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Method for synthesizing bortezomib

A synthesis method and bortezomib technology are applied in the field of bortezomib synthesis, and can solve the problems of affecting the purity of the bortezomib finished product, being difficult to bortezomib, and the high cost of a condensing agent, achieving low price, few reaction steps, and high efficiency. The effect of purity

Active Publication Date: 2012-02-15
CHONGQING SINTAHO PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the existing synthetic method, the cost of the condensing agent in the condensation reaction is high and difficult to remove; the protection of the deboronate ester uses isobutyl boronic acid and hydrochloric acid, but isobutyl boronic acid is more expensive and the cost is higher; in the purification stage Existing methods all adopt methanol or ethyl acetate and methyl tert-butyl ether or n-hexane, because bortezomib has a large solubility in methanol and is not easy to separate out, so it is not easy to purify. At the same time, ethyl acetate / methyl Impurities in tert-butyl ether or n-hexane precipitate together with the product, making it difficult to obtain high-purity bortezomib, which affects the purity of bortezomib finished products

Method used

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  • Method for synthesizing bortezomib
  • Method for synthesizing bortezomib
  • Method for synthesizing bortezomib

Examples

Experimental program
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Effect test

Embodiment 1

[0055] Under the protection of nitrogen, 24.5g (0.1mol) 2(s) benzylamino-3-phenylpropionic acid and 6.22g N-methylmorpholine were added to 130mL freshly prepared THF, cooled to -20°C and poured into it Add 8.4g of isobutyryl chloride, after stirring for 0.5 hours, add dropwise 38g (0.1mol) (aR, 3aS, 4S, 6S, 7aR)-hexahydro-3a,8,8-trimethyl-alpha at 20°C -(2-methylpropyl)-4,6-methylbridge-1,3,2-benzodioxaborane-2-methylamine 2,2,2-trifluoroacetate solution, followed by Add 16mL of N,N-diisopropylethylamine to adjust the pH to 9-10, then raise the temperature to room temperature and stir for 6 hours under the protection of nitrogen. After the reaction is completed, concentrate to dryness under reduced pressure, and add 340mL of methyl tert-butyl to the residue base ether, and washed twice with 175 mL of 1.5% hydrochloric acid. The acid layer was back-extracted with methyl tert-butyl ether, the organic phase was washed once with 175 mL of water and saturated sodium chloride succe...

Embodiment 2

[0061] Under the protection of nitrogen, 24.5g (0.1mol) 2(s) benzylamino-3-phenylpropionic acid and 6.22g N-methylmorpholine were added to 130mL freshly prepared THF, cooled to -20°C and poured into it Add 8.4g of isobutyryl chloride, after stirring for 0.5 hours, add dropwise 38g (0.1mol) (aR, 3aS, 4S, 6S, 7aR)-hexahydro-3a,8,8-trimethyl-alpha at 20°C -(2-methylpropyl)-4,6-methylbridge-1,3,2-benzodioxaborane-2-methylamine 2,2,2-trifluoroacetate solution, followed by Add 16mL of N,N-diisopropylethylamine to adjust the pH to 10-11, then raise the temperature to room temperature and stir for 4 hours under nitrogen protection. After the reaction is completed, concentrate to dryness under reduced pressure, and add 340mL of methyl tert-butyl to the residue base ether, and washed twice with 175 mL of 1.5% hydrochloric acid. The acid layer was back-extracted with methyl tert-butyl ether, the organic phase was successively washed once with 175 mL of water and saturated sodium chlorid...

Embodiment 3

[0067] Under the protection of nitrogen, 24.5g (0.1mol) 2(s) benzylamino-3-phenylpropionic acid and 6.22g N-methylmorpholine were added to 130mL freshly prepared THF, cooled to -20°C and poured into it Add 8.4g of isobutyryl chloride, after stirring for 0.5 hours, add dropwise 38g (0.1mol) (aR, 3aS, 4S, 6S, 7aR)-hexahydro-3a,8,8-trimethyl-alpha at 20°C -(2-methylpropyl)-4,6-methylbridge-1,3,2-benzodioxaborane-2-methylamine 2,2,2-trifluoroacetate solution, followed by Add 16mL of N,N-diisopropylethylamine to adjust the pH to 11~12, then raise the temperature to room temperature and stir for 3 hours under nitrogen protection. After the reaction is completed, concentrate to dryness under reduced pressure, and add 340mL of methyl tert-butyl to the residue base ether, and washed twice with 175 mL of 1.5% hydrochloric acid. The acid layer was back-extracted with methyl tert-butyl ether, the organic phase was washed once with 175mL water and saturated sodium chloride successively, a...

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Abstract

The invention relates to the field of chemical synthesis, in particular to a method for synthesizing bortezomib shown as a structural formula I. The method comprises the followings steps of: performing condensation, debenzylation, condensation and oxidation deprotection on raw materials; and purifying with acetone, toluene and methyl tert-butyl ether to obtain bortezomib. The method for synthesizing the bortezomib provided by the invention has the advantages of low reagent price, a small number of reaction steps, mild reaction condition, increase in the purity of bortezomib tablets and contribution to industrial production. The formula I is shown in the specifications.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a synthesis method of bortezomib. Background technique [0002] Bortezomib, chemical name: [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinyl)amino]propyl]amino] Butyl]-boronic acid, foreign name (or) common name: Bortezomib (trade name: Vanke), molecular formula: C 19 h 25 BN 4 o 4 , as shown in formula I. [0003] [0004] Formula I [0005] Bortezomib is a new type of anti-tumor drug developed by Millennium Pharmaceutical Company of the United States. Studies in recent years have confirmed that bortezomib, as a proteasome inhibitor, can induce apoptosis in a variety of tumor cell lines and cancerous cells, and significantly enhance the efficacy of certain chemotherapy drugs and ionizing radiotherapy in inducing tumor cell apoptosis, while The toxic effect on normal cells is relatively small. Bortezomib is a synthetic highly selective 26S borate proteasome inhibit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02
Inventor 朱小锋李靖姚全兴
Owner CHONGQING SINTAHO PHARM CO LTD
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