Preparation method of Ritlecitinib

Abstract

According to the preparation method of the Ritlecitinib, D-glutamine which is easy to obtain and low in price is used as a starting raw material, the Ritlecitinib is prepared through eight-step reaction, chiral resolution is not needed in the reaction process, and the whole route is novel in design, high in practicability, high in yield, high in reaction speed, few in by-product and very suitable for industrial application.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, and relates to Ritlecitinib, specifically to a method for preparing Ritlecitinib. Background Technology

[0002] Ritlecitinib is an oral, specific JAK3 / TEC inhibitor developed by Pfizer and is being developed for the treatment of alopecia areata, Crohn's disease, rheumatoid arthritis, ulcerative colitis, or vitiligo. The structural formula of Ritlecitinib is as follows:

[0003]

[0004] In existing technologies, 5-methyl-3-aminopyridine is used as a raw material. For example, WO2010048012A discloses the use of a rhodium catalyst to reduce the pyridine ring to a piperidine ring; WO2016112298A discloses the use of PtO2 as a catalyst to reduce the pyridine ring. However, metal catalysts are expensive, and hydrogen reduction is generally used, requiring prolonged high-pressure heating and harsh reaction conditions. For instance, the platinum black produced using PtO2 is flammable, posing a production hazard. Existing technologies use (R)-N-3,5-dinitrobenzoylphenylglycine as a resolving agent, which is expensive. Furthermore, literature (Organic Process Research & Development (2019), Ahead of Print) records that the resolving agent exhibits severe exothermic phenomena during use, posing a safety hazard if not properly controlled during production. Summary of the Invention

[0005] To address the problems in the prior art, the present invention aims to provide a method for preparing Ritlecitinib that does not require chiral resolution, is highly practical, has a high yield, a fast reaction rate, and few byproducts, making it very suitable for industrial applications.

[0006] Unless otherwise specified, all parts mentioned in this invention are parts by weight, and all percentages are mass percentages.

[0007] To achieve the above objectives, the technical solution of the present invention is as follows:

[0008] A method for preparing Ritlecitinib involves using D-glutamine as a starting material, reducing it to obtain compound 2, then protecting it with an amino group to obtain compound 3, cyclizing it to obtain compound 4, reacting it with trimethylchlorosilane to obtain compound 5, reacting it with methyllithium to obtain compound 6, and then hydrogenating it to obtain compound 7; then coupling compound 7 with compound 8 to obtain compound 9, and finally reacting compound 9 with acryloyl chloride to obtain Ritlecitinib (compound 10).

[0009] The reaction route is as follows:

[0010]

[0011] In the process of preparing compound 2 by reacting compound 1 under Ru-C, in order to reduce the formation of imine, obtain a more satisfactory yield, and accelerate the reaction process, dilute hydrochloric acid was used as solvent, and the reaction was carried out at 20-30℃ for 10-12 h under a hydrogen atmosphere.

[0012] In the process of preparing compound 3 from compound 2, in order to obtain a more satisfactory yield and accelerate the reaction process, anhydrous N,N-dicarboxamide was used as the reaction solvent. After dissolving in potassium carbonate, it was reacted with benzyl bromide under nitrogen protection at 40-60℃ for 8-10 hours.

[0013] In the process of cyclizing compound 3 to prepare compound 4, in order to reduce the loss of the nitrogen-substituted benzyl group and obtain a more satisfactory yield, dry tetrahydrofuran was used as solvent and sodium hydride as catalyst. The mixture was first stirred at 0-5℃ under nitrogen for 3-7 min, then methanesulfonyl chloride was added and stirred overnight at room temperature. Then sodium hydride was added and the reaction temperature was raised to 55-65℃ and stirred for 10-12 h.

[0014] In the process of preparing compound 5 by reacting compound 4 with trimethylchlorosilane, in order to obtain a more satisfactory yield and accelerate the reaction process, toluene was used as solvent, and the mixture was stirred at 40-45°C for 5-6 hours under a nitrogen atmosphere with the action of triethylamine.

[0015] In the process of preparing compound 6 by reacting compound 5 with methyllithium, under nitrogen protection, a diethyl ether solution of methyllithium was added dropwise while stirring at -25 to -20°C. The reaction solution was then stirred at -25 to -20°C for 0.5 to 1 hour, then heated to room temperature and stirred for 1 to 2 hours. Finally, an aqueous solution containing ammonium chloride was added and stirred for another 0.5 to 1 hour.

[0016] In the preparation of compound 7 from compound 6, if not properly controlled, configuration inversion, an increase in the content of chiral impurities, and a low ee value of compound 7 may occur. To improve the yield of compound 7, tetrahydrofuran was used as the solvent, and the mixture was stirred for 6-8 hours after hydrogen purging at 20-30°C.

[0017] In the preparation of compound 9 from compound 7, in order to obtain a more satisfactory yield, potassium carbonate was used as a catalyst, and a mixed solvent of water and 1-methyl-2-pyrrolidone was used as the reaction solvent. The reaction was carried out at 100-120℃ with stirring for 15-18 hours.

[0018] Compound 9 was reacted with acryloyl chloride under alkaline conditions, using tetrahydrofuran as a solvent, at 0-5°C to prepare compound 10; the base was sodium bicarbonate.

[0019] Specifically, a method for preparing (3R,6S)-3-amino-6-methylpiperidine includes the following steps:

[0020] (1) Compound 1 and Ru-C were added to a two-necked flask, and then 1 mol / L dilute hydrochloric acid was added. The reaction was carried out at room temperature under a hydrogen atmosphere. After the reaction was completed, the pH of the solution was adjusted to 8-9 with 1 mol / L NaOH. The solution was extracted with ethyl acetate, and the organic layer was dried with anhydrous Na2SO4, filtered, and concentrated to obtain compound 2.

[0021] (2) Compound 2 and potassium carbonate were added to a reaction flask containing anhydrous N,N-dicarboxamide. Benzyl bromide was added at room temperature. The mixture was stirred at 40-60°C for 8-10 h under nitrogen protection. The reaction mixture was then cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and compound 3 was obtained.

[0022] (3) Add compound 3 and sodium hydride to a two-necked flask containing dry tetrahydrofuran. Stir at 0-5℃ under nitrogen for 3-7 min, then add methanesulfonyl chloride. Stir overnight at room temperature, then add sodium hydride. Raise the reaction temperature to 55-65℃ and continue stirring for 10-12 h. Then cool the reaction solution to room temperature, add ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and separate to obtain compound 4.

[0023] (4) Compound 4 and triethylamine were added to a reaction flask containing toluene. Trimethylchlorosilane was added under a nitrogen atmosphere. The reaction solution was stirred at 40-45°C for 5-6 hours. The reaction solution was cooled to 0-5°C, filtered with diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain compound 5.

[0024] (5) Compound 5 was added to a reaction flask containing diethyl ether. Under nitrogen protection, a solution of diethyl ether containing methyl lithium was added dropwise while stirring at -25 to -20°C. The reaction solution was stirred at -25 to -20°C for 0.5 to 1 h. Then the temperature was raised to room temperature and stirring was continued for 1 to 2 h. Then an aqueous solution containing ammonium chloride was added and stirring was continued for 0.5 to 1 h. The layers were separated, the aqueous layer was extracted with dichloromethane, the combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and compound 6 was obtained.

[0025] (6) Compound 6 was added to a two-necked reaction flask containing THF, and after being replaced with hydrogen three times at room temperature, the mixture was stirred for 6-8 hours. Then, the mixture was filtered with diatomaceous earth, and the solvent was removed by vacuum evaporation to obtain compound 7.

[0026] (7) 4-chloropyrrolo[2,3-d]pyrimidine (compound 8), (3R,6S)-3-amine-6-methylpiperidine (compound 7), and potassium carbonate were added to a reactor containing water and 1-methyl-2-pyrrolidone. The mixture was stirred at 100-120°C for 15-18 h, cooled to room temperature, and water was added. A solid precipitated out. The mixture was stirred for another 2-3 h and filtered under reduced pressure to obtain a viscous crude product. The crude product was placed in ethanol and stirred at 50-60°C for 1-2 h. The product was then purified by crystallization at room temperature and filtered to obtain a white solid N-((3R,6S)-6-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (compound 9).

[0027] (8) Compound 9 was reacted with acryloyl chloride at 0-5°C under alkaline conditions with tetrahydrofuran as solvent to prepare compound 10; the base was sodium bicarbonate.

[0028] Beneficial effects

[0029] This invention provides a method for synthesizing Ritlecitinib using readily available and inexpensive D-glutamine as a starting material. Ritlecitinib is obtained through eight steps of reaction. The reaction process does not require chiral resolution. The entire route is novel, highly practical, and has a high yield, fast reaction rate, and few byproducts, making it very suitable for industrial applications. Detailed Implementation

[0030] The present invention will now be described in detail through specific embodiments. It should be noted that these embodiments are only for further illustration and should not be construed as limiting the scope of protection of the present invention. Those skilled in the art can make some non-essential improvements and adjustments to the present invention based on the above description. All raw materials and reagents used in this invention are commercially available products.

[0031] Example 1: Preparation of Ritlecitinib

[0032] The reaction route is as follows:

[0033]

[0034] Operating steps:

[0035] 5 g (3.42 mmol) of D-glutamine (compound 1) and 1 g of Ru-C were added to a 250 mL two-necked flask, followed by the addition of 100 mL of dilute hydrochloric acid (1 mol / L). Hydrogen gas was then introduced at -5 to 5 °C. The reaction was moved to room temperature and stirred under a hydrogen atmosphere for 11 h. TLC showed that the reaction was complete. The pH of the solution was adjusted to 8-9 with 1 mol / L NaOH, and the aqueous layer was extracted with ethyl acetate (300 mL x 4). The organic layer was dried over anhydrous Na₂SO₄, filtered, concentrated, and washed with an appropriate amount of ethyl acetate to give 4.52 g of a grayish-white solid (compound 2), with a yield of 85.2%. MS (m / z) 133 (M+1); 1HNMR (400MHz, CD3OD) δ: 3.26 (dd, J=10.5, 6.5Hz, 1H), 3.16 (dd, J=1 0.5,5.0Hz,1H),2.56(m,lH),2.14-2.46(m,2H),1.49-1.61(m,lH),1.22-1.35(m,1H).

[0036] 1 g (7.6 mmol) of compound 2 and 4.2 g (30 mmol) of potassium carbonate were added to a 100 mL reaction flask containing 60 mL of anhydrous N,N-dicarboxamide. 3.9 g (22.7 mmol) of benzyl bromide was added at room temperature. The mixture was stirred at 50 °C under nitrogen protection, and TLC showed completion after 9 h. The reaction mixture was cooled to room temperature, 250 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL x 4). The organic layer was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (MeOH / EA = 1 / 10) to give 1.7 g of a colorless viscous substance, compound 3, in 71% yield. MS(m / z)313(M+1);1HNMR(400MHz,CDCl3)δ:1.50-1.77(m,2H),2.10-2.22(m,2H),2.71(m,1H), 3.02(s,1H),3.41-3.61(m,4H),3.81(d,J=13.2Hz,2H),5.29-5.45(s,2H),7.23-7.36(m,10H).

[0037] 0.8 g (2.6 mmol) of compound 3 and 123 mg (3.1 mmol, 60%) of sodium hydride were added to a 100 mL two-necked flask containing 60 mL of dry tetrahydrofuran. The mixture was stirred at 0 °C for 5 min under nitrogen, followed by the addition of 0.4 g (2.8 mmol) of methanesulfonyl chloride. After stirring overnight at room temperature, another 123 mg (3.1 mmol, 60%) of sodium hydride was added to the reaction flask, and the reaction temperature was raised to 60 °C with stirring for 12 h. TLC (external echocardiography) showed complete reaction of the starting material. The reaction solution was cooled to room temperature, 200 mL of ethyl acetate was added, and the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (DCM / EA = 1 / 1) to obtain 0.63 g of a white solid (compound 4), with a yield of 62%. MS (m / z) 295 (M+1); 1HNMR (400MHz, CDCl3) δ: 1.73 (m, 1H), 2.04 (m, 1H), 2.48 (dd, J = 17.2, 5.6, 1H), 2.57 (m, 1H) ,3.01-3.11(m,2H),3.30(m,1H),3.62(d,J=14.1,2H),3.68(d,J=14.1,2H),5.90(s,1H),7.16-7.41(m,10H).

[0038] 0.88 g (3 mmol) of compound 4 and 0.36 g (3.6 mmol) of triethylamine were added to a 50 mL reaction flask containing 30 mL of toluene. 0.36 g (3.3 mmol) of trimethylchlorosilane was added under a nitrogen atmosphere. The reaction mixture was stirred at 40 °C for 5 h, and TLC showed that the reaction was complete. The reaction mixture was cooled to 0 °C, diluted with 20 mL of n-hexane / diethyl ether (1 / 1 v / v), filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 1.02 g of crude viscous product (compound 5). MS (m / z) 367 (M+1).

[0039] Compound 5 (1 g, 2.7 mmol) was added to a 25 mL reaction flask containing 10 mL of diethyl ether. Under nitrogen protection, 2 mL of a cold methyllithium solution in diethyl ether (1.5 M) was slowly added dropwise with stirring at -20 °C. The reaction mixture was stirred at -20 °C for 0.5 h, then heated to room temperature and stirred for another 1 h. TLC showed that the reaction was complete. 20 mL of an aqueous solution containing 150 mg of ammonium chloride was added and the mixture was stirred for another 0.5 h. The layers were separated, and the aqueous layer was extracted with dichloromethane (20 mL x 2). The combined organic layers were washed with saturated brine (20 mL x 2), dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (ether / methanol v / v 1 / 1) to give 0.68 g (86%) of a white solid (compound 6). MS (m / z) 293 (M+1).

[0040] Compound 6 (3 g, 10 mmol) and 3 g Pa-C (10%) were added to a 250 mL two-necked reaction flask containing 100 mL THF. After three hydrogen purgings at room temperature and stirring for 6 h, the reaction was complete by TLC. The mixture was filtered through diatomaceous earth, the solvent was evaporated under reduced pressure, and silica gel column chromatography was used to separate a colorless oil ((3R,6S)-3-amine-6-methylpiperidine, compound 7) 0.9 g, yield 76%. MS (m / z) 115 (M+1).

[0041] 4-Chloropyrrolo[2,3-d]pyrimidine (compound 8, 1.1 g, 7 mmol), (3R,6S)-3-amine-6-methylpiperidine (0.8 g, 7 mmol), and potassium carbonate (1 g, 7 mmol) were added to a 50 mL reactor containing water (5 mL) and 1-methyl-2-pyrrolidone (10 mL). The reactor was then placed in a 500 mL reaction vessel and stirred at 110 °C for 16 h. TLC (dichloromethane / methanol = 10:1) showed that the reaction was complete. The mixture was cooled to room temperature, and water (20 mL) was added. A solid precipitated out. Stirring was continued for 2 h, and the mixture was filtered under reduced pressure to obtain a viscous crude product. The crude product was placed in ethanol (20 ml), stirred at 60 °C for 1 h, and then purified by crystallization at room temperature. Filtration yielded a white solid N-((3R,6S)-6-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (compound 9, 1.3 g, 81%). MS: [M+H] = 232.

[0042] Compound 9 (1.3 g, 5.4 mmol) and 2.3 g sodium bicarbonate were added to a 50 mL three-necked flask containing 30 mL tetrahydrofuran. The mixture was cooled to 0 °C, and acryloyl chloride (0.6 g, 6.5 mmol) was added. The mixture was stirred at 0–5 °C for 4 h. TLC monitoring (dichloromethanol / methanol = 10:1, 1% triethylamine) showed that the starting material reacted completely. The mixture was diluted with water (25 mL) and extracted with ethyl acetate (25 mL x 2). The organic phases were combined and washed once with saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a white crude solid. In a 50 mL single-necked flask, the crude solid, ethyl acetate (5 mL), and n-hexane (10 mL) were added. The mixture was heated to 60 °C and stirred for 1 h, then stirred overnight at room temperature. The mixture was filtered under reduced pressure, and the filter cake was washed with n-hexane, dried, and then dried to obtain a white solid powder (compound 10, 0.9 g, 62%). MS:[M+H] + 286.

Claims

1. A method for preparing Ritlecitinib, comprising using D-glutamine as a starting material, reducing to obtain compound 2, then protecting with amino groups to obtain compound 3, then cyclizing to obtain compound 4, reacting with trimethylchlorosilane to obtain compound 5, reacting with methyllithium to obtain compound 6, then hydrogenating to obtain compound 7; then coupling compound 7 with compound 8 to obtain compound 9, and finally reacting compound 9 with acryloyl chloride to obtain compound 10 Ritlecitinib; The reaction route is as follows:

2. The method as described in claim 1, characterized in that, In the process of preparing compound 2 by reacting compound 1 under the action of Ru-C, hydrochloric acid was used as solvent and the reaction was carried out at 20-30℃ for 10-12h under a hydrogen atmosphere.

3. The method as described in claim 1, characterized in that, In the preparation of compound 3 from compound 2, anhydrous N,N-dicarboxamide was used as the reaction solvent. After dissolving in potassium carbonate, it was reacted with benzyl bromide under nitrogen protection at 40-60°C for 8-10 hours.

4. The method as described in claim 1, characterized in that, In the process of cyclizing compound 3 to prepare compound 4, dry tetrahydrofuran was used as solvent and sodium hydride as catalyst. The mixture was first stirred at 0-5℃ under nitrogen for 3-7 min, then methanesulfonyl chloride was added and stirred overnight at room temperature. Then sodium hydride was added and the reaction temperature was raised to 55-65℃ and stirred for 10-12 h.

5. The method as described in claim 1, characterized in that, In the process of preparing compound 5 by reacting compound 4 with trimethylchlorosilane, toluene was used as solvent, and the mixture was stirred at 40-45°C for 5-6 hours under a nitrogen atmosphere in the presence of triethylamine.

6. The method as described in claim 1, characterized in that, In the process of preparing compound 6 by reacting compound 5 with methyllithium, under nitrogen protection, a diethyl ether solution of methyllithium was added dropwise while stirring at -25 to -20°C. The reaction solution was then stirred at -25 to -20°C for 0.5 to 1 hour, then heated to room temperature and stirred for 1 to 2 hours. Finally, an aqueous solution containing ammonium chloride was added and stirred for another 0.5 to 1 hour.

7. The method according to any one of claims 1-6, characterized in that, In the preparation of compound 7 from compound 6, tetrahydrofuran was used as the solvent, and the mixture was stirred for 6-8 hours after hydrogen replacement at 20-30°C.

8. The method as described in claim 7, characterized in that, In the preparation of compound 9 from compound 7, potassium carbonate was used as a catalyst, and a mixed solvent of water and 1-methyl-2-pyrrolidone was used as the reaction solvent. The reaction was carried out at 100-120℃ with stirring for 15-18 hours.

9. The method as described in claim 8, characterized in that, Compound 9 was reacted with acryloyl chloride under alkaline conditions, using tetrahydrofuran as a solvent, at 0-5°C to prepare compound 10; the base was sodium bicarbonate.

10. The method of claim 1, comprising the following steps: (1) Compound 1 and Ru-C were added to a two-necked flask, and then 1 mol / L dilute hydrochloric acid was added. The reaction was carried out at room temperature under a hydrogen atmosphere. After the reaction was completed, the pH of the solution was adjusted to 8-9 with 1 mol / L NaOH. The solution was extracted with ethyl acetate, and the organic layer was dried with anhydrous Na2SO4, filtered, and concentrated to obtain compound 2. (2) Compound 2 and potassium carbonate were added to a reaction flask containing anhydrous N,N-dicarboxamide. Benzyl bromide was added at room temperature. The mixture was stirred at 40-60°C for 8-10 h under nitrogen protection. The reaction mixture was then cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, concentrated, and compound 3 was obtained. (3) Add compound 3 and sodium hydride to a two-necked flask containing dry tetrahydrofuran. Stir at 0-5℃ under nitrogen for 3-7 min, then add methanesulfonyl chloride. Stir overnight at room temperature, then add sodium hydride. Raise the reaction temperature to 55-65℃ and continue stirring for 10-12 h. Then cool the reaction solution to room temperature, add ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and separate to obtain compound 4. (4) Compound 4 and triethylamine were added to a reaction flask containing toluene. Trimethylchlorosilane was added under a nitrogen atmosphere. The reaction solution was stirred at 40-45°C for 5-6 hours. The reaction solution was cooled to 0-5°C, filtered with diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain compound 5. (5) Compound 5 was added to a reaction flask containing diethyl ether. Under nitrogen protection, a solution of diethyl ether containing methyl lithium was added dropwise while stirring at -25 to -20°C. The reaction solution was stirred at -25 to -20°C for 0.5 to 1 h. Then the temperature was raised to room temperature and stirring was continued for 1 to 2 h. Then an aqueous solution containing ammonium chloride was added and stirring was continued for 0.5 to 1 h. The layers were separated, the aqueous layer was extracted with dichloromethane, the combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and compound 6 was obtained. (6) Compound 6 was added to a two-necked reaction flask containing THF, and after being replaced with hydrogen three times at room temperature, the mixture was stirred for 6-8 hours. Then, it was filtered with diatomaceous earth, and the solvent was removed by vacuum evaporation to separate compound 7. (7) Add 4-chloropyrrolo[2,3-d]pyrimidine, compound 7, and potassium carbonate to a reactor containing water and 1-methyl-2-pyrrolidone. Stir at 100-120℃ for 15-18h, cool to room temperature, add water, and a solid precipitates. Continue stirring for 2-3h, filter under reduced pressure to obtain a viscous crude product. Place the crude product in ethanol, stir at 50-60℃ for 1-2h, and then crystallize and purify at room temperature. Filter to obtain a white solid compound 9. (8) Compound 9 was reacted with acryloyl chloride at 0-5°C under alkaline conditions with tetrahydrofuran as solvent to prepare compound 10; the base was sodium bicarbonate.

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