Synthetic method of 26S protease inhibitors

A technology of solvent and condensing agent, applied in the field of medicine, to achieve the effect of reducing production cost, avoiding side reactions and reducing product loss

Active Publication Date: 2015-02-04
NANJING CHIA TAI TIANQING PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Whether it is a linear route or a convergent route, the protecting group on the borate ester needs to be removed in the last step of the reaction, which leads to the extension of the production cycle and the increase of the cost , and will reduce the yield and purity of the product

Method used

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  • Synthetic method of 26S protease inhibitors
  • Synthetic method of 26S protease inhibitors
  • Synthetic method of 26S protease inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] The preparation of embodiment 1 (R)-1-amino-3-methylbutane-1-boron hydrochloride

[0048]

[0049]Add (R)-1-amino-3-methylbutane-1-boronic acid pinacol ester hydrochloride (2.5kg, 10mol) into a reaction kettle filled with 25L tetrahydrofuran, and stir to completely dissolve the reaction raw materials. Cool down to 0-5°C, add 2-methylpropaneboronic acid (2.02kg, 20mol) in batches under stirring, maintain the reaction temperature at 0-5°C, monitor the end point of the reaction by TLC, and the reaction ends after 5-8 hours. The reaction solution was neutralized with saturated sodium bicarbonate to pH 7-8. Add dichloromethane for extraction twice, 10 L each time, combine the organic layers, wash the organic layer thoroughly with 20 L of water, add 1 mol / L hydrochloric acid dropwise under stirring at room temperature until no solid precipitates out. After the precipitated solid was washed twice with water, it was vacuum-dried to obtain 1.58 kg of white solid, namely (R)-...

Embodiment 2

[0052] The preparation of embodiment 2 (R)-1-amino-3-methylbutane-1-boron hydrochloride

[0053] Step (1): Preparation of N-(tert-butylsulfinyl)-3-methyl-1-butylimine

[0054]

[0055] Put 3-methylbutyraldehyde (860 g, 10 mol) and tert-butylsulfinamide (1.21 kg, 10 mol) into a reaction kettle filled with 25 L of dichloromethane, stir to make the raw materials completely dissolve, and then add tetrabutyl titanate Ester (341g, 1mol) was refluxed for 8 hours. After the reaction is completed, wash with 10% acetic acid solution (10L), 10% sodium bicarbonate solution (10L) and saturated saline (20L) successively, and concentrate to obtain 1.8kg of colorless oil, which is detected by HPLC (internal standard control ), and its main component was determined to be N-(tert-butylsulfinyl)-3-methyl-1-butylimine with a purity of 95% and a yield of 90.5%.

[0056] Step (2): Preparation of (1R)-(S)-pinanediol-1-(tert-butylsulfinamido)-3-methylbutane-1-boronate

[0057]

[0058] The N...

Embodiment 3

[0067] Example 3 Preparation of N-(pyrazine-2-formyl)-L-phenylalanine

[0068]

[0069] Add pyrazine-2-carboxylic acid (1.24kg, 10mol) into a reaction kettle with 20L of dichloromethane, add O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoro Borate ester (3.2kg, 10mol) was used as a catalyst, and stirred until the raw material was completely dissolved. Cool down to 0-5°C, dissolve L-phenylalanine (1.65kg, 10mol) and N,N-diisopropylethylamine (1.74L, 10mol) in 5L of dichloromethane, and add dropwise to the reaction In the still, control the dropwise addition within 3 to 5 hours. After the dropwise addition was completed, the reaction mixture was kept at 0-5° C. and stirred for 2 hours, then the temperature was naturally raised to room temperature and stirred for 2 hours, and then the reaction was stopped. Use 1mol / L hydrochloric acid (10L), deionized water (10L), saturated NaHCO 3 (10L) and saturated brine (20L), the organic phase was dried, filtered, concentrated, and...

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Abstract

The invention relates to a preparation method of bortezomib. The preparation method of bortezomib comprises the following steps of: (1) carrying out a condensation reaction on L-phenylalanine and pyrazine-2-formic acid to obtain N-(pyrazine-2-formyl)-L-phenylalanine; (2) carrying out condensation reaction on (R)-1-amino-3-methyl butane-1-boric acid hydrochloride and N-(pyrazine-2-formyl)-L- phenylalanine to obtain bortezomib. The preparation method of bortezomib has the advantages that (R)-1-amino-3-methyl butane-1-boric acid hydrochloride is taken as a reaction raw material, and R)-1-amino-3-methyl butane-1-boric acid hydrochloride is dropwise added to a reaction liquid at a low temperature, so that a side reaction is avoided; meanwhile, a step of removing a protecting group from boric acid is eliminated, so that a reaction period is shortened, production cost is reduced, and product loss in a protection removing step is reduced, and the yield and purity of the bortezomib product are increased.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a preparation method of bortezomib. Background technique [0002] Bortezomib, chemical name: [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinecarboxy)amino]propyl]amino] Butyl] boronic acid, structural formula is as follows: [0003] [0004] 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. In 2003, the FDA approved bortezomib for the treatment of patients with progressive multiple myeloma, in 2006 it was approved for use in mantle cell lymphoma, and in 2008 it was approved as a first-line drug for multiple myeloma. Bortezomib is the first proteasome inhibitor used in clinical research. When used alone or in combination with other drugs, it shows superior anti-tumor effects and drug safety. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/078C07K1/02
CPCY02P20/55
Inventor 吴晶柴雨柱朱谧王珺徐丹杨治旻田舟山龚彦春吕伏生袁方
Owner NANJING CHIA TAI TIANQING PHARMA
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