate the water layer, adjust the pH to 3 with 1N hydrochloric acid, and then add acetic acid Ethyl ester was extracted, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 541.1 g of N,N-dibenzyl-L-leucine with a yield of 87%.

[0058] 1HNMR (400MHz, DMSO-d6): δppm12.48(br,1H),7.34-7.15(m,10H),4.19(s,4H),3.93-3.88(m,1H),1.72-1.65(m,2H ), 1.54-1.49 (m, 1H), 0.89-0.86 (m, 6H). ESI / MS: m / z=312 (M+H)+.

[0059] (2) Preparation of N,N-dibenzyl-L-leucine-N'-methoxy-N'-...

Embodiment 2

[0076] (1) Preparation of N,N-dibenzyl-L-leucine

[0077]

[0078] L-leucine (262g, 2mol) and benzyl chloride (519g, 4.1mol) were added to N,N-dimethylformamide (3000ml), then anhydrous potassium carbonate (552g, 4mol) was added, heated Reflux, react for 9 hours, TLC detects that the raw material spots disappear, concentrate to remove most of N,N-dimethylformamide, add water and ethyl acetate, extract, separate the water layer, adjust the pH to 3 with 1N hydrochloric acid, and then add acetic acid Ethyl ester was extracted, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 510 g of N,N-dibenzyl-L-leucine with a yield of 82%.

[0079] 1HNMR (400MHz, DMSO-d6): δppm12.48(br,1H),7.34-7.15(m,10H),4.19(s,4H),3.93-3.88(m,1H),1.72-1.65(m,2H ), 1.54-1.49 (m, 1H), 0.89-0.86 (m, 6H). ESI / MS: m / z=312 (M+H)+.

[0080] (2) Preparation of N,N-dibenzyl-L-leucine-N'-methoxy-N'-f...

Embodiment 3

[0095] (1) Preparation of N,N-dibenzyl-L-leucine

[0096]

[0097] L-leucine (262g, 2mol) and benzyl bromide (759.5g, 6mol) were added to N,N-dimethylformamide (3500ml), then anhydrous potassium carbonate (690g, 5mol) was added, heated Reflux, react for 10 hours, TLC detects that the raw material spots disappear, concentrate to remove most of N,N-dimethylformamide, add water and ethyl acetate, extract, separate the water layer, adjust the pH to 3 with 1N hydrochloric acid, and then add acetic acid Ethyl ester was extracted, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 578.4 g of N,N-dibenzyl-L-leucine with a yield of 93%.

[0098] 1HNMR (400MHz, DMSO-d6): δppm12.48(br,1H),7.34-7.15(m,10H),4.19(s,4H),3.93-3.88(m,1H),1.72-1.65(m,2H ), 1.54-1.49 (m, 1H), 0.89-0.86 (m, 6H). ESI / MS: m / z=312 (M+H)+.

[0099] (2) Preparation of N,N-dibenzyl-L-leucine-N'-methoxy-N'...

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Abstract

The invention discloses a novel preparation method of a carfilzomib key intermediate. L-leucine is taken as an original raw material, two reactive hydrogen on an amino group are protected, a chemical compound V is prepared and subjected to Weinreb amidation, a chemical compound IV is prepared, IV and 2-allyl magnesium bromide have a reaction, a chemical compound III is prepared and has an epoxidation reaction, a chemical compound II is prepared and subjected to deamination protection, and a chemical compound I is prepared. The invention further discloses intermediate chemical compounds II, III, IV and V of carfilzomib. The preparation method is simple to operate, the total yield is high, the cost is low, the selectivity is high, and the preparation method is suitable for industrial production.

Description

technical field [0001] The present invention relates to a key intermediate (2S)-2-amino-4-methyl-1-[(2R)-2-methyl ring used for multiple myeloma treatment drug Carfilzomib (Carfilzomib) The preparation method of oxyethyl]-1-pentanone trifluoroacetate belongs to the technical field of medicine manufacture. technical background [0002] Carfilzomib (Carfilzomib) is a protease inhibitor applied by the Onyx Pharmaceuticals Inc pharmaceutical company in the United States, with a trade name of Kyprolis, and is used for the treatment of multiple myeloma. The drug is an injection, which was approved by the US FDA in July 2012 for the treatment of patients with multiple myeloma who have failed other drug treatments. And (2S)-2-amino-4-methyl-1-[(2R)-2-methyloxiranyl]-1-pentanone trifluoroacetate I is a preparation carfilzomib key intermediates. (WO2005105827) [0003] [0004] For the synthesis of this key intermediate, the methods reported at present have the following severa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D303/36C07D301/00C07C225/14C07C221/00C07C227/18C07C229/14C07C259/06
CPCC07D303/36C07C221/00C07C225/14C07C227/18C07C229/14C07C259/06C07D301/00
Inventor 陈芳军
Owner 湖南华腾制药有限公司
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