Preparation method of sacubitril intermediate

Abstract

The invention provides a preparation method of a sacubitril intermediate, relates to the technical field of medical chemical synthesis, and particularly relates to a method for synthesizing a key material of sacubitril by taking a compound 4 as a raw material and chiral substituted glycine as a chiral auxiliary agent through the steps of cyclization, deprotection, ring opening, amidation and the like. Aiming at the current situation that a chiral raw material 8 is difficult to obtain, a brand new route from a compound 1 to a compound 8 is designed, the route totally comprises seven steps of chemical reactions, the average yield of each step of chemical reaction is 84%, a target product is successfully obtained, and the chemical purity of the product is 99% or above. The problems that in an existing process route, the optical purity of products is not high, materials are expensive and not easy to obtain, dangerous chemical reactions are not suitable for amplified production, cryogenic reactions do not conform to green chemistry and the like are solved, detailed process optimization is carried out on key steps of the route, and the optimal process conditions of the reactions of all the steps are determined.

Description

Technical Field

[0001] The invention provides a method for preparing a sacubitril intermediate, and belongs to the technical field of pharmaceutical chemical synthesis. Background Art

[0002] Sacubitril, chemically known as 4-[[(1S, 3R)-1-([1, 1′-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino]-4-oxobutanoic acid, is a neprilysin inhibitor first developed by Novartis, and is a trisodium salt 2.5 hydrate formed with the angiotensin receptor blocker valsartan. It is used to treat chronic heart failure with reduced ejection fraction.

[0003] Based on the existing synthesis routes of sacubitril, the preparation of sacubitril intermediates is limited by raw materials, reaction reagents, post-treatment processes, etc. on the one hand, and on the other hand, the long synthesis route, low diastereoisomer ratio, and environmental unfriendliness lead to high production costs, cumbersome operations, and are not conducive to industrialization.

[0004] Therefore, the present invention provides a production route that is simple to develop, economical and convenient for industrialization, which is conducive to improving the industrialization of Shakubiqu. Summary of the invention

[0005] In view of the current situation that chiral raw material 8 is difficult to obtain, the present invention provides a new route from compound 1 to compound 8 to solve the problems existing in the existing process route, such as the low optical purity of chiral raw material 8, expensive and difficult to obtain materials, dangerous chemical reactions are not suitable for scale-up production, and deep-cold reactions are not in line with green chemistry. The key steps of the route are optimized in detail and the optimal process conditions for each step of the reaction are determined.

[0006] According to the first aspect of the present invention, the present invention provides a method for preparing a sacubitril intermediate, comprising the following synthetic route: ; The compound 4 is obtained by reacting the compound 3; The compound 3 is prepared by reacting compound a with compound 2; The compound 2 is obtained by condensation reaction of 4-biphenylacetic acid and Michaelis acid; The structural formula of the compound a is ; The structural formula of the compound 2 is ; The structural formula of the compound 3 is .

[0007] Optionally, the synthesis route of compound 3 is as follows: .

[0008] Optionally, the sacubitril intermediate further comprises compound 7 and compound 8; The synthetic routes of compound 7 and compound 8 are as follows: .

[0009] Optionally, the preparation method of compound 2 includes: reacting a mixture containing 4-biphenylacetic acid, Michaelis acid, 4-dimethylaminopyridine, N,N'-dicyclohexylcarbodiimide and solvent 1, adding methanol under nitrogen protection, cooling to 0°C for reaction, filtering, and drying to obtain the compound 2.

[0010] Optionally, the molar ratio of the 4-biphenylacetic acid to the Michaelis acid is 1:(0.8-3).

[0011] Optionally, the molar ratio of the 4-biphenylacetic acid to the Michaelis acid is 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:2.0, 1:2.5 or 1:3.

[0012] Optionally, the mass ratio of the 4-biphenylacetic acid to the 4-dimethylaminopyridine is 1:(0.01~1).

[0013] Optionally, the mass ratio of the 4-biphenylacetic acid to the 4-dimethylaminopyridine is 1:0.01, 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9 or 1:1.

[0014] Optionally, the mass ratio of the 4-biphenylacetic acid to the N,N'-dicyclohexylcarbodiimide is 1:(0.8-2).

[0015] Optionally, the mass ratio of the 4-biphenylacetic acid to the N,N'-dicyclohexylcarbodiimide is 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5 or 1:2.0.

[0016] Optionally, the solvent 1 is selected from at least one of dichloromethane, toluene, ethyl acetate, isopropyl acetate and tetrahydrofuran.

[0017] Optionally, every 1 g of the 4-biphenylacetic acid is mixed with 2 ml to 25 ml of the solvent 1.

[0018] Optionally, every 1 g of the 4-biphenylacetic acid is mixed with 2 ml, 5 ml, 10 ml, 15 ml, 20 ml or 25 ml of the solvent 1.

[0019] Optionally, the temperature of the reaction 1 is 0-30°C.

[0020] Optionally, the temperature of reaction 1 is 0°C, 5°C, 10°C, 15°C, 20°C, 25°C or 30°C.

[0021] Optionally, the preparation method of compound 3 includes: reacting a mixture containing compound 2, NaoH, compound a and solvent 2, adding water and ethyl acetate to the reaction solution after the reaction is complete, stirring and separating the liquids, extracting the aqueous phase with ethyl acetate, combining the organic phases, and washing with water to obtain the compound 3.

[0022] Optionally, the molar ratio of the compound 2 to the compound a is 1:(0.8~3).

[0023] Optionally, the molar ratio of the compound 2 to the compound a is 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:2.0, 1:2.5 or 1:3.

[0024] Optionally, the solvent 2 is selected from at least one of dichloromethane, toluene, ethyl acetate, isopropyl acetate and tetrahydrofuran.

[0025] Optionally, every 1 g of the compound 2 is mixed with 2 ml to 30 ml of the solvent 2.

[0026] Optionally, every 1 g of the compound 2 is mixed with 2 ml, 5 ml, 10 ml, 15 ml, 20 ml, 25 ml or 30 ml of the solvent 2.

[0027] Optionally, the temperature of the reaction 2 is -10~40°C.

[0028] Optionally, the temperature of reaction 2 is -10°C, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C or 40°C.

[0029] Optionally, the preparation method of compound 4 comprises: reacting a mixture containing compound 3, tetrahydrofuran, lithium hydroxide or its hydrate, S-phenylethylamine and water for 3, filtering, washing the filter cake with acetone, and vacuum drying to obtain the compound 4.

[0030] Optionally, every 1 g of the compound 3 is mixed with 2 ml to 30 ml of the tetrahydrofuran.

[0031] Optionally, every 1 g of the compound 3 is mixed with 2 ml, 5 ml, 10 ml, 15 ml, 20 ml, 25 ml or 30 ml of the tetrahydrofuran.

[0032] Optionally, the molar ratio of the compound 3 to the lithium hydroxide or its hydrate is 1:(0.8~4).

[0033] Optionally, the molar ratio of the compound 3 to the lithium hydroxide or its hydrate is 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:2.0, 1:2.5, 1:3 or 1:4.

[0034] Optionally, the molar ratio of the compound 3 to the S-phenylethylamine is 1:(0.8~3).

[0035] Optionally, the molar ratio of the compound 3 to the S-phenylethylamine is 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:2.0, 1:2.5 or 1:3.

[0036] Optionally, every 1 g of the compound 3 is mixed with 2 ml to 30 ml of the water.

[0037] Optionally, every 1 g of the compound 3 is mixed with 2 ml, 5 ml, 10 ml, 15 ml, 20 ml, 25 ml or 30 ml of the water.

[0038] Optionally, the temperature of reaction 4 is 50-70°C.

[0039] Optionally, the temperature of reaction 4 is 50°C, 52°C, 55°C, 60°C, 65°C or 70°C.

[0040] Optionally, the preparation method of compound 5 comprises: reacting a mixture containing compound 4, D-phenylglycine and toluene, and cooling the reaction solution to 20-30° C. to obtain compound 5.

[0041] Optionally, the molar ratio of the compound 4 to the D-phenylglycine is 1:(0.8~3).

[0042] Optionally, the molar ratio of the compound 4 to the D-phenylglycine is 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:2.0, 1:2.5 or 1:3.

[0043] Optionally, every 1 g of the compound 4 is mixed with 2 ml to 30 ml of the toluene.

[0044] Optionally, every 1 g of the compound 4 is mixed with 2 ml, 5 ml, 10 ml, 15 ml, 20 ml, 25 ml or 30 ml of the toluene.

[0045] Optionally, the temperature of the reaction 4 is 80-120°C.

[0046] Optionally, the temperature of reaction 4 is 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C or 120°C.

[0047] Optionally, the preparation method of compound 6 includes: reacting a mixture containing compound 5, dichloromethane, zinc dichloride and triethylsilane under a nitrogen or inert gas atmosphere, adding an aqueous ammonium chloride solution to the reaction solution, separating the organic phase, and concentrating the organic phase under reduced pressure to obtain a product containing compound 6.

[0048] Optionally, the inert gas is selected from at least one of helium, neon, argon and krypton.

[0049] Optionally, the molar ratio of the compound 5 to the zinc dichloride is 1:(0.8~3).

[0050] Optionally, the molar ratio of the compound 5 to the zinc dichloride is 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:2.0, 1:2.5 or 1:3.

[0051] Optionally, the molar ratio of the compound 5 to the triethylsilane is 1:(0.8~3).

[0052] Optionally, the molar ratio of the compound 5 to the triethylsilane is 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:2.0, 1:2.5 or 1:3.

[0053] Optionally, every 1 g of the compound 5 is mixed with 2 ml to 30 ml of the dichloromethane.

[0054] Optionally, every 1 g of the compound 5 is mixed with 2 ml, 5 ml, 10 ml, 15 ml, 20 ml, 25 ml or 30 ml of the dichloromethane.

[0055] Optionally, the temperature of the reaction 5 is -20~30°C.

[0056] Optionally, the temperature of the reaction 5 is -20°C, -15°C, -10°C, 0°C, 10°C, 20°C or 30°C.

[0057] Optionally, the preparation method of compound 7 includes: reacting a mixture of a product containing compound 6, methanol, ammonium formate and palladium carbon, filtering to recover the catalyst, concentrating the organic phase under reduced pressure, adding ethyl acetate and water, stirring and standing to separate the liquids, washing the organic phase with water and then concentrating under reduced pressure to obtain a crude product, recrystallizing the crude product with ethyl acetate and n-heptane, and vacuum drying to obtain a product containing compound 7.

[0058] Optionally, the mass percentage of palladium in the palladium carbon is 1% to 10%.

[0059] Optionally, the mass percentage of palladium in the palladium carbon is 1%, 2%, 3%, 5%, 6%, 8%, 9% or 10%.

[0060] Optionally, the molar ratio of the product containing compound 6 to ammonium formate is 1:(0.8~4).

[0061] Optionally, the molar ratio of the product containing compound 6 to ammonium formate is 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:2.0, 1:2.5, 1:3 or 1:4.

[0062] Optionally, the molar ratio of the product containing compound 6 to palladium carbon is 1:(0.001~0.2).

[0063] Optionally, the molar ratio of the product containing compound 6 to palladium carbon is 1:0.001, 1:0.005, 1:0.01, 1:0.05, 1:0.1, 1:0.15 or 1:0.2.

[0064] Optionally, every 1 g of the product containing compound 6 is mixed with 2 ml to 30 ml of the methanol.

[0065] Optionally, every 1 g of the product containing compound 6 is mixed with 2 ml, 5 ml, 10 ml, 15 ml, 20 ml, 25 ml or 30 ml of the methanol.

[0066] Optionally, the temperature of the reaction 6 is 20-70°C.

[0067] Optionally, the temperature of the reaction 6 is 20°C, 25°C, 30°C, 35°C, 40°C, 50°C, 55°C, 60°C, 65°C or 70°C.

[0068] Optionally, the preparation method of compound 8 includes: reacting a mixture containing the product of compound 7, glacial acetic acid and concentrated hydrochloric acid for 7, cooling to room temperature, removing the solvent under reduced pressure, slowly adding ethyl acetate to slurry, filtering, and vacuum drying to obtain the compound 8.

[0069] Optionally, the mass ratio of the product containing compound 7 to the glacial acetic acid is 1:(1~40).

[0070] Optionally, the mass ratio of the product containing compound 7 to the glacial acetic acid is 1:1, 1:5, 1:10, 1:15, 1:20, 1:25, 1:30, 1:35 or 1:40.

[0071] Optionally, the molar ratio of the product containing compound 7 to concentrated hydrochloric acid is 1:(1~100).

[0072] Optionally, the molar ratio of the product containing compound 7 to concentrated hydrochloric acid is 1:1, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90 or 1:100.

[0073] Optionally, the temperature of the reaction 7 is 20-110°C.

[0074] Optionally, the temperature of the reaction 7 is 20°C, 30°C, 40°C, 50°C, 70°C, 90°C or 110°C.

[0075] Optionally, the concentration of the concentrated hydrochloric acid is 30% to 38%.

[0076] As an alternative embodiment, the present invention is synthesized by the following technical route: .

[0077] In view of the current situation that chiral raw material 8 is difficult to obtain, the present invention designs a new route from compound 1 to compound 8, completes the design and preparation of the route, and the synthesis route has a total of 7 chemical reactions. 4-biphenylacetic acid and Meldrum's acid are used as raw materials, and compound 2 is synthesized by Meldrum's acid condensation reaction. Meldrum's acid is acidic and can react with halogenated hydrocarbons to be alkylated, react with acyl halides to be acylated, and react with carboxylic acids to undergo condensation reaction under the action of a base; compound 2 reacts with compound a to generate compound 3; β-keto acid is decarboxylated to synthesize compound 4. This step of reaction is a hydrolysis decarboxylation reaction. The substrate compound 3 is a β-keto acid structure after hydrolysis. The β-keto acid is easily decarboxylated. The reaction process is a synergistic reaction through a six-membered ring, first generating an enol, and then rearranging to obtain a ketone; since the transition state of the reaction is a six-membered ring with low energy, the reaction is very easy to proceed. D-phenylglycine and γ-keto acid compound 4 are refluxed in toluene to produce compound 5, which is N,O-acetal in which the N atom is connected to the carbon group; the carbon-oxygen bond of the N,O-acetal structure is broken to synthesize compound 6. Since the N,O-acetal structure in which the N atom is connected to the carbon group is generally stable, the present invention uses Lewis acid zinc dichloride and hydrogen donor triethylsilane to break the carbon-oxygen bond in the N,O-acetal structure. Its mechanism is that after the intermediate state of the imide ion complexed with zinc dichloride, the configuration of the phenylglycine part and the presence of the oxygen-philic zinc salt complex structure block the entry of nucleophilic hydrogen on one side, and the biphenylmethyl group maintains the same configuration; compound 4 to compound 7 are reacted in three steps, and finally compound 7 is post-processed; lactam hydrolysis synthesizes compound 8. This step reaction is the high-temperature hydrolysis of lactam compound 7 under the action of concentrated hydrochloric acid, which is a common organic synthesis reaction. The average yield of each step of the chemical reaction is 82%, and the target product chiral raw material 8 is successfully obtained, and the chemical purity of the product is more than 99%. The paper solves the problems existing in the existing process routes, such as low optical purity of products, expensive and difficult-to-obtain materials, dangerous chemical reactions that are not suitable for scale-up production, and deep-cold reactions that do not conform to green chemistry. The paper also carries out detailed process optimization of the key steps of the route and determines the optimal process conditions for each step of the reaction.

[0078] The present invention aims at the problem that the materials are expensive and difficult to obtain. The cheap and easily available 4-biphenylacetic acid on the market is used as a raw material, and the key intermediate 4 is prepared by condensation, substitution and hydrolysis decarboxylation reaction. The difficulty of this synthetic route lies in the control of the optical purity of the product, especially the construction of the chiral amine group. In view of the problem that the optical purity of the product is not high, the present invention uses cheap chiral S-methyl lactate as a raw material to introduce the first chiral center; then D-phenylglycine is used as a chiral auxiliary agent and amine source for constructing a chiral lactam ring; then the important intermediate 8 of Sacubitril is obtained by cyclization reaction, zinc dichloride / triethylsilane chiral controlled reduction ring opening reaction, debenzylation reaction, and lactam ring opening; the chiral raw materials S-methyl lactate, D-phenylglycine and the starting material 4-biphenylacetic acid are cheap and easy to obtain; the problems of Grignard reaction and deep cold reaction conditions that appear many times in the existing route are successfully avoided; wherein the intermediates such as compound 5 and compound 6 are brand-new compound structures. Overall, the synthetic route provided by the present invention is novel, economical, environmentally friendly, safe and suitable for industrial production.

[0079] The beneficial effects that the present invention can produce include: The preparation method of the sacubitril intermediate provided by the present invention has the advantages that the chiral raw materials S-methyl lactate, D-phenylglycine and the starting material 4-felbinac acid are cheap and easily available; the Grignard reaction and deep cold reaction conditions that appear many times in the existing route are successfully avoided; intermediates such as compound 5 and compound 6 are brand-new compound structures. In short, the synthesis route of the sacubitril intermediate provided by the present invention is novel, economical, environmentally friendly, safe and suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0080] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0081] Figure 1 A synthetic route map of the key material of Shakubitqu provided by the present invention; Figure 2 The mechanism diagram for constructing the second chiral center (Compound 6) provided by the present invention.

[0082] Terminology In the following, all the numbers disclosed herein are approximate values, regardless of whether the words "about" or "approximately" are used. The value of each number may vary by 1%, 2%, 5%, 7%, 8%, 10%, 15% or 20%. Whenever a number with a value of N is disclosed, any number with a value of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, N+ / -10%, N+ / -15% or N+ / -20% will be explicitly disclosed, where "+ / -" means plus or minus. Whenever a lower limit, RL, and an upper limit, RU, are disclosed in a numerical range, any value within the disclosed range will be explicitly disclosed. In particular, the following values ​​within the range are included: R=RL+K*(RU-RL), where k is a variable from 1% to 100% that increases in 1% increments. For example: 1%, 2%, 3%, 4%, 5%...50%, 51%, 52%...95%, 96%, 97%, 98%, 99% or 100%. In addition, the numerical ranges defined by two R numbers disclosed herein are also specifically included.

[0083] In the description of the present invention, “plurality” means two or more than two, unless otherwise clearly and specifically defined.

[0084] The term "room temperature" means ambient temperature, referring to a temperature between about 10°C and about 30°C, or between about 20°C and 30°C, or about 25°C.

[0085] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0086] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulae and chemical formulae. The present invention is intended to cover all alternatives, modifications and equivalent technical solutions, which are all included within the scope of the present invention as defined in the claims. It should be recognized by those skilled in the art that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described techniques, etc.), the present application shall prevail.

[0087] It should be further appreciated that certain features of the invention, which for clarity are described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which for brevity are described in a single embodiment, may also be provided separately or in any suitable sub-combination.

[0088] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0089] Unless otherwise indicated, the following definitions used herein shall apply. For purposes of the present invention, chemical elements are consistent with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0090] Unless otherwise specified or there is a clear conflict in context, the articles "a", "an", and "the" as used herein are intended to include "at least one" or "one or more". Therefore, these articles as used herein refer to one or more than one (i.e., at least one) of the objects. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in the implementation of the described embodiment.

[0091] The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0092] "Stereoisomers" are compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, etc.

[0093] "Chiral" refers to a molecule that is non-superimposable on its mirror image; "achiral" refers to a molecule that is superimposable on its mirror image.

[0094] "Enantiomers" refer to two non-superimposable isomers of a compound that are mirror images of each other.

[0095] "Diastereoisomers" refer to stereoisomers that have two or more chiral neutrals and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example HPLC.

[0096] The stereochemical definitions and conventions used herein generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0097] Many organic compounds exist in optically active forms, i.e. they have the ability to rotate the plane of plane polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are the signs used to designate the rotation of plane polarized light caused by the compound, where (-) or l indicates that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0098] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R, S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)-configuration.

[0099] In the embodiments of the present invention, "DIPEA" is N,N-diisopropylethylamine; "THF" is tetrahydrofuran; "MeCN" is acetonitrile; and "PhMe" is toluene. DETAILED DESCRIPTION

[0100] The present application is described in detail below with reference to embodiments, but the present application is not limited to these embodiments.

[0101] Unless otherwise specified, the raw materials in the examples of this application were purchased through commercial channels.

[0102] like Figure 1 and 2 As shown, it is the synthesis route of the key materials of sacubitril provided by the present invention and the mechanism diagram for constructing the second chiral center (compound 6).

[0103] like Figure 2 As shown, the present invention utilizes a chiral auxiliary agent D-phenylglycine, which is also a chiral amine source, to cyclize with compound 4 to synthesize compound 5, and the ring is opened under a chiral controlled reduction reaction of zinc dichloride / triethylsilane to break the carbon-oxygen bond of the N,O-acetal structure to synthesize compound 6, thereby successfully constructing a second chiral center.

[0104] The reaction mechanism is as follows Figure 2 As shown in the figure, N,O-acetals are highly active because they will undergo hydrolysis under a variety of reaction conditions. However, if the N atom is connected to a carbon group, this type of acetal has considerable stability. Compound 5 is an N,O-acetal in which the N atom is connected to a carbon group. D-phenylglycine and γ-keto acid compound 4 can be refluxed in toluene to produce compound 5; when compound 5 is ring-opened, Lewis acid zinc dichloride and hydrogen donor triethylsilane are used to break the carbon-oxygen bond in the N,O-acetal structure. The mechanism is that through the intermediate state of the imide ion complexed with zinc dichloride, the configuration of the phenylglycine part and the presence of the oxygen-philic zinc salt complex structure block the entry of the nucleophilic hydrogen on one side, and the biphenylmethyl group maintains the same configuration.

[0105] Due to the electron-withdrawing effect of two carbonyl groups, Meldrum's acid is acidic and can react with halogenated hydrocarbons to undergo alkylation, react with acyl halides to undergo acylation, and react with carboxylic acids to undergo condensation. In the present invention, 4-biphenylacetic acid is reacted with Meldrum's acid under DCC condensation and DMAP catalysis to prepare 4-biphenyl-3-oxobutyrate.

[0106] Example 1 Synthesis of Compound 2 by Michaelis acid condensation reaction

[0107] Mix 10.00g of 4-biphenylacetic acid, 7.5g of Michaelis acid, 0.2g of 4-dimethylaminopyridine (DMAP), 11g of N, N'-dicyclohexylcarbodiimide (DCC) and 100ml of dichloromethane, cool to 0℃ and react for 12h. Filter to remove the precipitated solid, and concentrate the filtrate to obtain a light yellow oil containing compound 2. Add 70ml of methanol to the above oil, and heat to 55℃ under nitrogen protection to react. TLC detection shows that the raw material has reacted completely, the reaction solution is cooled to 0℃ and stirred for 3h, filtered, and the filter cake is vacuum dried at 60℃ to obtain compound 2 (11.60g of white solid, yield 91.8%, chemical purity 99.0%). 1HNMR (400 MHz, CDCl3) δ7.65-7.53 (m, 4H), 7.44 (t, 2H), 7.39 - 7.27 (m, 3H), 3.87 (s, 2H), 3.72 (s, 3H), 3.50 (d, 2H).

[0108] Example 2 Synthesis of Compound 3

[0109] Synthesis of compound 3: Mix 24.00g of compound 2, 4.65g of NaOH powder and 200mL of THF. The reaction solution was cooled to 0°C and stirred for 30min, and then a tetrahydrofuran solution containing 27.5g of compound a (27.5g of compound a dissolved in 100mL of THF) was slowly added dropwise, and the addition was completed in about 15 minutes. After the addition was completed, the temperature was raised to 10°C and the reaction was continued to stir for 4h. After the reaction was complete, 200mL of water and 200mL of ethyl acetate were added to the reaction solution, stirred and separated, the aqueous phase was extracted with 100mL of ethyl acetate, the organic phases were combined, washed with 200mL of water, and the organic phases were concentrated under reduced pressure to obtain an oily substance containing compound 3, which was directly fed into the next step of reaction without purification. The reaction purity of this step is 90%. The NMR data of the product oily substance are: 1HNMR (400 MHz, DMSO-D6) δ7.78 (d, 2H), 7.65 (d, 2H), 7.46 - 7.35 (m, 5H), 3.82 (d, 1H), 3.75 (d, 2H),3.70 (t, 1H), 3.66 (s, 3H), 3.61 (s, 3H) 1.15 (d, 3H).

[0110] The above reaction was preliminarily screened. First, the types of substrate esters were screened. The experimental results showed that when compound 2 contained ethyl ester and tert-butyl ester units, the intermediate control purity was generally not high, and the repeatability was poor, and the reaction failed frequently; when compound 2 contained methyl ester units, the preliminary intermediate control purity reached 80%, with good reproducibility, which may be due to the difference in conversion rate caused by the steric hindrance of the substrate and the product. At the same time, the earliest literature reported the use of sodium hydrogen as a base. Based on the danger of sodium hydrogen in the industrial amplification process, it is necessary to try to replace sodium hydrogen. The present invention carefully optimizes the types of bases and the coordination of different solvents. The results show that the intermediate control purity reaches more than 90% with good reproducibility when NaOH powder is used as a base. The reason is that powdered sodium hydroxide has good dispersibility, increases the solubility of sodium hydroxide in tetrahydrofuran THF, and the reaction steric hindrance is also very small, so it has a good reaction effect. The improvement here not only improves the safety factor of the process, but also reduces the material cost and the smoothness of operation. The specific results are shown in Table 1.

[0111] Table 1

[0112] Example 3 Synthesis of Compound 4 by Decarboxylation of β-Keto Acid

[0113] Decarboxylation of β-keto acid to synthesize compound 4 is a hydrolytic decarboxylation reaction. The substrate compound 3 is a β-keto acid structure after hydrolysis. β-keto acid is easily decarboxylated. The reaction process is a concerted reaction through a six-membered ring, first generating an enol, and then rearranging to obtain a ketone. Since the transition state of the reaction is a six-membered ring with low energy, the reaction is easy to proceed.

[0114] 158.5g of compound 3, 1200g of tetrahydrofuran THF, 1200g of water and 38g of lithium hydroxide monohydrate were stirred at room temperature, and the reaction solution was heated to 60°C for 3h. HPLC detected that the raw material reaction was complete, the reaction solution was cooled to 20°C, HCl aqueous solution was slowly added to adjust the pH to 2, and then 1000ml of ethyl acetate was added to extract twice, the two organic phases were combined, and the organic phase was washed with water and concentrated under reduced pressure to obtain an oil. The obtained oil was dissolved in acetone, heated to 50°C, and 81g of S-phenylethylamine was slowly added dropwise. After the addition was completed, stirring was continued for 1h, cooled to room temperature, and stirring was continued for 2h. Filter, wash the filter cake with 200mL of acetone, and vacuum dry at 60°C for 15h to obtain compound 4 phenylethylamine salt, and compound 4 was obtained after being freed; the reaction yield was 68%, the chemical purity was 99%, and the optical isomer content was <2%. 1HNMR (400 MHz, DMSO-D6) δ 12.15 (s, 1H), 7.65 (d, 2H), 7.61 (d, 2H), 7.46 (t, 2H), 7.35 (t, 1H), 7.28 (d, 2H), 3.82 (s, 2H), 2.85 (dd, 1H), 2.76 -2.70 (m, 1H), 2.62 (dd, 1H), 1.05 (d, 3H).

[0115] The present invention optimizes the process parameters such as the amount of lithium hydroxide monohydrate, reaction temperature, and reaction time. When the amount of lithium hydroxide monohydrate is 2.0 and 2.5 equivalents, although the enantiomer content is reduced, the reaction speed is slow, and the intermediate control purity is low. The amount of lithium hydroxide monohydrate should be controlled at 3.0 equivalents when the intermediate control purity is the highest. When the amount of lithium hydroxide monohydrate is 3.0 equivalents, the reaction temperature has little effect on the content of the enantiomer of compound 4, and has an effect on the reaction speed. When the reaction temperature is 50°C, the reaction speed is reduced, the intermediate control purity is low, and the reaction temperature of compound 4 is controlled between 60-70°C. The extension of the reaction time has little effect on the enantiomer content of compound 4. The raw materials react completely after 1.5h of reaction. The specific results are shown in Table 2 below.

[0116] Table 2

[0117] Example 4 Synthesis of Compound 5 Using Chiral Auxiliary D-Phenylglycine

[0118] Since N,O-acetals are hydrolyzed under a variety of reaction conditions, N,O-acetals are highly reactive, but if the N atom is connected to a carbon group, this type of acetal is quite stable. Compound 5 is an N,O-acetal with a N atom connected to a carbon group. D-phenylglycine and γ-keto acid compound 4 are refluxed in toluene to produce compound 5.

[0119] 20g of compound 4, 13.14g of D-phenylglycine and 180ml of toluene were mixed, stirred, heated to 110°C, refluxed and reacted for 18h. HPLC detected that the raw material reaction was complete, the reaction solution was cooled to 20°C, and concentrated under reduced pressure to obtain an oily substance, which was directly used for the next step without purification. The purity of the oil was about 90%, 1HNMR (400MHz, CDCl3) δ 7.73 (dd, 2H), 7.59 (d, 2H), 7.49 - 7.40 (m, 6H), 7.39 - 7.27 (m, 4H), 5.70 (t, 1H), 3.09 (d,1H), 2.92 (d, 1H), 2.70 (dd, 1H), 2.64 - 2.55 (m, 1H), 1.85 (t, 1H), 1.14 (d,3H).

[0120] Example 5 Synthesis of Compound 6 by Cleavage of the Carbon-Oxygen Bond of N,O-Acetal Structure

[0121] Since the N,O-acetal structure in which the N atom is connected to the carbon group is generally relatively stable, the present invention uses Lewis acid zinc dichloride and hydrogen donor triethylsilane to break the carbon-oxygen bond in the N,O-acetal structure. The mechanism is that through the intermediate state of the imide ion complexed with zinc dichloride, the configuration of the phenylglycine part and the presence of the oxygen-philic zinc salt complex structure block the entry of the nucleophilic hydrogen on one side, and the biphenylmethyl group maintains the same configuration.

[0122] 39.7g of compound 5, 320ml of dichloromethane and 14g of zinc dichloride were mixed, the reaction solution was cooled to -20°C, 12.8g of triethylsilane was slowly added dropwise under nitrogen protection, and the temperature was slowly raised to room temperature for reaction after the addition was completed. HPLC detected that the raw material reaction was complete, 200ml of ammonium chloride aqueous solution with a concentration of 10% was added to the reaction solution, and the organic phase was separated. The organic phase was concentrated under reduced pressure to obtain an oily substance, which was directly added to the next step of reaction without purification. The purity in this step of the reaction was controlled to be above 80%. 1HNMR(400MHz, CDCl3) δ12.65 (s, 1H), 7.66 (d, 2H), 7.51 (d, 2H), 7.48 - 7.34 (m, 8H), 7.01(d, 2H), 5.71 (s, 1H), 3.99 (dd, 1H), 3.56-3.52 (m, 2H), 2.52 -2.41 (m, 1H), 2.34 (dd, 1H), 2.25 (ddd, 1H), 1.22 (d, 3H). Example 6 Synthesis of Compound 7 by Catalytic Debenzylation

[0123] 9.9 g of compound 6 prepared in Example 5, 240 ml of methanol, 12.6 g of ammonium formate and 2 g of 5% palladium on carbon were mixed and heated to 68°C for reflux reaction. HPLC detected that the raw material reaction was complete, filtered to recover the catalyst, and the organic phase was concentrated under reduced pressure to obtain an oily substance. Ethyl acetate and water were added to the above oily substance, stirred and allowed to stand for separation, and the organic phase was washed with water and concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized from ethyl acetate and n-heptane and dried in vacuo to obtain compound 7 as a white solid. 1HNMR (400 MHz,CDCl3) δ 7.68 - 7.58 (m, 4H), 7.49 (t, 2H), 7.41 (t, 1H), 7.35 - 7.29 (m,3H), 3.82 - 3.92 (m, 1H), 2.88 (dd, 1H), 2.75 (dd, 1H), 2.48 - 2.39 (m, 1H),2.15 - 1.94 (m, 2H), 1.22 (d, 3H). In the synthetic route of the present invention, compound 4 to compound 7 are reacted in three steps, and finally compound 7 is post-treated. The average yield of each step is 85%, and the chemical purity of compound 7 is 99.0%.

[0124] Example 7: Synthesis of Compound 8 by Lactam Hydrolysis

[0125] Lactam hydrolysis to synthesize compound 8 This step is the high-temperature hydrolysis of lactam compound 7 under the action of concentrated hydrochloric acid, which is a common organic synthesis reaction.

[0126] 0.50g of compound 7, 2.5g of glacial acetic acid and 15mL of 30% hydrochloric acid were mixed and heated to 110℃ for reaction. HPLC detected that the raw material reacted completely, cooled to room temperature, removed the solvent under reduced pressure, slowly added ethyl acetate to slurry, filtered, and vacuum dried to obtain white solid compound 8; the reaction yield was 86%, and the chemical purity was 99.0%. 1HNMR (400 MHz, DMSO-D6) δ 8.25 (s,2H), 7.69 - 7.48 (m, 6H), 7.32 (t, 3H), 3.23 (d, 1H), 2.95 (dd, 1H), 2.76(dd, 1H), 2.55 (m, 1H), 1.86 (m, 1H), 1.65 (m, 1H), 1.07 (d, 3H).

[0127] In order to solve the problem of difficulty in obtaining starting materials, the present invention designed a new route from compound 1 to compound 8, completed the design of the route and the optimization of the preliminary process, with a total of 8 chemical reactions, and the average yield of each chemical reaction was 84%. The target product compound 8 was successfully obtained with a chemical purity of 99%, achieving the expected goal.

[0128] Compared with the prior art, the present invention has the following obvious advantages: The present invention provides a method for synthesizing the key material of sacurbitril using compound 4 as a raw material and chiral substituted glycine as a chiral auxiliary through the steps of cyclization, deprotection, ring opening, amidation and the like. Compared with the prior art, the expensive chiral auxiliary is replaced by phenylglycine, which is cheaper and more readily available, and the preparation method is simple. The reaction conditions of each step are mild and simple, there is no hazardous chemical reaction, and there is no high-energy chemical reaction such as deep cooling, and the method is suitable for industrial production. Among them, intermediates such as compound 5 and compound 6 are brand-new compound structures. Overall, the route is novel, economical, environmentally friendly, safe and suitable for industrial production.

[0129] The above are only a few embodiments of the present application and do not constitute any form of limitation to the present application. Although the present application is disclosed as above with preferred embodiments, it is not intended to limit the present application. Any technician familiar with the profession, without departing from the scope of the technical solution of the present application, using the technical content disclosed above to make slight changes or modifications are equivalent to equivalent implementation cases and fall within the scope of the technical solution.

Claims

1. A method for preparing a sacubitril intermediate, characterized in that: The following synthetic routes are included: ； The compound 4 is obtained by reacting with the compound 3, and the structural formula of the compound 3 is ; The compound 3 is prepared by reacting compound a with compound 2. The structural formula of the compound a is , the structural formula of the compound 2 is ; The compound 2 is obtained through a condensation reaction of 4-biphenylacetic acid and Michaelis acid.

2. The preparation method according to claim 1, characterized in that: The synthetic route of compound 3 is as follows: 。 3. The preparation method according to claim 1, characterized in that: The sacubitril intermediates also include compound 7 and compound 8; The synthetic routes of compound 7 and compound 8 are as follows: 。 4. The preparation method according to claim 1, characterized in that: The preparation method of compound 2 comprises: reacting a mixture containing 4-biphenylacetic acid, Michaelis acid, 4-dimethylaminopyridine, N,N'-dicyclohexylcarbodiimide and solvent 1 to obtain compound 2; The molar ratio of the 4-biphenylacetic acid to the Michaelis acid is 1:(0.8-3); The mass ratio of the 4-biphenylacetic acid to the 4-dimethylaminopyridine is 1: (0.01-1); The molar ratio of the 4-biphenylacetic acid to the N,N'-dicyclohexylcarbodiimide is 1:(0.8-2); The solvent 1 is selected from at least one of dichloromethane, toluene, ethyl acetate, isopropyl acetate and tetrahydrofuran; Every 1g of the 4-biphenylacetic acid is mixed with 2ml-25ml of the solvent 1; The temperature of the reaction 1 is 0-30°C.

5. The preparation method according to claim 1, characterized in that: The preparation method of compound 3 comprises: reacting a mixture containing compound 2, NaOH, compound a and solvent 2 to obtain compound 3; The molar ratio of the compound 2 to the compound a is 1:(0.8-3); The molar ratio of the compound 2 to the NaOH is 1:(0.8-3); The solvent 2 is selected from at least one of dichloromethane, toluene, ethyl acetate, isopropyl acetate and tetrahydrofuran; Every 1g of the compound 2 is mixed with 2ml-30ml of the solvent 2; The temperature of the reaction 2 is -10~40°C.

6. The preparation method according to claim 1, characterized in that: The preparation method of compound 4 comprises: reacting a mixture containing compound 3, tetrahydrofuran, lithium hydroxide or its hydrate, S-phenylethylamine and water to obtain compound 4; Mix 1g of the compound 3 with 2ml-30ml of tetrahydrofuran; The molar ratio of the compound 3 to the lithium hydroxide or its hydrate is 1:(0.8-4); The molar ratio of the compound 3 to the S-phenylethylamine is 1:(0.8-3); Mix 1g of the compound 3 with 2ml-30ml of the water; The temperature of the reaction 3 is 50-70°C.

7. The preparation method according to claim 1, characterized in that: The preparation method of compound 5 comprises: subjecting a mixture containing compound 4, D-phenylglycine and toluene to a reaction 4 to obtain compound 5; The molar ratio of the compound 4 to the D-phenylglycine is 1:(0.8-3); Every 1g of the compound 4 is mixed with 2ml-30ml of the toluene; The temperature of the reaction 4 is 80-120°C.

8. The preparation method according to claim 1, characterized in that: The preparation method of compound 6 comprises: reacting a mixture containing compound 5, dichloromethane, zinc dichloride and triethylsilane under nitrogen or inert gas atmosphere to obtain a product containing compound 6; The inert gas is selected from at least one of helium, neon, argon and krypton; The molar ratio of the compound 5 to the zinc dichloride is 1:(0.8-3); The molar ratio of the compound 5 to the triethylsilane is 1:(0.8-3); Every 1g of the compound 5 is mixed with 2ml-30ml of the dichloromethane; The temperature of the reaction 5 is -20~30°C.

9. The preparation method according to claim 3, characterized in that: The preparation method of compound 7 comprises: reacting a mixture containing a product of compound 6, methanol, ammonium formate and palladium on carbon to obtain a product containing compound 7; The mass percentage of palladium in the palladium carbon is 1% to 10%; The molar ratio of the product containing compound 6 to ammonium formate is 1:(0.8-4); The mass ratio of the product containing compound 6 to palladium carbon is 1: (0.001-0.2); Every 1g of the product containing compound 6 is mixed with 2ml-30ml of the methanol; The temperature of the reaction 6 is 20-70°C.

10. The preparation method according to claim 3, characterized in that: The preparation method of compound 8 comprises: reacting a mixture containing a product of compound 7, glacial acetic acid and concentrated hydrochloric acid to obtain compound 8; The mass ratio of the product containing compound 7 to the glacial acetic acid is 1:(1-40); The molar ratio of the product containing compound 7 to HCl in concentrated hydrochloric acid is 1:(1-100); The temperature of the reaction 7 is 20-110°C.

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