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Improved preparation method of sacubitril intermediate

A technology of sacubitril and compound, which is applied in the field of neutral endopeptidase inhibitors, and can solve the problems of high hydrogen pressure, high price, and difficulty in obtaining chiral catalysts.

Inactive Publication Date: 2017-02-15
SICHUAN HAISCO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Although this method has high chiral selectivity, there are factors that are not conducive to industrialization, such as chiral catalysts are not easily available, expensive, and hydrogen pressure is high.

Method used

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  • Improved preparation method of sacubitril intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] Example 1 Preparation of (2R, 4S)-5-(biphenyl-4-yl)-4-tert-butoxycarbonylamino-2-methylpentanoic acid (III)

[0082]

[0083] At 35~40°C, (E)-(R)-5-(biphenyl-4-yl)-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid (IV) 50.0 g (0.131mmol, 1eq), 10% palladium / carbon 2.5g and tetrahydrofuran 500ml were mixed in a hydrogenation reactor. After the replacement with hydrogen, 1.5-2 atmospheres of hydrogen was introduced, and the reaction was stirred for about 3 hours. Filtrate and concentrate the filtrate to obtain crude product of (2R,4S)-5-(biphenyl-4-yl)-4-tert-butoxycarbonylamino-2-methylpentanoic acid (compound of formula III), chiral HPLC: 85.6% .

[0084] Stir and mix about 20 g of the crude product of (2R,4S)-5-(biphenyl-4-yl)-4-tert-butoxycarbonylamino-2-methylpentanoic acid (compound of formula III) with 60 ml of acetone, Heated to reflux, and 120ml of n-heptane was added dropwise. After the addition, it was naturally lowered to room temperature, stirred an...

Embodiment 2

[0092] Example 2 Preparation of (2R, 4S)-5-(biphenyl-4-yl)-4-tert-butoxycarbonylamino-2-methylpentanoic acid diisopropylamine salt (XII)

[0093]

[0094] At 30~35°C, (E)-(R)-5-(biphenyl-4-yl)-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid (IV) 50.0 g (0.131mol, 1eq), 14.6g (0.144mol, 1.1eq) of diisopropylamine, 5.0g of 10% Pd / C and 250ml of ethanol were mixed in a hydrogenation reactor. After hydrogen replacement, 2-2.5 atmospheres of hydrogen was added, and the reaction was stirred for about 3 hours. Filtration, and the filtrate was concentrated to obtain (2R,4S)-5-(biphenyl-4-yl)-4-tert-butoxycarbonylamino-2-methylpentanoic acid diisopropylamine salt (compound of formula XII) crude product, chiral HPLC: 90.8%.

[0095] Mix the crude product of (2R,4S)-5-(biphenyl-4-yl)-4-tert-butoxycarbonylamino-2-methylpentanoic acid diisopropylamine salt (compound of formula XII) with 250ml of acetone, and stir . Heated to reflux, and 750ml of n-heptane was added dropwise. A...

Embodiment 3

[0096] Example 3 (2R, 4S)-5-(biphenyl-4-yl)-4-tert-butoxycarbonylamino-2-methylpentanoic acid (S)-(-)-α-phenethylamine salt ( XIII) Preparation

[0097]

[0098] At 25~30°C, add (E)-(R)-5-(biphenyl-4-yl)-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid (IV) 50.00g (0.131mol, 1eq), (S)-(-)-α-phenethylamine 12.7g (0.105mmol, 0.8eq), 5% Pd / C 10.0g and methyl tetrahydrofuran 600ml were mixed and stirred in a hydrogenation reactor. After hydrogen replacement, 2.5 to 3 atmospheres of hydrogen was added, and the reaction was stirred for about 3 hours. Filtration, and the filtrate was concentrated to obtain (2R,4S)-5-(biphenyl-4-yl)-4-tert-butoxycarbonylamino-2-methylpentanoic acid (S)-(-)-α-phenylethylamine Salt (compound of formula XIII), chiral HPLC: 99.1%.

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Abstract

The invention relates to an improved preparation method of an important intermediate (2R, 4S)-5-(biphenyl-4-yl)-4-tert-butoxycarbonylamino-2-methyl pentanoic acid (that is a compound shown in the formula III) for preparing sacubitril which is a neutral endopeptidase (NEP) inhibitor and of an analog or salt of the intermediate. The method mainly comprises that in the presence of a palladium catalyst, hydrogenation is carried out to make the compound shown in the formula III and having high optical purity and the analog or salt of the compound. The improved method is available in raw materials, mild in reaction condition, and simple and convenient to operate. The product quality is excellent and the cost is low, so that the method is suitable for industrial mass production.

Description

[0001] The invention relates to the fields of organic chemistry and pharmacy, in particular to an important intermediate (2R,4S)-5-(biphenyl-4-yl) for preparing neutral endopeptidase (NEP) inhibitor sacubitril An improved preparation method of )-4-tert-butoxycarbonylamino-2-methylpentanoic acid and its analogs or salts thereof. Background technique [0002] Sacubitril, English common name: Sacubitril, also known as: AHU-377, chemical name: 4-{[(2S,4R)-1-([1,1'-biphenyl]-4-yl)- 5-ethoxy-4-methyl-5-oxopent-2-yl]amino}-4-oxobutyric acid, the structure of which is shown in formula I, is a neutral endopeptidase inhibitor. [0003] [0004] When Sacubitril or its salt is administered in combination with angiotensin IIAT1 receptor antagonists, such as valsartan, it can simultaneously inhibit neprilysin and angiotensin receptors, that is, it can simultaneously act on renin -The angiotensin system and promotes the circulation of brain natriuretic peptide, acts in multiple ways on t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/22C07C269/06C07C233/47C07C231/02C07C227/18C07C227/20C07C229/34C07C211/27C07C211/06C07C211/05
CPCY02P20/55
Inventor 赵永龙陈大峰高炳坤何永耀程睿秦莉娜陆崇玉贾晓曼雷有成罗杰向志祥
Owner SICHUAN HAISCO PHARMA CO LTD
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