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Purification method for midbody of sacubitril

A technology of Shakubitqu and its purification method, which is applied in the field of purification of Shakubitqu intermediates, and can solve problems such as excessive impurities of isomers

Inactive Publication Date: 2017-06-30
常州沃腾化工科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] WO2014032627A1 reports a method for preparing (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate, according to The product prepared by the preparation method contains more than 1% of the S-type isomer impurity, which is (S)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3 -Hydroxypropan-2-yl) carbamate, this S-type isomer impurity will continue to participate in the subsequent synthesis steps of Sacubitril, resulting in the final Sacubitril isomer impurity exceeding the standard
However, there is no relevant preparation method for the removal of this isomer impurity in the currently reported literature

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0015] Example 1, 25g (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate, 250ml n-heptane, Add 21ml of ethyl acetate and .25g of activated carbon into a 500ml four-neck flask, heat to reflux for 10 minutes, (R)-tert-butyl(1-([1,1'-biphenyl]-4-yl)-3-hydroxy Propan-2-yl) carbamate contains 1.2% by weight of (S)-tert-butyl(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl ) carbamate; then filter the activated carbon while it is hot, rinse the activated carbon with 8ml ethyl acetate, combine all the washings with the filtrate, heat the combined solution to reflux for 10 minutes, cool to 25 degrees to crystallize, filter with suction, and use Rinse with 37.5ml of n-heptane and dry at 70°C to obtain the purified solid product (R)-tert-butyl(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl ) carbamate 19.25g, yield 77%, (S)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)aminomethyl The ester isomer content is 0.043%.

example 2

[0016] Example 2, 25g (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate (isomer content 1.2 %), 250ml of n-heptane, 25ml of ethyl acetate and 1.25g of activated carbon into a 500ml four-neck flask, heated to reflux for 10 minutes, (R)-tert-butyl (1-([1,1'-biphenyl]- 4-yl)-3-hydroxypropan-2-yl) carbamate contains 1.2% by weight of (S)-tert-butyl (1-([1,1'-biphenyl]-4-yl)- 3-hydroxypropan-2-yl) carbamate; then filter the activated carbon while it is hot, rinse the activated carbon with 8ml ethyl acetate, combine all the washings with the filtrate, heat the combined solution to reflux for 10 minutes, cool to 25 degrees and analyze crystallization, suction filtration, the filter cake was rinsed with 37.5ml n-heptane, and dried at 70 degrees to obtain the purified solid product (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)- 3-Hydroxypropan-2-yl) carbamate 17.45g, yield 69.8%, (S)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxyl Propan-2-yl) carbamate isomer conten...

example 3

[0017] Example 3: 25g (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate, 250ml n-heptane, Add 30ml of ethyl acetate and 1.25g of activated carbon into a 500ml four-neck flask, heat to reflux for 10 minutes, (R)-tert-butyl(1-([1,1'-biphenyl]-4-yl)-3-hydroxy Propan-2-yl) carbamate contains 1.2% by weight of (S)-tert-butyl(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl ) carbamate; then filter the activated carbon while it is hot, rinse the activated carbon with 8ml ethyl acetate, combine all the washings with the filtrate, heat the combined solution to reflux for 10 minutes, cool to 25 degrees to crystallize, filter with suction, and use Rinse with 37.5ml of n-heptane and dry at 70°C to obtain the purified solid product (R)-tert-butyl(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl ) carbamate 17.1g, yield 68.4%, (S)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)aminomethyl The ester isomer content is 0.031%.

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Abstract

The invention relates to a purification method for a midbody of sacubitril. The method is characterized by comprising adding (R)-tertiary butyl (1-([1.1'-biphenyl]-4-yl)-3-hydroxy-2-yl)carbamate including S-type isomer impurities and active carbon into solvent, wherein the solvent is mixed solution of n-heptane and ethyl acetate, then heating until flowing back for 8-15min, filtering when being hot to remove the active carbon, flushing the active carbon with the ethyl acetate, combining all scrubbing solution with filtrate, further heating the combined solution until flowing back, cooling to devitrifying, and performing suction filtration, flushing a filter cake with the n-heptane and drying; therefore, the purified finished midbody of sacubitril, the (R)-tertiary butyl (1-([1.1'-biphenyl]-4-yl)-3-hydroxy-2-yl)carbamate is acquired. The purification method has the advantages that content of the S-type isomer impurities in the midbody, the finished (R)-tertiary butyl (1-([1.1'-biphenyl]-4-yl)-3-hydroxy-2-yl)carbamate is less than 0.05wt%.

Description

technical field [0001] The present invention relates to a method for purifying a sacubitril intermediate, in particular to a (R)-tert-butyl(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane- 2-yl) carbamate purification method. Background technique [0002] Sacubitril is an anti-heart failure drug with the chemical name 4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4 -Methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid, its structural formula is: [0003] . [0004] Sacubitril / valsartan is a dual-effect angiotensin receptor neprilysin inhibitor, which has the advantages of significantly reducing the risk of cardiovascular death or hospitalization for heart failure. [0005] (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate is a key intermediate for the preparation of sacubitril. Its structural formula is: [0006] . [0007] WO2014032627A1 reports a method for preparing (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate, according t...

Claims

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Application Information

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IPC IPC(8): C07C269/08C07C271/16
CPCC07C269/08C07B2200/07C07C271/16
Inventor 巢国平王志超陈红元孙克周
Owner 常州沃腾化工科技有限公司
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