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Preparation method of tofacitinib intermediate

A technology for tofacitinib and intermediates, which is applied in the field of preparation of tofacitinib intermediates, can solve problems such as unfavorable industrial production, difficulty in separation and purification, low yield, etc. high rate effect

Active Publication Date: 2017-08-18
GUANGZHOU BAIYUSN GUANGHUA PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] According to the route reported in the literature, tofacitinib intermediate 1-benzyl-3-methylamino-4-methylpiperidine dihydrochloride will have problems such as separation and purification difficulties, low yield, and the preparation process Column chromatography is required to purify the product, which is not conducive to industrial production

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  • Preparation method of tofacitinib intermediate

Examples

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preparation Embodiment 1

[0061] Preparation Example 1: Preparation of Compound III

[0062]

[0063] Set up experimental groups 1 to 5 to prepare compound III respectively. The method is as follows: put compound II, acid, 100mL solvent, and 10% Pd / C (wet) in a hydrogenation kettle at 45 to 55°C under a hydrogen pressure of 4 to 8 MPa React for 16-24 hours until no hydrogen is absorbed, and TLC checks that the reaction of the raw materials is complete. Cool to room temperature, filter, and concentrate the filtrate under reduced pressure, add ethyl acetate (50 mL) to dissolve, adjust the pH to 12 with 5% aqueous sodium hydroxide solution, separate the layers, and extract the aqueous layer twice with ethyl acetate (30 mL×2) , combined organic phases, dried over anhydrous sodium sulfate for 6 h, filtered, and concentrated under reduced pressure to obtain compound III. The differences and experimental results of experimental groups 1 to 5 are shown in Table 1 below:

[0064] Table 1

[0065]

[00...

preparation Embodiment 2

[0067] Preparation Example 2: Preparation of Compound IV

[0068]

[0069] Set up experimental groups 1 to 6 to prepare compound III respectively. The method is as follows: add compound III, phthalic anhydride, and 40 mL of solvent to the reaction flask, and react at 60 to 150° C. for 1 to 12 hours under stirring conditions, and reduce to At room temperature, add 40 mL of ethanol solution saturated with hydrogen chloride, stir for 1 h until the solid precipitates, continue to stir for 5 h, stand at 0°C overnight until the solid precipitates completely, filter, and add the filter cake to the mixed solution of dichloromethane (50 mL) and water (20 mL) , the pH was adjusted to 9-10 with saturated aqueous sodium carbonate solution, the organic phase was extracted and collected, the aqueous phase was extracted twice with dichloromethane (50 mL×2), dried over anhydrous sodium sulfate for 6 h, filtered, and concentrated under reduced pressure to obtain compound IV. The differences...

preparation Embodiment 3

[0073] Preparation Example 3: Preparation of Compound V

[0074]

[0075] Set up experimental groups 1 to 6 to prepare compound V respectively. The method is as follows: add compound IV, 60mL solvent, and alkali to the reaction flask, add the solution (25mL) of the aforementioned solvent of benzyl bromide dropwise under ice bath, and rise to room temperature after dropping React at ~80°C for 2 hours, concentrate under reduced pressure and distill off the solvent, add water (50mL) and dichloromethane (100mL), stir for 10min, separate layers, wash the dichloromethane layer twice with saturated brine (50mL×2), organic The phase was dried with anhydrous sodium sulfate for 6 h, filtered, and concentrated under reduced pressure to obtain compound V. The differences and experimental results of experimental groups 1 to 6 are shown in Table 3 below:

[0076] table 3

[0077]

[0078] Characterization data of Compound V: 1 H-NMR(DMSO,300MHz)δ:1.02(m,3H,C H 3 CH); 1.25~1.29(m,...

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Abstract

The invention discloses a preparation method of a tofacitinib intermediate compound-1-benzyl-3-methyl amino-4-methyl piperidine dihydrochloride. The method comprises the following steps: (1) carrying out selective deprotection on a compound as shown in a structural formula (V) to synthesize a compound-1-benzyl-3-amino-4-methyl piperidine as shown in a structural formula (VI); (2) enabling the compound as shown in the structural formula (VI) to have a primary amine monomethylation reaction to generate the target compound-1-benzyl-3-methyl amino-4-methyl piperidine dihydrochloride as shown in a structural formula (I). The method has the characteristics of being easy in obtaining of raw materials, novel in route, less in by-products, simple and convenient to operate, high in yield, and the like.

Description

technical field [0001] The invention relates to a preparation method of a tofacitinib intermediate, in particular to a preparation method of a tofacitinib intermediate 1-benzyl-3-methylamino-4-methylpiperidine dihydrochloride. Background technique [0002] Tofacitinib is a new oral non-receptor tyrosine kinase (JAK) inhibitor developed by Pfizer, and its chemical name is 3-((3R,4R)-4-methyl-3-( Methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)aminopiperidin-1-yl)-3-oxopropionitrile, used clinically for the treatment of inadequate response to methotrexate or intolerable adult patients with moderately to severely active rheumatoid arthritis. [0003] According to relevant patents and literature reports, there are currently many alternative routes for preparing tofacitinib, but the synthetic routes that are widely used in production are as follows: [0004] [0005] The starting material for this route (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)methanamine is 1-benzyl-3-methylamino-4...

Claims

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Application Information

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IPC IPC(8): C07D211/56C07D401/04
Inventor 张俊华戴艳萍邹洪平葛婷胡卫林何敏儿
Owner GUANGZHOU BAIYUSN GUANGHUA PHARMA
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