CN102875555A - Synthetic method of JAK (janus kinase) inhibitor Tofacitinib - Google Patents

Abstract

The invention relates to a method for synthesizing JAK inhibitor Tofacitinib. This method uses N -methyl- N -[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-7-H-pyrrole[2,3-d]pyrimidine-4- Amine is used as a raw material, and methanol or ethanol is used as a solvent, and the benzyl group is removed by hydrogenation. After filtration, the next reaction is directly performed, and DBU is used as a catalyst to react with ethyl cyanoacetate to obtain Tofacitinib. Compared with the original method, the patented method has the advantages of mild conditions, simple operation and high yield, and is more suitable for industrial production.

Description

A kind of synthetic method of JAK inhibitor Tofacitinib

technical field

The invention belongs to the technical field of organic and pharmaceutical synthesis, and in particular relates to a synthesis method of a JAK inhibitor Tofacitinib.

Background technique

The chemical name of Tofacitinib is N -methyl- N -[(3R,4R)-1-cyanoacetyl-4-methylpiperidin-3-yl]-7-H-pyrrole[2,3-d]pyrimidine- 4-Amine, an oral anti-rheumatoid arthritis JAK inhibitor developed by Pfizer, has passed Phase III clinical trials and began FDA approval in May 2012. Tofacitinib is a first-generation oral drug for the treatment of rheumatoid arthritis, and it can also treat autoimmune diseases and organ transplant rejection. Rheumatoid arthritis is a chronic inflammatory autoimmune disease. At present, there are 1.6 million people in the United States suffering from this disease, while the number of patients in the world is as high as 23.7 million. Tofacitinib is one of the most promising new drugs of Pfizer.

The synthetic route of current drug Tofacitinib:

Ruggeri et al. reported the above-mentioned route for the first time. The debenzylation process used a mixed solvent of isopropanol/water=5:1, and the reaction time required about 24 hours. Post-processing is troublesome. The second step of ammonolysis uses triethylamine as a catalyst, which needs to be heated to 100°C for 24 hours, and the yield is only 65%. The conditions are relatively harsh, which is not conducive to industrial production. Therefore, the development of a new process for Tofacitinib has important application value.

references

1. Fan Ming. Anti-rheumatoid arthritis drug Tofacitinib [J]. Advances in Pharmacy, 2011, 35 (10): 480.

2. Jiang JK, Kamran G, Francesca D et al . Examining the chirality, conformation and selective kinase inhibition of 3-((3 R ,4 R )-4-methyl-3-(methyl(7H-pyrrolo[2,3 -d ]py

rimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (CP-690,550) [J]. J. Med. Chem. , 2008, 51 (24): 8012-8018.

3. Dolgin E. Companies hope for kinase inhibitor JAKpot [J]. Nature Review Drug Discovery, 2011, 10 (10): 717-718.

4. Ruggeri SG, Hawkins JM, Makowski TM et al . Pyrrolo[2,3-d] pyrimidine derivatives; their intermediates and synthesis: WO, 2007 012953[P]. 2007-02-01.

5. Mark EF, Todd AB, William HB et al . Discovery of CP-690,550: A potent and selective Janus Kinase (JAK) inhibitor for the treatment of autoimmune diseases and organ transplant rejection [J]. J. Med. Chem. , 2010, 53 (24): 8468-8484.

Contents of the invention

The object of the present invention is to provide a method for synthesizing JAK inhibitor Tofacitinib.

A kind of synthetic method of JAK inhibitor Tofacitinib proposed by the present invention, its synthetic route is as follows:

Specific steps are as follows:

(1) Add N -methyl- N -[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-7-H-pyrrole[2, 3-d to the reactor ] Pyrimidin-4-amine, 20%wt.Pd(OH) ₂ /C, acetic acid and solvent, then pass in hydrogen gas with a reaction pressure of 1.0-2.5atm and stir for 6-10h;

(2) The reactant obtained in step (1) was flushed three times with nitrogen, filtered, passed ammonia gas to a pH value of 8, then added ethyl cyanoacetate and alkali to the reactor, reacted for 6-10h, washed with water, and the column Separated and dried in vacuo to obtain the product.

Where: N -methyl- N -[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-7-H-pyrrole[2, 3-d]pyrimidin-4-amine , 20%wt.Pd(OH) ₂ /C, acetic acid, ethyl cyanoacetate and alkali in a molar ratio of 1:(0.5-1):1:(2-4):(0.2-0.4).

In the present invention, the solvent is one or two of methanol or ethanol, preferably ethanol.

In the present invention, described acid is acetic acid.

In the present invention, the reaction temperature in step (1) and step (2) is both 20-40°C.

In the present invention, the base is DBU.

The present invention uses N -methyl- N -[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-7-H-pyrrole[2, 3-d]pyrimidine-4- Use amine as the starting material, use methanol or ethanol as the solvent instead, after hydrogenation and debenzylation, filter and proceed directly to the next step. Under the catalysis of DBU, it reacts with ethyl cyanoacetate to obtain Tofacitinib. Compared with the existing methods, the method has the advantages of mild conditions, simple operation and high yield, and is more suitable for industrial production.

Detailed ways

Further illustrate the present invention by embodiment below, but content of the present invention can not be limited.

Embodiment 1: the synthesis of Tofacitinib

Add 20%wt.Pd(OH) ₂ /C (1g, 50% water), 40 mL of ethanol, N -methyl- N -[(3R,4R)-1-benzyl-4 to a clean reactor -Methylpiperidin-3-yl]-7-H-pyrrole[2,3-d]pyrimidin-4-amine (6.7 g, 0.02 mol), acetic acid (1.2 g, 0.02 mol), nitrogen gas first, then Pass hydrogen gas (1 atm), react at room temperature for about 7 hours, no more hydrogen gas is consumed, continue to react for 1 hour, rinse with nitrogen gas 3 times, pass ammonia gas to pH 8, filter, and directly react in the next step without separation.

Under the protection of nitrogen, add the above reaction liquid into the reactor, DBU (0.6 g, 4 mmol), ethyl cyanoacetate (4.6 g, 0.04 mol ) and react at room temperature for 8 h, stop the reaction, dissolve with dichloromethane, wash with water ( 10mL×3), the organic phase was concentrated, separated by a silica gel column, and dried under vacuum at 40-50°C to obtain a pale yellow product (5.2 g, the total yield of two steps was 83%). ¹ H NMR (500 MHz, CDCl ₃ ): δ: 10.57 (bs, 1H), 8.20 (s, 1H), 7.46 (d, J = 4.0 Hz, 1H), 6.55 (d, J = 4.0 Hz, 1H) , 5.24-5.25 (m, 1H), 4.19-4.23 (m, 2H), 4.05-4.10 (m, 1H), 3.80-3.85 (m, 1H), 3.60-3.67 (m, 1H), 3.49-3.54 ( m, 1H), 3.40 (s, 3H), 2.49-2.52 (m, 1H), 1.93-1.97 (m, 1H), 1.76-1.81 (m, 1H), 1.09 (d, J = 7.0 Hz, 3H) .

Embodiment 2: the synthesis of Tofacitinib

To a clean reactor add 20% wt. Pd(OH) ₂ /C (1 g, 50% water), methanol 40 mL, N -methyl- N -[(3R,4R)-1-benzyl-4 -Methylpiperidin-3-yl]-7-H-pyrrole[2,3-d]pyrimidin-4-amine (6.7 g, 0.02 mol), acetic acid (1.2 g, 0.02 mol), nitrogen gas first, then Pass hydrogen gas (1.8 atm), react at room temperature for about 7 hours, no more hydrogen consumption, continue to react for 1 hour, flush with nitrogen gas 3 times, pass ammonia gas to pH 8, filter, and directly react in the next step without separation.

Under the protection of nitrogen, add the above reaction liquid into the reactor, DBU (0.6 g, 4 mmol), ethyl cyanoacetate (4.6 g, 0.04 mol ) and react at room temperature for 8 h, stop the reaction, dissolve with dichloromethane, wash with water ( 10mL×3), the organic phase was concentrated, separated by a silica gel column, and dried in vacuo at 40-50°C to obtain a pale yellow product (5.0 g, the total yield of two steps was 80%). ¹ H NMR (500 MHz, CDCl ₃ ): δ: 10.57 (bs, 1H), 8.20 (s, 1H), 7.46 (d, J = 4.0 Hz, 1H), 6.55 (d, J = 4.0 Hz, 1H) , 5.24-5.25 (m, 1H), 4.19-4.23 (m, 2H), 4.05-4.10 (m, 1H), 3.80-3.85 (m, 1H), 3.60-3.67 (m, 1H), 3.49-3.54 ( m, 1H), 3.40 (s, 3H), 2.49-2.52 (m, 1H), 1.93-1.97 (m, 1H), 1.76-1.81 (m, 1H), 1.09 (d, J = 7.0 Hz, 3H) .

Embodiment 3: the synthesis of Tofacitinib

Add 20%wt.Pd(OH) ₂ /C (1g, 50% water), 40 mL of ethanol, N -methyl- N -[(3R,4R)-1-benzyl-4 to a clean reactor -Methylpiperidin-3-yl]-7-H-pyrrole[2,3-d]pyrimidin-4-amine (6.7 g, 0.02 mol), acetic acid (1.2 g, 0.02 mol), nitrogen gas first, then Flow hydrogen (2.5 atm), react at 40°C for about 6.5 hours, no more hydrogen is consumed, continue to react for 1 hour, flush with nitrogen three times, pass ammonia to pH 8, filter, and directly react in the next step without separation.

Under the protection of nitrogen, add the above reaction liquid into the reactor, DBU (0.6 g, 4 mmol), ethyl cyanoacetate (4.6 g, 0.04 mol ) and react at room temperature for 8 h, stop the reaction, dissolve with dichloromethane, wash with water ( 10mL×3), the organic phase was concentrated, separated by a silica gel column, and dried in vacuo at 40-50°C to obtain a pale yellow product (5.3 g, the total yield of two steps was 85%). ¹ H NMR (500 MHz, CDCl ₃ ): δ: 10.57 (bs, 1H), 8.20 (s, 1H), 7.46 (d, J = 4.0 Hz, 1H), 6.55 (d, J = 4.0 Hz, 1H) , 5.24-5.25 (m, 1H), 4.19-4.23 (m, 2H), 4.05-4.10 (m, 1H), 3.80-3.85 (m, 1H), 3.60-3.67 (m, 1H), 3.49-3.54 ( m, 1H), 3.40 (s, 3H), 2.49-2.52 (m, 1H), 1.93-1.97 (m, 1H), 1.76-1.81 (m, 1H), 1.09 (d, J = 7.0 Hz, 3H) .

Embodiment 4: the synthesis of Tofacitinib

To a clean reactor add 20% wt. Pd(OH) ₂ /C (1 g, 50% water), methanol 40 mL, N -methyl- N -[(3R,4R)-1-benzyl-4 -Methylpiperidin-3-yl]-7-H-pyrrole[2,3-d]pyrimidin-4-amine (6.7 g, 0.02 mol), acetic acid (1.2 g, 0.02 mol), nitrogen gas first, then Pass hydrogen gas (2.5 atm), react at room temperature for about 6.5 hours, no hydrogen consumption, continue reaction for 1 hour, flush with nitrogen gas 3 times, pass ammonia gas to pH 8, filter, and directly react in the next step without separation.

Under the protection of nitrogen, add the above reaction liquid into the reactor, DBU (0.6 g, 4 mmol), ethyl cyanoacetate (4.6 g, 0.04 mol ) and react at room temperature for 8 h, stop the reaction, dissolve with dichloromethane, wash with water ( 10mL×3), the organic phase was concentrated, separated by a silica gel column, and dried under vacuum at 40-50°C to obtain a pale yellow product (5.2 g, the total yield of two steps was 83%). ¹ H NMR (500 MHz, CDCl ₃ ): δ: 10.57 (bs, 1H), 8.20 (s, 1H), 7.46 (d, J = 4.0 Hz, 1H), 6.55 (d, J = 4.0 Hz, 1H) , 5.24-5.25 (m, 1H), 4.19-4.23 (m, 2H), 4.05-4.10 (m, 1H), 3.80-3.85 (m, 1H), 3.60-3.67 (m, 1H), 3.49-3.54 ( m, 1H), 3.40 (s, 3H), 2.49-2.52 (m, 1H), 1.93-1.97 (m, 1H), 1.76-1.81 (m, 1H), 1.09 (d, J = 7.0 Hz, 3H) .

Embodiment 5: the synthesis of Tofacitinib

Add 20%wt.Pd(OH) ₂ /C (1.5g, 50% water), 60 mL of ethanol, N -methyl- N -[(3R,4R)-1-benzyl- 4-Methylpiperidin-3-yl]-7-H-pyrrole[2,3-d]pyrimidin-4-amine (10.1 g, 0.03 mol), acetic acid (1.8 g, 0.03 mol), nitrogen first, Then pass hydrogen (1 atm), react at room temperature for about 7 hours, no more hydrogen consumption, continue to react for 1 hour, rinse with nitrogen three times, pass ammonia to pH 8, filter, and directly react in the next step without separation.

Under the protection of nitrogen, add the above reaction solution to the reactor, DBU (0.9 g, 6 mmol), ethyl cyanoacetate (6.9 g, 0.06 mol ) at room temperature for 8 h, stop the reaction, dissolve with dichloromethane, wash with water ( 10mL×3), the organic phase was concentrated, separated by a silica gel column, and dried under vacuum at 40-50°C to obtain a pale yellow product (7.8 g, the total yield of two steps was 83%). ¹ H NMR (500 MHz, CDCl ₃ ): δ: 10.57 (bs, 1H), 8.20 (s, 1H), 7.46 (d, J = 4.0 Hz, 1H), 6.55 (d, J = 4.0 Hz, 1H) , 5.24-5.25 (m, 1H), 4.19-4.23 (m, 2H), 4.05-4.10 (m, 1H), 3.80-3.85 (m, 1H), 3.60-3.67 (m, 1H), 3.49-3.54 ( m, 1H), 3.40 (s, 3H), 2.49-2.52 (m, 1H), 1.93-1.97 (m, 1H), 1.76-1.81 (m, 1H), 1.09 (d, J = 7.0 Hz, 3H) .

Embodiment 6: the synthesis of Tofacitinib

To a clean reactor, add 20% wt.Pd(OH) ₂ /C (1.5 g, 50% water), methanol 60 mL, N -methyl- N -[(3R,4R)-1-benzyl- 4-Methylpiperidin-3-yl]-7-H-pyrrole[2,3-d]pyrimidin-4-amine (10.1 g, 0.03 mol), acetic acid (1.8 g, 0.03 mol), nitrogen first, Then pass hydrogen (1.8 atm), react at room temperature for about 7 hours, no more hydrogen consumption, continue to react for 1 hour, flush with nitrogen three times, pass ammonia to pH 8, filter, and directly react in the next step without separation.

Under the protection of nitrogen, add the above reaction solution to the reactor, DBU (0.9 g, 6 mmol), ethyl cyanoacetate (6.9 g, 0.06 mol ) at room temperature for 8 h, stop the reaction, dissolve with dichloromethane, wash with water ( 10mL×3), the organic phase was concentrated, separated by a silica gel column, and dried under vacuum at 40-50°C to obtain a light yellow product (7.7 g, the total yield of two steps was 82%). ¹ H NMR (500 MHz, CDCl ₃ ): δ: 10.57 (bs, 1H), 8.20 (s, 1H), 7.46 (d, J = 4.0 Hz, 1H), 6.55 (d, J = 4.0 Hz, 1H) , 5.24-5.25 (m, 1H), 4.19-4.23 (m, 2H), 4.05-4.10 (m, 1H), 3.80-3.85 (m, 1H), 3.60-3.67 (m, 1H), 3.49-3.54 ( m, 1H), 3.40 (s, 3H), 2.49-2.52 (m, 1H), 1.93-1.97 (m, 1H), 1.76-1.81 (m, 1H), 1.09 (d, J = 7.0 Hz, 3H) .

Embodiment 7: the synthesis of Tofacitinib

Add 20%wt.Pd(OH) ₂ /C (1.5g, 50% water), 60 mL of ethanol, N -methyl- N -[(3R,4R)-1-benzyl- 4-Methylpiperidin-3-yl]-7-H-pyrrole[2,3-d]pyrimidin-4-amine (10.1 g, 0.03 mol), acetic acid (1.8 g, 0.03 mol), nitrogen first, Then pass hydrogen (1 atm), react at 40°C for about 7 hours, no more hydrogen is consumed, continue to react for 1 hour, flush with nitrogen for 3 times, pass ammonia to pH 8, filter, and directly react in the next step without separation.

Under the protection of nitrogen, add the above reaction solution to the reactor, DBU (0.9 g, 6 mmol), ethyl cyanoacetate (6.9 g, 0.06 mol ) at room temperature for 8 h, stop the reaction, dissolve with dichloromethane, wash with water ( 10mL×3), the organic phase was concentrated, separated by a silica gel column, and dried under vacuum at 40-50°C to obtain a pale yellow product (7.8 g, the total yield of two steps was 83%). ¹ H NMR (500 MHz, CDCl ₃ ): δ: 10.57 (bs, 1H), 8.20 (s, 1H), 7.46 (d, J = 4.0 Hz, 1H), 6.55 (d, J = 4.0 Hz, 1H) , 5.24-5.25 (m, 1H), 4.19-4.23 (m, 2H), 4.05-4.10 (m, 1H), 3.80-3.85 (m, 1H), 3.60-3.67 (m, 1H), 3.49-3.54 ( m, 1H), 3.40 (s, 3H), 2.49-2.52 (m, 1H), 1.93-1.97 (m, 1H), 1.76-1.81 (m, 1H), 1.09 (d, J = 7.0 Hz, 3H) .

Embodiment 8: the synthesis of Tofacitinib

To a clean reactor, add 20% wt.Pd(OH) ₂ /C (1.5 g, 50% water), methanol 60 mL, N -methyl- N -[(3R,4R)-1-benzyl- 4-Methylpiperidin-3-yl]-7-H-pyrrole[2,3-d]pyrimidin-4-amine (10.1 g, 0.03 mol), acetic acid (1.8 g, 0.03 mol), nitrogen first, Then pass hydrogen (2.5 atm), react at room temperature for about 6.5 hours, no more hydrogen is consumed, continue to react for 1 hour, flush with nitrogen three times, pass ammonia to pH 8, filter, and directly react in the next step without separation.

Under the protection of nitrogen, add the above reaction solution to the reactor, DBU (0.9 g, 6 mmol), ethyl cyanoacetate (6.9 g, 0.06 mol ) at room temperature for 8 h, stop the reaction, dissolve with dichloromethane, wash with water ( 10mL×3), the organic phase was concentrated, separated by a silica gel column, and vacuum-dried at 40-50°C to obtain a pale yellow product (7.9 g, the total yield of two steps was 84%). ¹ H NMR (500 MHz, CDCl ₃ ): δ: 10.57 (bs, 1H), 8.20 (s, 1H), 7.46 (d, J = 4.0 Hz, 1H), 6.55 (d, J = 4.0 Hz, 1H) , 5.24-5.25 (m, 1H), 4.19-4.23 (m, 2H), 4.05-4.10 (m, 1H), 3.80-3.85 (m, 1H), 3.60-3.67 (m, 1H), 3.49-3.54 ( m, 1H), 3.40 (s, 3H), 2.49-2.52 (m, 1H), 1.93-1.97 (m, 1H), 1.76-1.81 (m, 1H), 1.09 (d, J = 7.0 Hz, 3H) .

Claims (5)

1. a synthetic method of JAK inhibitor Tofacitinib, characterized in that its synthetic route is as follows:

Specific steps are as follows: Specific steps are as follows: (1) Add N -methyl- N -[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-7-H-pyrrole[2, 3-d to the reactor ] Pyrimidin-4-amine, 20%wt.Pd(OH) ₂ /C, acetic acid and solvent, then pass in hydrogen gas with a reaction pressure of 1.0-2.5atm and stir for 6-10h; (2) The reactant obtained in step (1) was flushed three times with nitrogen, filtered, passed ammonia gas to a pH value of 8, then added ethyl cyanoacetate and alkali to the reactor, reacted for 6-10h, washed with water, and the column Separation, vacuum drying, to obtain the product; Where: N -methyl- N -[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-7-H-pyrrole[2, 3-d]pyrimidin-4-amine , 20%wt.Pd(OH) ₂ /C, acetic acid, ethyl cyanoacetate and alkali in a molar ratio of 1:(0.5-1):1:(2-4):(0.2-0.4). 2. the synthetic method of JAK inhibitor Tofacitinib according to claim 1, is characterized in that, described solvent is one or both of methanol or ethanol. 3. the synthetic method of JAK inhibitor Tofacitinib according to claim 1, is characterized in that, described acid is acetic acid. 4. The method for synthesizing the JAK inhibitor Tofacitinib according to claim 1, characterized in that the reaction temperature in step (1) and step (2) is 20-40°C. 5. the synthetic method of JAK inhibitor Tofacitinib according to claim 1, is characterized in that, described alkali is DBU.