A preparation process of rituximab tosylate

Abstract

This invention relates to a preparation process of litexitinib tosylate. In the preparation process described in this invention, the raw material undergoes an amidation reaction of a carbonyl group and an amino group. After the amide is reduced, it is resolved by L-DBTA to obtain the desired chiral compound, and finally, it is salted with p-methanesulfonic acid to yield the target compound. The preparation process of this invention uses a readily available chiral isomer as the raw material, avoiding the two chiral column separations required in existing methods, thus offering better economic efficiency. Furthermore, the resolving agent L-DBTA is inexpensive and readily available, avoiding expensive reagents; the reaction is mild, the operation is safe, and the separation is highly secure; column chromatography purification is avoided, facilitating industrial production.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, specifically to a preparation process for litexitinib tosylate. Background Technology

[0002] Litlecitinib tosylate is a novel oral Janus kinase 3 (JAK3) inhibitor that effectively blocks the activity of signaling molecules and immune cells, which are believed to be the cause of alopecia areata. On June 23, 2023, Pfizer announced that the FDA had approved litlecitinib tosylate capsules (trade name: LITFULO) for the treatment of severe alopecia areata in individuals aged 12 years and older. In the field of alopecia areata treatment, this is the second targeted immunosuppressant approved by the FDA, and the only treatment specifically for adolescents with severe alopecia areata. On October 19, 2023, the China Center for Drug Evaluation (CDE) announced the approval of Pfizer's Class 1 innovative drug, litlecitinib tosylate capsules (trade name: Lefuno), for marketing, suitable for adolescents aged 12 years and older and adults with severe alopecia areata.

[0003] The chemical name of litexitinib tosylate is: 1-{(2S,5R)-2-methyl-5-[(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}prop-2-en-1-one 4-methylbenzene-1-sulfonic acid, and its chemical structure is shown in Formula I:

[0004] Formula I.

[0005] However, the current preparation process for litexitinib tosylate still needs improvement. Summary of the Invention

[0006] This invention aims to at least partially solve one of the technical problems in related technologies. To this end, one object of this invention is to provide a process for preparing litexitinib tosylate, a compound of Formula I. Compared to existing technologies, this route has shorter steps, consisting of three reactions. In the method of this invention, the raw materials undergo an amidation reaction of a carbonyl group and an amino group. After the amide is reduced, the desired chiral compound is resolved by L-DBTA, and finally, it forms a salt with p-methanesulfonic acid to obtain the target compound.

[0007] In one aspect of the present invention, a preparation process for litexitinib tosylate, a compound of formula I, is provided. According to an embodiment of the present invention, the preparation process includes:

[0008] (1) Contact the compound shown in Formula 1 with the compound shown in Formula 2, glacial acetic acid, and NaBH(OAc)3 to obtain the compound shown in Formula 3;

[0009] (2) Contact the compound shown in Formula 3 with L-DBTA to obtain the compound shown in Formula 4;

[0010] (3) Contact the compound shown in Formula 4 with p-toluenesulfonic acid to obtain the compound shown in Formula I, litexitinib tosylate.

[0011] .

[0012] The inventors discovered that by using the preparation process described in this invention, with the compounds shown in Formula 1 and Formula 2 as starting materials, the target product litexitinib tosylate can be successfully synthesized and prepared through a total of 3 reaction steps.

[0013] The term "contact" as used herein should be interpreted broadly, encompassing any method that enables at least two reactants to undergo a chemical reaction, such as mixing two reactants under appropriate conditions. If necessary, reactants requiring contact can be mixed under stirring; therefore, the type of stirring is not particularly limited, such as mechanical stirring, i.e., stirring under mechanical force.

[0014] In this document, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of indicated technical features. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of this invention, "a plurality of" means two or more, unless otherwise explicitly specified.

[0015] According to embodiments of the present invention, the methods for preparing the compounds shown in Formula 3, Formula 4, and Formula I may further have at least one of the following additional technical features:

[0016] According to embodiments of the present invention, the chemical reaction described herein can be carried out according to any method known in the art. The source of the starting materials for the compounds shown in Formula 3, Formula 4, and Formula I is not particularly limited; they can be prepared using any known method or be commercially available.

[0017] According to an embodiment of the present invention, in step (1), the contact mode between the compound of Formula 1 and the compound of Formula 2, glacial acetic acid, and NaBH(OAc)3 is not particularly limited. Therefore, the efficiency of the contact reaction between the compound of Formula 1 and the compound of Formula 2, glacial acetic acid, and NaBH(OAc)3 can be improved, the reaction rate can be accelerated, and the efficiency of preparing the compound of Formula 3 using this method can be further improved.

[0018] According to an embodiment of the present invention, step (1) includes the following steps: The compound shown in Formula 1, the compound shown in Formula 2, and glacial acetic acid are added to 1,2-dichloroethane at a temperature maintained at 5°C to 12°C. The mixture is stirred at 8°C to 10°C for 10 hours. Then, sodium triacetoxyborohydride (NaBH(OAc)3) is added to the reaction solution and the temperature is raised to 32°C to 40°C for 4 hours. The reaction solution is then cooled to room temperature, quenched with saturated ammonium chloride solution, washed with 1M NaOH aqueous solution, extracted twice with ethyl acetate, and the combined organic phases are washed with saturated brine. The mixture is dried over anhydrous sodium sulfate, and the organic phase is concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent to obtain the compound shown in Formula 3. This improves the efficiency of the reaction between the compound shown in Formula 1 and the compound shown in Formula 2, glacial acetic acid, and NaBH(OAc)3, accelerates the reaction rate, and further enhances the efficiency of preparing the compound shown in Formula 3 using this method.

[0019] According to an embodiment of the present invention, in step (1), the molar ratio of the compound shown in Formula 1 to the compound shown in Formula 2, glacial acetic acid, and NaBH(OAc)3 is 1:(1.0~1.15):1.0:(1.3~1.6), preferably 1:1.05:1.0:1.4. This further improves the efficiency of preparing the compound shown in Formula 3 using this method.

[0020] According to an embodiment of the present invention, in step (1), it is preferable to heat to 36°C and react for 4 hours.

[0021] According to an embodiment of the present invention, in step (1), the volume ratio of the petroleum ether / ethyl acetate mixed solvent is 1:(6~10), preferably 1:8.

[0022] According to a specific embodiment of the present invention, step (1) includes the following steps: At a temperature maintained at 5°C to 12°C, compound 1 (16.72 g, 0.10 mol), compound 2 (14.08 g, 0.105 mol), and glacial acetic acid (6.0 g, 0.10 mol) are added to 1,2-dichloroethane (200 mL), and the mixture is stirred at 8°C to 10°C for 10 hours. Then, NaBH(OAc)3 (29.67 g, 0.14 mol) is added to the reaction solution and the temperature is raised to 36°C for 4 hours. The reaction solution is then cooled to room temperature, quenched with saturated ammonium chloride solution (20 mL), washed with 1M NaOH aqueous solution (150 mL), extracted twice with ethyl acetate (150 mL each time), and the organic phases are combined and then 150 mL of ethyl acetate is added. Washed with saturated brine and dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography with a petroleum ether / ethyl acetate mixture at a volume ratio of 1:8 to obtain the compound shown in Formula 3, with a yield of 21.80 g and a yield of 76.4%.

[0023] According to an embodiment of the present invention, in step (2), the contact mode between the compound shown in Formula 3 and L-DBTA is not particularly limited. Therefore, the efficiency of the contact reaction between the compound shown in Formula 3 and L-DBTA can be improved, the reaction rate can be accelerated, and the efficiency of preparing the compound shown in Formula 4 using this method can be further improved.

[0024] According to an embodiment of the present invention, step (2) includes the following steps: At room temperature, methanol is added to a reaction flask containing the compound shown in Formula 3 and (-)-dibenzoyl-L-tartaric acid (L-DBTA) and stirred to dissolve. The mixture is heated to reflux and stirred for 10-12 hours. A large amount of solid is observed to precipitate in the solution. The reaction solution is cooled to room temperature, and after crystallization and stirring for 2 hours, it is filtered. Methanol is added to the filter cake for rinsing. Dichloromethane and 5% Na2CO3 solution are added, and the mixture is stirred to dissolve. The mixture is separated, and the organic phase is washed with saturated brine. After drying with anhydrous sodium sulfate, the mixture is concentrated under reduced pressure to obtain a solid, which is the compound shown in Formula 4. Therefore, the efficiency of the reaction between the compound shown in Formula 3 and L-DBTA can be improved, the reaction rate can be accelerated, and the efficiency of preparing the compound shown in Formula 4 using this method can be further improved.

[0025] According to an embodiment of the present invention, in step (2), the molar ratio of the compound shown in Formula 3 to L-DBTA is 1:(0.6~0.7), preferably 1:0.65. This further improves the efficiency of preparing the compound shown in Formula 4 using this method.

[0026] According to an embodiment of the present invention, in step (2), the time for heating to reflux and stirring reaction is preferably 11 hours.

[0027] According to a specific embodiment of the present invention, step (2) includes the following steps: At room temperature, 200 mL of methanol is added to a reaction flask containing the compound shown in Formula 3 (18.90 g, 66.24 mmol) and (-)-dibenzoyl-L-tartaric acid (L-DBTA) (15.43 g, 43.06 mmol) and stirred to dissolve. The mixture is heated to reflux and stirred for 11 hours. A large amount of solid is observed to precipitate in the solution. The reaction solution is cooled to room temperature, and after crystallization and stirring for 2 hours, it is filtered. 20 mL of methanol is added to the filter cake for rinsing. 150 mL of dichloromethane and 150 mL of 5% Na2CO3 solution are added and stirred to dissolve. The mixture is separated, and the organic phase is washed with 150 mL of saturated brine. The solution is dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a solid, which is the compound shown in Formula 4. The yield is 8.30 g, the purity is 98.4%, ee>98.5%, and the yield is 43.9%.

[0028] According to an embodiment of the present invention, in step (3), the manner in which the compound of formula 4 is contacted with p-toluenesulfonic acid is not particularly limited. Therefore, the efficiency of the reaction between the compound of formula 4 and p-toluenesulfonic acid can be improved, the reaction rate can be accelerated, and the efficiency of preparing the compound of formula I using this method can be further increased.

[0029] According to an embodiment of the present invention, step (3) includes the following steps: at room temperature, the compound shown in Formula 4 is dissolved in organic solvent C, p-toluenesulfonic acid is slowly added dropwise, and the mixture is stirred at room temperature for 1 hour, resulting in the precipitation of a large amount of solid. The solid is filtered, the filter cake is washed with an appropriate amount of ethylene glycol dimethyl ether, and then recrystallized with methanol. The filtered filter cake is then dried under vacuum to obtain the compound litexitinib tosylate shown in Formula I. Therefore, the efficiency of the reaction between the compound shown in Formula 4 and p-toluenesulfonic acid can be improved, the reaction rate can be accelerated, and the efficiency of preparing the compound litexitinib tosylate shown in Formula I using this method can be further improved.

[0030] According to an embodiment of the present invention, in step (3), the molar ratio of the compound shown in Formula 4 to p-toluenesulfonic acid is 1:(1.05~1.2), preferably 1:1.1. This further improves the efficiency of preparing the compound shown in Formula I using this method.

[0031] According to an embodiment of the present invention, in step (3), the organic solvent C is at least one selected from ethanol, acetone, or tetrahydrofuran.

[0032] According to a specific embodiment of the present invention, step (3) includes the following steps: at room temperature, the compound shown in Formula 4 (2.9 g, 10.16 mmol) is dissolved in 30 mL of ethanol, and p-toluenesulfonic acid (1.93 g, 11.20 mmol) is slowly added dropwise. The mixture is stirred at room temperature for 1 hour, and a large amount of solid is precipitated. The solid is filtered, and the filter cake is washed with an appropriate amount of ethylene glycol dimethyl ether. Then, it is recrystallized with 10 mL of methanol. The filtered filter cake is dried under vacuum to obtain the compound shown in Formula I, litexitinib tosylate, with a yield of 3.96 g, a yield of 85.2%, and an HPLC purity of 99.8%.

[0033] According to a specific embodiment of the present invention, the synthetic route of litexitinib tosylate, the compound of Formula I, can be as follows:

[0034] .

[0035] Compared with the prior art, the preparation process of litexitinib tosylate described in this invention has at least the following beneficial effects:

[0036] 1. The raw materials of the method described in this invention undergo an amidation reaction of carbonyl and amino groups. After the amide is reduced, the desired chiral compound is resolved by L-DBTA and finally formed as a salt with p-methanesulfonic acid to obtain the target compound litexitinib tosylate.

[0037] 2. Compared with existing technologies, the significant advantages of this invention are: (1) The chemical substances used in this synthetic route are all commercially available products. The operation methods, steps, reaction conditions, and intermediates used in the reaction are all highly operable. In addition, the reaction route of this design method is shorter, the experimental cycle is shorter, and it is easier to synthesize on a large scale. (2) The synthesis is carried out using a readily available chiral isomer, avoiding the two chiral column separations in existing technologies, which is more economical. (3) In existing technologies, (R)-N-3,5-dinitrobenzoylphenylglycine is used as the resolving agent, which is expensive. The resolving agent (L-DBTA) used in this preparation method is inexpensive and readily available, avoiding expensive reagents; the reaction is mild, the operation is safe, and the separation safety is high; column chromatography purification is avoided, which is conducive to industrial production. (4) The raw materials selected in this invention are readily available, the operation method is simple, and the product yield is high. Detailed Implementation

[0038] The embodiments of the present invention are described in detail below. These embodiments are exemplary and are only used to explain the present invention, and should not be construed as limiting the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments used, unless otherwise specified, are all commercially available conventional products.

[0039] Example 1: Synthesis of the compound shown in Formula 3

[0040] The compound shown in Formula 1 (16.72 g, 0.10 mol), the compound shown in Formula 2 (14.08 g, 0.105 mol), and glacial acetic acid (6.0 g, 0.10 mol) were added to 1,2-dichloroethane (200 mL) at a temperature maintained between 5°C and 12°C. The mixture was stirred at 8°C to 10°C for 10 hours. Then, sodium triacetoxyborohydride (NaBH(OAc)3) (29.67 g, 0.14 mol) was added to the reaction mixture, and the temperature was raised to 36°C for 4 hours. The reaction mixture was then cooled to room temperature, quenched with saturated ammonium chloride solution (20 mL), washed with 1M NaOH aqueous solution (150 mL), and extracted twice with ethyl acetate (150 mL each time). The organic phases were combined and then 150 mL of ethyl acetate was added to the mixture. Wash with saturated brine, dry with anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, and purify the concentrate by silica gel column chromatography with a petroleum ether / ethyl acetate mixed solvent at a volume ratio of 1:8 to obtain the compound shown in Formula 3, with a yield of 21.80 g and a yield of 76.4%.

[0041] LC-MS (APCI): m / z = 286.2 (M+1) + .

[0042] Example 2: Synthesis of the compound shown in Formula 3

[0043] At a temperature maintained between 5°C and 12°C, the compound shown in Formula 1 (16.72 g, 0.10 mol), the compound shown in Formula 2 (13.41 g, 0.10 mol), and glacial acetic acid (6.0 g, 0.10 mol) were added to 200 mL of 1,2-dichloroethane. The mixture was stirred at 8°C to 10°C for 10 hours. Then, NaBH(OAc)3 (27.55 g, 0.13 mol) was added to the reaction mixture, and the temperature was raised to 32°C for 4 hours. The reaction mixture was then cooled to room temperature, quenched with 20 mL of saturated ammonium chloride solution, washed with 150 mL of 1M NaOH aqueous solution, and extracted twice with 150 mL of ethyl acetate each time. The organic phases were combined and then 150 mL of ethyl acetate was added to the mixture. Wash with saturated brine, dry with anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, and purify the concentrate by silica gel column chromatography with a petroleum ether / ethyl acetate mixed solvent at a volume ratio of 1:6 to obtain the compound shown in Formula 3, with a yield of 21.23 g and a yield of 74.4%.

[0044] Example 3 Synthesis of the compound shown in Formula 3

[0045] The compound shown in Formula 1 (16.72 g, 0.10 mol), the compound shown in Formula 2 (15.43 g, 0.115 mol), and glacial acetic acid (6.0 g, 0.10 mol) were added to 1,2-dichloroethane (200 mL) at a temperature maintained between 5°C and 12°C. The mixture was stirred at 8°C to 10°C for 10 hours. Then, NaBH(OAc)3 (33.91 g, 0.16 mol) was added to the reaction mixture, and the temperature was raised to 40°C for 4 hours. The reaction mixture was then cooled to room temperature, quenched with saturated ammonium chloride solution (20 mL), washed with 1M NaOH aqueous solution (150 mL), and extracted twice with ethyl acetate (150 mL each time). The organic phases were combined and then 150 mL of ethyl acetate was added to the mixture. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the concentrate was purified by silica gel column chromatography with a petroleum ether / ethyl acetate mixture at a volume ratio of 1:10 to obtain the compound shown in Formula 3, with a yield of 21.63 g and a yield of 75.8%.

[0046] Comparative Example 1: Synthesis of the compound shown in Formula 3

[0047] The molar ratio of the compound shown in Formula 1 to the compound shown in Formula 2, glacial acetic acid, and NaBH(OAc)3 was adjusted to 1:0.98:1.2:1.1, and the temperature was maintained at 8°C~10°C with a stirring time of 9 hours.

[0048] The compound shown in Formula 1 (16.72 g, 0.10 mol), the compound shown in Formula 2 (13.14 g, 0.098 mol), and glacial acetic acid (7.2 g, 0.12 mol) were added to 1,2-dichloroethane (200 mL) at a temperature maintained between 5°C and 12°C. The mixture was stirred at 8°C to 10°C for 9 hours. Then, NaBH(OAc)3 (23.31 g, 0.11 mol) was added to the reaction mixture, and the temperature was raised to 36°C for 4 hours. The reaction mixture was then cooled to room temperature, quenched with saturated ammonium chloride solution (20 mL), washed with 1M NaOH aqueous solution (150 mL), and extracted twice with ethyl acetate (150 mL each time). The organic phases were combined and then 150 mL of ethyl acetate was added to the mixture. Wash with saturated brine, dry with anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, and purify the concentrate by silica gel column chromatography with a petroleum ether / ethyl acetate mixed solvent at a volume ratio of 1:8 to obtain the compound shown in Formula 3, with a yield of 21.55 g and a yield of 77.1%.

[0049] Comparative Example 2: Synthesis of the compound shown in Formula 3

[0050] The molar ratio of the compound shown in Formula 1 to the compound shown in Formula 2, glacial acetic acid, and NaBH(OAc)3 was adjusted to 1:1.3:1.0:1.8.

[0051] The compound shown in Formula 1 (16.72 g, 0.10 mol), the compound shown in Formula 2 (17.44 g, 0.13 mol), and glacial acetic acid (6.0 g, 0.10 mol) were added to 1,2-dichloroethane (200 mL) at a temperature maintained between 5°C and 12°C. The mixture was stirred at 8°C to 10°C for 10 hours. Then, NaBH(OAc)3 (38.15 g, 0.18 mol) was added to the reaction mixture, and the temperature was raised to 40°C for 4 hours. The reaction mixture was then cooled to room temperature, quenched with saturated ammonium chloride solution (20 mL), washed with 1M NaOH aqueous solution (150 mL), and extracted twice with ethyl acetate (150 mL each time). The organic phases were combined and then 150 mL of ethyl acetate was added to the mixture. Wash with saturated brine, dry with anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, and purify the concentrate by silica gel column chromatography with a petroleum ether / ethyl acetate mixed solvent at a volume ratio of 1:8 to obtain the compound shown in Formula 3, with a yield of 21.11 g and a yield of 74.0%.

[0052] Example 4: Synthesis of the compound shown in Formula 4

[0053] At room temperature, 200 mL of methanol was added to a reaction flask containing the compound shown in Formula 3 (18.90 g, 66.24 mmol) and (-)-dibenzoyl-L-tartaric acid (L-DBTA) (15.43 g, 43.06 mmol) and stirred to dissolve. The mixture was heated to reflux and stirred for 11 hours. A large amount of solid was observed to precipitate in the solution. The reaction solution was cooled to room temperature, and after crystallization and stirring for 2 hours, it was filtered. 20 mL of methanol was added to the filter cake for rinsing. 150 mL of dichloromethane and 150 mL of 5% Na2CO3 solution were added and stirred to dissolve. The mixture was separated, and the organic phase was washed with 150 mL of saturated brine. After drying with anhydrous sodium sulfate, the solution was concentrated under reduced pressure to obtain the solid, which is the compound shown in Formula 4. The yield was 8.30 g, the purity was 98.4%, ee > 98.5%, and the yield was 43.9%.

[0054] LC-MS (APCI): m / z = 286.2(M+1) + .

[0055] I H-NMR (400 MHz, DMSO- d6): δ ppm 11.52 (s, 1 H), 8.11 (d, 1 H), 7.44-7.20 (m, 1 H), 7.09 (s, 1 H), 6.81 (dd, J= 30.9, 17.3Hz, 1H), 6.54 (dd, 1H), 6.09 (dd, J= 16.7,2.0Hz, 1H), 5.66 (dd J= 10.5,1.9Hz, 1H), 4.81 (s, 0.5H), 4.55 (d, J= 13.2Hz,0.5H), 4.36 (s, 0.5H), 4.11-4.04 (m, 1.5H), 2.96 (t, 0.5H), 2.58 (t, 0.5H), 1.94-1.54 (m, 4H), 1.16-1.26 (m, 3H).

[0056] Example 5: Synthesis of the compound shown in Formula 4

[0057] At room temperature, 200 mL of methanol was added to a reaction flask containing the compound shown in Formula 3 (18.90 g, 66.24 mmol) and L-DBTA (14.24 g, 39.74 mmol) and stirred to dissolve. The mixture was heated to reflux and stirred for 10 hours. A large amount of solid was observed to precipitate in the solution. The reaction solution was cooled to room temperature, and after crystallization and stirring for 2 hours, it was filtered. 20 mL of methanol was added to the filter cake for rinsing. 150 mL of dichloromethane and 150 mL of 5% Na2CO3 solution were added and stirred to dissolve. The mixture was separated, and the organic phase was washed with 150 mL of saturated brine. After drying with anhydrous sodium sulfate, the solution was concentrated under reduced pressure to obtain the solid, which is the compound shown in Formula 4. The yield was 7.77 g, the purity was 98.1%, ee > 98.5%, and the yield was 41.1%.

[0058] Example 6 Synthesis of the compound shown in Formula 4

[0059] At room temperature, 200 mL of methanol was added to a reaction flask containing the compound shown in Formula 3 (18.90 g, 66.24 mmol) and L-DBTA (16.61 g, 46.37 mmol) and stirred to dissolve. The mixture was heated to reflux and stirred for 12 hours. A large amount of solid was observed to precipitate in the solution. The reaction solution was cooled to room temperature, and after crystallization and stirring for 2 hours, it was filtered. 20 mL of methanol was added to the filter cake for rinsing. 150 mL of dichloromethane and 150 mL of 5% Na2CO3 solution were added and stirred to dissolve. The mixture was separated, and the organic phase was washed with 150 mL of saturated brine. After drying with anhydrous sodium sulfate, the solution was concentrated under reduced pressure to obtain the solid, which is the compound shown in Formula 4. The yield was 8.18 g, the purity was 98.3%, ee > 98.5%, and the yield was 43.3%.

[0060] Example 7 Synthesis of litexitinib tosylate, the compound shown in Formula I

[0061] At room temperature, the compound shown in Formula 4 (2.9 g, 10.16 mmol) was dissolved in 30 mL of ethanol, and p-toluenesulfonic acid (1.93 g, 11.20 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 1 hour, and a large amount of solid precipitated. The solid was filtered, and the filter cake was washed with an appropriate amount of ethylene glycol dimethyl ether. Then, it was recrystallized with 10 mL of methanol. The filtered filter cake was dried under vacuum to obtain the compound shown in Formula I, litexitinib tosylate, with a yield of 3.96 g, a yield of 85.2%, and an HPLC purity of 99.8%.

[0062] LC-MS(APCI): m / z=286.2(M+1)+.

[0063] 1 H NMR (400 MHz, DMSO- d 6): δ ppm 12.69 (brs, 1H), 9.24 (brs, 1H), 8.42 (s, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.47 (m, 1H), 7.14 (d, J = 8.3 Hz, 2H), 6.95(d, J= 1.2 Hz, 1H), 6.88 (m, 1H), 6.15 (m, 1H), 5.75 (m, 1H), 4.82 (m, 0.5H), 4.58 (m, 0.5H), 4.43 (m, 0.5H), 4.13 (m, 0.5H), 3.98 (m, 1H), 3.14 (m, 0.5H), 2.84 (m, 0.5H), 2.28 (s, 3H), 1.90-1.75 (m, 4H), 1.28-1.19 (m, 3H).

[0064] Example 8 Synthesis of litexitinib tosylate, the compound shown in Formula I

[0065] At room temperature, the compound shown in Formula 4 (2.9 g, 10.16 mmol) was dissolved in 30 mL of ethanol, and p-toluenesulfonic acid (1.84 g, 10.67 mmol) was slowly added dropwise. The mixture was stirred at 20–25°C for 1 hour, and a large amount of solid precipitated. The solid was filtered, and the filter cake was washed with an appropriate amount of ethylene glycol dimethyl ether. Then, it was recrystallized with 10 mL of methanol. The filtered filter cake was dried under vacuum to obtain the compound shown in Formula I, litexitinib tosylate, with a yield of 3.81 g, a yield of 81.9%, and an HPLC purity of 99.6%.

[0066] Example 9 Synthesis of litexitinib tosylate, the compound shown in Formula I

[0067] At room temperature, the compound shown in Formula 4 (2.9 g, 10.16 mmol) was dissolved in 30 mL of ethanol, and p-toluenesulfonic acid (2.10 g, 12.19 mmol) was slowly added dropwise. The mixture was stirred at 20–25°C for 1 hour, and a large amount of solid precipitated. The solid was filtered, and the filter cake was washed with an appropriate amount of ethylene glycol dimethyl ether. Then, it was recrystallized with 10 mL of methanol. The filtered filter cake was dried under vacuum to obtain litexitinib tosylate, the compound shown in Formula I, with a yield of 3.92 g, a yield of 84.3%, and an HPLC purity of 99.5%.

[0068] Example 10 Synthesis of litexitinib tosylate, the compound shown in Formula I

[0069] At room temperature, the compound shown in Formula 4 (2.9 g, 10.16 mmol) was dissolved in 30 mL of acetone, and p-toluenesulfonic acid (1.93 g, 11.20 mmol) was slowly added dropwise. The mixture was stirred at 20–25°C for 1 hour, and a large amount of solid precipitated. The solid was filtered, and the filter cake was washed with an appropriate amount of ethylene glycol dimethyl ether. Then, it was recrystallized with 10 mL of methanol. The filtered filter cake was dried under vacuum to obtain the compound shown in Formula I, litexitinib tosylate, with a yield of 3.73 g, a yield of 80.2%, and an HPLC purity of 99.4%.

[0070] Example 11 Synthesis of litexitinib tosylate, the compound shown in Formula I

[0071] At room temperature, the compound shown in Formula 4 (2.9 g, 10.16 mmol) was dissolved in 30 mL of tetrahydrofuran, and p-toluenesulfonic acid (1.93 g, 11.20 mmol) was slowly added dropwise. The mixture was stirred at 20–25°C for 1 hour, and a large amount of solid precipitated. The solid was filtered, and the filter cake was washed with an appropriate amount of ethylene glycol dimethyl ether. Then, it was recrystallized with 10 mL of methanol. The filtered filter cake was dried under vacuum to obtain the compound shown in Formula I, litexitinib tosylate, with a yield of 3.67 g, a yield of 78.1%, and an HPLC purity of 99.9%.

[0072] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0073] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A preparation process for litexitinib tosylate, characterized in that, include: (1) Contact the compound shown in Formula 1 with the compound shown in Formula 2, glacial acetic acid, and NaBH(OAc)3 to obtain the compound shown in Formula 3; (2) Contact the compound shown in Formula 3 with L-DBTA to obtain the compound shown in Formula 4; (3) Contact the compound shown in Formula 4 with p-toluenesulfonic acid to obtain the compound shown in Formula I, litexitinib tosylate. ， In step (1), the following steps are included: At 5°C to 12°C, the compound shown in Formula 1, the compound shown in Formula 2, and glacial acetic acid are added to 1,2-dichloroethane. The temperature is maintained at 8°C to 10°C and stirred for 10 hours. Then, NaBH(OAc)3 is added to the reaction solution and the temperature is raised to 32°C to 40°C and reacted for 4 hours. Then, the reaction solution is cooled to room temperature and quenched with saturated ammonium chloride solution. Then, 1M NaOH aqueous solution is added for washing. Ethyl acetate is added for extraction twice. After combining the organic phases, saturated brine is added for washing. The organic phase is dried with anhydrous sodium sulfate. After the organic phase is concentrated under reduced pressure, the concentrate is purified by silica gel column chromatography with a petroleum ether / ethyl acetate mixed solvent to obtain the compound shown in Formula 3. In step (2), the following steps are included: at room temperature, methanol is added to a reaction flask containing the compound shown in Formula 3 and L-DBTA and stirred to dissolve. The mixture is heated to reflux and stirred for 10-12 hours. A large amount of solid is observed to precipitate in the solution. The reaction solution is cooled to room temperature and stirred for 2 hours to crystallize. The mixture is then filtered. Methanol is added to the filter cake for rinsing. Dichloromethane and 5% Na2CO3 solution are added and stirred to dissolve. The mixture is separated. The organic phase is washed with saturated brine and dried with anhydrous sodium sulfate. After concentration under reduced pressure, a solid is obtained, which is the compound shown in Formula 4. In step (3), the following steps are included: at room temperature, the compound shown in Formula 4 is dissolved in organic solvent C, p-toluenesulfonic acid is slowly added dropwise, and the mixture is stirred at room temperature for 1 hour to precipitate a large amount of solid. The solid is filtered, the filter cake is washed with an appropriate amount of ethylene glycol dimethyl ether, and then recrystallized with methanol. The filtered filter cake is dried under vacuum to obtain the compound litexitinib toluenesulfonic acid shown in Formula I.

2. The method according to claim 1, characterized in that, In step (1), the molar ratio of the compound shown in Formula 1 to the compound shown in Formula 2, glacial acetic acid, and NaBH(OAc)3 is 1:(1.0~1.15):1.0:(1.3~1.6).

3. The method according to claim 2, characterized in that, In step (1), the molar ratio of the compound shown in Formula 1 to the compound shown in Formula 2, glacial acetic acid, and NaBH(OAc)3 is 1:1.05:1.0:1.

4.

4. The method according to claim 1, characterized in that, In step (1), the reaction time is 4 hours after heating to 36°C.

5. The method according to claim 1, characterized in that, In step (1), the volume ratio of the petroleum ether / ethyl acetate mixed solvent is 1:(6~10).

6. The method according to claim 5, characterized in that, In step (1), the volume ratio of the petroleum ether / ethyl acetate mixed solvent is 1:

8.

7. The method according to claim 1, characterized in that, In step (2), the molar ratio of the compound shown in Formula 3 to L-DBTA is 1:(0.6~0.7).

8. The method according to claim 7, characterized in that, In step (2), the molar ratio of the compound shown in Formula 3 to L-DBTA is 1:0.

65.

9. The method according to claim 1, characterized in that, In step (2), the heating and stirring reaction time to reflux state is 11 hours.

10. The method according to claim 1, characterized in that, In step (3), the molar ratio of the compound shown in Formula 4 to p-toluenesulfonic acid is 1:(1.05~1.2).

11. The method according to claim 10, characterized in that, In step (3), the molar ratio of the compound shown in Formula 4 to p-toluenesulfonic acid is 1:1.

1.

12. The method according to claim 1, characterized in that, In step (3), the organic solvent C is at least one selected from ethanol, acetone, or tetrahydrofuran.

13. The method according to claim 1, characterized in that, Step (1) includes the following steps: 16.72 g of the compound shown in Formula 1, 14.08 g of the compound shown in Formula 2, and 6.0 g of glacial acetic acid were added to 200 mL of 1,2-dichloroethane at a temperature maintained at 5°C to 12°C. The mixture was stirred at 8°C to 10°C for 10 hours. Then, 29.67 g of NaBH(OAc)3 was added to the reaction solution and the temperature was raised to 36°C for 4 hours. The reaction solution was then cooled to room temperature and quenched with 20 mL of saturated ammonium chloride solution. Then, 150 mL of 1M NaOH aqueous solution was added for washing. Ethyl acetate was added for extraction twice, 150 mL each time. The organic phases were combined and washed with 150 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography with a petroleum ether / ethyl acetate mixed solvent at a volume ratio of 1:8 to obtain the compound shown in Formula 3, with a yield of 21.80 g and a yield of 76.4%. In step (2), the following steps are included: At room temperature, 200 mL of methanol is added to a reaction flask containing 18.90 g of the compound shown in Formula 3 and 15.43 g of L-DBTA and stirred to dissolve. The mixture is heated to reflux and stirred for 11 hours. A large amount of solid is observed to precipitate in the solution. The reaction solution is cooled to room temperature and stirred for 2 hours to crystallize. The mixture is then filtered. 20 mL of methanol is added to the filter cake for rinsing. 150 mL of dichloromethane and 150 mL of 5% Na2CO3 solution are added and stirred to dissolve. The mixture is separated. The organic phase is washed with 150 mL of saturated brine and dried with anhydrous sodium sulfate. After concentration under reduced pressure, a solid is obtained, which is the compound shown in Formula 4. The yield is 8.30 g, the purity is 98.4%, ee>98.5%, and the yield is 43.9%. Step (3) includes the following steps: at room temperature, 2.9 g of the compound shown in Formula 4 is dissolved in 30 mL of ethanol, and 1.93 g of p-toluenesulfonic acid is slowly added dropwise. The mixture is stirred at room temperature for 1 hour, and a large amount of solid is precipitated. The solid is filtered, and the filter cake is washed with an appropriate amount of ethylene glycol dimethyl ether. Then, it is recrystallized with 10 mL of methanol. The filtered filter cake is dried under vacuum to obtain the compound shown in Formula I, litexitinib tosylate, with a yield of 3.96 g, a yield of 85.2%, and an HPLC purity of 99.8%.

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