Isoxazole compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to an isoxazole compound and a preparation method and application thereof.The isoxazole compound is convenient to prepare and stable in structure; the invention also relates to a method for preparing baricitinib or rucotinib through the isoxazole compound. The baricitinib or rucotinib can be prepared with high yield and high purity, the preparation process is easy to operate, the cost is low, and the preparation method is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of drug synthesis, and particularly relates to a pharmaceutical intermediate of baricitinib or ruxolitinib and a preparation method thereof. BACKGROUND

[0002] Janus kinase (JAK) is a kind of non-receptor type tyrosine kinase which is associated with the composition of cytokine receptors. There are four members in the JAK family, which are JAK1, JAK2, TYK2 and JAK3, among which JAK1, JAK2 and TYK2 are widely distributed in various tissues and cells, and JAK3 only exists in the bone marrow and lymphatic system. Based on their specific distribution and functional characteristics, JAK1 has become a new target in the fields of immunity, inflammation and tumors; JAK2 has become an effective target for the treatment and prevention of blood system related diseases.

[0003] Ruxolitinib and baricitinib are both selective JAK1 / JAK2 kinase inhibitors.

[0004] Among them, ruxolitinib is developed by Incyte and Novartis, and was approved by the US FDA in November 2011 as the first drug for treating myelofibrosis, used for adult patients with primary myelofibrosis (PMF) (also known as chronic idiopathic myelofibrosis), secondary myelofibrosis (PPV-MF) or secondary myelofibrosis (PET-MF) in patients with primary thrombocytopenia, for the treatment of disease-related splenomegaly or disease-related symptoms. The chemical name of ruxolitinib is (R)-3-(4-(7H-pyrrolo[2,3[2,3-d]pyrimidin-4-yl]-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile, and its chemical structure is as follows:

[0005]

[0006] Baricitinib is developed by Eli Lilly and Incyte pharmaceutical companies, which is a selective and reversible JAK1 / JAK2 kinase inhibitor, used for treating autoimmune diseases and related inflammation, such as rheumatoid arthritis, psoriatic arthritis and reactive arthritis. The chemical name of baricitinib is 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidine acetonitrile, and the structure is as follows:

[0007]

[0008] Patent WO2023288197A1 discloses a method for preparing baricitinib from intermediate a and 2-(1-(ethylsulfonyl)-3-hydrazinylazetidin-3-yl)acetonitrile, wherein X is a counter anion, the reaction formula is as follows, and when X is perchlorate in Example 1 thereof, the reaction yield is 85%:

[0009]

[0010] Patents US2023 / 399331, US2022 / 56035 and CN116761792A disclose a method for preparing lucomitinib by reacting intermediate a and a' with compound (R)-3-cyclopentyl-3-hydrazinylpropionitrile, intermediate a in the reaction route thereof needs to be prepared by reacting in-situ generated vilsmeier reagent with 4-methyl-7H-pyrrolo[2,3-d]pyrimidine, and the in-situ generation of the vilsmeier reagent needs to involve acyl chloride (highly toxic and reacts violently with water) reagents such as phosphorus oxychloride and oxalyl chloride, and the vilsmeier reagent is prone to deterioration and is not easy to store, and generally can only be prepared on site, increasing the complexity of process operation. The reaction formula is as follows:

[0011]

[0012] Through analysis of the above routes, baricitinib or lucomitinib can be prepared by reacting the same substrate a or a' with 2-(1-(ethylsulfonyl)-3-hydrazinylazetidin-3-yl)acetonitrile and (R)-3-cyclopentyl-3-hydrazinylpropionitrile, respectively, but the preparation process of the substrates a and a' is complex, which limits industrialized production. The reaction groups of the substrates 2-(1-(ethylsulfonyl)-3-hydrazinylazetidin-3-yl)acetonitrile and (R)-3-cyclopentyl-3-hydrazinylpropionitrile are both related to hydrazino, so a new substrate needs to be found to meet the preparation of baricitinib or lucomitinib to solve the problems in the prior art. SUMMARY

[0013] The purpose of the present application is to overcome the deficiencies in the prior art, and to provide an intermediate, a synthesis method thereof and a method for preparing baricitinib or lucomitinib using the intermediate. The method has a simple process route, raw materials are easy to obtain, is easy to operate, has low cost and is suitable for industrialized production.

[0014] In order to achieve the above-mentioned purpose, the present application is realized by the following scheme:

[0015] In a first aspect, the present application provides an isoxazole compound, which has the following structural formula:

[0016]

[0017] In a second aspect, the present application provides a preparation method of an isoxazole compound, comprising the following steps:

[0018] Under inert gas, a reaction solvent is added to a reaction vessel, stirred and sequentially added with compound 1, compound 2 and a palladium catalyst, and then an aqueous solution of an inorganic base is added after uniform stirring. The system is controlled at a temperature T1 for stirring until the reaction is completed. After post-treatment, compound 3 is obtained. The route is as follows:

[0019]

[0020] Preferably, the reaction solvent is one of tert-butyl alcohol, n-butyl alcohol and 1,4-dioxane, preferably 1,4-dioxane.

[0021] Preferably, the molar ratio of compound 1, compound 2 and the palladium catalyst is 1.00: (1.00-1.50): (0.003-0.010), preferably 1.00:1.10:0.006.

[0022] Preferably, the palladium catalyst is one of Pd(PPh3)4, Pd(dppf)Cl2·CH2Cl2 and Pd(PPh3)2Cl2, preferably Pd(dppf)Cl2·CH2Cl2.

[0023] Preferably, the inorganic base is one of potassium carbonate, sodium carbonate, cesium carbonate and potassium phosphate, preferably potassium carbonate. The aqueous solution of the inorganic base is selected from potassium carbonate, cesium carbonate and potassium phosphate with a mass fraction of 30-40%. The aqueous solution of sodium carbonate is selected with a mass fraction of 17-18%.

[0024] Preferably, the molar ratio of compound 1 and the inorganic base is 1.00:2.00-3.00, preferably 1.00:2.50.

[0025] Preferably, the reaction temperature T1 is 85-95℃.

[0026] Preferably, the inert gas is nitrogen or argon.

[0027] Preferably, the post-treatment is as follows: after the reaction is completed, the system is cooled to room temperature and filtered. The filtrate is extracted with ethyl acetate, and the organic phases are combined and concentrated to dryness under reduced pressure. The obtained concentrate is heated to reflux with ethanol, filtered after cooling, and the filter cake is washed with ethanol and dried under vacuum at 50-60℃ to obtain compound 3.

[0028] In a third aspect, a preparation method of Rociominib using compound 3 is provided, comprising the following steps:

[0029] Into the reaction vessel, acetonitrile and hydrochloric acid were added successively, stirred and then compound 3, compound 4 and tungsten reagent were added successively, the system was stirred at temperature T2 until the reaction was completed, and then the target product was obtained by post-treatment. The route is as follows:

[0030]

[0031] Preferably, the molar ratio of compound 3, compound 4 and tungsten reagent is 1.0: (1.1-2.0): (0.3-1.0), preferably 1.0:1.2:0.5.

[0032] Preferably, the molar ratio of compound 3 and hydrochloric acid is 1.0:2.0-4.0, preferably 1.0:3.0. The hydrochloric acid is selected from a 1-4M hydrochloric acid aqueous solution.

[0033] Preferably, the tungsten reagent is one of W(CH3CN)2(CO)4, W(CH3CN)3(CO)3 and W(CO)6, preferably W(CH3CN)2(CO)4.

[0034] Preferably, the reaction temperature T2 is 75-85℃.

[0035] Preferably, the post-treatment is as follows: after the reaction is completed, the system is cooled to room temperature, then filtered, the pH of the obtained filtrate is adjusted to 6-7 using a base, the system is stirred to precipitate crystals, then filtered and the filter cake is washed with water. The obtained wet filter cake is recrystallized using an ethanol / water mixture, then dried at 60-70℃ under vacuum to obtain the target product.

[0036] Preferably, the base used for adjusting the pH is an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, preferably a 1-3M sodium hydroxide aqueous solution.

[0037] Preferably, the volume ratio of the ethanol / water mixture is 3:1.

[0038] In a fourth aspect, a method for preparing baricitinib using compound 3 is provided. The method comprises the following steps:

[0039] Into the reaction vessel, acetonitrile and hydrochloric acid were added successively, stirred and then compound 3, compound 5 and tungsten reagent were added successively, the system was stirred at temperature T3 until the reaction was completed, and then the target product was obtained by post-treatment. The route is as follows:

[0040]

[0041] Preferably, the molar ratio of compound 3, compound 5 and tungsten reagent is 1.0: (1.1-2.0): (0.3-1.0), preferably 1.0:1.2:0.5.

[0042] Preferably, the molar ratio of compound 3 to hydrochloric acid is 1.0:2.0-4.0, preferably 1.0:3.0. The hydrochloric acid is selected from a 1-4M aqueous hydrochloric acid solution.

[0043] Preferably, the tungsten reagent is one of W(CH3CN)2(CO)4, W(CH3CN)3(CO)3, and W(CO)6, preferably W(CH3CN)2(CO)4.

[0044] Preferably, the reaction temperature T3 is 75-85℃.

[0045] Preferably, the post-treatment is as follows: after the reaction is completed, the mixture is cooled to room temperature, then filtered, the obtained filtrate is adjusted to pH 6-7 with a base, then stirred to crystallize, filtered, and the filter cake is washed with water. The obtained wet filter cake is heated to reflux with ethanol, then filtered, and the filter cake is washed with ethanol and dried in vacuum at 60-70℃ to obtain baricitinib.

[0046] Preferably, the base used for adjusting pH is an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate, preferably a 1-3M aqueous sodium hydroxide solution.

[0047] Compared with the prior art, the present application has the following technical effects:

[0048] (1) The present application provides a new pharmaceutical intermediate and a preparation method thereof. The intermediate is easy to prepare, stable in structure, and can be prepared in high yield and high purity.

[0049] (2) The intermediate can be used as a raw material to prepare selective JAK1 / JAK2 kinase inhibitors baricitinib and ruxolitinib in high yield and high purity, which is easy to operate, low in cost, and suitable for industrial production. DETAILED DESCRIPTION

[0050] The present application is further illustrated by the following examples, which should be correctly understood as: the examples of the present application are only used to illustrate the present application, but not to limit the present application, so that simple improvements of the present application under the premise of the method of the present application are within the scope of the present application.

[0051] Preparation of compound 3:

[0052] Example 1

[0053] Compound 1 (28.38 g, 100 mmol, 1.00 eq.), compound 2 (21.45 g, 110 mmol, 1.10 eq.), Pd(dppf)Cl2CH2Cl2(0.49 g, 0.6 mmol, 0.006 eq.) were added into 1,4-dioxane (300 mL) under nitrogen atmosphere, after stirring uniformly, a mixture of potassium carbonate (34.55 g, 250 mmol, 2.50 eq.) and water (100 mL) was added. After stirring at 85-95 °C for 3-4 hours, the reaction was detected to be complete, cooled to room temperature and filtered, the filtrate was extracted with ethyl acetate (100 mL x 2), the combined organic phase solution was concentrated under reduced pressure. Ethanol (200 mL) was added to the concentrate, heated to reflux and slurried for 1-2 hours, after cooling to room temperature, suction filtration was performed, the filter cake was washed with ethanol (50 mL), and then dried under vacuum at 50-60 °C for 6-8 hours to obtain white compound 3 (yield 89.1%), HPLC purity 99.45%. ESI-MS (m / z): 317.49 [M+H] + ; 1 H NMR (400 MHz, d6-DMSO): δ = 8.89 (s, 1H), 8.77 (s, 1H), 8.65 (s, 1H), 7.75 (d, 1H), 7.24 (d, 1H), 5.64 (s, 2H), 3.53 (t, 2H), 0.84 (t, 2H), 0.15 (s, 9H).

[0054] Example 2

[0055] Compound 1 (28.38 g, 100 mmol, 1.00 eq.), compound 2 (21.45 g, 110 mmol, 1.10 eq.), Pd(PPh3)4(0.70 g, 0.6 mmol, 0.006 eq.) were added into 1,4-dioxane (300 mL) under nitrogen atmosphere, after stirring uniformly, a mixture of potassium carbonate (34.55 g, 250 mmol, 2.50 eq.) and water (100 mL) was added. After stirring at 85-95 °C for 3-4 hours, the reaction was detected to be complete, cooled to room temperature and filtered, the filtrate was extracted with ethyl acetate (100 mL x 2), the combined organic phase solution was concentrated under reduced pressure. Ethanol (200 mL) was added to the concentrate, heated to reflux and slurried for 1-2 hours, after cooling to room temperature, suction filtration was performed, the filter cake was washed with ethanol (50 mL), and then dried under vacuum at 50-60 °C for 6-8 hours to obtain white compound 3 (yield 88.3%), HPLC purity 99.32%.

[0056] Example 3

[0057] Compound 1 (28.38 g, 100 mmol, 1.00 eq.), compound 2 (21.45 g, 110 mmol, 1.10 eq.), Pd(PPh3)2Cl2(0.21 g, 0.3 mmol, 0.003 eq.) were added to n-butanol (300 mL) under nitrogen atmosphere, after stirring well, a mixture of sodium carbonate (26.50 g, 250 mmol, 2.50 eq.) and water (130 mL) was added. After stirring at 85-95 °C for 3-4 hours, the reaction was detected to be complete, cooled to room temperature and filtered, the filtrate was extracted with ethyl acetate (100 mL x 2), the combined organic phase solution was concentrated under reduced pressure. Ethanol (200 mL) was added to the concentrate, heated to reflux and slurried for 1-2 hours, after cooling to room temperature, suction filtration, the filter cake was washed with ethanol (50 mL) and dried under vacuum at 50-60 °C for 6-8 hours to obtain off-white compound 3 (yield 85.1%), HPLC purity 99.34%.

[0058] Example 4

[0059] Compound 1 (28.38 g, 100 mmol, 1.00 eq.), compound 2 (21.45 g, 110 mmol, 1.10 eq.), Pd(dppf)Cl2CH2Cl2(0.49 g, 0.6 mmol, 0.006 eq.) were added to t-butanol (300 mL) under nitrogen atmosphere, after stirring well, a mixture of potassium phosphate (42.46 g, 200 mmol, 2.00 eq.) and water (100 mL) was added. After stirring at 85-95 °C for 3-4 hours, the reaction was detected to be complete, cooled to room temperature and filtered, the filtrate was extracted with ethyl acetate (100 mL x 2), the combined organic phase solution was concentrated under reduced pressure. Ethanol (200 mL) was added to the concentrate, heated to reflux and slurried for 1-2 hours, after cooling to room temperature, suction filtration, the filter cake was washed with ethanol (50 mL) and dried under vacuum at 50-60 °C for 6-8 hours to obtain off-white compound 3 (yield 87.9%), HPLC purity 99.38%.

[0060] Preparation of Luseotinib:

[0061] Example 5

[0062] Compound 3 (31.64 g, 100 mmol, 1.0 eq.), compound 4 (18.39 g, 120 mmol, 1.2 eq.), W(CH3CN)2(CO)4 (18.90 g, 50 mmol, 0.5 eq.) were added to acetonitrile (300 mL) / 2 M HCI (150 mL) mixture and heated to 75-85 °C for 20-24 h. After cooling, the mixture was filtered under suction and the filtrate was adjusted to pH 6-7 with 1 M NaOH. After stirring for 1-2 h, the mixture was filtered under suction and the filter cake was washed with water. The wet filter cake was recrystallized from a mixture of ethanol / water (3:1, v / v) and dried under vacuum at 60-70 °C for 6-8 h to obtain off-white compound, Luspaterin (yield 90.2%), HPLC purity 99.59%.

[0063] Example 6

[0064] Compound 3 (31.64 g, 100 mmol, 1.0 eq.), compound 4 (18.39 g, 120 mmol, 1.2 eq.), W(CH3CN)2(CO)4 (18.90 g, 50 mmol, 0.5 eq.) were added to acetonitrile (300 mL) / 2 M HCI (150 mL) mixture and heated to 75-85 °C for 20-24 h. After cooling, the mixture was filtered under suction and the filtrate was adjusted to pH 6-7 with 1 M NaOH. After stirring for 1-2 h, the mixture was filtered under suction and the filter cake was washed with water. The wet filter cake was recrystallized from a mixture of ethanol / water (3:1, v / v) and dried under vacuum at 60-70 °C for 6-8 h to obtain off-white compound, Luspaterin (yield 90.2%), HPLC purity 99.59%.

[0065] Example 7

[0066] Compound 3 (31.64 g, 100 mmol, 1.0 eq.), compound 4 (18.39 g, 120 mmol, 1.2 eq.), W(CH3CN)2(CO)4 (18.90 g, 50 mmol, 0.5 eq.) were added to acetonitrile (300 mL) / 2 M HCI (150 mL) mixture and heated to 75-85 °C for 20-24 h. After cooling, the mixture was filtered under suction and the filtrate was adjusted to pH 6-7 with 1 M NaOH. After stirring for 1-2 h, the mixture was filtered under suction and the filter cake was washed with water. The wet filter cake was recrystallized from a mixture of ethanol / water (3:1, v / v) and dried under vacuum at 60-70 °C for 6-8 h to obtain off-white compound, Luspaterin (yield 90.2%), HPLC purity 99.59%.

[0067] Example 8

[0068] Compound 3 (31.64 g, 100 mmol, 1.0 eq.), compound 4 (18.39 g, 120 mmol, 1.2 eq.), W(CH3CN)2(CO)4(11.34 g, 30 mmol, 0.3 eq.) were added to a mixture of acetonitrile (300 mL) / 2 M HCI (150 mL) and heated to 75-85 °C with stirring for 20-24 h. After cooling, the mixture was filtered, the filtrate was adjusted to pH 6-7 with 1 M NaOH, stirred for 1-2 h, filtered and the filter cake was washed with water. The wet filter cake was recrystallized from a mixture of ethanol / water (3:1, v / v), and dried at 60-70 °C under vacuum for 6-8 h to obtain off-white compound Baricitinib (yield 84.2%) with 99.55% HPLC purity.

[0069] Preparation of Baricitinib:

[0070] Example 9

[0071] Compound 3 (31.64 g, 100 mmol, 1.0 eq.), compound 5 (26.19 g, 120 mmol, 1.2 eq.), W(CH3CN)2(CO)4(18.90 g, 50 mmol, 0.5 eq.) were added to a mixture of acetonitrile (300 mL) / 2 M HCI (150 mL) and heated to 75-85 °C with stirring for 20-24 h. After cooling, the mixture was filtered, the filtrate was adjusted to pH 6-7 with 1 M NaOH, stirred for 1-2 h, filtered and the filter cake was washed with water. The wet filter cake was slurried with ethanol (500 mL) at reflux for 1-2 h, filtered after cooling to room temperature, washed with ethanol (50 mL) and dried at 60-70 °C under vacuum for 6-8 h to obtain off-white compound Baricitinib (yield 91.6%) with 99.62% HPLC purity.

[0072] Example 10

[0073] Compound 3 (31.64 g, 100 mmol, 1.0 eq.), compound 5 (26.19 g, 120 mmol, 1.2 eq.), W(CH3CN)3(CO)3(19.55 g, 50 mmol, 0.5 eq.) were added to a mixture of acetonitrile (300 mL) / 2 M HCI (150 mL) and heated to 75-85 °C with stirring for 20-24 h. After cooling, the mixture was filtered, the filtrate was adjusted to pH 6-7 with 1 M NaOH, stirred for 1-2 h, filtered and the filter cake was washed with water. The wet filter cake was slurried with ethanol (500 mL) at reflux for 1-2 h, filtered after cooling to room temperature, washed with ethanol (50 mL) and dried at 60-70 °C under vacuum for 6-8 h to obtain off-white compound Baricitinib (yield 89.8%) with 99.58% HPLC purity.

[0074] Example 11

[0075] Compound 3 (31.64 g, 100 mmol, 1.0 eq.), compound 5 (26.19 g, 120 mmol, 1.2 eq.), W(CO)6(17.60 g, 50 mmol, 0.5 eq.) were added to a mixture of acetonitrile (300 mL) / 2 M HCI (150 mL) and heated to 75-85 °C with stirring for 20-24 h. After cooling, the mixture was filtered under suction, the filtrate was adjusted to pH 6-7 with 1 M NaOH, stirred for 1-2 h, filtered under suction and the filter cake was washed with water. The resulting wet filter cake was slurried with ethanol (500 mL) at reflux for 1-2 h, filtered under suction after cooling to room temperature, the filter cake was washed with ethanol (50 mL) and dried under vacuum at 60-70 °C for 6-8 h to give off-white compound baricitinib (yield 90.4 %), HPLC purity 99.48 %.

Claims

1. An isoxazole compound having the following structural formula:

2. A method for preparing the isoxazole compound according to claim 1, characterized in that: The steps include: Under inert gas, a reaction solvent was added to the reaction vessel, and compound 1, compound 2, and a palladium catalyst were added in sequence with stirring. After stirring evenly, an aqueous solution of an inorganic base was added. The system was stirred at a temperature of T1 until the reaction was complete. Compound 3 was obtained through post-treatment. The route is as follows:

3. The preparation method according to claim 2, characterized in that The reaction solvent is one of tert-butanol, n-butanol and 1,4-dioxane, preferably 1,4-dioxane.

4. The preparation method according to claim 2, characterized in that The molar ratio of compound 1, compound 2 and palladium catalyst is 1.00:(1.00-1.50):(0.003-0.010), preferably 1.00:1.10:0.

006.

5. The preparation method according to claim 2, characterized in that The palladium catalyst is one of Pd(PPh3)4, Pd(dppf)Cl2·CH2Cl2, and Pd(PPh3)2Cl2, preferably Pd(dppf)Cl2·CH2Cl2.

6. The preparation method according to claim 2, characterized in that The inorganic base is one of potassium carbonate, sodium carbonate, cesium carbonate and potassium phosphate, preferably potassium carbonate; 7. The preparation method according to claim 2, characterized in that The molar ratio of compound 1 to the inorganic base is 1.00:2.00-3.00, preferably 1.00:2.

50.

8. The preparation method according to claim 2, characterized in that The reaction temperature T1 is 85-95°C.

9. A method for preparing ruxolitinib from the isoxazole compound according to claim 1, characterized in that: The steps include: Acetonitrile and hydrochloric acid were added to the reaction vessel in sequence, and compound 3, compound 4, and tungsten reagent were added in sequence after stirring. The system was kept at temperature T2 and stirred until the reaction was completed. Ruxolitinib was obtained by post-treatment. The route is as follows:

10. A method for preparing baricitinib from the isoxazole compound according to claim 1, characterized in that: The steps include: Acetonitrile and hydrochloric acid were added to the reaction vessel in sequence, and compound 3, compound 5, and tungsten reagent were added in sequence after stirring. The system was kept at temperature T3 and stirred until the reaction was completed. The target product was obtained through post-treatment. The route is as follows:

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