Preparation method of tofacitinib citrate

A technology of tofacitinib and citric acid, which is applied in the field of medicine and chemical industry, can solve the problems of difficult control and complete splitting of chiral isomers, low overall yield of chiral side chains, and instability of tert-butyl lithium. , to achieve the effect of reducing equipment cost and operation difficulty, sufficient market supply, and stable yield

Active Publication Date: 2016-08-24
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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Problems solved by technology

[0018] Cis-(1-benzyl-4-methylpyridin-3-yl)methanamine dihydrochloride was resolved by L-di-p-toluenesulfonyl tartaric acid (L-DTTA) to obtain (3R, 4R)-(1- Benzyl-4-methylpyridin-3-yl)methanamine-L-di-p-toluenesulfonyl tartaric acid, the problem of this step reaction is that cis-(1-benzyl-4-methyl has been synthesized by 4-step reaction in the early stage Pyridin-3-yl) methylamine dihydrochloride, long steps, low yield, the product obtaine

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  • Preparation method of tofacitinib citrate
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  • Preparation method of tofacitinib citrate

Examples

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Embodiment 1

[0047] Example 1: Synthesis of (3R, 4R)-cis-1-benzyl-4-methyl-3-methylamino-piperidine dihydrochloride

[0048] [Ir(COD)Cl] 2 (0.7g, 1mmol) and (R)-MEO-BiPhep (0.6g, 1mmol) were suspended in 200ml tetrahydrofuran, reacted for 2 hours, then added 1-benzyl-4-methyl-2,6-dihydro- 3-ketopiperidine (20.1 g, 100 mmol), at room temperature, was passed hydrogen gas into the reaction solution, and the pressure was controlled at 5 atm, and the reaction was completed by TLC monitoring. Add saturated brine for washing, dry the organic phase with anhydrous sulfuric acid, concentrate the organic phase, and recrystallize the residue with ethyl acetate to obtain 18.34 g of 1-benzyl-4-methyl-3-ketopiperidine, with a yield of 90.3%. Optical purity 99.0% (HPLC method).

[0049] TiCl 4 (0.2g, 1mmol), NEt 3 (0.1g, 1mmol) was suspended in 200ml tetrahydrofuran, then 1-benzyl-4-methyl-3-ketopiperidine (20.3g, 100mmol) was added, and methylamine solution (7.75g , 100mmol) reacted for 4 hours, add...

Embodiment 2

[0050] Example 2: Synthesis of (3R, 4R)-cis-1-benzyl-4-methyl-3-methylamino-piperidine dihydrochloride

[0051] [Ir(COD)Cl] 2 (0.7g, 1mmol) and (R)-MEO-BiPhep (0.5g, 0.9mmol) were suspended in 200ml of dichloromethane, reacted for 2 hours, then added 1-benzyl-4-methyl-2,6- Dihydro-3-ketopiperidine (20.1 g, 100 mmol) was controlled at a temperature of 0° C., hydrogen gas was introduced into the reaction solution, and the pressure was controlled at 5 atm. After the reaction was completed, TLC was monitored. Add saturated brine for washing, dry the organic phase with anhydrous sulfuric acid, concentrate the organic phase, and recrystallize the residue with ethyl acetate to obtain 18.55 g of 1-benzyl-4-methyl-3-ketopiperidine, with a yield of 91.3%. Optical purity 99.4% (HPLC method).

[0052] TiCl4 (0.2g, 1mmol), NEt3 (0.09g, 0.9mmol) were suspended in 200ml of dichloromethane, then 1-benzyl-4-methyl-3-ketopiperidine (20.3g, 100mmol) was added, Add methylamine solution (8.5g, ...

Embodiment 3

[0053] Example 3: Synthesis of (3R, 4R)-cis-1-benzyl-4-methyl-3-methylamino-piperidine dihydrochloride

[0054] [Ir(COD)Cl] 2 (0.7g, 1mmol) and (R)-MEO-BiPhep (0.9g, 1.5mmol) were suspended in 200ml toluene, reacted for 2 hours, then added 1-benzyl-4-methyl-2,6-dihydro -3-ketopiperidine (20.1 g, 100 mmol), temperature controlled at 35° C., hydrogen gas was introduced into the reaction liquid, the pressure was controlled at 5 atm, and TLC was monitored after the reaction was complete. Add saturated brine to wash, dry the organic phase with anhydrous sulfuric acid, concentrate the organic phase, and recrystallize the residue with ethyl acetate to obtain 18.69 g of 1-benzyl-4-methyl-3-ketopiperidine, with a yield of 92.0%. Optical purity 99.1% (HPLC method).

[0055] TiCl 4 (0.2g, 1mmol), NEt 3 (0.15g, 1.5mmol) was suspended in 200ml of toluene, then 1-benzyl-4-methyl-3-ketopiperidine (20.3g, 100mmol) was added, and methylamine solution was added to the reaction solution at a...

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Abstract

The invention belongs to the field of medicine and chemical engineering and particularly relates to a preparation method of tofacitinib citrate. The method comprises steps as follows: 1-benzyl-4-methyl-2,6-dihydro-3-piperidone taken as a starting material is subjected to an asymmetric reduction reaction, 1-benzyl-4-methyl-3-piperidone is obtained, and (3R,4R)-cis-1-benzyl-4-methyl-3-methylamino-piperidine dihydrochloride is produced under the action of a chiral catalyst; (3R,4R)-cis-1-benzyl-4-methyl-3-methylamino-piperidine dihydrochlorid and a paratoluensulfonyl chloride protection product 4-chloro-7-(methyl-4-benzenesulfonyl) pyrrolo[2,3-d]pyrimidine of 4-chloropyrrolo[2,3-d]pyrimidine are subjected to a condensation reaction, [(3R,4R)]-1-benzyl-4-methyl-piperidine-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-amine is obtained through deprotection, and tofacitinib citrate is obtained through debenzylation protection, an acylation reaction and citric acid salifying. The process route is short, the process cycle is short, chiral synthesis is performed by means of a catalyst, the product purity is improved, the cost is reduced, the yield is high, and the operation is simple and convenient.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of tofacitinib citrate. Background technique [0002] Tofacitinib Citrate (Tofacitinib Citrate) was developed by Pfizer of the United States and was approved by the FDA for marketing in the United States in November 2012. The product name is The preparation is a tablet with a specification of 5 mg (calculated as tofacitinib). Indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It can be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). [0003] The target molecules of the existing immunosuppressants are widely distributed in tissues, so the selectivity is poor, and pleiotropic toxic adverse reactions are likely to occur. In order to solve th...

Claims

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Application Information

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IPC IPC(8): C07D487/04B01J31/38B01J31/24
CPCB01J31/2409B01J31/38B01J2231/4283B01J2231/645B01J2531/827C07B2200/07C07D487/04
Inventor 李晓峰孙远龙杨林林
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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