Synthesis method of 5-biphenyl-4-amino-2-methylvaleric acid intermediate

A synthesis method and methyl technology, applied in the field of medicine, can solve the problems of low yield, poor methylation selectivity, difficult separation of diastereomers, etc., so as to solve the problem of poor reaction selectivity and good selectivity Effect

Active Publication Date: 2015-07-22
苏州中科新药篮生物医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Although the natural amino acid L-pyroglutamic acid that is easier to obtain is used as a raw material in this method, the selectivity of its methylation is relatively poor, and the resulting diastereoisomers are not easy to separate, which is the subsequent 5-biphenyl The synthesis of base-4-amino-2-methylpentanoic acid introduces impurity that is difficult to remove; On the other hand, the yield of this reaction is very low, which is unfavorable for suitability for industrialized production

Method used

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  • Synthesis method of 5-biphenyl-4-amino-2-methylvaleric acid intermediate
  • Synthesis method of 5-biphenyl-4-amino-2-methylvaleric acid intermediate
  • Synthesis method of 5-biphenyl-4-amino-2-methylvaleric acid intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Synthesis of compound (5a)

[0070]

[0071] Add 288g of compound 6 into 1.5L of dichloromethane, add 476g of p-toluenesulfonyl chloride and 25g of DMAP, drop the temperature to 0°C, add 610g of triethylamine dropwise, and stir at room temperature for 3 hours after dropping. The reaction solution was washed with water, washed with acid, dried, concentrated, and slurried by adding methyl tert-butyl ether to obtain 545 g of compound 5a.

Embodiment 2

[0073] Synthesis of compound (4a)

[0074]

[0075] Add 190g of 5a into 1L of ethyl acetate, add 169g of Boc-anhydride, 8.7g of DMAP, and heat to 50°C for 5 hours. The reaction solution was washed with water, dried and concentrated to obtain 243 g of compound 4a, with a yield of 96.4%.

Embodiment 3

[0077] Synthesis of compound (4b)

[0078]

[0079] 190g of 5a was added to 1L of ethyl acetate, 8.7g of DMAP and 86g of triethylamine were added, 94g of pivaloyl chloride was added dropwise at 0°C, and the reaction was completed for 3 hours. The reaction solution was washed with water, washed with acid, dried and concentrated to obtain 235 g of compound 4a with a yield of 93.6%.

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Abstract

The invention provides a synthesis method of a new compound (3) disclosed in the specification and a synthesis method for preparing a 5-biphenyl-4-amino-2-methylvaleric acid intermediate from the compound (3). The method has excellent selectivity, and generates few diastereoisomers in the reaction process. The generated diastereoisomers can be removed just by simple recrystallization. Thus, the method is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a method for synthesizing a 5-biphenyl-4-amino-2-methylpentanoic acid intermediate. Background technique [0002] AHU-377 is a prodrug that is a component of an experimental dual-acting angiotensin receptor neprilysin inhibitor developed by Novartis that works by blocking the 2-threat hormone responsible for lowering blood pressure. The mechanism of action of the peptide. Wherein 5-biphenyl-4-amino-2-methylpentanoic acid is an intermediate for the synthesis of AHU-377, and its structural formula is as follows: [0003] [0004] Compound (1) is a key intermediate in the synthesis of 5-biphenyl-4-amino-2-methylpentanoic acid. [0005] [0006] wherein R is a nitrogen protecting group. [0007] Patent CN200880008018.9 discloses a method for synthesizing compound (1) using L-pyroglutamic acid as a raw material through esterification, substitution, reduction, amino protection, and met...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/263C07D207/26
CPCY02P20/55C07D207/263C07D207/26
Inventor 不公告发明人
Owner 苏州中科新药篮生物医药科技有限公司
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