CN108822112B - Preparation method of tofacitinib compound - Google Patents
Preparation method of tofacitinib compound Download PDFInfo
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- CN108822112B CN108822112B CN201810917603.6A CN201810917603A CN108822112B CN 108822112 B CN108822112 B CN 108822112B CN 201810917603 A CN201810917603 A CN 201810917603A CN 108822112 B CN108822112 B CN 108822112B
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- 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
Abstract
The invention discloses a preparation method of tofacitinib compound, which comprises the steps of reacting 4-methylpiperidine-3-one hydrochloride (II) with benzyl chloride in the presence of alkali and solvent to prepare a compound III, carrying out acid catalysis to prepare a compound V, and carrying out asymmetric catalytic hydrogenation, deprotection, condensation and other reactions to finally obtain the final product tofacitinib (I).
Description
Technical Field
The invention relates to a preparation method of a tofacitinib compound, belonging to the technical field of medicine preparation.
Background
Tofacitinib (tofacitinib), which is chemically named 3- { (3R,4R) -4-methyl-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] piperidin-1-yl } -3-oxopropanenitrile, is a novel Janus kinase inhibitor developed by the American Girey company, can effectively inhibit the activity of JAK1 and JAK3, and can block signal transduction of various inflammatory cytokines. The Tofacitinib citrate (trade name: Xeljanz) is approved to be marketed by the US FDA at 11 months in 2012 and is approved by the US food and drug administration as a 'breakthrough therapy', and is approved to be marketed for adult patients with moderate to severe active rheumatoid arthritis with insufficient or intolerant response to methotrexate treatment, so that the Tofacitinib citrate is a novel oral JAK inhibitor. Research shows that tofacitinib has good treatment effect on various inflammation-related diseases such as ulcerative colitis, psoriasis and the like, and the chemical structural formula is shown as the formula (I):
at present, the synthetic routes of tofacitinib reported in the literature include the following:
1) the synthetic route reported in patent CN 103819474 a is as follows:
according to the method, benzyl bromide is used as a raw material and reacts with pyridine to form pyridinium salt, selective oxidation is carried out under the action of sodium borohydride and a mixed solution through sodium borohydride hydrogenation reduction, mitsunobu alkylation reaction, catalytic hydrogenation debenzylation and acylation to obtain tofacitinib, although the problem that the raw material is expensive is solved, a large amount of solvent is needed in post-treatment and separation of the route hydroboration reaction, and boron trifluoride ethyl ether is toxic, so that the method is not suitable for large-scale production and the total yield is not high.
2) The synthetic route reported in patent CN 106146507 a is as follows:
the method takes (4-methylpyridine-3-yl) methyl carbamate as a raw material, and prepares tofacitinib by catalytic hydrogenation, benzyl protection, reduction, salification, resolution, deprotection and amidation salification. The yield is reduced by applying the resolution in the synthetic route, the reduction is carried out by using the lithium aluminum hydride, the danger exists, and the synthetic route is long, so that the industrial production is not facilitated.
3) The synthetic route of Pfizer company (US6627754, CN1409712) uses 1-benzyl-4-methyl-piperidin-3-one as raw material to reductively aminate the upper methylamino group, and the tofacitinib is obtained by substitution, catalytic hydrogenation debenzylation, acylation and resolution. The final product in the route is subjected to resolution and purification, and the synthesis route is not subjected to resolution, so that isomer impurities are difficult to control, the cost is high, the yield is low, and the method is not suitable for industrial production. The synthetic route is as follows:
then, Pfizer company carries out process improvement on the original synthesis method, and the patent number is WO2007012953, the publication number of which in 2008 is CN 101233138A in China. Two methods for synthesizing tofacitinib are disclosed in the patent, wherein a specific synthetic route takes 3-amido-4-methylpyridine as a raw material, firstly, amido is esterified and protected, pyridine ring is reduced by rhodium catalysis, benzyl protection is carried out on reductive amination, lithium aluminum hydride is reduced, then, enantiomer is separated by di-p-toluoyl tartaric acid, aminolysis is carried out on the enantiomer and 4-chloropyrrolopyrimidine, and finally, acylation is carried out to obtain tofacitinib. The other route uses 3-amido-4-methylpyridine as a raw material, firstly, amido is esterified and protected, the raw material reacts with benzyl bromide to obtain pyridinium salt, pyridine rings are reduced by rhodium catalysis, lithium aluminum hydride is reduced, then, enantiomers are resolved by using di-p-toluoyl tartaric acid, aminolysis is carried out on the enantiomers and 4-chloropyrrolopyrimidine, and finally, acylation is carried out to obtain tofacitinib. The route has the disadvantages of long preparation process route, long reaction period, high cost and unsuitability for industrial production.
Disclosure of Invention
The invention aims to provide a preparation method of a tofacitinib compound, aiming at the defects of the prior art, the preparation method has the advantages of short synthetic route, higher yield and purity, less by-products of products, no need of a resolution step in the whole synthetic route, and suitability for industrial production.
The synthetic route of the invention is as follows:
a method for preparing a tofacitinib compound, comprising the steps of:
a. reacting an initial raw material 4-methylpiperidine-3-one hydrochloride (II) with benzyl chloride under an alkaline condition to obtain a compound III;
b. preparing a compound V from the compound III and N-methyl-7H-pyrrolo [2,3-d ] pyrimidine-4-amine (IV) under the action of a catalyst;
c. carrying out asymmetric catalytic hydrogenation reaction on the compound V under the action of a metal catalyst and a ligand to obtain a compound VI;
d. deprotecting the compound VI under the action of a catalyst, acid and hydrogen to obtain a compound VII;
e. preparing tofacitinib (I) from the compound VII and cyanoacetic acid under the action of a condensing agent and a solvent;
wherein, the alkali used in the step a is selected from sodium hydroxide or potassium hydroxide; the reaction solvent is a mixed solvent of water and toluene; the molar ratio of the compound II to the base to the benzyl chloride is 1: 1.5-3: 1-1.5.
The catalyst used in step b is HClO4-SiO2(ii) a The molar ratio of the compound III to the compound IV to the catalyst is 1: 1.05-1.2: 0.002-0.004, and the reaction temperature is 20-25 ℃.
The catalyst used in step c is (1, 5-cyclooctadiene) bis (methallyl) ruthenium [ Ru (COD) (Methylalyl)2]Ligand (R) - (+) -2,2 ' -bis (diphenylphosphino) -6,6 ' -dimethoxy-1, 1 ' -biphenyl [ (R) -MEO-BIPHEP](ii) a The molar ratio of the compound IV to the catalyst to the ligand is 1: 0.002-0.004: 0.004-0.008; the hydrogen pressure is 1.01-2.00 MPa, and the preferable pressure is 2.00 MPa; the reaction solvent is dichloromethane, methanol or isopropanol, and more preferably the organic solvent is dichloromethane.
The catalyst used in step d was 20% Pd (OH)2C; the reaction solvent is methanol; the acid is acetic acid, and the reaction temperature is 30-35 ℃.
The condensing agent used in the step e is N, N' -carbonyldiimidazole; the molar ratio of the compound VII, the cyanoacetic acid and the condensing agent is 1: 1.0-1.2: 1.2-2, and the reaction temperature is 20-25 ℃.
Compared with the prior art, the invention has the beneficial effects that:
(1) in the step b, the compound III and the compound IV generate enamine under the acidic catalysis condition by adopting HClO4-SiO2The catalyst is used, the reaction does not need a solvent to participate in the reaction, the reaction time is short, and the yield is up to 96%.
(2) The method has mild reaction conditions, short synthetic route and convenient post-treatment operation, can obtain a final product with high quality and high yield in the actual synthetic process, does not need a splitting step in the whole synthetic route, and is easy to industrialize.
Detailed Description
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited thereto.
Example 1
Preparation of Compound III
Adding 14.9g of 4-methylpiperidine-3-one hydrochloride (II), 50mL of distilled water and 50mL of toluene into a 250mL three-necked bottle in sequence, cooling to 0-5 ℃ under an ice bath condition, stirring, weighing 8.41g of potassium hydroxide, adding into the reaction bottle in batches, reacting for 2h, removing the ice bath condition, slowly heating to room temperature, dropwise adding 12.6g of benzyl chloride, continuing stirring after 30min of dropwise addition, heating to reflux reaction for 6h, standing for layering after the reaction is finished, separating out an organic phase, washing with water, removing anhydrous sodium sulfate, filtering, and evaporating the solvent toluene under reduced pressure to obtain 19.31g of colorless liquid, wherein the yield is 95.46%, and the HPLC purity is 99.76%.
Example 2
Preparation of Compound III
Adding 14.96g of 4-methylpiperidine-3-one hydrochloride (II), 50mL of distilled water and 50mL of toluene into a 250mL three-necked bottle in sequence, cooling to 0-5 ℃ under an ice bath condition, stirring, weighing 16.8g of sodium hydroxide, adding into the reaction bottle in batches, reacting for 2h, removing the ice bath condition, slowly heating to room temperature, dropwise adding 19g of benzyl chloride, continuously stirring after 30min of dropwise adding, heating to reflux reaction for 6h, standing for layering after the reaction is finished, separating out an organic phase, washing with water, anhydrous sodium sulfate, filtering, and evaporating the solvent toluene under reduced pressure to obtain 19.81g of colorless liquid, wherein the yield is 97.23% and the HPLC purity is 98.37%.
Example 3
Preparation of Compound III
Adding 14.96g of 4-methylpiperidine-3-one hydrochloride (II), 50mL of distilled water and 50mL of toluene into a 250mL three-necked bottle in sequence, cooling to 0-5 ℃ under an ice bath condition, stirring, weighing 27.64g of potassium carbonate, adding the mixture into the reaction bottle in batches, reacting for 2h, removing the ice bath condition, slowly heating to room temperature, dropwise adding 15.2g of benzyl chloride, continuing stirring after 30min of dropwise addition, heating to reflux reaction for 6h, standing for layering after the reaction is finished, separating an organic phase, washing with water, removing anhydrous sodium sulfate, filtering, and evaporating the solvent toluene under reduced pressure to obtain 17.68g of a colorless liquid, wherein the yield is 87.34% and the HPLC purity is 97.26%.
Example 4
Preparation of Compound V
Weighing 19.72g of compound III and N-methyl-7H-pyrrolo [2,3-d]Pyrimidin-4-amine N-methyl-7H-pyrrolo [2,3-d]Pyrimidin-4-amine (IV)15.09g and HClO4-SiO2Adding 31mg of solid into a 250mL three-necked flask, stirring and reacting for 20min at room temperature of 20-25 ℃, monitoring by TLC until the reaction is complete, adding dichloromethane for dilution, filtering to remove the solid, drying an organic phase by using anhydrous sodium sulfate, filtering and carrying out rotary evaporation, and concentrating 31.36g of the compound V, wherein the yield is 96.98% and the HPLC purity is 97.33%.
Example 5
Preparation of Compound V
19.72g of Compound III and 17.24g of 17.24g N-methyl-7H-pyrrolo [2,3-d ] are weighed]Pyrimidin-4-amine N-methyl-7H-pyrrolo [2,3-d]Pyrimidin-4-amine (IV) and 62mg HClO4-SiO2Adding the solid into a 250mL three-necked bottle, stirring and reacting for 20min at room temperature of 20-25 ℃, monitoring by TLC until the reaction is complete, adding dichloromethane for dilution, filtering to remove the solid, drying an organic phase by using anhydrous sodium sulfate, filtering and carrying out rotary evaporation, and concentrating 30.72g of a compound V, wherein the yield is 95.24%, and the HPLC purity is 97.78%.
Example 6
Preparation of Compound V
19.72g of the compound III, 17.24g of 17.24g N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine (IV) and 0.18g of acetic acid are weighed into a 250mL three-necked flask, stirred and reacted at room temperature of 20-25 ℃ for 20min, TLC monitors the reaction until the reaction is complete, dichloromethane is added for dilution, the solid is removed by filtration, the organic phase is dried over anhydrous sodium sulfate, rotary evaporation is carried out by filtration, 26.62g of the compound V is concentrated, the yield is 82.32%, and the HPLC purity is 93.22%.
Example 7
Preparation of Compound V
19.72g of the compound III, 17.24g of 17.24g N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine (IV) and 0.4g of anhydrous aluminum chloride are weighed into a 250mL three-necked flask, stirred and reacted at room temperature of 20-25 ℃ for 20min, TLC is used for monitoring the reaction to be complete, dichloromethane is added for dilution, the solid is removed by filtration, the organic phase is dried by anhydrous sodium sulfate, rotary evaporation is carried out by filtration, 23.10g of the compound V is concentrated, the yield is 71.42%, and the HPLC purity is 91.61%.
Example 8
Preparation of Compound VI
In a 250mL three-necked flask, 31.01g of the compound V, 100mg of Ru (COD) (Methallyl) were added in that order2And 0.226g of (R) -MEO-BIPHEP, dissolving in 100mL of dichloromethane solution, sequentially replacing nitrogen for three times, hydrogen for three times, and hydrogen for 1.01MPa, reacting at the temperature of 20-25 ℃, stirring for 12 hours, performing suction filtration, and concentrating to obtain 29.78g of a compound VI, wherein the yield is 95.48%, the HPLC purity is 98.69%, and the ee value is 98%.
Example 9
Preparation of Compound VI
In a 250mL three-necked flask, 31.01g of the compound V, 50mg of Ru (COD) (Methallyl) were added in that order2And 0.433g of (R) -MEO-BIPHEP, dissolving in 100mL of methanol, sequentially replacing nitrogen for three times, hydrogen for three times, and hydrogen for 2MPa, reacting at 20-25 ℃, stirring for 12h, performing suction filtration, and concentrating to obtain 29.4g of a compound VI, wherein the yield is 94.24%, the HPLC purity is 97.61%, and the ee value is 97%.
Example 10
Preparation of Compound VI
In a 250mL three-necked flask, 31.01g of the compound V, 25mg of Ru (COD) (Methallyl) were added in that order2And 0.325g of (R) -MEO-BIPHEP, dissolving in 100mL of isopropanol, sequentially replacing nitrogen for three times, hydrogen for three times, and hydrogen for 1.01MPa, reacting at 20-25 ℃, stirring for 12h, performing suction filtration, and concentrating to obtain 26.3g of a compound VI (0.078mol, molecular weight 335.45), wherein the yield is 84.33%, the HPLC purity is 94.35%, and the ee value is 92%.
Example 11
Preparation of Compound VI
31.01g of Compound V, 0.2g of Ru (COD) (Methallyl) were added in that order to a 250mL three-necked flask2And 0.541g of (R) -MEO-BIPHEP, dissolving in 100mL of isopropanol, sequentially replacing nitrogen for three times, hydrogen for three times, reacting at 2MPa at the reaction temperature of 20-25 ℃, stirring for 12h, filtering, and concentrating to obtain the final productCompound VI 24.4g (0.073mol, MW 335.45), yield 78.22%, HPLC purity 94.35%, ee 86%.
Example 12
Preparation of Compound VII
In a 250mL three-necked flask, VI 33.5g of the compound, 20% Pd (OH) were added2C (5.8g, 50% water), 6g acetic acid and 100ml methanol, and mixing by stirring. Replacing nitrogen for three times in sequence, controlling the hydrogen pressure at 0.4-0.6MPa after hydrogen is replaced for three times, and reacting at 50 ℃ for l2 h. Suction filtration was carried out, the solvent was distilled off under reduced pressure from the filtrate, and the residue was dried to give 19.95g of compound VII in 92.38% yield and 99.21% HPLC purity.
Example 13
Preparation of tofacitinib
Dissolving 7.23g of cyanoacetic acid in 20mL of dichloromethane, adding 16.54g of CDI (condensation agent) in batches, carrying out tracking reaction by TCL (trichloromethyl cellulose), adding the solution after the reaction into a constant-pressure funnel, adding 20.86g of compound VII and 80mL of dichloromethane into a reaction bottle for dissolving, dropwise adding the solution in the constant-pressure funnel into the reaction bottle, finishing the dropwise adding, keeping the reaction temperature at 40 ℃, reacting for 10 hours, washing an organic phase by water, drying by anhydrous sodium sulfate, filtering and concentrating to obtain 23.68g of tofacitinib, wherein the yield is 89.21% and the HPLC purity is 98.38%.
Example 14
Preparation of tofacitinib
Dissolving 8.16g of cyanoacetic acid in 20mL of dichloromethane, adding 15.94g of CDI in batches, carrying out TCL tracking reaction, adding the reacted solution into a constant-pressure funnel, adding 24.5g of compound VII and 80mL of dichloromethane into a reaction bottle for dissolving, dropwise adding the solution in the constant-pressure funnel into the reaction bottle, finishing dropping, keeping the reaction temperature at 40 ℃, reacting for 10 hours, washing with water after the reaction is finished, drying with anhydrous sodium sulfate, filtering and concentrating to obtain 22.22g of tofacitinib, the yield is 88.92%, and the HPLC purity is 96.37%.
Claims (8)
1. A preparation method of tofacitinib compound, which is characterized by comprising the following steps:
a. reacting an initial raw material 4-methylpiperidine-3-one hydrochloride (II) with benzyl chloride under an alkaline condition to obtain a compound III;
b. preparing a compound V from the compound III and N-methyl-7H-pyrrolo [2,3-d ] pyrimidine-4-amine (IV) under the action of a catalyst;
c. carrying out asymmetric catalytic hydrogenation reaction on the compound V under the action of a metal catalyst and a ligand to obtain a compound VI; the catalyst is Ru (COD) or (Methylalyl)2The ligand is (R) - (+) -2,2 ' -bis (diphenylphosphino) -6,6 ' -dimethoxy-1, 1 ' -biphenyl;
d. deprotecting the compound VI under the action of a catalyst, acid and hydrogen to obtain a compound VII;
e. preparing tofacitinib (I) from the compound VII and cyanoacetic acid under the action of a condensing agent and a solvent;
the synthetic route is as follows:
2. the method according to claim 1, wherein the base in step a is sodium hydroxide or potassium hydroxide, the molar ratio of the base to the benzyl chloride in formula II is 1: 1.5-3: 1-1.5, and the reaction solvent is one or both of water and toluene.
3. The method of claim 1, wherein the catalyst of step b is HClO4-SiO2。
4. The method of claim 1, wherein the molar ratio of the formula III, the formula IV and the catalyst in the step b is 1: 1.05-1.2: 0.002-0.004.
5. The method of claim 1, wherein the hydrogen pressure used in step c is 1.01MPa to 2.00 MPa.
6. The process of claim 1, wherein the reaction solvent used in step c is dichloromethane, methanol or isopropanol.
7. The method of claim 1, wherein the catalyst of step d is 20% Pd (OH)2and/C, the reaction solvent is methanol, and the acid is acetic acid.
8. The method according to claim 1, wherein the condensing agent in step e is N, N' -carbonyldiimidazole, and the molar ratio of the compound VII, the cyanoacetic acid and the condensing agent is 1: 1.0-1.2: 1.2-2.
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| CN112679506A (en) * | 2021-01-12 | 2021-04-20 | 山东天铭医药科技有限公司 | Preparation method of tofacitinib citrate |
| CN114315607B (en) * | 2021-12-29 | 2024-02-02 | 万华化学集团股份有限公司 | Preparation method of secondary diamine |
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Inventor after: Li Minghua Inventor after: Hou Junkai Inventor after: Zhang Han Inventor after: Huang Chunyan Inventor before: Hou Junkai Inventor before: Zhang Han Inventor before: Huang Qingyan |