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Method for increasing synthetic reaction rate of ixabepilone

A synthesis reaction, ixabepilone technology, applied in the direction of organic chemistry, can solve the problems of unfavorable product quality and industrial production, slow reaction, incomplete epothilone B reaction, etc., to improve process efficiency and product quality, The effect of speeding up the reaction rate

Pending Publication Date: 2021-03-09
HUBEI HONCH PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] The existing synthetic ixabepilone method reacts slowly after adding trimethylphosphine, at least 12 hours, and sometimes the raw material epothilone B reacts incompletely, and a certain amount of by-products are produced, which is not conducive to product quality and Industrial production

Method used

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  • Method for increasing synthetic reaction rate of ixabepilone
  • Method for increasing synthetic reaction rate of ixabepilone
  • Method for increasing synthetic reaction rate of ixabepilone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] (1) In 50ml one-mouth bottle A: put 0.5g of epothilone B (1.0eq) into TBAN 3 [i.e. tetrabutylammonium azide] (1.4eq) in THF [i.e. tetrahydrofuran] solution or DMF [i.e. dimethylformamide] solution or aqueous solution (which contains 0.4gTBAN 3 ), shake well to dissolve.

[0030] (2) In the 50ml three-neck bottle B: put 0.08g of Pd 2 (dba) 3 [i.e. tris(dibenzylideneacetone) dipalladium (0)] (0.09eq) and 0.05g of NH 4 Cl [i.e. ammonium chloride] (1eq), protected by argon, heated to 20°C, and then injected 2ml of PMe 3 [Trimethylphosphine] in THF (2.0eq). After stirring for 20 minutes, the solution in bottle A was injected.

[0031] (3) After keeping at 20° C. for 30 minutes, TLC monitors: the raw material point disappears.

[0032] (4) Filtration, and the filter residue was washed once with 3.0 ml of THF to obtain a dark blue clear solution, which was stored under refrigerated conditions at 0-10°C.

[0033] (5) In 50ml one-mouth bottle C: put 1.8ml of DMF and 1.8ml...

Embodiment 2

[0038] (1) In 50ml one-mouth bottle A: put 0.1g of epothilone B (1.0eq) into TBAN 3 (1.4eq) solution (which contains 0.08g TBAN 3 ), shake well to dissolve.

[0039] (2) In the 50ml three-neck bottle B: put 0.02g of Pd 2 (dba) 3 (0.09eq) and 0.015g of NH 4 Cl (1.5eq), protected by argon, heated up to 35°C, and then injected 0.5ml of PMe 3 solution in THF (2.0 eq). After stirring for 20 minutes, the solution in bottle A was injected.

[0040] (3) After keeping at 22° C. for 40 minutes, TLC monitors: the starting point disappears.

[0041] (4) Filtration, and the filter residue was washed once with 1.0 ml of THF to obtain a dark blue clear solution, which was stored under refrigerated conditions at 0-10°C.

[0042] (5) 50ml one-mouth bottle C: put 0.5ml of DMF and 0.5ml of THF in sequence, stir in a water bath at 10°C, then add 0.08g of EDCI (2.2eq) and 0.02g of K 2 CO 3 (0.4eq) and 0.05g of HOBT (1.7eq), stirred for 0.5 hours.

[0043] (6) Add the above-mentioned filt...

Embodiment 3

[0047] (1) In 250ml one-mouth bottle A: put 5g of epothilone B (1.0eq) into TBAN 3 (1.4eq) solution (which contains 4g TBAN 3 ), shake well to dissolve.

[0048] (2) In 250ml three-neck bottle B: put 0.8g of Pd 2 (dba)3 (0.09eq) and 0.25g of NH 4 Cl (0.5eq), protected by argon, heated up to 20°C, and then injected 20ml of PMe 3 solution in THF (2.0 eq). After stirring for 15 minutes, the solution in bottle A was injected.

[0049] (3) After keeping at 20° C. for 50 minutes, TLC monitors: the raw material point disappears.

[0050] (4) Filtration, and the filter residue was washed once with 30 ml of THF to obtain a dark blue clear solution, which was stored under refrigerated conditions at 0-10°C.

[0051] (5) In 500ml one-mouth bottle C: put 20ml of DMF and 20ml of THF in sequence, stir in a water bath at 10°C, then add 4g of EDCI (2.2eq) and 0.7g of K 2 CO 3 (0.4eq) and 2.3g of HOBT (1.7eq), stirred for 0.5 hours.

[0052] (6) Add the above-mentioned filtrate stored ...

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Abstract

The invention belongs to the field of chemical industry, and particularly relates to a method for increasing the ixabepilone synthesis reaction rate. The method comprises the following steps: adding aTBAN3 solution into a first container containing epothilone B, shaking up, and dissolving to obtain a first mixed system; putting a catalyst Pd2(dba)3 and NH4Cl into a second container, adding a THFsolution of PMe3 under the protection of argon to obtain a second mixing system, and mixing the first mixing system an the second mixing system to obtain an ixabepilone solution. According to the scheme, the catalyst Pd2(dba)3 and the catalyst PMe3 interact with each other and then react with the substrate epothilone B, so that the azidation and reduction reaction rates are increased, the reactioncan be completed within 0.5-1.0 hour generally, basically no other byproducts are generated, the process efficiency and the product quality are improved, and the method is more suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of chemical industry, in particular to a method for improving the reaction rate of ixabepilone synthesis. Background technique [0002] The existing synthetic ixabepilone method reacts slowly after adding trimethylphosphine, at least 12 hours, and sometimes the raw material epothilone B reacts incompletely, and a certain amount of by-products are produced, which is not conducive to product quality and Industrial production. Contents of the invention [0003] In order to solve the above problems, the invention provides a method for improving the synthetic reaction rate of ixabepilone, wherein Pd 2 (dba) 3 act as a catalyst. [0004] Technical scheme of the present invention is a kind of method that improves the synthetic reaction rate of ixabepilone, comprises the following steps: [0005] S1. Add TBAN to the first container with epothilone B 3 solution, shake well and dissolve as the first mixed system; [000...

Claims

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Application Information

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IPC IPC(8): C07D491/044
CPCC07D491/044
Inventor 徐有安付光明龚美芳
Owner HUBEI HONCH PHARMA
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