Preparation method of 3-cyanomethyl-5-methylbenzamide

Abstract

The invention provides a preparation method of 3-cyanomethyl-5-methyl benzamide, and belongs to the technical field of medicine preparation.The preparation method comprises the steps that 5-methyl isophthalic acid serves as a raw material, 5-methyl isophthalic acid diester is prepared through a double-esterification reaction, then 3-hydroxymethyl-5-methyl benzoate is obtained through a selective reduction reaction, and the 3-cyanomethyl-5-methyl benzamide is obtained. The preparation method comprises the following steps: taking 3-hydroxymethyl-5-methylbenzoic acid as a raw material, carrying out hydrolysis to obtain 3-hydroxymethyl-5-methylbenzoic acid, then carrying out a hydroxymethyl substitution reaction, carrying out amidation to obtain 3-substituted methyl-5-methylbenzamide, and finally carrying out a cyanation reaction to obtain the target product 3-cyanomethyl-5-methylbenzamide. The preparation method disclosed by the invention is simple in process, easy to operate, milder in reaction and high in overall product yield, has the characteristics of economy and environmental protection, and has relatively high industrial production and commercial application prospects.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine preparation, and particularly relates to a new preparation process of 3-cyanomethyl-5-methylbenzamide which is a key material for preparing ainoferen. BACKGROUND

[0002] Ainoferen is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with a novel structure, which inhibits viral replication by non-competitive binding to HIV-1 reverse transcriptase. Ainoferen has excellent pharmacological properties such as strong antiviral activity, low central nervous system side effects, less cross-resistance, high target selectivity, and less drug-drug interactions, and is a drug with great application value. The chemical structure of ainoferen is as follows:

[0003] .

[0004] Patent document CN118063395A reports a preparation method of ainoferen with mild reaction conditions, environmental friendliness, good mass yield, and great industrialization prospects. The preparation process route is described as follows:

[0005] ,

[0006] Among them, compound 3-cyanomethyl-5-methylbenzamide (SM2) is a key starting material for the preparation process, and its chemical structure is as follows:

[0007] .

[0008] Patent document CN118063395A discloses a synthesis route of 3-cyanomethyl-5-methylbenzamide which is a key material for ainoferen. 3,5-Dimethylbenzoic acid is used as a raw material, 3,5-dimethylbenzamide is prepared by amidation reaction with thionyl chloride (SOCl2) and ammonia as reagents, 3-bromomethyl-5-methylbenzamide is prepared by bromination reaction with azobisisobutyronitrile (AIBN) as a catalyst and N-bromosuccinimide (NBS), and finally 3-cyanomethyl-5-methylbenzamide is obtained by cyanation reaction with potassium carbonate as an acid-binding agent and trimethylsilyl cyanide as a cyanation reagent. .

[0009] The process route is prone to excessive production of by-product 3,5-dibromobenzamide in the bromination reaction process because both benzyl groups of 3,5-dimethylbenzamide can be brominated in the same environment, and the existing NBS bromination reaction does not have regioselectivity. According to CN118063395A, the ratio of target product 3-bromomethyl-5-methylbenzamide to by-product 3,5-dibromobenzamide is 3:1, and because of the similarity between the two, their physical and chemical properties are similar, and it is difficult to purify them by conventional crystallization purification and other industrial acceptable methods, greatly reducing their industrial value.

[0010] .

[0011] In addition, in the cyanation reaction step, column chromatography is required for the purification of the reaction product, further limiting the feasibility of process scale-up. SUMMARY

[0012] In view of the deficiencies of the prior art, the purpose of the present application is to provide a preparation method of 3-cyanomethyl-5-methylbenzamide. The preparation method of the present application is simple, easy to operate, meets environmental protection requirements, and has very high industrial value.

[0013] To achieve this purpose, the present application adopts the following technical solutions:

[0014] On the one hand, the present application provides a preparation method of 3-cyanomethyl-5-methylbenzamide, which comprises the following steps:

[0015] (a) esterification of intermediate 1 compound 5-methylisophthalic acid to obtain intermediate 2 compound 5-methylisophthalic acid diester;

[0016] (b) selective reduction of intermediate 2 compound under the action of a reducing agent to obtain intermediate 3 compound 3-hydroxymethyl-5-methylbenzoic acid methyl ester;

[0017] (c) hydrolysis of intermediate 3 compound to obtain intermediate 4 compound 3-hydroxymethyl-5-methylbenzoic acid;

[0018] (d) hydroxymethyl substitution of intermediate 4 compound, followed by amidation to obtain intermediate 5 compound 3-substituted methyl-5-methylbenzamide;

[0019] (e) cyanation of intermediate 5 compound in the presence of a base to obtain compound 1 (i.e. 3-cyanomethyl-5-methylbenzamide;

[0020] The reaction flow of the preparation method is as follows:

[0021] ;

[0022] R1is selected from C1-C6alkyl (e.g., C1, C2, C3, C4, C5, or C6), benzyl, or at least one halo, cyano, nitro, C1-C6 (e.g., C1, C2, C3, C4, C5, or C6) alkoxy substituted benzyl;

[0023] X is halogen, methanesulfonate (OMs), trifluoromethanesulfonate (OTf), or 4-methylbenzenesulfonyloxy (OTs).

[0024] The preparation method of the present application takes 5-methylisophthalic acid as raw material, prepares 5-methylisophthalic acid diester through double esterification reaction, then obtains 3-hydroxymethyl-5-methylbenzoate through selective reduction reaction, obtains 3-hydroxymethyl-5-methylbenzoic acid through ester hydrolysis, then obtains 3-substituted methyl-5-methylbenzamide through hydroxymethyl substitution reaction and amidation, and finally prepares the target material 3-cyanomethyl-5-methylbenzamide through cyano reaction.

[0025] The present application takes commonly used chemical material 5-methylisophthalic acid as raw material, adopts selective ester hydrolysis to prepare 3-hydroxymethyl-5-methylbenzoate, avoids the problem of poor selectivity in the original preparation process by adopting bromination reaction, greatly reduces the generation of 3,5-dibromobenzamide byproduct, and makes the purification process of 3-hydroxymethyl-5-methylbenzoate simple and easy to implement and low in cost. The chemical reaction process is mild, and all are conventional chemical reaction processes. The corresponding intermediates are all prepared by purification and preparation methods such as crystallization separation, the industrialization amplification is highly feasible, the corresponding material quality is good in controllability, and the method has extremely strong commercial value.

[0026] Preferably, the esterification reaction in step (a) comprises: first reacting with an acylating agent, and then reacting with an esterification agent.

[0027] Preferably, the acylating agent in step (a) is selected from any one or a combination of at least two of phosphorus trichloride, phosphorus pentachloride, thionyl chloride, or oxalyl chloride; further preferably thionyl chloride.

[0028] Preferably, the molar ratio of the intermediate 1 compound 5-methylisophthalic acid to the acylating agent in step (a) is 1: (1-5), such as 1:1, 1:2, 1:3, 1:4, or 1:5, etc.; further preferably 1:2-2.5;

[0029] Preferably, the temperature for the reaction of the intermediate 1 compound with the acylating agent in step (a) is -50-50°C, such as -50°C, -40°C, -30°C, -20°C, -10°C, 0°C, 10°C, 20°C, 30°C, 40°C, or 50°C, etc.; further preferably 0-10°C.

[0030] Preferably, the time for the intermediate 1 compound to react with the esterifying agent in step (a) is 1-6h, such as 1h, 2h, 3h, 4h, 5h or 6h, etc.; further preferably 3-4h.

[0031] Preferably, the esterifying agent in step (a) is C1-C6 aliphatic alcohol, benzyl alcohol or benzyl alcohol substituted by at least one halogen, cyano, nitro, C1-C6 alkoxy, such as methanol, ethanol, propanol, isopropanol, benzyl alcohol, etc.; further preferably C1-C6 aliphatic alcohol.

[0032] Preferably, the molar ratio of the intermediate 1 compound 5-methyl isophthalic acid to the esterifying agent in step (a) is 1:(2-4), such as 1:2, 1:2.2, 1:2.4, 1:2.6, 1:2.8, 1:3, 1:3.2, 1:3.4, 1:3.6 or 1:4, etc.; further preferably 1:(2-2.5).

[0033] Preferably, the temperature for the reaction with the esterifying agent in step (a) is -50-50℃, such as -50℃, -40℃, -30℃, -20℃, -10℃, 0℃, 10℃, 20℃, 30℃, 40℃ or 50℃, etc.; further preferably 0-10℃.

[0034] Preferably, the time for the reaction with the esterifying agent in step (a) is 1-6h, such as 1h, 2h, 3h, 4h, 5h or 6h, etc.; further preferably 1-2h.

[0035] Preferably, step (a) is carried out in a solvent selected from any one or a combination of at least two of C1-C8 alkane solvents, C2-C8 ether solvents, C6-C10 aromatic hydrocarbon solvents; further preferably any one or a combination of at least two of chloroform, tetrahydrofuran or dichloromethane; more preferably dichloromethane.

[0036] Preferably, the reducing agent in step (b) is selected from any one or a combination of at least two of lithium aluminum hydride, sodium borohydride, potassium borohydride, lithium borohydride, borane solvent complex or iron powder; further preferably sodium borohydride and / or potassium borohydride, and in the present application, the borane solvent complex can be used, for example, borane tetrahydrofuran complex.

[0037] Preferably, the molar ratio of the intermediate 2 compound to the reducing agent in step (b) is 1:(1-2), such as 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8 or 1:2, etc.; further preferably 1:(1-1.2).

[0038] Preferably, the reaction temperature of the reduction reaction in step (b) is -50-30°C, such as -50°C, -41°C, -32°C, -23°C, -14°C, -5°C, 4°C, 13°C, 22°C or 30°C, etc.; further preferably -10-0°C.

[0039] Preferably, the reaction time of the reduction reaction in step (b) is 2-8h, such as 2h, 2h, 2h, 2h, 2h, 2h, 2h or 8h, etc.; further preferably 4-5h.

[0040] Preferably, the reduction reaction in step (b) is carried out in a solvent selected from any one or a combination of at least two of C1-C8 alkane solvents, C1-C8 alcohol solvents or C6-C10 aromatic hydrocarbon solvents; further any one or a combination of at least two of chloroform, methanol or dichloromethane; further methanol.

[0041] Preferably, the hydrolysis in step (c) is carried out in the presence of a hydrolysis reagent selected from any one or a combination of at least two of strong base, strong acid or weak acid, further preferably strong base sodium hydroxide and / or potassium hydroxide.

[0042] Preferably, the molar ratio of the intermediate 3 compound to the hydrolysis reagent in step (c) is 1:(1-3), such as 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2, 1:2.2, 1:2.4, 1:2.6, 1:2.8 or 1:3, etc.; further preferably 1:(1-2).

[0043] Preferably, the reaction temperature of the hydrolysis reaction in step (c) is 30-80°C, such as 30°C, 36°C, 42°C, 48°C, 54°C, 60°C, 66°C, 72°C, 78°C or 80°C, etc.; further preferably 65-75°C.

[0044] Preferably, the reaction time of the hydrolysis reaction in step (c) is 5-10h, such as 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 8.5h, 9h, 9.5h or 10h, etc.; further preferably 7-9h.

[0045] Preferably, the hydrolysis reaction in step (c) is carried out with or without a solvent, preferably without a solvent.

[0046] Preferably, when the hydrolysis reaction is carried out with a solvent, the solvent is selected from any one or a combination of at least two of C1-C8 alkane solvents, C2-C8 ether solvents, C6-C10 aromatic hydrocarbon solvents or water, further preferably any one or a combination of at least two of toluene, tetrahydrofuran, dichloromethane or water.

[0047] Preferably, the substituting reagent used in the hydroxymethyl-substituting reaction of step (d) is selected from any one of oxalyl chloride, sulphurous chloride, phosphorous oxychloride, phosphorous trichloride, phosphorous tribromide or triflic anhydride, and further preferably sulphurous chloride.

[0048] Preferably, the molar ratio of the intermediate 4 compound to the substituting reagent is 1:(1-4), such as 1:1, 1:1.3, 1:1.6, 1:1.9, 1:2.2, 1:2.5, 1:2.8, 1:3.1, 1:3.4, 1:3.7 or 1:4, and further preferably 1:(2-3).

[0049] Preferably, the temperature of the hydroxymethyl-substituting reaction of step (d) is -20-50°C, such as -20°C, -12°C, -4°C, 4°C, 12°C, 20°C, 28°C, 36°C, 44°C or 50°C, and further preferably 0-20°C.

[0050] Preferably, the time of the hydroxymethyl-substituting reaction of step (d) is 1-6h, such as 1h, 2h, 3h, 4h, 5h or 6h, and further preferably 3-4h.

[0051] Preferably, the amidating reagent used in the amidation of step (d) is selected from aqueous ammonia or ammonia gas, and further preferably aqueous ammonia. More preferably, the concentration of the aqueous ammonia is 6-8mol / L, such as 6mol / L, 6.5mol / L, 7mol / L, 7.5mol / L or 8mol / L.

[0052] Preferably, the molar ratio of the intermediate 4 compound to the amidating reagent is 1:(1-4), such as 1:1, 1:1.3, 1:1.6, 1:1.9, 1:2.2, 1:2.5, 1:2.8, 1:3.1, 1:3.4 or 1:4, and further preferably 1:(2-3).

[0053] Preferably, the temperature of the amidation of step (d) is -20-50°C, such as -20°C, -12°C, -4°C, 4°C, 12°C, 20°C, 28°C, 36°C, 44°C or 50°C, and further preferably 0-20°C.

[0054] Preferably, the time of the amidation of step (d) is 1-6h, such as 1h, 2h, 3h, 4h, 5h or 6h, and further preferably 1-2h.

[0055] Preferably, step (d) is carried out in a solvent selected from any one or a combination of at least two of C1-C8 alkane solvents, C2-C8 ether solvents or C6-C10 aromatic hydrocarbon solvents, further preferably any one or a combination of at least two of chloroform, tetrahydrofuran or dichloromethane, and more further preferably dichloromethane.

[0056] Preferably, the base in step (e) is selected from any one or a combination of at least two of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide or potassium phosphate, and further preferably sodium carbonate.

[0057] Preferably, the cyanation reagent used in the cyanation reaction in step (e) is selected from any one or a combination of at least two of hydrogen cyanide, sodium cyanide, potassium cyanide, zinc cyanide, trimethylsilyl cyanide, potassium ferricyanide or potassium ferrocyanide, and further preferably trimethylsilyl cyanide.

[0058] Preferably, the molar ratio of the intermediate 5 compound to the cyanation reagent in step (e) is 1:(1-3), such as 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2, 1:2.2, 1:2.4, 1:2.6 or 1:3, and the like; and further preferably 1:(1-2).

[0059] Preferably, the molar ratio of the intermediate 5 compound to the base in step (e) is 1:(0-3), such as 1:0, 1:0.3, 1:0.6, 1:0.9, 1:1.2, 1:1.5, 1:1.8, 1:2.1, 1:2.4 or 1:3, and the like; and further preferably 1:(1-2).

[0060] Preferably, the temperature of the cyanation reaction in step (e) is 30-80℃, such as 30℃, 36℃, 42℃, 48℃, 54℃, 60℃, 66℃, 72℃, 78℃ or 80℃, and the like; and further preferably 70-80℃.

[0061] Preferably, the time of the cyanation reaction in step (e) is 5-15h, such as 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h or 15h, and the like; and further preferably 11-13h.

[0062] Preferably, step (e) is carried out in a solvent selected from any one or a combination of at least two of C2-C8 nitrile solvents, C2-C8 ether solvents or C6-C10 aromatic hydrocarbon solvents, further preferably any one or a combination of at least two of acetonitrile, tetrahydrofuran, 1,4-dioxane or toluene, and further preferably acetonitrile.

[0063] Compared with the prior art, the present application has the following beneficial effects:

[0064] The present application uses 5-methylisophthalic acid as raw material, and the key material 3-cyanomethyl-5-methylbenzamide for preparing amonovirine is obtained through double esterification, selective reduction, hydrolysis, hydroxymethyl substitution and amidation. The process is more gentle, the overall yield of the product is high, it has the characteristics of economic and environmental protection, and has high prospects for industrial production and commercial application. DETAILED DESCRIPTION

[0065] The technical solutions of the present application will be further described through specific embodiments. Those skilled in the art should understand that the embodiments are only to help understand the present application, and should not be regarded as specific limitations on the present application.

[0066] Exemplarily, the present application uses 5-methylisophthalic acid (CAS No.: 499-49-0) as raw material intermediate 1, and the specific synthesis route is as follows:

[0067] .

[0068] The present application will be described in detail through the following examples.

[0069] In the following examples, the raw materials and reagents used are commercially available unless otherwise specified.

[0070] In the following examples, the products prepared are identified by nuclear magnetic resonance and mass spectrometry, and the purity detected by HPLC is more than 95%.

[0071] Example 1: Preparation of intermediate 2 (5-methylisophthalic acid dimethyl ester)

[0072] In a 2000 mL reaction bottle, 5-methylisophthalic acid (150 g, 833 mmol), dichloromethane (750 mL), N,N-dimethylformamide (1 mL) were added, stirred and cooled to 0°C, and slowly added with sulfur monochloride (247.63 g, 2.08 mol). After dropping for 4 h, the reaction process was tracked by TLC, and after the raw material was completely reacted, methanol (66.56 g, 2.08 mol) was added, stirred for 1 h, washed twice with saturated sodium bicarbonate solution, and then washed once with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, 5-methylisophthalic acid dimethyl ester 170 g was obtained by concentration, with a yield of 98.1%.

[0073] HRMS: 209.08167 [M+H] + , 1H NMR: (400 MHz, DMSO-d6) δ 8.20 (td, J = 1.6, 0.7 Hz, 1H), 7.94 (dd, J = 1.7, 0.8 Hz, 2H), 3.86 (s, 6H), 2.40 (d, J = 0.8 Hz, 3H).

[0074] Example 2: Preparation of Intermediate 2 (5-methyl isophthalic acid dimethyl ester)

[0075] Into a 250 mL reaction flask was added 5-methyl isophthalic acid (20 g, 111 mmol), dichloromethane (100 mL), N,N-dimethylformamide (1 mL), stirred and cooled to 0 °C, slowly added dropwise oxalyl chloride (35.25 g, 278 mmol), after dropwise addition, the reaction was carried out for 4 h, the reaction process was tracked by TLC, after the raw material was completely reacted, methanol (8.90 g, 278 mmol) was added dropwise, stirred for 1 h, washed twice with saturated sodium bicarbonate solution, then washed once with saturated sodium chloride solution, dried with anhydrous sodium sulfate, concentrated to give 5-methyl isophthalic acid dimethyl ester 18.6 g, yield 80.5%.

[0076] Example 3: Preparation of Intermediate 2 (5-methyl isophthalic acid dimethyl ester)

[0077] Into a 2000 mL reaction flask was added 5-methyl isophthalic acid (20 g, 111 mmol), dichloromethane (100 mL), N,N-dimethylformamide (1 mL), stirred and cooled to 0 °C, slowly added dropwise thionyl chloride (19.82 g, 167 mmol), after dropwise addition, the reaction was carried out for 4 h, the reaction process was tracked by TLC, after the raw material was completely reacted, methanol (5.34 g, 167 mol) was added dropwise, stirred for 1 h, washed twice with saturated sodium bicarbonate solution, then washed once with saturated sodium chloride solution, dried with anhydrous sodium sulfate, concentrated to give 5-methyl isophthalic acid dimethyl ester 12.5 g, yield 54.1%.

[0078] Example 4: Preparation of Intermediate 2 (5-methyl isophthalic acid diethyl ester)

[0079] Into a 2000 mL reaction flask was added 5-methyl isophthalic acid (20 g, 111 mmol), dichloromethane (100 mL), N,N-dimethylformamide (1 mL), stirred and cooled to 0 °C, slowly added dropwise thionyl chloride (19.82 g, 167 mmol), after dropwise addition, the reaction was carried out for 4 h, the reaction process was tracked by TLC, after the raw material was completely reacted, ethanol (12.79 g, 278 mol) was added dropwise, stirred for 1 h, washed twice with saturated sodium bicarbonate solution, then washed once with saturated sodium chloride solution, dried with anhydrous sodium sulfate, concentrated to give 5-methyl isophthalic acid diethyl ester 19.9 g, yield 75.9%.

[0080] Example 5: Preparation of Intermediate 2 (5-methyl-isophthalic acid dibenzyl ester)

[0081] In a 2000 mL reaction flask, 5-methyl-isophthalic acid (20 g, 111 mmol), dichloromethane (100 mL), N,N-dimethylformamide (1 mL) were added, and the temperature was reduced to 0 °C with stirring. Sulfurous acid chloride (19.82 g, 167 mmol) was slowly added dropwise, and the reaction was allowed to proceed for 4 h. TLC was used to track the progress of the reaction. After the starting material was completely consumed, benzyl alcohol (30.02 g, 278 mol) was added, and the mixture was stirred for 1 h. The reaction mixture was washed twice with saturated sodium bicarbonate solution and once with saturated sodium chloride solution. Anhydrous sodium sulfate was added for drying, and the mixture was concentrated to obtain 5-methyl-isophthalic acid dibenzyl ester (29.1 g) with a yield of 72.7%.

[0082] Example 6: Preparation of Intermediate 3 (methyl 3-hydroxymethyl-5-methylbenzoate)

[0083] In a 2000 mL reaction flask, 5-methyl-isophthalic acid dimethyl ester (150 g, 720 mmol) and methanol (1500 mL) were added, and the mixture was stirred to dissolve. The temperature was reduced to -10 °C, and sodium borohydride (32.7 g, 865 mmol) was added in portions. The reaction was allowed to proceed for 5 h. TLC was used to track the progress of the reaction. After the reaction was completed, water was added to quench the reaction, and the mixture was concentrated. The residue was dissolved in dichloromethane, washed twice with saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to obtain methyl 3-hydroxymethyl-5-methylbenzoate (107.2 g) with a yield of 82.6% and a purity of ≥95% by HPLC.

[0084] Example 7: Preparation of Intermediate 3 (methyl 3-hydroxymethyl-5-methylbenzoate)

[0085] In a 500 mL reaction flask, 5-methyl-isophthalic acid dimethyl ester (10 g, 48 mmol) and anhydrous tetrahydrofuran (100 mL) were added, and the mixture was protected with nitrogen. Boron trifluoride etherate (6.82 g, 48 mmol) was added, and the mixture was stirred to dissolve. The temperature was reduced to -10 °C, and borane tetrahydrofuran complex (72 mL, 72 mmol) was slowly added dropwise. The reaction was allowed to proceed for 5 h. TLC was used to track the progress of the reaction. After the reaction was completed, methanol was added to quench the reaction, and water (100 mL) was added. The mixture was extracted with ethyl acetate, washed twice with saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to obtain methyl 3-hydroxymethyl-5-methylbenzoate (6.0 g) with a yield of 69.3%.

[0086] Example 8: Preparation of Intermediate 3 (methyl 3-hydroxymethyl-5-methylbenzoate)

[0087] In a 250 mL reaction flask was added 5-methyl-isophthalic acid diethyl ester (11.34 g, 48 mmol), tetrahydrofuran (100 mL), stirred to dissolve, cooled to -10 °C, lithium aluminum hydride (2.19 g, 58 mmol) was added in portions, after addition, the reaction was carried out for 5 h, TLC was used to track the reaction process, after the reaction was completed, water, 15% NaOH solution was added to quench, the reaction liquid was filtered, the filtrate was concentrated, then dissolved in dichloromethane, washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3-hydroxymethyl-5-methyl benzoic acid ethyl ester 5.7 g, with a yield of 61.1%.

[0088] Example 9: Preparation of intermediate 3 (benzyl 3-hydroxymethyl-5-methylbenzoate)

[0089] In a 2000 mL reaction flask was added 5-methyl-isophthalic acid dibenzyl ester (17.30 g, 48 mmol), methanol (100 mL), stirred to dissolve, cooled to -10 °C, sodium borohydride (1.82 g, 48 mmol) was added in portions, after addition, the reaction was carried out for 5 h, TLC was used to track the reaction process, after the reaction was completed, water was added to quench, concentrated, then dissolved in dichloromethane, washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain benzyl 3-hydroxymethyl-5-methylbenzoate 9.1 g, with a yield of 70.1%.

[0090] Example 10: Preparation of intermediate 4 (3-hydroxymethyl-5-methylbenzoic acid)

[0091] In a 250 mL reaction flask was added 3-hydroxymethyl-5-methylbenzoic acid methyl ester (80 g, 444 mmol), sodium hydroxide (35.52 g, 888 mmol), stirred to warm to 70 °C, the reaction was carried out for 8 h, TLC was used to track the reaction process, after the reaction was completed, the temperature was lowered to room temperature, dichloromethane and water were added, 2M hydrochloric acid was used to adjust the pH to 2, the liquid was separated, the aqueous phase was extracted again, the dichloromethane phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3-hydroxymethyl-5-methylbenzoic acid 63.1 g, with a yield of 85.5%, HPLC purity: ≥95%.

[0092] HRMS: 165.05464 [M-H] - , 1 H NMR: (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 7.73 (d, J = 1.7 Hz, 1H), 7.64 (d, J = 1.9 Hz, 1H), 7.36 (dq, J = 1.8, 0.9 Hz, 1H), 5.28 (s, 1H), 4.52 (s, 2H), 2.35 (s, 3H).

[0093] Example 11: Preparation of Intermediate 4 (3-hydroxymethyl-5-methylbenzoic acid)

[0094] In a 250 mL reaction flask, 3-hydroxymethyl-5-methylbenzoic acid ethyl ester (10 g, 51 mmol), 20% sodium hydroxide aqueous solution (containing sodium hydroxide 4.08 g, 102 mmol) were added, stirred to 70 °C, reacted for 10 h, TLC was used to track the reaction process, after the reaction was completed, it was cooled to room temperature, dichloromethane was added, the pH was adjusted to 2 with 2M hydrochloric acid, the liquid was separated, the aqueous phase was extracted again, the dichloromethane phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3-hydroxymethyl-5-methylbenzoic acid 6.2 g, with a yield of 72.5%.

[0095] Example 12: Preparation of Intermediate 4 (3-hydroxymethyl-5-methylbenzoic acid)

[0096] In a 250 mL reaction flask, 3-hydroxymethyl-5-methylbenzoic acid ethyl ester (10 g, 51 mmol), 20% sodium hydroxide aqueous solution (containing sodium hydroxide 4.08 g, 102 mmol) were added, stirred to 70 °C, reacted for 10 h, TLC was used to track the reaction process, after the reaction was completed, it was cooled to room temperature, dichloromethane was added, the pH was adjusted to 2 with 2M hydrochloric acid, the liquid was separated, the aqueous phase was extracted again, the dichloromethane phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3-hydroxymethyl-5-methylbenzoic acid 6.2 g, with a yield of 72.5%.

[0097] Example 13: Preparation of Intermediate 5 (3-chloromethyl-5-methylbenzamide)

[0098] In a 500 mL reaction flask, 3-hydroxymethyl-5-methylbenzoic acid (50 g, 301 mmol), dichloromethane (250 mL), N,N-dimethylformamide (1 mL) were added, stirred to 0 °C, dropwise added with sulfur monochloride (89.49 g, 752 mmol), reacted for 4 h, TLC was used to track the reaction process, after confirming that the raw material was completely reacted, the reaction liquid was concentrated under reduced pressure, then added with ammonia water (84.2 g, the total content of NH3 was 602 mmol), reacted for 1 h, filtered and washed to obtain a white solid, which was slurried with a n-heptane / isopropyl alcohol mixed solution, filtered and dried to obtain 3-chloromethyl-5-methylbenzamide 49.7 g, with a yield of 90.0%, and a liquid phase purity of ≥95%.

[0099] HRMS: 184.05219 [M+H] + , 1H NMR: (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.75(d, J = 1.7 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 4.6 Hz, 2H), 4.76(s, 2H), 2.35 (s, 3H).

[0100] Example 14: Preparation of intermediate 5 (3-chloromethyl-5-methylbenzamide)

[0101] 3-Hydroxymethyl-5-methylbenzoic acid (5 g, 30 mmol), dichloromethane (25 mL), and N,N-dimethylformamide (1 mL) were added to a 100 mL reaction flask. The mixture was stirred and cooled to 0 °C. Oxaloyl chloride (9.55 g, 75 mmol) was added dropwise, and the reaction was carried out for 4 h. The reaction process was monitored by TLC. After confirming that the starting materials had reacted completely, the reaction solution was concentrated under reduced pressure and ammonia water (8.4 g, with a total NH3 content of 60 mmol) was added dropwise. The reaction was carried out for 1 h, and the mixture was filtered and washed to obtain a white solid. The solid was slurried with a mixture of n-heptane / isopropanol, filtered, and dried to obtain 3.8 g of 3-chloromethyl-5-methylbenzoamide, with a yield of 68.8%.

[0102] Example 15: Preparation of intermediate 5 (3-chloromethyl-5-methylbenzamide)

[0103] 3-Hydroxymethyl-5-methylbenzoic acid (5 g, 30 mmol), dichloromethane (25 mL), and N,N-dimethylformamide (1 mL) were added to a 100 mL reaction flask. The mixture was stirred and cooled to 0 °C. Phosphorus oxychloride (11.53 g, 75 mmol) was added dropwise. The reaction was carried out for 4 h, and the reaction was monitored by TLC. After confirming that the reactants had reacted completely, the reaction solution was concentrated under reduced pressure and ammonia water (8.4 g, with a total NH3 content of 60 mmol) was added dropwise. The reaction was carried out for 1 h, and the mixture was filtered and washed to obtain a white solid. The solid was slurried with a mixture of n-heptane and isopropanol, filtered, and dried to obtain 3.4 g of 3-chloromethyl-5-methylbenzoamide, with a yield of 61.5%.

[0104] Example 16: Preparation of intermediate 5 (3-chloromethyl-5-methylbenzamide)

[0105] 3-Hydroxymethyl-5-methylbenzoic acid (5 g, 30 mmol), dichloromethane (25 mL), and N,N-dimethylformamide (1 mL) were added to a 500 mL reaction flask. The mixture was stirred and cooled to 0 °C. Thionyl chloride (5.37 g, 45 mmol) was added dropwise, and the reaction was allowed to proceed for 4 h. The reaction was monitored by TLC. After confirming that the reactants had reacted completely, the reaction solution was concentrated under reduced pressure and then ammonia water (8.4 g, with a total NH3 content of 60 mmol) was added dropwise. The reaction was allowed to proceed for 1 h, and the mixture was filtered and washed to obtain a white solid. The solid was then slurried with a mixture of n-heptane and isopropanol, filtered, and dried to obtain 3.1 g of 3-chloromethyl-5-methylbenzoamide, with a yield of 56.1%.

[0106] Example 17: Preparation of intermediate 5 (3-bromomethyl-5-methylbenzamide)

[0107] 3-Hydroxymethyl-5-methylbenzoic acid (5 g, 30 mmol), dichloromethane (25 mL), and N,N-dimethylformamide (1 mL) were added to a 100 mL reaction flask. The mixture was stirred and cooled to 0 °C. Phosphorus tribromide (12.18 g, 45 mmol) was added dropwise, and the reaction was allowed to proceed for 2 h. The reaction was monitored by TLC. After confirming that the reactants had reacted completely, water (10 mL) was slowly added to quench the phosphorus tribromide. The mixture was stirred and separated. The organic phase was dried with anhydrous sodium sulfate and filtered. The mixture was then cooled and stirred to 0 °C. Thionyl chloride (5.36 g, 45 mmol) was added dropwise, and the reaction was allowed to proceed for 4 h. The reaction was monitored by TLC. After confirming that the reaction was complete, the reaction solution was concentrated under reduced pressure and ammonia (8.4 g, total NH3 content 60 mmol) was added dropwise. The reaction was allowed to proceed for 1 h. The mixture was filtered and washed to obtain a white solid. The solid was slurried with a mixture of n-heptane / isopropanol, filtered, and dried to obtain 4.7 g of 3-bromomethyl-5-methylbenzamide, with a yield of 68.5%.

[0108] Example 18: Preparation of Intermediate 5 (3-carbamoyl-5-methylphenylmethyltrifluoromethanesulfonate)

[0109] In a 500 mL reaction flask, add 3-hydroxymethyl-5-methylbenzoic acid (5 g, 30 mmol), dichloromethane (25 mL), pyridine (2.37 g, 30 mmol), stir and cool to -10 °C, drop trifluoromethanesulfonic anhydride (12.69 g, 45 mmol), dropwise, after dropping, 0 °C reaction for 4 h, TLC track the reaction process, confirm that the raw material is completely reacted, slowly add 0.1 N hydrochloric acid aqueous solution (50 ml) and stir to separate the liquid, the organic phase is dried over anhydrous sodium sulfate, filtered, stirred and cooled to 0 °C, drop sulfoxide chloride (5.36 g, 45 mmol), reaction for 4 h, TLC track the reaction process, confirm that the reaction is complete, the reaction liquid is concentrated under reduced pressure, drop into ammonia water (8.4 g, NH3total content is 60 mmol), reaction for 1 h, filter and wash to obtain white solid, and then wash with a mixture of n-heptane / isopropyl alcohol to obtain 3- carbamoyl-5-methylphenyl methyl trifluoromethanesulfonate 4.7 g, yield 52.6%.

[0110] Example 19: Preparation of compound 1 (3-cyanomethyl-5-methylbenzamide)

[0111] In a 1000 mL reaction flask, add 3-chloromethyl-5-methylbenzamide (45 g, 245 mmol), acetonitrile (450 mL), trimethylsilyl cyanide (24.31 g, 245 mmol), sodium carbonate (25.98 g, 245 mmol), stir and warm to 75 °C, reaction for 12 h, TLC track the reaction process, after the reaction is completed, the reaction liquid is concentrated, dichloromethane, water, stirred to separate the liquid, the aqueous phase is extracted with dichloromethane, the dichloromethane phase is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the concentrate is washed with a mixture of n-heptane / isopropyl alcohol, filtered and dried to obtain 3-cyanomethyl-5-methylbenzamide 38.1 g, yield 89.4%, liquid phase purity: ≥97%.

[0112] HRMS: 175.08623 [M+H] + , 1 H NMR: (400 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.66(d, J = 1.7 Hz, 2H), 7.38 (s, 1H), 7.31 (t, J = 1.6 Hz, 1H), 4.05 (s, 2H),2.36 (s, 3H).

[0113] Example 20: Preparation of compound 1 (3-cyanomethyl-5-methylbenzamide)

[0114] In a 100 mL reaction flask was added 3-chloromethyl-5-methylbenzamide (5 g, 27 mmol), acetonitrile (50 mL), trimethylsilyl cyanide (2.16 g, 22 mmol), sodium carbonate (1.44 g, 14 mmol), stirred to 75 °C, reacted for 12 h, TLC tracked the reaction process, after the reaction was completed, the reaction liquid was concentrated, dichloromethane, water was added, stirred and separated, the aqueous phase was extracted with dichloromethane, the dichloromethane phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the concentrate was added to a mixture of n-heptane / isopropyl alcohol to slurry, filtered and dried to obtain 3-cyanomethyl-5-methylbenzamide 2.5 g, yield 52.7%.

[0115] Example 21: Preparation of compound 1 (3-cyanomethyl-5-methylbenzamide)

[0116] In a 100 mL reaction flask was added 3-chloromethyl-5-methylbenzamide (5 g, 27 mmol), acetonitrile (50 mL), trimethylsilyl cyanide (2.16 g, 22 mmol), sodium carbonate (1.44 g, 14 mmol), stirred to 75 °C, reacted for 12 h, TLC tracked the reaction process, after the reaction was completed, the reaction liquid was concentrated, dichloromethane, water was added, stirred and separated, the aqueous phase was extracted with dichloromethane, the dichloromethane phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the concentrate was added to a mixture of n-heptane / isopropyl alcohol to slurry, filtered and dried to obtain 3-cyanomethyl-5-methylbenzamide 2.5 g, yield 52.7%.

[0117] Example 22: Preparation of compound 1 (3-cyanomethyl-5-methylbenzamide)

[0118] In a 100 mL reaction flask was added 3-chloromethyl-5-methylbenzamide (5 g, 27 mmol), acetonitrile (50 mL), trimethylsilyl cyanide (2.16 g, 22 mmol), sodium carbonate (1.44 g, 14 mmol), stirred to 75 °C, reacted for 12 h, TLC tracked the reaction process, after the reaction was completed, the reaction liquid was concentrated, dichloromethane, water was added, stirred and separated, the aqueous phase was extracted with dichloromethane, the dichloromethane phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the concentrate was added to a mixture of n-heptane / isopropyl alcohol to slurry, filtered and dried to obtain 3-cyanomethyl-5-methylbenzamide 2.5 g, yield 52.7%.

[0119] Example 23: Preparation of compound 1 (3-cyanomethyl-5-methylbenzamide)

[0120] In a 100 mL reaction flask, 3-chloromethyl-5-methylbenzamide (5 g, 27 mmol), acetonitrile (50 mL), trimethylsilyl cyanide (2.70 g, 27 mmol), sodium carbonate (1.44 g, 14 mmol) were added, stirred and warmed to 75 °C, reacted for 12 h, the reaction process was tracked by TLC, after the reaction was completed, the reaction solution was concentrated, dichloromethane, water were added, the liquid was stirred and separated, the aqueous phase was extracted with dichloromethane, the dichloromethane phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the concentrate was slurried with a n-heptane / isopropyl alcohol mixed solution, filtered and dried to obtain 3-cyanomethyl-5-methylbenzamide 2.3 g, with a yield of 48.5%.

[0121] Example 24: Preparation of compound 1 (3-cyanomethyl-5-methylbenzamide)

[0122] In a 100 mL reaction flask, 3-chloromethyl-5-methylbenzamide (5 g, 27 mmol), acetonitrile (50 mL), trimethylsilyl cyanide (2.70 g, 27 mmol), sodium hydroxide (1.09 g, 27 mmol) were added, stirred and warmed to 75 °C, reacted for 12 h, the reaction process was tracked by TLC, after the reaction was completed, the reaction solution was concentrated, dichloromethane, water were added, the liquid was stirred and separated, the aqueous phase was extracted with dichloromethane, the dichloromethane phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the concentrate was slurried with a n-heptane / isopropyl alcohol mixed solution, filtered and dried to obtain 3-cyanomethyl-5-methylbenzamide 1.6 g, with a yield of 33.7%.

[0123] The applicant states that the preparation process of the present application is illustrated by the above examples, but the present application is not limited to the above examples, that is, it does not mean that the present application must rely on the above examples to be implemented. It should be understood by those skilled in the art that any improvement of the present application, equivalent replacement of each raw material of the product of the present application, addition of auxiliary ingredients, selection of specific modes, etc. fall within the protection scope and disclosure scope of the present application.

Claims

1. A process for the preparation of 3-cyanomethyl-5-methylbenzamide, characterized in that, The preparation method comprises the following steps: (a) esterification of intermediate 1 compound 5-methyl isophthalic acid to obtain intermediate 2 compound 5-methyl isophthalic acid diester; (b) selective reduction of intermediate 2 compound under the action of a reducing agent to obtain intermediate 3 compound 3-hydroxymethyl-5-methyl benzoate; (c) hydrolysis of intermediate 3 compound to obtain intermediate 4 compound 3-hydroxymethyl-5-methyl benzoic acid; (d) hydroxymethyl substitution of intermediate 4 compound, followed by amidation to obtain intermediate 5 compound 3-substituted methyl-5-methyl benzamide; (e) cyanation of intermediate 5 compound in the presence of a base to obtain compound 1, i.e. 3-cyanomethyl-5-methyl benzamide; The reaction flow of the preparation method is as follows: ； R1 is selected from C1-C6 alkyl, benzyl or at least one halogen, cyano, nitro, C1-C6 alkoxy-substituted benzyl; X is halogen, methanesulfonate, trifluoromethanesulfonate or 4-methylbenzenesulfonyloxy.

2. The production method according to claim 1, characterized by, The esterification reaction in step (a) comprises: first reacting with an acylating agent, and then reacting with an esterifying agent; The acylating agent in step (a) is selected from any one or a combination of at least two of phosphorus trichloride, phosphorus pentachloride, thionyl chloride or oxalyl chloride; The molar ratio of the intermediate 1 compound to the acylating agent in step (a) is 1:(1-5); The reaction temperature of the intermediate 1 compound with the acylating agent in step (a) is -50-50°C, and the reaction time is 1-6h; The esterifying agent in step (a) is C1-C6 aliphatic alcohol, benzyl alcohol or benzyl alcohol substituted by at least one halogen, cyano, nitro, C1-C6 alkoxy; The molar ratio of the intermediate 1 compound to the esterifying agent in step (a) is 1:(2-4); The reaction temperature of the intermediate 1 compound with the esterifying agent in step (a) is -50-50°C, and the reaction time is 1-6h; Step (a) is carried out in a solvent selected from any one or a combination of at least two of C1-C8 alkane solvents, C2-C8 ether solvents and C6-C10 aromatic hydrocarbon solvents.

3. The preparation method according to claim 2, characterized in that, The acylating agent in step (a) is thionyl chloride; The molar ratio of the intermediate 1 compound to the acylating agent in step (a) is 1:(2-2.5); The reaction temperature of the intermediate 1 compound with the acylating agent in step (a) is 0-10°C, and the reaction time is 3-4h; The molar ratio of the intermediate 1 compound to the esterifying agent in step (a) is 1:(2-2.5); The reaction temperature of the intermediate 1 compound with the esterifying agent in step (a) is 0-10°C, and the reaction time is 1-2h; The solvent used in step (a) is selected from any one or a combination of at least two of chloroform, tetrahydrofuran or dichloromethane.

4. The production method according to claim 1, characterized by, The reducing agent in step (b) is selected from any one or a combination of at least two of lithium aluminum hydride, sodium borohydride, potassium borohydride, lithium borohydride, borane solvent complex or sodium hyposulfite; The molar ratio of the intermediate 2 compound to the reducing agent in step (b) is 1:(1-2); The reaction temperature of the reduction reaction in step (b) is -50-30°C, and the reaction time is 2-8h; The reducing reaction in step (b) is carried out in a solvent selected from any one or a combination of at least two of C1-C8 alkane solvents, C1-C8 alcohol solvents or C6-C10 aromatic hydrocarbon solvents.

5. The preparation method according to claim 4, characterized in that, The reducing agent in step (b) is sodium borohydride and / or potassium borohydride; The molar ratio of the intermediate 2 compound to the reducing agent in step (b) is 1:(1-1.2); The reaction temperature of the reducing reaction in step (b) is -10-0℃, and the reaction time is 4-5h; The solvent for the reducing reaction in step (b) is any one or a combination of at least two of chloroform, methanol or dichloromethane.

6. The method of claim 1, wherein, The hydrolysis in step (c) is carried out in the presence of a hydrolysis reagent selected from any one or a combination of at least two of strong base, strong acid or weak acid; The molar ratio of the intermediate 3 compound to the hydrolysis reagent in step (c) is 1:(1-3); The reaction temperature of the hydrolysis reaction in step (c) is 30-80℃, and the reaction time is 5-10h; The hydrolysis reaction in step (c) is carried out with or without a solvent; The solvent used in step (c) is selected from any one or a combination of at least two of C1-C8 alkane solvents, C2-C8 ether solvents, C6-C10 aromatic hydrocarbon solvents or water.

7. The preparation method according to claim 6, characterized in that, The hydrolysis reagent is selected from sodium hydroxide and / or potassium hydroxide; The molar ratio of the intermediate 3 compound to the hydrolysis reagent in step (c) is 1:(1-2); The reaction temperature of the hydrolysis reaction in step (c) is 65-75℃; and the reaction time is 7-9h; The hydrolysis reaction in step (c) is carried out without a solvent.

8. The method of claim 1, wherein, The substitution reagent used in the hydroxymethyl substitution reaction in step (d) is selected from any one of oxalyl chloride, sulfurous chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide or triflic anhydride; The molar ratio of the intermediate 4 compound to the substitution reagent is 1:(1-4); The temperature of the hydroxymethyl substitution reaction in step (d) is -20-50℃, and the reaction time is 1-6h; The amidation reagent used in the amidation in step (d) is selected from aqueous ammonia or ammonia gas; The molar ratio of the intermediate 4 compound to the amidation reagent is 1:(1-4); The reaction temperature of the amidation in step (d) is -20-50℃, and the reaction time is 1-6h; The amidation in step (d) is carried out in a solvent selected from any one or a combination of at least two of C1-C8 alkane solvents, C2-C8 ether solvents or C6-C10 aromatic hydrocarbon solvents.

9. The method of claim 1, wherein, The base in step (e) is selected from any one or a combination of at least two of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide or potassium phosphate; The cyanylating reagent used in the cyanylating reaction in step (e) is selected from any one or a combination of at least two of hydrogen cyanide, sodium cyanide, potassium cyanide, zinc cyanide, trimethylsilyl cyanide, potassium ferricyanide or potassium ferrocyanide; The molar ratio of the intermediate 5 compound to the cyanylating reagent in step (e) is 1:(1-3); The molar ratio of the intermediate 5 compound to the base in step (e) is 1:(0-3); The temperature of the cyanation reaction in step (e) is 30-80°C, and the reaction time is 5-15h; Step (e) is carried out in a solvent selected from any one or a combination of at least two of C2-C8 nitrile solvents, C2-C8 ether solvents or C6-C10 aromatic hydrocarbon solvents.

10. The production method according to claim 8 or 9, characterized by, The substituting reagent used in the hydroxymethyl substitution reaction in step (d) is thionyl chloride; The molar ratio of the intermediate 4 compound to the substituting reagent is 1:(2-3); The temperature of the hydroxymethyl substitution in step (d) is 0-20°C, and the reaction time is 3-4h; The amidation reagent used in the amidation in step (d) is aqueous ammonia; The molar ratio of the intermediate 4 compound to the amidation reagent is 1:(2-3); The temperature of the amidation in step (d) is 0-20°C, and the reaction time is 1-2h; Step (d) is carried out in a solvent selected from any one or a combination of at least two of chloroform, tetrahydrofuran or dichloromethane; The base in step (e) is sodium carbonate; The cyanation reagent used in the cyanation reaction in step (e) is trimethylsilyl cyanide; The molar ratio of the intermediate 5 compound to the cyanation reagent in step (e) is 1:(1-2); The molar ratio of the intermediate 5 compound to the base in step (e) is 1:(1-2); The temperature of the cyanation reaction in step (e) is 70-80°C, and the reaction time is 11-13h; Step (e) is carried out in a solvent selected from any one or a combination of at least two of acetonitrile, tetrahydrofuran, 1,4-dioxane or toluene.

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