Novel method for synthesizing besudil mesylate

Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to a synthesis method of besudil mesylate. The preparation method comprises the following steps: firstly, taking 2-chloroquinazoline-4-amine a as a raw material, sequentially carrying out nucleophilic substitution reaction with 5-bromoindazole b, carrying out Suzuki coupling reaction with 3-hydroxyphenylboronic acid d, carrying out Mitsunobu reaction with 2-hydroxy-N-isopropyl acetamide f, and finally carrying out salt forming reaction with methanesulfonic acid to prepare besudil mesylate. The main route is short, and compared with an existing route, the yield is higher, and industrial production is facilitated.

Description

Technical Field

[0001] The invention relates to a synthesis method of besudil mesylate, and belongs to the field of pharmaceutical chemistry. Background Art

[0002] Chronic graft-versus-host disease (cGVHD) is a type of post-transplantation complication, generally referring to a clinical pathological syndrome (including classic cGVHD and overlap syndrome) caused by lymphocytes from the donor attacking the recipient's organs during the process of reconstructing the donor's immunity after allogeneic hematopoietic stem cell transplantation (allo-HSCT). It is one of the main complications after transplantation, with an incidence rate of 30% to 70%. After the onset of the disease, patients show rejection symptoms of varying severity, which seriously affects the patient's health and quality of life after surgery, and even leads to death in severe cases.

[0003] Belumosudil Mesylate, the structure is as follows;

[0004] It is a small molecule drug used to treat chronic graft-versus-host disease (cGVHD). In 2021, Belumosudil Mesylate was developed by Kadmon, Inc. of the United States and approved by the FDA for use in adults and children aged 12 years and above with cGVHD.

[0005] The prior art has the following synthetic routes: Route 1: This route has been reported in WO 2006105081, WO 2008054599, WO2010104851 and WO 2012040499, specifically: .

[0006] This route has as many as ten reaction steps and uses more reagents. Moreover, due to the large number of reaction steps, the corresponding yield is lower.

[0007] Route 2: This route was reported in CN 101208094A: .

[0008] This route still has many steps, and the key step (compound 7 reacts with N-isopropyl-2-chloroacetamide to produce compound 8) has a low yield (45%). Summary of the invention

[0009] The invention provides a method for synthesizing besudil mesylate to solve the above defects of the prior art. The method has short reaction steps, uses fewer raw materials and reagents, and has the advantages of high yield, low cost, environmental friendliness, etc.

[0010] The technical solution of the present invention is as follows: a method for synthesizing besudil mesylate, characterized in that it comprises the following steps: (1) In an organic solvent, methyl glycolate reacts with isopropylamine to obtain 2-hydroxy-N-isopropylacetamide f; (2) In an organic solvent, 2-chloroquinazolin-4-amine a reacts with 5-bromoindazole b to obtain 2-chloro-N-(1H-indazol-5-yl)quinazolin-4-amine c; (3) In an organic solvent, 2-chloro-N-(1H-indazol-5-yl)quinazolin-4-amine c is coupled with 3-hydroxyphenylboronic acid d to obtain 3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenol e; (4) In an organic solvent, 3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenol e and 2-hydroxy-N-isopropylacetamide f are reacted by Mitsunobu reaction to obtain 2-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide g; (5) In an organic solvent, 2-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide g is reacted with methanesulfonic acid to form a salt to obtain besudil mesylate.

[0011] The reaction route of the synthesis method is as follows: .

[0012] Preferably, step (1) comprises mixing methyl glycolate and isopropylamine in a round-bottom flask equipped with a reflux condenser and a drying tube. The reaction mixture is refluxed for 16 hours. Excess amine is evaporated under reduced pressure. The residue is purified by recrystallization with chloroform-hexane. A white solid 2-hydroxy-N-isopropylacetamide f is obtained. The amount of methyl glycolate and isopropylamine added is 1 mmol: 2.2 mmol.

[0013] Preferably, step (2) comprises adding 2-chloroquinazolin-4-amine a, 5-bromoindazole b, and DIEA to DMF, stirring at 65° C., extracting after the reaction, drying, spin drying, and column chromatography to obtain 2-chloro-N-(1H-indazole-5-yl)quinazolin-4-amine c. The amounts of 2-chloroquinazolin-4-amine a, 5-bromoindazole b, DIEA, and DMF added are 100 mmol: 100 mmol: 100-110 mmol: 20 mL, respectively.

[0014] Preferably, step (3) comprises adding 2-chloro-N-(1H-indazole-5-yl)quinazolin-4-amine c (0.1 mmol) to a mixed solution of toluene (1 mL), n-BuOH (0.5 mL) and Na2CO3 (0.5 mL, 2M aqueous solution). Nitrogen is introduced for 20 minutes, and then 3-hydroxyphenylboronic acid d (0.4 mmol) and Pd-catalyst Pd(PPh3)4 (0.05 mmol) are added under nitrogen protection, and the mixture is heated to reflux and stirred for 72 hours. The solvent is removed in vacuo, and the residue is subjected to preparative silica gel TLC (5% MeOH / CH2Cl2) to obtain 3-(4-((1H-indazole-5-yl)amino)quinazolin-2-yl)phenol e.

[0015] Preferably, step (4) comprises dissolving 3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenol e, 2-hydroxy-N-isopropylacetamide f, and triphenylphosphine in tetrahydrofuran, cooling to zero degrees, and then slowly dropping diethyl azodicarboxylate (DEAD), and stirring at 70°C after the addition. After the reaction is completed, the mixture is evaporated and concentrated under reduced pressure, and purified by column chromatography to obtain 2-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide g. The amounts of 3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenol e, 2-hydroxy-N-isopropylacetamide f, triphenylphosphine, DEAD, and tetrahydrofuran added are, in order: 10 mmol: 10-12 mmol: 10 mmol: 20 mL.

[0016] Preferably, step (5) comprises adding an ethanol solution of methanesulfonic acid (0.31 mL) to an ethanol solution of 2-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide g (2.0 g) (40.0 mL) at 25-30° C., heating to 45-55° C., stirring at the same temperature for 2 h, and then cooling the reaction mixture to 25-30° C. and stirring for 0.5 h. The solid is filtered, washed with ethanol, and dried to obtain besudil mesylate.

[0017] Compared with the prior art, the present invention has the following beneficial effects: The main route of the invention is relatively short, and the target product besudil mesylate can be obtained through the steps of nucleophilic substitution, Suzuki coupling reaction, Mitsunobu reaction, salt formation and the like. The method has a short reaction route, a high yield and is conducive to industrial production.

[0018] Compared with the existing route 2, the compound g obtained by the present invention through Mitsunobu reaction has a higher yield than the compound 8 obtained by nucleophilic substitution in route 2. Of course, any product of the present invention does not necessarily need to achieve all the advantages mentioned above at the same time. DETAILED DESCRIPTION

[0019] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of protection of the present invention. Improvements and adjustments made by those skilled in the art in practical applications according to the present invention still belong to the scope of protection of the present invention.

[0020] Embodiment 1: (1) Synthesis of 2-hydroxy-N-isopropylacetamide f: Methyl glycolate (9.00 g, 100 mmol) and isopropylamine (12.9 g, 219 mmol) were added to a 50 mL round-bottom flask equipped with a condenser and a drying tube, and the reaction mixture was refluxed for 16 hours. After the reaction was completed, the excess amine was evaporated under reduced pressure, and the residue was purified by recrystallization from chloroform-hexane. 2-Hydroxy-N-isopropylacetamide f was obtained as white crystals (yield 37%).

[0021] (2) Synthesis of 2-chloro-N-(1H-indazol-5-yl)quinazoline-4-amine c: 2-Chloroquinazoline-4-amine a (17.9 g, 100 mmol), 5-bromoindazole b (19.6 g, 100 mmol), and DIEA (110 mmol) were added to 20 mL DMF and stirred at 65°C. After the reaction was completed by TLC monitoring, heating and stirring were stopped, water was added to quench, the organic layer was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous Na2SO4, and dried by spin drying. 2-Chloro-N-(1H-indazole-5-yl)quinazoline-4-amine c was obtained by column chromatography as a white solid (yield 83%).

[0022] (3) Synthesis of 3-(4-((1H-indazol-5-yl)amino)quinazoline-2-yl)phenol e: 2-Chloro-N-(1H-indazol-5-yl)quinazolin-4-amine c (1 mmol) was dissolved in toluene (10 mL), and n-BuOH (5 mL) and Na2CO3 (5 mL, 2M aqueous solution) were added. Nitrogen was introduced for 20 minutes, and then 3-hydroxyphenylboronic acid d (4 mmol) and Pd(PPh3)4 (0.5 mmol) were added under nitrogen protection. The mixture was heated to reflux and stirred for 72 hours. After the reaction was completed, DCM (100 mL) and water (50 mL) were added after cooling to room temperature. The organic layer and the aqueous layer were separated, and the aqueous layer was extracted with DCM (2x75 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. 3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenol e was obtained by silica gel chromatography as a yellow solid (yield 91%).

[0023] (4) Synthesis of 2-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide g: 3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenol e (10 mmol), 2-hydroxy-N-isopropylacetamide f (12 mmol), triphenylphosphine (10 mmol) were dissolved in 20 mL tetrahydrofuran, cooled to zero degrees, and then diethyl azodicarboxylate (DEAD) (10 mmol) was slowly added dropwise, and stirred at 70°C after the addition was complete. TLC monitoring, after the reaction was completed, the mixture was evaporated and concentrated under reduced pressure, and purified by column chromatography to obtain 2-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide g as a white solid (yield 89%).

[0024] (5) Synthesis of Besudiol Mesylate: At 25-30°C, a solution of methanesulfonic acid (0.31 mL) in ethanol (4.0 mL) was added to a solution of 2-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide g (2.0 g) in ethanol (40.0 mL), heated to 45-55°C, and stirred at the same temperature for 2 h. The reaction mixture was cooled to 25-30°C and stirred for 0.5 h. The solid was filtered and washed with ethanol and dried to obtain besudil mesylate as a yellow-white solid (yield 95%).

[0025] Embodiment 2: (1) Synthesis of 3-(4-((1H-indazol-5-yl)amino)quinazoline-2-yl)phenol e: 5-((2-(3-hydroxyphenyl)quinazolin-4-yl)amino)-1H-indazole-1-carboxylic acid tert-butyl ester 7 can be prepared by referring to the method of existing route 2 mentioned in patent CN101208094A; 5-((2-(3-hydroxyphenyl)quinazolin-4-yl)amino)-1H-indazole-1-carboxylic acid tert-butyl ester 7 (10 mmol) and 10 mmol trifluoroacetic acid were added to 20 mL dichloromethane solution and stirred at room temperature. After the reaction was completed, water was added to quench, the layers were separated, and the dichloromethane was extracted twice. The dichloromethane layers were combined and dried by rotation to obtain 3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenol e as a yellow solid (99%).

[0026] (2) Synthesis of 2-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide g: 3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenol e (10 mmol), 2-hydroxy-N-isopropylacetamide f (10 mmol), triphenylphosphine (10 mmol) were dissolved in 20 mL tetrahydrofuran, cooled to zero degrees, and then diethyl azodicarboxylate (DEAD) (10 mmol) was slowly added dropwise, and stirred at 70°C after the addition was complete. TLC monitoring, after the reaction was completed, the mixture was evaporated and concentrated under reduced pressure, and purified by column chromatography to obtain 2-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide g as a white solid (yield 92%).

[0027] (3) Synthesis of Besudiol Mesylate: At 25-30°C, a solution of methanesulfonic acid (0.31 mL) in ethanol (4.0 mL) was added to a solution of 2-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide g (2.0 g) in ethanol (40.0 mL), heated to 45-55°C, and stirred at the same temperature for 2 h. The reaction mixture was cooled to 25-30°C and stirred for 0.5 h. The solid was filtered and washed with ethanol and dried to obtain besudil mesylate as a yellow-white solid (yield 94%).

[0028] Embodiment three: (1) Synthesis of 2-hydroxy-N-isopropylacetamide f: Methyl glycolate (15 mmol) was dissolved in 10 mL 1,4-dioxane, and then a solution of isopropylamine (15 mmol) in 1,4-dioxane (10 mL) was slowly added and reacted at 80°C. After the reaction was completed, the temperature was lowered to room temperature, and solids precipitated. The solids were filtered and dried to obtain 2-hydroxy-N-isopropylacetamide f as white crystals (yield 90%).

[0029] (2) Synthesis of 2-chloro-N-(1H-indazol-5-yl)quinazoline-4-amine c: 2-Chloroquinazoline-4-amine a (17.9 g, 100 mmol), 5-bromoindazole b (19.6 g, 100 mmol), and DIEA (100 mmol) were added to 20 mL DMF and stirred at 65°C. After the reaction was completed by TLC monitoring, heating and stirring were stopped, water was added to quench, the organic layer was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous Na2SO4, and dried by spin drying. 2-Chloro-N-(1H-indazole-5-yl)quinazoline-4-amine c was obtained by column chromatography as a white solid (yield 85%).

[0030] (3) Synthesis of 3-(4-((1H-indazol-5-yl)amino)quinazoline-2-yl)phenol e: 2-Chloro-N-(1H-indazol-5-yl)quinazolin-4-amine c (1 mmol) was dissolved in toluene (10 mL), and n-BuOH (5 mL) and Na2CO3 (5 mL, 2M aqueous solution) were added. Nitrogen was introduced for 20 minutes, and then 3-hydroxyphenylboronic acid d (4 mmol) and Pd(PPh3)4 (0.5 mmol) were added under nitrogen protection. The mixture was heated to reflux and stirred for 72 hours. After the reaction was completed, DCM (100 mL) and water (50 mL) were added after cooling to room temperature. The organic layer and the aqueous layer were separated, and the aqueous layer was extracted with DCM (2x75 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. 3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenol e was obtained by silica gel chromatography as a yellow solid (yield 91%).

[0031] (4) Synthesis of 2-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide g: 3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenol e (10 mmol), 2-hydroxy-N-isopropylacetamide f (12 mmol), triphenylphosphine (10 mmol) were dissolved in 20 mL tetrahydrofuran, cooled to zero degrees, and then diethyl azodicarboxylate (DEAD) (10 mmol) was slowly added dropwise, and stirred at 70°C after the addition was complete. TLC monitoring, after the reaction was completed, the mixture was evaporated and concentrated under reduced pressure, and purified by column chromatography to obtain 2-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide g as a white solid (yield 89%).

[0032] (5) Synthesis of Besudiol Mesylate: At 25-30°C, a solution of methanesulfonic acid (0.31 mL) in ethanol (4.0 mL) was added to a solution of 2-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide g (2.0 g) in ethanol (40.0 mL), heated to 45-55°C, and stirred at the same temperature for 2 h. The reaction mixture was cooled to 25-30°C and stirred for 0.5 h. The solid was filtered and washed with ethanol and dried to obtain besudil mesylate as a yellow-white solid (yield 95%).

[0033] The preferred embodiments of the present invention disclosed above are only used to help illustrate the present invention. The preferred embodiments do not describe all the details in detail, nor do they limit the invention to the specific implementation methods described. Obviously, many modifications and changes can be made according to the content of this specification. This specification selects and specifically describes these embodiments in order to better explain the principles and practical applications of the present invention, so that those skilled in the art can understand and use the present invention well. The present invention is limited only by the claims and their full scope and equivalents.

Claims

1. A method for synthesizing besudil mesylate, characterized in that: The following steps are involved: (1) In an organic solvent, methyl glycolate reacts with isopropylamine to obtain 2-hydroxy-N-isopropylacetamide f; (2) In an organic solvent, 2-chloroquinazolin-4-amine a reacts with 5-bromoindazole b to obtain 2-chloro-N-(1H-indazol-5-yl)quinazolin-4-amine c; (3) In an organic solvent, 2-chloro-N-(1H-indazol-5-yl)quinazolin-4-amine c is coupled with 3-hydroxyphenylboronic acid d to obtain 3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenol e; (4) In an organic solvent, 3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenol e and 2-hydroxy-N-isopropylacetamide f are reacted by Mitsunobu reaction to obtain 2-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide g; (5) In an organic solvent, 2-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide g is reacted with methanesulfonic acid to form a salt to obtain besudil mesylate.

2. The method for synthesizing besudil mesylate according to claim 1, characterized in that: Step (1) comprises mixing methyl glycolate and isopropylamine in a round-bottom flask equipped with a reflux condenser and a drying tube. The reaction mixture is refluxed for 16 hours. Excess amine is evaporated under reduced pressure. The residue is purified by recrystallization with chloroform-hexane. A white solid 2-hydroxy-N-isopropylacetamide f is obtained. The amount of methyl glycolate and isopropylamine added is 1 mmol: 2.2 mmol.

3. The method for synthesizing besudil mesylate according to claim 1, characterized in that: Step (2) comprises adding 2-chloroquinazolin-4-amine a, 5-bromoindazole b, and DIEA to DMF, stirring at 65° C., extracting after the reaction, drying, spin drying, and column chromatography to obtain 2-chloro-N-(1H-indazole-5-yl)quinazolin-4-amine c. The amounts of 2-chloroquinazolin-4-amine a, 5-bromoindazole b, DIEA, and DMF added are 100 mmol: 100 mmol: 100-110 mmol: 20 mL, respectively.

4. The method for synthesizing besudil mesylate according to claim 1, characterized in that: Step (3) comprises adding 2-chloro-N-(1H-indazol-5-yl)quinazolin-4-amine c (0.1 mmol) to a mixed solution of toluene (1 mL), n-BuOH (0.5 mL) and Na2CO3 (0.5 mL, 2M aqueous solution). Nitrogen is introduced for 20 minutes, and then 3-hydroxyphenylboronic acid (0.4 mmol) and Pd-catalyst Pd(PPh3)4 (0.05 mmol) are added under nitrogen protection, and the mixture is heated to reflux and stirred for 72 hours. The solvent is removed in vacuo, and the residue is subjected to preparative silica gel TLC (5% MeOH / CH2Cl2) to obtain 3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenol e.

5. The method for synthesizing besudil mesylate according to claim 1, characterized in that: Step (4) comprises dissolving 3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenol e, 2-hydroxy-N-isopropylacetamide f, and triphenylphosphine in tetrahydrofuran, cooling to zero degrees, and then slowly dropping diethyl azodicarboxylate (DEAD), and stirring at 70°C after the addition. After the reaction is completed, the mixture is evaporated and concentrated under reduced pressure, and purified by column chromatography to obtain 2-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide g. The amounts of 3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenol e, 2-hydroxy-N-isopropylacetamide f, triphenylphosphine, DEAD, and tetrahydrofuran added are: 10 mmol: 10-12 mmol: 10 mmol: 20 mL, respectively.

6. The method for synthesizing besudil mesylate according to claim 1, characterized in that: Step (5) comprises adding an ethanol solution of methanesulfonic acid (0.31 mL) to an ethanol solution of 2-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide g (2.0 g) (40.0 mL) at 25-30° C., heating to 45-55° C., stirring at the same temperature for 2 h, and then cooling the reaction mixture to 25-30° C. and stirring for 0.5 h. The solid is filtered, washed with ethanol, and dried to obtain besudil mesylate.

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