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Preparation method and application of biaryl substituted 4-amino-butyric acid or derivative of biaryl substituted 4-amino-butyric acid

A carboxyl group and compound technology, which is applied in the application field of preparing NEP inhibitors, can solve the problems of low selectivity, low stability, and can not guarantee selectivity, etc., and achieves the effect of high stereoselectivity

Active Publication Date: 2016-11-23
BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the selectivity of this method is not very high. Although some examples show that the ee% is 99%, there are also examples that show that the ee% is 89%, which shows that the stability of this method is not very high, and it cannot guarantee that the selectivity is better.

Method used

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  • Preparation method and application of biaryl substituted 4-amino-butyric acid or derivative of biaryl substituted 4-amino-butyric acid
  • Preparation method and application of biaryl substituted 4-amino-butyric acid or derivative of biaryl substituted 4-amino-butyric acid
  • Preparation method and application of biaryl substituted 4-amino-butyric acid or derivative of biaryl substituted 4-amino-butyric acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041]

[0042] Add [Rh(COD) 2 ] BF 4 (315mg, 0.78mmol), the chiral phosphine ligand BICP (556mg, 0.84mmol) was added, the mixture was stirred for 30 minutes, 1(ii-a) (30g, 0.078mol), triethylamine (3.93g, 0.039 mmol). The hydrogenation was carried out at room temperature under hydrogen for 24 hours. After careful release of hydrogen gas, the reaction mixture was washed with methanol, then concentrated in vacuo. The residue was passed through a short silica gel column to remove the catalyst. Enantiomeric content was measured by capillary GC or HPLC. The reaction conversion rate is 100%, and the ee% is 99%.

[0043]

Embodiment 2

[0045]

[0046] Add [Rh(COD) 2 ] BF 4 (315mg, 0.78mmol), the chiral phosphine ligand BICPO (452mg, 0.84mmol) was added, and after the mixture was stirred for 30 minutes, 1(ii-a) (30g, 0.078mol) was added in sequence. The hydrogenation was carried out at room temperature under hydrogen for 24 hours. After careful release of hydrogen gas, the reaction mixture was washed with methanol, then concentrated in vacuo. The residue was passed through a short silica gel column to remove the catalyst. Enantiomeric content was measured by capillary GC or HPLC. The reaction conversion rate is 100%, and the ee% is 99%.

[0047]

Embodiment 3

[0049]

[0050] Add [Rh(COD) 2 ] BF 4 (315mg, 0.78mmol), chiral phosphine ligand L6 (475mg, 0.84mmol) was added, and after the mixture was stirred for 30 minutes, 1(ii-a) (30g, 0.078mol) was added in sequence. The hydrogenation was carried out at room temperature under hydrogen for 24 hours. After careful release of hydrogen gas, the reaction mixture was washed with methanol, then concentrated in vacuo. The residue was passed through a short silica gel column to remove the catalyst. Enantiomeric content was measured by capillary GC or HPLC. The reaction conversion rate is 100%, and the ee% is 96%.

[0051]

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PUM

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Abstract

The invention relates to a preparation method of biaryl substituted 4-amino-butyric acid or a derivative of biaryl substituted 4-amino-butyric acid. The preparation method comprises the step as follows: a compound (II) is subjected to a reaction with hydrogen under the condition of presence of a transition metal catalyst and a chiral ligand, and a compound (I) is generated, wherein the transition metal catalyst is a rhodium catalyst, the chiral ligand is a chiral phosphorous ligand with a conformational stiffening ring structure, phosphorus can be in bond linkage with the ring structure or taken as one part of the ring structure, and biaryl substituted 4-amino-butyric acid or the derivative of biaryl substituted 4-amino-butyric acid is prepared from the compound (I) through further processing.

Description

technical field [0001] The invention relates to a method for preparing biaryl-substituted 4-aminobutyric acid or derivatives thereof, and an application in preparing NEP inhibitors. Background technique [0002] Endogenous atrial natriuretic peptide (ANP) has diuretic, natriuretic and vasodilation functions in mammals. Native ANP is metabolically inactivated, in particular by the degradative enzyme of neutral endopeptidase (NEP, EC 3.4.24.11 ), which is also responsible for the metabolic inactivation of eg enkephalins. [0003] In the prior art, it is known that biaryl-substituted phosphonic acid derivatives are useful as neutral endopeptidase (NEP) inhibitors, for example as inhibitors of mammalian ANP-degrading enzymes, thereby inhibiting ANP Degradation to less active metabolites prolongs and potentiates the diuretic, natriuretic and vasodilatory properties of ANP in mammals. NEP inhibitors are therefore particularly useful in the treatment of conditions and disorders r...

Claims

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Application Information

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IPC IPC(8): C07C271/22C07C269/06C07C233/47C07C231/02B01J31/24
CPCY02P20/55
Inventor 袁建栋徐安佗王萌
Owner BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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