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Chiral alpha-amino boric acid esters, a preparation method and an application in the synthesis of bortezomib thereof

A technology of amino borate and amino, which is applied in the field of chiral α-amino borate intermediates, which can solve the problems of high energy consumption in reaction conditions and harsh production environment conditions

Inactive Publication Date: 2013-07-17
CHENGDU AIQUN TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0037] The technical problem to be solved by the present invention is to overcome defects such as the processing route of prior

Method used

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  • Chiral alpha-amino boric acid esters, a preparation method and an application in the synthesis of bortezomib thereof
  • Chiral alpha-amino boric acid esters, a preparation method and an application in the synthesis of bortezomib thereof
  • Chiral alpha-amino boric acid esters, a preparation method and an application in the synthesis of bortezomib thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090]

[0091] 1.89 kg (10 mol) of (R)-2-methyl-N-(3-methylbutylene)propane-2-sulfinamide was added to a 20-liter reactor, and then 4 liters of tert-butyl methyl ether was added to stir and disperse evenly. Under the atmosphere of nitrogen protection, 2.72 kilograms (12mol) of neopentyl glycol diborate were added successively, and 329 grams of copper trifluorosulfonate (1mol) were added several times within 30 minutes. After the addition was completed, the reaction solution was allowed to react at room temperature. After 18 hours, TLC monitored the progress of the reaction. After the reaction was completed, 2 liters of ethyl acetate was added to disperse the reaction solution, and then 1N NaHCO was added. 3 3 liters of aqueous solution was washed once, the upper organic phase was washed three times with saturated brine, the aqueous phase was separated and discarded, and the organic phase was stirred and dried with 200 g of anhydrous sodium sulfate for at least 2 hours. The...

Embodiment 2

[0099]

[0100] Add 1.89 kg (10 mol) of (R)-2-methyl-N-(3-methylbutylene) propane-2-sulfinamide to a 20-liter reactor, then add 4 liters of tetrahydrofuran and stir to disperse and mix evenly. Under the atmosphere of protection, add 5.08 kilograms (20mol) of diboronic acid (2-methyl-2,4-pentanediol) respectively successively, add 177 grams of copper propionate (1.0mol) several times in 30 minutes, add , let the reaction solution react at 0°C for 48 hours, TLC monitors the progress of the reaction, after the reaction is completed, add 2 liters of ethyl acetate to disperse the reaction solution, and then add 1N NaHCO 3 3 liters of aqueous solution was washed once, and then the upper organic phase was washed three times with saturated brine, the aqueous phase was separated and discarded, and the organic phase was stirred and dried with 200 g of anhydrous sodium sulfate for at least 2 hours. The organic phase was concentrated under reduced pressure to obtain the compound R-N-(R...

Embodiment 3

[0108]

[0109] Add 1.89 kg (10 mol) of (R)-2-methyl-N-(3-methylbutylene) propane-2-sulfinamide to a 20-liter reactor, then add 4 liters of n-pentane and stir to disperse and mix evenly. Under the atmosphere of nitrogen protection, 3.38 kilograms (12mol) of diboronic acid (2,4-dimethyl-2,4-pentanediol) were added successively, and 221 grams of copper sulfate (1mol) were added several times within 30 minutes. , after adding, let the reaction solution react at room temperature for 18 hours, TLC monitors the progress of the reaction, after the reaction is completed, add 2 liters of ethyl acetate to disperse the reaction solution, then add 1N NaHCO 3 3 liters of aqueous solution was washed once, the upper organic phase was washed three times with saturated brine, the aqueous phase was separated and discarded, and the organic phase was stirred and dried with 200 g of anhydrous sodium sulfate for at least 2 hours. The organic phase was concentrated under reduced pressure to obtai...

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Abstract

The present invention discloses intermediates of chiral alpha-amino boric acid esters, chiral alpha-amino boric acid esters and salts thereof, and key intermediates for the synthesis of bortezomib. The invention also discloses a preparation method for the intermediates of the alpha-amino boric acid esters, and a method for synthesis of the bortezomib by using chiral alpha-amino boric acid esters and salts thereof and using a convergent strategy. According to the present invention, the bortezomib synthesis process route is low in cost, key intermediates are low in production cost, and operations are simple, very easy for industrial production.

Description

Technical field: [0001] The invention specifically relates to a chiral α-amino borate intermediate, a chiral α-amino borate, a key intermediate of bortezomib and its application in the synthesis of bortezomib. Background technique: [0002] Bortezomib (Bortezomib), trade name ( Velcade ) is a new type of anti-tumor drug developed by the American Millennium Pharmaceutical Company. It is a synthetic dipeptide boronic acid derivative. The drug is a 26S protease inhibitor. , leading to tumor cell death. A large number of studies have found that bortezomib has strong anti-tumor activity against various tumors, especially multiple myeloma, mantle cell lymphoma, other B-cell lymphoma, and Hodgkin's lymphoma in hematological tumors. In addition, bortezomib is used in combination with chemotherapy drugs to treat acute myeloid leukemia, acute lymphoblastic leukemia, and adult T lymphocytic leukemia. Plasma cell leukemia has achieved varying degrees of curative effect, and the ad...

Claims

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Application Information

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IPC IPC(8): C07F5/04C07F5/02C07B53/00
Inventor 张明
Owner CHENGDU AIQUN TECH
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