Preparation method of intermediate

Abstract

The invention provides a preparation method of an intermediate. The preparation method comprises the following steps: reacting 2-methyl-3-nitrobenzoic acid with an acyl chloride reagent to obtain a product 1; reacting the product 1 with malonate or malonate salt under an alkaline condition to generate a product 2; hydrolyzing the product 2 in an aqueous solution of acid to obtain a product 3; carrying out reduction reaction on the product 3 in the presence of a catalyst to obtain a product 4; carrying out Sandmeyer reaction on the product 4 to obtain a product 5; the product 5 is subjected to a Rosenmund-von Braun reaction, and a product 6 is obtained; and reacting the product 5 with cyanide or the product 6 under the condition that enzyme is used as a catalyst to obtain (R)-3-(1-aminoethyl)-2-methylbenzonitrile. The route for preparing (R)-3-(1-aminoethyl)-2-methylbenzonitrile has the characteristics of short route, high yield, relatively mild reaction conditions and the like. The used raw materials are easy to obtain, the cost is low, no special operation process is needed, the requirement for equipment is not high, and the method is suitable for large-scale industrial production.

Description

Technical Field

[0001] The present application relates to the field of organic chemical synthesis of pharmaceutical intermediates, and in particular to a method for preparing an intermediate, specifically a method for preparing (R)-3-(1-aminoethyl)-2-methylbenzonitrile. Background Art

[0002] MRTX-0902 (M647526), a highly potent phthalazine-based SOS1:KRAS complex inhibitor developed by MRTX, has entered Phase I / II clinical trials. It is a potent, selective, brain-penetrating, and orally bioavailable SOS1 binder. It disrupts the SOS1:KRAS G12C interaction by forming a salt bridge between the phthalazine core and Glu902. The electron-withdrawing properties of the 3-cyano substituent enhance π-π stacking with Phe890, while the substituted phenyl ring provides a shape that is complementary to the SOS1 back pocket. Combining MRTX-0902 with the KRAS G12C inhibitor MRTX-849 (Adagrasib) enhances MAPK pathway inhibition, significantly improving its anti-tumor activity and nearly completely eliminating tumors in the MIA PaCa-2 tumor xenograft model.

[0003]

[0004] MRTX-0902 has a complex molecular structure consisting of a pyrido[3,4-d]pyridazine core and a chiral amine molecule, making it extremely challenging to prepare the drug on a large scale to support clinical studies, especially since (R)-3-(1-aminoethyl)-2-methylbenzonitrile is an important intermediate in the synthesis of MRTX-0902 and other SOS1 inhibitors.

[0005] Mirati Therapeutics published a method for preparing (R)-3-(1-aminoethyl)-2-methylbenzonitrile in WO2021127429, WO2022271679, and WO2023250165. The synthesis route of this compound was also reported in Journal of Medicinal Chemistry, 65(14), 9678-9690 and Journal of Organic Chemistry (2024), 89(6), 3875-3882. The reaction equation is as follows:

[0006]

[0007] Solvents and reagents: (a) HATU, DIPEA, DMF; (b) methylmagnesium bromide, 40-45°C; (c) tetraethyl titanate, 80°C, 24h; (d) -78°C, 2h; (e) HCl / dioxane, 0°C, 30min, methanol; (f) BOC2O, DIPEA, DCM; (g) zinc cyanide, tetrakistriphenylphosphine palladium, DMF, 110°C, 3h; (h) TFA, DCM, 0°C, 30min.

[0008] In addition, Zhejiang Hisun Pharmaceutical Co., Ltd. (ZHEJIANG HISUN PHARMACEUTICAL CO., LTD.) and Shanghai ARYL PHARMTECH CO., LTD. jointly published similar synthetic routes in patents WO2022160931 and WO2023030216, and Shanghai Haihe Pharmaceutical Research and Development Co., Ltd. (HAIHE BIOPHARMACO., LTD.) published similar synthetic routes in WO2023051628 and WO2023246837.

[0009] The above process route is long, requiring eight reaction steps to produce (R)-3-(1-aminoethyl)-2-methylbenzonitrile, and requires the use of hazardous reagents such as Grignard reagent and L-selectride (lithium tri-sec-butylborohydride). The purification of isomers must rely on column chromatography, which places very high demands on production equipment and results in a low overall yield.

[0010] Nanjing Medshine Discovery Inc.

[0011] WO2022199635 and WO2023280317 disclose a synthesis method using 3-bromo-2-methylbenzonitrile as a starting material, and the route is as follows:

[0012]

[0013] Solvents and reagents: (a) bistriphenylphosphine palladium dichloride, toluene, 120°C, 12h; (b) hydrochloric acid, acetone, 20°C, 1h; (c) tetraethyl titanate, tetrahydrofuran, 80°C, 24h; (d) sodium borohydride, tetrahydrofuran, 0°C, 1h; (e) HCl / dioxane, 20°C, 2h.

[0014] In addition, Sichuan Huiyu Pharmaceutical Co., Ltd. (SICHUAN HUIYU PHARMACEUTICAL CO., LTD.) also disclosed a similar process in patent WO2022268209.

[0015] The above process can produce the hydrochloride salt of the product in five steps. Although it avoids the use of expensive and dangerous reagents such as L-selectride (lithium tri-sec-butylborohydride) for reduction, the raw material 3-bromo-2-methylbenzonitrile is relatively expensive and must be produced in-house. In addition, the purification of isomers must rely on column chromatography, which places very high demands on production equipment. Summary of the Invention

[0016] In response to the problems existing in the prior art, the present application provides a method for preparing an intermediate, specifically a method for preparing (R)-3-(1-aminoethyl)-2-methylbenzonitrile, which avoids the shortcomings of the existing route, such as high cost, low yield, complex operation, cumbersome post-processing, and unsuitability for large-scale production.

[0017] 1. A method for preparing an intermediate, comprising:

[0018] Step 1: 2-methyl-3-nitrobenzoic acid reacts with an acyl chloride reagent to obtain product 1, as shown in Formula I;

[0019]

[0020] Step 2: reacting the product 1 with a malonate or malonate salt under alkaline conditions to generate a product 2, as shown in Formula II-1 or II-2;

[0021]

[0022] wherein R1 is CH3, C2H5 or CH(CH3)2; R2 is H, COOH, COOCH3, COOC2H5 or COOCH(CH3)2;

[0023] Step 3: hydrolyzing the product 2 in an acid aqueous solution to obtain product 3, as shown in Formula III;

[0024]

[0025] Step 4: The product 3 is subjected to a reduction reaction under a catalyst to obtain a product 4, as shown in Formula IV;

[0026]

[0027] Step 5: The product 4 is subjected to a Sandmeyer reaction to obtain a product 5, which is a bromide, iodide or cyanide, as described in Formula V or VI;

[0028]

[0029] Wherein, X is Br or I;

[0030]

[0031] Step 6: When the product 5 is a bromide or iodide, the product 5 is subjected to a Rosenmund-von Braun reaction to obtain product 6, as shown in Formula VI. When the product 5 is a cyanide, this step is skipped;

[0032] Step 7: The product 5 cyanide or product 6 reacts with an enzyme as a catalyst to obtain (R)-3-(1-aminoethyl)-2-methylbenzonitrile, as shown in Formula VII.

[0033]

[0034] 2. The preparation method according to item 1, wherein the malonate in step 2 is dimethyl malonate, diethyl malonate, isopropylidene malonate, tert-butyl acetoacetate or diisopropyl malonate; and / or,

[0035] The malonate salt in step 2 is potassium monomethyl malonate, sodium monomethyl malonate, potassium monoethyl malonate or sodium monoethyl malonate; and / or,

[0036] The base used in step 2 is magnesium methoxide, magnesium ethoxide, barium oxide, triethylamine or diisopropylethylamine; and / or,

[0037] When step 2 is carried out under catalyst conditions, the catalyst used is magnesium chloride or magnesium bromide.

[0038] 3. The preparation method according to item 1, wherein the product 1 in step 2 is reacted with a malonate, preferably dimethyl malonate.

[0039] 4. The preparation method according to item 1, wherein the acyl chloride reagent in step 1 comprises one of phosphorus oxychloride, thionyl chloride, oxalyl chloride and a corresponding Vilsmeier-Haack reagent formed with N,N-dimethylformamide; and / or

[0040] The acid in step 3 is hydrochloric acid, hydrobromic acid or sulfuric acid.

[0041] 5. The preparation method according to claim 1, wherein the reducing agent used in the reduction reaction in step 4 is hydrogen, reduced iron powder, hydrazine hydrate or stannous chloride, preferably hydrogen; and / or

[0042] The catalyst in step 4 comprises one or more of ammonium chloride, hydrochloric acid, acetic acid, Raney nickel, palladium carbon, platinum carbon, ferric chloride and activated carbon, preferably Raney nickel.

[0043] 6. The preparation method according to item 1, wherein the reaction system used in the Sandmeyer reaction in step 5 comprises: one or more of a hydrobromic acid / sodium nitrite system, a hydrochloric acid or sulfuric acid / sodium nitrite / sodium iodide or potassium iodide system, a hydrochloric acid or sulfuric acid / sodium nitrite / potassium cyanide or sodium cyanide / copper sulfate system, and an isoamyl nitrite or tert-butyl nitrite / cuprous cyanide system.

[0044] 7. The preparation method according to item 1, wherein the Rosenmund-von Braun reaction in step 6 comprises: dissolving the product 5 in an organic solvent, adding a metal cyanide, and reacting under catalyst conditions to generate the product 6.

[0045] 8. The preparation method according to item 7, wherein the organic solvent comprises one or more of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and sulfolane; and / or

[0046] The metal cyanide includes one or more of cuprous cyanide, zinc cyanide, sodium cyanide, and potassium cyanide; and / or,

[0047] The catalyst is a palladium catalyst, including one or more of palladium acetate, diphenylphosphinocene palladium dichloride, tetrakistriphenylphosphine palladium, and dichlorobistriphenylphosphine palladium.

[0048] 9. The preparation method according to item 1, wherein the enzyme in step 7 is an amino ω-transaminase, preferably an enzyme in the ω-transaminase ATA series, further preferably one or more of ω-transaminase ATA-117, ω-transaminase ATA-254, ω-transaminase ATA-415, and ω-transaminase ATA-P2-A07, and further preferably ω-transaminase ATA-254.

[0049] 10. Use of (R)-3-(1-aminoethyl)-2-methylbenzonitrile prepared by the method described in any one of items 1 to 9 in the preparation of SOS1 inhibitor intermediates.

[0050] Compared with the existing synthetic routes, this application has the following advantages:

[0051] 1. This application proposes a new route for preparing (R)-3-(1-aminoethyl)-2-methylbenzonitrile, which has the characteristics of a short route, high yield, and relatively mild reaction conditions.

[0052] 2. The synthetic route proposed in this application uses readily available raw materials, has low cost, does not require special operation processes, has low equipment requirements, and is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1 This is the NMR spectrum of dimethyl 3-(2-methyl-3-nitrobenzoyl)malonate.

[0054] Figure 2 This is the NMR spectrum of ethyl 3-(2-methyl-3-nitrophenyl)-3-oxopropanoate.

[0055] Figure 3 This is the NMR spectrum of diethyl 3-(2-methyl-3-nitrobenzoyl)malonate.

[0056] Figure 4 This is the NMR spectrum of 1-(2-methyl-3-nitrophenyl)ethanone.

[0057] Figure 5 This is the NMR spectrum of 1-(3-amino-2-methylphenyl)ethanone.

[0058] Figure 6 This is the NMR spectrum of 1-(3-bromo-2-methylphenyl)ethanone.

[0059] Figure 7 This is the NMR spectrum of 1-(3-iodo-2-methylphenyl)ethanone.

[0060] Figure 8 This is the NMR spectrum of 1-(3-cyano-2-methylphenyl)ethanone.

[0061] Figure 9 This is the NMR spectrum of (R)-3-(1-aminoethyl)-2-methylbenzonitrile.

[0062] Figure 10 This is the MS chart of (R)-3-(1-aminoethyl)-2-methylbenzonitrile. DETAILED DESCRIPTION

[0063] The specific embodiments of the present application will be described in more detail below. Although specific embodiments of the present application are shown, it should be understood that the present application can be implemented in various forms and should not be limited by the embodiments set forth herein. On the contrary, these embodiments are provided to enable a more thorough understanding of the present application and to fully convey the scope of the present application to those skilled in the art.

[0064] Yield in this application refers to the ratio of the amount of target product actually obtained in a chemical reaction or chemical production process to the amount of target product theoretically calculated based on the chemical reaction equation, usually expressed as a percentage. The calculation formula is: Yield = (Actual Yield / Theoretical Yield) * 100%. For example, in a chemical reaction, according to the stoichiometric relationship, theoretically 100 grams of product should be produced, but only 80 grams of product is actually produced. Then the yield of the reaction is: 80%.

[0065] The Sandmeyer reaction in this application refers to a chemical reaction in which a diazonium salt reacts with a halogen salt under the catalysis of CuX to produce a halogenated hydrocarbon, wherein X can be bromine, chlorine, sulfurous acid or cyanide anion.

[0066] The substituents on the benzene ring (such as hydroxyl, alkoxy, acyl, carboxyl, nitro and halogen, etc.), whether electron-withdrawing or electron-donating groups, have no special effect on the reaction. Chlorination uses the CuCl / HCl system, bromination uses the CuBr / HBr system, and iodination generally uses hydrochloric acid as the diazonium salt. Iodobenzene can be obtained by directly adding KI or NaI without the need for Cu salt catalysis.

[0067]

[0068] Wherein, X=CN, Br, Cl or SO3H.

[0069] The Rosenmund-von Braun reaction in this application refers to the heating reaction of aryl halide and cuprous cyanide in an organic solvent such as pyridine, where the halogen atom is replaced by a cyano group to generate an aromatic nitrile.

[0070]

[0071] Wherein, X=I, Br or Cl.

[0072] The Vilsmeier-Haack reagent in this application refers to a structure having a chloroimide cation prepared by the reaction of N,N-dimethylformamide with a chloroacid (POCl3, SOCl2, oxalyl chloride, etc.), the central carbon atom of which carries a partial positive charge, making the reagent highly electrophilic and capable of reacting with electron-rich substrates.

[0073]

[0074] TLC detection in this application (also referred to as TLC in this application) refers to thin layer chromatography detection, which is a commonly used separation and analysis technique, mainly used for the separation, identification and purity detection of organic compounds.

[0075] Flash column chromatography, also known as rapid column chromatography, is a technique widely used in the separation and purification of organic compounds.

[0076] In this application, overnight reaction refers to reaction for 12-16 hours.

[0077] The present application provides a method for preparing an intermediate, which specifically comprises the following steps:

[0078] Step 1, 2-methyl-3-nitrobenzoic acid reacts with an acyl chloride reagent to obtain product 1;

[0079] Step 2, reacting the product 1 with a malonate or malonate salt under alkaline conditions to generate a product 2;

[0080] Step 3, hydrolyzing the product 2 in an acid aqueous solution to obtain product 3;

[0081] Step 4: The product 3 is subjected to a reduction reaction under a catalyst to obtain the product 4;

[0082] Step 5: The product 4 is subjected to a Sandmeyer reaction to obtain a product 5, which is a bromide, iodide or cyanide;

[0083] Step 6: The product 5 is subjected to a Rosenmund-von Braun reaction to obtain product 6;

[0084] Step 7: The product 6 reacts under the condition of an enzyme as a catalyst to obtain (R)-3-(1-aminoethyl)-2-methylbenzonitrile.

[0085] The specific reaction formula is shown below.

[0086]

[0087] Wherein, R1 in Formula II is CH3, C2H5 or CH(CH3)2, and R2 is H, COOH, COOCH3, COOC2H5 or COOCH(CH3)2;

[0088] X in formula V is Br or I.

[0089] Specifically, in some embodiments, in step 1, dichloromethane, 2-methyl-3-nitrobenzoic acid, and DMF (N,N-dimethylformamide) are mixed in appropriate proportions under stirring to form a white suspension. The mixture is heated to a gentle reflux temperature, and an acyl chloride reagent is added dropwise. After the addition is complete, the reaction is continued for 1 to 10 hours. After the reaction is complete as determined by TLC, the mixture is distilled under reduced pressure to obtain product 1.

[0090] In some embodiments, the acyl chloride reagent is phosphorus oxychloride, thionyl chloride or oxalyl chloride. In some embodiments, the acyl chloride reagent is phosphorus oxychloride, thionyl chloride or oxalyl chloride and N,N-dimethylformamide to form the corresponding Vilsmeier-Haack reagent.

[0091] In some preferred embodiments, the acyl chloride reagent is thionyl chloride or a Vilsmeier-Haack reagent formed by thionyl chloride and N,N-dimethylformamide.

[0092] Specifically, in step 2, an organic solvent and a malonate or malonate salt are added to a reaction vessel in proportion, with or without a catalyst, and the reaction is carried out under alkaline conditions for 1 to 10 hours. Subsequently, the product 1 in step 1 is added to the reaction system, stirred for reaction, and after TLC detection, the pH is adjusted and the reaction product is cooled. After post-treatment (for example, drying with anhydrous sodium sulfate, concentration, and flash column separation treatment in sequence), the product 2 (mainly in the enol form) is obtained.

[0093] In the present invention, the post-treatment is a technique conventionally used in the art, for example, it can be at least one of extraction, washing, concentration, distillation, column chromatography (such as flash column separation treatment), and liquid phase separation.

[0094] In some embodiments, the malonate in step 2 is dimethyl malonate, diethyl malonate, isopropylidene malonate, tert-butyl acetoacetate, or diisopropyl malonate. In some embodiments, the malonate salt is monomethyl malonate potassium salt, monomethyl malonate sodium salt, monoethyl malonate potassium salt, or monoethyl malonate sodium salt.

[0095] Product 2 in step 2 has two structural formulas. When the reaction reagent is dimethyl malonate, diethyl malonate, tert-butyl acetoacetate, diisopropyl malonate, potassium salt of monomethyl malonate, sodium salt of monomethyl malonate, potassium salt of monoethyl malonate or sodium salt of monoethyl malonate, the structural formula of product 2 is shown in formula II-1. When the reaction reagent is isopropylidene malonate, the structural formula of product 2 is shown in formula II-2.

[0096]

[0097] When the reaction reagents are dimethyl malonate, diethyl malonate, tert-butyl acetoacetate, diisopropyl malonate, potassium salt of monomethyl malonate, sodium salt of monomethyl malonate, potassium salt of monoethyl malonate and sodium salt of monoethyl malonate, isopropylidene malonate, the structural formulas of product 2 are shown as formula II-1-1, formula II-1-2, formula II-1-3, formula II-1-4, formula II-1-5, formula II-1-5, formula II-1-6, formula II-1-6, and II-2, respectively.

[0098]

[0099] In some preferred embodiments, the product 1 in step 2 is reacted with a malonate.

[0100] In some preferred embodiments, the malonate is dimethyl malonate.

[0101] In step 2, the reaction is carried out in an alkaline environment, and an inorganic base such as barium oxide can be used, or an organic base such as magnesium methoxide, magnesium ethoxide, triethylamine, diisopropylethylamine, etc. In some preferred embodiments, an organic base is used.

[0102] In some preferred embodiments, the organic base is triethylamine.

[0103] In some embodiments, the reaction of step 2 is carried out under catalyst conditions, and the catalyst used is magnesium chloride or magnesium bromide, preferably magnesium chloride or magnesium bromide is magnesium chloride or magnesium bromide without crystal water. In some preferred embodiments, considering the reaction yield and cost, the catalyst used is magnesium chloride.

[0104] Specifically, in step 3, water, acid and product 2 in step 2 are added to the reaction vessel in proportion, the temperature is raised to reflux, the reaction is carried out for 1 to 10 hours, TLC detection is used to determine whether the raw materials are completely consumed, the solid product is cooled and precipitated, and post-processing (for example, drying and flash column separation treatment) is performed to obtain product 3.

[0105] In some embodiments, the acid in step 3 is an inorganic acid, such as hydrochloric acid, hydrobromic acid or sulfuric acid. In some preferred embodiments, the acid in step 3 is hydrochloric acid.

[0106] Specifically, in step 4, ethanol, solvent and product 3 in step 3 are taken in proportion, a catalyst is added, the temperature is increased and a reduction reaction is carried out, and the product 4 is obtained by post-treatment (for example, filtration or flash column separation).

[0107] In some embodiments, the reducing agent used in the reduction reaction is hydrogen, reduced iron powder, hydrazine hydrate or stannous chloride. In some preferred embodiments, in order to further improve the yield, the reducing agent used in the reduction reaction is hydrogen.

[0108] In some embodiments, the catalyst in step 4 comprises one or more of ammonium chloride, hydrochloric acid, acetic acid, Raney nickel, palladium on carbon, platinum on carbon, ferric chloride, and activated carbon. Any one of these may be selected or used in combination. In some preferred embodiments, the catalyst in step 4 is Raney nickel.

[0109] In step 5, the product 4 in step 4 is first reacted to form a diazonium salt, and then substituted with a halogen or cyano group to obtain product 5. The product 5 is a halogenated compound, such as bromide, iodide, or cyanide.

[0110] When the product 5 is a bromide or iodide, specifically, in one reaction vessel, the product 4 of step 4 is mixed with an acid, and sodium nitrite is added dropwise to prepare a diazonium salt. In another reaction vessel, an acid (e.g., hydrobromic acid, hydrochloric acid, sulfuric acid, etc.) and a halogen-containing compound (e.g., cuprous bromide, sodium iodide, potassium iodide, etc.) are added, and the prepared diazonium salt solution is added dropwise to react. TLC detection confirms complete consumption of the starting material, and post-treatment is performed to obtain the product 5.

[0111] In some embodiments, when product 5 is a bromide or iodide, the reaction system that can be used in the Sandmeyer reaction described in step 5 includes: a hydrobromic acid / sodium nitrite system, a hydrochloric acid / sodium nitrite / sodium iodide system, a sulfuric acid / sodium nitrite / sodium iodide system, a hydrochloric acid / sodium nitrite / potassium iodide system, and a sulfuric acid / sodium nitrite / potassium iodide system. One of the above systems can be selected or used in combination. In some preferred embodiments, in order to further improve the yield, the reaction system used in the Sandmeyer reaction described in step 5 is a hydrobromic acid / sodium nitrite system.

[0112] When the product 5 is a cyanide, specifically, in one reaction vessel, the product 4 of step 4 is mixed with an acid (e.g., hydrochloric acid, sulfuric acid, etc.) or a nitrite compound (e.g., isoamyl nitrite or tert-butyl nitrite) to prepare a diazonium salt. In another reaction vessel, a cyanide (e.g., potassium cyanide, sodium cyanide, etc.) and copper sulfate are added, and the prepared diazonium salt solution is added dropwise to react, or cuprous cyanide is directly added to the diazonium salt solution to react. TLC detection confirms complete consumption of the starting material, and post-processing is performed to obtain the product 5.

[0113] In some embodiments, when product 5 is cyanide, the reaction systems that can be used in the Sandmeyer reaction described in step 5 include: hydrochloric acid / sodium nitrite / potassium cyanide / copper sulfate system, hydrochloric acid / sodium nitrite / sodium cyanide / copper sulfate system, sulfuric acid / sodium nitrite / potassium cyanide / copper sulfate system, sulfuric acid / sodium nitrite / sodium cyanide / copper sulfate system, isoamyl nitrite / cuprous cyanide system, and tert-butyl nitrite / cuprous cyanide system. Any one of the above systems can be selected or used in combination.

[0114] When product 5 is a bromide or iodide, the bromide or iodide needs to undergo a Rosenmund-von Braun reaction to generate a cyanide. Specifically, in step 6, product 5 is dissolved in an organic solvent in a reaction vessel, metal cyanide is added, and then a catalyst is added. After the reaction is completed, product 6 is obtained through post-treatment.

[0115] In some embodiments, the organic solvent comprises one or more of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and sulfolane. In some preferred embodiments, considering the reaction yield and cost, the organic solvent is N-methylpyrrolidone.

[0116] In some embodiments, the metal cyanide includes cuprous cyanide, zinc cyanide, sodium cyanide, potassium cyanide, etc., which can be used alone or in combination. In some preferred embodiments, considering the reaction yield and cost, the metal cyanide is cuprous cyanide.

[0117] In some preferred embodiments, the product 5 is a bromide.

[0118] In some preferred embodiments, the catalyst is a palladium catalyst, including one or more of palladium acetate, diphenylphosphinocene palladium dichloride, tetrakistriphenylphosphine palladium, dichlorobistriphenylphosphine palladium, and the like.

[0119] When the product 5 in step 5 is cyanide, step 6 is skipped and the product 5 cyanide can be directly processed to step 7.

[0120] Specifically, in step 7, deionized water is added to the reaction vessel, stirred and heated, isopropylamine is added, and the pH is adjusted to alkaline. Product 5 cyanide or product 6 and ethanol are added to the system to maintain the pH value of the system. Amino ω-transaminase is added as a catalyst to react, and then the pH is adjusted. After post-treatment (for example, filtering, extraction, washing, drying, and distillation), the product (R)-3-(1-aminoethyl)-2-methylbenzonitrile, which is used as an intermediate of the SOS1 inhibitor, is obtained.

[0121] In some embodiments, the amino ω-transaminase is an enzyme in the ω-transaminase ATA series, for example, it can be one or more of the transaminases such as ω-transaminase ATA-117, ω-transaminase ATA-254, ω-transaminase ATA-415, and ω-transaminase ATA-P2-A07. In some preferred embodiments, the amino ω-transaminase is ω-transaminase ATA-254.

[0122] The preparation method described in the present application can be applied to the synthesis of compounds containing the structure of Formula VII, such as the SOS1 inhibitor MRTX-0902.

[0123] Example

[0124] Example 1: Synthesis of 2-methyl-3-nitrobenzoyl chloride

[0125]

[0126] Under stirring, dichloromethane (600 mL), 2-methyl-3-nitrobenzoic acid (181.2 g, 1.00 eq), and DMF (5 mL) formed a white suspension. The temperature was raised to a gentle reflux, and thionyl chloride (142.7 g, 1.20 eq) was added dropwise. After the addition was complete, the reaction was continued at this temperature for 2 to 4 hours. After the reaction was complete as determined by TLC, dichloromethane was distilled under reduced pressure to obtain 2-methyl-3-nitrobenzoyl chloride (i.e., product 1) as an off-white solid with a melting point of 60 to 70°C. The product was directly used in the next step without purification.

[0127] Example 2: Synthesis of dimethyl 3-(2-methyl-3-nitrobenzoyl)malonate

[0128]

[0129] Ethyl acetate (840 mL) was added to the reaction flask, followed by dimethyl malonate (219.1 g, 1.66 mol), anhydrous magnesium chloride (120.0 g, 1.26 mol) and triethylamine (423.0 g, 4.18 mol). The temperature was raised to 65-70° C. and the reaction was carried out for 3-5 h. 2-Methyl-3-nitrobenzoyl chloride was added to the reaction system and the reaction was stirred for 0.5 h. After the reaction was completed by TLC, 2 M hydrochloric acid was added dropwise to adjust the pH to 6-7. The mixture was cooled to 42.5±2.5° C., separated, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by flash column chromatography to obtain 268.7 g of dimethyl 3-(2-methyl-3-nitrobenzoyl) malonate (i.e., product 2, mainly in the enol form). The two-step yield was 91.1%. 1H NMR(400MHz,Chloroform-d)δ13.52(s,1H),7.93(dd,J=8.1,1.4Hz,1H),7.46(dd ,J=7.7,1.5Hz,1H),7.38(t,J=7.9Hz,1H),3.94(s,3H),3.46(s,3H),2.54(s,3H).

[0130] Example 3: Synthesis of ethyl 3-(2-methyl-3-nitrophenyl)-3-oxopropionate

[0131]

[0132] Under stirring, nitrogen protection, and 20-35°C, acetonitrile (2750 mL), potassium monoethyl malonate (212.8 g, 1.25 mol, 1.25 eq), and triethylamine (253.0 g, 2.50 mol, 2.50 eq) were added to the reaction flask, and anhydrous magnesium chloride (238.0 g, 2.50 mol, 2.50 eq) was added in batches. The reaction was stirred for 2 h, and then the temperature was lowered to 0-10°C. 2-methyl-3-nitrobenzoyl chloride was added to the reaction system, and the reaction was stirred at 20-25°C overnight. TLC detection confirmed that the starting material was completely consumed. Hydrochloric acid was added dropwise to adjust the pH to 6-7. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by flash column chromatography to obtain 223.6 g of ethyl 3-(2-methyl-3-nitrophenyl)-3-oxopropionate (i.e., product 2, mainly in the enol form). The two-step yield was 89.0%, and the melting point was 52-55°C. 1H NMR (400MHz, Chloroform-d): δ12.49(s,1H),7.88(d,J=8.1Hz,1H),7.61(d,J=7.6Hz,1H),7.39(t ,J=7.9Hz,1H),5.30(d,J=0.9Hz,1H),4.37–4.26(m,2H),2.57(s,3H),1.37(td,J=7.1,0.9Hz,3H).

[0133] Example 4: Synthesis of ethyl 3-(2-methyl-3-nitrophenyl)-3-oxopropionate

[0134]

[0135] The difference between this example and example 3 is that the base used is replaced by magnesium ethoxide. Yield: 85.2%.

[0136] Example 5: Synthesis of ethyl 3-(2-methyl-3-nitrophenyl)-3-oxopropionate

[0137]

[0138] The difference between this example and Example 3 is that the catalyst anhydrous magnesium chloride is not used. Yield: 68.0%.

[0139] Example 6: Synthesis of diethyl 3-(2-methyl-3-nitrobenzoyl)malonate

[0140]

[0141] THF (840 mL), diethyl malonate (192.2 g, 1.2 mol), and magnesium ethoxide (125.9 g, 1.10 mol) were added to the reaction flask, and the temperature was raised to 67.5±2.5° C. for reaction for 4±1 h, then cooled to room temperature. 2-methyl-3-nitrobenzoyl chloride was added to the reaction system, and the reaction was stirred for 0.5 h, then the temperature was raised to reflux and the reaction was allowed to proceed overnight. After the reaction was completed by TLC, the temperature was lowered to room temperature and 2M hydrochloric acid was added dropwise to adjust the pH to 6-7. The mixture was then extracted with ethyl acetate, the layers were separated, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and passed through a flash column to obtain 298.4 g of diethyl 3-(2-methyl-3-nitrobenzoyl) malonate (i.e., product 2, mainly in the enol form) as an oily liquid with a two-step yield of 92.3%. 1H NMR(400MHz,Chloroform-d)δ13.58(s,1H),7.95–7.89(m,1H),7.46(dd,J=7.7,1.5Hz,1H),7.38(t,J=7.9Hz,1H),4.40( qd,J=7.2,0.9Hz,2H),3.92(qd,J=7.1,0.9Hz,2H),2.54(s,3H),1.40(td,J=7.2,1.0Hz,3H),0.88(td,J=7.1,1.0Hz,3H).

[0142] Example 7: Synthesis of 1-(2-methyl-3-nitrophenyl)ethanone

[0143]

[0144] Water (650 mL), 30% hydrochloric acid (325 mL) and ethyl 3-(2-methyl-3-nitrophenyl)-3-oxopropionate (325.0 g, 1.30 mol) were added to the reaction flask, and the temperature was raised to reflux for 6 h. TLC confirmed that the raw materials were completely consumed. The mixture was cooled to 5-10° C. to precipitate a dark yellow solid. The solid was dried at 37.5±2.5° C. overnight. The crude product was treated with a flash column to obtain 205.0 g (1.14 mol) of 1-(2-methyl-3-nitrophenyl)ethanone (i.e., product 3) with a yield of 87.7% and a melting point of 49-51° C. 1H NMR (400MHz, Chloroform-d) δ7.86 (d, J = 8.1Hz, 1H), 7.74 (d, J = 7.7Hz, 1H), 7.44 (t, J = 7.9Hz, 1H), 2.63 (d, J = 0.8Hz, 3H), 2.55 (s, 3H).

[0145] Example 8: Synthesis of 1-(2-methyl-3-nitrophenyl)ethanone

[0146]

[0147] According to the method of Example 7, the difference between this example and Example 7 is that this example uses 3-(2-methyl-3-nitrobenzoyl) dimethyl malonate (383.8 g, 1.30 mol) instead of 3-(2-methyl-3-nitrophenyl)-3-oxopropionic acid ethyl ester, and finally obtains 1-(2-methyl-3-nitrophenyl) ethanone (i.e., product 3) 198.0 g (1.10 mol), with a yield of 85.0%.

[0148] Example 9: Synthesis of 1-(2-methyl-3-nitrophenyl)ethanone

[0149]

[0150] According to the method of Example 7, the difference between this example and Example 7 is that this example uses diethyl 3-(2-methyl-3-nitrobenzoyl)malonate (420.3 g, 1.30 mol) instead of ethyl 3-(2-methyl-3-nitrophenyl)-3-oxopropionate, and 176.5 g (0.98 mol) of 1-(2-methyl-3-nitrophenyl)ethanone (i.e., product 3) is obtained by flash column treatment, with a yield of 75.8%.

[0151] Example 10: Synthesis of 1-(2-methyl-3-nitrophenyl)ethanone

[0152]

[0153] The difference between this embodiment and embodiment 8 is that 20% by mass sulfuric acid is used instead of 30% by mass hydrochloric acid, and other conditions are the same as those of embodiment 8. Yield: 83.6%.

[0154] Example 11: Synthesis of 1-(3-amino-2-methylphenyl)ethanone

[0155]

[0156] Ethanol (1600 mL), THF (400 mL), 1-(2-methyl-3-nitrophenyl)ethanone (i.e., product 3) (179.2 g, 1.00 mol) and Raney nickel catalyst (20.0 g) were added to an autoclave. The temperature was raised to 80-100° C., hydrogen was introduced to 2.5-4.0 MPa, and the reaction was hydrogenated overnight. The temperature was lowered to room temperature, diatomaceous earth was added to a suction filtration funnel, and the mixture was filtered. The ethanol was distilled to precipitate a solid, which was filtered and treated with a flash column to obtain 1-(3-amino-2-methylphenyl)ethanone (i.e., product 4) (137.2 g) in a yield of 92.1%. 1HNMR (400MHz, Chloroform-d) δ7.10(t,J=7.7Hz,1H),7.04(dd,J=7.7,1.4Hz,1H),6.84(dd,J=7.7,1.4Hz,1H),3.98(s,2H),2.57(s,3H),2.27(s,3H).

[0157] Example 12: Synthesis of 1-(3-amino-2-methylphenyl)ethanone

[0158]

[0159] According to the method of Example 11, the difference between this example and Example 11 is that 5% palladium carbon catalyst (20.0g) is used instead of Raney nickel catalyst, the temperature is raised to 60°C, hydrogen is introduced to 0.5-1.0 MPa, and the hydrogenation reaction is carried out overnight. According to the method of Example 11, 1-(3-amino-2-methylphenyl)ethanone (i.e., product 4) (92.0g) is obtained, with a yield of 61.6%.

[0160] Example 13: Synthesis of 1-(3-amino-2-methylphenyl)ethanone

[0161]

[0162] Add ethanol (1600mL), water (320mL), reduced iron powder (560.0g, 10.00mol), and ammonium chloride (17.9g, 0.34mol) to the reaction flask, heat to 80°C, and reflux slightly. Add 1-(2-methyl-3-nitrophenyl)ethanone (i.e., product 3) (179.2g, 1.00mol) in batches. After the addition is complete, stir the reaction at 80°C until the raw material is completely consumed by TLC detection. Process according to the method of Example 11 to obtain 1-(3-amino-2-methylphenyl)ethanone (i.e., product 4) (107.0g), with a yield of 71.7%.

[0163] Example 14: Synthesis of 1-(3-bromo-2-methylphenyl)ethanone

[0164]

[0165] In a reaction flask, 1-(3-amino-2-methylphenyl)ethanone (i.e., product 4) (49.2 g, 0.33 mol) was added to 48% hydrobromic acid (170 mL) by mass, cooled to -2.5±2.5°C, and a mixed solution of sodium nitrite (24.0 g, 0.35 mol) and water (100 mL) was added dropwise. After the addition, stirring was continued for 1 hour to prepare the diazonium salt. In another reaction flask, 48% hydrobromic acid (70 mL) and cuprous bromide (8.6 g, 0.06 mol) were added dropwise. The temperature was controlled at 20-30°C, and the prepared diazonium salt solution was added dropwise. Stirring was continued overnight. TLC analysis confirmed complete consumption of the starting material. The product was extracted with ethyl acetate, and the organic layer was washed with brine. After flash column chromatography, 1-(3-bromo-2-methylphenyl)ethanone (i.e., product 5) (61.8 g) was obtained in a yield of 87.9%. 1H NMR (400MHz, Chloroform-d): δ7.57 (dd, J=8.0, 1.3Hz, 1H), 7.42 (dd, J=7.7, 1.3Hz, 1H), 7.04 (t, J=7.8Hz, 1H), 2.50 (s, 3H), 2.44 (s, 3H).

[0166] Example 15: Synthesis of 1-(3-iodo-2-methylphenyl)ethanone

[0167]

[0168] This example was prepared according to the method of Example 14, except that 20% sulfuric acid (350 mL) was used instead of 48% hydrobromic acid; and water (300 mL) and sodium iodide (64.5 g, 0.43 mol) were used instead of 48% hydrobromic acid (70 mL) and cuprous bromide. After post-treatment, 1-(3-iodo-2-methylphenyl)ethanone (i.e., product 5) (61.7 g) was obtained in a yield of 71.9%. 1H NMR (400 MHz, Chloroform-d): δ 7.95 (dd, J = 7.8, 1.3 Hz, 1H), 7.49 (dd, J = 7.7, 1.2 Hz, 1H), 6.96 (t, J = 7.8 Hz, 1H), 2.56 (s, 3H), 2.54 (s, 3H).

[0169] Example 16: Synthesis of 1-(3-iodo-2-methylphenyl)ethanone

[0170]

[0171] This embodiment was prepared according to the method of Example 14, except that 20% by mass sulfuric acid (350 mL) was used instead of 48% by mass hydrobromic acid; and water (300 mL) and potassium iodide (71.4 g, 0.43 mol) were used instead of 48% by mass hydrobromic acid (70 mL) and cuprous bromide. The yield was 68.4%.

[0172] Example 17: Synthesis of 1-(3-cyano-2-methylphenyl)ethanone

[0173]

[0174] According to the method of Example 14, the diazonium salt was prepared by replacing the 48% hydrobromic acid with 15% hydrochloric acid (350 mL), and the pH was adjusted to 6.0 with saturated sodium bicarbonate. In another reaction flask, potassium cyanide (97.7 g, 1.5 mol) or sodium cyanide (73.5 g, 1.5 mol) was added to water (400 mL), and a solution of copper sulfate pentahydrate (99.9 g, 0.40 mol) dissolved in water (400 mL) was added dropwise at 0°C. After the addition was complete, the mixture was stirred for 1 hour, the temperature was raised to 60°C, the prepared diazonium salt solution was added dropwise, and the reaction was stirred at 60-70°C for 1-3 hours. GC (gas chromatography) analysis confirmed that the starting material remained essentially unchanged. The product was extracted with ethyl acetate, the organic layer washed with brine, and treated with a flash column chromatography to yield 1-(3-cyano-2-methylphenyl)ethanone (i.e., product 5) (33.2 g). The yield was 63.2% when using potassium cyanide and 64.0% when using sodium cyanide. 1H NMR (400 MHz, Chloroform-d): δ 7.84 (dd, J = 7.8, 1.3 Hz, 1H), 7.74 (dd, J = 7.8, 1.4 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 2.72 (s, 3H), 2.62 (s, 3H).

[0175] Example 18: Synthesis of 1-(3-cyano-2-methylphenyl)ethanone

[0176]

[0177] In a reaction flask, 1-(3-bromo-2-methylphenyl)ethanone (i.e., product 5 in Example 14) (127.8 g, 0.60 mol) was dissolved in N-methylpyrrolidone (400 mL), and cuprous cyanide (64.5 g, 0.72 mol) and tetrakistriphenylphosphine palladium (34.6 g, 0.03 mol) were added. The temperature was raised to 120° C. and the reaction was allowed to proceed for 4 h. GC analysis confirmed that the starting material remained essentially unchanged. Water (800 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and treated with a flash column chromatography to obtain 1-(3-cyano-2-methylphenyl)ethanone (i.e., product 6) (77.9 g) in a yield of 81.6%.

[0178] Example 19: Synthesis of 1-(3-cyano-2-methylphenyl)ethanone

[0179]

[0180] According to the method of Example 18, the difference between this example and Example 18 is that the tetrakistriphenylphosphine palladium catalyst is not added in this example, and the temperature is correspondingly raised to 160-180°C for reaction overnight to obtain 1-(3-cyano-2-methylphenyl)ethanone (i.e., product 6) (41.6 g), with a yield of 43.6%.

[0181] Example 20: Synthesis of 1-(3-cyano-2-methylphenyl)ethanone

[0182]

[0183] According to the method of Example 18, the difference between this example and Example 18 is that 1-(3-iodo-2-methylphenyl)ethanone (i.e., product 5 in Example 15) (156.0 g, 0.60 mol) is used instead of 1-(3-bromo-2-methylphenyl)ethanone (i.e., product 5 in Example 11) (127.8 g, 0.60 mol), the temperature is raised to 60-80°C and the reaction is carried out overnight to obtain 1-(3-cyano-2-methylphenyl)ethanone (i.e., product 6) (41.6 g), with a yield of 60.8%.

[0184] Example 21: Synthesis of 1-(3-cyano-2-methylphenyl)ethanone

[0185]

[0186] According to the method of Example 18, the difference between this example and Example 18 is that DMF (400 mL) is used instead of N-methylpyrrolidone as the solvent. The yield is 79.5%.

[0187] Example 22: Synthesis of 1-(3-cyano-2-methylphenyl)ethanone

[0188]

[0189] In a reaction flask, 1-(3-iodo-2-methylphenyl)ethanone (127.8 g, 0.60 mol) was dissolved in toluene (400 mL). Cuprous iodide (11.4 g, 0.06 mol), potassium iodide (19.9 g, 0.12 mol), N,N'-dimethylethylenediamine (63.5 g, 0.72 mol), and sodium cyanide (35.3 g, 0.72 mol) were added. The reaction mixture was heated to reflux for 24 hours. GC analysis confirmed that the starting material remained essentially unchanged. Water (800 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and treated with a flash column chromatography to obtain 1-(3-cyano-2-methylphenyl)ethanone (i.e., product 6) (82.3 g) in a yield of 86.2%.

[0190] Example 23: Synthesis of (R)-3-(1-aminoethyl)-2-methylbenzonitrile

[0191]

[0192] Add deionized water (1000 mL) to the reaction flask, start stirring and heat to 40-45 ° C, add isopropylamine (120.0 g, 2.00 mol), and adjust the pH to 9.0 with hydrochloric acid. Add 1-(3-cyano-2-methylphenyl)ethanone (i.e., product 6) (32.0 g, 0.20 mol) and ethanol (100 mL) to the system, and adjust the pH to 9.0 with hydrochloric acid or isopropylamine. Add PLP (0.05 g), ω-transaminase ATA-254 (32.0 g, ATA Screening Kit was used, and the generated acetone was removed during the reaction. The pH was adjusted to approximately 9.0 with hydrochloric acid or isopropylamine. After 60 hours of reaction, GC analysis confirmed that the starting material had essentially remained unchanged, with a conversion of approximately 90%. The reaction was cooled to room temperature, and the pH was adjusted to approximately 1.0 with hydrochloric acid. The reaction was filtered, and the unreacted starting material was extracted with ethyl acetate. The pH was adjusted to approximately 9.0 with 10% by weight NaOH. The reaction was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and the solvent was recovered under reduced pressure. Vacuum distillation afforded (R)-3-(1-aminoethyl)-2-methylbenzonitrile (27.3 g) as a colorless oily liquid. Yield: 85.4%, ee% = 99.9%. MS [M-16] + :144.04..1H NMR (400MHz, Chloroform-d): δ7.73 (dd, J=8.0, 1.4Hz, 1H), 7.40 (dd, J=7.7, 1.4Hz, 1 H),7.23(t,J=7.8Hz,1H),4.36(q,J=6.5Hz,1H),2.48(s,3H),1.27(d,J=6.5Hz,3H).

[0193] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0194] The above-described embodiments merely represent several implementation methods of the present application. While the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present application. It should be noted that a person of ordinary skill in the art may make various modifications and improvements without departing from the spirit of the present application, all of which fall within the scope of protection of the present application. Therefore, the scope of protection of the present patent application shall be determined by the appended claims.

Claims

1. A method for preparing an intermediate, comprising: Step 1: 2-methyl-3-nitrobenzoic acid reacts with an acyl chloride reagent to obtain product 1, as shown in Formula I; Step 2: reacting the product 1 with a malonate or malonate salt under alkaline conditions to generate a product 2, as shown in Formula II-1 or II-2; wherein R1 is CH3, C2H5 or CH(CH3)2; R2 is H, COOH, COOCH3, COOC2H5 or COOCH(CH3)2; Step 3: hydrolyzing the product 2 in an acid aqueous solution to obtain product 3, as shown in Formula III; Step 4: The product 3 is subjected to a reduction reaction under a catalyst to obtain a product 4, as shown in Formula IV; Step 5: The product 4 is subjected to a Sandmeyer reaction to obtain a product 5, which is a bromide, iodide or cyanide, as described in Formula V or VI; Wherein, X is Br or I; Step 6: When the product 5 is a bromide or iodide, the product 5 is subjected to a Rosenmund-von Braun reaction to obtain product 6, as shown in Formula VI. When the product 5 is a cyanide, this step is skipped; Step 7: The product 5 cyanide or product 6 reacts with an enzyme as a catalyst to obtain (R)-3-(1-aminoethyl)-2-methylbenzonitrile, as shown in Formula VII.

2. The preparation method according to claim 1, wherein The malonate in step 2 is dimethyl malonate, diethyl malonate, isopropylidene malonate, tert-butyl acetoacetate or diisopropyl malonate; and / or, The malonate salt in step 2 is potassium monomethyl malonate, sodium monomethyl malonate, potassium monoethyl malonate or sodium monoethyl malonate; and / or, The base used in step 2 is magnesium methoxide, magnesium ethoxide, barium oxide, triethylamine or diisopropylethylamine; and / or, When step 2 is carried out under catalyst conditions, the catalyst used is magnesium chloride or magnesium bromide.

3. The preparation method according to claim 1, wherein In step 2, the product 1 is reacted with a malonate, preferably dimethyl malonate.

4. The preparation method according to claim 1, wherein The acyl chloride reagent in step 1 includes one of phosphorus oxychloride, thionyl chloride, oxalyl chloride and the corresponding Vilsmeier-Haack reagent formed by reacting with N,N-dimethylformamide; and / or The acid in step 3 is hydrochloric acid, hydrobromic acid or sulfuric acid.

5. The preparation method according to claim 1, wherein The reducing agent used in the reduction reaction in step 4 is hydrogen, reduced iron powder, hydrazine hydrate or stannous chloride, preferably hydrogen; and / or The catalyst in step 4 comprises one or more of ammonium chloride, hydrochloric acid, acetic acid, Raney nickel, palladium carbon, platinum carbon, ferric chloride and activated carbon, preferably Raney nickel.

6. The preparation method according to claim 1, wherein The reaction system used in the Sandmeyer reaction in step 5 includes: one or more of a hydrobromic acid / sodium nitrite system, a hydrochloric acid or sulfuric acid / sodium nitrite / sodium iodide or potassium iodide system, a hydrochloric acid or sulfuric acid / sodium nitrite / potassium cyanide or sodium cyanide / copper sulfate system, and an isoamyl nitrite or tert-butyl nitrite / copper cyanide system.

7. The preparation method according to claim 1, wherein The Rosenmund-von Braun reaction in step 6 includes: dissolving the product 5 in an organic solvent, adding a metal cyanide, and reacting under catalyst conditions to generate the product 6.

8. The preparation method according to claim 7, wherein The organic solvent includes one or more of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and sulfolane; and / or The metal cyanide includes one or more of cuprous cyanide, zinc cyanide, sodium cyanide, and potassium cyanide; and / or, The catalyst is a palladium catalyst, including one or more of palladium acetate, diphenylphosphinocene palladium dichloride, tetrakistriphenylphosphine palladium, and dichlorobistriphenylphosphine palladium.

9. The preparation method according to claim 1, wherein The enzyme in step 7 is an amino ω-transaminase, preferably an enzyme in the ω-transaminase ATA series, more preferably one or more of ω-transaminase ATA-117, ω-transaminase ATA-254, ω-transaminase ATA-415, and ω-transaminase ATA-P2-A07, and further preferably ω-transaminase ATA-254.

10. Use of (R)-3-(1-aminoethyl)-2-methylbenzonitrile prepared by the method according to any one of claims 1 to 9 in the preparation of an SOS1 inhibitor intermediate.

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