A process for the preparation of 3-cyanomethyl-5-methylbenzamide

Abstract

This invention provides a method for preparing 3-cyanomethyl-5-methylbenzamide, belonging to the field of pharmaceutical preparation technology. The method uses 5-methylisophthalic acid as a raw material, preparing 5-methylisophthalate diester via diesterization, followed by selective reduction to obtain 3-hydroxymethyl-5-methylbenzoic acid ester, which is then hydrolyzed to obtain 3-hydroxymethyl-5-methylbenzoic acid. Subsequently, a hydroxymethyl substitution reaction and amidation are performed to obtain 3-substituted methyl-5-methylbenzamide, which is finally prepared by cyanolation to obtain the target product, 3-cyanomethyl-5-methylbenzamide. The preparation method of this invention is simple, easy to operate, and involves a milder reaction, resulting in a high overall product yield. It is economical and environmentally friendly, and has high prospects for industrial production and commercial application.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a new preparation process for 3-cyanomethyl-5-methylbenzamide, a key material in the preparation of enovilin. Background Technology

[0002] Enavirlin is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) that inhibits viral replication by non-competitively binding to HIV-1 reverse transcriptase. Enavirlin possesses excellent pharmacological properties, including strong antiviral activity, low central nervous system side effects, low cross-resistance, high target selectivity, and minimal drug interactions, making it a drug of great application value. The chemical structure of enavirlin is shown below:

[0003] .

[0004] Patent document CN118063395A reports a method for preparing enovirine that features mild reaction conditions, environmental friendliness, high yield, and significant industrialization potential. The preparation process route is described as follows:

[0005] ,

[0006] Among them, compound 3-cyanomethyl-5-methylbenzamide (SM2) is the key starting material in its preparation process, and its chemical structure is shown below:

[0007] .

[0008] Patent document CN118063395A discloses the synthetic route of 3-cyanomethyl-5-methylbenzamide, a key material of enovetine. It uses 3,5-dimethylbenzoic acid as a raw material and prepares 3,5-dimethylbenzamide by amidation reaction with thionyl chloride (SOCl2) and ammonia water as reagents. Then, it undergoes bromination reaction with N-bromosuccinimide (NBS) under the catalysis of azobisisobutyronitrile (AIBN) to prepare 3-bromomethyl-5-methylbenzamide. Finally, it undergoes cyanidation reaction with potassium carbonate as an acid binder and trimethylcyanosilane as a cyanidating reagent to obtain 3-cyanomethyl-5-methylbenzamide. .

[0009] In this process, the bromination reaction of 3,5-dimethylbenzamide is prone to excessive production of the bromination byproduct 3,5-dibromobenzamide because both benzyl groups of 3,5-dimethylbenzamide can be brominated under the same environmental conditions, and the existing NBS bromination reaction lacks regioselectivity. According to CN118063395A, the ratio of the target product 3-bromomethyl-5-methylbenzamide to the byproduct 3,5-dibromobenzamide is 3:1. Furthermore, due to the similarity of their chemical structures, their physicochemical properties are very similar, making purification difficult using conventional industrially acceptable methods such as crystallization, thus significantly reducing their industrialization value.

[0010] .

[0011] In addition, the purification of the reaction product in the cyanation reaction step requires column chromatography, which further limits the feasibility of its scale-up. Summary of the Invention

[0012] To address the shortcomings of existing technologies, the present invention aims to provide a method for preparing 3-cyanomethyl-5-methylbenzamide. The preparation method of the present invention is simple, easy to operate, meets environmental protection requirements, and has extremely high industrialization value.

[0013] To achieve this objective, the present invention adopts the following technical solution:

[0014] On one hand, the present invention provides a method for preparing 3-cyanomethyl-5-methylbenzamide, the method comprising the following steps:

[0015] (a) Intermediate 1, 5-methyl isophthalic acid, is subjected to esterification to give intermediate 2, 5-methyl isophthalic acid diester;

[0016] (b) Intermediate 2 undergoes selective reduction under the action of a reducing agent to give intermediate 3, methyl 3-hydroxymethyl-5-methylbenzoate;

[0017] (c) Intermediate 3 undergoes hydrolysis to give intermediate 4, 3-hydroxymethyl-5-methylbenzoic acid;

[0018] (d) Intermediate 4 undergoes a hydroxymethyl substitution reaction, followed by amidation, to give intermediate 5, 3-substituted methyl-5-methylbenzamide;

[0019] (e) In the presence of a base, intermediate 5 is cyano-treated to give compound 1 (i.e., 3-cyanomethyl-5-methylbenzamide).

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

[0021] ;

[0022] R1 is selected from C1-C6 alkyl (e.g., C1, C2, C3, C4, C5 or C6), benzyl or at least one halogen, cyano, nitro, C1-C6 (e.g., C1, C2, C3, C4, C5 or C6) alkoxy-substituted benzyl.

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

[0024] The preparation method of the present invention uses 5-methylisophthalic acid as raw material, prepares 5-methylisophthalic acid diester through diesterization reaction, then obtains 3-hydroxymethyl-5-methylbenzoate through selective reduction reaction, obtains 3-hydroxymethyl-5-methylbenzoic acid through ester hydrolysis, then obtains 3-hydroxymethyl-5-methylbenzoic acid through hydroxymethyl substitution reaction and amidation to obtain 3-substituted methyl-5-methylbenzamide, and finally obtains the target material 3-cyanomethyl-5-methylbenzamide through cyanoation reaction.

[0025] This invention uses 5-methylisophthalic acid, a commonly used chemical material, as a raw material to prepare 3-hydroxymethyl-5-methylbenzoate via selective ester hydrolysis. This avoids the poor selectivity problem of bromination reactions in the original preparation process, significantly reducing the generation of 3,5-dibromobenzamide byproducts. This makes the purification process of 3-hydroxymethyl-5-methylbenzoate simple, easy, and low-cost. The chemical reaction process is mild and involves conventional chemical reactions. The corresponding intermediates are purified and prepared using methods such as crystallization separation. This process has high feasibility for industrial scale-up, excellent controllability of material quality, and strong commercial value.

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

[0027] Preferably, the acylation reagent 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; more preferably, it is thionyl chloride.

[0028] Preferably, the molar ratio of intermediate 1 compound 5-methylisophthalic acid to the acylation reagent in step (a) is 1:(1-5), for example 1:1, 1:2, 1:3, 1:4 or 1:5, etc.; more preferably 1:2-2.5;

[0029] Preferably, the reaction temperature of intermediate 1 compound with acylation reagent in step (a) is -50 to 50°C, for example -50°C, -40°C, -30°C, -20°C, -10°C, 0°C, 10°C, 20°C, 30°C, 40°C or 50°C; more preferably 0-10°C;

[0030] Preferably, the reaction time of intermediate 1 compound with the acylation reagent in step (a) is 1-6 hours, such as 1 hour, 2 hours, 3 hours, 4 hours, 5 hours or 6 hours; more preferably 3-4 hours.

[0031] Preferably, the esterification agent in step (a) is a C1-C6 fatty alcohol, benzyl alcohol, or benzyl alcohol substituted with at least one halogen, cyano, nitro, or C1-C6 alkoxy group, such as methanol, ethanol, propanol, isopropanol, benzyl alcohol, etc.; more preferably, it is a C1-C6 fatty alcohol.

[0032] Preferably, the molar ratio of intermediate 1 compound 5-methylisophthalic acid to the esterification reagent in step (a) is 1:(2-4), for example 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.; more preferably 1:(2-2.5).

[0033] Preferably, the temperature for reacting with the esterifying agent in step (a) is -50 to 50°C, for example -50°C, -40°C, -30°C, -20°C, -10°C, 0°C, 10°C, 20°C, 30°C, 40°C, or 50°C; more preferably, it is 0-10°C.

[0034] Preferably, the reaction time with the esterification reagent in step (a) is 1-6 hours, such as 1 hour, 2 hours, 3 hours, 4 hours, 5 hours or 6 hours; more preferably 1-2 hours.

[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, and C6-C10 aromatic solvents; more preferably, any one or a combination of at least two of chloroform, tetrahydrofuran, or dichloromethane; and even 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 sodium hydrosulfite; more preferably sodium borohydride and / or potassium borohydride. In this invention, the borane solvent complex can be, for example, a borane tetrahydrofuran complex.

[0037] Preferably, the molar ratio of intermediate compound 2 to reducing agent in step (b) is 1:(1-2), for example 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.; more preferably 1:(1-1.2).

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

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

[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 solvents; further, it is any one or a combination of at least two of chloroform, methanol, or dichloromethane; further, it is 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 bases, strong acids, or weak acids, and more preferably strong bases sodium hydroxide and / or potassium hydroxide.

[0042] Preferably, the molar ratio of intermediate compound 3 to hydrolysis reagent in step (c) is 1:(1-3), for example 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.; more preferably 1:(1-2).

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

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

[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 in the presence of 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 solvents, or water, and more preferably from any one or a combination of at least two of toluene, tetrahydrofuran, dichloromethane, or water.

[0047] Preferably, the substituted reagent used in the hydroxymethyl substitution reaction in step (d) is selected from any one of oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, or trifluoromethanesulfonic anhydride, and more preferably thionyl chloride.

[0048] Preferably, the molar ratio of intermediate compound 4 to the substituted reagent is 1:(1-4), for example 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, etc.; more preferably 1:(2-3).

[0049] Preferably, the temperature of the hydroxymethyl substitution reaction in step (d) is -20 to 50°C, for example -20°C, -12°C, -4°C, 4°C, 12°C, 20°C, 28°C, 36°C, 44°C or 50°C; more preferably, it is 0-20°C.

[0050] Preferably, the hydroxymethyl substitution reaction in step (d) takes 1-6 hours, for example, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours or 6 hours; more preferably, it takes 3-4 hours.

[0051] Preferably, the amidating agent used in step (d) is selected from ammonia water or ammonia gas, and more preferably ammonia water. Even more preferably, the concentration of the ammonia water is 6-8 mol / L, for example, 6 mol / L, 6.5 mol / L, 7 mol / L, 7.5 mol / L, or 8 mol / L.

[0052] Preferably, the molar ratio of intermediate compound 4 to the amidating agent is 1:(1-4), for example 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, etc.; more preferably 1:(2-3).

[0053] Preferably, the reaction temperature for amidation in step (d) is -20 to 50°C, for example -20°C, -12°C, -4°C, 4°C, 12°C, 20°C, 28°C, 36°C, 44°C, or 50°C; more preferably, it is 0-20°C.

[0054] Preferably, the reaction time for the amidation in step (d) is 1-6 hours, such as 1 hour, 2 hours, 3 hours, 4 hours, 5 hours or 6 hours; more preferably 1-2 hours.

[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 solvents, more preferably any one or a combination of at least two of chloroform, tetrahydrofuran or dichloromethane, and even more preferably dichloromethane.

[0056] Preferably, the alkali 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 more preferably sodium carbonate.

[0057] Preferably, the cyaniding reagent used in the cyanidation 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, trimethylcyanosilane, potassium ferrocyanide or potassium ferrocyanide, and more preferably trimethylcyanosilane.

[0058] Preferably, the molar ratio of intermediate compound 5 to cyaniding agent in step (e) is 1:(1-3), for example 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, etc.; more preferably 1:(1-2).

[0059] Preferably, the molar ratio of intermediate compound 5 to base in step (e) is 1:(0-3), for example 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, etc.; more preferably 1:(1-2).

[0060] Preferably, the temperature of the cyanidation reaction in step (e) 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; more preferably 70-80°C.

[0061] Preferably, the cyanidation reaction in step (e) takes 5-15 hours, such as 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours or 15 hours; more preferably 11-13 hours.

[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 solvents, more preferably any one or a combination of at least two of acetonitrile, tetrahydrofuran, 1,4-dioxane, or toluene, more preferably acetonitrile.

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

[0064] This invention uses 5-methylisophthalic acid as raw material, and through diesterization, selective reduction, hydrolysis, hydroxymethyl substitution and amidation, and finally cyanotylation, obtains 3-cyanomethyl-5-methylbenzamide, the key material for preparing enovetine. This process is more gentle, has a high overall product yield, and is economical and environmentally friendly, with high prospects for industrial production and commercial application. Detailed Implementation

[0065] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention in any way.

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

[0067] .

[0068] The present invention will be described in detail below through embodiments.

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

[0070] In the following examples, the structure of the obtained products was identified by NMR and mass spectrometry, and the purity detected by HPLC was above 95%.

[0071] Example 1: Preparation of Intermediate 2 (Dimethyl 5-methylisophthalate)

[0072] 5-Methylisophthalic acid (150 g, 833 mmol), dichloromethane (750 mL), and N,N-dimethylformamide (1 mL) were added to a 2000 mL reaction flask. The mixture was stirred and cooled to 0 °C. Thionyl chloride (247.63 g, 2.08 mol) was slowly added dropwise. After the addition was complete, the reaction was monitored by TLC. After the reactants had completely reacted, methanol (66.56 g, 2.08 mol) was added dropwise. The mixture was stirred for 1 h. The mixture was washed twice with saturated sodium bicarbonate solution, then once with saturated sodium chloride solution. The solution was dried over anhydrous sodium sulfate and concentrated to obtain 170 g of dimethyl 5-methylisophthalate, 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 = 0.8Hz, 3H).

[0074] Example 2: Preparation of Intermediate 2 (Dimethyl 5-methylisophthalate)

[0075] 20 g (111 mmol) of 5-methylisophthalic acid, 100 mL of dichloromethane, and 1 mL of N,N-dimethylformamide were added to a 250 mL reaction flask. The mixture was stirred and cooled to 0 °C. Oxaloyl chloride (35.25 g, 278 mmol) was slowly added dropwise. After the addition was complete, the reaction was monitored by TLC. After the reactants had reacted completely, methanol (8.90 g, 278 mmol) was added dropwise. The mixture was stirred for 1 h. The mixture was washed twice with saturated sodium bicarbonate solution and then once with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate and concentrated to obtain 18.6 g of dimethyl isophthalate, with a yield of 80.5%.

[0076] Example 3: Preparation of Intermediate 2 (Dimethyl 5-methylisophthalate)

[0077] 20 g (111 mmol) of 5-methylisophthalic acid, 100 mL of dichloromethane, and 1 mL of N,N-dimethylformamide were added to a 2000 mL reaction flask. The mixture was stirred and cooled to 0 °C. Thionyl chloride (19.82 g, 167 mmol) was slowly added dropwise. After the addition was complete, the reaction was monitored by TLC. After the reactants had reacted completely, methanol (5.34 g, 167 mol) was added dropwise. The mixture was stirred for 1 h. The mixture was washed twice with saturated sodium bicarbonate solution, then once with saturated sodium chloride solution. The solution was dried over anhydrous sodium sulfate and concentrated to obtain 12.5 g of dimethyl isophthalate, with a yield of 54.1%.

[0078] Example 4: Preparation of Intermediate 2 (Diethyl 5-methylisophthalate)

[0079] 20 g (111 mmol) of 5-methylisophthalic acid, 100 mL of dichloromethane, and 1 mL of N,N-dimethylformamide were added to a 2000 mL reaction flask. The mixture was stirred and cooled to 0 °C. Thionyl chloride (19.82 g, 167 mmol) was slowly added dropwise. After the addition was complete, the reaction was monitored by TLC. After the reactants had reacted completely, 12.79 g (278 mol) of ethanol was added dropwise. The mixture was stirred for 1 h. The mixture was washed twice with saturated sodium bicarbonate solution and then once with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate and concentrated to obtain 19.9 g of diethyl 5-methylisophthalate, with a yield of 75.9%.

[0080] Example 5: Preparation of Intermediate 2 (Dibenzyl 5-methylisophthalate)

[0081] 20 g (111 mmol) of 5-methylisophthalic acid, 100 mL of dichloromethane, and 1 mL of N,N-dimethylformamide were added to a 2000 mL reaction flask. The mixture was stirred and cooled to 0 °C. Thionyl chloride (19.82 g, 167 mmol) was slowly added dropwise. After the addition was complete, the reaction was monitored by TLC. After the reactants had reacted completely, benzyl alcohol (30.02 g, 278 mol) was added dropwise. The mixture was stirred for 1 h. The mixture was washed twice with saturated sodium bicarbonate solution, then once with saturated sodium chloride solution. The solution was dried over anhydrous sodium sulfate and concentrated to obtain 29.1 g of dibenzyl 5-methylisophthalate, with a yield of 72.7%.

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

[0083] Dimethyl 5-methylisophthalate (150 g, 720 mmol) and methanol (1500 mL) were added to a 2000 mL reaction flask and stirred to dissolve. The mixture was then cooled to -10 °C, and sodium borohydride (32.7 g, 865 mmol) was added in portions. The reaction was allowed to proceed for 5 h after the addition was complete. The reaction was monitored by TLC. After the reaction was completed, the mixture was quenched with water, concentrated, dissolved in dichloromethane, washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 107.2 g of methyl 3-hydroxymethyl-5-methylbenzoate, with a yield of 82.6% and an HPLC purity of ≥95%.

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

[0085] Dimethyl 5-methylisophthalate (10 g, 48 mmol) and anhydrous tetrahydrofuran (100 mL) were added to a 500 mL reaction flask under nitrogen purging protection. Boron trifluoride diethyl ether (6.82 g, 48 mmol) was added and stirred to dissolve. The mixture was cooled to -10 °C, and borane tetrahydrofuran complex (72 mL, 72 mmol) was slowly added dropwise. The reaction was carried out for 5 h after the addition was complete. The reaction was monitored by TLC. After the reaction was completed, methanol was added to quench the reaction, and water (100 mL) was added. The mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 6.0 g of methyl 3-hydroxymethyl-5-methylbenzoate, with a yield of 69.3%.

[0086] Example 8: Preparation of intermediate 3 (ethyl 3-hydroxymethyl-5-methylbenzoate)

[0087] Diethyl 5-methylisophthalate (11.34 g, 48 mmol) and tetrahydrofuran (100 mL) were added to a 250 mL reaction flask and stirred to dissolve. The mixture was then cooled to -10 °C, and lithium aluminum hydride (2.19 g, 58 mmol) was added in portions. The reaction was allowed to proceed for 5 h after the addition was complete. The reaction was monitored by TLC. After the reaction was completed, the mixture was quenched with water and 15% NaOH solution. The reaction solution was filtered, concentrated, dissolved in dichloromethane, washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5.7 g of ethyl 3-hydroxymethyl-5-methylbenzoate, with a yield of 61.1%.

[0088] Example 9: Preparation of Intermediate 3 (Benzyl 3-hydroxymethyl-5-methylbenzoate)

[0089] Dibenzyl 5-methylisophthalate (17.30 g, 48 mmol) and methanol (100 mL) were added to a 2000 mL reaction flask and stirred to dissolve. The mixture was then cooled to -10 °C, and sodium borohydride (1.82 g, 48 mmol) was added in portions. The reaction was allowed to proceed for 5 h after the addition was complete. The reaction was monitored by TLC. After the reaction was completed, the mixture was quenched with water, concentrated, dissolved in dichloromethane, washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 9.1 g of benzyl 3-hydroxymethyl-5-methylbenzoate, with a yield of 70.1%.

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

[0091] 80 g (444 mmol) of methyl 3-hydroxymethyl-5-methylbenzoate and 35.52 g (888 mmol) of sodium hydroxide were added to a 250 mL reaction flask. The mixture was stirred and heated to 70 °C and reacted for 8 h. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, and dichloromethane and water were added. The pH was adjusted to 2 with 2 M hydrochloric acid. The mixture was separated, and 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 63.1 g of 3-hydroxymethyl-5-methylbenzoic acid, with a yield of 85.5% and an HPLC purity of ≥95%.

[0092] HRMS: 165.05464 [MH] - , 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] Ethyl 3-hydroxymethyl-5-methylbenzoate (10 g, 51 mmol) and a 20% sodium hydroxide aqueous solution (containing 4.08 g, 102 mmol of sodium hydroxide) were added to a 250 mL reaction flask. The mixture was stirred and heated to 70 °C and reacted for 10 h. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, dichloromethane was added, and the pH was adjusted to 2 with 2 M hydrochloric acid. The mixture was separated, and 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 6.2 g of 3-hydroxymethyl-5-methylbenzoic acid, with a yield of 72.5%.

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

[0096] 10 g (55 mmol) of methyl 3-hydroxymethyl-5-methylbenzoate and a 50% sulfuric acid aqueous solution (containing 10.9 g (111 mmol) of sulfuric acid) were added to a 250 mL reaction flask. The mixture was stirred and heated to 70 °C and reacted for 12 h. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, and dichloromethane was added. The mixture was stirred and separated. The aqueous phase was extracted again, and the dichloromethane phases were combined. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5.8 g of 3-hydroxymethyl-5-methylbenzoic acid, with a yield of 62.9%.

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

[0098] 3-Hydroxymethyl-5-methylbenzoic acid (50 g, 301 mmol), dichloromethane (250 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 (89.49 g, 752 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 then ammonia water (84.2 g, total NH3 content 602 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 49.7 g of 3-chloromethyl-5-methylbenzoamide, 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 5 g (30 mmol) of 3-hydroxymethyl-5-methylbenzoic acid, 25 mL of dichloromethane, and 2.37 g (30 mmol). Stir and cool to -10 °C. Add 12.69 g (45 mmol) of trifluoromethanesulfonic anhydride dropwise. After the addition is complete, react at 0 °C for 4 h. Monitor the reaction process by TLC. Once the reactants have reacted completely, slowly add 50 mL of 0.1 N hydrochloric acid aqueous solution, stir, and separate the liquid. Dry the organic phase with anhydrous sodium sulfate. The mixture was filtered, stirred, and cooled to 0°C. Thionyl chloride (5.36 g, 45 mmol) was added dropwise, and the reaction was carried out for 4 h. The reaction process was monitored by TLC. After confirming that the reaction was complete, the reaction solution was concentrated under reduced pressure and then ammonia water (8.4 g, total NH3 content of 60 mmol) was added dropwise. The reaction was carried out for 1 h, 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-carbamoyl-5-methylphenylmethyltrifluoromethanesulfonate, with a yield of 52.6%.

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

[0111] 3-Chloromethyl-5-methylbenzamide (45 g, 245 mmol), acetonitrile (450 mL), trimethylcyanosilane (24.31 g, 245 mmol), and sodium carbonate (25.98 g, 245 mmol) were added to a 1000 mL reaction flask. The mixture was stirred and heated to 75 °C and reacted for 12 h. The reaction process was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, and dichloromethane and water were added. The mixture was stirred and separated. The aqueous phase was extracted with dichloromethane, and the dichloromethane phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was slurried with a mixture of n-heptane / isopropanol, filtered, and dried to obtain 38.1 g of 3-cyanomethyl-5-methylbenzamide, with a yield of 89.4% and a liquid chromatography purity of ≥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] 3-Chloromethyl-5-methylbenzamide (5 g, 27 mmol), acetonitrile (50 mL), trimethylcyanosilane (2.16 g, 22 mmol), and sodium carbonate (1.44 g, 14 mmol) were added to a 100 mL reaction flask. The mixture was stirred and heated to 75 °C and reacted for 12 h. The reaction process was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, and dichloromethane and water were added. The mixture was stirred and separated. The aqueous phase was extracted with dichloromethane, and the dichloromethane phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was then mixed with a heptane / isopropanol solution and stirred. After filtration and drying, 2.5 g of 3-cyanomethyl-5-methylbenzamide was obtained, with a yield of 52.7%.

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

[0116] 3-Bromomethyl-5-methylbenzamide (6.16 g, 27 mmol), acetonitrile (50 mL), sodium cyanide (1.32 g, 27 mmol), and sodium carbonate (2.89 g, 27 mmol) were added to a 100 mL reaction flask. The mixture was stirred and heated to 75 °C and reacted for 12 h. The reaction was monitored by TLC. After the reaction was completed, dichloromethane and water were added, and the mixture was stirred and separated. The aqueous phase was extracted with dichloromethane, and the dichloromethane phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was then mixed with a heptane / isopropanol solution and stirred. After filtration and drying, 2.7 g of 3-cyanomethyl-5-methylbenzamide was obtained, with a yield of 57.4%.

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

[0118] 3-Carbamoyl-5-methylphenylmethyltrifluoromethanesulfonate (8.02 g, 27 mmol), acetonitrile (50 mL), potassium ferricyanide (8.96 g, 27 mmol), and sodium carbonate (2.89 g, 27 mmol) were added to a 100 mL reaction flask. The mixture was stirred and heated to 75 °C and reacted for 12 h. The reaction process was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, and dichloromethane and water were added. The mixture was stirred and separated. The aqueous phase was extracted with dichloromethane, and the dichloromethane phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was mixed with a heptane / isopropanol solution and stirred. After filtration and drying, 2.1 g of 3-cyanomethyl-5-methylbenzamide was obtained, with a yield of 44.7%.

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

[0120] 3-Chloromethyl-5-methylbenzamide (5 g, 27 mmol), acetonitrile (50 mL), trimethylcyanosilane (2.70 g, 27 mmol), and sodium carbonate (1.44 g, 14 mmol) were added to a 100 mL reaction flask. The mixture was stirred and heated to 75 °C and reacted for 12 h. The reaction process was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, and dichloromethane and water were added. The mixture was stirred and separated. The aqueous phase was extracted with dichloromethane, and the dichloromethane phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was then mixed with a heptane / isopropanol solution and stirred. After filtration and drying, 2.3 g of 3-cyanomethyl-5-methylbenzamide was obtained, with a yield of 48.5%.

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

[0122] 3-Chloromethyl-5-methylbenzamide (5 g, 27 mmol), acetonitrile (50 mL), trimethylcyanosilane (2.70 g, 27 mmol), and sodium hydroxide (1.09 g, 27 mmol) were added to a 100 mL reaction flask. The mixture was stirred and heated to 75 °C and reacted for 12 h. The reaction process was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, and dichloromethane and water were added. The mixture was stirred and separated. The aqueous phase was extracted with dichloromethane, and the dichloromethane phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was added to a mixed solution of n-heptane / isopropanol and stirred. The mixture was filtered and dried to obtain 1.6 g of 3-cyanomethyl-5-methylbenzamide, with a yield of 33.7%.

[0123] The applicant declares that the preparation process of this invention is illustrated by the above embodiments, but this invention is not limited to the above embodiments, that is, it does not mean that this invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to this invention, equivalent substitutions of the raw materials for the product of this invention, addition of auxiliary components, and selection of specific methods, etc., all fall within the protection scope and disclosure scope of this invention.

Claims

1. A method for preparing 3-cyanomethyl-5-methylbenzamide, characterized in that, The preparation method includes the following steps: (a) Intermediate 1, 5-methyl isophthalic acid, is subjected to esterification to give intermediate 2, 5-methyl isophthalic acid diester; (b) Intermediate 2 undergoes selective reduction under the action of a reducing agent to give intermediate 3, 3-hydroxymethyl-5-methylbenzoate; (c) Intermediate 3 undergoes hydrolysis to give intermediate 4, 3-hydroxymethyl-5-methylbenzoic acid; (d) Intermediate 4 undergoes a hydroxymethyl substitution reaction, followed by amidation, to give intermediate 5, 3-substituted methyl-5-methylbenzamide; (e) In the presence of a base, intermediate 5 is cyano-treated to give compound 1, namely 3-cyanomethyl-5-methylbenzamide; The reaction process of the preparation method is as follows: ； R1 is selected from C1-C6 alkyl, benzyl, or at least one halogen, cyano, nitro, or C1-C6 alkoxy-substituted benzyl group; X is a halogen or trifluoromethanesulfonate group; 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, and borane solvent complexes; The substituted reagent used in step (d) for the hydroxymethyl substitution reaction is selected from any one of oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, or trifluoromethanesulfonic anhydride; The amidation reagent used in step (d) is selected from ammonia water or ammonia gas.

2. The preparation method according to claim 1, characterized in that, The esterification reaction in step (a) includes: first reacting with an acylation reagent, and then reacting with an esterification reagent; The acylation reagent 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; In step (a), the molar ratio of intermediate 1 compound to acylation reagent is 1:(1-5). In step (a), the intermediate 1 compound reacts with the acylation reagent at a temperature of -50 to 50°C for 1 to 6 hours. The esterification agent in step (a) is a C1-C6 fatty alcohol, benzyl alcohol, or benzyl alcohol substituted with at least one halogen, cyano, nitro, or C1-C6 alkoxy group; In step (a), the molar ratio of intermediate 1 compound to the esterifying agent is 1:(2-4); The reaction temperature with the esterification reagent in step (a) is -50 to 50°C, and the reaction time is 1 to 6 hours. 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 solvents.

3. The preparation method according to claim 2, characterized in that, The acylation reagent in step (a) is thionyl chloride; In step (a), the molar ratio of intermediate 1 compound to the acylation reagent is 1:(2-2.5); The reaction temperature with the acylation reagent in step (a) is 0-10℃, and the reaction time is 3-4h; In step (a), the molar ratio of intermediate 1 compound to the esterifying agent is 1:(2-2.5); The reaction temperature with the esterification reagent in step (a) is 0-10℃, 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 preparation method according to claim 1, characterized in that, In step (b), the molar ratio of intermediate compound 2 to reducing agent is 1:(1-2); The reduction reaction in step (b) is carried out at a temperature of -50 to 30°C for 2 to 8 hours. 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 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; In step (b), the molar ratio of intermediate compound 2 to the reducing agent is 1:(1-1.2). The reduction reaction in step (b) is carried out at a temperature of -10 to 0°C for 4-5 hours. The solvent for the reduction reaction in step (b) is any one or a combination of at least two of chloroform, methanol, or dichloromethane.

6. The preparation method according to claim 1, characterized in that, 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 bases, strong acids, or weak acids. In step (c), the molar ratio of intermediate compound 3 to the hydrolysis reagent is 1:(1-3); The hydrolysis reaction in step (c) is carried out at a temperature of 30-80℃ for 5-10 hours. The hydrolysis reaction described 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 the following: C1-C8 alkane solvents, C2-C8 ether solvents, C6-C10 aromatic 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; In step (c), the molar ratio of intermediate compound 3 to the hydrolysis reagent is 1:(1-2); The hydrolysis reaction in step (c) is carried out at a temperature of 65-75℃ for 7-9 hours. The hydrolysis reaction described in step (c) is carried out in the absence of solvent.

8. The preparation method according to claim 1, characterized in that, The molar ratio of intermediate compound 4 to the substituted reagent is 1:(1-4); The temperature for the hydroxymethyl substitution reaction in step (d) is -20 to 50°C, and the reaction time is 1 to 6 hours. The molar ratio of intermediate compound 4 to the amidating agent is 1:(1-4); The amidation reaction in step (d) is carried out at a temperature of -20 to 50°C for 1 to 6 hours. 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 solvents.

9. The preparation method according to claim 1, characterized in that, 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 cyaniding reagent used in step (e) is selected from any one or a combination of at least two of hydrogen cyanide, sodium cyanide, potassium cyanide, zinc cyanide, trimethylcyanosilane, potassium ferrocyanide or potassium ferrocyanide; In step (e), the molar ratio of intermediate compound 5 to the cyaniding agent is 1:(1-3); In step (e), the molar ratio of intermediate compound 5 to the base is 1:(0-3); The cyanidation reaction in step (e) is carried out at a temperature of 30-80°C for 5-15 hours. 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 solvents.

10. The preparation method according to claim 8 or 9, characterized in that, The substituted reagent used in step (d) of the hydroxymethyl substitution reaction is thionyl chloride; The molar ratio of intermediate compound 4 to the substituted reagent is 1:(2-3); The temperature for the hydroxymethyl substitution in step (d) is 0–20 °C, and the reaction time is 3–4 h. The amidation reagent used in step (d) is ammonia. The molar ratio of intermediate compound 4 to the amidating agent is 1:(2-3); The amidation reaction in step (d) is carried out at a temperature of 0–20 °C for 1–2 h. 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 mentioned in step (e) is sodium carbonate; The cyaniding reagent used in step (e) is trimethylcyanosilane; In step (e), the molar ratio of intermediate compound 5 to the cyaniding agent is 1:(1-2); In step (e), the molar ratio of intermediate compound 5 to the base is 1:(1-2); The cyanidation reaction in step (e) is carried out at a temperature of 70-80°C for 11-13 hours. 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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