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Synthetic method of bortezomib

A synthetic method, bortezomib technology, applied in the direction of peptides, etc., can solve the problems of inability to obtain compounds with a single configuration, expensive catalysts, low ee value, etc., to reduce the cost of synthetic raw materials, good quality of raw materials, and reaction The effect of mild conditions

Active Publication Date: 2012-09-12
HEFEI UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This synthetic route has been improved on the basis of the previous route, has adopted cheaper 3-methylbutyraldehyde as raw material, has reduced reaction cost; But selects (R)-1-phenylethylamine as the chiral reagent product The ee value (enantiomeric excess) is low, and more pure single-configuration compounds cannot be obtained, and catalytic hydrogenation requires the use of Pd / C as a catalyst, the catalyst is more expensive, and the reaction conditions require heating and pressure for industrial equipment High standard
Considering this synthetic route comprehensively, although it has been improved on the previous basis, there are still deficiencies and needs to be improved

Method used

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  • Synthetic method of bortezomib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1: Preparation of (R,E)-2-methyl-N-(3-methylbutylene)propane-2-sulfinamide (Intermediate 1)

[0039] 1.1 Weigh 12.1g (100mmol) of (R)-tert-butylsulfinamide, 1.8g (15mmol) of magnesium sulfate and 0.37g (1.5mmol) of pyridinium 4-methylbenzenesulfonate into a 500mL round bottom flask, and then Take 13mL (120mmol) of isovaleraldehyde into the flask, and add 300mL of dichloromethane as a solvent, stir and react at room temperature for 23h, filter the reaction solution after the reaction, wash the filter residue three times with dichloromethane, keep the filtrate, and put it in a rotary evaporator The solvent was removed to obtain the crude product as a pale yellow liquid. The crude product was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1), and finally a colorless liquid was obtained which was Intermediate 1. The mass is 18.2g, and the yield is 95%.

[0040] 1.2 Weigh 12.1g (100mmol) of (R)-tert-butylsulfinamide into a 500mL round...

Embodiment 2

[0044] Example 2: Preparation of (R)-1-N-tert-butylsulfinyl-3-methylbutane-1-pinacol boronate (Intermediate 2)

[0045] 2.1 Under nitrogen protection, weigh 12.9g (50mmol) of pinacol diboron, 1.3g (5mmol) of 1,3-bicyclohexylimidazole hydrochloride, 0.5g (5mmol) of cuprous chloride and 0.96 sodium tert-butoxide g (10mmol) in a 250mL three-necked round-bottomed flask, add 18.8mL (50mmol) of the intermediate, and add 150mL of benzene as a solvent, stir at room temperature for 24 hours, add 100mL of ethyl acetate to the reaction solution after the reaction, filter, and keep Organic phase; the organic phase was washed with 100 mL of saturated sodium bicarbonate solution and separated, the aqueous phase was extracted with ethyl acetate and the organic phase was combined, dried and filtered with magnesium sulfate, concentrated, and separated by column chromatography with deactivated silica gel (washing Deliquified to petroleum ether: ethyl acetate = 10:1), spin-dried to obtain a colo...

Embodiment 3

[0050] Example 3: Preparation of pinacol-(R)-1-amino-3-methylbutane-1-boron ester hydrochloride (intermediate 3)

[0051] 3.1 Weigh 29.5g (30mmol) of the intermediate into a 250mL round bottom flask, add 150mL of 1,4-dioxane as a solvent to dissolve it completely, and then slowly add 4.0mol / L hydrogen chloride dioxane solution 7.5mL ( 30mmol), stirred at room temperature for 2h, and the solvent was removed by rotary evaporation to obtain a solid. The solid was washed three times with ether to obtain a white product which was Intermediate 3. The mass is 7.1 g, and the yield is 95%.

[0052] 3.2 Weigh 210.0g (31.5mmol) of the intermediate into a 250mL round bottom flask, add 150mL of 1,4-dioxane as a solvent to dissolve it completely, and then slowly add 4.0mol / L hydrogen chloride dioxane solution 7.8mL (31.5mmol), stirred at room temperature for 1.5h, and the solvent was removed by rotary evaporation to obtain a solid. The solid was washed three times with ether to obtain a wh...

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Abstract

The invention discloses a synthetic method of bortezomib, which comprises the following steps of: taking isovaleraldehyde as an initial raw material, taking (R)-methylpropane-2-sulfinamide as a chiral reagent, generating (R,E)-2-methyl-N-(3-methyl butylidene) propane-2-sulfinamide by a condensation and dehydration reaction, then carrying out a nucleophilic addition reaction with pinacol diboron so as to generate (R)-1-N-methylpropane sulfinyl-3-methyl butane-1-pinacol borate ester, afterwards hydrolyzing under an acidic condition so as to obtain pinacol-(R)-1-amino-3-methyl butane-1-borate ester hydrochloride, then reacting with (S)-3-phenyl-2-(pyrazine-2-formamido) propionic acid under the existence of a coupling agent and also hydrolyzing under the action of isobutyl borate so as to generate a final product of the bortezomib. According to the synthetic method of the bortezomib, the (R)-methylpropane-2-sulfinamide which is easy to obtain is used as the chiral induction reagent, so that an obtained intermediate enantiomorph has higher purity, and a bulk drug which is finally obtained has better quality.

Description

1. Technical field [0001] The invention relates to a preparation method of an anticancer drug, in particular to a synthesis method of bortezomib. 2. Background technology [0002] Bortezomib (bortezomib) is a dipeptidyl boronic acid compound. As a new type of highly efficient and specific protease inhibitor, it was first developed by Millennium Pharmaceuticals in the United States, and it was approved by the FDA on May 19, 2003. Velcade The trade name is listed on the market and is an injection. It was subsequently launched in the United Kingdom, Switzerland, Iceland, Australia, Malaysia, China and other countries, mainly for the treatment of relapsed and refractory multiple myeloma. With the continuous research of a large number of medical workers, it has been found that bortezomib not only has a good curative effect in the treatment of relapsed and refractory multiple myeloma, but also shows that it has a cellular effect on a variety of other human tumor cells. toxicity....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/078
Inventor 冯乙巳章丰丰徐中秋乔文龙郑波程月
Owner HEFEI UNIV OF TECH
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