CN108948022B - Synthesis method of tofacitinib - Google Patents
Synthesis method of tofacitinib Download PDFInfo
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- CN108948022B CN108948022B CN201810936532.4A CN201810936532A CN108948022B CN 108948022 B CN108948022 B CN 108948022B CN 201810936532 A CN201810936532 A CN 201810936532A CN 108948022 B CN108948022 B CN 108948022B
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Abstract
The invention discloses a synthetic method of tofacitinib. The method comprises the steps of reacting a compound II with methylamine to prepare a compound III, carrying out reduction reaction and acylation reaction on the compound III to prepare a compound IV, carrying out asymmetric hydrogenation reaction on the compound IV to prepare a compound V, and carrying out elimination reaction, substitution and asymmetric hydrogenation reaction on the compound V to prepare the final product of tofacitinib (I). The preparation method has the advantages of easily available starting materials, simple process route, high total yield and purity and few byproducts, and is suitable for industrial production.
Description
Technical Field
The invention relates to the field of synthesis of medicaments, in particular to a method for synthesizing tofacitinib.
Background
Tofacitinib is a novel Janus kinase inhibitor developed by the company picrorhiza, usa 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 has good treatment effect on various inflammation-related diseases such as rheumatoid arthritis, ulcerative colitis, psoriasis and the like.
Tofacitinib, having the chemical name 3- [ (3R,4R) -4-methyl-3- [ methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] piperidin-1-yl ] -3-oxopropanenitrile, has the chemical structure shown in 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 initial raw materials of the route are expensive, the final product is subjected to resolution and purification, and isomer impurities are difficult to controlThe preparation cost is high, the reaction time of the route is long, the total yield of the product is low, and the method is not suitable 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 synthetic method of tofacitinib, 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 synthetic route of the invention is as follows:
a synthetic method of tofacitinib is characterized by comprising the following steps:
a. refluxing the compound II and methylamine in an organic solvent to prepare a compound III;
b. carrying out reduction reaction on the compound III, and carrying out cyano-acetyl chloride substitution reaction to prepare a compound IV;
c. carrying out hydrogenation reaction on the compound IV under the conditions of alkali, a metal catalyst, a ligand and potassium bromide to obtain a compound V;
d. carrying out elimination reaction on the compound V under p-toluenesulfonic acid, and then reacting the compound V with a compound VI to prepare a compound VII;
e. the compound VII is subjected to asymmetric hydrogenation reaction under the condition of a catalyst to prepare a final product tofacitinib (I);
wherein the organic solvent used in the step a is toluene or dichloromethane, and the molar ratio of the compound II to methylamine is 1: 1-1.1.
The catalytic system used in the reduction reaction in the step b is LiAIH4-AlCl3Compound III, LiAIH4、AlCl3The molar ratio is 1:2-3: 1; the temperature of the reduction reaction is 20-25 ℃.
The organic solvent used in the step c is any one or a mixture of more than two of isopropanol, tert-butyl alcohol, tetrahydrofuran, dichloromethane, 1, 4-dioxane, ethyl acetate, benzene and toluene; the used alkali is sodium ethoxide, potassium tert-butoxide, triethylamine, N-diisopropylethylamine, sodium hydroxide or sodium carbonate; the metal catalyst is [ Rh (COD) ]2]BF4The ligand is 1,1' -bis(diphenylphosphino) ferrocene; the molar ratio of the metal catalyst, the ligand and the compound IV is 0.001-0.002:0.001-0.002: 1; the hydrogen pressure used is from 10 to 100bar, preferably 30 bar.
The elimination reaction temperature of the step d is 90-100 ℃, and the molar ratio of the compound V to the p-toluenesulfonic acid is 1: 0.2-0.3.
The catalyst in the step e is (R) -2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl ] ruthenium dichloride (II), and the molar ratio of the compound VII to the catalyst is 1: 0.001-0.005; the reaction solvent is tetrahydrofuran, dichloromethane, N, N-dimethylformamide or toluene; the pressure of the hydrogen used is 50-100 psi.
The invention relates to a synthetic method of tofacitinib, 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 method has the advantages of easily obtained starting materials, simple process route, simple and convenient operation, high total yield and purity and few byproducts, and 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.
Example 1
Preparation of Compound III
15.72g (0.1mol) of the compound II, 300ml of toluene and 3.11g (0.1mol) of methylamine are respectively added into a three-neck flask, the mixture is stirred and heated to reflux, the reaction is controlled for 1.5h, the TLC monitors and tracks the reaction progress, and when the raw materials are completely reacted, the heating is stopped. The solvent was removed under reduced pressure to give 16.01g of Compound III, 94% yield and 99.96% HPLC purity.
Example 2
Preparation of Compound III
15.72g (0.1mol) of the compound II, 300ml of dichloromethane and 3.11g (0.1mol) of methylamine are respectively added into a three-neck flask, the mixture is stirred and heated to reflux, the reaction is controlled for 1.5h, the TLC monitors and tracks the reaction progress, and when the raw materials are completely reacted, the heating is stopped. The solvent was removed under reduced pressure to give 15.33g of compound III in 90% yield and 99.91% HPLC purity.
Example 3
Preparation of Compound III
15.72g (0.1mol) of the compound II, 300ml of dichloromethane and 3.42g (0.11mol) of methylamine are respectively added into a three-neck flask, the mixture is stirred and heated to reflux, the reaction is controlled for 1.5h, the TLC monitors and tracks the reaction progress, and when the raw materials are completely reacted, the heating is stopped. The solvent was removed under reduced pressure to give 16.34g of Compound III, product yield 96%, HPLC purity 99.98%.
Example 4
Preparation of Compound IV
Mixing LiAIH410.70g (0.282mol) of 20ml of anhydrous ether are added to a reaction flask and AlCl is added portionwise at room temperature312.53g (0.094mol), stirring for 15min, slowly adding 16.01g (0.094mol) of compound III in 20ml of anhydrous ether solution dropwise, stirring at 20-30 deg.C for 30min, adding 2% ammonium carbonate solution in 20ml, filtering, washing the solid with ether, separating ether layer, extracting water layer with ether for three times, combining ether layers, drying with anhydrous sodium sulfate, and evaporating to remove ether to obtain oily liquid.
To the oily liquid was added 250ml of a 10:1 dichloromethane/pyridine solution, 9.73g (0.094mol) of cyanoacetyl chloride was added, the reaction was stirred at 20 to 30 ℃ for 10 hours, and after the reaction was completed, the mixture was washed with a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to dryness to obtain 17.32g of compound IV (molecular weight: 209.24), a product yield of 88%, and HPLC 99.92%.
Example 5
Preparation of Compound IV
Mixing LiAIH46.83g (0.18mol) of 20ml of anhydrous ether are added to a reaction flask and AlCl is added in portions at room temperature312.0g (0.09mol), stirring for 15min, slowly adding 15.33g (0.09mol) of compound III in 20ml of anhydrous ether solution dropwise, stirring at 20-30 ℃ for 30min after adding, adding 20ml of 2% ammonium carbonate aqueous solution, filtering, washing the solid with ether, separating an ether layer, extracting a water layer with ether for three times, combining the ether layers, drying with anhydrous sodium sulfate, and evaporating to remove the ether to obtain an oily liquid.
To the oily liquid, 250ml of a 10:1 dichloromethane/pyridine solution was added 9.32g (0.09mol) of cyanoacetyl chloride, the mixture was stirred at 20 to 30 ℃ for 10 hours, and after the reaction, the mixture was washed with a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to dryness to obtain 17.33g of a compound IV, which was obtained in 92% yield by HPLC, 99.95%.
Example 6
Preparation of Compound IV
Mixing LiAIH410.93g (0.288mol) of 20ml of anhydrous ether are added to a reaction flask and AlCl is added in portions at room temperature36.40g (0.048mol), stirring for 15min, slowly adding 16.34g (0.096mol) of compound III in 20ml of anhydrous ether solution dropwise, stirring at 20-30 deg.C for 30min after adding, adding 2% ammonium carbonate aqueous solution 20ml, filtering, washing the solid with ether, separating ether layer, extracting water layer with ether three times, combining ether layers, drying with anhydrous sodium sulfate, and evaporating to remove ether to obtain oily liquid.
To the oily liquid, 250ml of a 10:1 dichloromethane/pyridine solution was added 9.94g (0.096mol) of cyanoacetyl chloride, the reaction was stirred at 20-30 ℃ for 10 hours, and after the reaction was completed, the mixture was washed with a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to dryness to obtain 15.69g of a compound IV, which was produced in 78% yield by HPLC, 99.83%.
Example 7
Preparation of Compound V
Under the protection of nitrogen, 17.32g (0.083mol) of compound IV is added into a reaction bottle, 200ml of isopropanol is added for dissolution, and [ Rh (COD) ]is added2]BF4(0.083mmol), ligand 1,1' -bis (diphenylphosphino) ferrocene (0.083mmol), potassium bromide (0.083mmol), 0.083mol of potassium tert-butoxide added, 30bar of hydrogen gas passed through and stirred at 40 ℃ for 12 h. Suction filtration and rotary evaporation to remove the solvent gave 17.54g of Compound V as an off-white solid powder. The product yield is 95%, the HPLC purity is 99.96% and the ee value is 95%.
Example 8
Preparation of Compound V
Adding a compound IV into a reaction bottle under the protection of nitrogen17.33g (0.082mol), adding 200ml 1, 4-dioxane to dissolve, adding [ Rh (COD)2]BF4(0.164mmol), ligand 1,1' -bis (diphenylphosphino) ferrocene (0.082mmol), potassium bromide (0.082mmol), 0.082mol sodium ethoxide, 100bar hydrogen gas introduction, stirring at 40 deg.C for 12 h. Suction filtration and rotary evaporation to remove the solvent gave compound V16.42 g as an off-white solid powder. The product yield is 89%, the HPLC purity is 99.91% and the ee value is 94%.
Example 9
Preparation of Compound V
15.69g (0.075mol) of compound IV are introduced into a reaction flask under nitrogen protection, 200ml of tetrahydrofuran are added for dissolution, and [ Rh (COD) ]is added2]BF4(0.075mmol), ligand 1,1' -bis (diphenylphosphino) ferrocene (0.075mmol), potassium bromide (0.075mmol), 0.075mol of sodium hydroxide, 10bar of hydrogen and stirring at 40 ℃ for 12 h. Suction filtration and rotary evaporation to remove the solvent gave 15.35g of compound V as an off-white solid powder. The product yield is 92%, the HPLC purity is 99.93%, and the ee value is 95%.
Example 10
Preparation of Compound V
Under the protection of nitrogen, 17.32g (0.082mol) of compound IV is added into a reaction bottle, 200ml of ethanol is added for dissolution, and [ Rh (COD) ]is added2]BF4(0.164mmol), ligand 1,1' -bis (diphenylphosphino) ferrocene (0.164mmol), potassium bromide (0.082mmol), 0.082mol of sodium ethoxide, 100bar of hydrogen gas and stirring at 40 deg.C for 12 h. Suction filtration and rotary evaporation to remove the solvent gave 13.90g of compound V as an off-white solid powder. The product yield is 72%, the HPLC purity is 99.68%, and the ee value is 90%.
Example 11
Preparation of Compound VII
Adding 17.54g (0.079mol) of the compound V into a reaction bottle, adding 120ml of dried toluene, stirring and dissolving, adding (0.016mol) of p-toluenesulfonic acid, stirring and reacting at 90 ℃ for 2h, cooling, adding 120ml of saturated sodium bicarbonate solution, separating an organic layer, washing with 120ml of water, concentrating under reduced pressure, and performing column chromatography separation (developing agent: V)Ethyl acetate：VN-hexane1:3) to obtain solid.
200ml of DMF was added to the solid, 12.12g of the compound VI (0.079mol, molecular weight: 153.37) and potassium carbonate (0.079mol) were added thereto, the reaction flask was stirred at 90 ℃ for 9 hours, after the reaction was completed, the mixture was cooled to room temperature, and then filtered to obtain 21.84g of the compound VII with a product yield of 89% and an HPLC purity of 99.90%.
Example 12
Preparation of Compound VII
Adding 16.42g (0.073mol) of the compound V into a reaction bottle, adding 120ml of dry toluene, stirring and dissolving, adding (0.022mol) p-toluenesulfonic acid, stirring and reacting at 100 ℃ for 2h, cooling, adding 120ml of saturated sodium bicarbonate solution, separating an organic layer, washing with 120ml of water, concentrating under reduced pressure, and performing column chromatography separation (developing agent: V)Ethyl acetate：VN-hexane1:3) to obtain solid.
Adding 200ml of DMF into the solid, adding compound VI 11.19(0.073mol) and potassium carbonate (0.073mol), controlling the temperature of a reaction bottle at 90 ℃, stirring and reacting for 9h, cooling to room temperature after the reaction is finished, and filtering to obtain 20.63g of compound VII, wherein the product yield is 91%, and the HPLC purity is 99.93%.
Example 13
Preparation of Compound VII
Adding 15.35g (0.069mol) of the compound V into a reaction bottle, adding 120ml of dried tetrahydrofuran, stirring and dissolving, adding (0.014mol) of p-toluenesulfonic acid, stirring and reacting at 80 ℃ for 2h, cooling, adding 120ml of saturated sodium bicarbonate solution, separating an organic layer, washing with 120ml of water, concentrating under reduced pressure, and performing column chromatography separation (developing agent: V)Ethyl acetate：VN-hexane1:3) to obtain solid.
Adding 200ml of DMF into the solid, adding 10.58g (0.069mol) of the compound VI and 0.069mol of potassium carbonate, controlling the temperature of a reaction bottle at 90 ℃, stirring for reaction for 9 hours, cooling to room temperature after the reaction is finished, and filtering to obtain 16.76g of a compound VII, wherein the yield of the product is 78 percent, and the HPLC purity is 99.65 percent.
Example 14
Preparation of tofacitinib (I)
Under the protection of nitrogen, adding [ (R) -2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl ] into a reaction bottle in turn (0.35mmol)]Ruthenium (II) dichloride and 150mL of toluene are stirred at room temperature for 20min, then 21.84g (0.07mol) of the compound VII is added, the reaction bottle is placed into a stainless steel autoclave and replaced by hydrogen for three times, finally the required hydrogen pressure is flushed for 50psi, after the room temperature reaction for 12h, hydrogen is slowly released, 150mL of dichloromethane is used for diluting the reaction system, 150mL of saturated sodium carbonate solution is added, the stirring is carried out for 15min, an organic layer is separated, a dichloromethane (3X 150mL) is used for extracting an aqueous layer, the organic layers are combined and Na is used for Na2SO4Drying and removing the solvent to obtain 21.65g of tofacitinib (I), the yield is 96%, the HPLC purity is 99.95% and the ee value is 97%.
Example 15
Preparation of tofacitinib (I)
Under the protection of nitrogen, adding [ (R) -2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl ] into a reaction bottle in turn (0.33mmol)]Ruthenium (II) dichloride and 150mL dichloromethane are stirred for 20min at room temperature, 20.63g (0.066mol) of the compound VII are added, the reaction bottle is placed into a stainless steel autoclave and replaced by hydrogen for three times, finally, the required hydrogen pressure is flushed for 30psi, after the reaction for 12h at room temperature, hydrogen is slowly released, 150mL dichloromethane is used for diluting the reaction system, 150mL saturated sodium carbonate solution is added, the stirring is carried out for 15min, an organic layer is separated, a dichloromethane (3X 150mL) is used for extracting an aqueous layer, the organic layers are combined and Na is used for Na2SO4Drying and removing the solvent to obtain 17.83g of tofacitinib (I), the yield is 82%, the HPLC purity is 99.81%, and the ee value is 95%.
Example 16
Preparation of tofacitinib (I)
Under the protection of nitrogen, adding [ (R) -2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl ] into a reaction bottle in sequence (0.054mmol)]Ruthenium (II) dichloride and 150mL of N, N-dimethylformamide are stirred for 20min at room temperature, then 16.76g (0.054mol) of the compound VII is added, a reaction bottle is placed into a stainless steel autoclave and replaced by hydrogen for three times, finally the required hydrogen pressure of 100psi is filled, after 12h reaction at room temperature, hydrogen is slowly released, and 150mL of dichloromethane is usedDiluting the reaction system with alkane, adding 150mL saturated sodium carbonate solution, stirring for 15min, separating organic layer, extracting the aqueous layer with dichloromethane (3X 150mL), combining organic layers, and adding Na2SO4Drying and removing the solvent to obtain 17.06g of tofacitinib (I), the yield is 93%, the HPLC purity is 99.92% and the ee value is 92%.
Claims (11)
1. A synthetic method of tofacitinib is characterized by comprising the following steps:
a. refluxing the compound II and methylamine in an organic solvent to prepare a compound III;
b. carrying out reduction reaction on the compound III, and carrying out cyano-acetyl chloride substitution reaction to prepare a compound IV;
c. carrying out hydrogenation reaction on the compound IV under the conditions of alkali, a metal catalyst, a ligand and potassium bromide to obtain a compound V; the metal catalyst is [ Rh (COD) ]2]BF4The ligand is 1,1' -bis (diphenylphosphino) ferrocene;
d. carrying out elimination reaction on the compound V under p-toluenesulfonic acid, and then reacting the compound V with a compound VI to prepare a compound VII;
e. the compound VII is subjected to asymmetric hydrogenation reaction under the condition of a catalyst to prepare a final product tofacitinib (I); the catalyst is (R) -2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl ] ruthenium dichloride (II);
the synthetic route is as follows:
2. the process of claim 1 wherein the organic solvent in step a is toluene or dichloromethane and the molar ratio of compound ii to methylamine is 1:1 to 1.1.
3. The process of claim 1, wherein the catalyst system used in the reduction reaction in step b is LiAlH4-AlCl3(ii) a Compound III, LiAIH4、AlCl3The molar ratio is 1:2-3: 1; the temperature of the reduction reaction is 20-25 ℃.
4. The method according to claim 1, wherein the organic solvent used in step c is one or a mixture of two or more of isopropanol, t-butanol, tetrahydrofuran, dichloromethane, 1, 4-dioxane, ethyl acetate, benzene, and toluene.
5. The method of claim 1, wherein the base in step c is sodium ethoxide, potassium tert-butoxide, triethylamine, N-diisopropylethylamine, sodium hydroxide or sodium carbonate.
6. The process of claim 1 wherein the molar ratio of metal catalyst, ligand and compound IV in step c is from 0.001 to 0.002: 1.
7. The process according to claim 1, wherein the hydrogen used in the hydrogenation in step c is at a pressure of 10 to 100 bar.
8. The process according to claim 7, wherein the hydrogen used in the hydrogenation in step c is at a pressure of 30 bar.
9. The process of claim 1, wherein the elimination reaction temperature in step d is 90 to 100 ℃ and the molar ratio of compound V to p-toluenesulfonic acid is 1:0.2 to 0.3.
10. The process of claim 1, wherein the molar ratio of the compound VII to the catalyst in step e is from 1:0.001 to 0.005.
11. The process of claim 1 wherein the reaction solvent of step e is tetrahydrofuran, dichloromethane, N-dimethylformamide or toluene; the hydrogen pressure used for the hydrogenation reaction is 50-100 psi.
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| WO2014097150A1 (en) * | 2012-12-17 | 2014-06-26 | Ranbaxy Laboratories Limited | Process for the preparation of tofacitinib and intermediates thereof |
| EP2938616A4 (en) * | 2012-12-28 | 2016-06-15 | Glenmark Pharmaceuticals Ltd | The present invention relates to process for the preparation of tofacitinib and intermediates thereof. |
| CN105884781B (en) * | 2016-04-18 | 2018-04-20 | 山东罗欣药业集团股份有限公司 | Preparation method of tofacitinib citrate |
| CN106831538B (en) * | 2017-01-22 | 2019-06-25 | 苏州楚凯药业有限公司 | The preparation method of tropsch imatinib intermediate |
| CN108358930A (en) * | 2018-02-05 | 2018-08-03 | 南京法恩化学有限公司 | A kind of preparation method of citric acid tropsch imatinib |
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