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A kind of synthetic method of (r)-(1-amino-3-methyl)butyl-1-boronic acid pinanediol ester

A technology of pinanediol borate and synthesis method, which is applied in the field of medicine and chemical industry, can solve the problems of high price, harsh conditions, and high cost, and achieve the effects of being beneficial to industrial production, mild reaction conditions, and low production cost

Active Publication Date: 2020-02-07
宜昌天睿生物医药有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are serious deficiencies in this method: active metal lithium reagents (LDA, LHMDS) need to be used, which are expensive and highly active; there are two-step reactions that need to be carried out at ultra-low temperatures (-78 ° C); the chiral ee value of the resulting product is not high. High, only about 80%, utilize this product to directly carry out the synthesis of bortezomib according to the prior art, and through splitting, purifying, ee value also only has about 95%, is difficult to reach the requirement of drug standard; In a word, this method condition is harsh , the cost is high, and the products produced do not meet the requirements of the standard, which is not conducive to industrial production
The substrate of this route has less steric hindrance, and the reaction does not add a chiral catalyst; therefore, the stereoselectivity of this route is not very good

Method used

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  • A kind of synthetic method of (r)-(1-amino-3-methyl)butyl-1-boronic acid pinanediol ester
  • A kind of synthetic method of (r)-(1-amino-3-methyl)butyl-1-boronic acid pinanediol ester
  • A kind of synthetic method of (r)-(1-amino-3-methyl)butyl-1-boronic acid pinanediol ester

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] (R)-Benzyl-(3-methyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butane)carbamate Synthesis of Esters (Formula III)

[0049] Add (R)-1-amino-3-methylbutane-1-boronic acid pinacol ester hydrochloride (10mmol, 2.5g, formula II) and dichloromethane (30mL) into the there-necked flask, stir and wash with ice Cool in a water bath. Triethylamine (25mmol, 3.5mL) was added thereto, and stirred for 5-10min under an ice-water bath. A dichloromethane solution (10 ml) of benzyl chloroformate (11 mmol, 1.6 mL) was added slowly while keeping the temperature of the reaction mixture below 15° C. After the addition was complete, the reaction was continued at room temperature for 1 hour. Then add 1N dilute hydrochloric acid (10mL) under ice-water bath to quench the reaction, separate the organic layer, extract the aqueous layer with dichloromethane (2×30mL), combine the organic layers, wash with water (30mL), dry over anhydrous sodium sulfate, and filter , and concentrated to drynes...

Embodiment 2

[0059] (R)-tert-butyl-(3-methyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butane)aminomethyl Synthesis of esters (formula III)

[0060] Add (R)-1-amino-3-methylbutane-1-boronic acid pinacol ester hydrochloride (10mmol, 2.5g, formula II) and dichloromethane (30mL) into the there-necked flask, stir and wash with ice Cool in a water bath. Triethylamine (25mmol, 3.5mL) was added thereto, and stirred for 5-10min under an ice-water bath. A dichloromethane solution (10 ml) of di-tert-butyl dicarbonate (11 mmol, 2.4 g) was added slowly while keeping the temperature of the reaction mixture below 15° C. After the addition, the temperature was raised to room temperature to continue the reaction for 1 hour. Then add 1N dilute hydrochloric acid (10mL) under ice-water bath to quench the reaction, separate the organic layer, extract the aqueous layer with dichloromethane (2×30mL), combine the organic layers, wash with water (30mL), dry over anhydrous sodium sulfate, and filter , and ...

Embodiment 3

[0067] (R)-N-(3-methyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butane)acetamide (formula III) Synthesis

[0068] Add (R)-1-amino-3-methylbutane-1-boronic acid pinacol ester hydrochloride (10mmol, 2.5g, formula II) and dichloromethane (30mL) into the there-necked flask, stir and wash with ice Cool in a water bath. Triethylamine (25mmol, 3.5mL) was added thereto, and stirred for 5-10min under an ice-water bath. A dichloromethane solution (10 ml) of acetic anhydride (11 mmol, 1.1 g) was added slowly while keeping the temperature of the reaction mixture below 15° C. After the addition, the temperature was raised to room temperature to continue the reaction for 1 hour. Then add 1N dilute hydrochloric acid (10mL) under ice-water bath to quench the reaction, separate the organic layer, extract the aqueous layer with dichloromethane (2×30mL), combine the organic layers, wash with water (30mL), dry over anhydrous sodium sulfate, and filter , and concentrated to dryness under ...

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Abstract

The invention discloses a synthetic method of (R)-(1-amino-3-methyl) butyl-1-pinane borate terephthalate (The formula I). The synthetic method is characterized in that (R)-1-amino-3-methyl butane-1-boronic acid pinacol ester hydrochloride is taken as a raw material, and a target product is obtained by amino protection, boron ester exchange and deprotection. The method disclosed by the invention has the advantages of fewer reaction steps, mild reaction conditions, low price of used reagents, high purity of products and the like; in addition, the industrial production is facilitated.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a new method for preparing the intermediates of antitumor drugs bortezomib and ixazomib, in particular to (R)-(1-amino-3-methyl)butyl-1-boronic acid pinanedi The synthetic method of alcohol ester (formula I). Background technique [0002] Bortezomib (trade name: Velcade) is a new type of anti-tumor drug developed by Millennium Pharmaceutical Company of the United States. Studies have shown that, as the first proteasome inhibitor, bortezomib can induce apoptosis of various tumor cell lines and cancerous cells, and it can also be used for the treatment of mantle cell lymphoma in addition to the treatment of multiple myeloma. At the same time, bortezomib also has a good effect on the treatment of other types of plasma cell diseases, acute myeloid leukemia and some solid tumors. As a similar drug to bortezomib, Ixazomib was developed by Takeda Pharmaceutical Company of J...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F5/02
CPCC07B2200/07C07F5/025Y02P20/55
Inventor 廖宗权符义刚李仕群李莉娥田峦鸢吕金良曲龙妹杜文涛万治华张森翔
Owner 宜昌天睿生物医药有限责任公司