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Synthesis technology of alpha-chiral boric acid and boric acid ester

A boric acid ester and chiral technology, applied in the field of α-chiral boronic acid compounds, can solve the problems of increasing economic pressure on the country and patients, lack of effective treatment for patients, and increase in production costs, achieving low cost and total production. The effect of high rate and high overall yield of the route

Active Publication Date: 2010-12-01
SHANGHAI VIWIT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the synthesis processes of Plamondon and Fraser, the cyclic tripolyboronic anhydride (Boroxine) needs to be crystallized to achieve higher purity, resulting in increased production costs
[0012] α-Chiral boronic acid and borate ester compounds have great application potential in the field of medicine, but the existing synthetic processes have high production costs, or are limited in adapting to relatively small production scales, which greatly limit their use in medicine. In particular, some α-chiral boronic acids and borate compounds such as bortezomib (Bortzomib) that have been used in medicine and have shown very good curative effects, the high production cost is an important factor for the high price of its preparations, which It has greatly increased the economic pressure on the country and patients, especially in developing countries where the medical security system is not perfect, many patients cannot receive effective treatment due to economic reasons

Method used

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  • Synthesis technology of alpha-chiral boric acid and boric acid ester
  • Synthesis technology of alpha-chiral boric acid and boric acid ester
  • Synthesis technology of alpha-chiral boric acid and boric acid ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0205] Example 1: Synthesis of α-chiral borate with lower cost, easier control of process conditions and higher product purity: (1S)-(S)-pinanediol 1-chloro-3-methylbutane Base-1-boronate scale-up process:

[0206]

[0207]Step 1. Add 428 g of isopropyl boric acid and 1.5 kg of methyl tert-butyl ether into a 10-liter reaction vessel, and add a solution comprising 644 g of (S)-pinanediol and 1.5 kg of methyl tert-butyl ether under stirring. After the dropwise addition, continue to stir for more than 2 hours to track the reaction by TLC or GC, and confirm that all the (S)-pinanediols have reacted completely. Add 200 g of saturated aqueous sodium bicarbonate solution to the reaction solution for washing, and separate the liquids; add 200 g of water to wash the organic phase, and separate the liquids; add 200 g of saturated aqueous sodium chloride solution to wash the organic phase. Add 200g of anhydrous sodium sulfate and stir for more than 2 hours, filter to obtain (S)-pinan...

Embodiment 2

[0214] Embodiment two: lower cost, easier control of the conditions described in the process, and higher product purity Synthesis of α-aminoboronic acid ester or its salt with acid: (1R)-(S)-pinanediol Ammonium 1-trifluoroacetate-3-methylbutanyl-1-boronate scale-up process:

[0215]

[0216] Step 4. Synthesize (1S)-(S)-pinanediol 1-chloro-3-methylbutanyl-1-boronate 980g according to steps 1 to 3 in Example 1 and dissolve it into 3.0kg methyl ring In hexane; control the reaction temperature at about minus 20°C and add dropwise to a solution including 338g LiHMDS, 3.3kg of tetrahydrofuran and 1.0kg of n-hexane, and finish adding in about 1.0 hour. After the addition, control the temperature at about minus 10°C and continue stirring for 1.0 hour . After warming up to room temperature, 170g of diatomaceous earth and 2.0kg of methylcyclohexane were added. Rotary evaporation under reduced pressure until the tetrahydrofuran in the system was added. After adding 3.0 kg of methylc...

Embodiment 3

[0220] Embodiment 3: lower cost, easier control of process conditions, higher product purity Synthetic free boronic acid compound comprises dipeptide borate protease inhibitor bortezomib (Bortezomib)

[0221]

[0222] Or its boric acid anhydride (XXVII) can be applied to the improved process of mass production:

[0223]

[0224] Step 6. Synthesize (1R)-(S)-pinanediol 1-ammonium trifluoroacetate-3-methylbutanyl-1-boronate according to steps 4-5 in Example 2. Add the above-mentioned (1R)-(S)-pinanediol 1-ammonium trifluoroacetate-3-methylbutanyl-1-boronate 303g, N-Boc-L-phenylpropane to a 10-liter reaction vessel Amino acid 212g, TBTU 283g, dichloromethane 3.1kg; control the temperature at about 0°C and add 310g of diisopropylethylamine dropwise for about 0.5 hours, and continue stirring for 0.5 hours after the addition; TLC or HPLC track the reaction to confirm the raw materials ( 1R)-(S)-pinanediol 1-ammonium trifluoroacetate-3-methylbutanyl-1-boronate was converted com...

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Abstract

The invention discloses an alpha-chiral boric acid ester compound disclosed by a general formula (I) and a technology for forming the alpha-chiral boric acid ester compound by detracting chiral protecting groups R4 and R5 of boric acid ester (1), wherein the general formula (I), the definitions of substituted groups in the alpha-chiral boric acid ester compound and the alpha-chiral boric acid compound are the same with the definition in a specification. The invention discloses the boric acid ester compound disclosed by the general formula (I) and a boric acid compound corresponding to the boric acid ester compound and comprises a synthesis technology of a dipeptide boric acid protease inhibitor (bortezomib). The synthesis technology has the advantages of higher route total production rate, lower cost, easier control of technical conditions and higher purity of products, recycle of byproducts and suitability for mass production when being used for synthesizing the boric acid and the boric acid ester compounds.

Description

technical field [0001] The invention discloses an α-chiral boronic acid ester compound represented by general formula (I) and the corresponding "α-chiral boronic acid compound" of the boronic acid ester compound, including the dipeptide boronic acid protease inhibitor bortezomib (bortezomib) synthesis technique; it is characterized in that when applying the technique disclosed in the invention to synthesize α-chiral boronic acid and borate compounds, the total yield of the route is higher, the cost is lower, the conditions described in the technique are easier to control, and the product purity Higher, by-products can be recycled; the process involved in the invention is especially suitable for industrialized mass production of α-chiral boric acid and borate ester compounds. Background technique [0002] Boronic acids and boronate ester compounds exhibit a variety of pharmaceutical uses and biological activities. Shenvi et al. disclosed a patent on peptide boronic acids as ...

Claims

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Application Information

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IPC IPC(8): C07F5/04C07F5/02C07F5/05C07K5/078C07B57/00
CPCY02P20/55
Inventor 魏彦君于向达李世江邵钦
Owner SHANGHAI VIWIT PHARMA CO LTD
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