CN105440039A - Synthesis method of tofacitinib citrate - Google Patents
Synthesis method of tofacitinib citrate Download PDFInfo
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- CN105440039A CN105440039A CN201510823470.2A CN201510823470A CN105440039A CN 105440039 A CN105440039 A CN 105440039A CN 201510823470 A CN201510823470 A CN 201510823470A CN 105440039 A CN105440039 A CN 105440039A
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Abstract
The invention belongs to the field of medicine synthesis, and particularly relates to a synthetic method of tofacitinib citrate. TFTB-1 (N-methyl-N- ((3R,4R) -4-methyl-1-benzyl-3-piperidyl) -7- ((4-methylphenyl) sulfonyl) 7H-pyrrolo [2, 3-D)]Heating pyrimidine-4-amine), sodium hydroxide, ethanol and water for reaction to prepare TFTB-2, and reacting TFTB-2, ammonium acetate and ethanol in Pd (OH)2catalyst/C and H2Reacting under the condition to obtain TFTB-3 hydrochloride. Mixing TFTB-3 hydrochloride, triethylamine and ethyl acetate, adding DCC and DMAP, heating and stirring, and adding cyanoacetic acid for reaction; and adding citric acid monohydrate and n-butyl alcohol, heating for reaction, and refining to obtain tofacitinib citrate. The TFTB-3 hydrochloride is directly used for preparing a generated product, and a finished product is prepared by a one-pot method, so that the yield is high and the purity is high.
Description
Technical Field
The invention belongs to the field of medicine synthesis, and particularly relates to a synthetic method of tofacitinib citrate.
Background
Tofacitinib is a novel oral JAK pathway inhibitor developed by feverfew. Unlike most other RA therapeutics currently acting primarily on extracellular targets, tofacitinib 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 JAK 2. Tofacitinib is the pioneer drug for developing rheumatoid arthritis treatment, and the FDA approved a JAK inhibitor for treating adult active stages and moderate to severe rheumatoid arthritis patients who do not respond well to methotrexate on day 11, 6 of 2012. Tofacitinib may be used alone or in combination with methotrexate and other standard therapeutic agents.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a synthesis method of tofacitinib citrate, which adopts a one-pot method to prepare a finished product and has high yield and high purity.
Mixing TFTB-3 hydrochloride, triethylamine and ethyl acetate, adding DCC and DMAP, heating and stirring, and adding cyanoacetic acid to react; and then adding citric acid monohydrate and N-butyl alcohol, heating for reaction, and refining to obtain tofacitinib citrate, wherein TFTB-3 is N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-D ] pyrimidine-4-amine.
Wherein:
DCC is dicyclohexylcarbodiimide and DMAP is 4-dimethylaminopyridine.
The mass ratio of TFTB-3 hydrochloride, triethylamine, ethyl acetate, DCC, DMAP, cyanoacetic acid and citric acid monohydrate is 1: 0.8-0.9: 11.0-12.0: 1.7-1.8: 0.009-0.011: 0.40-0.42: 2.9-3.0, preferably 1: 0.88: 11.28: 1.75: 0.01: 0.41: 2.96.
wherein: the reaction temperature is 25-30 ℃, the inventor takes 20-25 ℃, 25-30 ℃ and 30-35 ℃ as the reaction temperature to carry out the test, and the result shows that: at the temperature of 20-25 ℃, the reaction is slow, the reaction time is long, and impurities are not obviously reduced; at 25-30 deg.c, less impurity. At 30-35 deg.C, the impurities are increased obviously, and the reaction temperature is preferably 25-30 deg.C.
The mass ratio of DCC to TFTB-3 hydrochloride is preferably 1.75:1, i.e. the molar ratio is 3: 1. A large number of researches find that when the molar ratio of DCC to TFTB-3 hydrochloride is 2.5 times, more raw materials are remained, more than 3.5 times, the reaction is complete in 5 hours, the purity of the product is the same, and the preferred molar ratio is 3: 1.
The mass ratio of cyanoacetic acid to TFTB-3 hydrochloride used is preferably 0.41:1, i.e.a molar ratio of 1.7: 1. Extensive studies have found that when the molar ratio of cyanoacetic acid to TFTB-3 hydrochloride is 1.5 times, more starting material remains; 1.7 times or more, the reaction is complete in 5 hours, the purity of the product is the same, and the preferred molar ratio is 1.7: 1.
The reaction time is preferably 5 hours, and in order to examine the influence of the reaction time on the reaction, the reaction is continued to be prolonged for 0.5 hour and 1 hour after the reaction is detected, and the change condition of impurities is examined. The results show that: after 0.5 and 1 hour of reaction, the reaction is not affected, no new impurities are generated, and the time tolerance of the reaction is stronger. Therefore, the reaction time is preferably 5 hours.
By optimizing the process, the optimal reaction conditions are as follows: ethyl acetate is used as a reaction solvent, DCC is used as a dehydrating agent, DMAP is used as a catalyst, the reaction temperature is 25-30 ℃, the reaction time is 5 hours, and the yield and the purity of the obtained product are stable.
As a preferable scheme, the method for synthesizing tofacitinib citrate comprises the following steps: adding TFTB-3 hydrochloride, triethylamine and ethyl acetate into a reaction bottle, stirring, adding DCC and DMAP, heating to 25-30 ℃, and stirring; adding cyanoacetic acid every 5min, and controlling the temperature to be 25-30 ℃; after the addition is finished, continuing the reaction, after the reaction is finished, adding part of the citric acid monohydrate and water, stirring and filtering, transferring the filter cake into a reaction bottle, adding water and n-butyl alcohol, heating and refluxing, then carrying out hot filtration, cooling the filtrate in an ice bath, adding the rest citric acid monohydrate, stirring and filtering, and drying the filter cake to obtain the product.
The reaction equation is as follows:
the preparation method of TFTB-3 hydrochloride comprises the following steps: TFTB-2, ammonium acetate and ethanol in Pd (OH)2catalyst/C and H2Reacting under the condition to obtain a product, wherein TFTB-2 is (3R,4R) - (1-benzyl-4-methyl-piperidine-3-yl) -methyl- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) -amines.
TFTB-2, ammonium acetate, ethanol, Pd (OH)2The mass ratio of/C is 1: 0.9-1.1: 5-6: 0.18-0.22, preferably 1: 1: 5.5: 0.2.
the reaction temperature is 60-65 ℃, the reaction temperature is 55 ℃, 60 ℃ and 65 ℃ respectively, the test is carried out, and the result shows that: at 55 ℃, the reaction is slow and hardly reacts; the reaction is preferably carried out at 60 ℃ and 65 ℃ because the reaction temperature is preferably 60 to 65 ℃.
Pd(OH)2The mass ratio of/C to TFTB-2 is preferably 0.2, and a large number of experiments show that when the mass ratio is 0.15 times, the reaction is not complete within 5 hours; when the mass ratio is 0.2 time and 0.25 time, the reaction is complete in 5 hours, and the purity of the product is the same. Therefore, the amount of palladium hydroxide carbon used is preferably 0.2 times.
The reaction time is 5 hours, and in order to examine the influence of the reaction time on the reaction, after the reaction is detected, the reaction is continued to be prolonged for 0.5 hour and 1 hour, and the change condition of impurities is examined. The results show that: after 0.5 and 1 hour of reaction, the reaction is not affected, no new impurities are generated, and the time tolerance of the reaction is stronger. Therefore, the reaction time is preferably 5 hours.
And (3) an over-optimization process, wherein the determined optimal reaction conditions are as follows: ethanol is used as a reaction solvent, ammonium acetate is used as a stabilizer, palladium hydroxide carbon is used as a catalyst, the reaction temperature is 60-65 ℃, the reaction time is 5 hours, and the yield and the purity of the obtained product are stable.
As a preferred scheme, the preparation method of TFTB-3 hydrochloride comprises the following steps: adding TFTB-2, ammonium acetate and ethanol into a reaction bottle, stirring, and introducing N2Protection, addition of Pd (OH)2C, stopping the supply of N2Introduction of H2Heating for reaction, performing suction filtration after the reaction is finished, distilling the filtrate at 75-80 ℃ under reduced pressure, adding dichloromethane and activated carbon for reflux after steaming until no liquid flows out, cooling to room temperature, performing suction filtration, distilling the filtrate under reduced pressure, adding ethanol for stirring until no liquid flows out, dropwise adding hydrochloric acid and ethanol, performing heat preservation for crystallization, performing suction filtration, and drying the solid to obtain the product.
The reaction equation is as follows:
the preparation method of TFTB-2 comprises the following steps: heating TFTB-1, sodium hydroxide, ethanol and water for reaction to prepare TFTB-2; TFTB-1 is N-methyl-N- ((3R,4R) -4-methyl-1-benzyl-3-piperidinyl) -7- ((4-methylphenyl) sulfonyl) 7H-pyrrolo [2,3-D ] pyrimidin-4-amine.
The mass ratio of TFTB-1 to sodium hydroxide to ethanol to water is 1: 0.4-0.5: 8-12: 8-12, preferably 1: 0.46: 10: 10.
the reaction time is 70-85 ℃, the reaction temperatures are 60 ℃, 70 ℃ and 85 ℃ respectively, and the test results show that: at 60 ℃, the reaction is not carried out; the reaction conditions are the same at 70 ℃ and 85 ℃, so the reaction temperature is preferably 70 to 85 ℃.
The optimized process determines the optimal reaction conditions as follows: and reacting for 3 hours at the temperature of below 80-85 ℃ by using ethanol and water as reaction solvents and sodium hydroxide as an acid-binding agent to obtain the product with stable yield and purity.
As a preferred technical scheme, the preparation method of TFTB-2 comprises the following steps: heating TFTB-1, sodium hydroxide, ethanol and water for reaction, distilling at 80-90 ℃ under reduced pressure after the reaction is finished until no liquid flows out, adding purified water, continuing stirring, cooling to room temperature, adding dichloromethane for extraction, evaporating an organic phase to dryness, adding acetone for reflux, cooling to 10-20 ℃, filtering, and drying a filter cake to obtain TFTB-2.
The reaction equation is as follows:
the refining is as follows: adding tofacitinib citrate, water and n-butanol into a reaction bottle, stirring, heating for refluxing, filtering while hot, cooling the filtrate to 10-20 ℃ in an ice bath, keeping the temperature, stirring, performing suction filtration, and drying a filter cake to obtain 254g of tofacitinib citrate powder with the yield of 85%.
The mass ratio of tofacitinib citrate to water to n-butanol is 1: 18-22: 1.5-1.8, preferably 1: 20: 1.6.
as a preferable technical scheme, the method for synthesizing tofacitinib citrate comprises the following steps:
(1) preparation of TFTB-2
Adding TFTB-1, sodium hydroxide, ethanol and water into a reaction bottle, heating to 70-85 ℃, and keeping the temperature to react for 3 hours; and (3) after the reaction is finished, distilling under reduced pressure at 80-90 ℃ until no liquid flows out, adding purified water, continuously stirring, cooling to room temperature, adding dichloromethane for extraction once, extracting the water layer once again with dichloromethane, combining organic layers, washing the organic layer once with purified water, and stirring and drying the organic layer for 2 hours with anhydrous sodium sulfate. Filtering, evaporating filtrate, adding acetone, refluxing for 30min, cooling to 10-20 deg.C, filtering, placing filter cake in drying oven, and drying at 60 + -5 deg.C for 4 hr to obtain off-white solid, i.e. TFTB-2.
(2) Preparation of TFTB-3 hydrochloride
Adding TFTB-2, ammonium acetate and ethanol into a reaction bottle, starting stirring, and introducing N2Protection, stirring at room temperature for 0.5h, adding Pd (OH)2C, continuing stirring for 0.5h, stopping introducing N2Introduction of H2Stirring at room temperature for 0.5H, heating to 60-65 ℃, reacting at a constant temperature for 5H, cooling to room temperature, and stopping introducing H2Filtering, washing the filter cake twice with ethanol, and mixing the filtrates. Adding the filtrate into a 5L reaction bottle, distilling at 75-80 ℃ under reduced pressure, steaming until no liquid flows out, adding dichloromethane and active carbon, refluxing for 0.5h, cooling to room temperature, stirring for 0.5h, performing suction filtration, washing the filter cake with dichloromethane, and combining the filtrates. Adding the filtrate into a 5L reaction bottle, distilling under reduced pressure, steaming until no liquid flows out, adding ethanol, stirring, cooling to 0-5 ℃ after materials in the reaction bottle are completely dissolved, slowly dropwise adding hydrochloric acid ethanol, continuing to perform heat preservation crystallization for 5 hours after dropwise adding is finished, performing suction filtration, washing the reaction bottle with ethanol, washing a filter cake with a washing solution, and performing suction filtration. And (3) putting the wet product into a drying oven, and drying for 4h at the temperature of 80 +/-5 ℃ to obtain off-white solid TFTB-3 hydrochloride.
(3) Preparation of tofacitinib citrate
Adding TFTB-3 hydrochloride, triethylamine and ethyl acetate into a reaction bottle, starting stirring to fully disperse the TFTB-3 hydrochloride, the triethylamine and the ethyl acetate, adding DCC and DMAP, heating to 25-30 ℃, and stirring for 0.5 h. Adding cyanoacetic acid every 5min, and controlling the temperature to be 25-30 ℃. After the addition, the reaction was continued for 5 hours. And (5) sampling and carrying out HPLC detection until the content of TFTB-2 in the reaction solution is less than 0.5 percent relative to tofacitinib, namely ending the reaction, and otherwise, continuing the reaction until the reaction is ended. The liquid phase detection conditions are as follows: a chromatographic column: cossill c184.6 × 150mm5um, mobile phase: a: 0.2% perchloric acid, B: 0.2% perchloric acid-acetonitrile 30:70, wavelength: 210nm, flow rate: 1.0ml/min, column temperature: and (4) room temperature. Adding citric acid monohydrate and 346g of water, stirring for 1h, and filtering. Transferring the filter cake into a reaction bottle, adding water and n-butanol, heating to 100 ℃, refluxing for 30min, carrying out hot filtration at 80-90 ℃, cooling the filtrate to 10-20 ℃ in an ice bath, adding citric acid monohydrate, stirring for 30min, and filtering. And (3) putting the wet product into a drying oven, controlling the temperature to be 90 +/-5 ℃ and drying for 4 hours to obtain the off-white solid tofacitinib citrate.
(4) Refining
Adding tofacitinib citrate, water and n-butanol into a 10L reaction bottle, stirring, heating to 100 ℃, refluxing for 30min, performing hot filtration at 80-90 ℃, cooling the filtrate to 10-20 ℃ in an ice bath, keeping the temperature, stirring for 30min, performing suction filtration, putting the filter cake into a drying oven, controlling the temperature to 90 +/-5 ℃, and drying for 4h to obtain the white powdery tofacitinib citrate.
(5) Re-refining
Adding tofacitinib citrate, water and n-butanol into a 10L reaction bottle, stirring, heating to 100 ℃, refluxing for 30min, performing hot filtration at 80-90 ℃, cooling the filtrate to 10-20 ℃ in an ice bath, keeping the temperature, stirring for 30min, performing suction filtration, putting the filter cake into a drying oven, controlling the temperature to 90 +/-5 ℃, and drying for 4h to obtain the white powdery tofacitinib citrate.
The ethanol hydrochloride in the step (2) is a mixture obtained by mixing HCl gas and absolute ethanol, wherein the solute is HCl and the solvent is ethanol.
In summary, the invention has the following advantages:
(1) in the reaction of the step, the TFTB-3 hydrochloride is directly used for preparing a product, rather than desalting and then reacting; after the reaction is finished, the monohydrate citric acid is directly added to generate the citric acid TFTB, a finished product is prepared by adopting a one-pot method, and the working procedures of material separation, refining, drying and the like in the reaction process are reduced.
(2) TFTB-3 hydrochloride was prepared as TFTB-2 by catalytic hydrogenation of palladium on carbon hydroxide to remove the benzyl group, the N-protecting group. Ammonium acetate is added as a hydrogen donor, and ammonium acetate acts as a buffer salt, so that hydrogen is supplied during the reaction, and the pH of the reaction solution is maintained stable, thereby reducing the formation of impurities. After the reaction is finished, ethanol hydrochloride is adopted for crystallization, the obtained product is TFTB-3 hydrochloride, and no technical report for directly preparing TFTB by using hydrochloride exists at present.
(3) Preparation of TFTB-2 was generated from TFTB-1 by removal of the N-protecting group from p-toluenesulfonyl. The common removing conditions of the p-toluenesulfonyl are acidic conditions such as hydrobromic acid, sulfuric acid and the like, and the sodium hydroxide aqueous solution is innovatively adopted as the removing agent of the N-protecting group of the TFTB-1 for the p-toluenesulfonyl, so that the effect is obvious. The innovation point is that the removed p-toluenesulfonyl and sodium hydroxide generate water-soluble sodium p-toluenesulfonate, which is easy to be completely removed in the post-treatment process so as to ensure that no p-toluenesulfonic acid remains in TFTB-2, and the residual p-toluenesulfonic acid is found to poison the catalyst in the next reaction (the catalyst can be deactivated due to palladium hydroxide carbon poisoning).
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1
A synthetic method of tofacitinib citrate comprises the following steps:
(1) preparation of TFTB-2
Adding TFTB-1, sodium hydroxide, ethanol and water into a 20L reaction bottle, heating to 70 ℃, and carrying out heat preservation reaction for 3 hours; and (3) after the reaction is finished, distilling under reduced pressure at 80-90 ℃ until no liquid flows out, adding purified water, continuously stirring, cooling to room temperature, adding dichloromethane for extraction once, extracting the water layer once again with dichloromethane, combining organic layers, washing the organic layer once with purified water, and stirring and drying the organic layer for 2 hours with anhydrous sodium sulfate. Filtering, evaporating filtrate to dryness, adding acetone, refluxing for 30min, cooling to 10 deg.C, filtering, placing filter cake in drying oven, and drying at 60 + -5 deg.C for 4 hr to obtain off-white solid, i.e. TFTB-2264g, with yield of 85%. The charging amount of each raw material in the step (1) is shown in table 1.
TABLE 1 charging amounts of the respective raw materials in step (1)
| Name of material | Proportioning (w/w) |
| TFTB-1 | 1.00 |
| Sodium hydroxide | 0.4 |
| Ethanol | 12 |
| Purified water | 15.00 |
| Methylene dichloride | 10.00 |
| Anhydrous sodium sulfate | 4.00 |
| Acetone (II) | 3.00 |
(2) Preparation of TFTB-3 hydrochloride
Adding TFTB-2, ammonium acetate and ethanol into a 5L reaction bottle, starting stirring, and introducing N2Protection, stirring at room temperature for 0.5h, adding Pd (OH)2C, continuing stirring for 0.5h, stopping introducing N2Introduction of H2Stirring at room temperature for 0.5H, heating to 65 deg.C, reacting for 5H, cooling to room temperature, and stopping introducing H2Filtering, washing the filter cake twice with ethanol, and mixing the filtrates. Adding the filtrate into a 5L reaction bottle, distilling at 75-80 ℃ under reduced pressure, steaming until no liquid flows out, adding dichloromethane and active carbon, refluxing for 0.5h, cooling to room temperature, stirring for 0.5h, performing suction filtration, washing the filter cake with dichloromethane, and combining the filtrates. Adding the filtrate into a 5L reaction bottle, distilling under reduced pressure, steaming until no liquid flows out, adding ethanol, stirring, cooling to 5 ℃ after the materials in the reaction bottle are completely dissolved, slowly dropwise adding hydrochloric acid ethanol, continuing to perform heat preservation crystallization for 5 hours after the dropwise adding is finished, performing suction filtration, washing the reaction bottle with ethanol, washing the filter cake with the washing liquid, and performing suction filtration. And (3) putting the wet product into a drying oven, and drying at 80 +/-5 ℃ for 4h to obtain 234g of off-white solid TFTB-3 hydrochloride with the yield of 83.8%. The charging amount of each raw material in the step (2) is shown in table 2.
TABLE 2 feed rates of the respective raw materials in step (2)
(3) Preparation of tofacitinib citrate
Adding TFTB-3 hydrochloride, triethylamine and ethyl acetate into a 5L reaction bottle, starting stirring to fully disperse the TFTB-3 hydrochloride, the triethylamine and the ethyl acetate, adding DCC and DMAP, heating to 25-30 ℃, and stirring for 0.5 h. Adding cyanoacetic acid every 5min, and controlling the temperature to be 30 ℃. After the addition, the reaction was continued for 5 hours. And (5) sampling and carrying out HPLC detection until the content of TFTB-2 in the reaction solution is less than 0.5 percent relative to tofacitinib, namely ending the reaction, and otherwise, continuing the reaction until the reaction is ended. The liquid phase detection conditions are as follows: a chromatographic column: cossill c184.6 × 150mm5um, mobile phase: a: 0.2% perchloric acid, B: 0.2% perchloric acid-acetonitrile 30:70, wavelength: 210nm, flow rate: 1.0ml/min, column temperature: and (4) room temperature. Adding citric acid monohydrate and 346g of water, stirring for 1h, and filtering. Transferring the filter cake into a reaction bottle, adding water and n-butanol, heating to 100 deg.C, refluxing for 30min, hot filtering at 90 deg.C, cooling the filtrate to 20 deg.C in ice bath, adding citric acid monohydrate, stirring for 30min, and filtering. And (3) putting the wet product into a drying oven, controlling the temperature to be 90 +/-5 ℃ and drying for 4 hours to obtain 300g of off-white solid tofacitinib citrate with the yield of 90%. The amounts of the raw materials in step (3) are shown in Table 3.
TABLE 3 feed rates of the respective raw materials in step (3)
| Name of material | Molar ratio of | Proportioning (w/w) | Feed amount |
| TFTB-3 hydrochloride | 1.00 | 1.00 | 234g |
| Triethylamine | 3.18 | 0.88 | 206g |
| DCC (dicyclohexylcarbodiimide) | 3.00 | 1.75 | 410g |
| DMAP (4-dimethylaminopyridine) | — | 0.01 | 2.34g |
| Ethyl acetate | — | 11.28 | 2640g |
| Cyanoacetic acid | 1.70 | 0.41 | 96g |
| Citric acid monohydrate | 2.50 | 2.96 | 692g |
| Water (W) | — | 21.48 | 5026g |
| N-butanol | — | 0.80 | 187g |
(4) Refining
Adding 300g of tofacitinib citrate, 6000g of water and 480g of n-butanol into a 10L reaction bottle, stirring, heating to 100 ℃, refluxing for 30min, performing hot filtration at 80 ℃, cooling the filtrate to 10 ℃ in an ice bath, keeping the temperature, stirring for 30min, performing suction filtration, putting the filter cake into a drying oven, controlling the temperature to be 90 +/-5 ℃, and drying for 4h to obtain 254g of tofacitinib citrate powder with the yield of 85%.
(5) Re-refining
254g of tofacitinib citrate, 5080g of water and 408g of n-butanol are added into a 10L reaction bottle, stirred, heated to 100 ℃ for reflux for 30min, filtered at 80 ℃, cooled to 10 ℃ in ice bath, kept warm and stirred for 30min, filtered, and a filter cake is put into a drying oven and dried for 4h at the temperature of 90 +/-5 ℃ to obtain 204g of tofacitinib citrate powder with the yield of 85%.
Example 2
A synthetic method of tofacitinib citrate comprises the following steps:
(1) preparation of TFTB-2
Adding TFTB-1, sodium hydroxide, ethanol and water into a 20L reaction bottle, heating to 85 ℃, and carrying out heat preservation reaction for 3 hours; and (3) after the reaction is finished, distilling under reduced pressure at 80-90 ℃ until no liquid flows out, adding purified water, continuously stirring, cooling to room temperature, adding dichloromethane for extraction once, extracting the water layer once again with dichloromethane, combining organic layers, washing the organic layer once with purified water, and stirring and drying the organic layer for 2 hours with anhydrous sodium sulfate. Filtering, evaporating filtrate to dryness, adding acetone, refluxing for 30min, cooling to 20 deg.C, filtering, placing filter cake in drying oven, and drying at 60 + -5 deg.C for 4 hr to obtain off-white solid, i.e. TFTB-2, with yield of 86%. The amounts of the raw materials used in step (1) are shown in Table 4.
TABLE 4 feed amounts of the respective raw materials in step (1)
| Name of material | Molar ratio of | Proportioning (w/w) | Feed amount |
| TFTB-1 | 1.00 | 1.00 | 459g |
| Sodium hydroxide | 3.00 | 0.46 | 211g |
| Ethanol | — | 10.00 | 4590g |
| Purified water | — | 16.00 | 7344g |
| Methylene dichloride | — | 8.00 | 3672g |
| Anhydrous sodium sulfate | — | 3.00 | 1377g |
| Acetone (II) | — | 2.00 | 918g |
(2) Preparation of TFTB-3 hydrochloride
Adding TFTB-2, ammonium acetate and ethanol into a 5L reaction bottle, starting stirring, and introducing N2Protection, stirring at room temperature for 0.5h, adding Pd (OH)2C, continuing stirring for 0.5h, stopping introducing N2Introduction of H2Stirring at room temperature for 0.5H, heating to 60 deg.C, reacting for 5H, cooling to room temperature, and stopping introducing H2Filtering, washing the filter cake twice with ethanol, and mixing the filtrates. Adding the filtrate into a 5L reaction bottle, distilling at 75-80 ℃ under reduced pressure, steaming until no liquid flows out, adding dichloromethane and active carbon, refluxing for 0.5h, cooling to room temperature, stirring for 0.5h, performing suction filtration, washing the filter cake with dichloromethane, and combining the filtrates. Adding the filtrate into a 5L reaction bottle, distilling under reduced pressure, steaming until no liquid flows out, adding ethanol, stirring, cooling to 0 ℃ after the materials in the reaction bottle are completely dissolved, slowly dropwise adding hydrochloric acid ethanol, continuing to perform heat preservation crystallization for 5 hours after the dropwise adding is finished, performing suction filtration, washing the reaction bottle with ethanol, washing the filter cake with the washing liquid, and performing suction filtration. And (3) putting the wet product into a drying oven, and drying at 80 +/-5 ℃ for 4h to obtain off-white solid TFTB-3 hydrochloride with the yield of 84%. The amounts of the raw materials in step (2) are shown in Table 5.
TABLE 5 feed amounts of raw materials in step (2)
| Name of material | Proportioning (w/w) 7 --> |
| TFTB-2 | 1.00 |
| Ammonium acetate | 1.1 |
| Pd(OH)2/C | 0.21 |
| Activated carbon | 0.05 |
| Ethanol for reaction | 6.0 |
| Methylene dichloride | 15 |
| 35% hydrochloric acid ethanol (calculated as HCl) | 1.4 |
(3) Preparation of tofacitinib citrate
Adding TFTB-3 hydrochloride, triethylamine and ethyl acetate into a 5L reaction bottle, starting stirring to fully disperse the TFTB-3 hydrochloride, the triethylamine and the ethyl acetate, adding DCC and DMAP, heating to 25 ℃, and stirring for 0.5 h. Cyanoacetic acid was added every 5min, and the temperature was controlled at 25 ℃. After the addition, the reaction was continued for 5 hours. And (5) sampling and carrying out HPLC detection until the content of TFTB-2 in the reaction solution is less than 0.5 percent relative to tofacitinib, namely ending the reaction, and otherwise, continuing the reaction until the reaction is ended. The liquid phase detection conditions are as follows: a chromatographic column: cossill c184.6 × 150mm5um, mobile phase: a: 0.2% perchloric acid, B: 0.2% perchloric acid-acetonitrile 30:70, wavelength: 210nm, flow rate: 1.0ml/min, column temperature: and (4) room temperature. Adding citric acid monohydrate and 346g of water, stirring for 1h, and filtering. Transferring the filter cake into a reaction bottle, adding water and n-butanol, heating to 100 deg.C, refluxing for 30min, hot filtering at 80 deg.C, cooling the filtrate to 10 deg.C in ice bath, adding citric acid monohydrate, stirring for 30min, and filtering. And (3) putting the wet product into a drying oven, controlling the temperature to be 90 +/-5 ℃ and drying for 4 hours to obtain the off-white solid tofacitinib citrate with the yield of 90%. The amounts of the raw materials in step (3) are shown in Table 6.
TABLE 6 feed rate of each raw material in step (3)
| Name of material | Proportioning (w/w) |
| TFTB-3 hydrochloride | 1.00 |
| Triethylamine | 0.8 |
| DCC (dicyclohexylcarbodiimide) | 1.8 |
| DMAP (4-dimethylaminopyridine) | 0.01 |
| Ethyl acetate | 12 |
| Cyanoacetic acid | 0.42 |
| Citric acid monohydrate | 3.0 |
| Water (W) | 22 |
| N-butanol | 0.9 |
(4) Refining
Adding 300g of tofacitinib citrate, 6000g of water and 480g of n-butyl alcohol into a 10L reaction bottle, stirring, heating to 100 ℃, refluxing for 30min, performing hot filtration at 90 ℃, cooling the filtrate to 20 ℃ in an ice bath, keeping the temperature, stirring for 30min, performing suction filtration, putting the filter cake into a drying oven, controlling the temperature to 90 +/-5 ℃ and drying for 4h to obtain 254g of tofacitinib citrate powder with the yield of 85%.
(5) Re-refining
254g of tofacitinib citrate, 5080g of water and 408g of n-butanol are added into a 10L reaction bottle, stirred, heated to 100 ℃ for reflux for 30min, filtered at 90 ℃, cooled to 20 ℃ in ice bath, kept warm and stirred for 30min, filtered, and a filter cake is put into a drying oven and dried for 4h at the temperature of 90 +/-5 ℃ to obtain 204g of tofacitinib citrate powder with the yield of 85%.
Claims (10)
1. A synthetic method of tofacitinib citrate is characterized by comprising the following steps: mixing TFTB-3 hydrochloride, triethylamine and ethyl acetate, adding DCC and DMAP, heating and stirring, and adding cyanoacetic acid for reaction; adding monohydrate citric acid and n-butyl alcohol, heating for reaction, and refining to obtain tofacitinib citrate; TFTB-3 is N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-D ] pyrimidin-4-amine.
2. The method for synthesizing tofacitinib citrate according to claim 1, wherein the method comprises the following steps: the mass ratio of TFTB-3 hydrochloride, triethylamine, ethyl acetate, DCC, DMAP, cyanoacetic acid and citric acid monohydrate is 1: 0.8-0.9: 11.0-12.0: 1.7-1.8: 0.009-0.011: 0.40-0.42: 2.9-3.0.
3. The method for synthesizing tofacitinib citrate according to claim 1, wherein the method comprises the following steps: adding TFTB-3 hydrochloride, triethylamine and ethyl acetate into a reaction bottle, stirring, adding DCC and DMAP, heating to 25-30 ℃, and stirring; adding cyanoacetic acid every 5min, and controlling the temperature to be 25-30 ℃; after the addition is finished, continuing the reaction, after the reaction is finished, adding part of the citric acid monohydrate and water, stirring and filtering, transferring the filter cake into a reaction bottle, adding water and n-butyl alcohol, heating and refluxing, then carrying out hot filtration, cooling the filtrate in an ice bath, adding the rest citric acid monohydrate, stirring and filtering, and drying the filter cake to obtain the product.
4. The method for synthesizing tofacitinib citrate according to claim 1, wherein the method comprises the following steps: the preparation method of TFTB-3 hydrochloride comprises the following steps: TFTB-2, ammonium acetate and ethanol in Pd (OH)2catalyst/C and H2Reacting under the condition to obtain a product; TFTB-2 is (3R,4R) - (1-benzyl-4-methyl-piperidin-3-yl) -methyl- (7H-pyrrolo [2,3-d]Pyrimidin-4-yl) -amines.
5. The method for synthesizing tofacitinib citrate according to claim 4, wherein the synthesis method comprises the following steps: TFTB-2, ammonium acetate, ethanol, Pd (OH)2The mass ratio of/C is 1: 0.9-1.1: 5-6: 0.18-0.22.
6. The method for synthesizing tofacitinib citrate according to claim 4, wherein the synthesis method comprises the following steps: the preparation method of TFTB-3 hydrochloride comprises the following steps: adding TFTB-2, ammonium acetate and ethanol into a reaction bottle, stirring, and introducing N2Protection, addition of Pd (OH)2C, stopping the supply of N2Introduction of H2Heating for reaction, performing suction filtration after the reaction is finished, distilling the filtrate at 75-80 ℃ under reduced pressure, adding dichloromethane and activated carbon for reflux after steaming until no liquid flows out, cooling to room temperature, performing suction filtration, distilling the filtrate under reduced pressure, adding ethanol for stirring until no liquid flows out, dropwise adding hydrochloric acid and ethanol, performing heat preservation for crystallization, performing suction filtration, and drying the solid to obtain the product.
7. The method for synthesizing tofacitinib citrate according to any one of claims 4 to 6, wherein the method comprises the following steps: the preparation method of TFTB-2 comprises the following steps: heating TFTB-1, sodium hydroxide, ethanol and water for reaction to prepare TFTB-2; TFTB-1 is N-methyl-N- ((3R,4R) -4-methyl-1-benzyl-3-piperidinyl) -7- ((4-methylphenyl) sulfonyl) 7H-pyrrolo [2,3-D ] pyrimidin-4-amine.
8. The method for synthesizing tofacitinib citrate according to claim 7, wherein the synthesis method comprises the following steps: the mass ratio of TFTB-1 to sodium hydroxide to ethanol to water is 1: 0.4-0.5: 8-12: 8-12.
9. The method for synthesizing tofacitinib citrate according to claim 7, wherein the synthesis method comprises the following steps: the preparation method of TFTB-2 comprises the following steps: heating TFTB-1, sodium hydroxide, ethanol and water for reaction, distilling at 80-90 ℃ under reduced pressure after the reaction is finished until no liquid flows out, adding purified water, continuing stirring, cooling to room temperature, adding dichloromethane for extraction, evaporating an organic phase to dryness, adding acetone for reflux, cooling to 10-20 ℃, filtering, and drying a filter cake to obtain TFTB-2.
10. The method for synthesizing tofacitinib citrate according to claim 1, wherein the method comprises the following steps: the refining is as follows: adding tofacitinib citrate, water and n-butanol into a reaction bottle, stirring, heating for refluxing, filtering while hot, cooling the filtrate to 10-20 ℃ in an ice bath, keeping the temperature, stirring, performing suction filtration, and drying a filter cake to obtain the tofacitinib citrate powder similar to white.
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