CN113735860A - Synthesis method of tofacitinib citrate - Google Patents
Synthesis method of tofacitinib citrate Download PDFInfo
- Publication number
- CN113735860A CN113735860A CN202110990874.6A CN202110990874A CN113735860A CN 113735860 A CN113735860 A CN 113735860A CN 202110990874 A CN202110990874 A CN 202110990874A CN 113735860 A CN113735860 A CN 113735860A
- Authority
- CN
- China
- Prior art keywords
- tofa
- reaction
- stirring
- tofacitinib citrate
- steps
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
Abstract
The invention discloses a synthetic method of tofacitinib citrate, which belongs to the technical field of preparation of tofacitinib citrate, wherein tofacitinib citrate is a Janus kinase inhibitor, can effectively inhibit the activity of JAK1 and JAK3 and block signal conduction of various inflammatory cytokines, the existing synthetic steps have expensive and large-amount catalyst, and the yield and purity of tofacitinib citrate need to be improved, the invention uses dihydrochloride of 1-benzyl-4-methyl-3- (methylamino) piperidine and 4-chloro-7-tosyl-7H-pyrrole [2,3-D ] pyrimidine as raw materials to prepare a crude product of tofacitinib citrate through four steps, and then refined tofacitinib citrate is obtained through two-time refining, the invention has common price and simple steps, the yield and the purity of the product are both improved.
Description
Technical Field
The invention relates to the technical field of tofacitinib citrate preparation, and particularly relates to a synthetic method of tofacitinib citrate.
Background
The chemical name of tofacitinib citrate is 3- { (3R,4R) -4-methyl-3- [ methyl (7H-pyrrole [2,3-d ] pyrimidine-4-yl) amino ] piperidine-1-yl } -3-oxopropanenitrile mono-citrate, and the tofacitinib citrate is a Janus kinase (JAK) inhibitor, can effectively inhibit the activity of JAK1 and JAK3, and can block the signal conduction of various inflammatory cytokines.
The Rh/C catalyst, the palladium hydroxide catalyst and the like which are frequently used in the existing synthesis steps have the defects of high price and large using amount of the catalyst, and the expensive raw materials and reagents are generally used at the present stage if high yield is obtained, so that improvement is needed for improving the yield and the purity of the tofacitinib citrate.
Disclosure of Invention
Technical problem to be solved
Aiming at the defects of the prior art, the invention provides a method for synthesizing tofacitinib citrate, which is used for solving the problems that Rh/C catalyst, palladium hydroxide catalyst and other catalysts with high price and large using amount of the catalysts are often used in the existing synthesis steps, and expensive raw materials and reagents are generally used at the current stage if higher yield is obtained, so that improvement is needed for improving the yield and purity of tofacitinib citrate.
(II) technical scheme
In order to achieve the purpose, the invention is realized by the following technical scheme: a synthetic method of tofacitinib citrate specifically comprises the following steps:
step S1: adding deionized water into a clean and dry flask, dissolving dihydrochloride of 1-benzyl-4-methyl-3- (methylamino) piperidine, 4-chloro-7-tosyl-7H-pyrrole [2,3-D ] pyrimidine and potassium carbonate into the deionized water in the beaker, stirring and reacting at 100 ℃, monitoring the reaction by using TCL, cooling the reaction liquid to room temperature, performing suction filtration, taking a filter cake to obtain TOFA-3, concentrating the filtrate, adding acetone, and performing suction filtration again to obtain filter residue which is excessive 4-chloro-7-tosyl-7H-pyrrole [2,3-D ] pyrimidine;
the reaction equation is as follows:
step S2: adding methanol into a clean and dry flask, dissolving TOFA-3 in the methanol in the flask, adding potassium hydroxide, stirring at room temperature for 0.5h after the addition is finished, heating to 45 ℃, keeping the constant temperature of 45 ℃ for reacting for 2.8-3.2h, monitoring by TLC to determine that the reaction is finished, cooling the reaction liquid to 5-10 ℃, performing suction filtration to obtain a filter cake, adding the filter cake into deionized water, and performing suction filtration again to obtain TOFA-4;
the reaction equation is as follows:
step S3: adding deionized water and glacial acetic acid into a clean and dry flask, dissolving TOFA-4 in a mixed solution of the deionized water and the glacial acetic acid, adding 10% Pd/C, replacing reaction liquid by using nitrogen for three times, then replacing by using hydrogen for three times, stirring and reacting for 7.5-8.5h under the conditions of hydrogen atmosphere, temperature of 45-55 ℃ and rotation speed of 200 plus materials of 300r/min, adjusting the reaction liquid to be alkaline after the reaction is determined to be finished by monitoring TLC, extracting for three times by using dichloromethane, concentrating an organic layer to be dry after the extraction is finished, and washing obtained solids for 1-3 times by using ethyl acetate to obtain TOFA-5;
the reaction equation is as follows:
step S4: adding n-butanol into a clean and dry flask, dissolving TOFA-5, DBU and ethyl cyanoacetate in the n-butanol, stirring and reacting for 11-13h at the temperature of 45 ℃ and the rotation speed of 200 and 400r/min, cooling the reaction liquid to room temperature after TLC monitoring determines that the reaction is finished, adding 43% (w/v) citric acid, heating the reaction liquid to 40 ℃, reacting for 2h, cooling to 5-10 ℃ after the reaction is finished, performing suction filtration to obtain a filter cake to obtain TOFA-6, and refining the TOFA-6 to obtain TOFA citrate tofacitinib;
the reaction equation is as follows:
further, the dihydrochloride of 1-benzyl-4-methyl-3- (methylamino) piperidine, 4-chloro-7-tosyl-7H-pyrrolo [2,3-D ] at step S1]The using amount ratio of the pyrimidine to the potassium carbonate is 0.069 mol: 0.165 mol: 114.3g, the developing agent used for TCL monitoring is CHCl3Mixing with MeOH in a volume ratio of 9: 1.
Further, in step S2, the dosage ratio of the methanol, the TOFA-3 and the potassium hydroxide is 600 mL: 0.053 mol: 0.1 mol.
Further, in step S3, the dosage ratio of the deionized water, the glacial acetic acid, the TOFA-4, and the 10% Pd/C is 60 mL: 4.2 mL: 0.049 mol: 2.4 g.
Further, the amount ratio of n-butanol, TOFA-5, DBU and ethyl cyanoacetate in the step S4 is 0.08 mol: 0.08 mol: 27.68 g: 100 mL.
Further, the developing solvent used for TCL monitoring in steps S2, S3, and S4 is CHCl3And MeOH in a volume ratio of 4: 1.
Further, the refining in step S4 specifically includes the following steps:
step S11: adding TOFA-6 into a flask filled with the mixed solution A, heating to 100 ℃ for dissolution, adding activated carbon after dissolution, refluxing for 1-2h, carrying out suction filtration while the solution is hot, cooling the filtrate to 50-55 ℃ at the speed of 1 ℃/min, stirring for 12h at the rotation speed of 200 plus materials at 400r/min, then continuously cooling to 25-30 ℃ at the speed of 1 ℃/min, stirring for 1h at the rotation speed of 200 plus materials at 400r/min, carrying out suction filtration after stirring to obtain a filter cake, and washing the filter cake for 3 times by using a mixed solution of butanol, isopropanol and deionized water in the same ratio to obtain a refined product 1;
step S12: adding the refined product 1 into the mixed solution B, heating to 90 ℃ for dissolution, cooling to 50-55 ℃ at the speed of 1 ℃/min, stirring for 12h at the rotation speed of 200-400r/min, then continuously cooling to 25-30 ℃ at the speed of 1 ℃/min, stirring for 1h at the rotation speed of 200-400r/min, pumping and filtering to obtain a filter cake after stirring is finished, and washing the filter cake for 3 times by using the mixed solution of butanone, ethanol and deionized water with the same ratio to obtain the tofacitinib citrate.
Further, in step S11, the mixed solution a is butanone, isopropanol, and deionized water in a volume ratio of 1: 1: 2, the dosage ratio of the TOFA-6, the mixed liquor A and the active carbon is 1 g: 16mL of: 100 mg; step S12, the mixed solution B is butanone, ethanol and deionized water according to the volume ratio of 1: 1: 1.5, the dosage ratio of the refined product 1 to the mixed liquid B is 1 g: 14 mL.
(III) advantageous effects
The invention provides a synthetic method of tofacitinib citrate. Compared with the prior art, the method has the following beneficial effects: the invention uses 1-benzyl-4-methyl-3- (methylamino) piperidine dihydrochloride amino and 4-chlorine-7-tosyl-7H-pyrrole [2,3-D ] acyl chloride to carry out substitution reaction to prepare TOFA-3, the TOFA-3 removes tosyl in methanol to obtain TOFA-4, then uses 10% Pd/C to remove benzyl from TOFA-4 in glacial acetic acid to obtain TOFA-5, then makes TOFA-5 react with ethyl cyanoacetate to prepare a citric acid tofacitinib crude product, and then carries out refining twice to obtain the refined tofacib. The purity of the product can reach more than 99.5% after refining. The method effectively solves the problems that Rh/C catalyst, palladium hydroxide catalyst and other catalysts with high price and large catalyst usage are frequently used in the existing synthesis steps, and expensive raw materials and reagents are generally used at the present stage if higher yield is obtained, so that improvement is needed for improving the yield and purity of tofacitinib citrate.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
A synthetic method of tofacitinib citrate specifically comprises the following steps:
step S1: adding deionized water into a clean and dry flask, dissolving dihydrochloride of 1-benzyl-4-methyl-3- (methylamino) piperidine, 4-chloro-7-tosyl-7H-pyrrole [2,3-D ] pyrimidine and potassium carbonate into the deionized water in the beaker, stirring and reacting at 100 ℃, monitoring the reaction by using TCL, cooling the reaction liquid to room temperature, performing suction filtration, taking a filter cake to obtain TOFA-3, concentrating the filtrate, adding acetone, and performing suction filtration again to obtain filter residue which is excessive 4-chloro-7-tosyl-7H-pyrrole [2,3-D ] pyrimidine;
step S2: adding methanol into a clean and dry flask, dissolving TOFA-3 in the methanol in the flask, adding potassium hydroxide, stirring at room temperature for 0.5h after the addition is finished, heating to 45 ℃, keeping the constant temperature of 45 ℃ for reacting for 2.8h, monitoring by TLC to determine that the reaction is finished, cooling the reaction liquid to 5 ℃, performing suction filtration to obtain a filter cake, adding the filter cake into deionized water, and performing suction filtration again to obtain TOFA-4;
step S3: adding deionized water and glacial acetic acid into a clean and dry flask, dissolving TOFA-4 in a mixed solution of the deionized water and the glacial acetic acid, adding 10% Pd/C, replacing reaction liquid with nitrogen for three times, replacing with hydrogen for three times, stirring and reacting for 7.5 hours at 45 ℃ and 200r/min in hydrogen atmosphere, adjusting the reaction liquid to be alkaline after the reaction is determined to be finished by TLC monitoring, extracting with dichloromethane for three times, concentrating an organic layer to be dry after the extraction is finished, and washing the obtained solid with ethyl acetate for 1 time to obtain TOFA-5;
step S4: adding n-butanol into a clean and dry flask, dissolving TOFA-5, DBU and ethyl cyanoacetate in the n-butanol, stirring and reacting for 11h at the temperature of 45 ℃ and the rotation speed of 200r/min, cooling the reaction liquid to room temperature after TLC monitoring determines that the reaction is finished, adding 43% (w/v) citric acid, heating the reaction liquid to 40 ℃, reacting for 2h, cooling to 5 ℃ after the reaction is finished, carrying out suction filtration, and taking a filter cake to obtain TOFA-6.
Example 2
A synthetic method of tofacitinib citrate specifically comprises the following steps:
step S1: adding deionized water into a clean and dry flask, dissolving dihydrochloride of 1-benzyl-4-methyl-3- (methylamino) piperidine, 4-chloro-7-tosyl-7H-pyrrole [2,3-D ] pyrimidine and potassium carbonate into the deionized water in the beaker, stirring and reacting at 100 ℃, monitoring the reaction by using TCL, cooling the reaction liquid to room temperature, performing suction filtration, taking a filter cake to obtain TOFA-3, concentrating the filtrate, adding acetone, and performing suction filtration again to obtain filter residue which is excessive 4-chloro-7-tosyl-7H-pyrrole [2,3-D ] pyrimidine;
step S2: adding methanol into a clean and dry flask, dissolving TOFA-3 in the methanol in the flask, adding potassium hydroxide, stirring at room temperature for 0.5h after the addition is finished, heating to 45 ℃, keeping the constant temperature of 45 ℃ for reacting for 3h, cooling reaction liquid to 7 ℃ after the reaction is finished by TLC monitoring, carrying out suction filtration to obtain a filter cake, adding the filter cake into deionized water, and carrying out suction filtration again to obtain TOFA-4;
step S3: adding deionized water and glacial acetic acid into a clean and dry flask, dissolving TOFA-4 in a mixed solution of the deionized water and the glacial acetic acid, adding 10% Pd/C, replacing reaction liquid with nitrogen for three times, replacing with hydrogen for three times, stirring and reacting for 8 hours under the conditions of hydrogen atmosphere, 50 ℃ and 250r/min of rotation speed, regulating the reaction liquid to be alkaline after confirming that the reaction is finished by TLC monitoring, extracting with dichloromethane for three times, concentrating an organic layer to be dry after the extraction is finished, and washing the obtained solid with ethyl acetate for 2 times to obtain TOFA-5;
step S4: adding n-butanol into a clean and dry flask, dissolving TOFA-5, DBU and ethyl cyanoacetate in the n-butanol, stirring and reacting for 12 hours at the temperature of 45 ℃ and the rotation speed of 300r/min, cooling the reaction liquid to room temperature after TLC monitoring determines that the reaction is finished, adding 43% (w/v) citric acid, heating the reaction liquid to 40 ℃, reacting for 2 hours, cooling to 7 ℃ after the reaction is finished, carrying out suction filtration, and taking a filter cake to obtain TOFA-6.
Example 3
A synthetic method of tofacitinib citrate specifically comprises the following steps:
step S1: adding deionized water into a clean and dry flask, dissolving dihydrochloride of 1-benzyl-4-methyl-3- (methylamino) piperidine, 4-chloro-7-tosyl-7H-pyrrole [2,3-D ] pyrimidine and potassium carbonate into the deionized water in the beaker, stirring and reacting at 100 ℃, monitoring the reaction by using TCL, cooling the reaction liquid to room temperature, performing suction filtration, taking a filter cake to obtain TOFA-3, concentrating the filtrate, adding acetone, and performing suction filtration again to obtain filter residue which is excessive 4-chloro-7-tosyl-7H-pyrrole [2,3-D ] pyrimidine;
step S2: adding methanol into a clean and dry flask, dissolving TOFA-3 in the methanol in the flask, adding potassium hydroxide, stirring at room temperature for 0.5h after the addition is finished, heating to 45 ℃, keeping the constant temperature of 45 ℃ for reacting for 3.2h, monitoring by TLC to determine that the reaction is finished, cooling the reaction liquid to 10 ℃, performing suction filtration to obtain a filter cake, adding the filter cake into deionized water, and performing suction filtration again to obtain TOFA-4;
step S3: adding deionized water and glacial acetic acid into a clean and dry flask, dissolving TOFA-4 in a mixed solution of the deionized water and the glacial acetic acid, adding 10% Pd/C, replacing reaction liquid with nitrogen for three times, replacing with hydrogen for three times, stirring and reacting for 8.5 hours under the conditions of hydrogen atmosphere, temperature of 55 ℃ and rotating speed of 300r/min, adjusting the reaction liquid to be alkaline after the reaction is determined to be finished by TLC monitoring, extracting with dichloromethane for three times, concentrating an organic layer to be dry after the extraction is finished, and washing the obtained solid with ethyl acetate for 3 times to obtain TOFA-5;
step S4: adding n-butanol into a clean and dry flask, dissolving TOFA-5, DBU and ethyl cyanoacetate in the n-butanol, stirring and reacting for 13h at the temperature of 45 ℃ and the rotation speed of 400r/min, cooling the reaction liquid to room temperature after TLC monitoring determines that the reaction is finished, adding 43% (w/v) citric acid, heating the reaction liquid to 40 ℃, reacting for 2h, cooling to 10 ℃ after the reaction is finished, carrying out suction filtration, and taking a filter cake to obtain TOFA-6.
Example 4
The TOFA-6 obtained in example 2 was purified by the following specific steps:
step S11: adding TOFA-6 into a flask filled with the mixed solution A, heating to 100 ℃ for dissolution, adding activated carbon after dissolution, refluxing for 1h, carrying out suction filtration while the solution is hot, cooling the filtrate to 50 ℃ at the speed of 1 ℃/min, stirring for 12h at the rotation speed of 200r/min, then continuously cooling to 25 ℃ at the speed of 1 ℃/min, stirring for 1h at the rotation speed of 200r/min, carrying out suction filtration after stirring to obtain a filter cake, and washing the filter cake for 3 times by using a mixed solution of butanol, isopropanol and deionized water in the same ratio to obtain a refined product 1;
step S12: and adding the refined product 1 into the mixed solution B, heating to 90 ℃ for dissolution, cooling to 50 ℃ at the speed of 1 ℃/min, stirring for 12 hours at the rotating speed of 200r/min, then continuously cooling to 25 ℃ at the speed of 1 ℃/min, stirring for 1 hour at the rotating speed of 200r/min, after stirring, performing suction filtration to obtain a filter cake, and washing the filter cake for 3 times by using the mixed solution of butanone, ethanol and deionized water in the same ratio to obtain the tofacitinib citrate.
Example 5
The TOFA-6 obtained in example 2 was purified by the following specific steps:
step S11: adding TOFA-6 into a flask filled with the mixed solution A, heating to 100 ℃ for dissolution, adding activated carbon after dissolution, refluxing for 1.5h, carrying out suction filtration while the solution is hot, cooling the filtrate to 52.5 ℃ at the speed of 1 ℃/min, stirring for 12h at the rotation speed of 300r/min, then continuously cooling to 27.5 ℃ at the speed of 1 ℃/min, stirring for 1h at the rotation speed of 300r/min, carrying out suction filtration after stirring to obtain a filter cake, and washing the filter cake for 3 times by using a mixed solution of butanol, isopropanol and deionized water in the same ratio to obtain a refined product 1;
step S12: and adding the refined product 1 into the mixed solution B, heating to 90 ℃ for dissolution, cooling to 52.5 ℃ at the speed of 1 ℃/min, stirring for 12 hours at the rotating speed of 300r/min, then continuously cooling to 25-30 ℃ at the speed of 1 ℃/min, stirring for 1 hour at the rotating speed of 300r/min, after stirring, performing suction filtration to obtain a filter cake, and washing the filter cake for 3 times by using the mixed solution of butanone, ethanol and deionized water in the same ratio to obtain the tofacitinib citrate.
Example 6
The TOFA-6 obtained in example 2 was purified by the following specific steps:
step S11: adding TOFA-6 into a flask filled with the mixed solution A, heating to 100 ℃ for dissolution, adding activated carbon after dissolution, refluxing for 2h, carrying out suction filtration while the solution is hot, cooling the filtrate to 55 ℃ at the speed of 1 ℃/min, stirring for 12h at the rotation speed of 400r/min, then continuously cooling to 30 ℃ at the speed of 1 ℃/min, stirring for 1h at the rotation speed of 400r/min, carrying out suction filtration after stirring to obtain a filter cake, and washing the filter cake for 3 times by using a mixed solution of butanol, isopropanol and deionized water in the same ratio to obtain a refined product 1;
step S12: and adding the refined product 1 into the mixed solution B, heating to 90 ℃ for dissolution, cooling to 55 ℃ at the speed of 1 ℃/min, stirring for 12 hours at the rotating speed of 400r/min, then continuously cooling to 30 ℃ at the speed of 1 ℃/min, stirring for 1 hour at the rotating speed of 400r/min, after stirring, performing suction filtration to obtain a filter cake, and washing the filter cake for 3 times by using the mixed solution of butanone, ethanol and deionized water in the same proportion to obtain the tofacitinib citrate.
Comparative example: example 2 was not purified.
The purity and yield of tofacitinib citrate obtained in examples 4-6 and comparative example were tested and the results were as follows:
as can be seen from the above table, the ratio of the yield to the purity of tofacitinib citrate obtained in examples 4-6 is high.
It is noted that, herein, relational terms such as first and second, and the like may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Also, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (8)
1. A synthetic method of tofacitinib citrate is characterized by comprising the following steps: the method specifically comprises the following steps:
step S1: adding deionized water into a flask, dissolving dihydrochloride of 1-benzyl-4-methyl-3- (methylamino) piperidine, 4-chloro-7-tosyl-7H-pyrrole [2,3-D ] pyrimidine and potassium carbonate into the deionized water for reaction, cooling reaction liquid to room temperature after the reaction is finished, performing suction filtration, and taking a filter cake to obtain TOFA-3;
step S2: adding methanol into a flask, dissolving TOFA-3 in the methanol, adding potassium hydroxide, stirring at room temperature, heating for reaction, cooling and filtering after the reaction is finished to obtain a filter cake, adding the filter cake into deionized water, and filtering again to obtain TOFA-4;
step S3: adding deionized water and glacial acetic acid into a flask, dissolving TOFA-4 into a mixed solution of the deionized water and the glacial acetic acid, adding 10% Pd/C, replacing reaction liquid for three times by using nitrogen, replacing the reaction liquid for three times by using hydrogen, stirring and reacting under a hydrogen atmosphere, adjusting the reaction liquid to be alkaline after the reaction is finished, extracting by using dichloromethane, concentrating an organic layer to be dry after the extraction is finished, and washing the obtained solid by using ethyl acetate to obtain TOFA-5;
step S4: adding n-butanol into a flask, dissolving TOFA-5, DBU and ethyl cyanoacetate into the n-butanol, stirring for reaction, cooling the reaction liquid to room temperature after the reaction is finished, adding citric acid, heating the reaction liquid for reaction, cooling and filtering after the reaction is finished, taking a filter cake to obtain TOFA-6, and refining the TOFA-6 to obtain tofacitinib citrate.
2. The method for synthesizing tofacitinib citrate according to claim 1, wherein the method comprises the following steps: dihydrochloride of 1-benzyl-4-methyl-3- (methylamino) piperidine, 4-chloro-7-tosyl-7H-pyrrolo [2,3-D ] at step S1]The using amount ratio of the pyrimidine to the potassium carbonate is 0.069 mol: 0.165 mol: 114.3g, the developing agent used for TCL monitoring is CHCl3Mixing with MeOH in a volume ratio of 9: 1.
3. The method for synthesizing tofacitinib citrate according to claim 1, wherein the method comprises the following steps: the dosage ratio of the methanol, the TOFA-3 and the potassium hydroxide in the step S2 is 600 mL: 0.053 mol: 0.1 mol.
4. The method for synthesizing tofacitinib citrate according to claim 1, wherein the method comprises the following steps: in step S3, the dosage ratio of the deionized water, the glacial acetic acid, the TOFA-4 and the 10% Pd/C is 60 mL: 4.2 mL: 0.049 mol: 2.4 g.
5. The method for synthesizing tofacitinib citrate according to claim 1, wherein the method comprises the following steps: the dosage ratio of the n-butanol, the TOFA-5, the DBU and the ethyl cyanoacetate in the step S4 is 0.08 mol: 0.08 mol: 27.68 g: 100 mL.
6. The method for synthesizing tofacitinib citrate according to claim 1, wherein the method comprises the following steps: the developing solvent used for TCL monitoring in steps S2, S3, and S4 is CHCl3And MeOH in a volume ratio of 4: 1.
7. The method for synthesizing tofacitinib citrate according to claim 1, wherein the method comprises the following steps: the refining in step S4 specifically includes the steps of:
step S11: adding TOFA-6 into a flask filled with the mixed solution A, heating to dissolve, adding activated carbon, refluxing, carrying out suction filtration while the solution is hot, cooling the filtrate, stirring for 12 hours, then continuously cooling and stirring for 1 hour, carrying out suction filtration after stirring to obtain a filter cake, and washing the filter cake to obtain a refined product 1;
step S12: and adding the refined product 1 into the mixed solution B, heating to dissolve, cooling and stirring for 12h, continuously cooling and stirring for 1h, filtering after stirring to obtain a filter cake, and washing the filter cake to obtain tofacitinib citrate.
8. The method for synthesizing tofacitinib citrate according to claim 7, wherein the synthetic method comprises the following steps: step S11, the mixed solution A is butanone, isopropanol and deionized water according to the volume ratio of 1: 1: 2, the dosage ratio of the TOFA-6, the mixed liquor A and the active carbon is 1 g: 16mL of: 100 mg; step S12, the mixed solution B is butanone, ethanol and deionized water according to the volume ratio of 1: 1: 1.5, the dosage ratio of the refined product 1 to the mixed liquid B is 1 g: 14 mL.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110990874.6A CN113735860A (en) | 2021-08-26 | 2021-08-26 | Synthesis method of tofacitinib citrate |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110990874.6A CN113735860A (en) | 2021-08-26 | 2021-08-26 | Synthesis method of tofacitinib citrate |
Publications (1)
Publication Number | Publication Date |
---|---|
CN113735860A true CN113735860A (en) | 2021-12-03 |
Family
ID=78733242
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110990874.6A Pending CN113735860A (en) | 2021-08-26 | 2021-08-26 | Synthesis method of tofacitinib citrate |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN113735860A (en) |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101233138A (en) * | 2005-07-29 | 2008-07-30 | 辉瑞产品公司 | Pyrrolo[2,3-d]pyrimidine derivatives, their intermediates and synthesis |
CN104788461A (en) * | 2015-04-30 | 2015-07-22 | 南京臣功制药股份有限公司 | Industrial production method applicable to citric acid tofacitinib |
CN105440039A (en) * | 2015-11-24 | 2016-03-30 | 山东淄博新达制药有限公司 | Synthesis method of tofacitinib citrate |
CN105884781A (en) * | 2016-04-18 | 2016-08-24 | 山东罗欣药业集团股份有限公司 | Preparation method of tofacitinib citrate |
CN108794491A (en) * | 2018-08-16 | 2018-11-13 | 山东罗欣药业集团恒欣药业有限公司 | Refining method of tofacitinib citrate |
CN108948020A (en) * | 2018-07-03 | 2018-12-07 | 南京正大天晴制药有限公司 | Refining method of tofacitinib citrate |
CN109776547A (en) * | 2019-03-22 | 2019-05-21 | 北京新领先医药科技发展有限公司 | Preparation method of tofacitinib citrate |
-
2021
- 2021-08-26 CN CN202110990874.6A patent/CN113735860A/en active Pending
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101233138A (en) * | 2005-07-29 | 2008-07-30 | 辉瑞产品公司 | Pyrrolo[2,3-d]pyrimidine derivatives, their intermediates and synthesis |
CN104788461A (en) * | 2015-04-30 | 2015-07-22 | 南京臣功制药股份有限公司 | Industrial production method applicable to citric acid tofacitinib |
CN105440039A (en) * | 2015-11-24 | 2016-03-30 | 山东淄博新达制药有限公司 | Synthesis method of tofacitinib citrate |
CN105884781A (en) * | 2016-04-18 | 2016-08-24 | 山东罗欣药业集团股份有限公司 | Preparation method of tofacitinib citrate |
CN108948020A (en) * | 2018-07-03 | 2018-12-07 | 南京正大天晴制药有限公司 | Refining method of tofacitinib citrate |
CN108794491A (en) * | 2018-08-16 | 2018-11-13 | 山东罗欣药业集团恒欣药业有限公司 | Refining method of tofacitinib citrate |
CN109776547A (en) * | 2019-03-22 | 2019-05-21 | 北京新领先医药科技发展有限公司 | Preparation method of tofacitinib citrate |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP3257855B1 (en) | Method for preparing ibrutinib | |
CN111763170B (en) | Preparation method of flumatinib intermediate | |
CN103204801A (en) | Synthesis method for N-Boc-3-piperidone | |
CN115232106A (en) | Preparation method of vorexan fumarate impurity | |
CN110240586A (en) | The preparation method of 2,3- dihydro -1H- benzo [f] chroman -2- amine derivative | |
CN107698643B (en) | A kind of preparation method of dehydroepiandros-sterone | |
CN108640923A (en) | A kind of support method replaces the preparation method of cloth key intermediate | |
CN113735860A (en) | Synthesis method of tofacitinib citrate | |
CN110066240B (en) | Synthesis method of nitrendipine | |
CN111533746A (en) | Synthesis method of tofacitinib citrate | |
CN112679508B (en) | Preparation method of tofacitinib intermediate | |
CN110963946B (en) | Preparation method of sodium methyl taurate | |
CN114181117B (en) | Preparation method of peramivir intermediate | |
CN111100042B (en) | Preparation method of 2-methoxy-5-sulfonamide benzoic acid | |
CN101565380A (en) | Preparation method of L(+)-p-fluorophenyl glycine | |
CN114149360B (en) | Preparation method of high-purity nitrendipine bulk drug | |
CN102516098B (en) | Preparation method of tolterodine tartrate | |
CN111072543B (en) | Preparation method and application of (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid compound | |
CN116589410B (en) | Synthesis method of 6-chloro-2-methyl-2H-indazole-5-amine | |
CN112898277B (en) | Preparation method of afatinib intermediate | |
CN115448886A (en) | Preparation method of olapari | |
CN109836341B (en) | Preparation method of salicylamine acetate | |
CN107880097B (en) | Preparation method of deuterated telaprevir | |
CN116023377A (en) | Preparation method of non-nereirenone and key chiral intermediate thereof | |
CN116514716A (en) | Preparation method of (S) -1, 3-dihydro spiro [ indene-2, 4' -piperidine ] -1-amine-dihydrochloride |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
RJ01 | Rejection of invention patent application after publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20211203 |