CN110343113B - Preparation method of tofacitinib intermediate - Google Patents
Preparation method of tofacitinib intermediate Download PDFInfo
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- CN110343113B CN110343113B CN201910726827.3A CN201910726827A CN110343113B CN 110343113 B CN110343113 B CN 110343113B CN 201910726827 A CN201910726827 A CN 201910726827A CN 110343113 B CN110343113 B CN 110343113B
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Abstract
The invention provides a preparation method of a tofacitinib intermediate, and belongs to the technical field of biochemistry. The preparation method of the tofacitinib intermediate provided by the invention comprises the following steps: and (3) carrying out debenzylation reaction on the compound A, sodium formate, palladium carbon and a solvent to obtain the tofacitinib intermediate. The preparation method provided by the invention adopts sodium formate as a hydrogen donor to debenzylate to prepare the tofacitinib citrate intermediate, and compared with a preparation method adopting hydrogen as a hydrogen donor, the preparation method provided by the invention does not need pressurization and has safe reaction conditions; compared with hydrazine hydrate as a hydrogen donor, the method has no risk of flammability and explosiveness; compared to ammonium formate as hydrogen donor, there is no risk of the reactor being blocked by volatilization of the hydrogen donor. The preparation method provided by the invention has the advantages of safe reaction conditions, high yield and high purity, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of biochemistry, and particularly relates to a preparation method of a tofacitinib intermediate.
Background
Rheumatoid Arthritis (RA) is a systemic autoimmune disease mainly caused by chronic progressive joint disease, and if the disease is not treated regularly in time, the disease condition gradually worsens, finally deformity, joint rigidity and function loss are caused, and the Rheumatoid Arthritis (RA) is one of the clinically common main disabling diseases. The number of RA patients in China is nearly 500 thousands, the disability rate is high, and heavy burden is caused to both society and patients. There are three general classes of drugs used to treat RA: non-steroidal anti-inflammatory drugs (NSAIDs), cortisol drugs, and anti-rheumatic drugs (DMARDs). Researches prove that only DMARD in the three medicines can delay the damage and the progress of joint structures, and the curative effect on the improvement amplitude of RA symptoms is more obvious.
Tofacitinib citrate is a drug developed by the pharmaceutical company of pfeiri, usa for treating rheumatoid arthritis, with trade name Xeljanz, and is used for treating moderate to severe active Rheumatoid Arthritis (RA) with insufficient or intolerant response to methotrexate treatment.
The synthetic route of tofacitinib citrate is as follows:
the traditional preparation methods of tofacitinib intermediate mainly comprise three methods: firstly, a palladium carbon/hydrogen system is adopted, namely, the compound A is prepared by removing benzyl under the action of hydrogen (hydrogen donor) in the presence of palladium carbon (catalyst), but hydrogen and pressurization are required in the method, so that the method has large potential safety hazard and is not beneficial to large-scale industrial safety production; secondly, a palladium carbon/hydrazine hydrate system is adopted; the reaction is carried out in a neutral medium, the condition is mild, the debenzylation product can be obtained at high yield under normal pressure, but hydrazine is a flammable and explosive product, and has larger potential safety hazard in the processes of transportation, storage and production, and meanwhile, the hydrazine and the derivatives thereof have potential genotoxicity structures and are used in the production of medicines, the residual control requirement is high, and the potential safety hazard of the product is large; thirdly, a palladium-carbon/ammonium formate system is adopted, the method is mild in condition, the debenzylation product can be obtained at high yield under normal pressure, but in the debenzylation reflux reaction process, ammonium formate is easy to volatilize and condense to block a condensing pipe, the material proportion is high, and a closed system is easy to form due to the blocking of the condensing pipe, so that potential safety hazards can be caused due to the closed system in the reflux operation.
Disclosure of Invention
The invention aims to provide a preparation method of a tofacitinib intermediate. The preparation method provided by the invention has the advantages of high yield, high purity and safety, and is suitable for industrial production.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of a tofacitinib intermediate, which comprises the following steps:
carrying out debenzylation reaction on the compound A, sodium formate, palladium carbon and a solvent to obtain a tofacitinib intermediate;
the structural formulas of the compound A and the tofacitinib intermediate are as follows:
preferably, the mass ratio of the compound A to the sodium formate to the palladium carbon is 1: (0.4-1.5) and (0.05-0.15).
Preferably, the solvent is an ethanol water solution, and the mass concentration of the ethanol water solution is 70-98%.
Preferably, the mass ratio of the compound A to the solvent is 1 (5.5-22).
Preferably, the temperature of the debenzylation reaction is 40-90 ℃, and the time of the debenzylation reaction is 2-10 h.
Preferably, after the debenzylation reaction is completed, the method further comprises the steps of sequentially extracting, crystallizing and drying the obtained reaction liquid.
Preferably, the extractant used for the extraction comprises tetrahydrofuran, ethyl acetate or dichloromethane.
Preferably, the solvent used for the crystallization includes ethyl acetate, toluene or n-heptane.
Preferably, the crystallization temperature is 0-40 ℃, and the crystallization time is 0.5-8 h.
Preferably, the drying temperature is 20-80 ℃, and the drying time is 2-8 h.
The invention provides a preparation method of a tofacitinib intermediate, which comprises the following steps: and (3) carrying out debenzylation reaction on the compound A, sodium formate, palladium carbon and a solvent to obtain the intermediate of tofacitinib. The preparation method provided by the invention adopts sodium formate as a hydrogen donor to debenzylate to prepare the tofacitinib citrate intermediate, and compared with a preparation method adopting hydrogen as a hydrogen donor, the preparation method provided by the invention does not need pressurization and has safe reaction conditions; compared with hydrazine hydrate as a hydrogen donor, the method has no risk of flammability and explosiveness; compared to ammonium formate as hydrogen donor, there is no risk of the reactor being blocked by volatilization of the hydrogen donor. The preparation method provided by the invention has the advantages of safe reaction conditions, high yield and high purity, and is suitable for industrial production. As shown in the results of the examples, the yield of the intermediate of the tofacitinib intermediate is as high as 86%, and the purity is as high as 99.75%.
Drawings
FIG. 1 is a process flow diagram for the preparation of a tofacitinib intermediate of the present invention;
FIG. 2 is a graph showing the results of purity measurements of the tofacitinib intermediate prepared in example 1;
FIG. 3 is a hydrogen spectrum of the tofacitinib intermediate prepared in example 1;
FIG. 4 is a mass spectrum of the tofacitinib intermediate prepared in example 1;
FIG. 5 is a graph showing the results of purity measurements of the tofacitinib intermediate prepared in example 2;
FIG. 6 is a graph showing the results of purity measurements of the tofacitinib intermediate prepared in example 3;
FIG. 7 is a graph showing the results of purity measurement of tofacitinib citrate prepared in example 4;
FIG. 8 is a graph showing the results of purity measurement of tofacitinib citrate prepared in example 5;
FIG. 9 is a graph showing the results of purity measurement of tofacitinib citrate prepared in example 6.
Detailed Description
The invention provides a preparation method of a tofacitinib intermediate, which comprises the following steps:
mixing the compound A, sodium formate, palladium carbon and a solvent, and carrying out debenzylation reaction to obtain a tofacitinib intermediate;
the structural formulas of the compound A and the tofacitinib intermediate are as follows:
in the present invention, all the raw material components are commercially available products well known to those skilled in the art unless otherwise specified.
In the invention, the mass ratio of the compound A (N- (3R,4R) -1-benzyl-4-methylpiperidine-7H-pyrrolo [2,3-d ] pyrimidine-4-amine), sodium formate and palladium carbon is preferably 1 (0.4-1.5) to 0.05-0.15, more preferably 1 (0.5-1.2) to 0.08-0.12, and most preferably 1 (0.5-1) to 0.09-0.11.
In the invention, the solvent is preferably an ethanol aqueous solution, and the mass concentration of the ethanol aqueous solution is preferably 70-98%, more preferably 75-95%, and most preferably 80-95%.
In the invention, the mass ratio of the compound A to the solvent is preferably 1 (5.5-22), more preferably 1 (8-15), and most preferably 1 (10-12).
In the invention, the mixing is preferably carried out under the condition of stirring, and the stirring speed is preferably 50-200 r/min. In the invention, the temperature of the debenzylation reaction is preferably 40-90 ℃, more preferably 50-80 ℃, and most preferably 50-60 ℃; the debenzylation reaction time is preferably 2-10 h, more preferably 3-8 h, and most preferably 5-6 h.
In the present invention, after the debenzylation reaction is completed, preferably, the method further comprises sequentially extracting, crystallizing and drying the obtained reaction solution.
In the present invention, the extractant used for the extraction preferably comprises tetrahydrofuran, ethyl acetate or dichloromethane. In the present invention, the number of the extractions is preferably two; the total dosage of the extracting agent required by the two-time extraction is preferably 1-4 times of the mass of the compound A.
After the extraction is completed, the invention preferably further comprises concentrating the obtained extract to obtain a viscous liquid containing the intermediate. In the present invention, the concentration is preferably performed by distillation under reduced pressure. In the invention, the temperature of the reduced pressure distillation is preferably 50-80 ℃, and more preferably 60-70 ℃; the pressure of the reduced pressure distillation is preferably less than 0.1MPa, and more preferably 0.06-0.09 MPa; the time of the reduced pressure distillation is not particularly limited, and the solvent in the organic phase can be ensured to be distilled completely.
In the present invention, the solvent used for the crystallization preferably includes ethyl acetate, toluene or n-heptane. In the present invention, the amount of the crystallization solvent is preferably 1 to 4 times the mass of the compound a. In the invention, a crystallization solvent is added into the viscous liquid containing the tofacitinib intermediate, then the temperature is preferably raised to 80-100 ℃ so as to fully dissolve the tofacitinib intermediate, and then crystallization is carried out to obtain a tofacitinib intermediate crystallization solution. In the invention, the crystallization is preferably carried out under a stirring condition, and the stirring speed is preferably 50-200 r/min. The stirring speed is too high, so that the product has fine particles and is not easy to separate and filter; too slow a stirring speed can result in large product particles, explosiveness and increased impurities. In the invention, the crystallization temperature is preferably 0-40 ℃, more preferably 10-40 ℃, and further preferably 30-40 ℃; the crystallization time is preferably 0.5 to 8 hours, more preferably 2 to 8 hours, and further preferably 3 to 6 hours. In the present invention, too high a temperature of the crystallization results in low product yield; too low a temperature can result in a viscous feed solution that is not easily filtered. The invention can greatly improve the yield and purity of the product by controlling the crystallization conditions.
In the invention, after the crystallization is completed, the method preferably further comprises the steps of performing solid-liquid separation on the crystal solution of the tofacitinib intermediate, and washing and drying the obtained crystal to obtain the tofacitinib intermediate. The solid-liquid separation method of the present invention is not particularly limited, and a solid-liquid separation method known in the art may be used, specifically, centrifugation or filtration. The speed and time of the centrifugation in the present invention are not particularly limited, and those known in the art may be used. In the present invention, the solvent used for the washing preferably includes ethyl acetate, toluene or n-heptane. In the present invention, the drying method is preferably atmospheric forced air drying or vacuum drying under reduced pressure. The drying temperature is preferably 20-80 ℃, more preferably 40-70 ℃, and most preferably 50-60 ℃; the drying time is preferably 2-8 h, more preferably 3-7 h, and most preferably 4-6 h.
The preparation method provided by the invention adopts sodium formate as a hydrogen donor to perform debenzylation to prepare the tofacitinib intermediate, performs debenzylation reaction in a neutral medium, has mild reaction conditions, can obtain a debenzylation product at high yield under normal pressure, is efficient and safe, and is easy to realize industrial mass production. The tofacitinib intermediate prepared by the method has high yield and high purity, and a high-purity tofacitinib citrate product can be prepared through subsequent processes.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. 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
The preparation is carried out according to the process flow chart shown in figure 1:
mixing a compound A (10g), sodium formate (6g), palladium carbon (1g) and ethanol aqueous solution (105g, 95.24 wt%) under the stirring condition, and reacting at 50 ℃ for 4 hours to obtain reaction liquid containing a tofacitinib intermediate;
adding tetrahydrofuran (20 g in total) into the reaction liquid containing the tofacitinib intermediate, extracting for two times, combining the extract liquids, and then carrying out reduced pressure distillation to obtain viscous liquid containing the tofacitinib intermediate;
adding ethyl acetate (20 g in total) into the viscous liquid containing the tofacitinib intermediate, heating to 80 ℃, cooling to 50 ℃ under the condition of stirring and extracting, and crystallizing for 3 hours to obtain a solid material mixed solution containing the tofacitinib intermediate;
and (3) carrying out suction filtration on the solid material mixed liquor containing the tofacitinib intermediate, washing the obtained crystal twice by using ethyl acetate (10g), and carrying out forced air drying at the temperature of 70 ℃ for 4h to obtain the tofacitinib intermediate (6.3g, the molar yield is 86%).
The purity of the prepared tofacitinib intermediate is detected by high performance liquid chromatography, and the test result is shown in figure 2. The purity of the prepared tofacitinib intermediate was 99.75% as calculated from the data in fig. 2.
The hydrogen spectrum and the mass spectrum of the tofacitinib intermediate are shown in figures 3 and 4 respectively. As can be seen from fig. 3 and 4, the present invention successfully produced tofacitinib intermediates having the structures shown.
Example 2
Mixing a compound A (10g), sodium formate (6g), palladium carbon (1g) and ethanol aqueous solution (105g, 95.24 wt%) under the stirring condition, and reacting at 50 ℃ for 5 hours to obtain reaction liquid containing a tofacitinib intermediate;
adding tetrahydrofuran (20 g in total) into the reaction liquid of the tofacitinib intermediate, extracting for two times, combining the extract liquids, and then carrying out reduced pressure distillation to obtain viscous liquid containing the tofacitinib intermediate;
adding toluene (20 g in total) into the viscous liquid containing the tofacitinib intermediate, heating to 80 ℃, cooling to 40 ℃ under the condition of stirring and extracting, and crystallizing for 4 hours to obtain a solid material mixed solution containing the tofacitinib intermediate;
and (3) carrying out suction filtration on the solid material mixed liquor containing the tofacitinib intermediate, washing the obtained crystal twice by adopting methylbenzene (10g), and carrying out forced air drying for 6h at the temperature of 50 ℃ to obtain the tofacitinib intermediate (6.2g, the molar yield is 85%).
The purity of the prepared tofacitinib intermediate is detected by high performance liquid chromatography, and the test result is shown in fig. 5. The purity of the prepared tofacitinib intermediate was 99.71% as calculated from the data in fig. 5.
Example 3
Mixing a compound A (10g), sodium formate (6g), palladium carbon (1g) and ethanol aqueous solution (105g, 95.24 wt%) under the stirring condition, and reacting at 50 ℃ for 5 hours to obtain reaction liquid containing a tofacitinib intermediate;
adding dichloromethane (20 g in total) into the reaction liquid containing the tofacitinib intermediate, extracting for two times, combining the extract liquids, and then carrying out reduced pressure distillation to obtain viscous liquid containing the intermediate;
adding n-heptane (20 g in total) into the viscous liquid containing the tofacitinib intermediate, heating to 80 ℃, cooling to 50 ℃ under the condition of stirring and extracting, and crystallizing for 3 hours to obtain a solid material mixed solution containing the tofacitinib intermediate;
and (3) carrying out suction filtration on the solid material mixed liquor containing the tofacitinib intermediate, washing the obtained crystal twice by adopting n-heptane (10g), and carrying out forced air drying for 4h at the temperature of 70 ℃ to obtain the tofacitinib intermediate (6.0g, the molar yield is 82%).
The purity of the prepared tofacitinib intermediate is detected by high performance liquid chromatography, and the test result is shown in fig. 6. The purity of the prepared tofacitinib intermediate was 99.49% as calculated from the data in fig. 6.
Example 4
Under the stirring condition, the tofacitinib intermediate (6g) prepared in example 1, tetrahydrofuran (18mL) and diazabicyclo (DBU, 3.6g) are stirred and mixed uniformly, ethyl cyanoacetate (6.5g) is added after the temperature is raised to 50 ℃, stirring is carried out for 12 hours at the temperature of 50 ℃, suction filtration is carried out, and the solid material obtained by suction filtration and citric acid react in the presence of acetone/water to obtain tofacitinib citrate.
The purity of the prepared tofacitinib citrate is detected by high performance liquid chromatography, and the test result is shown in figure 7. The purity of the prepared tofacitinib citrate is 99.87 percent calculated by the data in figure 7.
Example 5
Tofacitinib citrate was prepared according to the preparation method of example 5, differing from example 5 only in that the tofacitinib intermediate was prepared from example 2.
The purity of the prepared tofacitinib citrate is detected by high performance liquid chromatography, and the test result is shown in figure 8. The purity of the prepared tofacitinib citrate is 100 percent calculated by the data in figure 8.
Example 6
Tofacitinib citrate was prepared according to the preparation method of example 5, differing from example 5 only in that the tofacitinib intermediate was prepared from example 3.
The purity of the prepared tofacitinib citrate is detected by high performance liquid chromatography, and the test result is shown in figure 9. The purity of the prepared tofacitinib citrate is 99.99% calculated by the data in figure 9.
The test results of the embodiment show that the yield of the tofacitinib intermediate prepared by the invention is as high as 86%, and the purity is as high as 99.75%; the purity of tofacitinib citrate prepared by taking the tofacitinib intermediate prepared by the invention as a raw material is up to 100%.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (6)
1. A preparation method of a tofacitinib intermediate is characterized by comprising the following steps:
carrying out debenzylation reaction on the compound A, sodium formate, palladium carbon and a solvent, and sequentially extracting, crystallizing and drying the obtained reaction liquid to obtain a tofacitinib intermediate;
the mass ratio of the compound A to the sodium formate to the palladium carbon is 1 (0.4-1.5) to 0.05-0.15;
the solvent is ethanol water solution, and the mass concentration of the ethanol water solution is 70-98%;
the extractant used for extraction is tetrahydrofuran or ethyl acetate;
the structural formulas of the compound A and the tofacitinib intermediate are as follows:
2. the preparation method according to claim 1, wherein the mass ratio of the compound A to the solvent is 1 (5.5-22).
3. The preparation method according to claim 1, wherein the temperature of the debenzylation reaction is 40-90 ℃ and the time is 2-10 h.
4. The method according to claim 1, wherein the solvent used for the crystallization is ethyl acetate, toluene or n-heptane.
5. The method according to claim 1, wherein the crystallization temperature is 0 to 40 ℃ and the crystallization time is 0.5 to 8 hours.
6. The preparation method according to claim 1, wherein the drying temperature is 20-80 ℃ and the drying time is 2-8 h.
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| US11827598B1 (en) | 2022-07-15 | 2023-11-28 | Chunghwa Chemical Synthesis & Biotech Co. Ltd. | Preparation method of tofacitinib citrate |
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| CN106146517B (en) * | 2016-06-20 | 2018-08-28 | 山东大学 | A kind of synthetic method of citric acid tropsch imatinib |
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