Process for the preparation of molindone and key intermediates

Abstract

The application discloses a preparation method and a key intermediate of momelotinib and belongs to the technical field of medicinal chemistry.The application discloses a preparation method and a key intermediate of momelotinib, which comprises the following steps: taking methyl 4-acetylbenzoate as a starting material, performing condensation and one-pot reaction with urea to construct a pyrimidine ring to obtain a key intermediate 4-(2-hydroxypyrimidine-4-yl)benzoic acid, performing chlorination and nucleophilic substitution reaction, and finally performing coupling with 4-morpholinyl aniline to obtain momelotinib.The raw materials and reagents in the synthetic route are cheap and easy to obtain, the use of expensive metal catalysts and column chromatography purification is avoided, the amide is prepared after the carboxyl group is converted into acyl chloride, the use of condensing agents is avoided, and the method is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of a midbody of moluatinib and moluatinib. BACKGROUND

[0002] Myelofibrosis is a myeloproliferative neoplasm characterized by splenomegaly, debilitating fatigue, and bone marrow failure. Disease-related anemia is also common and contributes to reduced quality of life and survival in patients with myelofibrosis. However, few therapies exist to improve anemia in patients with myelofibrosis. Moluatinib is a JAK1 / 2 selective inhibitor developed by biopharmaceutical company Sierra Oncology for the treatment of MF, which can not only treat myelofibrosis, but also antagonize ACVR1, leading to down-regulation of hepcidin expression, increasing the availability of iron required for erythropoiesis, and improving anemia symptoms in patients with myelofibrosis.

[0003] The chemical name of moluatinib is N-(cyanomethyl)-4-{2-[(4-morpholinophenylamino)pyrimidin-4-yl]}benzamide, and its structural formula is:

[0004]

[0005] Patent US 8486941 B2 reports that 4-ethoxycarbonylphenylboronic acid and 2,4-dichloropyrimidine are used as starting materials, and a Suzuki coupling reaction occurs under the catalysis of tetrakis(triphenylphosphine)palladium to obtain ethyl 4-(2-chloropyrimidin-4-yl)benzoate, followed by C-N coupling reaction with 4-morpholinyl aniline catalyzed by p-toluenesulfonic acid monohydrate to obtain ethyl 4-[2-(4-morpholinylphenylamino)pyrimidin-4-yl]benzoate, and then ester hydrolysis under the condition of LiOH to obtain 4-[2-(4-morpholinylphenylamino)pyrimidin-4-yl]benzoic acid, and finally condensation with aminoacetonitrile under the action of EDCI and HOBt to obtain moluatinib.

[0006]

[0007] Patent WO 2009029998 reports that 4-carboxyphenylboronic acid is used as a starting material, and chlorination reaction with oxalyl chloride to obtain [4-(chlorocarbonyl)phenyl]boronic acid, followed by condensation reaction with aminoacetonitrile to obtain {4-[(cyanomethyl)aminocarbonyl]phenyl}boronic acid, and then Suzuki coupling reaction with 2,4-dichloropyrimidine under the catalysis of tetrakis(triphenylphosphine)palladium to obtain N-(cyanomethyl)-4-(2-chloropyrimidin-4-yl)benzamide, and finally C-N coupling reaction with 4-morpholinyl aniline catalyzed by p-toluenesulfonic acid monohydrate to obtain moluatinib.

[0008]

[0009] Both routes use substituted phenylboronic acid to react with dichloropyrimidine by Suzuki coupling reaction. The leaving group of Suzuki coupling reaction in both routes is borate anion, which has poor leaving ability. The starting material cannot be completely reacted, so it needs to be purified and separated by column chromatography. This reaction is carried out under heavy metal catalysis, which is easy to produce by-product pyrimidine derivatives, has low yield, high price of heavy metal, easy to pollute the environment, strict operation conditions, and is difficult to remove.

[0010] Patent CN105837515 A reports that methyl 4-acetylbenzoate is used as the starting material to condense with DMF-DMA to obtain methyl 4-{[(2E)-3-dimethylamino-acryloyl]} benzoate; 4-morpholinyl aniline is used as the starting material to react with 50% cyanamide aqueous solution and concentrated hydrochloric acid to obtain 1-(4-morpholinyl phenyl) guanidine. Then, cyclization reaction occurs under NaOH condition, followed by hydrolysis under LiOH condition, and finally condensation with aminoacetonitrile under the action of EDCI and HOBt to obtain moluatinib.

[0011]

[0012] Patent CN108707119 A2 uses 4-acetylbenzoic acid as the starting material to condense with aminoacetonitrile under the action of EDCI and HOBt to obtain N-(cyanomethyl)-4-acetylbenzamide, and then condenses with DMF-DMA to obtain N-(cyanomethyl)-4-[3-(dimethylamino) acryloyl] benzamide; p-chloronitrobenzene is used as the starting material to react with morpholine to obtain 4-(4-nitrophenyl) morpholine, which is then reduced by iron powder and dilute hydrochloric acid, and then reacts with cyanamide, and finally cyclizes to obtain moluatinib.

[0013]

[0014] The above two routes use toxic amino cyanide as the starting material, which is easy to polymerize, and is not suitable for mass production.

[0015] Du Shimei, et al. (Synthesis of JAK1 / 2 inhibitor momelotinib [J]. Chinese Journal of Medicinal Chemistry, 2019, 29(02): 131-134) used 4-methylphenylboronic acid as the starting material, and KMnO4 oxidation to obtain the intermediate p-carboxyphenylboronic acid, then esterification with pinacol to obtain the intermediate 4-carboxyphenylboronic acid pinacol ester, then Suzuki coupling reaction with 2,4-dichloropyrimidine under the catalysis of bis-triphenylphosphine palladium dichloride to obtain 4-(2-chloropyrimidin-4-yl)benzoic acid, then condensation with aminoacetonitrile under the action of CDI to obtain N-(cyanomethyl)-4-(2-chloropyrimidin-4-yl)benzamide. With p-fluoronitrobenzene as the raw material, nucleophilic substitution with morpholine and then reduction with Pd-C / H2 to obtain 4-morpholinyl aniline, and finally C-N coupling reaction in the presence of trifluoroacetic acid to obtain momelotinib.

[0016]

[0017] This route involves Suzuki coupling reaction of p-carboxyphenylboronic acid in the form of phenylboronic acid ester, which needs to use bis-triphenylphosphine palladium dichloride heavy metal catalyst, and the cost is high. SUMMARY

[0018] The purpose of the present application is to provide a method for preparing momelotinib and its intermediates, which is environment-friendly, low-cost, simple to operate and suitable for industrial production. The main raw materials involved are 4-morpholinyl aniline, methyl 4-acetylbenzoate, urea, N,N-dimethylformamide dimethyl acetal (DMF-DMA) and aminoacetonitrile hydrochloride, all of which are inexpensive and readily available starting materials. The reaction conditions of each step are mild, avoiding the use of expensive metal catalysts, condensing agents and column chromatography purification, greatly reducing the production cost.

[0019] The present application is realized by the following technical solutions:

[0020]

[0021] The preparation method of the momelotinib specifically comprises the following process steps:

[0022] (1) The raw material methyl 4-acetylbenzoate (compound 2) is reacted with DMF-DMA to prepare methyl 4-{[(2E)-3-dimethylamino-acryloyl]}benzoate (intermediate 3);

[0023] (2) Methyl 4-{[(2E)-3-dimethylamino-acryloyl]}benzoate (intermediate 3) is reacted with urea to generate (Z)-methyl 4-(3-ureidoacryloyl)benzoate (intermediate 4);

[0024] (3) Methyl (Z)-4-(3-ureidoacryloyl)benzoate (Intermediate 4) is reacted with a base to give 4-(2-hydroxypyrimidin-4-yl)benzoic acid (Intermediate 5);

[0025] (4) 4-(2-hydroxypyrimidin-4-yl)benzoic acid (Intermediate 5) is reacted with a halogenating reagent to give 4-(2-chloropyrimidin-4-yl)benzoyl chloride (Intermediate 6);

[0026] (5) 4-(2-chloropyrimidin-4-yl)benzoyl chloride (Intermediate 6) is reacted with aminoacetonitrile hydrochloride to give N-(cyanomethyl)-4-(2-chloropyrimidin-4-yl)benzamide (Intermediate 7);

[0027] (6) N-(cyanomethyl)-4-(2-chloropyrimidin-4-yl)benzamide (Intermediate 7) is reacted with 4-morpholinyl aniline to give the target product, moluatinib.

[0028] In the step (1), the molar ratio of methyl 4-acetylbenzoate to DMF-DMA is 1:1-1:5, preferably 1:2-1:4. The solvent used is methanol, ethanol, water, dichloromethane, tetrahydrofuran, benzene, toluene, xylene, formic acid, acetic acid or acetonitrile. The reaction time is 1-18 h, preferably 1-4 h. The reaction temperature is 40-120 °C, preferably 60-120 °C.

[0029] In the step (2), the catalyst is methanesulfonic acid, hydrochloric acid, sulfuric acid or acetic acid. The reaction solvent is ethanol, methanol, water, acetonitrile, DMF, toluene, xylene, dichloromethane or tetrahydrofuran.

[0030] In the step (2), the molar ratio of methyl 4-{[(2E)-3-dimethylamino-acryloyl]}benzoate (Intermediate 3) to urea is 1:1-1:5, preferably 1:1-1:3. The molar ratio of methyl 4-{[(2E)-3-dimethylamino-acryloyl]}benzoate (Intermediate 3) to catalyst is 1:1-1:5, preferably 1:1-1:3. The reaction time is 5-11 h, preferably 8-10 h. The reaction temperature is 30-90 °C, preferably 50-80 °C.

[0031] In the step (3), the reaction reagent base is sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, sodium bicarbonate, triethylamine, pyridine, diisopropylethylamine, sodium hydroxide or potassium hydroxide. The molar ratio of (Z)-methyl 4-(3-ureidoacryloyl)benzoate (Intermediate 4) to base is 1:1-1:5. The reaction solvent is methanol, ethanol, n-butanol, isopropanol, water, dichloromethane, tetrahydrofuran, benzene, toluene or DMF. The reaction time is 2-10 h, preferably 3-5 h. The reaction temperature is 40-150 °C, preferably 80-120 °C.

[0032] In the step (4), the halogenating reagent is phosphorus oxychloride, dichlorosulfoxide, phosphorus trichloride, phosphorus pentachloride or oxalyl chloride, preferably dichlorosulfoxide. The molar ratio of 4-(2-hydroxypyrimidin-4-yl)benzoic acid (intermediate 5) to the halogenating reagent is 1:2-1:15, preferably 1:4-1:10. The reaction solvent is dichloromethane, tetrahydrofuran, benzene, toluene or DMF. The reaction time is 1-6 h, preferably 2-4 h. The reaction temperature is 40-180℃.

[0033] In the step (5), the reaction solvent is dichloromethane, trichloromethane, tetrahydrofuran, benzene, toluene or DMF.

[0034] In the step (6), the catalyst used is methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid or p-toluenesulfonic acid monohydrate. The reaction solvent is acetonitrile, 1,4-dioxane, dichloromethane, trichloromethane, tetrahydrofuran, benzene, toluene or DMF.

[0035] In the step (6), the molar ratio of N-(cyanomethyl)-4-(2-chloropyrimidin-4-yl)benzamide (intermediate 7) to 4-morpholinyl aniline is 1:1-1:5. The reaction time is 8-24 h, preferably 12-18 h. The reaction temperature is 20-150℃, preferably 40-90℃.

[0036] Advantages of the present application:

[0037] (1) The present application uses more common 4-morpholinyl aniline, methyl 4-acetylbenzoate, urea, N,N-dimethylformamide dimethyl acetal (DMF-DMA), aminoacetonitrile hydrochloride, etc. as raw materials, and the reaction conditions of each step are mild.

[0038] (2) The synthesis method of the present application has simple process steps, strong controllability, does not need complicated reactions and subsequent treatment processes, high yield, low cost, high product purity, and is suitable for industrial production.

[0039] (3) The present application uses a new method to prepare moluatin intermediates 5, 6 and 7, and then synthesizes moluatin. Intermediate 3 and urea are reacted by "one-pot method" to construct a pyrimidine ring to synthesize the key intermediate 5, avoiding the use of expensive metal catalysts such as tetrakis(triphenylphosphine)palladium, reducing cost and pollution. This step does not need the column chromatography step in the original route, simplifying the operation and being suitable for large-scale production. The carboxyl group of intermediate 5 is first converted into acyl chloride intermediate 6, and then into amide intermediate 7, avoiding the use of condensing agents such as EDCI and HOBt, reducing the production cost. DETAILED DESCRIPTION

[0040] The present application will be further described below in conjunction with examples, but is not limited thereto.

[0041] Example 1

[0042] Preparation of methyl 4-{[(2E)-3-dimethylamino-acryloyl]} benzoate (Intermediate 3)

[0043] Into a 250 mL round flask, methyl 4-acetylbenzoate 15.00 g (84.24 mmol), N,N-dimethylformamide dimethyl acetal 20.01 g (0.17 mol) and toluene 40 mL were added in turn, and refluxed for 2 h. The reaction solution was slowly cooled to room temperature with stirring, and a large amount of solid was precipitated and filtered. The filter cake was dried to give a yellowish solid 17.5 g, with a yield of 89.5%. m.p. 168-169 °C, ESI-MS m / z: 234.1 [M+H] + , 256.1 [M+Na] + , 1 H-NMR (600 MHz, Chloroform-d) δ (ppm): 8.05 (d, J = 8.3 Hz, 2H), 7.91 (d, J = 8.3 Hz, 2H), 7.80 (d, J = 12.3 Hz, 1H), 5.68 (d, J = 12.3 Hz, 1H), 3.91 (s, 3H), 3.14 (s, 3H), 2.92 (s, 3H).

[0044] Example 2

[0045] Preparation of methyl (Z)-4-(3-ureidoacryloyl)benzoate (Intermediate 4)

[0046] Into a 250 mL three-necked flask, methyl 4-{[(2E)-3-dimethylamino-acryloyl]} benzoate 10.00 g (42.90 mmol), urea 6.18 g (102.96 mmol), concentrated hydrochloric acid 10.04 mL (120.12 mmol) and anhydrous ethanol 100 mL were added in turn, and refluxed for 10 h. The reaction solution was cooled to room temperature, filtered, and the filter cake was dried to give a white solid 9.18 g, with a yield of 86.3%. m.p. 216-217 °C, ESI-MS m / z: 271.0 [M+Na] + , 246.8 [M-H] - , 1 H-NMR (600 MHz, DMSO-d6) δ (ppm): 11.11 (d, J = 11.9 Hz, 1H), 8.06 (s, 4H), 7.64 (dd, J = 11.9, 8.6 Hz, 1H,), 7.49 (s, 1H), 6.98 (s, 1H), 6.24 (d, J = 8.7 Hz, 1H), 3.88 (s, 3H).

[0047] Example 3

[0048] Preparation of 4-(2-hydroxypyrimidin-4-yl)benzoic acid (Intermediate 5)

[0049] Into a 100 mL flask, sequentially added (Z)-methyl 4-(3-ureidoacryloyl)benzoate 5.00 g (20.15 mmol), NaOH 2.42 g (60.46 mmol) and n-butanol 30 mL, refluxed for 3 h, and then cooled to room temperature. The reaction solution was adjusted to pH 2-3 with hydrochloric acid, stirred for 15 min, and a large amount of solid was precipitated and filtered. The filter cake was washed with water (10 mL x 3) and dried to obtain white solid 3.60 g, with a yield of 82.7%. ESI-MS m / z: 216.96 [M+H] -1 The pH was adjusted to 2-3 with hydrochloric acid, stirred for 15 min, and a large amount of solid was precipitated and filtered. The filter cake was washed with water (10 mL x 3) and dried to obtain white solid 3.60 g, with a yield of 82.7%. ESI-MS m / z: 216.96 [M+H] + , 1 H-NMR (600MHz, DMSO-d6) δ (ppm): 12.70 (s, 2H), 8.20 (d, J = 8.4 Hz, 2H), 8.11 (d, J = 6.5 Hz, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 6.5 Hz, 1H).

[0050] Example 4

[0051] Preparation of 4-(2-chloropyrimidin-4-yl)benzoyl chloride (Intermediate 6)

[0052] Into a 100 mL flask, sequentially added 4-(2-hydroxypyrimidin-4-yl)benzoic acid 5.00 g (23.14 mmol), thionyl chloride 8.4 mL (0.11 mol) and 10 mL DMF, refluxed for 2 h, and then concentrated under reduced pressure to obtain yellow solid 5.33 g, with a yield of 91.4%. Without purification, it was directly used in the next step.

[0053] Example 5

[0054] Preparation of N-(cyanomethyl)-4-(2-chloropyrimidin-4-yl)benzamide (Intermediate 7)

[0055] Into a 100 mL single-neck flask, 2.15 g (23.27 mmol) of aminoacetonitrile hydrochloride, 10 mL of anhydrous dichloromethane, 7.3 mL (52.88 mmol) of triethylamine, 5.33 g (21.15 mmol) of 4-(2-chloropyrimidin-4-yl)benzoyl chloride were sequentially added, and the reaction was refluxed for 3 h. To the reaction liquid, 50 mL of water was added, the organic phase was collected, the aqueous phase was extracted with dichloromethane (20 mL x 2), the combined organic phase was washed once with saturated sodium bicarbonate aqueous solution, water, and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, the drying agent was removed, and the filtrate was concentrated under reduced pressure to obtain 5.25 g of a yellowish solid with a yield of 91.3%. m.p. 180-181 °C, ESI-MS m / z: 271.0 [M-H] - , 1 H-NMR (600 MHz, DMSO-d6) δ (ppm): 9.42 (t, J = 5.5 Hz, 1H), 8.88 (d, J = 5.3 Hz, 1H), 8.32 (d, J = 8.2 Hz, 2H), 8.23 (d, J = 5.3 Hz, 1H), 8.05 (d, J = 8.2 Hz, 2H), 4.36 (d, J = 5.4 Hz, 2H).

[0056] Example 6

[0057] Preparation of Mubritinib

[0058] Into a 100 mL single-neck flask, 2.15 g (23.27 mmol) of aminoacetonitrile hydrochloride, 10 mL of anhydrous dichloromethane, 7.3 mL (52.88 mmol) of triethylamine, 5.33 g (21.15 mmol) of 4-(2-chloropyrimidin-4-yl)benzoyl chloride were sequentially added, and the reaction was refluxed for 3 h. To the reaction liquid, 50 mL of water was added, the organic phase was collected, the aqueous phase was extracted with dichloromethane (20 mL x 2), the combined organic phase was washed once with saturated sodium bicarbonate aqueous solution, water, and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, the drying agent was removed, and the filtrate was concentrated under reduced pressure to obtain 5.25 g of a yellowish solid with a yield of 91.3%. m.p. 180-181 °C, ESI-MS m / z: 271.0 [M-H] -1 The pH was adjusted to 5-6 with hydrochloric acid, and the organic phase was discarded. The aqueous phase was adjusted to pH 9-10 with saturated potassium carbonate solution, extracted with dichloromethane, the combined organic phase was washed once with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, the drying agent was removed, and the filtrate was concentrated under reduced pressure to obtain 6.12 g of a yellow solid with a yield of 80.4%. ESI-MS m / z: 415.19 [M+H] + , 1H-NMR (600 MHz, DMSO-d6) δ (ppm): 9.54 (s, 1H), 9.40 (t, J = 5.5 Hz, 1H), 8.53 (d, J = 5.1 Hz, 1H), 8.27 (d, J = 8.2 Hz, 2H), 8.04 (d, J = 8.3 Hz, 2H), 7.67 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 5.1 Hz, 1H), 6.93 (d, J = 8.5 Hz, 2H), 4.37 (d, J = 5.4 Hz, 2H), 3.74 (t, J = 4.7 Hz, 4H), 3.04 (t, J = 4.7 Hz, 4H). 13 C NMR (151 MHz, DMSO-d6) δ (ppm): 166.15, 162.46, 160.36, 159.28, 146.47, 139.98, 134.55, 132.93, 127.94, 126.97, 120.36, 117.64, 115.69, 107.66, 66.36, 49.32, 27.80.

[0059] Example 7

[0060] A preparation method of Moluotin and a key intermediate involved, comprising the following steps:

[0061] (1) 4-acetyl benzoic acid methyl ester (intermediate 2) is reacted with DMF-DMA at 60°C for 1h to prepare 4-{[(2E)-3-dimethylamino-acryloyl]} benzoic acid methyl ester (intermediate 3); compared with Example 1, the molar ratio of 4-acetyl benzoic acid methyl ester (intermediate 2): DMF-DMA is 1:2; the solvent used is dichloromethane.

[0062] (2) The prepared 4-{[(2E)-3-dimethylamino-acryloyl]} benzoic acid methyl ester (intermediate 3) is reacted with urea at 50°C for 10h to generate (Z)-4-(3-ureidoacryloyl) benzoic acid methyl ester (intermediate 4); compared with Example 1, the molar ratio of (Z)-4-(3-ureidoacryloyl) benzoic acid methyl ester (intermediate 4): urea is 1:1.2; the solvent used is methanol, and the catalyst used is acetic acid.

[0063] (3) The prepared (Z)-4-(3-ureidoacryloyl) benzoic acid methyl ester (intermediate 4) is reacted with sodium hydroxide at 110°C for 4h to obtain 4-(2-hydroxy-pyrimidin-4-yl) benzoic acid (intermediate 5); compared with Example 1, the molar ratio of (Z)-4-(3-ureidoacryloyl) benzoic acid methyl ester (intermediate 4): sodium hydroxide is 1:1.2; the solvent used is toluene.

[0064] (4) The prepared 4-(2-hydroxypyrimidin-4-yl)benzoic acid (Intermediate 5) was reacted with oxalyl chloride at 40 °C for 2 h to form 4-(2-chloropyrimidin-4-yl)benzoyl chloride (Intermediate 6); compared with Example 1, the molar ratio of 4-(2-hydroxypyrimidin-4-yl)benzoic acid (Intermediate 5) to oxalyl chloride was 1:5; the solvent used was dichloromethane.

[0065] (5) The prepared 4-(2-chloropyrimidin-4-yl)benzoyl chloride (Intermediate 6) was reacted with aminoacetonitrile hydrochloride at 60 °C for 1 h to form N-(cyanomethyl)-4-(2-chloropyrimidin-4-yl)benzamide (Intermediate 7); compared with Example 1, the solvent used was chloroform.

[0066] (6) The prepared N-(cyanomethyl)-4-(2-chloropyrimidin-4-yl)benzamide (Intermediate 7) was reacted with 4-morpholinyl aniline at 50 °C for 12 h to form the target product, moluatinib. Compared with Example 1, the molar ratio of N-(cyanomethyl)-4-(2-chloropyrimidin-4-yl)benzamide (Intermediate 7) to 4-morpholinyl aniline was 1:1.6; the solvent used was tetrahydrofuran, and the catalyst was methanesulfonic acid.

[0067] Example 8

[0068] A method for preparing moluatinib and the key intermediates involved, comprising the following steps:

[0069] (1) Methyl 4-acetylbenzoate (Intermediate 2) was refluxed with DMF-DMA in xylene for 2 h to prepare methyl 4-{[(2E)-3-dimethylamino-acryloyl]}benzoate (Intermediate 3); the molar ratio of methyl 4-acetylbenzoate (Intermediate 2) to DMF-DMA was 1:4; the solvent used was xylene.

[0070] (2) Methyl 4-{[(2E)-3-dimethylamino-acryloyl]}benzoate (Intermediate 3) generated in step (1) was reacted with urea at 80 °C for 8 h to form (Z)-methyl 4-(3-ureidoacryloyl)benzoate (Intermediate 4); the molar ratio of methyl 4-{[(2E)-3-dimethylamino-acryloyl]}benzoate (Intermediate 3) to urea was 1:1.3; the solvent used was DMF, and the catalyst used was sulfuric acid.

[0071] (3) (Z)-methyl 4-(3-ureidoacryloyl)benzoate (Intermediate 4) generated in step (2) was reacted with potassium hydroxide at 100 °C for 5 h to obtain 4-(2-hydroxypyrimidin-4-yl)benzoic acid (Intermediate 5); the molar ratio of (Z)-methyl 4-(3-ureidoacryloyl)benzoate (Intermediate 4) to sodium hydroxide was 1:1.2; the solvent used was water.

[0072] (4) 4-(2-hydroxy pyrimidin-4-yl) benzoic acid (Intermediate 5) generated in step (3) was reacted with phosphorus oxychloride at 60 °C for 4 h to generate 4-(2-chloro pyrimidin-4-yl) benzoyl chloride (Intermediate 6); molar ratio of 4-(2-hydroxy pyrimidin-4-yl) benzoic acid (Intermediate 5) : phosphorus oxychloride = 1 : 4; solvent: tetrahydrofuran.

[0073] (5) 4-(2-chloro pyrimidin-4-yl) benzoyl chloride (Intermediate 6) generated in step (4) was reacted with aminoacetonitrile hydrochloride at 50 °C for 2 h to generate N-(cyanomethyl)-4-(2-chloro pyrimidin-4-yl) benzamide (Intermediate 7); solvent: DMF.

[0074] (6) N-(cyanomethyl)-4-(2-chloro pyrimidin-4-yl) benzamide (Intermediate 7) generated in step (5) was reacted with 4-morpholinyl aniline at 80 °C for 14 h to generate the target product, moluatinib. Molar ratio of N-(cyanomethyl)-4-(2-chloro pyrimidin-4-yl) benzamide (Intermediate 7) : 4-morpholinyl aniline = 1 : 1.3; solvent: toluene; catalyst: trifluoroacetic acid.

[0075] The above examples are only to illustrate the technical concept and characteristics of the present application, and cannot limit the protection scope of the present application. Any equivalent changes or modifications made according to the spirit and essence of the present application shall be covered within the protection scope of the present application.

Claims

1. A method for preparing molotinib, comprising the following steps: (1) Methyl 4-{[(2E)-3-dimethylamino-acryloyl]}benzoate was prepared by reacting the raw material methyl 4-acetylbenzoate with DMF-DMA; (2) Methyl 4-{[(2E)-3-dimethylamino-acryloyl]}benzoate is reacted with urea to generate (Z)-4-(3-ureidoacryloyl)benzoate; the catalyst used in the reaction is methanesulfonic acid, hydrochloric acid, sulfuric acid or acetic acid; (3) Methyl (Z)-4-(3-ureidoacryloyl)benzoate reacts with a base to obtain 4-(2-hydroxypyrimidin-4-yl)benzoic acid; the base of the reaction reagent is sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, sodium bicarbonate, triethylamine, pyridine, diisopropylethylamine, sodium hydroxide or potassium hydroxide; (4) 4-(2-hydroxypyrimidin-4-yl)benzoic acid is reacted with a halogenating agent to generate 4-(2-chloropyrimidin-4-yl)benzoyl chloride; wherein the halogenating agent is phosphorus oxychloride, sulfoxide, phosphorus trichloride, phosphorus pentachloride or oxalyl chloride; (5) Reacting 4-(2-chloropyrimidin-4-yl)benzoyl chloride with aminoacetonitrile hydrochloride to generate N-(cyanomethyl)-4-(2-chloropyrimidin-4-yl)benzamide; (6) Reaction of N-(cyanomethyl)-4-(2-chloropyrimidin-4-yl)benzamide with 4-morpholinoaniline to generate the target product molotinib; the catalyst used in the reaction is methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid or p-toluenesulfonic acid monohydrate; The reaction route is as follows: 。 2. The method for preparing molotinib according to claim 1, characterized in that, In step (1), the molar ratio of methyl 4-acetylbenzoate to DMF-DMA is 1:1 to 1:5; the solvent used is methanol, ethanol, water, dichloromethane, tetrahydrofuran, benzene, toluene, xylene, formic acid, acetic acid, or acetonitrile; the reaction time is 1 to 18 hours; and the reaction temperature is 40 to 120°C.

3. The method for preparing molotinib according to claim 1, characterized in that, In step (2), the reaction solvent is ethanol, methanol, water, acetonitrile, DMF, toluene, xylene, dichloromethane, or tetrahydrofuran; the molar ratio of methyl 4-{[(2E)-3-dimethylamino-acryloyl]}benzoate to urea is 1:1 to 1:5; the molar ratio of methyl 4-{[(2E)-3-dimethylamino-acryloyl]}benzoate to catalyst is 1:1 to 1:5; the reaction time is 5 to 11 hours; and the reaction temperature is 30 to 90 degrees Celsius.

4. The method for preparing molotinib according to claim 1, characterized in that, In step (3), the molar ratio of (Z)-4-(3-ureidoacryloyl)benzoate to alkali is 1:1-1:5; the reaction solvent is methanol, ethanol, n-butanol, isopropanol, water, dichloromethane, tetrahydrofuran, benzene, toluene or DMF; the reaction time is 2-10 h; and the reaction temperature is 40-150 °C.

5. The method for preparing molotinib according to claim 1, characterized in that, In step (4), the molar ratio of 4-(2-hydroxypyrimidin-4-yl)benzoic acid to the halogenated reagent is 1:2 to 1:15; the reaction solvent is dichloromethane, tetrahydrofuran, benzene, toluene or DMF; the reaction time is 1 to 6 h; and the reaction temperature is 40 to 180 °C.

6. The method for preparing molotinib according to claim 1, characterized in that, In step (5), the reaction solvent is dichloromethane, trichloromethane, tetrahydrofuran, benzene, toluene, or DMF; in step (6), the reaction solvent is acetonitrile, 1,4-dioxane, dichloromethane, trichloromethane, tetrahydrofuran, benzene, toluene, or DMF.

7. The method for preparing molotinib according to claim 1, characterized in that, In step (6), the molar ratio of N-(cyanomethyl)-4-(2-chloropyrimidin-4-yl)benzamide to 4-morpholinoaniline is 1:1 to 1:5; the reaction time is 8 to 24 h; and the reaction temperature is 20 to 100 °C.

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