A preparation method of sacubitril intermediate

Abstract

The present invention provides a method for preparing a sacubitril intermediate, which relates to the technical field of pharmaceutical chemical synthesis. Using compound 4 as a raw material and chiral substituted glycine as a chiral auxiliary, a method for synthesizing the key material of sacubitril is carried out through steps such as cyclization, deprotection, ring opening, and amidation. In view of the current situation that it is difficult to obtain the chiral raw material 8, the present invention designs a new route from compound 1 to compound 8. This route involves a total of 7 chemical reactions, and the average yield of each chemical reaction is 84%. The target product is successfully obtained, and the chemical purity of the product is over 99%. It solves the problems existing in the existing process route, such as low optical purity of the product, expensive and difficult-to-obtain materials, dangerous chemical reactions not suitable for scale-up production, and cryogenic reactions not meeting the requirements of green chemistry. And the key steps of this route are optimized in detail, and the optimal process conditions for each step of the reaction are determined.

Description

Technical Field

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

[0002] Sacubitril, chemically named 4-[[(1S,3R)-1-([1,1′-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino]-4-oxobutanoic acid, is an enkephalinase inhibitor pioneered by Novartis, and is the 3-sodium 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 synthetic routes of sacubitril, the preparation of the sacubitril intermediate is restricted by aspects such as raw materials, reaction reagents, and post-treatment processes on the one hand. On the other hand, problems such as long synthetic routes, low diastereoisomer ratios, and environmental unfriendliness have led to high production costs, cumbersome operations, and are not conducive to industrialization.

[0004] Therefore, the present invention provides a simple, economical, and industrialization-friendly production route, which is conducive to improving the industrialization of sacubitril. Summary of the Invention

[0005] In view of the current situation that the existing 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 low optical purity of the chiral raw material 8, expensive and difficult-to-obtain materials, dangerous chemical reactions not suitable for large-scale production, and cryogenic reactions not meeting the requirements of green chemistry. The key steps of this 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, including the following synthetic route:

[0007] ;

[0008] The compound 4 is obtained by reacting the compound 3;

[0009] The compound 3 is prepared by reacting the compound a with the compound 2;

[0010] The compound 2 is obtained by the condensation reaction of 4-biphenylacetic acid and Meldrum's acid;

[0011] The structural formula of the compound a is ;

[0012] The structural formula of the compound 2 is ;

[0013] The structural formula of the said Compound 3 is .

[0014] Optionally, the synthetic route of the said Compound 3 is as follows:

[0015] .

[0016] Optionally, the sacubitril intermediate further comprises Compound 7 and Compound 8;

[0017] The synthetic routes of the said Compound 7 and Compound 8 are as follows:

[0018] .

[0019] Optionally, the preparation method of Compound 2 includes: reacting a mixture containing 4-biphenylacetic acid, Meldrum's 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 said Compound 2.

[0020] Optionally, the molar ratio of the said 4-biphenylacetic acid to the said Meldrum's acid is 1:(0.8~3).

[0021] Optionally, the molar ratio of the said 4-biphenylacetic acid to the said Meldrum's 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.

[0022] Optionally, the mass ratio of the said 4-biphenylacetic acid to the said 4-dimethylaminopyridine is 1:(0.01~1).

[0023] Optionally, the mass ratio of the said 4-biphenylacetic acid to the said 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.

[0024] Optionally, the mass ratio of the said 4-biphenylacetic acid to the said N,N'-dicyclohexylcarbodiimide is 1:(0.8~2).

[0025] Optionally, the mass ratio of the said 4-biphenylacetic acid to the said 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.

[0026] Optionally, the said Solvent 1 is selected from at least one of dichloromethane, toluene, ethyl acetate, isopropyl acetate and tetrahydrofuran.

[0027] Optionally, every 1 g of the 4-biphenylacetic acid is mixed with 2 ml to 25 ml of the solvent 1.

[0028] 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.

[0029] Optionally, the temperature of the reaction 1 is 0 to 30°C.

[0030] Optionally, the temperature of the reaction 1 is 0°C, 5°C, 10°C, 15°C, 20°C, 25°C or 30°C.

[0031] Optionally, the preparation method of the compound 3 includes: reacting a mixture containing the compound 2, NaOH, the compound a and the solvent 2 in the reaction 2, adding water and ethyl acetate to the reaction solution after the reaction is complete, stirring and separating the layers, extracting the aqueous phase with ethyl acetate, combining the organic phases, and washing with water to obtain the compound 3.

[0032] Optionally, the molar ratio of the compound 2 to the compound a is 1:(0.8 to 3).

[0033] 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.

[0034] Optionally, the solvent 2 is selected from at least one of dichloromethane, toluene, ethyl acetate, isopropyl acetate and tetrahydrofuran.

[0035] Optionally, every 1 g of the compound 2 is mixed with 2 ml to 30 ml of the solvent 2.

[0036] 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.

[0037] Optionally, the temperature of the reaction 2 is -10 to 40°C.

[0038] Optionally, the temperature of the reaction 2 is -10°C, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C or 40°C.

[0039] Optionally, the preparation method of the compound 4 includes: reacting a mixture containing the compound 3, tetrahydrofuran, lithium hydroxide or its hydrate, S-phenylethylamine and water in the reaction 3, filtering, washing the filter cake with acetone, and drying under vacuum to obtain the compound 4.

[0040] Optionally, 1 g of the compound 3 is mixed with 2 ml to 30 ml of the tetrahydrofuran.

[0041] Optionally, 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.

[0042] Optionally, the molar ratio of the compound 3 to the lithium hydroxide or its hydrate is 1:(0.8 - 4).

[0043] 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.

[0044] Optionally, the molar ratio of the compound 3 to the S - phenethylamine is 1:(0.8 - 3).

[0045] Optionally, the molar ratio of the compound 3 to the S - phenethylamine 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.

[0046] Optionally, 1 g of the compound 3 is mixed with 2 ml to 30 ml of the water.

[0047] Optionally, 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.

[0048] Optionally, the temperature of the reaction 4 is 50 - 70 °C.

[0049] Optionally, the temperature of the reaction 4 is 50 °C, 52 °C, 55 °C, 60 °C, 65 °C or 70 °C.

[0050] Optionally, the preparation method of the compound 5 includes: reacting a mixture containing the compound 4, D - phenylglycine and toluene in the reaction 4, and cooling the reaction solution to 20 - 30 °C to obtain the compound 5.

[0051] Optionally, the molar ratio of the compound 4 to the D - phenylglycine is 1:(0.8 - 3).

[0052] 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.

[0053] Optionally, 1 g of the compound 4 is mixed with 2 ml to 30 ml of the toluene.

[0054] Optionally, 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.

[0055] Optionally, the temperature of the reaction 4 is 80 to 120 °C.

[0056] Optionally, the temperature of the reaction 4 is 80 °C, 85 °C, 90 °C, 95 °C, 100 °C, 105 °C, 110 °C, 115 °C or 120 °C.

[0057] Optionally, the preparation method of the compound 6 includes: under a nitrogen or inert gas atmosphere, reacting a mixture containing the compound 5, dichloromethane, zinc dichloride and triethylsilane in reaction 5, 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 the compound 6.

[0058] Optionally, the inert gas is selected from at least one of helium, neon, argon, and krypton.

[0059] Optionally, the molar ratio of the compound 5 to the zinc dichloride is 1:(0.8 to 3).

[0060] 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.

[0061] Optionally, the molar ratio of the compound 5 to the triethylsilane is 1:(0.8 to 3).

[0062] 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.

[0063] Optionally, 1 g of the compound 5 is mixed with 2 ml to 30 ml of the dichloromethane.

[0064] Optionally, 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.

[0065] Optionally, the temperature of the reaction 5 is -20 to 30 °C.

[0066] Optionally, the temperature of the reaction 5 is -20°C, -15°C, -10°C, 0°C, 10°C, 20°C or 30°C.

[0067] Optionally, the method for preparing compound 7 includes: reacting a mixture of the product containing compound 6, methanol, ammonium formate and palladium carbon in reaction 6, filtering to recover the catalyst, concentrating the organic phase under reduced pressure, adding ethyl acetate and water, stirring, standing for liquid separation, 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 drying under vacuum to obtain the product containing compound 7.

[0068] Optionally, the mass percentage of palladium in the palladium carbon is 1% - 10%.

[0069] Optionally, the mass percentage of palladium in the palladium carbon is 1%, 2%, 3%, 5%, 6%, 8%, 9% or 10%.

[0070] Optionally, the molar ratio of the product containing compound 6 to ammonium formate is 1:(0.8 - 4).

[0071] 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.

[0072] Optionally, the molar ratio of the product containing compound 6 to palladium carbon is 1:(0.001 - 0.2).

[0073] 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.

[0074] Optionally, every 1 g of the product containing compound 6 is mixed with 2 ml - 30 ml of the methanol.

[0075] 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.

[0076] Optionally, the temperature of the reaction 6 is 20 - 70°C.

[0077] 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.

[0078] Optionally, the method for preparing compound 8 comprises: reacting a mixture of a product containing compound 7, glacial acetic acid and concentrated hydrochloric acid in reaction 7, cooling to room temperature, removing the solvent under reduced pressure, slowly adding ethyl acetate dropwise for pulping, filtering, and drying in vacuo to obtain the said compound 8.

[0079] Optionally, the mass ratio of the product containing compound 7 to the glacial acetic acid is 1:(1 - 40).

[0080] 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.

[0081] Optionally, the molar ratio of the product containing compound 7 to the concentrated hydrochloric acid is 1:(1 - 100).

[0082] Optionally, the molar ratio of the product containing compound 7 to the 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.

[0083] Optionally, the temperature of the said reaction 7 is 20 - 110 °C.

[0084] Optionally, the temperature of the said reaction 7 is 20 °C, 30 °C, 40 °C, 50 °C, 70 °C, 90 °C or 110 °C.

[0085] Optionally, the concentration of the said concentrated hydrochloric acid is 30% - 38%.

[0086] As an optional embodiment, the present invention is synthesized through the following technical route:

[0087] 。

[0088] In view of the current situation that it is difficult to obtain the chiral raw material 8, a new route from compound 1 to compound 8 has been designed, and the design and preparation of this route have been completed. This synthetic route involves a total of 7 chemical reactions. Using 4-biphenylacetic acid and Meldrum's acid as raw materials, compound 2 is synthesized by the condensation reaction of Meldrum's acid. Meldrum's acid has acidity and can react with halogenated hydrocarbons for alkylation, with acyl halides for acylation, and with carboxylic acids for condensation reaction under the action of a base; compound 2 reacts with compound a to form compound 3; the decarboxylation of β-keto acid synthesizes compound 4. This step of reaction is a hydrolysis decarboxylation reaction. The substrate compound 3 is in the β-keto acid structure after hydrolysis, and β-keto acid is prone to decarboxylation. The reaction process proceeds through a concerted reaction of a six-membered ring. First, enol is generated, and then it is rearranged 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, and compound 5 is an N,O-acetal with the N atom connected to the carbonyl group; the carbon-oxygen bond of the N,O-acetal structure is broken to synthesize compound 6. Since the N,O-acetal structure with the N atom connected to the carbonyl group is generally relatively stable, in this invention, zinc dichloride as a Lewis acid and triethylsilane as a hydrogen donor are used to break the carbon-oxygen bond in the N,O-acetal structure. Its mechanism is through an imide ion intermediate state complexed with zinc dichloride. The configuration of the phenylglycine part and the existence of the oxyzinc salt complex structure block the entry of nucleophilic hydrogen on one side, and the biphenylmethyl group maintains its configuration unchanged; the reactions from compound 4 to compound 7 are carried out in three consecutive steps, and finally the post-treatment of compound 7 is carried out; the hydrolysis of lactam synthesizes compound 8. This step of 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, with the chemical purity of the product being over 99%. It solves the problems existing in the existing process routes, such as low optical purity of the product, expensive and difficult-to-obtain materials, dangerous chemical reactions not being suitable for large-scale production, and cryogenic reactions not conforming to green chemistry, and detailed process optimization has been carried out on the key steps of this route to determine the optimal process conditions for each step of the reaction.

[0089] In view of the problem that the materials are expensive and difficult to obtain, the present invention uses 4-biphenylacetic acid, which is cheap and easily available in the market, as a raw material, and prepares the key intermediate 4 through condensation, substitution, and hydrolysis decarboxylation reactions. The difficulty of this synthetic route lies in the control of the optical purity of the product, especially the construction of chiral amino groups. To address the problem of low optical purity of the product, the present invention uses cheap chiral methyl S-lactate as a raw material to introduce the first chiral center; then uses D-phenylglycine as a chiral auxiliary and amine source to construct a chiral lactam ring; and then obtains the important intermediate 8 of Sacubitril through cyclization reaction, chiral-controlled reduction ring-opening reaction with zinc dichloride / triethylsilane, debenzylation reaction, and lactam ring-opening; the chiral raw materials methyl S-lactate, D-phenylglycine, and the starting material 4-biphenylacetic acid are cheap and easily available; it successfully avoids the problems of Grignard reaction and cryogenic reaction conditions that often appear in the existing routes; among them, intermediates such as compound 5 and compound 6 have novel compound structures. Generally speaking, the synthetic route provided by the present invention is novel, economical, environmentally friendly, safe, and suitable for industrial production.

[0090] The beneficial effects that the present invention can produce include:

[0091] The preparation method of the Sacubitril intermediate provided by the present invention has the advantages that the chiral raw materials methyl S-lactate, D-phenylglycine, and the starting material 4-biphenylacetic acid are cheap and easily available; it successfully avoids the Grignard reaction and cryogenic reaction conditions that often appear in the existing routes; intermediates such as compound 5 and compound 6 have novel compound structures. In short, the synthetic route of the Sacubitril intermediate provided by the present invention is novel, economical, environmentally friendly, safe, and suitable for industrial production. Description of the Drawings

[0092] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can be obtained based on these drawings.

[0093] Figure 1 It is the synthetic route diagram of the key materials of Sacubitril provided by the present invention;

[0094] Figure 2 It is the mechanism diagram for constructing the second chiral center (compound 6) provided by the present invention.

[0095] Term Explanation

[0096] In the following content, all the numbers disclosed herein are approximate values, whether the words "about" or "approximate" are used or not. The numerical value of each number may vary by 1%, 2%, 5%, 7%, 8%, 10%, 15% or 20%, etc. 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, of a numerical range are disclosed, any numerical value within the disclosed range will be explicitly disclosed. In particular, the following numerical values within the range are included: R = RL + K*(RU - RL), where k is a variable that increases in 1% increments from 1% to 100%. Such as: 1%, 2%, 3%, 4%, 5%...50%, 51%, 52%...95%, 96%, 97%, 98%, 99% or 100%. Additionally, the numerical ranges defined by the above two R numbers disclosed herein are specifically included.

[0097] In the description of the present invention, the meaning of "a plurality" is two or more, unless otherwise specifically defined.

[0098] The term "room temperature" refers to the ambient temperature, which means a temperature of about 10°C to about 30°C, or about 20°C to 30°C, or about 25°C.

[0099] In the description of this specification, the description with reference to terms such as "an embodiment", "some embodiments", "example", "specific example", or "some examples", etc. means that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic expressions of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in a suitable manner in any one or more embodiments or examples. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0100] Certain embodiments of the present invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. 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 by the claims. Those skilled in the art should recognize 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 case where one or more of the incorporated documents, patents, and similar materials are different from or inconsistent with the present application (including but not limited to the defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0101] It should be further recognized that certain features of the present invention are described in multiple separate embodiments for clarity, but can also be provided in combination in a single embodiment. Conversely, various features of the present invention are described in a single embodiment for brevity, but can also be provided separately or in any suitable sub-combination.

[0102] Unless otherwise stated, all scientific and 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 pertains. All patents and published publications referred to in the present invention are incorporated herein by reference in their entirety.

[0103] Unless otherwise stated, the following definitions shall apply to the terms used herein. For the purposes of the present invention, chemical elements are in accordance with the CAS version of the Periodic Table of the Elements and the Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, general principles of organic chemistry can be referred to the descriptions 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.

[0104] Unless otherwise specified or there is an obvious conflict in the context, the articles "a", "an", and "the" used herein are intended to include "at least one" or "one or more". Therefore, these articles used herein refer to articles for one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, that is, there may be more than one component considered to be adopted or used in the implementation of the described embodiment.

[0105] The term "comprising" is an open-ended expression, that is, it includes the content specified in the present invention, but does not exclude other aspects.

[0106] "Stereoisomers" refer to compounds with the same chemical structure but different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), atropisomers, and so on.

[0107] "Chiral" refers to a molecule that has the property of not being superimposable on its mirror image; while "achiral" refers to a molecule that is superimposable on its mirror image.

[0108] "Enantiomers" refer to two isomers of a compound that are non-superimposable but mirror images of each other.

[0109] "Diastereomers" refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical operations such as electrophoresis and chromatography, e.g., HPLC.

[0110] The stereochemical definitions and rules used in this invention generally follow S.P. 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.

[0111] Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are used to specify the sign of the rotation of plane-polarized light caused by the compound, where (-) or l indicates that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. A specific type of stereoisomer is an enantiomer, and a mixture of such isomers is called a racemic 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.

[0112] Any asymmetric atom (e.g., carbon, etc.) of the disclosed compounds of the present invention can exist in racemic or enantiomerically enriched form, such as in the form of (R)-, (S)-, or (R,S)-configurations. In certain embodiments, each asymmetric atom has an enantiomeric excess of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% in terms of the (R)- or (S)-configuration.

[0113] In the examples of the present invention, "DIPEA" is N,N-diisopropylethylamine; "THF" is tetrahydrofuran; "MeCN" is acetonitrile; "PhMe" is toluene. Detailed Description of the Invention

[0114] The present application will be described in detail below in conjunction with examples, but the present application is not limited to these examples.

[0115] Unless otherwise specified, the raw materials in the examples of the present application are all purchased through commercial channels.

[0116] As Figure 1 and 2 shown, it is the synthetic route of the key materials of sacubitril provided by the present invention and the mechanism diagram for constructing the second chiral center (Compound 6).

[0117] As Figure 2 shown, the present invention utilizes the chiral auxiliary D-phenylglycine, which is also a chiral amine source, to cyclize with Compound 4 to synthesize Compound 5, and the chiral-controlled reduction reaction of zinc dichloride / triethylsilane is used to open the ring to break the carbon-oxygen bond of the N,O-acetal structure to synthesize Compound 6, thus successfully constructing the second chiral center.

[0118] The reaction mechanism is as Figure 2 shown. Since N,O-acetals will undergo hydrolysis under various reaction conditions and have high activity, but if the N atom is connected to a carbonyl group, such acetals have considerable stability. Compound 5 is an N,O-acetal with the N atom connected to a carbonyl group. D-phenylglycine and γ-keto acid Compound 4 can react in refluxing toluene to produce Compound 5; when opening the ring of Compound 5, the Lewis acid zinc dichloride and the hydrogen donor triethylsilane are used to break the carbon-oxygen bond in the N,O-acetal structure. The mechanism is through an imide ion intermediate complexed with zinc dichloride, and the configuration of the phenylglycine part and the existence of the oxygenophilic zinc salt complex structure block the entry of nucleophilic hydrogen on one side, and the biphenylmethyl group maintains its configuration unchanged.

[0119] Due to the electron-withdrawing effect of two carbonyl groups, Meldrum's acid is acidic and can react with halogenated hydrocarbons for alkylation, acyl halides for acylation, and carboxylic acids for condensation reaction under the action of a base. In the present invention, 4-biphenylacetic acid reacts with Meldrum's acid under the condensation of DCC and catalysis of DMAP to prepare 4-biphenyl-3-oxobutyrate.

[0120] Example 1 Synthesis of Compound 2 by Condensation Reaction of Meldrum's Acid

[0121]

[0122] 10.00 g of 4-biphenylacetic acid, 7.5 g of Meldrum's acid, 0.2 g of 4-dimethylaminopyridine (DMAP), 11 g of N,N'-dicyclohexylcarbodiimide (DCC) and 100 ml of dichloromethane were mixed and the temperature was lowered to 0 °C for reaction for 12 h. After filtration, the precipitated solid was removed by filtration, and the filtrate was concentrated to obtain a light yellow oily product containing Compound 2. 70 ml of methanol was added to the above oily product, and the temperature was raised to 55 °C for reaction under nitrogen protection. TLC detection showed that the raw materials had completely reacted. The reaction solution was cooled to 0 °C and stirred for 3 h, then filtered, and the filter cake was dried in vacuo at 60 °C to obtain Compound 2 (11.60 g of white solid, yield 91.8%, chemical purity 99.0%). 1H NMR (400 MHz, CDCl3) δ 7.65 - 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).

[0123] Example 2 Synthesis of Compound 3

[0124]

[0125] Synthesis of Compound 3: 24.00 g of Compound 2, 4.65 g of NaOH powder and 200 mL of THF were mixed. The reaction solution was cooled to 0 °C and stirred for 30 min, then a tetrahydrofuran solution containing 27.5 g of Compound a (27.5 g of Compound a was dissolved in 100 mL 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 with stirring for 4 h. After the reaction was complete, 200 mL of water and 200 mL of ethyl acetate were added to the reaction solution, stirred and separated, the aqueous phase was extracted with 100 mL of ethyl acetate, the organic phases were combined, washed with 200 mL of water, and the organic phase was concentrated under reduced pressure to obtain an oily substance containing Compound 3, which was directly fed without purification for the next reaction. The purity of this step of the reaction was 90%. NMR data of the product oily substance: 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).

[0126] Preliminary screening was carried out on the above reaction. First, the category of the substrate ester was 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 often failed; when Compound 2 contained methyl ester units, the preliminary intermediate control purity reached 80%, with good reproducibility, which might 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 using sodium hydride as the base. Due to the danger of sodium hydride in industrial scale-up, it was necessary to replace sodium hydride. The present invention carefully optimized the type of base and the combination of different solvents. The results showed that when NaOH powder was used as the base, the intermediate control purity reached more than 90%, and it had good reproducibility. The reason was that powdered sodium hydroxide had good dispersibility, increased the solubility of sodium hydroxide in tetrahydrofuran (THF), and the reaction steric hindrance was also very small, so it had good reaction effects. This improvement not only increased the safety factor of the process, but also reduced the material cost and the smoothness of the operation. The specific results are shown in Table 1.

[0127] Table 1

[0128]

[0129] Example 3 Decarboxylation of β-keto acid to synthesize Compound 4

[0130]

[0131] Synthesis of Compound 4 by Decarboxylation of β-Keto Acid This step is a hydrolysis decarboxylation reaction. After hydrolysis of the substrate compound 3, it has a β-keto acid structure. β-Keto acids are prone to decarboxylation. The reaction process proceeds through a concerted reaction via a six-membered ring. First, enol is formed, and then it is rearranged to form a ketone. Since the transition state of the reaction is a six-membered ring with low energy, the reaction is very easy to proceed.

[0132] 158.5 g of compound 3, 1200 g of tetrahydrofuran (THF), 1200 g of water, and 38 g of lithium hydroxide monohydrate were stirred at room temperature, and the reaction solution was heated to 60 °C and reacted for 3 h. HPLC detected that the raw materials reacted completely. The reaction solution was cooled to 20 °C, and HCl aqueous solution was slowly added dropwise to adjust the pH to 2. Then, 1000 ml of ethyl acetate was added for extraction twice, and the two organic phases were combined. After washing with water, the organic phase was concentrated under reduced pressure to obtain an oily substance. The obtained oily substance was dissolved in acetone, heated to 50 °C, and 81 g of S-phenethylamine was slowly added dropwise. After the addition was completed, stirring was continued for 1 h, and then cooled to room temperature and stirred for another 2 h. Filtration was carried out, and the filter cake was washed with 200 mL of acetone and dried in vacuo at 60 °C for 15 h to obtain the phenethylamine salt of compound 4, and compound 4 was obtained after liberation; the reaction yield was 68%, the chemical purity was 99%, and the content of optical isomers was <2%. 1H NMR (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).

[0133] The present invention optimized process parameters such as the dosage of lithium hydroxide monohydrate, reaction temperature, and reaction time. When the dosage of lithium hydroxide monohydrate was 2.0 or 2.5 equivalents, although the content of enantiomers decreased, the reaction rate was slow and the in-process purity was low. The in-process purity was the highest when the dosage of lithium hydroxide monohydrate was controlled at 3.0 equivalents. When the dosage of lithium hydroxide monohydrate was 3.0 equivalents, the reaction temperature had little effect on the content of enantiomers of compound 4, and at the same time, it had an impact on the reaction rate. When the reaction temperature was 50 °C, the reaction rate decreased and the in-process purity was low. The reaction temperature of compound 4 was controlled between 60 - 70 °C. The extension of the reaction time had little effect on the content of enantiomers of compound 4, and the raw materials reacted completely after 1.5 h of reaction. The specific results are shown in Table 2 below.

[0134] Table 2

[0135]

[0136] Example 4 Synthesis of Compound 5 Using Chiral Auxiliary D-Phenylglycine

[0137]

[0138] Since N,O - acetals undergo hydrolysis under various reaction conditions and have high reactivity, but if the N atom is connected to a carbonyl group, such acetals have considerable stability. Compound 5 is an N,O - acetal with the N atom connected to a carbonyl group. Compound 5 can be produced by refluxing D - phenylglycine and γ - keto acid compound 4 in toluene.

[0139] Mix 20 g of compound 4, 13.14 g of D - phenylglycine and 180 ml of toluene, stir and heat up to 110 °C for reflux and water - separation reaction for 18 h. Detect by HPLC that the raw materials have completely reacted. Cool the reaction solution to 20 °C and concentrate it under reduced pressure to obtain an oily substance, which is directly fed for the next reaction without purification. The purity of the oily substance is about 90%. 1HNMR(400 MHz, 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).

[0140] Example 5 Synthesis of Compound 6 by Cleavage of the Carbon - Oxygen Bond in the N,O - Acetal Structure

[0141]

[0142] Since the N,O - acetal structure with the N atom connected to a carbonyl group is generally stable, in this invention, zinc dichloride as a Lewis acid and triethylsilane as a hydrogen donor are used to cleave the carbon - oxygen bond in the N,O - acetal structure. The mechanism is through an imide ion intermediate state complexed with zinc dichloride. The configuration of the phenylglycine part and the existence of the oxophilic zinc salt complex structure block the entry of nucleophilic hydrogen on one side, and the biphenylmethyl group maintains its configuration unchanged.

[0143] 39.7 g of Compound 5, 320 ml of dichloromethane and 14 g of zinc dichloride were mixed. The reaction solution was cooled to -20 °C, and 12.8 g of triethylsilane was slowly added dropwise under nitrogen protection. After the addition was complete, the reaction was slowly warmed to room temperature. HPLC detection showed that the raw materials had completely reacted. 200 ml of 10% ammonium chloride aqueous solution 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 fed into the next reaction without purification. The purity control in this step was above 80%. 1H NMR (400 MHz, CDCl3) δ 12.65 (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).

[0144] Example 6 Catalytic Debenzylation to Synthesize Compound 7

[0145]

[0146] 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 detection showed that the raw materials had completely reacted. The catalyst was recovered by filtration, 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, allowed to stand and separated. The organic phase was washed with water and then concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized with ethyl acetate and n-heptane and dried in vacuo to obtain white solid Compound 7. 1H NMR (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).

[0147] In the synthetic route of the present invention, the reactions of Compound 4 to Compound 7 were carried out in three steps with continuous feeding, and finally the post-treatment of Compound 7 was carried out. The average yield of each step was 85%, and the chemical purity of Compound 7 was 99.0%.

[0148] Example 7 Lactam Hydrolysis to Synthesize Compound 8

[0149]

[0150] Synthesis of Compound 8 by lactam hydrolysis. This step involves the high-temperature hydrolysis of lactam compound 7 under the action of concentrated hydrochloric acid, which is a common organic synthesis reaction.

[0151] Mix 0.50 g of compound 7, 2.5 g of glacial acetic acid and 15 mL of 30% hydrochloric acid, heat up to 110 °C for reaction. When HPLC detects that the raw materials have completely reacted, cool down to room temperature, remove the solvent under reduced pressure, slowly add ethyl acetate for pulping, filter, and vacuum dry to obtain white solid compound 8; the reaction yield is 86%, and the chemical purity is 99.0%. 1H NMR (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).

[0152] In view of the problem that the starting materials are difficult to obtain, the present invention designs a new route from compound 1 to compound 8, completes the design of this route and the optimization of the preliminary process. There are a total of 8 chemical reactions, and the average yield of each chemical reaction is 84%. The target product compound 8 is successfully obtained, and the chemical purity of the product is 99%, achieving the expected goal.

[0153] Compared with the prior art, the present invention has the following obvious advantages:

[0154] The present invention provides a method for synthesizing the key material of sacubitril using compound 4 as the raw material and chiral substituted glycine as the chiral auxiliary. Compared with the prior art, this method replaces the expensive chiral auxiliary with phenylglycine, which is cheaper and easier to obtain. The preparation method is simple, the reaction conditions of each step are mild and simple, there are no dangerous chemical reactions, and there are no high-energy-consuming chemical reactions such as cryogenic cooling, which is suitable for industrial production; among them, intermediates such as compound 5 and compound 6 have novel compound structures; overall, this route is novel, economical, environmentally friendly, safe and suitable for industrial production.

[0155] The above are only several embodiments of the present application, and do not impose any form of limitation on the present application. Although the present application is disclosed above with preferred embodiments, it is not intended to limit the present application. Any person skilled in the art, without departing from the scope of the technical solution of the present application, makes some changes or modifications using the technical content disclosed above, which are equivalent to equivalent implementation cases and all fall within the scope of the technical solution.

Claims

1. A method for preparing a sacubitril intermediate, characterized in that, It includes the following synthetic routes: Compound 4 is obtained by reacting with Compound 3, and the structural formula of Compound 3 is The compound 3 is prepared by reacting compound a with compound 2. The structural formula of compound a is The structural formula of compound 2 is The said compound 2 is obtained through the condensation reaction of 4-biphenylacetic acid and Meldrum's acid; The preparation method of compound 5 includes: reacting a mixture containing compound 4, D-phenylglycine and toluene for 4 to obtain the said compound 5; The molar ratio of the said compound 4 to the said D-phenylglycine is 1:(0.8 - 3); Every 1 g of the said compound 4 is mixed with 2 ml to 30 ml of the said toluene; The temperature of the said reaction 4 is 80 - 120 °C; The preparation method of compound 6 includes: under a nitrogen or inert gas atmosphere, reacting a mixture containing compound 5, dichloromethane, zinc dichloride and triethylsilane for 5 to obtain a product containing compound 6; The said inert gas is selected from at least one of helium, neon, argon, krypton; The molar ratio of the said compound 5 to the said zinc dichloride is 1:(0.8 - 3); The molar ratio of the said compound 5 to the said triethylsilane is 1:(0.8 - 3); Every 1 g of the said compound 5 is mixed with 2 ml to 30 ml of the said dichloromethane; The temperature of the said reaction 5 is -20 - 30 °C.

2. A preparation method of a sacubitril intermediate, characterized in that, Step 1, obtaining compound 6 based on the preparation method as described in claim 1; Step 2, preparing compound 7 and compound 8 based on compound 6; The synthetic routes of the said compound 7 and compound 8 are as follows:

3. The preparation method according to claim 1, characterized in that, The preparation method of compound 2 includes: reacting a mixture containing 4-biphenylacetic acid, Meldrum's acid, 4-dimethylaminopyridine, N,N'-dicyclohexylcarbodiimide and solvent 1 for 1 to obtain the said compound 2; The molar ratio of the said 4-biphenylacetic acid to the said Meldrum's acid is 1:(0.8 - 3); The mass ratio of the said 4-biphenylacetic acid to the said 4-dimethylaminopyridine is 1:(0.01 - 1); The molar ratio of the said 4-biphenylacetic acid to the said N,N'-dicyclohexylcarbodiimide is 1:(0.8 - 2); The said solvent 1 is selected from at least one of dichloromethane, toluene, ethyl acetate, isopropyl acetate, tetrahydrofuran; Every 1 g of the said 4-biphenylacetic acid is mixed with 2 ml to 25 ml of the said solvent 1; The temperature of the said reaction 1 is 0 - 30 °C.

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

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

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

7. The preparation method according to claim 2, characterized in that, The preparation method of compound 8 includes: reacting a mixture of the product containing compound 7, glacial acetic acid and concentrated hydrochloric acid in reaction 7 to obtain the said compound 8; The mass ratio of the said product containing compound 7 to the said glacial acetic acid is 1:(1 - 40); The molar ratio of the said product containing compound 7 to HCl in concentrated hydrochloric acid is 1:(1 - 100); The temperature of the said reaction 7 is 20 - 110 °C.

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