Synthesis method of oxiratinib maleate

Abstract

The invention discloses a synthesis method of olatinib maleate. The synthesis method comprises the following steps: step 1, carrying out reaction on trans-4-hydroxycyclohexane ethyl formate under the action of a chlorination reagent to obtain a compound I; step 2, obtaining a compound II from the compound I under the action of methylamine; step 3, reacting the compound II with 4-chloro-7-toluenesulfonyl-7H-pyrrole [2, 3-D] pyrimidine under the action of alkali to obtain a compound III; 4, obtaining a compound IV from the compound III under the action of a reducing agent and a chlorination reagent; step 5, obtaining a compound V from the compound IV under the action of thiourea; step 6, obtaining VI from the compound V under the action of an oxidizing agent; step 7, obtaining a compound VII from the compound VI under the action of methylamine; step 8, preparation of the olatinib; and step 9, preparation of the maleate olatinib: the maleate olatinib is obtained from the olatinib under the action of the maleic acid. The synthesis method is simple and feasible, simple to operate and suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a method for synthesizing oclacitinib maleate. Background Art

[0002] Oclacitinib Maleate was developed by Zoetis, a US company. It belongs to the Janus kinase (JAK) inhibitor class of drugs. It works by inhibiting a variety of cytokines that are dependent on the activity of JAK1 and JAK3 enzymes and that induce pruritus and inflammation, as well as cytokines related to allergies. Studies have shown that Oclacitinib can quickly, effectively and safely control the itching caused by allergic and atopic dermatitis in dogs. The drug was first approved for marketing by the US Food and Drug Administration on May 14, 2013; in early 2019, Oclacitinib Maleate tablets produced by Zoetis, US, were approved for registration in China after review and issued the "Imported Veterinary Drug Registration Certificate". The chemical name of Oclacitinib Maleate is: (trans)-N-methyl-1-(-3-methyl-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonamide maleate, and its chemical structure is as follows:

[0003]

[0004] Currently, the following synthetic routes are reported for (trans)-N-methyl-1-(-3-methyl-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonamide maleate:

[0005] Route 1:

[0006] Patent CN107365312A reports that N-benzyl-N-methylmethanesulfonamide and 1,4-cyclohexanedione alcohol acetal are used as starting materials, and the final product is obtained through condensation, chlorination, elimination, catalytic hydrogenation, hydrolysis, reductive amination, condensation, deprotection, and salt formation. The synthesis route is as follows:

[0007]

[0008] Although this route is shorter than other routes, the first condensation step uses n-butyl lithium, which is relatively dangerous in industrial production. In addition, the catalyst he uses is expensive, and the waste liquid of the methylamine alcohol solution is difficult to handle.

[0009] Route 2:

[0010] Patent US2017 / 0233397 reports that p-bromobenzyl bromide is used as the starting material, and oclacitinib maleate is obtained through substitution, methylamine substitution, reduction, condensation, chlorination, and amine salt formation. The synthetic route is as follows:

[0011]

[0012] Although the synthetic route has fewer steps, a mixture of cis and trans isomers is generated during hydrogenation, which is difficult to separate, has a large recrystallization loss, and has a low overall yield of the final product, which is not conducive to industrial production.

[0013] Route 3:

[0014] Patent WO2010 / 020905 reported that (trans) 4-tert-butoxyformamide cyclohexanecarboxylic acid was used as the starting material, and red aluminum was first used for reduction to obtain (trans) 4-methylaminocyclohexylmethanol, which was then condensed with 4-chloro-7H-pyrrolo[2,3d]pyrimidine in the presence of a base to obtain (trans) 4(methyl(7H-pyrrolo[2,3d]pyrimidin-4-yl)amino)cyclohexyl)methanol, followed by p-toluenesulfonyl protection, potassium thioacetate substitution, hydrogen peroxide / formic acid oxidation, chlorination, methyl amination and Ts removal to obtain oclacitinib, and finally salified with maleic acid to obtain the target product oclacitinib maleate. The synthetic route is as follows:

[0015]

[0016] This route is relatively complicated, uses hydrogen peroxide, is dangerous, and is not suitable for industrial production. In addition, methyl amination requires methylamine tetrahydrofuran solution, the raw materials are expensive, and the wastewater contains tetrahydrofuran, which makes wastewater treatment difficult.

[0017] Route 4:

[0018] Patent CN114605420A uses trans-4[(tert-butyloxycarbonyl)amino]cyclohexanecarboxylic acid and 4-chloro-7-tosyl-7H-pyrrolo[2,3d]pyrimidine as starting materials, and obtains oclacitinib maleate through reduction, condensation, esterification, sulfonation, deprotection, chlorination, methylamination, and salt formation. The synthesis route is as follows:

[0019]

[0020] Methanesulfonyl chloride is a highly toxic substance and is unsafe to use in large quantities in industrial production. The addition of protecting reagents, protection and deprotection increases costs and the yield during deprotection is not ideal, so it cannot be produced stably in industry.

[0021] According to the above-mentioned deficiencies in the production methods of oclacitinib maleate, it is particularly important to develop a method that is simple, easy to operate and suitable for industrial production. Summary of the invention

[0022] The object of the present invention is to provide a method for synthesizing oclacitinib maleate to solve one or more of the above-mentioned problems in the prior art.

[0023] The present invention provides a method for synthesizing oclacitinib maleate, comprising the following steps:

[0024] Step 1, preparation of compound I: trans-4-hydroxycyclohexanecarboxylic acid ethyl ester is treated with a chlorinating agent to obtain compound I;

[0025] Step 2, preparation of compound II: Compound I is reacted with methylamine to obtain compound II;

[0026] Step 3, preparation of compound III: Compound II is reacted with 4-chloro-7-tosyl-7H-pyrrolo[2,3-D]pyrimidine in the presence of a base to obtain compound III;

[0027] Step 4, preparation of compound IV: Compound III is reacted with a reducing agent and a chlorinating agent to obtain compound IV;

[0028] Step 5, preparation of compound V: Compound IV is reacted with thiourea to obtain compound V;

[0029] Step 6, preparation of compound VI: Compound V is reacted with an oxidant to obtain compound VI;

[0030] Step 7, preparation of compound VII: Compound VI is reacted with methylamine to obtain compound VII;

[0031] Step 8, preparation of oclacitinib: deprotecting compound VII under the action of a base to obtain oclacitinib;

[0032] Step 9, preparation of oclacitinib maleate: oclacitinib maleate is obtained by reacting oclacitinib with maleic acid;

[0033] The reaction formula is as follows:

[0034]

[0035] In certain embodiments, in step 1, the chlorinating agent is selected from dithionyl chloride and acetyl chloride; the molar ratio of the chlorinating agent to trans-4-hydroxycyclohexanecarboxylic acid ethyl ester is 1.0-1.2:1; and the reaction temperature is 30-50°C.

[0036] In certain embodiments, in step 1, the chlorinating agent is selected from thionyl chloride; the molar ratio of the chlorinating agent to trans-4-hydroxycyclohexanecarboxylic acid ethyl ester is 1.2:1; and the temperature is 40°C.

[0037] In certain embodiments, in step 2, methylamine is an aqueous solution; the molar ratio of methylamine to compound I is 5.0-10.0:1; the solvent is selected from tetrahydrofuran or dichloromethane; the dropping temperature is 0-10°C; and the reaction temperature is 0-10°C.

[0038] In certain embodiments, in step 2, the molar ratio of the aqueous methylamine solution to compound I is 9.0:1; the selected solvent is selected from dichloromethane; and the reaction temperature is 10°C.

[0039] In certain embodiments, in step 3, the molar ratio of 4-chloro-7-tosyl-7H-pyrrolo[2,3-D]pyrimidine to compound II is 0.7-1.0:1; the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate; the molar ratio of the base to compound II is 1.5-2.0:1; the selected solvent is selected from acetonitrile, ethanol, methanol, water or dioxane; and the reaction temperature is 75-90°C.

[0040] In certain embodiments, in step 3, the molar ratio of 4-chloro-7-tosyl-7H-pyrrolo[2,3-D]pyrimidine to compound II is 0.9:1; the base is sodium carbonate; the molar ratio of the base to compound II is 2.0:1; the selected solvent is acetonitrile; and the reaction temperature is 90°C.

[0041] In certain embodiments, in step 4, the reducing agent is selected from dihydrobis(2-methoxyethoxy)aluminate, sodium borohydride or lithium aluminum tetrahydride; the molar ratio of the reducing agent to compound III is 3.0-5.0:1; the temperature for adding the reducing agent is 0-10°C; the temperature for dripping dihydrobis(2-methoxyethoxy)aluminate is 0-10°C; the solvent is selected from xylene or toluene; the temperature for the completion of the dripping reaction is 90-110°C. The chlorinating agent is selected from thionyl chloride or acetyl chloride; the molar ratio of the chlorinating agent to compound III is 1.0-1.5:1; the base is triethylamine or pyridine; the molar ratio of the base to compound III is 2.5-3.0:1; the selected solvent is dichloromethane, tetrahydrofuran or toluene; the reaction temperature is 25-40°C.

[0042] In certain embodiments, the reducing agent in step 4 is sodium dihydrobis(2-methoxyethoxy)aluminate; the molar ratio of the reducing agent to compound III is 4.0:1; the temperature for adding the reducing agent is 0-10°C; the temperature for dripping dihydrobis(2-methoxyethoxy)aluminate is 0-10°C; the solvent is toluene; the temperature for the reaction after dripping is 100°C. The chlorinating agent is p-thionyl chloride; the molar ratio of the chlorinating agent to compound III is 1.1:1; the base is triethylamine; the molar ratio of the base to compound III is 2.5:1; the selected solvent is toluene; the reaction temperature is 30°C.

[0043] In certain embodiments, the molar ratio of thiourea to compound IV in step 5 is 1.0-1.2:1; the selected solvent is methanol, ethanol, isopropanol, acetonitrile; and the reaction temperature is 80-100°C.

[0044] In certain embodiments, the molar ratio of thiourea to compound IV in step 5 is 1.0:1; the selected solvent is ethanol; and the reaction temperature is 80°C.

[0045] In certain embodiments, the oxidant selected in step 6 is selected from sodium chlorite and N-chlorosuccinimide; the molar ratio of the oxidant to compound V is 6.0-10:1; the selected solvent is methanol, ethanol, acetonitrile; and the reaction temperature is 15-20°C.

[0046] In certain embodiments, the oxidant selected in step 6 is sodium chlorite; the molar ratio of the oxidant to compound V is 6.0:1; the selected solvent is ethanol; and the reaction temperature is 20°C.

[0047] In certain embodiments, in step 7, methylamine is an aqueous solution; the molar ratio of methylamine to compound VI is 5.0-10.0:1; the solvent is selected from tetrahydrofuran, dichloromethane, and ethanol; the dropping temperature is 0-10°C; and the reaction temperature is 0-10°C.

[0048] In certain embodiments, in step 7, methylamine is an aqueous solution; the molar ratio of methylamine to compound VI is 9.0:1; the solvent is ethanol; the dropping temperature is 0-10°C; and the reaction temperature is 10°C.

[0049] In certain embodiments, in step 8, the base is selected from lithium hydroxide, sodium hydroxide or potassium hydroxide; the molar ratio of the base to compound VII is 3.0-5.0:1; the solvent is selected from water, methanol or ethanol; and the reaction temperature is 30-40°C.

[0050] In certain embodiments, in step 8, the base is lithium hydroxide; the molar ratio of the base to compound VII is 4.0:1; the solvent is water or ethanol; and the reaction temperature is 40°C.

[0051] In certain embodiments, in step 9, the molar ratio of maleic acid to oclacitinib is 0.9-1.0:1; the solvent is selected from methanol, ethanol, isopropanol, n-butanol, and methyl tert-butyl ether; and the reaction temperature is 70-80°C.

[0052] In certain embodiments, in step 9, the molar ratio of maleic acid to oclacitinib is 0.9:1; the solvent is ethanol; and the reaction temperature is 80°C.

[0053] Beneficial effects of the present invention:

[0054] The present invention provides a method for synthesizing oclacitinib maleate. In step 1, dichloromethane is selected as the solvent, and two-thirds of the solvent reaction liquid can be directly concentrated and added directly to the methylamine aqueous solution, and the concentrated dichloromethane can be recycled. In step 3, 4-chloro-7-tosyl-7H-pyrrole [2,3-D] pyrimidine is selected for condensation. The advantage is that the price of 4-chloro-7-tosyl-7H-pyrrole [2,3-D] pyrimidine is similar to that of 4-chloropyrrolopyrimidine, and the step of protecting the amino group is reduced, the use of the protecting reagent is reduced, the cost is reduced, and the reaction time is greatly shortened. In step 4, the reducing agent is selected as sodium dihydrobis (2-methoxyethoxy) aluminum acid as a toluene solution, and the reaction solvent is also toluene, which can be recycled. After reduction, the hydroxyl group is chlorinated, and p-toluenesulfonyl chloride and other protecting reagents are not selected. The reason is that the chlorination reagent is cheap, the reaction is simple, and it is easy to operate. The solvents selected in the following steps are all ethanol, which can be continuously cast, reducing the processing time, and it is more convenient to recycle and apply than using multiple solvents. DETAILED DESCRIPTION

[0055] The present invention is further described in detail below in conjunction with specific implementation methods so that those skilled in the art can better understand the present invention, but this is not a limitation of the present invention. Any equivalent replacements in the art made in accordance with the contents disclosed in the present invention shall fall within the scope of protection of the present invention.

[0056] Example 1

[0057] Preparation of compound Ⅰ:

[0058] Add 500 mL of dichloromethane to a 2L three-necked flask, add 100 g (0.58 mol) of trans-4-hydroxycyclohexanecarboxylic acid ethyl ester under stirring, replace the air with nitrogen, cool to 0°C, control the temperature below 10°C and add 82.8 g (0.696 mol) of dichlorothionyl dropwise. After the addition is complete, react at an internal temperature of 40 degrees for 3 hours, concentrate two-thirds of the dichloromethane, and directly use it in the next step without purification.

[0059] Example 2

[0060] Preparation of compound Ⅰ:

[0061] Add 500 mL of dichloromethane to a 2L three-necked flask, add 100 g (0.58 mol) of trans-4-hydroxycyclohexanecarboxylic acid ethyl ester under stirring, replace the air with nitrogen, cool to 0°C, control the temperature below 10°C and add 103.5 g (0.87 mol) of dichlorothionyl, after the addition is complete, react at 30 degrees for 3 hours at an internal temperature, concentrate two-thirds of the dichloromethane and directly use it in the next step without purification.

[0062] Example 3

[0063] Preparation of compound II:

[0064] Into a 3L single-necked bottle, add 405g (5.22mol) of methylamine aqueous solution (40%), cool to 0°C, add dichloro solution of compound Ⅰ with stirring, control the temperature between 0°C and 10°C, stir at 10°C for 1 hour after the addition is complete, a white solid precipitates, add 1500ml of water, stir at 10°C for another hour, filter, and dry to obtain 101g (two-step yield 93%) with HPLC purity 98.5%.

[0065] Example 4

[0066] Preparation of compound II:

[0067] Into a 3L single-necked bottle, add 225.185 g (2.9 mol) of methylamine aqueous solution (40%), cool to 0°C, add dichloro solution of compound Ⅰ with stirring, control the temperature between 0°C and 10°C, stir at 5°C for 1 hour after the addition is complete, a white solid precipitates, add 1500 ml of water, stir at 5°C for another hour, filter, and dry to obtain 94 g (two-step yield 87%) with HPLC purity of 98.2%.

[0068] Example 5

[0069] Preparation of compound III:

[0070] 101g (0.55mol) of compound II in a 1L three-necked flask was dissolved in 500mL of acetonitrile, and 116.578 (1.1mol) of sodium carbonate was added, followed by 1.82g (0.01mol) of potassium iodide, and finally 152.3g (0.495mol) of 4-chloro-7-toluenesulfonyl-7H-pyrrole [2,3-D] pyrimidine. The external temperature was raised to 90°C for 12h. After post-treatment, the temperature was lowered to 50 degrees and stirred for 30min. Filter, rinse the filter solid with methanol, concentrate the filtrate to remove two-thirds of the solvent, add 100ml of ethyl acetate, and stir at 0°C for 1h. Filter, rinse the filter solid with cold ethyl ester, and dry to obtain 232.5g of compound III (yield 93%) with HPLC purity of 98.5%.

[0071] Example 6

[0072] Preparation of compound III:

[0073] 94g (0.507mol) of compound II in a 1L three-necked flask was dissolved in 500mL of ethanol, 30g (0.76mol) of sodium hydroxide was added, followed by 1.82g (0.01mol) of potassium iodide, and finally 152.3g (0.35mol) of 4-chloro-7-toluenesulfonyl-7H-pyrrole [2,3-D] pyrimidine. The external temperature was raised to 80°C and reacted for 12h. After post-treatment, the temperature was lowered to 50 degrees and stirred for 30min. Filter, rinse the filter solid with methanol, concentrate the filtrate to remove two-thirds of the solvent, add 100ml of ethyl acetate, and stir at 0°C for 1h. Filter, rinse the filter solid with cold ethyl ester, and dry to obtain 212g of compound III (yield 91.7%) with HPLC purity of 98.3

[0074] Example 7

[0075] Preparation of compound IV:

[0076] 232.5 g (0.51 mol) of compound III in a 2L three-necked flask was dissolved in 400 mL of toluene, the air was replaced by nitrogen, the temperature was lowered to 0°C, and 588.27 g (2.03 mol) of 70% sodium dihydrobis(2-methoxyethoxy)aluminate toluene solution was added dropwise at 0-10°C, the internal temperature was raised to 100°C, the reaction was carried out for 18 h, the temperature was lowered to 0°C, 270 g (0.675 mol) of 10% sodium hydroxide solution was added to quench the reaction, and the temperature was controlled at 0°C- 10 ℃, separate the liquids, dry over anhydrous sodium sulfate, filter into a 2L three-necked flask, add 129g (1.275mol) of triethylamine, replace the air with nitrogen, cool to 0 ℃, add 66.74g (0.561) of dichlorothionyl dropwise, control the temperature at 0 ℃-10 ℃, react at 30 ℃ for 1 hour after the addition is completed, concentrate to dryness after post-treatment, add 200ml of anhydrous ethanol, pulp at 0 ℃, filter and dry to obtain 201.3g (yield 91%), HPLC purity 99.2%.

[0077] Example 8

[0078] Preparation of compound IV:

[0079] 212g (0.46mol) of compound III in a 2L three-necked flask was dissolved in 400mL of toluene, and the air was replaced by nitrogen. The temperature was lowered to 0°C, and the temperature was controlled at 0-10°C. 70% sodium dihydrobis(2-methoxyethoxy)aluminate toluene solution 398.5 (1.38mol) was added dropwise. The internal temperature was raised to 90°C, and the reaction was carried out for 18h. The temperature was lowered to 0°C, and 240g (0.598) of 10% sodium hydroxide solution was added to quench the reaction. The temperature was controlled at 0°C-10°C. The mixture was separated, dried over anhydrous sodium sulfate, filtered into a 2L three-necked flask, 90.9 g (1.15 mol) of pyridine was added, the air was replaced by nitrogen, the temperature was lowered to 0°C, 60.1 g (0.506 mol) of thionyl chloride was added dropwise, and the temperature was controlled at 0°C-10°C. After the addition was completed, the mixture was reacted at 40°C for 1 hour, concentrated to dryness after post-treatment, 200 ml of anhydrous ethanol was added, and the mixture was pulped at 0°C, filtered and dried to obtain 181 g (yield 90%), with HPLC purity 98.7%.

[0080] Example 9

[0081] Preparation of compound VII:

[0082] To 201.3 g (0.46 mol) of compound IV in a 3L three-necked flask, 35 g (0.46 mol) of thiourea was added with stirring. After the addition was completed, the mixture was reacted at 80°C for 14 h. The temperature was lowered to 10°C and 249.6 g (2.76 mol) of sodium chlorite was added. After the addition was completed, the mixture was reacted at 20°C for 20 h. After post-treatment, two-thirds of the ethanol was concentrated and directly added to 321.4 g (2.76 mol) of 40% methylamine aqueous solution cooled to 0°C. The temperature was controlled at 0°C-10°C. After the addition was completed, the mixture was reacted at 10°C for 1 h. 900 ml of water was added, the temperature was controlled at 10°C and stirring was continued for 1 h. Filtered and dried to obtain 207 g (yield 90%) with HPLC purity 99.2%.

[0083] Example 10

[0084] Preparation of compound VII:

[0085] To 181 g (0.42 mol) of compound IV in a 3L three-necked flask, add 31.8 g (0.42 mol) of thiourea under stirring. After the addition is completed, react at 80 degrees for 14 hours, cool to 10 degrees, add 227.9 g (2.52 mol) of sodium chlorite, and react at 20 degrees for 20 hours after the addition is completed. After post-treatment, concentrate two-thirds of methanol and add it directly to 293.5 g (3.78 mol) of 40% methylamine aqueous solution cooled to 0 degrees, control the temperature at 0-10 degrees, react at 10 degrees for 1 hour after the addition is completed, add 900 ml of water, control the temperature at 10 degrees and continue stirring for 1 hour, filter and dry to obtain 183 g (yield 89%), HPLC purity 99.3%.

[0086] Embodiment 11

[0087] Preparation of Oclacitinib:

[0088] 640 mL of ethanol was added to a 2L single-mouth bottle, and compound VII 207 g (0.42 mol) was added, and water 128 mL was added, and lithium hydroxide 40.23 g (1.68 mol) was added, and then the external temperature was raised to 40 ° C, and the reaction was carried out for 8 hours. The reaction solution was adjusted to pH 2 and stirred for 1 hour, concentrated to remove ethanol, and the aqueous phase was extracted with ethyl acetate. The saturated sodium bicarbonate solution was adjusted to pH 7-8, and a white solid was precipitated. The mixture was stirred at 10 ° C for 1 hour. Filtered and dried to obtain 142.2 g of oclacitinib, with a yield of 91% and a HPLC purity of 99.0%.

[0089] Example 12

[0090] Preparation of Oclacitinib:

[0091] 640 mL of methanol was added to a 2L single-mouth bottle, and 183 g (0.37 mol) of compound VI was added, 128 mL of water was added, and 59.2 g (1.48 mol) of sodium hydroxide was added, and the external temperature was raised to 40°C, and the reaction was carried out for 8 hours. The reaction solution was adjusted to pH 2 and stirred for 1 hour, concentrated to remove methanol, and the aqueous phase was extracted with ethyl acetate. The saturated sodium bicarbonate solution was adjusted to pH 7-8, and a white solid was precipitated. The mixture was stirred at 10°C for 1 hour. Filtered and dried to obtain 113.6 g of oclacitinib, with a yield of 90% and a HPLC purity of 99.0%.

[0092] Example 13

[0093] Preparation of Oclacitinib Maleate:

[0094] In a 1L single-necked bottle, 400mL of anhydrous ethanol, 142.2g (0.42mol) of oclacitinib and 43.87g (0.378mol) of maleic acid were added. The mixture was reacted at 80°C for 2h under nitrogen protection, cooled to 0°C, stirred for 1h, filtered, and the filter cake was rinsed with anhydrous ethanol. The filter cake was dried under vacuum to obtain 176.6g of oclacitinib maleate with a yield of 92.7%.

[0095] Embodiment 14

[0096] Preparation of Oclacitinib Maleate:

[0097] In a 1L single-mouth bottle, 400mL of n-butanol, 113.6g (0.34mol) of oclacitinib and 35g (0.3mol) of maleic acid were added. The mixture was reacted at 80°C for 2h under nitrogen protection, cooled to 0°C, stirred for 1h, filtered, and the filter cake was rinsed with anhydrous ethanol. The filter cake was dried under vacuum to obtain 137.6g of oclacitinib maleate with a yield of 90%.

[0098] In summary: The present invention provides a method for synthesizing oclacitinib maleate. In step 1, dichloromethane is selected as the solvent, and two-thirds of the solvent reaction liquid can be directly concentrated and added directly to the methylamine aqueous solution, and the concentrated dichloromethane can be recycled. In step 3, 4-chloro-7-tosyl-7H-pyrrole [2,3-D] pyrimidine is selected for condensation. The advantage is that the price of 4-chloro-7-tosyl-7H-pyrrole [2,3-D] pyrimidine is similar to that of 4-chloropyrrolopyrimidine, and the step of protecting the amino group is reduced, the use of protective reagents is reduced, the cost is reduced, and the reaction time is greatly shortened. In step 4, the reducing agent is selected as sodium dihydrobis (2-methoxyethoxy) aluminum salt as a toluene solution, and the reaction solvent is also toluene, which can be recycled. After reduction, the hydroxyl group is chlorinated instead of p-toluenesulfonyl chloride and other protective reagents because the chlorination reagent is cheap, the reaction is simple, and it is easy to operate. In the following steps, ethanol is used as the solvent, which allows for continuous operation, reduces processing time, and is easier to recycle and reuse than using multiple solvents.

[0099] The above description is only a preferred embodiment of the present invention. It should be pointed out that, for ordinary technicians in this field, several modifications and improvements can be made without departing from the creative concept of the present invention, and these should also be regarded as within the scope of protection of the invention.

Claims

1. A method for synthesizing oclacitinib maleate, characterized in that: The following steps are involved: Step 1, preparation of compound I: trans-4-hydroxycyclohexanecarboxylic acid ethyl ester is treated with a chlorination agent to obtain compound I; Step 2, preparation of compound II: Compound I is reacted with methylamine to obtain compound II; Step 3, preparation of compound III: Compound II is reacted with 4-chloro-7-tosyl-7H-pyrrolo[2,3-D]pyrimidine in the presence of a base to obtain compound III; Step 4, preparation of compound IV: Compound III is reacted with a reducing agent and a chlorinating agent to obtain compound IV; Step 5, preparation of compound V: Compound IV is reacted with thiourea to obtain compound V; Step 6, preparation of compound VI: Compound V is reacted with an oxidant to obtain compound VI; Step 7, preparation of compound VII: Compound VI is reacted with methylamine to obtain compound VII; Step 8, preparation of oclacitinib: deprotecting compound VII under the action of a base to obtain oclacitinib; Step 9, preparation of oclacitinib maleate: oclacitinib maleate is obtained by reacting oclacitinib with maleic acid; The reaction formula is as follows:

2. The method for synthesizing oclacitinib maleate according to claim 1, characterized in that: In step 1, the chlorination agent is selected from thionyl chloride or acetyl chloride, preferably thionyl chloride; the molar ratio of the chlorination agent to trans-4-hydroxycyclohexanecarboxylic acid ethyl ester is 1.0-1.2:1, preferably 1.2:1; the solvent is dichloromethane; and the reaction temperature is 30-50° C., preferably 40° C.

3. The method for synthesizing oclacitinib maleate according to claim 1, characterized in that: In step 2, methylamine is an aqueous solution; the molar ratio of methylamine to compound I is 5.0-10.0:1, preferably 9.0:1; the solvent is selected from tetrahydrofuran or dichloromethane, preferably dichloromethane; the dropping temperature is 0-10°C; the reaction temperature is 0-10°C, preferably 10°C.

4. The method for synthesizing oclacitinib maleate according to claim 1, characterized in that: In step 3, the molar ratio of 4-chloro-7-tosyl-7H-pyrrolo[2,3-D]pyrimidine to compound II is 0.7-1.0, preferably 0.9; the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, preferably sodium carbonate; the molar ratio of the base to compound II is 1.5-2.0:1, preferably 2.0:1; the selected solvent is selected from acetonitrile, ethanol, methanol, water or dioxane, preferably acetonitrile; the reaction temperature is 75-90°C, preferably 90°C.

5. The method for synthesizing oclacitinib maleate according to claim 1, characterized in that: In step 4, the reducing agent is selected from dihydrobis(2-methoxyethoxy)aluminate, sodium borohydride or lithium aluminum tetrahydride, preferably sodium dihydrobis(2-methoxyethoxy)aluminate; the molar ratio of the reducing agent to compound III is 3.0-5.0, preferably 4.0; the reducing agent is added at a temperature of 0-10°C; the temperature for dropwise addition of dihydrobis(2-methoxyethoxy)aluminate is 0-10°C; the solvent is selected from xylene or toluene, preferably toluene; the reaction temperature after dropwise addition is 90-110°C, preferably 100°C. The chlorination agent is selected from thionyl chloride or acetyl chloride, preferably thionyl chloride; the molar ratio of the chlorination agent to the compound III is 1.0-1.5, preferably 1.1; the base is triethylamine or pyridine, preferably triethylamine; the molar ratio of the base to the compound III is 2.5-3.0, preferably 2.5; the selected solvent is dichloromethane, tetrahydrofuran, toluene, preferably toluene; the reaction temperature is 25-40°C, preferably 30°C.

6. The method for synthesizing oclacitinib maleate according to claim 1, characterized in that: In step 5, the molar ratio of thiourea to compound IV is 1.0-1.2:1, preferably 1.0:1; the selected solvent is methanol, ethanol, isopropanol, acetonitrile, preferably ethanol; the reaction temperature is 80-100°C, preferably 80°C.

7. The method for synthesizing oclacitinib maleate according to claim 1, characterized in that: The oxidant selected in step 6 is selected from sodium chlorite and N-chlorosuccinimide, preferably sodium chlorite; the molar ratio of the oxidant to compound V is 6.0-10:1, preferably 6.0:1; the selected solvent is methanol, ethanol, acetonitrile, preferably ethanol; the reaction temperature is 15-20°C, preferably 20°C.

8. The method for synthesizing oclacitinib maleate according to claim 1, characterized in that: In step 7, methylamine is an aqueous solution; the molar ratio of methylamine to compound VI is 5.0-10.0:1, preferably 9.0:1; the solvent is selected from tetrahydrofuran, dichloromethane, ethanol, preferably ethanol; the dropping temperature is 0-10°C; the reaction temperature is 0-10°C, preferably 10°C.

9. The method for synthesizing oclacitinib maleate according to claim 1, characterized in that: In step 8, the base is selected from lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably lithium hydroxide; the molar ratio of the base to compound VII is 3.0-5.0:1, preferably 4.0:1; the solvent is selected from water, methanol or ethanol, preferably water or ethanol; the reaction temperature is 30-40°C, preferably 40°C.

10. The method for synthesizing oclacitinib maleate according to claim 1, characterized in that: In step 9, the molar ratio of maleic acid to oclacitinib is 0.9-1.0:1, preferably 0.9:1; the solvent is selected from methanol, ethanol, isopropanol, n-butanol, methyl tert-butyl ether, preferably ethanol; the reaction temperature is 70-80°C, preferably 80°C.

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