CN111533746A - Synthesis method of tofacitinib citrate - Google Patents
Synthesis method of tofacitinib citrate Download PDFInfo
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- CN111533746A CN111533746A CN202010476927.8A CN202010476927A CN111533746A CN 111533746 A CN111533746 A CN 111533746A CN 202010476927 A CN202010476927 A CN 202010476927A CN 111533746 A CN111533746 A CN 111533746A
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- SYIKUFDOYJFGBQ-YLAFAASESA-N tofacitinib citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 SYIKUFDOYJFGBQ-YLAFAASESA-N 0.000 title claims abstract description 37
- 229960004247 tofacitinib citrate Drugs 0.000 title claims abstract description 37
- 238000001308 synthesis method Methods 0.000 title description 6
- 238000001816 cooling Methods 0.000 claims abstract description 33
- 238000001914 filtration Methods 0.000 claims abstract description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- OFBLHCZYUXCKJZ-UHFFFAOYSA-N N1C(O)=NC(O)=C2N=CC=C21 Chemical compound N1C(O)=NC(O)=C2N=CC=C21 OFBLHCZYUXCKJZ-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 22
- 239000007787 solid Substances 0.000 claims abstract description 22
- 238000001035 drying Methods 0.000 claims abstract description 21
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 20
- 238000003756 stirring Methods 0.000 claims abstract description 20
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 20
- 238000005406 washing Methods 0.000 claims abstract description 16
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 14
- 238000010438 heat treatment Methods 0.000 claims abstract description 13
- QSKPIOLLBIHNAC-UHFFFAOYSA-N 2-chloro-acetaldehyde Chemical compound ClCC=O QSKPIOLLBIHNAC-UHFFFAOYSA-N 0.000 claims abstract description 9
- LNDZXOWGUAIUBG-UHFFFAOYSA-N 6-aminouracil Chemical compound NC1=CC(=O)NC(=O)N1 LNDZXOWGUAIUBG-UHFFFAOYSA-N 0.000 claims abstract description 9
- 230000008569 process Effects 0.000 claims abstract description 9
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims abstract description 5
- 229940040526 anhydrous sodium acetate Drugs 0.000 claims abstract description 5
- 239000007864 aqueous solution Substances 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 24
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 18
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 16
- DYXMNZRXOLJCKW-UHFFFAOYSA-N N1C(Cl)=NC(Cl)=C2N=CC=C21 Chemical compound N1C(Cl)=NC(Cl)=C2N=CC=C21 DYXMNZRXOLJCKW-UHFFFAOYSA-N 0.000 claims description 15
- 239000000706 filtrate Substances 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 12
- 230000008025 crystallization Effects 0.000 claims description 12
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 claims description 12
- 239000013078 crystal Substances 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 10
- 239000012046 mixed solvent Substances 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 238000004042 decolorization Methods 0.000 claims description 8
- 238000001704 evaporation Methods 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 claims description 7
- 229960002303 citric acid monohydrate Drugs 0.000 claims description 7
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 235000019441 ethanol Nutrition 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- XRIARWQZLGCQDM-KOLCDFICSA-N n-methyl-n-[(3r,4r)-4-methylpiperidin-3-yl]-7h-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound C[C@@H]1CCNC[C@@H]1N(C)C1=NC=NC2=C1C=CN2 XRIARWQZLGCQDM-KOLCDFICSA-N 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 238000010189 synthetic method Methods 0.000 claims description 4
- 238000000967 suction filtration Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 17
- 239000012535 impurity Substances 0.000 abstract description 10
- 238000011403 purification operation Methods 0.000 abstract description 3
- 239000004012 Tofacitinib Substances 0.000 description 11
- 229960001350 tofacitinib Drugs 0.000 description 11
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 description 11
- 239000000047 product Substances 0.000 description 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 230000008901 benefit Effects 0.000 description 5
- 230000002035 prolonged effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 102000015617 Janus Kinases Human genes 0.000 description 2
- 108010024121 Janus Kinases Proteins 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 229960004106 citric acid Drugs 0.000 description 2
- LWPPASWKWXDDFK-UHFFFAOYSA-N 2-chloro-5h-pyrrolo[3,2-d]pyrimidine Chemical compound ClC1=NC=C2NC=CC2=N1 LWPPASWKWXDDFK-UHFFFAOYSA-N 0.000 description 1
- 229940122245 Janus kinase inhibitor Drugs 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
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
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
- C07C59/265—Citric acid
Abstract
The invention relates to the technical field of pharmaceutical chemistry, and discloses a method for synthesizing tofacitinib citrate, which comprises the following steps: 1) preparation of 2, 4-dihydroxypyrrolopyrimidine: adding 4-aminouracil and anhydrous sodium acetate into water (the molar ratio is 1: 3-1: 5), heating to 60-80 ℃, slowly adding 40% of 2-chloroacetaldehyde aqueous solution, stirring for reaction for 4-6 hours, cooling to room temperature, filtering, washing the solid with water, and drying under reduced pressure to obtain the 2, 4-dihydroxy pyrrolopyrimidine. According to the method for synthesizing tofacitinib citrate, impurity removal operation is performed twice, so that the produced tofacitinib citrate finished product is higher in purity, subsequent purification operation is not needed, the synthesis time is short, the process is simple, the method is suitable for production in factories, the production time can be saved, the production efficiency is improved, and the method is more convenient to use.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to a method for synthesizing tofacitinib citrate.
Background
Tofacitinib citrate is a Janus kinase (JASK) inhibitor developed by the U.S. Perey company, and the U.S. food and drug administration approves tofacitinib citrate to be on the market in 11/6/2012, is used for treating adult patients with moderate to severe active rheumatoid arthritis with insufficient or intolerant response to methotrexate treatment, and is a novel oral JAK inhibitor.
Most of tofacitinib citrate on the market is low in purity, more impurities exist in the existing synthesis process, the pure tofacitinib citrate needs to be further purified and processed, the production time of tofacitinib citrate can be prolonged, the period is long, the production efficiency is reduced, the cost is improved, the production benefit is reduced, and the tofacitinib citrate synthesis method is inconvenient to use, so that the problems are solved.
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 has the advantages of high purity of finished products and the like, and solves the problems that most of tofacitinib citrate in the current market is not high in purity, more impurities exist in the existing synthesis process, the tofacitinib citrate needing to be purified is further purified and processed, the time required by the production of the tofacitinib citrate is prolonged, the period is longer, the production efficiency is reduced, the cost is increased, the production benefit is reduced, and the use is inconvenient.
(II) technical scheme
In order to achieve the purpose of high purity of the finished product, the invention provides the following technical scheme: a synthetic method of tofacitinib citrate comprises the following steps:
1) preparation of 2, 4-dihydroxypyrrolopyrimidine:
adding 4-aminouracil and anhydrous sodium acetate into water (the molar ratio is 1: 3-1: 5), heating to 60-80 ℃, slowly adding 40% of 2-chloroacetaldehyde aqueous solution, stirring for reaction for 4-6 hours, cooling to room temperature, filtering, washing the solid with water, and drying under reduced pressure to obtain 2, 4-dihydroxy pyrrolopyrimidine;
2) synthesis of 2, 4-dichloro pyrrolopyrimidine:
dissolving 2, 4-dihydroxypyrrolopyrimidine into phosphorus oxychloride, adding organic base diisopropylethylamine, heating to 80-85 ℃, stirring for reaction for 3 hours, evaporating redundant phosphorus oxychloride, cooling to normal temperature, slowly dropwise adding the concentrated solution into an ammonia water solution, controlling the temperature to be below 20 ℃, controlling the pH to be 6-8, filtering, washing, and drying under reduced pressure to obtain 2, 4-dichloropyrrolopyrimidine;
3) synthesis of N- [ (3R, 4R) -1-benzyl-4-methylpiperidin-3-yl ] -N-methyl-7H-2-chloro-pyrrolo [2, 3-d ] pyrimidin-4-amine:
adding cis-1-benzyl-4-methyl-3-methylaminopiperidine hydrochloride, water and dioxane into a reaction vessel, stirring to dissolve, adding 2, 4-dichloropyrrolopyrimidine and potassium carbonate, heating to 50-60 ℃, reacting for 20h, evaporating the solvent under reduced pressure, adding ethyl acetate and water, layering, extracting a water layer twice with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and adding petroleum ether for crystallization to obtain a light yellow solid;
4) synthesis of N- [ (3R, 4R) -4-methylpiperidin-3-yl ] -N-methyl-7H-pyrrolo [2, 3-d ] pyrimidin-4-amine:
adding the compound, 10% pd/C (0.9g, water content of 50%), acetic acid and ethanol into a hydrogenation reaction kettle, introducing hydrogen, reacting for 4 hours at 40-45 ℃, wherein the pressure in the kettle is 0.12-0.15 MPa, after the reaction is finished, performing suction filtration, decompressing filtrate, distilling off the solvent, and drying the remainder to obtain a white-like solid (mpl 57-159 ℃);
5) synthesizing tofacitinib citrate:
adding the compound, cyanoacetic acid, 1-hydroxybenzotriazole and dichloromethane into a three-neck flask, reacting at room temperature for 12 hours, adding water after the reaction is finished, then adding absolute ethyl alcohol and citric acid monohydrate, reacting at 40 ℃ for 2 hours, cooling, putting the solution into a mixed solvent of methanol and butanone, stirring, controlling the temperature to be 30-40 ℃, adding activated carbon for decolorization, filtering, cooling the filtrate to-10-0 ℃ at a certain cooling speed, crystallizing, growing crystals, filtering, washing the filtered solid with absolute ethyl alcohol, and drying in vacuum to obtain the refined tofacitinib citrate.
Preferably, in the first step, 4-aminouracil and chloroacetaldehyde are reacted to form 2, 4-dihydroxypyrrolopyrimidine.
Preferably, in the second step, the 2, 4-dihydroxypyrrolopyrimidine is chlorinated into 2, 4-dichloropyrrolopyrimidine in phosphorus oxychloride under the catalysis of organic base diisopropylethylamine.
Preferably, in the fifth step, the decoloring time of the activated carbon is 20-30min, and the crystal growing time is 3-4 h; the cooling speed in the crystallization process is controlled to be 10-15 ℃/h.
Preferably, the stirring time of the solution in the fifth step is 30 min.
(III) advantageous effects
Compared with the prior art, the invention provides a method for synthesizing tofacitinib citrate, which has the following beneficial effects:
1. the synthesis method of tofacitinib citrate comprises the steps of adding the compound, cyanoacetic acid, 1-hydroxybenzotriazole and dichloromethane into a three-neck flask, adding water after reaction, then adding anhydrous ethanol and citric acid monohydrate, cooling, then putting the solution into a mixed solvent of methanol and butanone, stirring, adding activated carbon for decolorization, filtering, cooling the filtrate at a certain cooling speed, then crystallizing, growing crystals, filtering, washing the filtered solid with anhydrous ethanol, and during synthesis, the mixed solvent of methanol and butanone can better absorb and dissolve tofacitinib citrate generated by reaction, thereby avoiding other reactions of tofacib citrate, filtering redundant impurities in a decoloring and filtering manner by adding activated carbon, taking out, crystallizing, primarily filtering, and the solid filtered out is washed by absolute ethyl alcohol for secondary impurity removal, and the impurity removal operation is performed twice, so that the produced tofacitinib citrate finished product has higher purity, subsequent purification operation is not needed, and the use is more convenient.
2. According to the method for synthesizing tofacitinib citrate, anhydrous ethanol and citric acid monohydrate are added, the solution is placed into a mixed solvent of methanol and butanone after cooling and stirred, activated carbon is added for decoloration and filtration, the filtrate is subjected to crystallization according to a certain cooling speed, the crystals are grown and filtered, and the filtered solids are washed by the anhydrous ethanol for synthesis.
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.
The first embodiment is as follows:
a synthetic method of tofacitinib citrate comprises the following steps:
1) preparation of 2, 4-dihydroxypyrrolopyrimidine:
adding 4-aminouracil and anhydrous sodium acetate into water (the molar ratio is 1: 3), heating to 60 ℃, slowly adding 40% aqueous solution of 2-chloroacetaldehyde, stirring for reacting for 6 hours, cooling to room temperature, filtering, washing the solid with water, and drying under reduced pressure to obtain 2, 4-dihydroxy pyrrolopyrimidine;
reacting 4-aminouracil with chloroacetaldehyde to generate 2, 4-dihydroxypyrrolopyrimidine;
2) synthesis of 2, 4-dichloro pyrrolopyrimidine:
dissolving 2, 4-dihydroxy pyrrolopyrimidine into phosphorus oxychloride, adding organic base diisopropylethylamine, heating to 80 ℃, stirring for reaction for 3 hours, evaporating redundant phosphorus oxychloride, cooling to normal temperature, slowly dropwise adding the concentrated solution into an ammonia water solution, controlling the temperature to be below 20 ℃, controlling the pH to be 6-8, filtering, washing, and drying under reduced pressure to obtain 2, 4-DEG C chloropyrrolopyrimidine;
in the second step, the 2, 4-dihydroxypyrrolopyrimidine is chloridized into 2, 4-dichloropyrrolopyrimidine in phosphorus oxychloride under the catalysis of organic base diisopropylethylamine;
3) synthesis of N- [ (3R, 4R) -1-benzyl-4-methylpiperidin-3-yl ] -N-methyl-7H-2-chloro-pyrrolo [2, 3-d ] pyrimidin-4-amine:
adding cis-1-benzyl-4-methyl-3-methylaminopiperidine hydrochloride, water and dioxane into a reaction vessel, stirring to dissolve, adding 2, 4-dichloropyrrolopyrimidine and potassium carbonate, heating to 50 ℃ for reaction for 20 hours, evaporating the solvent under reduced pressure, adding ethyl acetate and water, layering, extracting a water layer twice with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and adding petroleum ether for crystallization to obtain a light yellow solid;
4) synthesis of N- [ (3R, 4R) -4-methylpiperidin-3-yl ] -N-methyl-7H-pyrrolo [2, 3-d ] pyrimidin-4-amine:
adding the compound, 10% pd/C (0.9g, water content of 50%), acetic acid and ethanol into a hydrogenation reaction kettle, introducing hydrogen, reacting at 40 ℃ for 4 hours, wherein the pressure in the kettle is 0.12MPa, filtering after the reaction is finished, decompressing the filtrate, distilling off the solvent, and drying the remainder to obtain a white-like solid;
5) synthesizing tofacitinib citrate:
adding the compound, cyanoacetic acid, 1-hydroxybenzotriazole and dichloromethane into a three-neck flask, reacting at room temperature for 12h, adding water after the reaction is finished, then adding absolute ethyl alcohol and citric acid monohydrate, reacting at 40 ℃ for 2h, cooling, then putting the solution into a mixed solvent of methanol and butanone, stirring, controlling the temperature to be 40 ℃, adding activated carbon for decolorization, filtering, cooling the filtrate to-10 ℃ for crystallization according to a certain cooling speed, growing crystals, filtering, washing the filtered solid with absolute ethyl alcohol, and drying in vacuum to obtain refined citric acid tofacitinib, wherein the decolorization time of the activated carbon is 30min, and the crystallization time is 3-4 h; the cooling speed in the crystallization process is controlled at 15 ℃/h.
Example two:
a synthetic method of tofacitinib citrate comprises the following steps:
1) preparation of 2, 4-dihydroxypyrrolopyrimidine:
adding 4-aminouracil and anhydrous sodium acetate into water (the molar ratio is 1: 5), heating to 80 ℃, slowly adding 40% aqueous solution of 2-chloroacetaldehyde, stirring for reacting for 6 hours, cooling to room temperature, filtering, washing the solid with water, and drying under reduced pressure to obtain 2, 4-dihydroxy pyrrolopyrimidine;
reacting 4-aminouracil with chloroacetaldehyde to generate 2, 4-dihydroxypyrrolopyrimidine;
2) synthesis of 2, 4-dichloro pyrrolopyrimidine:
dissolving 2, 4-dihydroxypyrrolopyrimidine into phosphorus oxychloride, adding organic base diisopropylethylamine, heating to 85 ℃, stirring for reaction for 3 hours, evaporating redundant phosphorus oxychloride, cooling to normal temperature, slowly dropwise adding the concentrated solution into an ammonia water solution, controlling the temperature to be below 20 ℃ and the pH to be 6-8, filtering, washing, and drying under reduced pressure to obtain 2, 4-dichloropyrrolopyrimidine;
2, 4-dihydroxy pyrrolopyrimidine is chloridized into 2, 4-dichloro pyrrolopyrimidine in phosphorus oxychloride under the catalysis of organic base diisopropylethylamine;
3) synthesis of N- [ (3R, 4R) -1-benzyl-4-methylpiperidin-3-yl ] -N-methyl-7H-2-chloro-pyrrolo [2, 3-d ] pyrimidin-4-amine:
adding cis-1-benzyl-4-methyl-3-methylaminopiperidine hydrochloride, water and dioxane into a reaction vessel, stirring to dissolve, adding 2, 4-dichloropyrrolopyrimidine and potassium carbonate, heating to 60 ℃ for reaction for 20 hours, evaporating the solvent under reduced pressure, adding ethyl acetate and water, layering, extracting a water layer twice with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and adding petroleum ether for crystallization to obtain a light yellow solid;
4) synthesis of N- [ (3R, 4R) -4-methylpiperidin-3-yl ] -N-methyl-7H-pyrrolo [2, 3-d ] pyrimidin-4-amine:
adding the compound, 10% pd/C (0.9g, water content of 50%), acetic acid and ethanol into a hydrogenation reaction kettle, introducing hydrogen, reacting at 45 ℃ for 4 hours, reacting under the pressure of 0.15MPa in the kettle, filtering after the reaction is finished, decompressing the filtrate, distilling off the solvent, and drying the residue to obtain a white-like solid (mp 157-159 ℃);
5) synthesizing tofacitinib citrate:
adding the compound, cyanoacetic acid, 1-hydroxybenzotriazole and dichloromethane into a three-neck flask, reacting at room temperature for 12h, adding water after the reaction is finished, then adding absolute ethyl alcohol and citric acid monohydrate, reacting at 40 ℃ for 2h, cooling, then putting the solution into a mixed solvent of methanol and butanone, stirring, controlling the temperature to be 40 ℃, adding activated carbon for decolorization, filtering, cooling the filtrate to 0 ℃ at a certain cooling speed, crystallizing, growing crystals, filtering, washing the filtered solid with absolute ethyl alcohol, and drying in vacuum to obtain refined citric acid tofacitinib, wherein the activated carbon is decolorized for 30min, and the growing crystals are 3-4 h; the cooling speed in the crystallization process is controlled at 15 ℃/h.
The invention has the beneficial effects that: the synthesis method of tofacitinib citrate comprises the steps of adding the compound, cyanoacetic acid, 1-hydroxybenzotriazole and dichloromethane into a three-neck flask, adding water after reaction, then adding anhydrous ethanol and citric acid monohydrate, cooling, then putting the solution into a mixed solvent of methanol and butanone, stirring, adding activated carbon for decolorization, filtering, cooling the filtrate at a certain cooling speed, then crystallizing, growing crystals, filtering, and washing the filtered solid with anhydrous ethanol, wherein during synthesis, the mixed solvent of methanol and butanone can better absorb and dissolve tofacitinib citrate generated by reaction, so that the tofacib citrate can be prevented from other reactions, redundant impurities can be filtered and taken out by adding activated carbon for decolorization and filtering, then crystallization, growing crystals, primary filtering, washing the filtered solid with anhydrous ethanol for secondary impurity removal, the purity of the produced tofacitinib finished product is higher through twice impurity removal operations, subsequent purification operation is not needed, the tofacitinib finished product is more convenient to use, the method is short in synthesis time, simple in process and suitable for being produced by factories, the production time of the tofacitinib finished product can be saved, the production efficiency of the tofacitinib finished product can be improved, the period is shorter, the production cost can be reduced, the production benefit can be improved, the production environment is easy to obtain, the adaptability is strong, the tofacitinib finished product is more convenient to use, the problem that the existing synthesis method of the tofacitinib on the market is solved, the purity of most of the tofacitinib is not high, more impurities exist in the existing synthesis process, the pure tofacitinib needs to be further purified and processed, and the production time of the tofacitinib can be prolonged, the period is longer, the production efficiency is reduced, the cost is improved, the production benefit is reduced, and the use is inconvenient.
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 (5)
1. A synthetic method of tofacitinib citrate is characterized by comprising the following steps:
1) preparation of 2, 4-dihydroxypyrrolopyrimidine:
adding 4-aminouracil and anhydrous sodium acetate into water (the molar ratio is 1: 3-1: 5), heating to 60-80 ℃, slowly adding 40% of 2-chloroacetaldehyde aqueous solution, stirring for reaction for 4-6 hours, cooling to room temperature, filtering, washing the solid with water, and drying under reduced pressure to obtain 2, 4-dihydroxy pyrrolopyrimidine;
2) synthesis of 2, 4-dichloro pyrrolopyrimidine:
dissolving 2, 4-dihydroxypyrrolopyrimidine into phosphorus oxychloride, adding organic base diisopropylethylamine, heating to 80-85 ℃, stirring for reaction for 3 hours, evaporating redundant phosphorus oxychloride, cooling to normal temperature, slowly dropwise adding the concentrated solution into an ammonia water solution, controlling the temperature to be below 20 ℃, controlling the pH to be 6-8, filtering, washing, and drying under reduced pressure to obtain 2, 4-dichloropyrrolopyrimidine;
3) synthesis of N- [ (3R, 4R) -1-benzyl-4-methylpiperidin-3-yl ] -N-methyl-7H-2-chloro-pyrrolo [2, 3-d ] pyrimidin-4-amine:
adding cis-1-benzyl-4-methyl-3-methylaminopiperidine hydrochloride, water and dioxane into a reaction vessel, stirring to dissolve, adding 2, 4-dichloropyrrolopyrimidine and potassium carbonate, heating to 50-60 ℃, reacting for 20h, evaporating the solvent under reduced pressure, adding ethyl acetate and water, layering, extracting a water layer twice with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and adding petroleum ether for crystallization to obtain a light yellow solid;
4) synthesis of N- [ (3R, 4R) -4-methylpiperidin-3-yl ] -N-methyl-7H-pyrrolo [2, 3-d ] pyrimidin-4-amine:
adding the compound, 10% pd/C (0.9g, water content of 50%), acetic acid and ethanol into a hydrogenation reaction kettle, introducing hydrogen, reacting at 40-45 ℃ for 4 hours, wherein the pressure in the kettle is 0.12-0.15 MPa, performing suction filtration after the reaction is finished, decompressing filtrate, distilling off a solvent, and drying residues to obtain a white-like solid (mp 157-159 ℃);
5) synthesizing tofacitinib citrate:
adding the compound, cyanoacetic acid, 1-hydroxybenzotriazole and dichloromethane into a three-neck flask, reacting at room temperature for 12 hours, adding water after the reaction is finished, then adding absolute ethyl alcohol and citric acid monohydrate, reacting at 40 ℃ for 2 hours, cooling, putting the solution into a mixed solvent of methanol and butanone, stirring, controlling the temperature to be 30-40 ℃, adding activated carbon for decolorization, filtering, cooling the filtrate to-10-0 ℃ at a certain cooling speed, crystallizing, growing crystals, filtering, washing the filtered solid with absolute ethyl alcohol, and drying in vacuum to obtain the refined tofacitinib citrate.
2. The method for synthesizing tofacitinib citrate according to claim 1, wherein in the first step, 4-aminouracil reacts with chloroacetaldehyde to form 2, 4-dihydroxypyrrolopyrimidine.
3. The method for synthesizing tofacitinib citrate according to claim 1, wherein in the second step, the 2, 4-dihydroxypyrrolopyrimidine is chlorinated into 2, 4-dichloropyrrolopyrimidine in phosphorus oxychloride under the catalysis of diisopropylethylamine which is an organic base.
4. The method for synthesizing tofacitinib citrate according to claim 1, wherein in the fifth step, the decolorizing time of the activated carbon is 20-30min, and the crystal growing time is 3-4 h; the cooling speed in the crystallization process is controlled to be 10-15 ℃/h.
5. The method for synthesizing tofacitinib citrate according to claim 1, wherein the solution in the fifth step is stirred for 30 min.
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| CN111995627A (en) * | 2020-09-15 | 2020-11-27 | 山东金城昆仑药业有限公司 | Tofacitinib citrate intermediate and preparation method and application thereof |
| CN114230572A (en) * | 2021-12-24 | 2022-03-25 | 四川新迪医药化工有限公司 | Preparation method of 2, 4-dichloro-7H-pyrrolo [2,3-D ] pyrimidine |
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| CN104987339A (en) * | 2015-07-29 | 2015-10-21 | 张燕梅 | Synthesis method of tofacitinib citrate |
| CN110668995A (en) * | 2018-07-03 | 2020-01-10 | 江苏海悦康医药科技有限公司 | Tofacitinib citrate intermediate and preparation method of tofacitinib citrate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104987339A (en) * | 2015-07-29 | 2015-10-21 | 张燕梅 | Synthesis method of tofacitinib citrate |
| CN110668995A (en) * | 2018-07-03 | 2020-01-10 | 江苏海悦康医药科技有限公司 | Tofacitinib citrate intermediate and preparation method of tofacitinib citrate |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111995627A (en) * | 2020-09-15 | 2020-11-27 | 山东金城昆仑药业有限公司 | Tofacitinib citrate intermediate and preparation method and application thereof |
| CN111995627B (en) * | 2020-09-15 | 2021-04-27 | 山东金城昆仑药业有限公司 | Tofacitinib citrate intermediate and preparation method and application thereof |
| CN114230572A (en) * | 2021-12-24 | 2022-03-25 | 四川新迪医药化工有限公司 | Preparation method of 2, 4-dichloro-7H-pyrrolo [2,3-D ] pyrimidine |
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