CN113549075A - Synthesis method of tofacitinib citrate diastereoisomer impurity - Google Patents
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Abstract
The invention discloses a method for synthesizing tofacitinib diastereoisomer impurities, which relates to the technical field of medicine organic synthesis, and is characterized in that 3-amino-4-methylpyridine is used as a starting raw material, and the tofacitinib diastereoisomer impurities are prepared through quaternary ammonium salt, reduction, methylation, salification, coupling, reduction and condensation reactions.
Description
The technical field is as follows:
the invention relates to the technical field of organic synthesis of medicines, in particular to a method for synthesizing tofacitinib citrate diastereoisomer impurities.
Background art:
tofacitinib citrate is developed by the company of fevery, is approved by FDA at the earliest 11 months in 2012, is the first globally approved JAK inhibitor for treating Rheumatoid Arthritis (RA), and is also the first globally approved JAK inhibitor for treating rheumatoid arthritis in China (5 mg standard tofacitinib citrate tablet approved by imported fevery company at 3 months and 10 days in 2017). The medicine can be used for treating adult patients with moderate-to-severe active Rheumatoid Arthritis (RA) with insufficient response or intolerance to methotrexate treatment, can be used as single treatment or be used together with methotrexate or other disease-improving antirheumatic drugs (DMARD), and meanwhile, three 3-phase clinical test result researches for treating ulcerative colitis prove that the treatment of tofacitinib is effective in patients with moderate-to-severe ulcerative colitis, and the curative effect of a plurality of patients can last for more than one year.
At present, more methods for preparing tofacitinib citrate are disclosed, but the research on the impurities of the diastereoisomers of tofacitinib is not much, and the patent disclosure of the impurities of the diastereoisomers of tofacitinib is not inquired. J.Med.chem.2008,5, 8012-one 8018 discloses a method for synthesizing tofacitinib diastereoisomer impurities, but the method is synthesized through 11 steps and uses Grubss reagent and PtO2The reagents are expensive and the experimental conditions are harsh, and the quality of the obtained product is low, so that a simple and mild method capable of large-scale synthesis is urgently needed.
In the national drug standards, the reference substance can be used for the operation of standard substances such as inspection, identification, content determination, inspection of impurities and related substances, and the like, so that the impurity reference substance plays a key role in the quality control of the drug. The invention aims to provide a method for synthesizing tofacitinib citrate diastereoisomer impurities, so as to be used as a reference substance to detect and control the content of the impurities in tofacitinib citrate bulk drug.
The invention content is as follows:
the technical problem to be solved by the invention is to provide a method for synthesizing tofacitinib citrate diastereoisomer impurities, wherein the purity of the tofacitinib diastereoisomer impurities prepared by the method is higher than 95%, and the tofacitinib citrate diastereoisomer impurities can be used as a high-purity impurity reference substance for researching the tofacitinib diastereoisomer impurities.
The technical problem to be solved by the invention is realized by adopting the following technical scheme:
a synthetic method of tofacitinib citrate diastereoisomer impurities comprises the steps of obtaining an intermediate I through a condensation reaction of 3-amino-4-methylpyridine and benzyl bromide, obtaining an intermediate II through a reduction reaction of the intermediate I and sodium borohydride, obtaining an intermediate III through a methylation reaction of the intermediate II and paraformaldehyde under the action of sodium methoxide and sodium borohydride, obtaining a hydrochloride of the intermediate III in ethanol, filtering to obtain a solid as an intermediate IV, adjusting the pH of the obtained mother liquor to 9-10 with alkali liquor, adding an organic solvent for extraction, performing reduced pressure concentration to obtain a crude product of the intermediate V, performing salt formation and purification on the crude product and diacid to obtain a pure product of the intermediate V, performing coupling reaction on the pure product and 2, 4-dichloro-7H pyrrole [2,3-D ] pyrimidine under the action of inorganic base to obtain an intermediate VI, performing a reduction reaction on the intermediate VI, a reducing agent and formic acid to obtain an intermediate VII, and carrying out condensation reaction on the intermediate VII and ethyl cyanoacetate under the action of organic alkali to obtain tofacitinib citrate diastereoisomer impurities.
The specific synthetic route is as follows:
the inorganic base is at least one of potassium carbonate, sodium hydroxide and sodium carbonate, and the reaction solvent of the coupling reaction in which the inorganic base participates is at least one of methanol, ethanol and water. Preferably, the inorganic base is potassium carbonate and the reaction solvent is water.
The reducing agent is at least one of palladium carbon, palladium hydroxide carbon and Raney nickel, and the reaction solvent of the reducing agent participating in the reduction reaction is at least one of methanol, ethanol and water. Preferably, the reducing agent is palladium hydroxide carbon and the reaction solvent is water.
The organic base is at least one of DBU, triethylamine and diisopropylethylamine, and the reaction solvent of the condensation reaction in which the organic base participates is at least one of n-butanol, ethanol and tetrahydrofuran. Preferably, the organic base is DBU and the reaction solvent is ethanol.
The organic solvent for extraction is one of dichloromethane, ethyl acetate, n-hexane, methyl tert-butyl ether and diethyl ether. Preferably, the solvent is dichloromethane or n-hexane.
The selected diacid is one of malonic acid, fumaric acid, maleic acid and tartaric acid. Preferably, the diacid is fumaric acid.
The molar ratio of the 3-amino-4-methylpyridine to the benzyl bromide is 1 (1-2).
The molar ratio of the intermediate I to the sodium borohydride is 1 (2-5).
The molar ratio of the intermediate II to the paraformaldehyde to the sodium methoxide to the sodium borohydride is 1 (1-2) to 1 (2).
The molar ratio of the crude product of the intermediate V to the diacid is 1:1.
The molar ratio of the pure product of the intermediate V, the 2, 4-dichloro-7H pyrrole [2,3-D ] pyrimidine and the inorganic base is 1 (1-1.5) to 6-8.
The dosage of the reducing agent is 10-30% of the intermediate VI by mass, and the molar ratio of the intermediate VI to the formic acid is 1 (2-6).
The molar ratio of the intermediate VII, ethyl cyanoacetate and organic base is 1 (1-2) to 1-2.
The invention has the beneficial effects that: the method takes 3-amino-4-methylpyridine as an initial raw material, and prepares the tofacitinib diastereoisomer impurity through quaternary ammonium salt, reduction, methylation, salification, coupling, reduction and condensation reaction, the raw materials of the whole synthesis route are easy to obtain, the reaction conditions are mild, the separation and purification operation of post-treatment is simple and easy, the repeatability of the preparation method is good, and the tofacitinib diastereoisomer impurity with high yield and high purity can be prepared, so that the method is suitable for being used as an impurity reference substance of tofacitinib citrate.
Description of the drawings:
FIG. 1 is an HPLC plot of tofacitinib;
FIG. 2 is an HPLC plot of diastereomeric impurities;
FIG. 3 is an HPLC comparison of tofacitinib with diastereomeric impurities;
FIG. 4 is a hydrogen spectrum of a diastereomer;
FIG. 5 is a hydrogen spectrum of tofacitinib;
FIG. 6 is a MS spectrum of a diastereomer;
figure 7 is an HPLC profile of intermediate V.
The specific implementation mode is as follows:
in order to make the technical means, the original characteristics, the achieved purposes and the effects of the invention easy to understand, the invention is further explained by combining the specific embodiments and the drawings.
The concentration of organic solvent and water of 1g/X mL in the following examples refers to the mass-to-volume ratio relative to the substrate (intermediate I-intermediate VII).
Example 1
Preparation of 3-amino-1-benzyl-4-methylpyridinium salt (intermediate I):
benzyl bromide is dropwise added into a dichloromethane solution of 3-amino-4-methylpyridine with the concentration of 1g/10mL at the temperature of 20-25 ℃, after the dropwise addition is finished, the mixture is stirred for 12 hours at room temperature and filtered to obtain an intermediate I with the yield of 95%. Wherein the mol ratio of the 3-amino-4-methylpyridine to the benzyl bromide is 1: 1.02.
Preparation of 1-benzyl-4-methyl-3-amino-piperidine (intermediate II):
adding an ethanol solution of the intermediate I with the concentration of 1g/10mL into a three-necked bottle, cooling to 0-5 ℃, dropwise adding an aqueous solution of sodium borohydride, heating to 55-60 ℃ after adding, reacting for 2 hours, performing TLC (thin layer chromatography) controlled reaction, cooling to 0-5 ℃, quenching the reaction by using a 10% ammonium chloride aqueous solution, extracting for 3 times by using 1g/10mL of DCM, and concentrating to obtain an intermediate II with the yield of 90%. Wherein the molar ratio of the intermediate I to the sodium borohydride is 1: 2.
Preparation of (1-benzyl-4-methyl-3-piperidinyl) -methylamine (intermediate III):
adding 1g/10mL of methanol solution of the intermediate II into a three-necked bottle, adding paraformaldehyde, dropwise adding 5M sodium methoxide solution, stirring at room temperature for 8 hours after the addition is finished, adding sodium borohydride in batches, stirring for 4 hours after the addition is finished, quenching reaction by 10% ammonium chloride aqueous solution, concentrating, extracting for 3 times by using 1g/10mL of DCM, and concentrating to obtain the intermediate III with the yield of 85%. Wherein the molar ratio of the intermediate II, paraformaldehyde, sodium methoxide solution and sodium borohydride is 1:2:1.5: 1.
Preparation of (trans-1-benzyl-4-methyl-3-piperidinyl) -methylamine (intermediate V):
adding 1g/3mL of ethanol solution of (1-benzyl-4-methyl-3-piperidyl) -methylamine (intermediate III) into a three-necked bottle, dropwise adding concentrated hydrochloric acid, stirring for 1h after dropwise adding, filtering, adjusting the pH of the filtrate to 9-10 by using 2N sodium hydroxide solution, extracting three times by using 1g/10mL of N-hexane, and concentrating to obtain a trans isomer crude product (SR, RS type). Wherein the molar ratio of the intermediate III to the hydrochloric acid is 1: 2.
Adding 1g/5mL of ethyl acetate into the trans isomer crude product for dissolving, dissolving fumaric acid in ethanol, dropwise adding the ethanol into the system, slowly separating out a solid along with stirring, filtering, adjusting the pH of the obtained solid to 9-10 by using a 2N NaOH solution, extracting the obtained solid for three times by using 1g/10mL of N-hexane, and concentrating to obtain a pure trans isomer (SR, RS type) with the yield of 80%. Wherein the molar ratio of the fumaric acid to the trans isomer crude product is 1:1.
Preparation of N- (trans-1-benzyl-4-methylpiperidin-3-yl) -2-chloro-N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine (intermediate VI):
adding the intermediate V, potassium carbonate and 1g/10mL of water into a three-necked bottle, adding 2, 4-dichloro-7H pyrrole [2,3-D ] pyrimidine under mechanical stirring, heating to reflux and stirring for 18H, cooling to 20-25 ℃, filtering, adding 1g/5mL of acetone solution into a filter cake, heating to reflux and pulping for 1H, cooling to room temperature, filtering and drying to obtain an intermediate VI, wherein the yield is 92%. Wherein the molar ratio of the intermediate V, potassium carbonate and 2, 4-dichloro-7H pyrrolo [2,3-D ] pyrimidine is 1:6: 1.
Preparation of N-methyl-N- ((trans-4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (intermediate VII):
adding the intermediate VI into a three-necked flask, adding 1g/8mL of water, adding formic acid, stirring until the system is clear, adding palladium hydroxide carbon, heating to 50-55 ℃, reacting for 2h, performing TLC (thin layer chromatography) control, filtering after the reaction is finished, adjusting the pH of the filtrate to 9-10 by using 2N sodium hydroxide solution, adding 1g/10mL of DCM solution, extracting for 3 times, combining organic phases, and concentrating to obtain an intermediate VII with the yield of 92%. Wherein the molar ratio of the intermediate VI to the formic acid is 1:2, and the dosage of the palladium hydroxide carbon is 10 percent of the mass of the intermediate VI.
Preparation of 3- (trans-4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanenitrile:
adding the intermediate VII into a three-necked bottle, adding 1g/5mL of ethanol solution, adding ethyl cyanoacetate and DBU, heating to 40-45 ℃ under the protection of nitrogen, stirring for 12 hours, separating out more solids from the system, filtering, and drying a filter cake to obtain diastereoisomeric impurities with the yield of 84%.
Wherein the molar ratio of the intermediate VII, ethyl cyanoacetate and DBU is 1:1.5: 1.2.
Example 2
Preparation of 3-amino-1-benzyl-4-methylpyridinium salt (intermediate I):
benzyl bromide is dropwise added into a dichloromethane solution of 3-amino-4-methylpyridine with the concentration of 1g/10mL at the temperature of 20-25 ℃, after the dropwise addition is finished, the mixture is stirred for 12 hours at room temperature, filtered and filtered to obtain an intermediate I with the yield of 93 percent. Wherein the mol ratio of the 3-amino-4-methylpyridine to the benzyl bromide is 1: 1.2.
Preparation of 1-benzyl-4-methyl-3-amino-piperidine (intermediate II):
adding an ethanol solution of the intermediate I with the concentration of 1g/10mL into a three-necked bottle, cooling to 0-5 ℃, dropwise adding an aqueous solution of sodium borohydride, heating to 55-60 ℃ after adding, reacting for 2h, performing TLC (thin layer chromatography) controlled reaction, cooling to 0-5 ℃, quenching by 300mL of a 10% ammonium chloride aqueous solution, extracting for 3 times by using 1g/10mL of DCM, and concentrating to obtain an intermediate II with the yield of 88%. Wherein the molar ratio of the intermediate I to the sodium borohydride is 1: 4.
Preparation of (1-benzyl-4-methyl-3-piperidinyl) -methylamine (intermediate III):
adding a methanol solution of the intermediate II with the concentration of 1g/10mL into a three-necked bottle, adding paraformaldehyde, dropwise adding a 5M sodium methoxide solution, stirring at room temperature for 8 hours after the addition is finished, adding sodium borohydride in batches, stirring for 4 hours after the addition is finished, quenching the reaction by using a 10% ammonium chloride aqueous solution, concentrating, extracting for 3 times by using 1g/10mL of DCM, and concentrating to obtain an intermediate III with the yield of 87%. Wherein the molar ratio of the intermediate II, paraformaldehyde, sodium methoxide solution and sodium borohydride is 1:1.5:1.2: 1.
Preparation of (trans-1-benzyl-4-methyl-3-piperidinyl) -methylamine (intermediate V):
adding 1g/3mL ethanol solution of intermediate III into a three-necked bottle, dropwise adding concentrated hydrochloric acid, stirring for 1h after dropwise adding, filtering, adjusting pH of the filtrate to 9-10 with 2N sodium hydroxide solution, extracting with 1g/10mL diethyl ether, and concentrating to obtain trans isomer (SR, RS type). Wherein the molar ratio of the intermediate III to the hydrochloric acid is 1: 2.
Adding 1g/5mL of ethyl acetate into the trans isomer crude product for dissolving, dissolving the used fumaric acid in ethanol, dropwise adding the fumaric acid into the system, slowly separating out a solid along with stirring, filtering, adjusting the pH of the obtained solid to 9-10 by using a 2N NaOH solution, extracting the solid by using 1g/10mL of N-hexane for three times, and concentrating to obtain a pure trans isomer (SR, RS type) with the yield of 85%. Wherein the molar ratio of the fumaric acid to the trans isomer crude product is 1:1.
Preparation of N- ((3S, 4S) -1-benzyl-4-methylpiperidin-3-yl) -2-chloro-N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine (intermediate VI):
adding the intermediate V, potassium carbonate and 1g/10mL of water into a three-necked bottle, adding 2, 4-dichloro-7H pyrrole [2,3-D ] pyrimidine under mechanical stirring, heating to reflux and stirring for 18H, cooling to 20-25 ℃, filtering, adding 1g/5mL of acetone solution into a filter cake, heating to reflux and pulping for 1H, cooling to room temperature, filtering and drying to obtain an intermediate VI with the yield of 94%. Wherein the molar ratio of the intermediate V, potassium carbonate and 2, 4-dichloro-7H pyrrolo [2,3-D ] pyrimidine is 1:8: 1.5.
Preparation of N-methyl-N- ((trans-4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (intermediate VII):
adding the intermediate VI into a three-necked flask, adding 1g/8mL of water, adding formic acid, stirring until the system is clear, adding palladium hydroxide carbon, heating to 50-55 ℃, reacting for 2h, performing TLC (thin layer chromatography) control, filtering after the reaction is finished, adjusting the pH of the filtrate to 9-10 by using 2N sodium hydroxide solution, adding 1g/10mL of DCM solution, extracting for 3 times, combining organic phases, and concentrating to obtain an intermediate VII with the yield of 95%. Wherein the molar ratio of the intermediate VI to the formic acid is 1:4, and the dosage of the palladium hydroxide carbon is 15 percent of the mass of the intermediate VI.
Preparation of 3- (trans-4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanenitrile:
adding the intermediate VII into a three-necked bottle, adding 1g/5mL of ethanol solution, adding ethyl cyanoacetate and DBU, heating to 40-45 ℃ under the protection of nitrogen, stirring for 12 hours, separating out more solids from the system, filtering, and drying a filter cake to obtain diastereoisomeric impurities with the yield of 86%. Wherein the molar ratio of the intermediate VII, ethyl cyanoacetate and DBU is 1:2: 2.
The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (10)
1. A method for synthesizing tofacitinib citrate diastereoisomer impurities is characterized by comprising the following steps: condensing 3-amino-4-methylpyridine and benzyl bromide to obtain an intermediate I, carrying out reduction reaction on the intermediate I and sodium borohydride to obtain an intermediate II, carrying out methylation reaction on the intermediate II and paraformaldehyde under the action of sodium methoxide and sodium borohydride to obtain an intermediate III, preparing the intermediate III into hydrochloride in ethanol, filtering to obtain a solid as an intermediate IV, adjusting the pH of a mother solution to 9-10 by using alkali liquor, adding an organic solvent for extraction, carrying out reduced pressure concentration to obtain a crude product of the intermediate V, carrying out salification and purification on the crude product and diacid to obtain a pure product of the intermediate V, carrying out coupling reaction on the pure product and 2, 4-dichloro-7H pyrrole [2,3-D ] pyrimidine under the action of inorganic alkali to obtain an intermediate VI, and carrying out coupling reaction on the intermediate VI and a reducing agent, reducing formic acid to obtain an intermediate VII, and carrying out condensation reaction on the intermediate VII and ethyl cyanoacetate under the action of organic alkali to obtain tofacitinib citrate diastereoisomer impurities;
the specific synthetic route is as follows:
2. the method of synthesizing tofacitinib citrate diastereomer impurity of claim 1, wherein: the inorganic base is at least one of potassium carbonate, sodium hydroxide and sodium carbonate, and the reaction solvent of the coupling reaction in which the inorganic base participates is at least one of methanol, ethanol and water.
3. The method of synthesizing tofacitinib citrate diastereomer impurity of claim 1, wherein: the reducing agent is at least one of palladium carbon, palladium hydroxide carbon and Raney nickel, and the reaction solvent of the reducing agent participating in the reduction reaction is at least one of methanol, ethanol and water.
4. The method of synthesizing tofacitinib citrate diastereomer impurity of claim 1, wherein: the organic base is at least one of DBU, triethylamine and diisopropylethylamine, and the reaction solvent of the condensation reaction in which the organic base participates is at least one of n-butanol, ethanol and tetrahydrofuran.
5. The method of synthesizing tofacitinib citrate diastereomer impurity of claim 1, wherein: the organic solvent for extraction is one of dichloromethane, ethyl acetate, n-hexane, methyl tert-butyl ether and diethyl ether.
6. The method of synthesizing tofacitinib citrate diastereomer impurity of claim 1, wherein: the selected diacid is one of malonic acid, fumaric acid, maleic acid and tartaric acid.
7. The method of synthesizing tofacitinib citrate diastereomer impurity of claim 1, wherein: the molar ratio of the 3-amino-4-methylpyridine to the benzyl bromide is 1 (1-2); the molar ratio of the intermediate I to the sodium borohydride is 1 (2-5).
8. The method of synthesizing tofacitinib citrate diastereomer impurity of claim 1, wherein: the molar ratio of the intermediate II to the paraformaldehyde to the sodium methoxide to the sodium borohydride is 1 (1-2) to 1 (2).
9. The method of synthesizing tofacitinib citrate diastereomer impurity of claim 1, wherein: the molar ratio of the crude product of the intermediate V to the diacid is 1: 1; the molar ratio of the pure product of the intermediate V, the 2, 4-dichloro-7H pyrrole [2,3-D ] pyrimidine and the inorganic base is 1 (1-1.5) to 6-8.
10. The method of synthesizing tofacitinib citrate diastereomer impurity of claim 1, wherein: the dosage of the reducing agent is 10-30% of the mass of the intermediate VI, and the molar ratio of the intermediate VI to the formic acid is 1 (2-6); the molar ratio of the intermediate VII, ethyl cyanoacetate and organic base is 1 (1-2) to 1-2.
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