Process for the preparation of a jak inhibitor and intermediates thereof

Abstract

This invention provides a method for preparing a JAK inhibitor and its intermediates, comprising the following steps: Compound III and Compound IV undergo a Suzuki coupling reaction under the action of a catalyst to generate Compound II. In a certain solvent, Compound II is resolved by L-(-)-di-p-methoxybenzoyl tartaric acid to obtain Compound I. Compound I has not been reported in the literature, and the chemical purity and chiral purity of Compound I obtained after resolution and crystallization are high, with a purity of 99.8% and an ee value of 99.9%. Compound I is further alkali-free and phosphate-formed to obtain ruxolitinib phosphate, with a purity of 99.9% and an ee value of 99.9%, suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a method for preparing ruxolitinib and its intermediates. Background Technology

[0002] Ruxolitinib is an oral JAK1 and JAK2 tyrosine kinase inhibitor primarily used to treat polycythemia vera (PV) with inadequate or intolerable response to thiourea; intermediate- to high-risk myelofibrosis (MF); and steroid-refractory acute graft-versus-host disease (GVHD). Its chemical structure is shown below:

[0003]

[0004] Ruxolitinib is an (R)-isomer. The existing preparation methods are mainly two: asymmetric synthesis and chemical resolution. The former requires asymmetric catalysts, which are expensive; the latter mostly uses chiral columns and 2,3-dibenzoyl-D-tartaric acid, but the efficiency or yield is low, which is not conducive to industrial production.

[0005] WO2016035014A1 discloses a method for resolving the free base of a racemic ruxolitinib. The method involves dissolving 59.5 g of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile in acetonitrile (1190 mL), heating to 50 °C, adding (+)-2,3-dibenzoyl-D-tartaric acid (34.79 g), stirring for 15 minutes, gradually cooling to 25 °C, then stirring at 20–25 °C for 1–2 hours. The reaction mixture is then heated again to 68–70 °C, stirred for 30 minutes, gradually cooled to 25 °C, and stirred at 20–25 °C for 1–2 hours. The solid is filtered and washed with acetonitrile (100 mL). The resulting wet solid is further washed with acetonitrile (3… * The solution was purified three times using 600 mL of acetonitrile, acetone, and tetrahydrofuran (300 mL (225:37.5:37.5); 220 mL (165:27.5:27.5); 188 mL (141:23.5:23.5)). The resulting wet solid was dried under reduced pressure at 40–42 °C to give 9 g of compound V, with a chiral purity of 99.95%, a chromatographic purity of 99.91%, and a yield of 7.0%. It was then hydrolyzed and salted to form ruxolitinib phosphate.

[0006]

[0007]

[0008] WO2016063294 discloses a method for resolving the chaotic free base of ruxolitinib. The method involves reacting the chaotic free base of ruxolitinib with phosphoric acid in toluene, stirring at 25-30°C for 2 hours, cooling, crystallizing, washing with toluene, and drying to obtain the chaotic ruxolitinib phosphate. A mixture of the chaotic ruxolitinib phosphate (100 g), ethyl acetate (250 ml), and water (200 ml) is then stirred at 25-30°C for 15 minutes. The reaction mixture is alkalized with an aqueous sodium carbonate solution (35.7 g) at 25-30°C and stirred for 30 minutes. The aqueous layer is separated, and the organic layer is washed with water. The solvent in the organic layer is completely evaporated. Isopropanol (70 ml) and acetonitrile (850 ml) are added to the resulting compound at 25-30°C, followed by the addition of (+)-dibenzoyl tartaric acid (65 g) at 25-30°C, and stirring for 6 hours. The reaction mixture was heated to 80-85°C and stirred for 45 minutes. The reaction mixture was cooled to 25-30°C and stirred at the same temperature for 4 hours. The solid was filtered and washed with acetonitrile. The resulting compound was purified from a mixture of acetonitrile and isopropanol to give compound V, yield: 37.7 g, chiral purity: 99.75%. The yield of compound V was calculated to be 22.9% using the runoff of ruxolitinib phosphate as the starting material. The compound was then hydrolyzed and salted to form ruxolitinib phosphate.

[0009] There is an urgent need to find a simple method for preparing ruxolitinib that has high chemical and optical purity and is suitable for industrial production. Summary of the Invention

[0010] This invention provides a simple, industrially suitable method for preparing optically pure ruxolitinib or its intended drug salt.

[0011] The first aspect of the present invention provides a method for preparing compound I, the method comprising resolving a racemic compound II with L-(-)-di-p-methoxybenzoyl tartaric acid to obtain compound I, as follows:

[0012]

[0013] A second aspect of the present invention provides a method for preparing ruxolitinib or a pharmaceutical salt thereof, the method comprising resolving the racemic compound II with L-(-)-di-p-methoxybenzoyl tartaric acid to obtain compound I.

[0014] Preferably, the preparation method of the second aspect of the present invention includes:

[0015] (1) Compound I was obtained by resolving the racemic compound II with L-(-)-di-p-methoxybenzoyl tartaric acid;

[0016] (2) Compound I was treated with alkali to obtain ruxolitinib;

[0017] The reaction is as follows:

[0018]

[0019] More preferably, the preparation method of the second aspect of the present invention includes:

[0020] (1) Compound III and compound IV undergo a coupling reaction under the action of a catalyst to obtain a racemic compound II; (2) Compound I is obtained by resolving the racemic compound II with L-(-)-di-p-methoxybenzoyl tartaric acid.

[0021] (3) Compound I was treated with alkali to obtain ruxolitinib.

[0022] The reaction is as follows:

[0023]

[0024] A third aspect of the invention provides compound I, with the structure shown below.

[0025]

[0026] A fourth aspect of the invention provides the use of compound I in the preparation of ruxolitinib or a pharmaceutically acceptable salt thereof.

[0027]

[0028] The ruxolitinib obtained by the preparation method described in this invention can be further prepared into pharmaceutically acceptable salts, such as sulfates, maleates, and phosphates, preferably phosphates.

[0029] In this invention, the process of resolving the racemic compound II with L-(-)-di-p-methoxybenzoyl tartaric acid to obtain compound I specifically includes the following steps:

[0030] (1) The mixture of compound II and L-(-)-di-p-methoxybenzoyl tartaric acid was added to organic solvent 1, heated and stirred until dissolved, cooled and crystallized to obtain crude compound I.

[0031] (2) The crude compound I obtained in step (1) is purified with organic solvent 2.

[0032] Furthermore, the molar ratio of the racemic compound II to L-(-)-di-p-methoxybenzoyl tartaric acid is 1:0.5 to 1, preferably 0.5 to 0.7.

[0033] Furthermore, the mass-to-volume ratio of the racemic compound II to the organic solvent 1 is 1:8–25, preferably 1:10–20.

[0034] Furthermore, the mass-to-volume ratio of the racemic compound II to the organic solvent 2 is 1:5 to 20, preferably 1:10 to 15.

[0035] Furthermore, organic solvent 1 and organic solvent 2 can be the same or different. Preferably, organic solvent 1 and organic solvent 2 are the same solvent.

[0036] Furthermore, the organic solvent 1 and organic solvent 2 are selected from one or more of alcohol solvents, chlorine solvents, ketone solvents, polar aprotic solvents, nitrile solvents, ester solvents, and hydrocarbon solvents.

[0037] Furthermore, the organic solvent 1 and organic solvent 2 are selected from one or more of methanol, ethanol, isopropanol, dichloromethane, acetone, 2-butanone, tetrahydrofuran, 1,4-dioxane, acetonitrile, ethyl acetate, methyl acetate, propyl acetate and butyl acetate.

[0038] Furthermore, organic solvent 1 and organic solvent 2 are selected from 2-butanone and acetone.

[0039] Furthermore, in step (1), the heating temperature is 50-70℃, preferably 50-60℃.

[0040] Furthermore, in step (1), the cooling and crystallization temperature is 10-30℃, preferably 10-20℃.

[0041] Furthermore, in step (2), the crude product of compound I, refined in step (2), is dissolved in organic solvent 2 by heating, followed by cooling to crystallize. The crystallization temperature is 10-30℃, preferably 10-20℃.

[0042] The racemic compound II can be prepared by methods known in the art, such as those described in WO2016063294, or as described herein.

[0043] When preparing compound II according to the preparation method of the present invention, the coupling reaction is carried out in a solvent in the presence of a base and an organometallic catalyst. The base may be an inorganic or organic base, preferably one or more of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, and potassium tert-butoxide; the solvent is selected from one or more of acetonitrile, 1,4-dioxane, toluene, tetrahydrofuran, and water; the organometallic catalyst is selected from Pd(dppf)₂Cl₂, Pd(PPh₃)₄, Pd(PPh₃)₂Cl₂, or palladium acetate.

[0044] Compound II can optionally be separated by filtration, extraction, distillation, evaporation, precipitation, concentration, crystallization, centrifugation, or recrystallization. Optionally, compound II can be dried using conventional techniques, such as drying, vacuum drying, spray drying, freeze drying, and stirred film drying.

[0045] In this invention, the preparation of ruxolitinib by treating compound I with an alkali is carried out in a solvent. The alkali may be an inorganic or organic base; preferably, it is one or more of sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, and potassium tert-butoxide; more preferably, it is sodium bicarbonate. The solvent is selected from one or more of water, esters, halogenated hydrocarbons, and ketones; preferably, it is one or more of water, methanol, ethanol, ethyl acetate, methyl acetate, propyl acetate, butyl acetate, dichloromethane, dichloroethane, chloroform, methyl vinyl ketone, methyl isobutyl ketone, butanone, 2-pentanone, and 3-pentanone; more preferably, it is dichloromethane. Detailed Implementation

[0046] The present invention will be further described in conjunction with embodiments. The following embodiments are merely illustrative of the invention and are not intended to limit the invention in any way.

[0047] the term:

[0048] The terms “include” or “contain” should be interpreted as open-ended, indicating the presence of the listed elements but excluding the presence, occurrence, or addition of any other unlisted elements.

[0049] All ranges described in this article include those endpoints that list the range between two values. Whether indicated or not, all values ​​listed in this article include the expected degree of experimental, technical, and instrumental error of the given technique used to measure that value.

[0050] The reagents and raw materials used in this invention are commercially available or prepared using existing technologies. In cases where the Chinese nomenclature of a compound conflicts with its structural formula, the structural formula shall prevail, except where the structural formula is obviously incorrect.

[0051] The abbreviations used in this invention are explained as follows:

[0052] 1 H NMR: Hydrogen nuclear magnetic resonance

[0053] ESI-MS: Electrospray ionization mass spectrometry

[0054] Pd(dppf)2Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride

[0055] Pd(PPh3)4: Tetra(triphenylphosphine)palladium

[0056] Pd(PPh3)2Cl2: Bis(triphenylphosphine)palladium dichloride

[0057] Reference Example 1: Preparation of Compound II

[0058] Compound III (10.0 g, 31.7 mmol) and Compound IV (5.9 g, 38.0 mmol) were mixed, and 80 mL of dioxane, 40 mL of water, potassium carbonate (8.8 g, 63.4 mmol), and bis(triphenylphosphine)palladium dichloride (0.5 g, 5% wt) were added sequentially. After three N2 substitutions, the mixture was heated to 80-90 °C and reacted for 18-24 h. The reaction was checked for complete reaction of Compound II, and the mixture was cooled. The reaction solution was quenched in 100 mL of ethyl acetate and 100 mL of water, stirred for 1 h, and allowed to stand for separation. The organic layer was washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate, and concentrated to remove the organic solvent, yielding crude Compound II in approximately 85.6% yield.

[0059] Example 1: Preparation of Compound I

[0060] An 83 mL solution of 2-butanone containing compound II (8.3 g, 27.1 mmol) was heated to 50-60 °C, and L-(-)-di-p-methoxybenzoyl tartaric acid (6.8 g, 16.3 mmol) was added. After stirring until dissolved, the solution was cooled to 10-20 °C to induce crystallization. The crystals were filtered to obtain a gray solid. This solid was then added to 83 mL of 2-butanone, heated to 65-75 °C, stirred until dissolved, and then cooled to 10-20 °C to induce crystallization. The crystals were filtered, and the wet product was dried under vacuum at 40 °C to obtain 7.8 g of gray solid, which was the target compound I. Yield: 40.0%, purity: 99.8%, ee value: 99.9%.

[0061] ESI-MS (m / z): 307.1 [M+H] +

[0062] 1H NMR(600MHz,MeOD)δ8.71(d,J=7.9Hz,2H),8.43(s,1H),8.09–8.02(m,4H),7.59(d,J=3.6Hz,1H), 7.04–7.02(m,3H),7.01–6.99(m,2H),5.94(s,2H),4.52(td,J=9.9,3.9Hz,1H),3.88(s,6H),3.24( dd,J=17.2,9.7Hz,1H),3.15(dd,J=17.2,3.9Hz,1H),2.57(dd,J=17.3,8.1Hz,1H),2.02–1.89(m,1 H),1.79–1.70(m,1H),1.70–1.60(m,2H),1.60–1.52(m,1H),1.51–1.34(m,2H),1.33–1.24(m,1H).

[0063] Example 2: Preparation of Compound I

[0064] An 83 mL solution of 2-butanone containing compound II (8.3 g, 27.1 mmol) was heated to 50-60 °C, and L-(-)-di-p-methoxybenzoyl tartaric acid (6.8 g, 16.3 mmol) was added. After stirring until dissolved, the solution was cooled to 10-20 °C to induce crystallization. The crystals were filtered to obtain a gray solid. This solid was added to 100 mL of 2-butanone, heated to 65-75 °C, stirred until dissolved, and then cooled to 10-20 °C to induce crystallization. The crystals were filtered, and the wet product was dried under vacuum at 40 °C to obtain 7.8 g of gray solid, which was the target compound I. Yield: 38.0%, purity: 99.8%, ee value: 99.9%. (Note: ESI-MS (m / z) and...) 1 H NMR data are the same as in Example 1)

[0065] Example 3: Preparation of Ruxolitinib Phosphate

[0066] Compound I (5 g, 6.9 mmol) was added to 50 mL of dichloromethane. 30 mL of 5.0% sodium bicarbonate aqueous solution was slowly added at 20-30 °C. After addition, the mixture was stirred at 20-30 °C for 2 h, then allowed to stand and separate. The aqueous layer was extracted once with dichloromethane (25 mL). The organic phases were combined, concentrated, and dissolved in 50 mL of isopropanol. A mixed solution of 0.7 g of phosphoric acid and 10 mL of isopropanol was added dropwise to the filtrate at 15-30 °C. After the addition was complete, the mixture was stirred at 10-20 °C for 2 h. After filtration, the wet product was vacuum dried in a vacuum drying oven at 40 °C for 16-24 h to obtain 2.6 g of white solid (yield: 93.2%), which is ruxolitinib phosphate. Purity: 99.9%, ee value: 99.9%.

[0067] ESI-MS(m / z):307.1[M+H] +

[0068] 1 H NMR(600MHz,DMSO-d6)δ12.15(s,1H),8.83(d,J=31.1Hz,1H),8.69(s,1H),8.39(s,1H),7.65–7.56(m,1H),7.48–7.04(m,3H),7.00(d,J=2.4Hz,1H),4.54(td,J=9.8,3.8Hz,1H),3.27(dd,J=17.2,9.9Hz,1H),3.19(dd,J=17.2,3.9Hz,1H),2.46–2.35(m,1H),1.85–1.75(m,1H),1.65–1.57(m,1H),1.56–1.48(m,2H),1.47–1.37(m,1H),1.36–1.23(m,2H),1.22–1.14(m,1H).。

Claims

1. A method for preparing compound I, comprising the following steps: resolving a racemic compound II with L-(-)-di-p-methoxybenzoyl tartaric acid to obtain compound I, the reaction being as follows: ， The process of resolving the racemic compound II with L-(-)-di-p-methoxybenzoyl tartaric acid to obtain compound I specifically includes the following steps: (1) The mixture of compound II and L-(-)-di-p-methoxybenzoyl tartaric acid was added to organic solvent 1, heated and stirred until dissolved, cooled and crystallized to obtain crude compound I; (2) The crude compound I obtained in step (1) is purified with organic solvent 2.

2. A method for preparing ruxolitinib or its pharmaceutical salt, characterized in that, Including the method for preparing compound I according to claim 1.

3. A method for preparing ruxolitinib or its pharmaceutical salt, characterized in that, Includes the following steps: (1) Compound III and compound IV undergo a coupling reaction under the action of a catalyst to obtain the racemic compound II; (2) Compound I was obtained by resolving the racemic compound II with L-(-)-di-p-methoxybenzoyl tartaric acid; (3) Compound I was treated with alkali to obtain ruxolitinib; The reaction is as follows: ； The process of resolving the racemic compound II with L-(-)-di-p-methoxybenzoyl tartaric acid to obtain compound I specifically includes the following steps: (1) The mixture of compound II and L-(-)-di-p-methoxybenzoyl tartaric acid was added to organic solvent 1, heated and stirred until dissolved, cooled and crystallized to obtain crude compound I; (2) The crude compound I obtained in step (1) is purified with organic solvent 2.

4. The preparation method according to claim 3, characterized in that, The coupling reaction in step (1) is carried out in a solvent in the presence of a base and an organometallic catalyst; in, The alkali is selected from one or more of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, and potassium tert-butoxide. The solvent is selected from one or more of acetonitrile, 1,4-dioxane, toluene, tetrahydrofuran, and water; The organometallic catalyst is selected from Pd(dppf)2Cl2, Pd(PPh3)4, Pd(PPh3)2Cl2 or palladium acetate.

5. The preparation method according to claim 3, characterized in that, The step of treating compound I with alkali to obtain ruxolitinib in step (3) is carried out in a solvent; in, The alkali is selected from one or more of sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, and potassium tert-butoxide. The solvent is selected from one or more of water, esters, halogenated hydrocarbons, and ketones.

6. The preparation method according to claim 5, characterized in that, In step (3), the base is sodium bicarbonate; the solvent is selected from one or more of water, methanol, ethanol, ethyl acetate, methyl acetate, propyl acetate, butyl acetate, dichloromethane, dichloroethane, chloroform, methyl vinyl ketone, methyl isobutyl ketone, butanone, 2-pentanone, and 3-pentanone.

7. The preparation method according to claim 6, characterized in that, In step (3), the solvent is dichloromethane.

8. The preparation method according to any one of claims 1 to 3, characterized in that, In step (1), the molar ratio of the racemic compound II to L-(-)-di-p-methoxybenzoyl tartaric acid is 1:0.5~1; the mass-volume ratio of the racemic compound II to organic solvent 1 is 1:8~25 (g / mL); the heating temperature is 50-75℃; and the cooling crystallization temperature is 10-30℃.

9. The preparation method according to claim 8, characterized in that, In step (1), the molar ratio of the racemic compound II to L-(-)-di-p-methoxybenzoyl tartaric acid is 1:0.5~0.7; the mass-volume ratio of the racemic compound II to organic solvent 1 is 1:10~20 (g / mL); the heating temperature is 50-60℃; and the cooling crystallization temperature is 10-20℃.

10. The preparation method according to any one of claims 1 to 3, characterized in that, The organic solvent 1 and the organic solvent 2 may be the same or different.

11. The preparation method according to claim 10, characterized in that, Organic solvent 1 and organic solvent 2 are the same solvent.

12. The preparation method according to any one of claims 1 to 3, characterized in that, The organic solvent 1 and the organic solvent 2 are selected from one or more of alcohol solvents, chlorine solvents, ketone solvents, polar aprotic solvents, nitrile solvents, ester solvents, and hydrocarbon solvents.

13. The preparation method according to claim 12, characterized in that, The organic solvent 1 and the organic solvent 2 are selected from one or more of methanol, ethanol, isopropanol, dichloromethane, acetone, 2-butanone, tetrahydrofuran, 1,4-dioxane, acetonitrile, ethyl acetate, methyl acetate, propyl acetate and butyl acetate.

14. The preparation method according to claim 13, characterized in that, Both organic solvent 1 and organic solvent 2 are 2-butanone.

15. The preparation method according to any one of claims 1 to 3, characterized in that, The purification in step (2) includes the following steps: the crude compound I is heated and dissolved in organic solvent 2, and then cooled to crystallize at a temperature of 10-30℃; the volume-to-mass ratio of the organic solvent 2 to the compound II mixed in step (1) is 5-20:1 (mL / g).

16. The preparation method according to claim 15, characterized in that, In the purification process of step (2), the crystallization temperature is 10-20℃; the volume-to-mass ratio of the organic solvent 2 to the compound II that was mixed in step (1) is 10-15:1 (mL / g).

17. A compound I has the following structure: 。 18. Use of compound I according to claim 17 in the preparation of ruxolitinib or its pharmaceutical salt.

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