Preparation method of molotinib and key intermediate

Abstract

The invention relates to a preparation method of molotinib and a key intermediate, belongs to the technical field of medicinal chemistry, and discloses a preparation method of molotinib and a key intermediate, and the preparation method comprises the following steps: taking methyl 4-acetylbenzoate as an initial raw material, and carrying out a reaction at the temperature of 60-80 DEG C for 1-2 hours to obtain the molotinib. The preparation method comprises the following steps: carrying out condensation and one-pot reaction with urea to construct a pyrimidine ring to obtain a key intermediate 4-(2-hydroxypyrimidine-4-yl) benzoic acid, carrying out chlorination and nucleophilic substitution reaction, and finally coupling with 4-morpholinyl aniline to obtain the molotinib. The raw materials and reagents in the synthesis route are cheap and easily available, an expensive metal catalyst and column chromatography purification are avoided, the amide is prepared after carboxyl is converted into acyl chloride, the use of a condensing agent is avoided, and the method is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a molotinib intermediate and a method for preparing molotinib. Background Art

[0002] Myelofibrosis is a myeloproliferative neoplasm characterized by splenomegaly, weakness, and bone marrow failure. Disease-related anemia is also common and can lead to reduced quality of life and survival in patients with myelofibrosis. However, there are few therapies to improve anemia in patients with myelofibrosis. Molotinib is a JAK1 / 2 selective inhibitor developed by the biopharmaceutical company Sierra Oncology for the treatment of MF. It can not only treat myelofibrosis, but also antagonize ACVR1, leading to downregulation of hepcidin expression, increasing the utilization of iron required for erythropoiesis, and improving anemia symptoms in patients with myelofibrosis.

[0003] The chemical name of molotinib 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 is carried out under the catalysis of tetrakis(triphenylphosphine)palladium to obtain ethyl 4-(2-chloropyrimidin-4-yl)benzoate, which is then subjected to a CN coupling reaction with 4-morpholinoaniline under the catalysis of p-toluenesulfonic acid monohydrate to obtain ethyl 4-[2-(4-morpholinophenylamino)pyrimidin-4-yl]benzoate, and then the ester is hydrolyzed under LiOH conditions to obtain 4-[2-(4-morpholinophenylamino)pyrimidin-4-yl]benzoic acid, which is finally condensed with aminoacetonitrile under the action of EDCI and HOBt to obtain molotinib.

[0006]

[0007] Patent WO 2009029998 reports that 4-carboxyphenylboronic acid is used as a starting material, and undergoes a chlorination reaction with oxalyl chloride to obtain [4-(chlorocarbonyl)phenyl]boric acid, which is then subjected to a condensation reaction with aminoacetonitrile to obtain {4-[(cyanomethyl)carbamoyl]phenyl}boric acid, which is then subjected to a 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 subjected to a CN coupling reaction with 4-morpholinoaniline under the catalysis of p-toluenesulfonic acid monohydrate to obtain molotinib.

[0008]

[0009] The above two routes both use substituted phenylboronic acid and dichloropyrimidine to undergo Suzuki coupling reaction. The leaving groups of the Suzuki coupling reaction of the two routes are all borate anions, which have poor leaving ability and the raw materials cannot react completely, so they need to be purified and separated by column chromatography. In addition, this reaction is easy to obtain by-product pyrimidine derivatives under heavy metal catalysis, with low yield, high heavy metal prices, easy to pollute the environment, strict operating conditions, and difficult to remove.

[0010] Patent CN105837515 A reports that 4-acetylbenzoic acid methyl ester is used as the starting material, and 4-{[(2E)-3-dimethylamino-acryloyl]}benzoic acid methyl ester is obtained by condensation with DMF-DMA; 4-morpholinoaniline is used as the raw material, and 50% cyanamide aqueous solution and concentrated hydrochloric acid are reacted to obtain 1-(4-morpholinophenyl)guanidine. Then a cyclization reaction occurs under NaOH conditions, followed by hydrolysis under LiOH conditions, and finally condensation with aminoacetonitrile under the action of EDCI and HOBt to obtain molotinib.

[0011]

[0012] Patent CN108707119 A2 uses 4-acetylbenzoic acid as a starting material, and condenses it with aminoacetonitrile under the action of EDCI and HOBt to obtain N-(cyanomethyl)-4-acetylbenzamide, which is then condensed with DMF-DMA to obtain N-(cyanomethyl)-4-[3-(dimethylamino)acryloyl]benzamide; p-chloronitrobenzene is used as a raw material, and nucleophilic substitution with morpholine is performed to obtain 4-(4-nitrophenyl)morpholine, which is then reduced with iron powder and dilute hydrochloric acid, and then reacted with cyanamide, and finally cyclized to obtain molotinib.

[0013]

[0014] The above two routes use highly toxic amino nitrile as raw material, which is prone to polymerization and is not suitable for mass production.

[0015] Du Shimei et al. (Study on the 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, KMnO 4 Oxidation to obtain the intermediate p-carboxyphenylboronic acid, followed by esterification with pinacol to obtain the intermediate 4-carboxyphenylboronic acid pinacol ester, which then undergoes Suzuki coupling reaction with 2,4-dichloropyrimidine under the catalysis of bistriphenylphosphine palladium dichloride to obtain 4-(2-chloropyrimidin-4-yl)benzoic acid, which is then condensed with aminoacetonitrile under the action of CDI to obtain N-(cyanomethyl)-4-(2-chloropyrimidin-4-yl)benzamide. Using p-fluoronitrobenzene as the raw material, it is nucleophilically substituted with morpholine and then subjected to Pd-C / H 2Reduction affords 4-morpholinoaniline, which is then subjected to a CN coupling reaction in the presence of trifluoroacetic acid to afford molotinib.

[0016]

[0017] This route involves p-carboxyphenylboronic acid in the form of phenylboronic acid ester in the Suzuki coupling reaction, which requires the use of a heavy metal catalyst of bistriphenylphosphine palladium dichloride, which is relatively expensive. Summary of the invention

[0018] The invention aims to provide a method for preparing molotinib and its intermediates which is environmentally friendly, low in cost, simple in operation and suitable for industrial production. The main raw materials involved are 4-morpholinoaniline, methyl 4-acetylbenzoate, urea, N,N-dimethylformamide dimethyl acetal (DMF-DMA) and aminoacetonitrile hydrochloride, which are all cheap and readily available starting raw materials. The reaction conditions of each step are mild, and the use of expensive metal catalysts, condensation agents and column chromatography purification is avoided, thereby greatly reducing the production cost.

[0019] The present invention is achieved through the following technical solutions:

[0020]

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

[0022] (1) reacting the raw material 4-acetylbenzoic acid methyl ester (compound 2) with DMF-DMA to prepare 4-{[(2E)-3-dimethylamino-acryloyl]}benzoic acid methyl ester (intermediate 3);

[0023] (2) reacting 4-{[(2E)-3-dimethylamino-acryloyl]}benzoic acid methyl ester (Intermediate 3) with urea to produce (Z)-4-(3-ureidoacryloyl)benzoic acid methyl ester (Intermediate 4);

[0024] (3) reacting (Z)-4-(3-ureidoacryloyl)benzoic acid methyl ester (intermediate 4) with a base to obtain 4-(2-hydroxypyrimidin-4-yl)benzoic acid (intermediate 5);

[0025] (4) reacting 4-(2-hydroxypyrimidin-4-yl)benzoic acid (intermediate 5) with a halogenating agent to generate 4-(2-chloropyrimidin-4-yl)benzoyl chloride (intermediate 6);

[0026] (5) reacting 4-(2-chloropyrimidin-4-yl)benzoyl chloride (Intermediate 6) with aminoacetonitrile hydrochloride to generate 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-morpholinoaniline to produce the target product molotinib.

[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 to 18 hours, preferably 1 to 4 hours. The reaction temperature is 40 to 120°C, preferably 60 to 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 to 1:5, preferably 1:1 to 1:3. The molar ratio of methyl 4-{[(2E)-3-dimethylamino-acryloyl]}benzoate (intermediate 3) to the catalyst is 1:1 to 1:5, preferably 1:1 to 1:3. The reaction time is 5 to 11 hours, preferably 8 to 10 hours. The reaction temperature is 30 to 90°C, preferably 50 to 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)-4-(3-ureidoacryloyl)benzoic acid methyl ester (intermediate 4) to the 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 to 10 hours, preferably 3 to 5 hours. The reaction temperature is 40 to 150°C, preferably 80 to 120°C.

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

[0033] In the step (5), the reaction solvent is dichloromethane, chloroform, 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, chloroform, 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-morpholinoaniline is 1:1 to 1:5. The reaction time is 8 to 24 hours, preferably 12 to 18 hours. The reaction temperature is 20 to 150°C, preferably 40 to 90°C.

[0036] Beneficial effects of the present invention:

[0037] (1) The present invention uses relatively common 4-morpholinoaniline, 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 invention has simple process steps, strong controllability, does not require complicated reactions and subsequent treatment processes, and has high yield, low cost, high product purity, and is suitable for industrial production.

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

[0040] The present invention will be further described below with reference to the embodiments, but is not limited thereto.

[0041] Example 1

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

[0043] In a 250 mL eggplant-shaped bottle, 15.00 g (84.24 mmol) of methyl 4-acetylbenzoate, 20.01 g (0.17 mol) of N,N-dimethylformamide dimethyl acetal and 40 mL of toluene were added in sequence, and refluxed for 2 h. The reaction solution was slowly cooled to room temperature under stirring, and a large amount of solid precipitated and filtered. After the filter cake was dried, 17.5 g of light yellow solid was obtained, with a yield of 89.5%. mp 168-169 ° C, ESI-MS m / z: 234.1 [M+H] + ,256.1[M+Na] + , 1 H-NMR (600MHz, Chloroform-d) δ (ppm): 8.05 (d, J = 8.3 Hz, 2H), 7.91 (d, J = 8.3 Hz, 2H), 7 .80(d,J=12.3Hz,1H),5.68(d,J=12.3Hz,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] In a 250mL three-necked flask, 10.00g (42.90mmol) of methyl 4-{[(2E)-3-dimethylamino-acryloyl]}benzoate, 6.18g (102.96mmol) of urea, 10.04mL (120.12mmol) of concentrated hydrochloric acid and 100mL of anhydrous ethanol were added to the reaction flask and refluxed for 10h. The reaction solution was cooled to room temperature, filtered, and the filter cake was dried to obtain 9.18g of a white solid with a yield of 86.3%. mp216-217℃, ESI-MS m / z:271.0[M+Na] + , 246.8[MH] - , 1 H-NMR (600 MHz, DMSO-d 6 )δ(ppm): 11.11(d,J=11.9Hz,1H),8.06(s,4H),7.64(dd,J=11.9,8.6Hz,1H,),7.49(s,1H),6.98(s,1H),6.24(d,J=8.7Hz,1H),3.88(s,3H).

[0047] Example 3

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

[0049] In a 100 mL eggplant-shaped bottle, 5.00 g (20.15 mmol) of methyl (Z)-4-(3-ureidoacryloyl)benzoate, 2.42 g (60.46 mmol) of NaOH and 30 mL of n-butanol were added in sequence and refluxed for 3 h. -1 Adjust the pH to 2-3 with hydrochloric acid, stir for 15 min, a large amount of solid precipitated and filter, wash the filter cake with water (10 mL x 3), and dry to obtain 3.60 g of white solid, with a yield of 82.7%. ESI-MS m / z: 216.96 [M+H] + , 1 H-NMR (600 MHz, DMSO-d 6 )δ (ppm): 12.70 (s, 2H), 8.20 (d, J = 8.4Hz, 2H), 8.11 (d, J = 6.5Hz, 1H), 8.06 (d, J = 8.4Hz, 2H), 7.05 (d, J = 6.5Hz, 1H).

[0050] Example 4

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

[0052] 5.00 g (23.14 mmol) of 4-(2-hydroxypyrimidin-4-yl)benzoic acid, 8.4 mL (0.11 mol) of dichlorothionyl, and 10 mL of DMF were added to a 100 mL eggplant-shaped bottle, refluxed for 2 h, and concentrated under reduced pressure to obtain 5.33 g of a yellow solid with a yield of 91.4%. The solid was used directly in the next step without purification.

[0053] Example 5

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

[0055] In a 100mL single-mouth bottle, 2.15g (23.27mmol) of aminoacetonitrile hydrochloride, 10mL of anhydrous dichloromethane, 7.3mL (52.88mmol) of triethylamine, and 5.33g (21.15mmol) of 4-(2-chloropyrimidin-4-yl)benzoyl chloride were added in sequence, and the mixture was refluxed for 3h. 50mL of water was added to the reaction solution, and the organic phase was collected. The aqueous phase was extracted with dichloromethane (20mL×2). The organic phases were combined, washed once with a saturated sodium bicarbonate aqueous solution, water, and a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the desiccant was removed. The filtrate was concentrated under reduced pressure to obtain 5.25g of a light yellow solid with a yield of 91.3%. mp180-181℃, ESI-MS m / z:271.0[MH] - , 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 molotinib

[0058] In a 100 mL eggplant-shaped bottle, 5.00 g (18.38 mmol) of N-(cyanomethyl)-4-(2-chloropyrimidin-4-yl)benzamide, 4.58 g (25.73 mmol) of 4-morpholinoaniline, 4.20 g (22.06 mmol) of p-toluenesulfonic acid monohydrate and 30 mL of acetonitrile were added in sequence and refluxed for 14 h. The reaction solution was poured into 100 mL of ice water and heated with 4 mol·L -1 Adjust the pH to 5-6 with hydrochloric acid, extract with ethyl acetate, discard the organic phase, adjust the pH of the aqueous phase to 9-10 with saturated potassium carbonate solution, extract with dichloromethane, combine the organic phases, wash once with water and saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, remove the desiccant, and concentrate the filtrate under reduced pressure to obtain 6.12 g of yellow solid, with a yield of 80.4%. ESI-MS m / z: 415.19 [M+H] + , 1 H-NMR (600 MHz, DMSO-d 6 )δ (ppm): 9.54 (s, 1H), 9.40 (t, J = 5.5Hz, 1H), 8.53 (d, J = 5.1Hz, 1H), 8.27 (d, J = 8.2Hz, 2H), 8.04 (d, J = 8.3Hz, 2H), 7.67 (d, J = 8.7Hz,2H),7.40(d,J=5.1Hz,1H),6.93(d,J=8.5Hz,2H),4.37(d,J=5.4Hz,2H),3.74(t,J=4.7Hz,4H),3.04(t,J=4.7Hz,4H). 13 C NMR (151 MHz, DMSO-d 6 )δ(ppm): 166.15,162.46,160.36,159.28,146.47,139.98,134.55,132.9 3,127.94,126.97,120.36,117.64,115.69,107.66,66.36,49.32,27.80.

[0059] Example 7

[0060] A method for preparing molotinib and the key intermediates involved, comprising the following steps:

[0061] (1) Methyl 4-acetylbenzoate (Intermediate 2) was reacted with DMF-DMA at 60° C. for 1 h to prepare methyl 4-{[(2E)-3-dimethylamino-acryloyl]}benzoate (Intermediate 3); compared with Example 1, the molar ratio of methyl 4-acetylbenzoate (Intermediate 2):DMF-DMA was 1:2; the solvent used was dichloromethane.

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

[0063] (3) The prepared (Z)-4-(3-ureidoacryloyl)benzoic acid methyl ester (intermediate 4) was reacted with sodium hydroxide at 110° C. for 4 h to obtain 4-(2-hydroxypyrimidin-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 = 1:1.2; the solvent used was 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 generate 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): oxalyl chloride = 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 generate 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-morpholinoaniline at 50° C. for 12 h to generate the target product, molotinib. Compared with Example 1, the molar ratio of N-(cyanomethyl)-4-(2-chloropyrimidin-4-yl)benzamide (intermediate 7):4-morpholinoaniline was 1:1.6; the solvent used was tetrahydrofuran, and the catalyst was methanesulfonic acid.

[0067] Example 8

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

[0069] (1) Methyl 4-acetylbenzoate (Intermediate 2) and DMF-DMA were refluxed 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):DMF-DMA=1:4; the solvent was xylene.

[0070] (2) reacting the 4-{[(2E)-3-dimethylamino-acryloyl]}benzoic acid methyl ester (intermediate 3) produced in step (1) with urea at 80° C. for 8 h to produce (Z)-4-(3-ureidoacryloyl)benzoic acid methyl ester (intermediate 4); the molar ratio of 4-{[(2E)-3-dimethylamino-acryloyl]}benzoic acid methyl ester (intermediate 3): urea = 1:1.3; the solvent is DMF and the catalyst is sulfuric acid.

[0071] (3) The (Z)-4-(3-ureidoacryloyl)benzoic acid methyl ester (intermediate 4) produced in step (2) is 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)-4-(3-ureidoacryloyl)benzoic acid methyl ester (intermediate 4) to sodium hydroxide is 1:1.2; and water is used as the solvent.

[0072] (4) The 4-(2-hydroxypyrimidin-4-yl)benzoic acid (intermediate 5) generated in step (3) is reacted with phosphorus oxychloride at 60° C. for 4 h to generate 4-(2-chloropyrimidin-4-yl)benzoyl chloride (intermediate 6); the molar ratio of 4-(2-hydroxypyrimidin-4-yl)benzoic acid (intermediate 5): phosphorus oxychloride = 1:4; the solvent is tetrahydrofuran.

[0073] (5) The 4-(2-chloropyrimidin-4-yl)benzoyl chloride (intermediate 6) generated in step (4) is reacted with aminoacetonitrile hydrochloride at 50° C. for 2 h to generate N-(cyanomethyl)-4-(2-chloropyrimidin-4-yl)benzamide (intermediate 7); DMF is used as the solvent.

[0074] (6) The N-(cyanomethyl)-4-(2-chloropyrimidin-4-yl)benzamide (intermediate 7) produced in step (5) is reacted with 4-morpholinoaniline at 80° C. for 14 h to produce the target product molotinib. The molar ratio of N-(cyanomethyl)-4-(2-chloropyrimidin-4-yl)benzamide (intermediate 7):4-morpholinoaniline is 1:1.3; the solvent is toluene, and the catalyst is trifluoroacetic acid.

[0075] The above embodiments are only for illustrating the technical concept and features of the present invention, and cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing molotinib, comprising the following steps: (1) reacting the raw material 4-acetylbenzoic acid methyl ester with DMF-DMA to prepare 4-{[(2E)-3-dimethylamino-acryloyl]}benzoic acid methyl ester; (2) reacting 4-{[(2E)-3-dimethylamino-acryloyl]}benzoic acid methyl ester with urea to produce (Z)-4-(3-ureidoacryloyl)benzoic acid methyl ester; (3) reacting (Z)-4-(3-ureidoacryloyl)benzoic acid methyl ester with a base to obtain 4-(2-hydroxypyrimidin-4-yl)benzoic acid; (4) reacting 4-(2-hydroxypyrimidin-4-yl)benzoic acid with a halogenating agent to generate 4-(2-chloropyrimidin-4-yl)benzoyl chloride; (5) reacting 4-(2-chloropyrimidin-4-yl)benzoyl chloride with aminoacetonitrile hydrochloride to generate N-(cyanomethyl)-4-(2-chloropyrimidin-4-yl)benzamide; (6) reacting N-(cyanomethyl)-4-(2-chloropyrimidin-4-yl)benzamide with 4-morpholinoaniline to produce the target product molotinib; The reaction route is:

2. The method for preparing molotinib according to claim 1, characterized in that: In the step (1), the molar ratio of methyl 4-acetylbenzoate to DMF-DMA is 1:1-1:5; 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 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; 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 the catalyst is 1:1 to 1:5; the reaction time is 5 to 11 hours; and the reaction temperature is 30 to 90°C.

4. The method for preparing molotinib according to claim 1, characterized in that: 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 feeding molar ratio of (Z)-4-(3-ureidoacryloyl)benzoic acid methyl ester to the 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 to 10 hours; and the reaction temperature is 40 to 150°C.

5. The method for preparing molotinib according to claim 1, characterized in that: In the step (4), the halogenating agent is phosphorus oxychloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride or oxalyl chloride; the molar ratio of 4-(2-hydroxypyrimidin-4-yl)benzoic acid to the halogenating agent is 1:2 to 1:15; the reaction solvent is dichloromethane, tetrahydrofuran, benzene, toluene or DMF; the reaction time is 1 to 6 hours; and the reaction temperature is 40 to 180°C.

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

7. The method for preparing molotinib according to claim 1, characterized in that: In the 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 hours; and the reaction temperature is 20 to 100°C.

8. The intermediate 5 obtained by the method for preparing molotinib according to any one of claims 1 to 7 9. The intermediate 6 obtained by the method for preparing molotinib according to any one of claims 1 to 7

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