Synthesis method of upatinib intermediate

Abstract

The invention discloses a synthesis method of an upatinib intermediate (3R, 4S)-1-((benzyloxy) carbonyl)-4-ethyl pyrrolidine-3-formic acid, which adopts a process route with N-benzyloxycarbonyl glycine ethyl ester and ethyl acrylate as raw materials, and carries out detailed research on key steps of reactions such as ring closing, acylation and bromination in the synthesis route. And the (3R. 4S) benzyl 3-(2-bromoacetyl)-4-ethyl pyrrolidine-1-formate is obtained at the total yield of 45%. The synthesis method of the upatinib intermediate is high in yield and purity, simple in post-treatment and suitable for industrial mass production.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical synthesis, and relates to a method for synthesizing an upadacitinib intermediate by using a chiral catalysis method. Background Art

[0002] Upadacitinib was approved for marketing by the US Food and Drug Administration (FDA) in August 2019 and was approved by the European Medicines Agency (EMA) in December 2019 for the treatment of adult patients with moderate to severe rheumatoid arthritis who are insufficiently responsive or intolerant to one or more disease-modifying anti-rheumatic drugs. In China, the original research upadacitinib sustained-release tablets were approved by the NMPA in 2022 and have currently been approved for five indications, successively approved for atopic dermatitis, psoriatic arthritis, rheumatoid arthritis, ulcerative colitis and Crohn's disease. The structural formula of upadacitinib is as follows:

[0003]

[0004] Upadacitinib contains two chiral centers, so the introduction of chiral groups is the key to the preparation process. (3R,4S)-benzyl 3-(2-bromoacetyl)-4-ethylpyrrolidine-1-carboxylate (Compound 9) is a key chiral intermediate for the preparation of upadacitinib, and its chiral purity has an important impact on the product quality of the final upadacitinib. Its structural formula is as follows:

[0005]

[0006] Currently, the synthetic methods of upadacitinib reported in the literature are mainly divided into chiral catalytic synthesis methods and chemical resolution methods. The main synthetic methods are as follows:

[0007] CN110627755A discloses a synthetic route that optimizes the synthetic route starting from ethyl 2-pentynoate as the starting material. Although this synthetic route solves the chiral resolution problem of the bromomethyl ketone intermediate, its synthetic steps are lengthy and the unit step yield is low, which is not suitable for industrial production.

[0008]

[0009] CN110615753A discloses another synthetic route that uses tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate as the starting material and obtains (3R,4S)-benzyl 3-(2-bromoacetyl)-4-ethylpyrrolidine-1-carboxylate of the intermediate through a series of reactions such as epoxidation and asymmetric catalytic reduction.

[0010]

[0011] Therefore, it is necessary to further study the synthesis method of upadacitinib or its intermediates to meet the requirements of simple and readily available raw materials, simple process operation, low process economic cost of products, and high chiral purity of the obtained products. Summary of the Invention

[0012] The present invention provides a synthesis method of upadacitinib intermediate compound 9. The raw materials of this method are cheap and readily available, the process operation is simple, the chiral purity of the product is high, and it is suitable for industrial production.

[0013] The synthesis method includes seven reaction steps:

[0014]

[0015] (1): Compound 1 and compound 2 react under alkaline conditions to obtain compound 3;

[0016] Among them, the alkaline conditions are provided in the presence of one or more of sodium tert-butoxide, potassium tert-butoxide, and lithium tert-butoxide;

[0017] The reaction is carried out in an organic solvent, and the organic solvent is selected from one or more of toluene, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, and dimethyl sulfoxide; preferably, the organic solvent is tetrahydrofuran;

[0018] The temperature and time of the reaction are 25 °C for 12 h;

[0019] After the reaction in step (1), the yield of compound 3 can reach 82.4%.

[0020] (2): Compound 3 is dissolved in an organic solvent and reacts with an acylating agent to obtain compound 4;

[0021] Among them, the acylating agent is one of p-toluenesulfonic anhydride, p-toluenesulfonyl chloride, acetyl chloride, acetic anhydride, and pivaloyl chloride; preferably, the acylating agent is acetic anhydride;

[0022] The organic solvent is one of toluene, tetrahydrofuran, 1,4-dioxane, dichloromethane, N,N-dimethylformamide, and dimethyl sulfoxide; preferably, the organic solvent is dichloromethane;

[0023] In the above process, the temperature and time of the reaction are 0 - 5 °C for 2 h;

[0024] After the reaction in step (2), the yield of compound 3 can reach 93.4%.

[0025] (3): Compound 4 and ethyl Grignard reagent react in an organic solvent at -10 °C to obtain compound 5;

[0026] Among them, the organic solvent is one of toluene, tetrahydrofuran, 1,4-dioxane, dichloromethane, N,N-dimethylformamide, and dimethyl sulfoxide; preferably, the solvent is toluene;

[0027] The temperature of the reaction is -20°C to 0°C; preferably, it is -10°C;

[0028] (4): Compound 5 undergoes a hydrolysis reaction in an organic solvent under basic conditions to obtain Compound 6;

[0029] Among them, the basic conditions are provided in the presence of one or more of sodium hydroxide, lithium hydroxide, and potassium hydroxide; preferably, the basic conditions are provided in the presence of sodium hydroxide;

[0030] The organic solvent is one of tetrahydrofuran, ethanol, and methanol; preferably, the solvent is tetrahydrofuran;

[0031] Among them, the temperature of the hydrolysis reaction is 40 - 80°C; the preferred reaction temperature is 50°C.

[0032] (5): Compound 6 undergoes a catalytic hydrogenation reaction under the action of a chiral catalyst to obtain Compound 7;

[0033] Among them, the chiral catalyst is the S-segphos 0Ru(OAc) 2 complex, and the molar amount of the complex is 0.001 - 0.1 equivalent of the molar amount of Compound 6; preferably, the molar amount of the catalyst S-segphos 0Ru(OAc) 2 added is 0.002 equivalent of the molar amount of Intermediate (6);

[0034] The solvent for the reaction is one or both of methanol and ethanol;

[0035] The hydrogen pressure for the reaction is 30 - 50 atm, and more preferably 30 atm;

[0036] The temperature of the reaction is 60°C;

[0037] The time for the reaction is 2 hours.

[0038] After the reaction is completed, the solvent is removed, and recrystallization is carried out using ethyl acetate, etc. to obtain the compound 7.

[0039] (6): Compound 7 reacts with trimethylsulfoxonium chloride under the mediation of CDI to obtain Compound 8;

[0040] The reaction in step (6) includes the following steps:

[0041] Step A: Compound 7 reacts with CDI in tetrahydrofuran to obtain reaction system ①;

[0042] Step B: Trimethylsulfoxonium chloride reacts with potassium tert-butoxide to obtain reaction system ②;

[0043] Step C: Add reaction system ① to reaction system ② and react to obtain compound 8.

[0044] (7): Compound 8 and a halogenating reagent undergo a substitution reaction under a catalyst to obtain compound 9;

[0045] Wherein the halogenating reagent is one or more of lithium bromide, hydrogen bromide, liquid bromine; preferably, the brominating reagent is lithium bromide;

[0046] The catalyst is one or more of acetic acid, trifluoroacetic acid, p-toluenesulfonic acid; preferably, the catalyst is p-toluenesulfonic acid;

[0047] The temperature and time of the substitution reaction are preferably 40 °C for 12 h;

[0048] The ratio of compound 8 to the halogenating reagent is n(compound 8):n(lithium bromide):n(p-toluenesulfonic acid) = 1:2.4:1;

[0049] The yield of (3R,4S)-benzyl 3-(2-bromoacetyl)-4-ethylpyrrolidine-1-carboxylate (compound 9) is 88.6%.

[0050] The following provides examples to help understand the present invention. However, it should be understood that these examples are only used to illustrate the present invention, but do not constitute any limitation. The actual protection scope of the present invention is set forth in the claims. It should be understood that any modifications and changes can be made without departing from the spirit of the present invention. Detailed Description of the Invention

[0051] To make the objectives, technical solutions and advantages of the present invention more clearly understood, the present invention will be further described in detail below in conjunction with examples. The specific examples described herein are only used to explain the present invention and do not constitute any limitation to the present invention. In addition, in the following description, the description of well-known structures and technologies is omitted to avoid unnecessarily confusing the concepts of the present invention. Such structures and technologies are also described in many publications.

[0052] Unless otherwise defined, all technical terms and scientific and technical terms used in the present invention have the same meaning as commonly used in the field to which the present invention belongs. For the purpose of explaining this specification, the following definitions will be applied, and where appropriate, terms used in the singular form will also include the plural form, and vice versa.

[0053] Unless the context clearly indicates otherwise, as used herein, the expressions "a" and "an" include plural referents. For example, reference to "a cell" includes a plurality of such cells and equivalents known to those skilled in the art, and the like.

[0054] As used herein, the term "about" refers to a range of ±20% of the value that follows. In some embodiments, the term "about" refers to a range of ±10% of the value that follows. In some embodiments, the term "about" refers to a range of ±5% of the value that follows.

[0055] The solvents used herein are commercially available. The following abbreviations are used herein:

[0056] TLC: Thin layer chromatography

[0057] THF: Tetrahydrofuran

[0058] DCM: Dichloromethane

[0059] DMF: N,N-Dimethylformamide

[0060] CDI: N,N-Carbonyldiimidazole

[0061] eq: Equivalent

[0062] Concentration N: g / L

[0063] The compounds were named by hand or software, and commercially available compounds were named using the supplier catalog name.

[0065] The technical solutions of the present invention will be described in detail below in conjunction with the examples, but the protection scope of the present invention is not limited thereto.

[0066] Example 1 Synthesis of Compound 9

[0067]

[0068] First step: Weigh 20.479 g of N-benzyloxycarbonylglycine ethyl ester (Compound 1) and add it to a 500 mL round-bottom flask. Then add 204.57 mL of tetrahydrofuran, cool to 0 °C, and then add 9.19 mL of ethyl acrylate (Compound 2) solution. Add 8.295 g of sodium tert-butoxide in proportion, and then heat the mixture to 25 °C and stir for 15 hours. Then add an appropriate amount of distilled water to quench the reaction, spin out the tetrahydrofuran with a rotary evaporator, extract with ethyl acetate 3 times, collect the aqueous phase, adjust the pH value to 4-5 and then extract with ethyl acetate 3 times, collect the organic phase, wash the organic phase with saturated sodium chloride solution, dry with anhydrous sodium sulfate, and concentrate to obtain 20.719 g of Compound 3 with a yield of 82.4%. 1 1H NMR (500 MHz, DMSO-d6 ) δ 7.44–7.31 (m, 5H), 5.14 (d, J=17.4 Hz, 2H), 4.25–4.09 (m, 4H), 3.98–3.84 (m, 2H), 1.22 (td, J=7.1, 5.3 Hz, 3H) ppm.

[0069] Step 2: Weigh 15.439 g of Compound 3 and place it in a 500 mL round-bottom flask. Add 125.61 mL of dichloromethane to dissolve Compound 3, then cool the temperature to 0 °C. Next, add 5.51 mL of acetic anhydride and 14.69 mL of triethylamine. React for 1 - 2 hours. Add an appropriate amount of distilled water to quench the reaction, separate the layers, wash the organic phase with water twice, add anhydrous sodium sulfate for drying, and concentrate to obtain Compound 4, weighing 18.117 g. Calculate the yield to be 93.4%. 1 H NMR (500 MHz, CD 3 Cl) δ 7.40–7.29 (m, 5H), 5.16 (d, J=4.4 Hz, 2H), 4.44–4.36 (m, 4H), 4.19 (qd, J=7.2, 3.8 Hz, 2H), 2.25 (d, J=7.1 Hz, 3H), 1.27 (td, J=7.1, 1.9 Hz, 3H) ppm.

[0070] Step 3: Weigh 12.43 g of Compound 4 and add it to a 250 mL round-bottom flask. Add 81 mL of toluene solution to dissolve it, then add 0.242 g of iron(III) acetylacetonate. Cool the temperature to -20 °C. Under the condition that the temperature is lower than -10 °C, add 50.3 mL of ethylmagnesium bromide. Monitor the reaction by TLC after reacting for 15 minutes, and perform post-treatment after the reaction is completed. Under the reaction condition of -20 °C, add an appropriate amount of ethanol solution to quench the reaction. After 30 minutes, add an appropriate amount of 6N hydrochloric acid solution, spin out the ethanol in the reaction solution, extract the aqueous phase with ethyl acetate three times, collect the organic phase, and wash it successively with dilute hydrochloric acid, aqueous potassium phosphate solution, and saturated sodium chloride aqueous solution, and dry it with anhydrous sodium sulfate. Concentrate to obtain Compound 5 as a yellow liquid, weighing 9.35 g. Calculate the yield to be 92.8%. 1 H NMR (500 MHz, CD 3 Cl) δ 7.44–7.32 (m, 5H), 5.20 (d, J=1.8 Hz, 2H), 4.47–4.33 (m, 4H), 4.24 (q, J=7.1 Hz, 2H), 2.73–2.64 (m, 2H), 1.33 (t, J=7.1 Hz, 3H), 1.12 (q, J=7.6 Hz, 3H) ppm.

[0071] Step 4: Weigh 7.461 g of Compound 5 and place it in a 100 mL round-bottom flask. Add 32.8 mL of THF solution, and then add 16.4 mL of 30% aqueous sodium hydroxide solution at room temperature. Heat the resulting mixture to 50 °C and stir for 7 hours. After the reaction is complete, cool it to room temperature, adjust the pH to 9 - 10 with concentrated hydrochloric acid, rotary evaporate the THF solution, then extract the aqueous phase twice with ethyl acetate. Collect the aqueous phase, adjust the pH of the solution to 4 - 5 with 6N hydrochloric acid to precipitate a white solid. After stirring for 1 hour, collect the solid. The actual weight after weighing is 5.396 g, and the calculated yield is 84.1%. 1 H NMR(500MHz,DMSO-d 6 )δ12.71(s,1H),7.46–7.28(m,5H),5.11(s,2H),4.39–4.19(m,4H),2.63–2.53(m,2H),1.03(td,J=7.5,6.2Hz,3H)ppm。

[0072] Step 5: Weigh 6.762 g of Compound 6 and place it in a pressure reactor. Dissolve it with 69 mL of methanol, then add 3.75 mL of triethylamine solution and 0.408 g of S-segphos 0Ru(OAc) 2 catalyst. Replace the gas in the pressure reactor three times with nitrogen, then replace it three times with hydrogen, maintain 30 atm, stir at 60 °C overnight, and monitor the reaction completion by TLC. After the reaction is complete, filter it through diatomaceous earth, wash the filter cake with methanol, collect the filtrate and concentrate it to obtain an oily liquid. The resulting product is Compound 7, weighing 6.130 g, and the calculated yield is 90.10%. 1 H NMR(500MHz,DMSO-d 6 )δ12.58(s,1H),7.36(d,J=5.6Hz,5H),5.07(s,2H),3.47(d,J=95.3Hz,4H),3.06(d,J=56.2Hz,2H),2.29(dq,J=15.7,7.5Hz,1H),1.32(d,J=85.1Hz,2H),0.96–0.84(m,3H)ppm。

[0073] Step 6: Solution ①: Take a 250 mL round-bottom flask, add 7.962 g of Compound 7 weighed, then dissolve it in 40 mL of tetrahydrofuran solution. After that, add 6.56 g of N,N-carbonyldiimidazole within 30 minutes and stir for 1 hour. Solution ②: Place 7.394 g of trimethylsulfoxonium chloride and 6.6119 g of potassium tert-butoxide in a round-bottom flask, add 40 mL of tetrahydrofuran, heat to 80 °C and reflux for 2 hours, then place it in a cold well and cool to -5 °C. Slowly add the solution obtained in the above Step ① to Solution ② within 15 min while maintaining the internal temperature below -1 °C. After the reaction is completed, quench the reaction with 10% sodium chloride solution, extract the aqueous phase 3 times with an appropriate amount of ethyl acetate solution, combine the organic phases, wash with saturated sodium chloride solution, collect the organic phase, dry it with anhydrous sodium sulfate, filter, concentrate, and obtain a yellow oily liquid. Place the obtained yellow oily liquid in a 250 mL round-bottom flask, add 34 mL of water, dry the water using a rotary evaporator, repeat three times, then add 130 mL of water to the flask, heat to 70 °C, and stir. After 30 min, cool to room temperature, filter to obtain 2.627 g of white solid Compound 8 with a yield of 93.9%. 1 HNMR(500MHz,DMSO-d 6 )δ7.39–7.28(m,5H),5.05(d,J=4.8Hz,2H),4.77(d,J=1.4Hz,1H),3.49–3.45(m,1H),3.44–3.41(m,6H),3.40–3.35(m,1H),3.33–3.27(m,1H),3.19–3.10(m,1H),2.80(dtd,J=23.5,7.0,4.0Hz,1H),2.14(dq,J=15.7,7.7Hz,1H),1.45(tdd,J=13.1,6.7,3.6Hz,1H),1.27–1.15(m,1H),0.88(td,J=7.4,3.6Hz,3H)ppm。

[0074] Step 7: Take a 100 mL round-bottom flask, add 2.476 g of Compound 8 and 1.468 g of lithium bromide in sequence, then add 25 mL of THF solution to dissolve, and then add 1.474 g of p-toluenesulfonic acid. Heat the obtained mixture to 40 °C and stir overnight. After the reaction is completed, wait for it to cool to room temperature, add water to quench the reaction. Extract the reaction solution twice with ethyl acetate, combine the organic phases, wash with saturated sodium bicarbonate solution and saturated sodium chloride in sequence, collect the organic phase, dry it with anhydrous sodium sulfate, filter, concentrate, and obtain a light yellow oily liquid. Weigh 2.203 g with a yield of 88.6%. 1 H NMR(500MHz,CD 3Cl) δ 7.37–7.27 (m, 5H), 5.19–5.02 (m, 2H), 3.95–3.85 (m, 2H), 3.72–3.63 (m, 1H), 3.61–3.48 (m, 3H), 3.35 (ddd, J=27.8, 10.6, 6.8 Hz, 1H), 2.37 (dq, J=10.2, 4.7 Hz, 1H), 1.42–1.18 (m, 2H), 0.91 (q, J=7.3 Hz, 3H) ppm。

[0075] As described above, it is only the specific implementation manner of the present invention and cannot be used to limit the protection scope of the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing an upadacitinib intermediate compound 9, comprising the following reaction steps: (1) Compound 1 and Compound 2 react under alkaline conditions to obtain Compound 3; (2) Compound 3 is dissolved in an organic solvent and reacted with an acylating agent to obtain compound 4; (3) Compound 4 reacts with an ethyl Grignard reagent in an organic solvent at -10°C to obtain compound 5; (4) Compound 5 undergoes hydrolysis in an organic solvent under alkaline conditions to obtain compound 6; (5) Compound 6 is subjected to catalytic hydrogenation reaction under the action of a chiral catalyst to obtain compound 7; (6) Compound 7 reacts with trimethyl sulfoxide chloride under CDI mediation to obtain compound 8; (7) Compound 8 undergoes a substitution reaction with a halogenating agent in the presence of a catalyst to give compound 9.

2. The synthesis method according to claim 1, wherein The alkaline condition in step (1) is provided in the presence of one or more of sodium tert-butoxide, potassium tert-butoxide, and lithium tert-butoxide; The organic solvent in step (1) is one or more of toluene, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide and dimethyl sulfoxide.

3. The synthesis method according to claim 1, wherein The acylating agent described in step (2) is one of p-toluenesulfonic anhydride, p-toluenesulfonyl chloride, acetyl chloride, acetic anhydride, and pivaloyl chloride; The organic solvent in step (2) is one of toluene, tetrahydrofuran, 1,4-dioxane, dichloromethane, N,N-dimethylformamide and dimethyl sulfoxide.

4. The synthesis method according to claim 1, wherein The alkaline condition in step (4) is provided in the presence of one or more of sodium hydroxide, lithium hydroxide, and potassium hydroxide; The organic solvent in step (4) is one of tetrahydrofuran, ethanol and methanol.

5. The synthesis method according to claim 1, wherein The chiral catalyst structure in step (5) is as follows: The amount of the chiral catalyst added is 0.001 to 0.01 molar equivalent of compound 6; The temperature of the catalytic hydrogenation reaction is 40-80°C.

6. The synthesis method according to claim 1, wherein Step (6) includes the following steps: Step A: Compound 7 reacts with CDI in tetrahydrofuran to obtain reaction system ①; Step B: Trimethyl sulfoxide chloride and potassium tert-butoxide react to obtain reaction system ②; Step C: Add reaction system ① into reaction system ② to obtain compound 8.

7. The synthesis method according to claim 1, wherein The halogenating agent in step (7) is one or more of lithium bromide, hydrogen bromide, and liquid bromine; The catalyst in step (7) is selected from one or more of acetic acid, trifluoroacetic acid and p-toluenesulfonic acid.

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