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Sacubitril intermediate and preparation method thereof

The technology of a compound and an alkyl group, which is applied in the field of Sacubitril intermediates and their preparation, can solve the problems such as difficulty in obtaining raw materials and complicated reactions, and achieve the effects of easy availability of raw materials and simple process.

Active Publication Date: 2017-07-25
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] In the process for preparing Shakubiqu, the raw materials are not easy to obtain, and the reaction is relatively cumbersome

Method used

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  • Sacubitril intermediate and preparation method thereof
  • Sacubitril intermediate and preparation method thereof
  • Sacubitril intermediate and preparation method thereof

Examples

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preparation example Construction

[0079] b) The compound represented by formula (03) is subjected to a deprotection reaction to prepare the compound represented by formula (04). In some embodiments, the preparation method of the compound represented by the formula (04) of the present invention comprises the following steps,

[0080]

[0081] where the R 1 and R 2 can be a group as previously described,

[0082] a) using the compound represented by formula (00) as the starting material, and preparing the compound represented by formula (01) through condensation reaction;

[0083]

[0084] in,

[0085] The R 1 and R 5 may be a group as previously described;

[0086] b) a compound represented by formula (01) and a compound represented by formula (02) undergo a substitution reaction to introduce a chiral methyl group to prepare a compound represented by formula (03),

[0087]

[0088] in,

[0089] The R 1 , R 2 , R 5 and R 6 may be a group as previously described;

[0090] c) The compound rep...

specific Embodiment approach

[0157] In order to enable those skilled in the art to better understand the technical solutions of the present invention, the present invention provides some examples of preparation examples, and some non-limiting examples are further disclosed below to further describe the present invention in detail.

[0158] The reagents used in the present invention can be purchased from the market or can be prepared by the methods described in the present invention.

[0159] In the present invention, mmol means millimole, mol / L and N means mole / liter, h means hour, g means gram, ml means milliliter, L means liter, °C means degree Celsius, ESI-MS means electrospray ionization mass spectrometry, TLC means TLC.

Embodiment 1-a

[0161] Example 1-a: Preparation of ethyl 4-([1,1'-biphenyl]-4-yl)-3-oxobutanoate

[0162]

[0163] Add 200mL of ethyl acetate and 28.64g of N,N'-carbonyldiimidazole to a 500mL three-necked reaction flask A at room temperature, and add 25.00g of 4-biphenylacetic acid into reaction flask A in batches to control the gas generation rate. After the addition, the temperature of the reaction solution was raised to 45°C for 3 hours, then cooled to 20-30°C, reduced and vacuumed for 1 hour, and set aside. Add 280mL ethyl acetate, 28.06g EtO to 1L reaction flask B at room temperature 2 CCH 2 COOK and 15.70g magnesium chloride (MgCl 2 ), the temperature was controlled at 20-30°C, and 19.07 g of triethylamine (TEA) was slowly added dropwise, and stirring was continued for 1 h after the dropwise addition was completed. Add the materials in the reaction bottle A to the reaction bottle B at room temperature, raise the temperature to 45° C., and keep the reaction for 16 hours. Cool the ...

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Abstract

The invention relates to a sacubitril intermediate and a preparation method thereof, the sacubitril intermediate is a compound shown as formula (04), and the sacubitril intermediate is prepared by deprotection reaction of a compound shown as formula (03). Further, the invention also provides the preparation method of the compound shown as the formula (04) as the intermediate. The method has the advantages of easy availability of raw materials, simple process, economy and environmental protection, and the like, and is very suitable for industrial production.

Description

technical field [0001] The present invention relates to the field of medicine and chemical industry, and more specifically relates to a Shakubiqu intermediate and a preparation method thereof. Background technique [0002] Sacubitril, the chemical name is 4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl- 5-oxopentane-2-yl)amino)-4-oxobutanoic acid, its structural formula is as follows: [0003] [0004] In July 2015, the US FDA approved the anti-heart failure drug Entresto, which is a compound combination of the angiotensin II inhibitor valsartan and the neprilysin inhibitor Sacubitril. Valsartan can improve vasodilation, stimulate the body to excrete sodium and water, and sacubitril can block the mechanism of action of two polypeptides that threaten to lower blood pressure, so it is called the combination of angiotensin II receptor and enkephalinase. Dual inhibitor; it clinically shows a unique mode of action, which is superior to standard drugs in reducing blood...

Claims

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Application Information

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IPC IPC(8): C07C231/02C07C233/47C07C51/38C07C59/84C07C67/32C07C69/738C07C45/65C07C49/255C07C49/245C07F7/18C07D309/12C07C231/12C07C235/78
CPCC07C45/65C07C51/38C07C67/32C07C231/02C07C231/12C07D309/12C07F7/1804C07F7/1892C07C233/47C07C59/84C07C69/738C07C49/255C07C49/245C07C235/78
Inventor 孙国栋陈磊韩小东李顺曾洁滨王仲清罗忠华
Owner SUNSHINE LAKE PHARM CO LTD
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