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Improved method of bortezomib process

A bortezomib and process technology, applied in the field of pharmaceutical synthesis, can solve the problems of product purity, low yield, easy falling off of protective groups, easy decomposition of condensing agents, etc., achieving easy operation, inhibiting the generation of condensation by-products, and inhibiting products. The effect of racemization

Active Publication Date: 2014-01-29
SHANDONG NEWTIME PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The invention provides a method for improving the process of the pharmaceutical compound bortezomib, aiming at the complex reaction preparation process existing in the prior art, the protection group is easy to fall off in the condensation process, and the product is easy to oxidize to cause side reactions and condensing agents. It is easy to decompose and difficult to remove during the reaction, which leads to technical problems such as product purity and yield are generally low. The inventor has continuously optimized the synthesis route through repeated experiments, and through screening raw materials and proportioning, controlling reaction conditions and suitable treatment process, The occurrence of side reactions is effectively avoided, and the yield and purity of the product are greatly improved. The invention is easy to operate and has mild reaction conditions, and is suitable for industrial production

Method used

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  • Improved method of bortezomib process

Examples

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Effect test

Embodiment 1

[0032] Example 1 (αR)-(1S, 2S, 3R, 5S)-pinanediol-N-(N-trifluoroacetoxy-phenylpropylamino)-1-amino-3-methylbutane-1 - Preparation of boroesters

[0033] Add 5.4 g of N-trifluoroacetyl-L-phenylalanine into 55 ml of dichloromethane, stir and cool down to 8°C, add EDCI [1-(3-dimethylaminopropyl)-3-ethyl carbon Diimine hydrochloride] 4.4g, (αR)-(1S, 2S, 3R, 5S)-pinanediol-1-amino-3-methylbutane-1-boronic acid trifluoroacetate 8.3g , add triethylamine dropwise to adjust the pH to 8. After the dropwise addition, keep warm for 2 hours, then rise to 25°C within 1 hour, keep warm for 2 hours, concentrate under reduced pressure, add 30ml of ethyl acetate to dissolve the oil, and add 20ml of water Washing, washing with 20ml of saturated sodium bicarbonate solution, washing with 20ml of water again, discarding the aqueous layer, drying the organic layer over anhydrous sodium sulfate, filtering, and concentrating under reduced pressure below 35°C to obtain compound V(αR)-(1S, 2S, 3R, 5S)...

Embodiment 2

[0034] Example 2 (αR)-(1S, 2S, 3R, 5S)-pinanediol-N-(N-trifluoroacetoxy-phenylpropylamino)-1-amino-3-methylbutane-1 - Preparation of boroesters

[0035] Add 5 g of N-trifluoroacetyl-L-phenylalanine into 60 ml of dichloromethane, stir and cool down to 10°C, add 8.9 g of TBTU+HOBT (molar ratio 1:1), (1S, 2S, 3R, 5S )-pinanediol L-phenylalanine-L-leucine boric acid trifluoroacetate 8.5g, add dropwise triethylamine to adjust the pH=9.6, after the dropwise addition is completed, keep the reaction for 2.5h, then in 1 hour Rise to 18°C, keep warm for 2.3 hours, concentrate under reduced pressure, add 30ml of ethyl acetate to dissolve the oil, wash with 45ml of water, 45ml of 3% citric acid aqueous solution, 45ml of saturated sodium bicarbonate solution, and wash again with 45ml of water , discard the aqueous layer, dry the ethyl acetate layer over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure at 35°C to obtain compound V (αR)-(1S, 2S, 3R, 5S)-...

Embodiment 3

[0036] Example 3 (αR)-(1S, 2S, 3R, 5S)-pinanediol-N-(N-trifluoroacetoxy-phenylpropylamino)-1-amino-3-methylbutane-1 - Preparation of boroesters

[0037] Add 5.3 g of N-trifluoroacetyl-L-phenylalanine into 65 ml of dichloromethane, stir and cool down to 5°C, add 6.8 g of EDCI+HOOBT (molar ratio 1:1.3), (1S, 2S, 3R, 5S)-pinanediol L-phenylalanine-L-leucine boric acid trifluoroacetate 8.5g, add dropwise triethylamine to adjust pH=10, after the dropwise addition is completed, keep warm for 1.8h, then in 1 Rise to 18°C ​​within 1 hour, keep warm for 2.1h, concentrate under reduced pressure, add 30ml of ethyl acetate to dissolve the oil, wash with 40ml of water, 40ml of 3% citric acid aqueous solution, 40ml of saturated sodium bicarbonate solution, and again with 40ml of Wash with water, discard the aqueous layer, dry the ethyl acetate layer over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure at 35°C to obtain compound V (αR)-(1S, 2S, 3R, 5S)-...

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Abstract

The invention belongs to the field of pharmaceutical synthesis, and specifically relates to an improved method of a medical compound bortezomib process. Bortezomib is prepared by the following steps of condensation, deprotection, coupling and the like by taking N-trifluoroacetyl-L-phenylalanine, alpha R)-(1S, 2S, 3S, 5S)-pinane diol-1-amino-3-methyl butane-1-borate trifluoroacetate. Side reactions are effectively avoided through optimization of raw materials and proportioning, control of reaction conditions and an appropriate treatment process, so that the product yield and the purity are improved to a greater extent. The total recovery of four steps is over 50% and the liquid detection purity reaches 99.83%.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to an improved method for the process of the drug compound bortezomib. Background technique [0002] Bortezomib, chemical name: [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinecarbonyl)amino]propyl ]amino]butyl]-boronic acid, molecular formula: C 19 h 25 BN 4 o 4 , the structural formula is as follows: [0003] [0004] Bortezomib is a new type of anti-tumor drug developed by Millennium Pharmaceutical Company of the United States. Bortezomib is a dipeptide borate, which is a reversible proteasome inhibitor, and can selectively bind to threonine in the active site of protease , Inhibit the chymotrypsin and (or) trypsin activity of the 26S subunit of the proteasome. Blocking NF-kB, thereby preventing tumor cell apoptosis and participating in cell drug resistance; acting on the myeloma microenvironment, inhibiting the growth and survival of tumor cells in the micro...

Claims

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Application Information

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IPC IPC(8): C07K5/078
Inventor 赵志全提文利肖月华
Owner SHANDONG NEWTIME PHARMA
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