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CN109053737A - Preparation method of tofacitinib citrate compound - Google Patents

Preparation method of tofacitinib citrate compound Download PDF

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Publication number
CN109053737A
CN109053737A CN201810935556.8A CN201810935556A CN109053737A CN 109053737 A CN109053737 A CN 109053737A CN 201810935556 A CN201810935556 A CN 201810935556A CN 109053737 A CN109053737 A CN 109053737A
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compound
reaction
carrying
preparation
tofacitinib citrate
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CN109053737B (en
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侯俊凯
杨玉发
刘飞飞
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Shandong Yuxin Pharmaceutical Co ltd
Shandong Luoxin Pharmaceutical Group Hengxin Pharmaceutical Co ltd
Shandong Luoxin Pharmaceutical Group Co Ltd
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Shandong Yuxin Pharmaceutical Co ltd
Shandong Luoxin Pharmaceutical Group Hengxin Pharmaceutical Co ltd
Shandong Luoxin Pharmaceutical Group Co Ltd
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    • 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
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a preparation method of tofacitinib citrate compound. The method comprises the steps of carrying out Grignard reaction and dehydration reaction on 3-bromo-4-piperidone (II) and methyl magnesium bromide to obtain a compound III, carrying out asymmetric hydrogenation on the compound III to obtain a compound IV, carrying out substitution and acylation reaction on the compound IV to obtain a compound VI, and carrying out deprotection and salt formation on the obtained compound VI to obtain the tofacitinib citrate (I). The reaction process has the advantages of simple route, easy operation, high total yield and purity, and suitability for industrial production.

Description

Preparation method of tofacitinib citrate compound
Technical Field
The invention relates to the field of synthesis of medicaments, in particular to a preparation method of a tofacitinib citrate compound.
Background
Tofacitinib citrate is a novel Janus kinase inhibitor developed by Perey, USA, and is sold under the trade name Xeljanz. The product can effectively inhibit the activity of JAK1 and JAK3 and block the signal transmission of various inflammatory cytokines. The existing research shows that tofacitinib citrate has good treatment effect on various inflammation-related diseases such as rheumatoid arthritis, ulcerative colitis, psoriasis and the like.
The chemical name of tofacitinib citrate is 3- [ (3R,4R) -4-methyl-3- [ methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] piperidin-1-yl ] -3-oxopropanenitrile citrate, and the tofacitinib citrate has a chemical structure shown in a formula I:
the current reports on the synthetic method of tofacitinib are as follows:
1. the original U.S. Pat. No. 6,6627754 and Chinese patent CN1409712 report the following routes:
the route uses 1-benzyl-4-methyl-piperidine-3-ketone as raw material, and through reductive amination of methylamino, substitution and palladium hydroxide/H2And (3) carrying out catalytic hydrogenation, debenzylation and acylation, and then splitting to obtain the tofacitinib. The method has the advantages of expensive starting raw materials, difficult control of isomer impurities and high cost because the final product is subjected to resolution and purification, long reaction time, low total product yield and unsuitability for industrial production.
2. The patent WO2007012953, originally filed in 2006, discloses a synthetic route of the patent as follows:
the method uses 3-amido-4-methylpyridine as a raw material, firstly esterifies and protects amido, rhodium catalyzes and reduces a pyridine ring, performs reductive amination and benzyl protection, reduces lithium aluminum hydride, then uses di-p-toluoyl tartaric acid to split an enantiomer, aminolyzes the enantiomer with 4-chloro-pyrrolopyrimidine, and finally acidylates to obtain tofacitinib.
3. The synthetic route reported in patent CN201310537835.6 is as follows:
although the invention solves the problems of high price of raw materials, resolution and purification of final products, long synthesis route, high cost and the like, the reaction needs toxic boron trifluoride diethyl etherate and still has the problem of total yield of products.
4. The synthetic route disclosed in patent CN201610181030.6 is as follows:
although the reaction route is shortened, the method is beneficial to controlling the impurity quality, the solvent can be recycled, and the pollution is small; however, the reaction raw materials, namely, the 2, 4-dichloro-7H pyrrole [2,3-D ] and the (3R,4R) -N, 4-dimethyl-1- (phenylmethyl) -3-piperidine amine hydrochloride, are expensive, have competitive reaction, influence on the product yield, bring difficulty to the subsequent product separation, and are still not suitable for industrial production.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a novel preparation method of tofacitinib citrate compound, which has the advantages of easily obtained starting raw materials, simple process route, high total yield and purity and few byproducts and is suitable for industrial production.
The preparation route of the invention is as follows:
a preparation method of tofacitinib citrate compound is characterized by comprising the following steps:
a. 3-bromo-4-piperidone (II) reacts with methyl magnesium bromide, and then a dehydration reaction is carried out to obtain a compound III;
b. carrying out asymmetric hydrogenation reaction on the compound III under the condition of a catalyst to obtain a compound IV;
c. carrying out substitution reaction on the compound IV and a compound V under the conditions of a metal catalyst and a ligand, and carrying out acylation reaction on the compound IV and cyano acetyl chloride to obtain a compound VI;
d. and (3) deprotecting the compound VI, and salifying the deprotected compound VI with a citric acid aqueous solution to obtain tofacitinib citrate (I).
Wherein, the molar ratio of the 3-bromo-4-piperidone (II) to the methyl magnesium bromide in the step a is 1:1, the reaction solvent is diethyl ether, and the reaction time is 3-5 h; the reaction is carried out by dropwise adding 3-bromo-4-piperidone (II) into methyl magnesium bromide solution.
The catalyst used in the step b is [ (R) - (+) -2, 2-di (di-p-tolylphosphinyl) -1, 1-binaphthyl ] ruthenium diacetate (II), and the molar dosage of the catalyst is 0.001-0.003 times of that of the compound III; the reaction solvent is tetrahydrofuran, methanol, acetone, isopropanol or dichloromethane; the pressure of the hydrogen used is 2atm to 4 atm.
The catalyst used in step c is pbCl2The ligand 1,2,3,4, 5-pentaphenyl-1' - (di-tert-butylphosphine) ferrocene; compound IV, pbCl21,2,3,4, 5-pentaphenyl-1' - (di-tert-butylphosphine) ferrocene in a molar ratio of 1:0.001: 0.001-0.003; the used base is potassium tert-butoxide or sodium ethoxide, and the reaction solvent is 1, 4-dioxane or tetrahydrofuran.
The deprotection system used in step d consists of phenol and trifluoroacetic acid.
The invention relates to a preparation method of tofacitinib citrate compound, which has the following beneficial effects:
(1) the asymmetric catalysis technology is adopted to solve the problem of low yield of the split product in the prior art, and the total yield of the product is greatly improved.
(2) The reaction raw materials are easy to obtain, the synthesis route is short, the reaction conditions are mild, the total yield and purity are high, the byproducts are few, and the method is suitable for industrial production.
Detailed Description
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited thereto.
Preparation of Compound V
Adding 74.08g (0.5mol) of N-methyl-7H-pyrrolo [2,3-d ] pyrimidine-4-amine, 20g of sodium hydroxide and 1000mL of acetonitrile into a reaction bottle, stirring at room temperature for 30 ℃, then dropwise adding 95.35g (0.5mol) of p-methylsulfonyl chloride, heating to 50 ℃ for reaction after dropwise adding, and monitoring the reaction by TLC. After the reaction, the reaction mixture is cooled to room temperature, the solvent is removed by rotary evaporation, 1000mL of water and 1000mL of ethyl acetate are added, the mixture is stirred, the mixture is kept stand and separated, the water layer is extracted by 800mL of ethyl acetate, the organic phases are combined, dried by anhydrous sodium sulfate and dried under reduced pressure, and the compound V143.11 g is obtained, the yield is 94.5 percent, and the purity is 99.83 percent.
Example 1
Preparation of methyl magnesium bromide:
adding 0.5mol of polished magnesium chips and 400ml of anhydrous ether into a dry three-neck flask under the protection of nitrogen, starting stirring, slowly introducing 0.55mol of methyl bromide gas, controlling the temperature to be 30-50 ℃, reacting for 5 hours to generate a methyl magnesium bromide solution, and then cooling to room temperature. And storing the prepared methyl magnesium bromide solution in a closed reagent bottle for later use.
Example 2
Preparation of Compound III
Under the protection of nitrogen, adding 80ml of anhydrous ether into a reaction bottle, adding 0.1mol of the prepared methyl magnesium bromide solution at the temperature of 0 ℃, dropwise adding 17.8g (0.1mol) of 3-bromo-4-piperidone (II), after dropwise adding, heating and refluxing for 3h, cooling to 0 ℃, adding 10% ammonium chloride aqueous solution for hydrolysis, extracting with ethanol, washing an oil layer with sodium bicarbonate and deionized water respectively, drying with anhydrous magnesium sulfate, filtering, removing ether, adding 20% concentrated sulfuric acid into the obtained product, dehydrating at the temperature of 120 ℃ and 150 ℃, and recrystallizing with petroleum ether to obtain 15.51g of a compound III, wherein the product yield is 88% and the product purity is 99.86%.
Example 3
Preparation of Compound III
Under the protection of nitrogen, adding 80ml of anhydrous ether into a reaction bottle, adding 0.1mol of the prepared methyl magnesium bromide solution at the temperature of 0 ℃, dropwise adding 17.8g (0.1mol) of 3-bromo-4-piperidone (II), after dropwise adding, heating and refluxing for 5h, cooling to 0 ℃, adding 10% of ammonium chloride aqueous solution for hydrolysis, extracting with ethanol, washing an oil layer with sodium bicarbonate and deionized water respectively, drying with anhydrous magnesium sulfate, filtering, removing ether, adding 20% of concentrated sulfuric acid into the obtained product, dehydrating at the temperature of 120 ℃ and 150 ℃, and recrystallizing with petroleum ether to obtain 15.86g of a compound III, wherein the product yield is 90% and the product purity is 99.92%.
Example 4
Preparation of Compound IV
Under the protection of nitrogen, 15.51g (0.088mol) of the compound III is added into a reaction bottle, 200ml of tetrahydrofuran is added for dissolution, 0.088mmol of [ (R) - (+) -2, 2-di (di-p-tolylphosphono) -1, 1-binaphthyl ] ruthenium diacetate (II) is added, 0.088mol of potassium tert-butoxide is added, 4atm of hydrogen is introduced, and the mixture is stirred for 10 hours at the temperature of 35 ℃. Suction filtration and rotary evaporation are carried out to remove the solvent, thus obtaining 15.99g of the compound IV. The product yield was 99%, the HPLC purity was 99.95%, and the ee value was 97%.
Comparative example 4
The preparation method of example 4 is followed, the solvent is replaced, and the influence of different solvents on the molar yield, purity and ee value of the compound IV is examined, wherein the specific examination conditions are shown in the following table:
comparative example Kind of solvent Molar yield (%) Purity (%) ee(％)
1 Acetone (II) 88 98.32 87
2 Methylene dichloride 82 98.45 88
3 Benzene and its derivatives 78 97.86 65
4 Toluene 71 95.57 68
5 Chloroform 66 93.36 59
Example 5
Preparation of Compound IV
Under the protection of nitrogen, 15.86g (0.090mol) of the compound III is added into a reaction bottle, 200ml of isopropanol is added to dissolve the compound III, 0.270mmol of [ (R) - (+) -2, 2-di (di-p-tolylphosphono) -1, 1-binaphthyl ] ruthenium diacetate (II) is added, 0.090mol of potassium tert-butoxide is added, 2atm of hydrogen is introduced, and the mixture is stirred at 35 ℃ for 10 hours. Suction filtration and rotary evaporation are carried out to remove the solvent, thus obtaining 16.22g of compound IV. The product yield was 96%, the HPLC purity was 99.82%, and the ee value was 95%.
Example 6
Preparation of Compound VI
Under the protection of nitrogen, 15.99g (0.087mol) of the compound IV, 26.31g (0.087mol) of the compound V and pbCl are added into a reaction bottle in sequence2(0.087mmol), 1,2,3,4, 5-pentaphenyl-1' - (di-tert-butylphosphine) ferrocene (0.087mmol), potassium tert-butoxide 0.087mol, and 1, 4-dioxane (300 ml) were stirred at room temperature for 5 hours, and after the reaction was completed, the solvent was removed by rotation to obtain an oily liquid.
Adding 250ml of 10:1 dichloromethane/pyridine solution into the oily liquid, adding 9.01g (0.087mol) of cyanoacetyl chloride into the oily liquid, controlling the temperature to be 20-30 ℃, stirring and reacting for 10 hours, washing the oily liquid with saturated sodium bicarbonate solution after the reaction is finished, drying the oily liquid with anhydrous sodium sulfate, and concentrating the oily liquid in vacuum until the oily liquid is dried to obtain 35.35g of a compound VI, wherein the product yield is 87%, and the HPLC is 99.89%.
Example 7
Preparation of Compound VI
Under the protection of nitrogen, 16.22g (0.086mol) of compound IV, 26.11g (0.086mol) of compound V and pbCl are added into a reaction bottle in sequence2(0.086mmol), 1,2,3,4, 5-pentaphenyl-1' - (di-tert-butylphosphine) ferrocene (0.258mmol), 0.087mol of sodium ethoxide and 300ml of tetrahydrofuran, stirring at room temperature for reaction for 5 hours, and after the reaction is finished, rotating to remove the solvent to obtain oily liquid.
And adding 250ml of 10:1 dichloromethane/pyridine solution into the oily liquid, adding 8.90g (0.086mol) of cyanoacetyl chloride into the oily liquid, controlling the temperature to be 20-30 ℃, stirring and reacting for 10 hours, washing the oily liquid with saturated sodium bicarbonate solution after the reaction is finished, drying the oily liquid with anhydrous sodium sulfate, and concentrating the oily liquid in vacuum until the oily liquid is dried to obtain 34.15g of a compound VI, wherein the product yield is 85 percent, and the HPLC is 99.86 percent.
Example 8
Preparation of tofacitinib citrate (I)
Under the protection of nitrogen, 35.32g (0.0757mol) of the compound VI is added into a reaction bottle and suspended in 20ml of hydrobromic acid solution, then phenol (0.0833mol) and trifluoroacetic acid (0.0833mol) are added, the temperature is controlled to be 40-50 ℃, the stirring reaction is carried out for 2h, the TLC is used for monitoring the reaction completion, the temperature is reduced to room temperature, saturated sodium bicarbonate aqueous solution is added in batches to ensure that the pH is 7, the stirring is carried out for 1h, 1M citric acid aqueous solution 75.7ml is directly added without post-treatment, the stirring crystallization is carried out, the temperature is kept for 2h, the filtration is carried out, the temperature is reduced and the drying is carried out at 45 ℃, and 33.62g of tofacitinib (I) is prepared, the yield is.
Example 9
Preparation of tofacitinib citrate (I)
Under the protection of nitrogen, 34.10g (0.0731mol) of the compound VI is added into a reaction bottle and suspended in 20ml of hydrobromic acid solution, then phenol (0.0804mol) and trifluoroacetic acid (0.0804mol) are added, the temperature is controlled to be 40-50 ℃, the stirring reaction is carried out for 2h, the TLC monitors the reaction to be finished, the temperature is reduced to room temperature, saturated sodium bicarbonate aqueous solution is added in batches to ensure that the pH is 7, the stirring is carried out for 1h, 73.1ml of 1M citric acid aqueous solution is directly added without post-treatment, the stirring and crystallization are carried out, the temperature is kept for 2h, the filtration is carried out, and the reduced pressure drying is carried out at 45 ℃ to prepare 31.73g of tofacitinib (I), the yield is 86%, and.

Claims (10)

1. A preparation method of tofacitinib citrate compound is characterized by comprising the following steps:
a. 3-bromo-4-piperidone (II) reacts with methyl magnesium bromide, and then a dehydration reaction is carried out to obtain a compound III;
b. carrying out asymmetric hydrogenation reaction on the compound III under the condition of a catalyst to obtain a compound IV;
c. carrying out substitution reaction on the compound IV and a compound V under the conditions of a metal catalyst and a ligand, and carrying out acylation reaction on the compound IV and cyano acetyl chloride to obtain a compound VI;
d. deprotecting the compound VI, and salifying the deprotected compound VI with a citric acid aqueous solution to obtain tofacitinib citrate (I);
2. the process of claim 1, wherein the molar ratio of 3-bromo-4-piperidone (II) to methylmagnesium bromide in step a is 1:1, the reaction solvent is diethyl ether, and the reaction time is 3-5 h.
3. The method of claim 1, wherein the reaction of step a is carried out by adding 3-bromo-4-piperidone (II) dropwise to a methylmagnesium bromide solution.
4. The process of claim 1, wherein the catalyst in step b is [ (R) - (+) -2, 2-bis (di-p-tolylphosphono) -1, 1-binaphthyl ] ruthenium diacetate (II) in a molar amount of 0.001 to 0.003 times that of compound III.
5. The process of claim 1, wherein the solvent used in the reaction of step b is tetrahydrofuran, methanol, acetone, isopropanol or dichloromethane.
6. The method as claimed in claim 1, wherein the pressure of the hydrogen used in the step b is 2atm to 4 atm.
7. The process of claim 1 wherein the catalyst of step c is pbCl2The ligand is 1,2,3,4, 5-pentaphenyl-1' - (di-tert-butylphosphine) ferrocene.
8. The process of claim 1 wherein in step c, the compound IV is pbCl2And the mol ratio of the 1,2,3,4, 5-pentaphenyl-1' - (di-tert-butylphosphine) ferrocene is 1:0.001: 0.001-0.003.
9. The process of claim 1, wherein the base used in step c is potassium tert-butoxide or sodium ethoxide and the reaction solvent is 1, 4-dioxane or tetrahydrofuran.
10. The process according to claim 1, wherein the deprotection system used in step d consists of phenol and trifluoroacetic acid.
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WO2015051252A1 (en) * 2013-10-03 2015-04-09 Duke University Compositions and methods for treating cancer with jak2 activity
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CN106176640A (en) * 2014-11-28 2016-12-07 四川海思科制药有限公司 Pharmaceutical composition containing tofacitinib citrate and preparation method thereof
CN107011347A (en) * 2017-04-18 2017-08-04 华东师范大学 A kind of synthetic method of 4 chlorine 7H pyrrolo-es [2,3 d] pyrimidines

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WO2015051252A1 (en) * 2013-10-03 2015-04-09 Duke University Compositions and methods for treating cancer with jak2 activity
CN103819474A (en) * 2013-11-04 2014-05-28 湖南华腾制药有限公司 Preparation method of tofacitinib
CN106176640A (en) * 2014-11-28 2016-12-07 四川海思科制药有限公司 Pharmaceutical composition containing tofacitinib citrate and preparation method thereof
CN104530055A (en) * 2014-12-23 2015-04-22 南京艾德凯腾生物医药有限责任公司 Preparation method of tofacitinib citrate
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