Preparation method of (R)-2-(N-tertbutyloxycarbonylamino)biphenylpropanol

A technology of tert-butoxycarbonylamino and aminobiphenylpropanol, which is applied in the field of preparation of Sacubitril intermediates, can solve the problems of high requirements for reaction operations, heavy environmental pollution, and inability to solve the synthesis of target compounds well

Inactive Publication Date: 2016-02-17
天台宜生生化科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] This method has a short route, and the price of raw and auxiliary materials is relatively low, but a large amount of toxic and harmful reagent triphenylphosphine is used in the ammoniation step, which causes great environmental pollution.
At the same time, the Grignard reagent has strong activity, requires high reaction operation, and is difficult for large-scale production.
[0021] It can be seen that the existing preparation scheme can not solve the synthesis of the target compound well.
Due to the limitations of many aspects such as raw materials, cost, equipment and environmental protection, it is not easy to industrialize

Method used

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  • Preparation method of (R)-2-(N-tertbutyloxycarbonylamino)biphenylpropanol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086]Embodiment 1: (R)-N-acetylbiphenylalanine ethyl ester

[0087] Step (1): (4Z)-4-Biphenylmethylene-2-methyl-1,3-oxazol-5-one

[0088] Under nitrogen protection, N-acetylglycine (0.45mol, 52.7g), anhydrous sodium acetate (0.5mol, 41.0g), and acetic anhydride (1mol, 102.1g) were successively put into a 1L three-necked flask, and mechanically stirred for 30min at room temperature , slowly add biphenyl formaldehyde (0.5mol, 91.1g), heat up to 90°C, keep the temperature of the reaction system at 85-95°C, follow TLC until the reaction of the raw material point is complete. Turn off the heating, cool down to 0-5°C in an ice bath, a large amount of yellow solid precipitates, and stand for 6 hours to crystallize. The material was extracted and dried in vacuo to obtain 102.5 g of a yellow solid product (4Z)-4-biphenylmethylene-2-methyl-1,3-oxazol-5-one, with a yield of 86.5%.

[0089] Step (2): (Z)-Ethyl 2-acetamido-3-biphenylacrylate

[0090] At room temperature, add the produc...

Embodiment 2

[0094] Embodiment 2: (R)-N-benzoyl biphenylalanine methyl ester

[0095] Step (1): (4Z)-4-Biphenylmethylene-2-phenyl-1,3-oxazol-5-one

[0096] Under nitrogen protection, N-benzoylglycine (0.5mol, 89.6g), anhydrous potassium acetate (0.6mol, 58.9g), acetic anhydride (2mol, 204.2g) were successively dropped into a 1L three-necked flask, and mechanically Stir for 30 minutes, add biphenyl formaldehyde (0.5mol, 91.1g) slowly, heat up to 95°C, keep the temperature of the reaction system at 90-100°C, follow TLC until the reaction of the raw material point is complete. Turn off the heating, cool down to 0-5°C in an ice bath, a large amount of yellow solid precipitates, and stand for 6 hours to crystallize. The material was extracted and dried in vacuo to obtain 150.3 g of a yellow solid product (4Z)-4-biphenylmethylene-2-phenyl-1,3-oxazol-5-one, with a yield of 92.4%.

[0097] Step (2): (Z)-Methyl 2-benzamido-3-biphenylacrylate

[0098] At room temperature, add the product obtained...

Embodiment 3

[0102] Embodiment 3: (R)-N-tert-butoxycarbonyl biphenylalanine

[0103] Step (1): (4Z)-4-Biphenylmethylene-2-tert-butoxy-1,3-oxazol-5-one

[0104] Under the protection of nitrogen, N-tert-butoxycarbonylglycine (0.6mol, 105.1g), anhydrous sodium acetate (0.55mol, 45.1g), and acetic anhydride (1.5mol, 153.1g) were successively added to a 1L three-necked flask at room temperature. Stir mechanically at low temperature for 30 minutes, slowly add biphenyl formaldehyde (0.5mol, 91.1g), heat up to 90°C, keep the temperature of the reaction system at 85-95°C, follow TLC until the reaction of the raw material point is complete. Turn off the heating, cool down to 0-5°C in an ice bath, a large amount of yellow solid precipitates, and stand for 6 hours to crystallize. The material was extracted and dried in vacuo to obtain 126.4 g of a yellow solid product (4Z)-4-biphenylmethylene-2-tert-butoxy-1,3-oxazol-5-one, with a yield of 78.7%.

[0105] Step (2): (Z)-2-tert-butoxycarbonylamino-3-b...

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Abstract

The invention discloses a preparation method of (R)-2-(N-tertbutyloxycarbonylamino)biphenylpropanol represented by formula (I). The method comprises the following steps: carrying out an Erlenmeyer-Plochl cyclization reaction on biphenylcarboxaldehyde and N-acylglycine, hydrolyzing or alcoholyzing, and carrying out asymmetric hydrogenation to obtain (R)-N-acylbiphenylalanine or an ester thereof; and carrying out acid hydrolysis, reduction and amino protection on the (R)-N-acylbiphenylalanine or the ester thereof, or carrying out reduction, acid hydrolysis and amino protection on the (R)-N-acylbiphenylalanine or the ester thereof, or directly reducing the (R)-N-acylbiphenylalanine or the ester thereof in order to obtain the product (R)-2-(N-tertbutyloxycarbonylamino)biphenylpropanol. The product is a key intermediate of Sacubitril (AHU-377) which is one of a novel blood pressure reducing medicine LCZ696. The method has the advantages of easily available raw materials, and suitableness for industrial production.

Description

technical field [0001] The invention relates to a preparation method of Sacubitril (Sacubitril, AHU-337) intermediate, in particular to a preparation method of (R)-2-(N-tert-butoxycarbonylamino)biphenylpropanol. Background technique [0002] LCZ696 is a new antihypertensive drug developed by Novartis, or the first successful ARNI inhibitor drug. ARNI inhibitors are angiotensin inhibitors, but at the same time they can enhance the action of endogenous natriuretic peptides (vasodilators). LCZ696 combines Novartis' Diovan (generic name: valsartan) and the experimental drug Sacubitril (AHU-377). Diovan improves vasodilation and stimulates the body to excrete sodium and water, while Sacubitril blocks Threatening the mechanism of action of the two polypeptides responsible for lowering blood pressure, the two are linked together through a reaction to exert pharmacological effects, so the drug has dual inhibitory effects on angiotensin II receptors and neprilysin, and has a unique ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/16C07C269/04C07C269/06
Inventor 夏建胜陈德响臧建伟李坚军贾建洪
Owner 天台宜生生化科技有限公司
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