CN110668995A - Tofacitinib citrate intermediate and preparation method of tofacitinib citrate - Google Patents
Tofacitinib citrate intermediate and preparation method of tofacitinib citrate Download PDFInfo
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- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a tofacitinib citrate intermediate and a preparation method of tofacitinib citrate. The preparation method of the tofacitinib citrate intermediate comprises the following steps: preparing N- (1-benzyl-4-methyl-1, 2,5, 6-tetrahydropiperidyl-3-yl) acetamide by using 3-amino-4-methyl-pyridine, acetyl chloride, benzyl chloride and sodium borohydride as raw materials; preparing 1-benzyl-N, 4-dimethylpiperidine-3-amine by using N- (1-benzyl-4-methyl-1, 2,5, 6-tetrahydropiperidin-3-yl) acetamide, hydrochloric acid, methylamine and sodium borohydride as raw materials; the 1-benzyl-N, 4-dimethylpiperidine-3-amine is obtained after the steps of resolution, dissociation and salification with hydrochloric acid. The invention provides a novel preparation method of tofacitinib citrate intermediate, and in the preparation process of tofacitinib citrate, the dosage of a catalytic hydrogenation catalyst is reduced, so that the cost is reduced; the generation of N-alkylation impurities can be better controlled by adopting an isopropanol/water mixed solvent.
Description
Technical Field
The invention relates to the field of pharmacy, and particularly relates to a tofacitinib citrate intermediate and a preparation method of tofacitinib citrate.
Background
Tofacitinib citrate is chemically 3- { (3R,4R) -4-methyl-3- [ methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -3-oxo-propionitrile, 2-hydroxypropane-1, 2, 3-tricarboxylate (1: 1), and has the following structural formula:
the tofacitinib citrate is a Janus kinase (JAK) inhibitor, can effectively inhibit the activity of JAK1 and JAK3, and can block the signal conduction of various inflammatory cytokines. Tofacitinib citrate was developed by Pfizer (Pfizer), approved by FDA breakthrough therapy in 2012, and marketed for rheumatoid arthritis treatment intolerant to methotrexate treatment.
The difficulty of the synthesis process of tofacitinib citrate is that a chiral center replaces a piperidine segment, the chemical name of the tofacitinib citrate is (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine, and the structure of the tofacitinib citrate is as follows:
the compound (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine has been reported to have more synthetic routes. The former company Pfizer was published in org.process res.dev., 07, 2003, 115-120 for early synthesis, followed by Pfizer in org.process res.dev., 09, 2005, 51-56 for improved synthesis. The synthesis process of the compound is always improved, and the early process has larger defects.
The synthetic routes of the document org.process res.dev., 09, 2005, 51-56 have the following disadvantages: the total yield of the route is about 55%. The use of 0.34kg of Rh/C catalyst per 1kg of product produced is costly.
In addition, many documents report the synthesis method of the intermediate, such as CN201510139871, CN201510648532, WO2007012953, WO2015087201 and the like, and the methods reported in the documents are not superior to the methods reported by Pfizer in org. Process Res.Dev., 09, 2005, 51-56. Or expensive reagents are used for achieving higher yield and chiral selectivity; or low yield and selectivity.
At present, the mainstream synthetic route of tofacitinib citrate is as follows:
the catalyst used for catalytic hydrogenation and debenzylation in the third step of the process is generally palladium hydroxide, and the use amount of the catalyst in the third step is very large and is a key for limiting the cost of the whole route. The reason for the higher catalyst usage is that the residual sulfides in the Ts in the previous step cause catalyst poisoning.
Therefore, it is necessary to develop a new production process of chiral intermediate (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride. Meanwhile, the development of a low-cost tofacitinib citrate production process is also needed.
Disclosure of Invention
The invention aims to provide a tofacitinib citrate intermediate and a preparation method of tofacitinib citrate, so as to solve the problems in the background technology.
In order to achieve the purpose, the invention provides the following technical scheme:
a preparation method of tofacitinib citrate intermediate is (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride, and comprises the following steps:
(1) preparation of N- (1-benzyl-4-methyl-1, 2,5, 6-tetrahydropyridin-3-yl) acetamide: 3-amino-4-methyl-pyridine, acetyl chloride, benzyl chloride and sodium borohydride are used as raw materials and are reacted to obtain N- (1-benzyl-4-methyl-1, 2,5, 6-tetrahydropiperidyl-3-yl) acetamide;
(2) preparation of 1-benzyl-N, 4-dimethylpiperidin-3-amine: taking N- (1-benzyl-4-methyl-1, 2,5, 6-tetrahydropiperidine-3-yl) acetamide, hydrochloric acid, methylamine and sodium borohydride as raw materials, and reacting to obtain 1-benzyl-N, 4-dimethylpiperidine-3-amine;
(3) preparation of (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine dihydrochloride: the 1-benzyl-N, 4-dimethylpiperidine-3-amine is subjected to the steps of resolution, dissociation and salification with hydrochloric acid to obtain (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride.
As a further scheme of the invention: the mass ratio of the 3-amino-4-methyl-pyridine to the acetyl chloride to the benzyl chloride to the sodium borohydride is as follows: 2.2: 1.7: 1.9: 1.5; the mass ratio of the N- (1-benzyl-4-methyl-1, 2,5, 6-tetrahydropiperidyl-3-yl) acetamide to the hydrochloric acid to the methylamine to the sodium borohydride is as follows: 4.5: 16: 4: 1.32.
As a further scheme of the invention: the step (1) specifically comprises the following steps:
A. adding 3-amino-4-methyl-pyridine into a mixed solution of dichloromethane and toluene, cooling to 0-10 ℃, dropwise adding acetyl chloride, and reacting for 10 hours at 20-25 ℃; controlling the temperature below 10 ℃, dropwise adding a sodium hydroxide aqueous solution, adjusting the pH to 8-9, and separating a lower-layer water phase;
B. adding benzyl chloride into the product obtained in the last step, heating to 70-80 ℃ for reaction, and separating distilled dichloromethane in the heating process; after the reaction is finished, cooling to 0-10 ℃;
C. controlling the temperature below 10 ℃, and simultaneously dropwise adding sodium borohydride and sodium hydroxide solution; after the dropwise addition, the temperature is maintained for continuous reaction for 14 hours;
D. filtering to obtain wet N- (1-benzyl-4-methyl-1, 2,5, 6-tetrahydropiperidyl-3-yl) acetamide, and drying to obtain N- (1-benzyl-4-methyl-1, 2,5, 6-tetrahydropiperidyl-3-yl) acetamide.
As a further scheme of the invention: the step (2) specifically comprises the following steps:
A. adding N- (1-benzyl-4-methyl-1, 2,5, 6-tetrahydropiperidine-3-yl) acetamide into concentrated hydrochloric acid for multiple times, adding N-heptane, heating to 70-75 ℃ and reacting for 4-5 hours;
B. cooling to 20-25 deg.C, adjusting pH to 8-9, and separating; under the protection of nitrogen, carrying out pressure concentration on the n-heptane phase to obtain an n-heptane concentrated solution;
C. adding anhydrous methanol into the n-heptane concentrated solution, cooling to 0-5 deg.C, and adding tetraisopropyl titanate; then controlling the temperature below 5 ℃, dropwise adding a mixed solution of methylamine and methanol, and stirring for 1 hour at 0-10 ℃ after dropwise adding;
D. adding sodium borohydride into the reaction liquid obtained in the last step for multiple times, and controlling the feeding process to be below 10 ℃; after the addition, the reaction is carried out for 2 hours under the condition of heat preservation;
E. after the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a pale yellow oily liquid for use.
As a further scheme of the invention: the step (3) specifically comprises the following steps:
A. dissolving the light yellow oily liquid in methanol, adding L-p-toluyl tartrate, stirring for 1 hour at the temperature of 50-55 ℃, then dropwise adding purified water, and cooling to 10-15 ℃ for crystallization after dropwise adding;
B. filtering to obtain precipitated crystals, and washing the crystals with a mixed solution of methanol and water; then adjusting the pH value to 8.6-9.0; then adding purified water, cooling to 0-5 deg.C, and separating insoluble substances;
C. adding the insoluble substance obtained in the previous step into methanol, and adjusting the pH value to 3.0; filtering, washing and vacuum drying to obtain (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride.
A preparation method of tofacitinib citrate comprises the following steps:
firstly, preparing a tofacitinib citrate intermediate;
preparation of di, N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7-p-toluenesulfonyl-pyrrolo [2,3-d ] pyrimidin-4-amine: taking (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine double hydrochloride, potassium carbonate and 4-chloro-7-p-toluenesulfonyl-pyrrolo [2,3-d ] pyrimidine-4-amine as raw materials, and reacting to obtain N- ((3R,4R) -1-benzyl-4-methylpiperidine-3-yl) -N-methyl-7-p-toluenesulfonyl-pyrrolo [2,3-d ] pyrimidine-4-amine;
preparation of tris, N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine: reacting N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7-p-toluenesulfonyl-pyrrolo [2,3-d ] pyrimidin-4-amine to obtain N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine;
preparation of tetra, N- ((3R,4R) -4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine hydrochloride:
n- ((3R,4R) -1-benzyl-4-methylpiperidine-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidine-4-amine and hydrochloric acid are used as raw materials, and N- ((3R,4R) -4-methylpiperidine-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidine-4-amine hydrochloride is obtained through reaction under the action of a Pd/C catalyst;
preparation of penta, 3- { (3R,4R) -4-methyl-3- [ methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -3-oxo-propionitrile:
taking N- ((3R,4R) -4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidine-4-amine hydrochloride, N-hydroxysuccinimide cyanoacetate and diisopropylethylamine as raw materials, and reacting to obtain a crude product of 3- { (3R,4R) -4-methyl-3- [ methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -3-oxo-propionitrile;
sixthly, preparing tofacitinib citrate: 3- { (3R,4R) -4-methyl-3- [ methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -3-oxo-propionitrile is reacted to obtain tofacitinib citrate.
As a further scheme of the invention: the mass ratio of (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride, potassium carbonate and 4-chloro-7-p-toluenesulfonyl-pyrrolo [2,3-d ] pyrimidin-4-amine is 1.7: 2.3: 1.8; the mass ratio of N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidine-4-amine to hydrochloric acid is 2: 1; the mass ratio of N- ((3R,4R) -4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine hydrochloride, cyanoacetic acid N-hydroxysuccinimide and diisopropylethylamine was 1.6:1.7: 1.6.
As a further scheme of the invention: the method comprises the following steps:
firstly, preparing a tofacitinib citrate intermediate;
preparation of di, N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7-p-toluenesulfonyl-pyrrolo [2,3-d ] pyrimidin-4-amine; the method specifically comprises the following steps:
A. mixing purified water, acetonitrile, (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride and potassium carbonate, and stirring until the mixture is dissolved;
B. adding 4-chloro-7-p-toluenesulfonyl-pyrrolo [2,3-d ] pyrimidine-4-amine into the product obtained in the last step for multiple times, heating to 75-85 ℃ and reacting for 10 hours;
C. cooling to 20-30 deg.C, vacuum filtering, and washing filter cake;
preparation of tris, N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine; the method specifically comprises the following steps:
A. adding the filter cake into a sodium hydroxide aqueous solution and isopropanol, and carrying out reflux reaction for 7-8 hours;
B. cooling to 40-45 deg.C, adding seed crystal, and stirring to get turbid solution; cooling and crystallizing;
C. filtering, and refluxing and pulping the obtained crystals by using a mixed solution of purified water and isopropanol;
D. filtering, and vacuum-drying the filtrate to obtain N- ((3R,4R) -1-benzyl-4-methylpiperidine-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidine-4-amine;
preparation of tetra, N- ((3R,4R) -4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine hydrochloride; the method specifically comprises the following steps:
A. adding N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine into absolute ethyl alcohol, then adding hydrochloric acid and a Pd/C catalyst, and hydrogenating for 5 hours at the pressure of 20-30Psi and the temperature of 30-35 ℃;
B. filtering to remove Pd/C catalyst, concentrating the filtrate under reduced pressure, adding anhydrous ethanol into the concentrated filtrate, and cooling for crystallization;
C. carrying out suction filtration on the obtained product, and carrying out vacuum drying to obtain N- ((3R,4R) -4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidine-4-amine hydrochloride;
preparation of penta, 3- { (3R,4R) -4-methyl-3- [ methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -3-oxo-propionitrile; the method specifically comprises the following steps:
A. adding N- ((3R,4R) -4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine hydrochloride into absolute ethanol, and then adding cyanoacetic acid N-hydroxysuccinimide and diisopropylethylamine; reacting for 6 hours at 25-35 ℃;
B. after the reaction is finished, cooling to 5-15 ℃ and stirring for 6 hours; filtering, and washing a filter cake with a mixed solution of ethanol and water; the filter cake was collected and dried in vacuo to give crude 3- { (3R,4R) -4-methyl-3- [ methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -3-oxo-propionitrile;
sixthly, preparing tofacitinib citrate; the method specifically comprises the following steps:
A. adding 3- { (3R,4R) -4-methyl-3- [ methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -3-oxo-propionitrile to a mixture of acetonitrile and water, and heating and refluxing until the solution is clear;
B. after the temperature of the product obtained in the previous step is kept to 70-75 ℃, the aqueous solution of citric acid is dripped into the product obtained in the previous step; after the dropwise addition, maintaining the temperature of 70-75 ℃, stirring for 1 hour, and then carrying out precision filtration to obtain a filtrate for later use;
C. and cooling the filtrate obtained in the previous step to 0-5 ℃, stirring for 2 hours, filtering to obtain a filter cake, washing the filter cake with a mixed solution of acetonitrile and water, and drying in vacuum to obtain the tofacitinib citrate.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a novel preparation method of tofacitinib citrate intermediate, and in the preparation process of tofacitinib citrate, a debenzylation reaction can be completed by improving the debenzylation reaction and catalyzing with a small amount of Pd/C, so that the cost is reduced; in the step C of the third step, the generation of N-alkylation impurities can be well controlled by adopting an isopropanol/water mixed solvent, and an isopropanol/water system has a good refining effect on a product; in the step A of the sixth step, the finished product of tofacitinib citrate with the purity of more than 99.9 percent can be obtained by taking the acetonitrile/water mixed solution as a solvent, and the obtained crystal form is a medicinal crystal form.
Detailed Description
The technical solution of the present patent will be described in further detail with reference to the following embodiments.
Example 1
A preparation method of tofacitinib citrate comprises the following steps:
firstly, preparing a tofacitinib citrate intermediate; the tofacitinib citrate intermediate is (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride;
preparation of di, N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7-p-toluenesulfonyl-pyrrolo [2,3-d ] pyrimidin-4-amine; the method specifically comprises the following steps:
A. mixing 10.0kg of purified water, 2.6kg of acetonitrile, 1.7kg of (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine dihydrochloride and 2.3kg of potassium carbonate, and stirring until the mixture is dissolved;
B. adding 1.8kg of 4-chloro-7-p-toluenesulfonyl-pyrrolo [2,3-d ] pyrimidine-4-amine into the product obtained in the last step for multiple times, heating to 75-85 ℃, reacting for 10 hours, and carrying out HPLC detection;
C. cooling to 20-30 ℃, preserving heat, stirring for 2 hours, carrying out suction filtration, and washing a filter cake with 3kg of purified water for later use;
preparation of tris, N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine; the method specifically comprises the following steps:
A. adding the filter cake into 8L of 10 mass percent sodium hydroxide aqueous solution and 7.5kg of isopropanol, and heating and carrying out reflux reaction for 7-8 hours;
B. cooling to 40-45 deg.C, adding seed crystal, and stirring to get turbid solution; continuously cooling to 10-15 ℃ for crystallization;
C. filtering, and refluxing and pulping the obtained crystal once by using a mixed solution of 4kg of purified water and 6kg of isopropanol;
D. filtering, and drying the filtrate in vacuum to obtain 2.0kg of N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidine-4-amine;
preparation of tetra, N- ((3R,4R) -4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine hydrochloride; the method specifically comprises the following steps:
A. adding 2.0kg of N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidine-4-amine into 15kg of absolute ethyl alcohol, then adding 1kg of 1N hydrochloric acid and 0.4kg of a Pd/C catalyst with the mass fraction of 5%, and hydrogenating for 5 hours at the pressure of 20-30Psi and the temperature of 30-35 ℃;
B. filtering to remove the Pd/C catalyst, and concentrating the filtrate under reduced pressure to half of the original volume; then adding 7kg of absolute ethyl alcohol into the concentrated filtrate, cooling to 10-15 ℃, and crystallizing for 3 hours;
C. carrying out suction filtration on the obtained product, and carrying out vacuum drying to obtain 1.6kg of N- ((3R,4R) -4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidine-4-amine hydrochloride;
preparation of penta, 3- { (3R,4R) -4-methyl-3- [ methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -3-oxo-propionitrile; the method specifically comprises the following steps:
A. 1.6kg of N- ((3R,4R) -4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine hydrochloride are added to 12kg of absolute ethanol, and then 1.7kg of cyanoacetic acid N-hydroxysuccinimide and 1.6kg of diisopropylethylamine are added; reacting for 6 hours at 25-35 ℃, and monitoring the reaction end point by adopting HPLC;
B. after the reaction is finished, cooling to 5-15 ℃ and stirring for 6 hours; filtering, washing filter cake with mixed solution of ethanol and water (volume ratio 1: 1, 2L); the filter cake was collected and dried under vacuum at 50 + -5 deg.C to give about 1.8kg of crude 3- { (3R,4R) -4-methyl-3- [ methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -3-oxo-propionitrile;
sixthly, preparing tofacitinib citrate; the method specifically comprises the following steps:
A. 1.8kg of 3- { (3R,4R) -4-methyl-3- [ methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -3-oxo-propionitrile was added to a mixed solution of 9kg of acetonitrile and 4kg of water, and heated under reflux until the solution was clear;
B. after the temperature of the product obtained in the previous step is kept to 70-75 ℃, the product obtained in the previous step is dropwise added with an aqueous solution of citric acid, and the aqueous solution of citric acid is formed by mixing citric acid and water according to the mass ratio of 1.3: 7; after the dropwise addition, maintaining the temperature of 70-75 ℃, stirring for 1 hour, and then carrying out precision filtration to obtain a filtrate for later use;
C. cooling the filtrate obtained in the previous step to 0-5 ℃, stirring for 2 hours, filtering to obtain a filter cake, washing the filter cake with a mixed solution of acetonitrile and water (volume ratio is 1: 1, 2L), and placing at 50 +/-5 ℃ for vacuum drying to obtain 2.3kg of tofacitinib citrate with the purity of more than 99.9%.
Example 2
On the basis of the embodiment 1, the preparation method of the tofacitinib citrate intermediate (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride specifically comprises the following steps:
(1) preparing N- (1-benzyl-4-methyl-1, 2,5, 6-tetrahydropiperidyl-3-yl) acetamide; the method specifically comprises the following steps:
A. adding 2.2kg of 3-amino-4-methyl-pyridine into 15kg of dichloromethane and 22kg of toluene, cooling to 0-10 ℃, dropwise adding 1.7kg of acetyl chloride, and reacting for 10 hours at 20-25 ℃; controlling the temperature below 10 ℃, dropwise adding a sodium hydroxide aqueous solution, adjusting the pH to 8-9, and separating a lower-layer water phase; concentrating the organic phase under reduced pressure to 23-25L;
B. adding 1.9kg of benzyl chloride into the product obtained in the last step, heating to 70-80 ℃ for reaction, and separating distilled dichloromethane in the heating process; after the reaction is finished, cooling to 0-10 ℃;
C. controlling the temperature below 10 ℃, and simultaneously dropwise adding 10kg of aqueous solution of 1.5kg of sodium borohydride and 60g of sodium hydroxide; after the dropwise addition, the temperature is maintained for continuous reaction for 14 hours;
D. filtering to obtain wet N- (1-benzyl-4-methyl-1, 2,5, 6-tetrahydropiperidyl-3-yl) acetamide as off-white solid, and drying to obtain 4.5kg of N- (1-benzyl-4-methyl-1, 2,5, 6-tetrahydropiperidyl-3-yl) acetamide with the purity of 94-97%;
(2) preparing 1-benzyl-N, 4-dimethylpiperidine-3-amine; the method specifically comprises the following steps:
A. adding 4.5kg of N- (1-benzyl-4-methyl-1, 2,5, 6-tetrahydropiperidyl-3-yl) acetamide into 16kg of concentrated hydrochloric acid for multiple times, then adding 12kg of N-heptane, heating to 70-75 ℃ and reacting for 4-5 hours;
B. cooling to 20-25 deg.C, adjusting pH to 8-9 with sodium hydroxide water solution, and separating; under the protection of nitrogen, concentrating the n-heptane phase under reduced pressure to half of the original volume to obtain n-heptane concentrated solution;
C. adding 13.6kg of anhydrous methanol into the n-heptane concentrated solution, cooling to 0-5 ℃, and adding 4.2kg of tetraisopropyl titanate; then 4kg of mixed solution of methylamine and methanol is dripped under the temperature controlled below 5 ℃, and the mixed solution is stirred for 1 hour at the temperature of 0-10 ℃ after the dripping is finished;
D. adding 1.32kg of sodium borohydride into the reaction solution obtained in the previous step for multiple times, and controlling the feeding process to be below 10 ℃; after the addition, the reaction is carried out for 2 hours under the condition of heat preservation;
E. after the reaction is finished, decompressing and concentrating to obtain light yellow oily liquid for later use;
(3) preparing (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride; the method specifically comprises the following steps:
A. dissolving the light yellow oily liquid in 14kg of methanol at the dissolving temperature of 50-55 ℃, then adding 3.6kg of L-p-toluyl tartrate, stirring for 1 hour at the temperature of 50-55 ℃, then dropwise adding 17kg of purified water, and cooling to 10-15 ℃ for crystallization after dropwise adding;
B. filtering to obtain precipitated crystals, and washing the crystals with a mixed solution of methanol and water; then adding the crystal into 20L of mixed solution of methanol and water with the volume ratio of 1: 1, and adjusting the pH to 8.6-9.0 by using 30% by mass of sodium hydroxide; then adding 30kg of purified water, cooling to 0-5 ℃, separating insoluble substances, and washing the insoluble substances with purified water;
C. adding the insoluble substance obtained in the previous step into 15kg of methanol, adjusting the pH to about 3.0 by using concentrated hydrochloric acid, adding seed crystals, continuously stirring for 2 hours, and repeatedly measuring the pH; filtered, washed with a little methanol and dried under vacuum at 45 ℃ to give 1.7kg of (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine dihydrochloride.
The peaks of the HPLC chromatogram of the crude tofacitinib citrate are shown in the following Table 1:
TABLE 1
Detector A287 nm
| Peak number | Retention time | Area of | Height | Area% |
| 1 | 9.953 | 155 | 23 | 0.001 |
| 2 | 10.277 | 488 | 51 | 0.002 |
| 3 | 11.503 | 2651 | 309 | 0.012 |
| 4 | 12.163 | 301 | 31 | 0.001 |
| 5 | 14.805 | 22583544 | 2115778 | 99.920 |
| 6 | 16.827 | 12642 | 1055 | 0.056 |
| 7 | 19.783 | 406 | 47 | 0.002 |
| 8 | 21.557 | 686 | 62 | 0.003 |
| 9 | 24.821 | 826 | 64 | 0.004 |
| Total of | 22601699 | 2117420 | 100.000 |
Although the preferred embodiments of the present patent have been described in detail, the present patent is not limited to the above embodiments, and various changes can be made without departing from the spirit of the present patent within the knowledge of those skilled in the art.
Claims (8)
1. A preparation method of tofacitinib citrate intermediate is characterized in that the tofacitinib citrate intermediate is (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride, and the preparation method comprises the following steps:
(1) preparation of N- (1-benzyl-4-methyl-1, 2,5, 6-tetrahydropyridin-3-yl) acetamide: 3-amino-4-methyl-pyridine, acetyl chloride, benzyl chloride and sodium borohydride are used as raw materials and are reacted to obtain N- (1-benzyl-4-methyl-1, 2,5, 6-tetrahydropiperidyl-3-yl) acetamide;
(2) preparation of 1-benzyl-N, 4-dimethylpiperidin-3-amine: taking N- (1-benzyl-4-methyl-1, 2,5, 6-tetrahydropiperidine-3-yl) acetamide, hydrochloric acid, methylamine and sodium borohydride as raw materials, and reacting to obtain 1-benzyl-N, 4-dimethylpiperidine-3-amine;
(3) preparation of (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine dihydrochloride: the 1-benzyl-N, 4-dimethylpiperidine-3-amine is subjected to the steps of resolution, dissociation and salification with hydrochloric acid to obtain (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride.
2. The preparation method of tofacitinib citrate intermediate according to claim 1, wherein the mass ratio of 3-amino-4-methyl-pyridine to acetyl chloride to benzyl chloride to sodium borohydride is: 2.2: 1.7: 1.9: 1.5; the mass ratio of the N- (1-benzyl-4-methyl-1, 2,5, 6-tetrahydropiperidyl-3-yl) acetamide to the hydrochloric acid to the methylamine to the sodium borohydride is as follows: 4.5: 16: 4: 1.32.
3. the preparation method of tofacitinib citrate intermediate as claimed in claim 1, wherein the step (1) comprises the following steps:
A. adding 3-amino-4-methyl-pyridine into a mixed solution of dichloromethane and toluene, cooling to 0-10 ℃, dropwise adding acetyl chloride, and reacting for 10 hours at 20-25 ℃; controlling the temperature below 10 ℃, dropwise adding a sodium hydroxide aqueous solution, adjusting the pH to 8-9, and separating a lower-layer water phase;
B. adding benzyl chloride into the product obtained in the last step, heating to 70-80 ℃ for reaction, and separating distilled dichloromethane in the heating process; after the reaction is finished, cooling to 0-10 ℃;
C. controlling the temperature below 10 ℃, and simultaneously dropwise adding sodium borohydride and sodium hydroxide solution; after the dropwise addition, the temperature is maintained for continuous reaction for 14 hours;
D. filtering to obtain wet N- (1-benzyl-4-methyl-1, 2,5, 6-tetrahydropiperidyl-3-yl) acetamide, and drying to obtain N- (1-benzyl-4-methyl-1, 2,5, 6-tetrahydropiperidyl-3-yl) acetamide.
4. The preparation method of tofacitinib citrate intermediate as claimed in claim 1, wherein the step (2) comprises the following steps:
A. adding N- (1-benzyl-4-methyl-1, 2,5, 6-tetrahydropiperidine-3-yl) acetamide into concentrated hydrochloric acid for multiple times, adding N-heptane, heating to 70-75 ℃ and reacting for 4-5 hours;
B. cooling to 20-25 deg.C, adjusting pH to 8-9, and separating; under the protection of nitrogen, carrying out pressure concentration on the n-heptane phase to obtain an n-heptane concentrated solution;
C. adding anhydrous methanol into the n-heptane concentrated solution, cooling to 0-5 deg.C, and adding tetraisopropyl titanate; then controlling the temperature below 5 ℃, dropwise adding a mixed solution of methylamine and methanol, and stirring for 1 hour at 0-10 ℃ after dropwise adding;
D. adding sodium borohydride into the reaction liquid obtained in the last step for multiple times, and controlling the feeding process to be below 10 ℃; after the addition, the reaction is carried out for 2 hours under the condition of heat preservation;
E. after the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a pale yellow oily liquid for use.
5. The preparation method of tofacitinib citrate intermediate as claimed in claim 1, wherein the step (3) comprises the following steps:
A. dissolving the light yellow oily liquid in methanol, adding L-p-toluyl tartrate, stirring for 1 hour at the temperature of 50-55 ℃, then dropwise adding purified water, and cooling to 10-15 ℃ for crystallization after dropwise adding;
B. filtering to obtain precipitated crystals, and washing the crystals with a mixed solution of methanol and water; then adjusting the pH value to 8.6-9.0; then adding purified water, cooling to 0-5 deg.C, and separating insoluble substances;
C. adding the insoluble substance obtained in the previous step into methanol, and adjusting the pH value to 3.0; filtering, washing and vacuum drying to obtain (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride.
6. The preparation method of tofacitinib citrate is characterized by comprising the following steps of:
firstly, preparing a tofacitinib citrate intermediate;
di, N- (1)3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7-p-toluenesulfonyl-pyrrolo [2,3-d]Preparation of pyrimidin-4-amine: using (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride, potassium carbonate and 4-chloro-7-p-toluenesulfonyl-pyrrolo [2,3-d ]]Pyrimidine-4-amine is used as raw material, and N- (A, B and C) is obtained through reaction3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7-p-toluenesulfonyl-pyrrolo [2,3-d]Pyrimidin-4-amine;
III, N- (1)3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d]Preparation of pyrimidin-4-amine: n- (A)3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7-p-toluenesulfonyl-pyrrolo [2,3-d]Pyrimidine-4-amine is reacted to obtain N- (R)3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d]Pyrimidin-4-amine;
tetra, N- (1)3R,4R) -4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d]Preparation of pyrimidin-4-amine hydrochloride:
with N- (1)3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d]Pyrimidine-4-amine and hydrochloric acid are used as raw materials, and N- (C) is obtained by reaction under the action of Pd/C catalyst3R,4R) -4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d]Pyrimidin-4-amine hydrochloride;
fifthly, 3- { (3R,4R) -4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) -amino]-preparation of piperidin-1-yl } -3-oxo-propionitrile:
with N- (1)3R,4R) -4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d]Pyrimidine-4-amine hydrochloride, cyanoacetic acid N-hydroxysuccinimide and diisopropylethylamine are used as raw materials to obtain 3- { (R) through reaction3R,4R) -4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) -amino]-piperidin-1-yl } -3-oxo-propionitrile crude;
sixthly, preparing tofacitinib citrate: 3- {(3R,4R) -4-methyl-3- [ methyl- (7H-pyrrolo [ ]2,3-d]Pyrimidin-4-yl) -amino]Reacting the-piperidine-1-yl } -3-oxo-propionitrile to obtain the tofacitinib citrate.
7. The method of claim 6, wherein the tofacitinib citrate is (3R,4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine dihydrochloride, potassium carbonate, 4-chloro-7-p-toluenesulfonyl-pyrrolo [2,3-d ]]The mass ratio of the pyrimidine-4-amine is 1.7: 2.3: 1.8; n- (A)3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d]The mass ratio of the pyrimidine-4-amine to the hydrochloric acid is 2: 1; n- (A)3R,4R) -4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d]The mass ratio of pyrimidine-4-amine hydrochloride, cyanoacetic acid N-hydroxysuccinimide and diisopropylethylamine was 1.6:1.7: 1.6.
8. The method of preparing tofacitinib citrate according to claim 6, comprising the steps of:
firstly, preparing a tofacitinib citrate intermediate;
di, N- (1)3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7-p-toluenesulfonyl-pyrrolo [2,3-d]Preparing pyrimidine-4-amine; the method specifically comprises the following steps:
A. mixing purified water, acetonitrile, (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride and potassium carbonate, and stirring until the mixture is dissolved;
B. adding 4-chloro-7-p-toluenesulfonyl-pyrrolo [2,3-d ] pyrimidine-4-amine into the product obtained in the last step for multiple times, heating to 75-85 ℃ and reacting for 10 hours;
C. cooling to 20-30 deg.C, vacuum filtering, and washing filter cake;
III, N- (1)3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d]Preparing pyrimidine-4-amine; the method specifically comprises the following steps:
A. adding the filter cake into a sodium hydroxide aqueous solution and isopropanol, and carrying out reflux reaction for 7-8 hours;
B. cooling to 40-45 deg.C, adding seed crystal, and stirring to get turbid solution; cooling and crystallizing;
C. filtering, and refluxing and pulping the obtained crystals by using a mixed solution of purified water and isopropanol;
D. filtering, vacuum drying the filtrate to obtain N- (A), (B), (C) and (C)3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d]Pyrimidin-4-amine;
tetra, N- (1)3R,4R) -4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d]Preparing pyrimidine-4-amine hydrochloride; the method specifically comprises the following steps:
A. mixing N- (A) and (B)3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d]Adding the pyrimidine-4-amine into absolute ethyl alcohol, then adding hydrochloric acid and a Pd/C catalyst, and hydrogenating for 5 hours at the pressure of 20-30Psi and the temperature of 30-35 ℃;
B. filtering to remove Pd/C catalyst, concentrating the filtrate under reduced pressure, adding anhydrous ethanol into the concentrated filtrate, and cooling for crystallization;
C. filtering the obtained product, and vacuum drying to obtain N- (A, B)3R,4R) -4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d]Pyrimidin-4-amine hydrochloride;
fifthly, 3- { (3R,4R) -4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) -amino]-preparation of piperidin-1-yl } -3-oxo-propionitrile; the method specifically comprises the following steps:
A. mixing N- (A) and (B)3R,4R) -4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d]Adding the pyrimidine-4-amine hydrochloride into absolute ethyl alcohol, and then adding cyanoacetic acid N-hydroxysuccinimide and diisopropylethylamine; reacting for 6 hours at 25-35 ℃;
B. after the reaction is finished, cooling to 5-15 ℃ and stirring for 6 hours; filtering, and washing a filter cake with a mixed solution of ethanol and water; the filter cake was collected and dried in vacuo to give 3- { (C: (C) (R))3R,4R) -4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) -amino]-piperidin-1-yl } -3-oxo-propionitrile crude;
sixthly, preparing tofacitinib citrate; the method specifically comprises the following steps:
A. a reaction of 3- { (3R,4R) -4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) -amino]-piperidin-1-yl } -3-oxo-propionitrile to a mixture of acetonitrile and water, and heating and refluxing the mixture to dissolveClarifying the solution;
B. after the temperature of the product obtained in the previous step is kept to 70-75 ℃, the aqueous solution of citric acid is dripped into the product obtained in the previous step; after the dropwise addition, maintaining the temperature of 70-75 ℃, stirring for 1 hour, and then carrying out precision filtration to obtain a filtrate for later use;
C. and cooling the filtrate obtained in the previous step to 0-5 ℃, stirring for 2 hours, filtering to obtain a filter cake, washing the filter cake with a mixed solution of acetonitrile and water, and drying in vacuum to obtain the tofacitinib citrate.
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| CN112592347A (en) * | 2020-12-14 | 2021-04-02 | 上海博悦生物科技有限公司 | Tofacitinib intermediate related substance and application thereof |
| CN112679508A (en) * | 2021-03-09 | 2021-04-20 | 正大天晴药业集团南京顺欣制药有限公司 | Preparation method of tofacitinib intermediate |
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| CN114835714A (en) * | 2022-04-01 | 2022-08-02 | 上海蓝乐鸟实业有限公司 | Preparation method of tofacitinib |
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| CN111533746A (en) * | 2020-05-29 | 2020-08-14 | 雅本化学股份有限公司 | Synthesis method of tofacitinib citrate |
| CN113896730A (en) * | 2020-06-22 | 2022-01-07 | 浙江晖石药业有限公司 | Preparation method of tofacitinib citrate and intermediate thereof |
| 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 |
| CN112592347A (en) * | 2020-12-14 | 2021-04-02 | 上海博悦生物科技有限公司 | Tofacitinib intermediate related substance and application thereof |
| 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 |
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| CN113248509A (en) * | 2021-05-17 | 2021-08-13 | 上海中西三维药业有限公司 | Preparation method of tofacitinib citrate intermediate |
| CN114835714A (en) * | 2022-04-01 | 2022-08-02 | 上海蓝乐鸟实业有限公司 | Preparation method of tofacitinib |
| CN114644636A (en) * | 2022-04-20 | 2022-06-21 | 江苏恒沛药物科技有限公司 | Method for preparing tofacitinib key intermediate |
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