CN111995627A - Tofacitinib citrate intermediate and preparation method and application thereof - Google Patents
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Abstract
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a tofacitinib citrate intermediate, and a preparation method and application thereof. The tofacitinib citrate intermediate is N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-D ] pyrimidin-4-amine dihydrochloride monohydrate. Adding N-methyl-N- ((3R,4R) -1-benzyl-4-methylpiperidine-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidine-4-amine into water and an organic solvent, adding hydrochloric acid and palladium hydroxide carbon, introducing hydrogen for reaction, and filtering the palladium hydroxide carbon; and cooling to room temperature, dropwise adding an organic solvent, crystallizing, filtering, and drying to obtain the tofacitinib citrate intermediate. The invention greatly improves the utilization rate of raw materials, reduces the production cost and improves the product quality.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a tofacitinib citrate intermediate, and a preparation method and application thereof.
Background
Tofacitinib citrate, compound name: 3- { (3R,4R) -4-methyl-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] 1-yl } -3-oxopropanenitrile, mono citrate, which targets intracellular signal transduction pathways, acting on the core of the cytokine network. The inhibition strength of tofacitinib on JAK3 is 5-100 times that of JAK1 and JAK2, the tofacitinib is an initial drug for treating rheumatoid arthritis, and the FDA approves the JAK inhibitor tofacitinib on 11/6 days 2012 for treating patients with moderate-to-severe Rheumatoid Arthritis (RA) with adult active period and poor response to Methotrexate (MTX).
N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-D ] pyrimidine-4-amine is an important intermediate of tofacitinib citrate and is a degradation impurity thereof, and the quality of a final product is directly influenced by controlling the residual quantity of the intermediate in the synthesis of tofacitinib.
Chinese patent CN 107793418A discloses an industrial production method of tofacitinib citrate, which comprises the following steps: (1) adding a compound SMA and a compound SMB into a mixed solvent 1 of DMSO and purified water, and reacting under the catalysis of DIPEA to obtain an intermediate INA; (2) carrying out homogeneous reaction on INA under an alkaline condition to prepare an intermediate INB crude product; (3) refining the crude product of INB with lower alcohol and water to obtain refined product of INB; (4) the refined product of INB is subjected to debenzylation and acidification to obtain an intermediate INC (in a salt form); (5) obtaining an intermediate IND (namely tofacitinib free alkali) after the reaction of INC and SMC is finished; (6) and salifying the IND and citric acid monohydrate in purified water to obtain tofacitinib citrate. The patent mentions that the yield of IND prepared from N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-D ] pyrimidin-4-amine dihydrochloride is only about 85%, INC reaction is incomplete, about 0.4% of IND remains in IND, IND is salified with citric acid monohydrate in purified water to obtain tofacitinib citrate, the yield is 92-93.1%, and the total yield of two steps from INC to tofacitinib citrate is about 78%. In this patent, the free N-methyl-N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-D ] pyrimidin-4-amine is obtained by hydrogenation reduction, and in anhydrous ethanol, hydrochloric acid is added to crystallize N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-D ] pyrimidin-4-amine dihydrochloride, and the product obtained here is an anhydride, and N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2 ], the yield of the tofacitinib citrate synthesized by 3-D pyrimidine-4-amine dihydrochloride can only reach about 78 percent.
Chinese patent CN104788461A discloses an industrial production method suitable for tofacitinib citrate, (1) SM is added according to a molar ratio of 1: 0.9-0.981a to b and SM2Dissolving in polar protic solvent, performing substitution reaction under the action of inorganic base, keeping the reaction temperature at 65-95 ℃ for 8-12 hours, cooling, washing with water, pulping, and centrifuging to obtain IIa-b; (2) dissolving IIa or II b in 10-60% sodium hydroxide aqueous solution according to a molar ratio of 1: 2-4, keeping the reaction temperature at 80-100 ℃, consuming 4-6 hours, cooling to 40-50 ℃, adding water, stirring, cooling, washing with water, pulping, and centrifuging to obtain a formula III; (3) dissolving the formula III in a polar protic solvent according to the mass ratio of 1: 10% -15% of the formula III to 20% of palladium hydroxide with the water content of 50%, adding palladium hydroxide and a catalytic amount of acetic acid, heating to 30-60 ℃, carrying out hydrogenation reaction for 8-12 hours, and filtering and concentrating to obtain a formula IV; (4) dissolving the formula IV in a polar protic solvent according to a molar ratio of 1: 1.2-2.0, and adding the formula SM3Carrying out condensation reaction under the condition of organic alkali, keeping the temperature of 40-90 ℃ for reaction, consuming 8-10 hours, centrifuging, and scattering and washing to obtain a formula V; (5) dissolving the formula V in a polar aprotic solvent according to a molar ratio of 1: 1.5-2.0, adding citric acid, keeping the temperature at 30-40 ℃ for reaction for 8-10 hours, centrifuging and washing to obtain a crude product of the formula I, and recrystallizing in the polar protic solvent to obtain the high-purity formula I with a specific crystal form, wherein the high-purity formula I meets the requirements of pharmaceutical-grade raw material medicines. This patent mentions the use of N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-D]the preparation method of tofacitinib from pyrimidine-4-amine has the advantages that about 4.0% of raw materials in a reaction solution and about 0.5% of raw materials in tofacitinib remain, and the raw materials are salified with citric acid, so that the process is complicated, and the total yield is only about 65%.
At present, the intermediate of tofacitinib citrate needs to be provided urgently, so that the production cost is reduced and the product quality is improved when the intermediate is used for preparing tofacitinib citrate.
Disclosure of Invention
The invention aims to provide a tofacitinib citrate intermediate, which is used for synthesizing tofacitinib citrate, so that the utilization rate of raw materials is greatly improved, the production cost is reduced, and the product quality is improved; the invention also provides a preparation method and application of the tofacitinib citrate intermediate.
The tofacitinib citrate intermediate is N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-D ] pyrimidine-4-amine dihydrochloride monohydrate, and has the following structural formula:
the preparation method of the tofacitinib citrate intermediate comprises the following steps:
(1) adding N-methyl-N- ((3R,4R) -1-benzyl-4-methylpiperidine-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidine-4-amine into water and an organic solvent, adding hydrochloric acid and palladium hydroxide carbon, introducing hydrogen for reaction, and filtering the palladium hydroxide carbon;
(2) and cooling to room temperature, dropwise adding an organic solvent, crystallizing, filtering, and drying to obtain the tofacitinib citrate intermediate.
The organic solvent in the step (1) is one of methanol, ethanol or isopropanol.
The ratio of the N-methyl-N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine to water in step (1) is 1: 0.5-1, N-methyl-N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine in g, water in ml.
The volume ratio of water to the organic solvent in the step (1) is 1: 10-30, preferably 1: 20-25.
The molar ratio of the N-methyl-N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine and hydrochloric acid in step (1) is 1: 1-2.
The mass ratio of the N-methyl-N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine to palladium hydroxide carbon in the step (1) is 1: 0.04-0.1.
The reaction temperature in the step (1) is 30-90 ℃, the reaction pressure is 0.10-0.50MPa, and the reaction time is 5-10 h; the reaction pressure is preferably from 0.25 to 0.35 MPa.
The N-methyl-N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine described in the step (1) is produced by Changzhou Dada pharmaceutical chemical Co.
The organic solvent in the step (2) is one of acetone, acetonitrile or tetrahydrofuran, and the volume ratio of the use amount of the organic solvent in the step (2) to the use amount of the organic solvent in the step (1) is 1: 1-3.
The drying temperature in the step (2) is 40-50 ℃, and the drying time is 3-5 h.
The application of the tofacitinib citrate intermediate is that the tofacitinib citrate intermediate is added into acetonitrile, DBU and ethyl cyanoacetate are added for reaction, citric acid monohydrate and water are added, and cooling and crystallization are carried out to obtain the tofacitinib citrate.
The molar ratio of the tofacitinib citrate intermediate to DBU to ethyl cyanoacetate to citric acid monohydrate is 1: 3-5: 2-3: 2-3.
The ratio of the tofacitinib citrate intermediate to acetonitrile to water is 1: 5-10: 5-8, taking the tofacitinib citrate intermediate as g, taking the acetonitrile as ml, and taking the water as ml.
The reaction temperature is 40-50 ℃, the reaction time is 5-8 hours, the cooling temperature is 0-10 ℃, and the crystallization time is 1-3 hours.
The route for synthesizing tofacitinib citrate by using the tofacitinib citrate intermediate is as follows:
the application of the tofacitinib citrate intermediate comprises the following specific steps:
(1) adding N-methyl-N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine into water and an organic solvent, adding hydrochloric acid and palladium hydroxide carbon, and stirring;
(2) heating the reaction mixture in the step (1), and introducing hydrogen to catalyze, hydrogenate and debenzylate;
(3) filtering out the palladium hydroxide carbon in the step (2) to obtain a clear reaction solution;
(4) cooling to room temperature, dropwise adding an organic solvent into the reaction liquid obtained in the step (3) for crystallization, and then carrying out suction filtration and drying to obtain a compound 1;
(5) adding the compound 1 into acetonitrile, adding DBU (1, 8-diazabicycloundecen-7-ene) and ethyl cyanoacetate, reacting for 5-8 hours at 40-50 ℃, adding citric acid monohydrate and water, cooling to 0-10 ℃, carrying out thermal insulation crystallization for 1-3 hours, carrying out suction filtration and drying to obtain tofacitinib citrate.
The reaction equation of the present invention is as follows:
according to the invention, water is added during the hydrogenation reduction reaction, the obtained monohydrate is dissolved out, the obtained monohydrate is dried for 3-5h at 40-50 ℃, the crystal water is not lost, and the total yield of the tofacitinib citrate prepared by the intermediate containing the crystal water through a one-pot method can reach more than 95%.
The invention has the following beneficial effects:
the method has good effect of synthesizing tofacitinib citrate by adopting an N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-D ] pyrimidine-4-amine dihydrochloride monohydrate one-pot method, and the tofacitinib citrate prepared by the compound has the yield of over 95 percent and the purity of over 99.9 percent, thereby reducing the production cost and improving the product quality.
The citric acid tofacitinib intermediate compound N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-D ] pyrimidine-4-amine dihydrochloride monohydrate has high reaction activity and high conversion rate of reaction preparation tofacitinib, avoids the problem of raw material waste caused by incomplete reaction of raw materials in the prior art, and greatly improves the industrial production efficiency.
Drawings
Figure 1 is a DSC diagram for compound 1.
Figure 2 is a TGA profile of compound 1.
FIG. 3 is a liquid chromatogram of tofacitinib citrate prepared in example 1.
FIG. 4 is a liquid chromatogram of tofacitinib citrate prepared in example 2.
FIG. 5 is a liquid chromatogram of tofacitinib citrate prepared in example 3.
Detailed Description
The present invention is further described below with reference to examples.
Example 1
(1) Synthesis of N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-D ] pyrimidin-4-amine dihydrochloride monohydrate
Adding 33.5g (0.10mol) of N-methyl-N- ((3R,4R) -1-benzyl-4-methylpiperidine-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine into an autoclave, adding 20ml of water and 400ml of ethanol, adding 10g (0.10mol) of hydrochloric acid and 1.5g of palladium-carbon hydroxide, stirring, replacing air in the autoclave with nitrogen, heating to 50 ℃, introducing hydrogen to 0.3MPa for reaction for 8 hours, emptying, filtering out the palladium-carbon hydroxide, dropwise adding 320ml of acetone into the reaction solution at room temperature, precipitating a large amount of solid, carrying out suction filtration, and drying at 45 ℃ for 3 hours to obtain 32.7g of compound 1 with the yield of 97.3%.
(2) Synthesis of tofacitinib citrate
26.9g (0.08mol) of compound 1, 200ml of acetonitrile, 45.7g (0.3mol) of DBU and 27.1g (0.24mol) of ethyl cyanoacetate are added into a glass bottle, the temperature is raised to 40 ℃ for reaction for 6h, then 50.4g (0.24mol) of citric acid monohydrate and 150ml of water are added, the temperature is lowered to 0-10 ℃, the temperature is kept for crystallization for 2h, and the citric acid tofacitinib is obtained by suction filtration and drying, the purity is 99.93 percent, the compound 1 is not detected (RRT0.3 is impurity relative to the main peak time on a liquid chromatogram), and the yield is 96.4 percent. The liquid chromatogram of the obtained tofacitinib citrate is shown in figure 3.
Example 2
(1) Synthesis of N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-D ] pyrimidin-4-amine dihydrochloride monohydrate
Adding 33.5g (0.10mol) of N-methyl-N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine into an autoclave, adding 30ml of water and 500ml of isopropanol, adding 15g (0.15mol) of hydrochloric acid and 1.8g of palladium hydroxide carbon, stirring, replacing air in the autoclave with nitrogen, heating to 60 ℃, introducing hydrogen to 0.5MPa for reaction for 5 hours, emptying, filtering out the palladium hydroxide carbon, dropwise adding 280ml of tetrahydrofuran into the reaction solution at room temperature, precipitating a large amount of solid, carrying out suction filtration, and drying at 40 ℃ for 5 hours to obtain 32.5g of compound 1, wherein the yield is 96.8%.
(2) Synthesis of tofacitinib citrate
The preparation method is the same as the synthesis of tofacitinib citrate in example 1, and 39.1g of tofacitinib citrate with the purity of 99.93 percent and the yield of 96.9 percent is obtained, and the compound 1 is not detected. The liquid chromatogram of the obtained tofacitinib citrate is shown in figure 4.
Example 3
(1) Synthesis of N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-D ] pyrimidin-4-amine dihydrochloride monohydrate
Adding 33.5g (0.10mol) of N-methyl-N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine into an autoclave, adding 25ml of water and 600ml of methanol, adding 20g (0.20mol) of hydrochloric acid and 3.0g of palladium carbon hydroxide, stirring, replacing air in the autoclave with nitrogen, heating to 60 ℃, introducing hydrogen to 0.4MPa for reaction for 8 hours, emptying, filtering out palladium carbon hydroxide, dropwise adding 200ml of acetonitrile into the reaction liquid at room temperature, precipitating a large amount of solid, carrying out suction filtration, and drying at 50 ℃ for 4 hours to obtain 32.6g of compound 1 with the yield of 97.1%.
(2) Synthesis of tofacitinib citrate
The preparation method is the same as the synthesis of tofacitinib citrate in example 1, and 39.2g of tofacitinib citrate with the purity of 99.93 percent and the yield of 97.1 percent is obtained without detecting the compound 1. The liquid chromatogram of the obtained tofacitinib citrate is shown in figure 5.
Comparative example 1
(1) Synthesis of N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-D ] pyrimidin-4-amine dihydrochloride
Adding 33.5g (0.10mol) of N-methyl-N- ((3R,4R) -1-benzyl-4-methylpiperidine-3-yl) -N-methyl-7H-pyrrolo [2,3-D ] pyrimidin-4-amine into a reaction bottle, adding 231g of absolute ethyl alcohol and 7.7g of palladium hydroxide carbon, stirring, replacing air in the reaction kettle with nitrogen, heating to 61 ℃, introducing hydrogen at normal pressure for reaction for 12H, emptying, filtering off the palladium hydroxide carbon, adding 26.8g of hydrochloric acid, cooling to-5 ℃, crystallizing for 1H, performing suction filtration, and drying at 65 ℃ for 3H to obtain 31.0g N-methyl-N- ((3R,4R) -4-methylpiperidine-3-yl) -7H-pyrrolo [2,3-D ] pyrimidin-4-amine dihydrochloride, the yield thereof was found to be 97.4%.
(2) Synthesis of tofacitinib citrate
26.9g (0.08mol) of N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-D ] pyrimidin-4-amine dihydrochloride, 200ml of acetonitrile, 1.5g (0.08mol) of purified water, 45.7g (0.3mol) of DBU, 27.1g (0.24mol) of ethyl cyanoacetate are added into a glass bottle, the temperature is raised to 40 ℃ for reaction for 6 hours, then 50.4g (0.24mol) of citric acid monohydrate and 150ml of water are added, the temperature is lowered to 0 ℃, the mixture is kept for crystallization for 2 hours, and the mixture is filtered, filtered and dried to obtain 31.7g of tofacitinib citrate with the yield of 78.5 percent.
Tofacitinib citrate was prepared by reacting the anhydrous compound N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-D ] pyrimidin-4-amine dihydrochloride prepared in comparative example 1 with water, and as a result, it was found that N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-D ] pyrimidin-4-amine dihydrochloride remained incompletely reacted and remained much. The N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-D ] pyrimidine-4-amine dihydrochloride monohydrate prepared by the invention has better solubility and is beneficial to thorough reaction in the preparation process of tofacitinib citrate. The yield of tofacitinib citrate prepared using N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-D ] pyrimidin-4-amine dihydrochloride monohydrate of the present invention is much higher than the yield of tofacitinib citrate prepared using the anhydrous compound of N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-D ] pyrimidin-4-amine dihydrochloride of comparative example 1 reacted with water.
Claims (10)
1. Tofacitinib citrate intermediate, characterized in that it is N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-D ] pyrimidin-4-amine dihydrochloride monohydrate, having the following structural formula:
2. a process for the preparation of tofacitinib citrate intermediate as claimed in claim 1, characterized by comprising the steps of:
(1) adding N-methyl-N- ((3R,4R) -1-benzyl-4-methylpiperidine-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidine-4-amine into water and an organic solvent, adding hydrochloric acid and palladium hydroxide carbon, introducing hydrogen for reaction, and filtering the palladium hydroxide carbon;
(2) and cooling to room temperature, dropwise adding an organic solvent, crystallizing, filtering, and drying to obtain the tofacitinib citrate intermediate.
3. The method for preparing tofacitinib citrate intermediate according to claim 2, wherein the organic solvent in step (1) is one of methanol, ethanol or isopropanol.
4. The process for preparing tofacitinib citrate intermediate as claimed in claim 2, wherein the ratio of N-methyl-N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine to water in step (1) is 1: 0.5-1, N-methyl-N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine in g, water in ml.
5. The method for preparing tofacitinib citrate intermediate according to claim 2, wherein the volume ratio of water to organic solvent in step (1) is 1: 10-30, N-methyl-N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine and hydrochloric acid in a molar ratio of 1: the mass ratio of 1-2, N-methyl-N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine to palladium hydroxide carbon is 1: 0.04-0.1.
6. The preparation method of tofacitinib citrate intermediate as claimed in claim 2, wherein the reaction temperature in step (1) is 30-90 ℃, the reaction pressure is 0.10-0.50MPa, and the reaction time is 5-10 h.
7. The preparation method of tofacitinib citrate intermediate according to claim 2, wherein the organic solvent in the step (2) is one of acetone, acetonitrile or tetrahydrofuran, the volume ratio of the amount of the organic solvent in the step (2) to the amount of the organic solvent in the step (1) is 1:1-3, the drying temperature is 40-50 ℃, and the drying time is 3-5 h.
8. The application of the tofacitinib citrate intermediate in claim 1, wherein the tofacitinib citrate intermediate is added into acetonitrile, DBU and ethyl cyanoacetate are added for reaction, citric acid monohydrate and water are added, and the mixture is cooled and crystallized to obtain the tofacitinib citrate.
9. The use of tofacitinib citrate intermediate according to claim 8, wherein the molar ratio of tofacitinib citrate intermediate, DBU, ethyl cyanoacetate and citric acid monohydrate is 1: 3-5: 2-3: 2-3; the ratio of the tofacitinib citrate intermediate to the acetonitrile to the water is 1: 5-10: 5-8, taking the tofacitinib citrate intermediate as g, taking the acetonitrile as ml, and taking the water as ml.
10. The application of the tofacitinib citrate intermediate as claimed in claim 8, wherein the reaction temperature is 40-50 deg.C, the reaction time is 5-8 hr, the cooling temperature is 0-10 deg.C, and the crystallization time is 1-3 hr.
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Cited By (3)
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| CN112679506A (en) * | 2021-01-12 | 2021-04-20 | 山东天铭医药科技有限公司 | Preparation method of tofacitinib citrate |
| CN113248509A (en) * | 2021-05-17 | 2021-08-13 | 上海中西三维药业有限公司 | Preparation method of tofacitinib citrate intermediate |
| TWI823476B (en) * | 2022-07-15 | 2023-11-21 | 中化合成生技股份有限公司 | Method of preparing tofacitinib citrate |
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