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Synthetic method of high-purity bortezomib and intermediate thereof

A bortezomib and high-purity technology, which is applied in the field of high-purity bortezomib synthesis and its intermediates, can solve the problems affecting product purity, cumbersome operation, slow reaction, etc., and achieve low cost, simple preparation process and operation, The effect of reducing impurities

Active Publication Date: 2013-04-03
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The use of these bases inevitably causes the racemization of the chiral part in the easily racemized phenylalanine structure, which affects the purity of the product
At the same time, in the current synthesis method, after the skeleton structure of bortezomib is completed, borate hydrolysis adopts a two-phase reaction, the reaction is slow, and both phases need to be extracted after the post-treatment, and the operation is more cumbersome

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Embodiment 1: the preparation of formula II compound

[0060] Under nitrogen protection, 2-pyrazinecarboxylic acid (34g, 0.27mol), L-phenylalanine benzyl ester hydrochloride (80g, 0.27mol) and O-benzotriazole-N,N,N', A mixture of N'-tetramethylurea tetrafluoroborate (96.8g, 0.30mol) in dichloromethane (400mL) was cooled to 0-5°C, and N,N-diisopropylethylamine (120mL , 0.69 mol), the resulting reaction mixture was kept at low temperature and stirred for 1 hour, then naturally warmed to room temperature and continued to stir for 2 hours. Add 1mol / L hydrochloric acid (300mL), deionized water (300mL), saturated NaHCO 3 (300 mL) and saturated brine, dried with dichloromethane and anhydrous sodium sulfate, filtered and concentrated to obtain 105 g of oil.

[0061] MS (ESI) m / z 362 (M+H) + .

[0062] 1 H NMR (CDCl 3 , 500 MHz): δ 9.40 (s, 1H), 8.77 (d, J = 2.0 Hz, 1H), 8.55 (d, J = 2.0Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.42-7.40 (m, 3H), 7.39-7.36 (m, 2H), 7.35-7....

Embodiment 2

[0064] Embodiment 2: the preparation of formula III compound

[0065] The oil obtained in Example 1 was dissolved in ethanol (300 mL), palladium carbon (5 g) was added, and hydrogen was passed through, and the reaction mixture was reacted at room temperature for 4 to 5 hours under 0.2 MPa. Palladium carbon was removed by filtration, and the solvent was removed by concentration. The obtained semi-solid was dissolved in acetone (90 mL), deionized water (120 mL) was added dropwise, stirred at room temperature for 30 minutes, cooled to 0-5°C and stirred for 2 hours. It was filtered to obtain a white solid, and dried under vacuum at 40-45°C for 3-4 hours to obtain 58 g of the compound of formula III.

[0066] 1 H NMR (DMSO-d6, 500 MHz): δ13.02 (brs, 1H), 9.13 (s, 1H), 8.87 (s, 1H), 8.82 (d, J = 5.6 Hz, 1H), 8.73 (s, 1H), 7.23 (s, 4H), 7.17 (s, 1H), 4.75-4.74 (m, 1H), 3.26-3.18 (m, 2H).

[0067] 13 C NMR (DMSO- d 6 , 500 MHz): δ 173.1, 168.9, 148.2, 144.4, 143.8, 143.7, 137.9...

Embodiment 3

[0068] Embodiment 3: the preparation of formula V compound

[0069] Under nitrogen protection, the compound of formula III (54g, 0.20mol), amino borate trifluoroacetate (75.6g, 0.20mol) and O-benzotriazole-N,N,N',N'- A mixture of tetramethylurea tetrafluoroborate (20.6g, 0.22mol) in dichloromethane (350mL) was cooled to 0-5°C, and N,N-diisopropylethylamine (87mL, 0.50mol) was added dropwise ), the resulting reaction mixture was kept under low temperature and stirred for 1 hour, then naturally warmed to room temperature and continued to stir for 3 hours. Add 1mol / L hydrochloric acid (300mL), deionized water (300mL), saturated NaHCO3 (300mL) and saturated brine to wash successively, let stand to separate layers, dry the dichloromethane phase with anhydrous sodium sulfate, then filter and concentrate to obtain 96g Oily substance, the oily substance is the compound of formula V.

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PUM

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Abstract

The invention belongs to the pharmaceutical and chemical fields and particularly relates to a synthetic method of high-purity bortezomib and an intermediate of the high-purity bortezomib. According to the invention, N-(2- pyrazine carbonyl)-L-phenylalanine benzyl ester is obtained from condensation reaction between 2-pyrazine carboxylic acid and L-phenylalanine benzyl ester; then the product is catalyzed and hydrogenated; and then the product is condensed and hydrolyzed with the hydrochloride of (aR,3aS,4S,6S,7aR)-hexahydro-3a,8,8-trimethyl-alpha-(2-methyl propyl)-4,6-methano-1,3,2- benzodioxoborane-2-methylamine or trifluoroacetate so that the bortezomib is obtained. The preparation process disclosed by the invention has the advantages of simplicity in operation, high purity and low cost. The bortezomib obtained through the method disclosed by the invention is in the form of white powder or crystals, the content is 99.8% or higher, and the total content of SS- and RR-isomers is not greater than 0.1%.

Description

[0001] technical field [0002] The invention belongs to the field of medicine and chemical industry, and more specifically relates to a synthesis method of high-purity bortezomib and an intermediate thereof. [0003] Background technique [0004] Bortezomib, chemical name: [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinecarboxy)amino]propyl]amino] Butyl]boronic acid, having the formula I [0005] . [0006] Bortezomib is a new type of antineoplastic drug developed by Millenium Pharmaceutical Company of the United States. It is a synthetic, highly selective and reversible inhibitor of chymotrypsin-like activity of the 26S proteasome. The FDA approved bortezomib in 2003 for the treatment of patients with multiple myeloma who had received at least one prior course of therapy and showed progression on the most recent course of therapy, in 2006 for mantle cell lymphoma, and in 2008 as a First-line drug for multiple myeloma. Bortezomib is the first proteasome inhibitor ...

Claims

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Application Information

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IPC IPC(8): C07K5/078
Inventor 赵小伟李晓昕赵宇
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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