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Synthetic method of tofacitinib

A synthetic method, the technology of tofacitinib, applied in the direction of organic chemistry, etc., can solve problems such as not being suitable for industrial production, affecting product yield, and difficulty in product separation, achieving high total yield and purity, improving total yield, The effect of simple process route

Active Publication Date: 2018-12-07
SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] Although the reaction route of the present invention is shortened, it is beneficial to control the quality of impurities, the solvent can be recycled and used mechanically, and the pollution is small; but the reaction raw materials 2,4-dichloro-7H pyrrole [2,3-D] and (3R,4R)-N,4 -Dimethyl-1-(phenylmethyl)-3-piperidinamine hydrochloride is expensive, and there is a competing reaction, which affects the product yield, and also brings difficulties to the separation of subsequent products, and is still not suitable for industrialization Production

Method used

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  • Synthetic method of tofacitinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Preparation of compound Ⅲ

[0038] In the three-necked flask, add 15.72g (0.1mol) of compound II, 300ml toluene and 3.11g (0.1mol) methylamine respectively, stir and raise the temperature to reflux, control the reaction for 1.5h, monitor and track the reaction process by TLC, when the raw materials are completely reacted, Turn off heat. The solvent was removed under reduced pressure to obtain 16.01 g of compound III, the product yield was 94%, and the HPLC purity was 99.96%.

Embodiment 2

[0040] Preparation of compound Ⅲ

[0041] In a three-necked flask, add 15.72g (0.1mol) of compound II, 300ml of dichloromethane and 3.11g (0.1mol) of methylamine, stir and raise the temperature to reflux, and control the reaction for 1.5h. TLC monitors and tracks the reaction progress. After that, stop heating. The solvent was removed under reduced pressure to obtain 15.33 g of compound III, the product yield was 90%, and the HPLC purity was 99.91%.

Embodiment 3

[0043] Preparation of compound Ⅲ

[0044] In the three-necked flask, add compound II 15.72g (0.1mol), dichloromethane 300ml and methylamine 3.42g (0.11mol), stir and heat up to reflux, control the reaction for 1.5h, TLC monitors and tracks the reaction progress, when the raw materials react completely After that, stop heating. The solvent was removed under reduced pressure to obtain 16.34 g of compound III, the product yield was 96%, and the HPLC purity was 99.98%.

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Abstract

The invention discloses a synthetic method of tofacitinib. The synthetic method comprises the following steps: carrying out a reaction on a compound II and methylamine to prepare a compound III; carrying out reduction reaction and methylamine o the compound III to prepare a compound IV; carrying out asymmetric hydrogenation on the compound IV to prepare a compound V; and carrying out elimination reaction, substituent reaction and asymmetric hydrogenation on the compound IV to obtain a final product tofacitinib (I). The preparation method is easily available in initial raw material, simple in process route, high in total yield and purity, few in side products and suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicine synthesis, in particular to a synthesis method of tofacitinib. Background technique [0002] Tofacitinib is a new type of Janus kinase inhibitor developed by Pfizer, the trade name is Xeljanz. This product can effectively inhibit the activity of JAK1 and JAK3, and block the signal transduction of various inflammatory cytokines. Existing studies have shown that tofacitinib has a good therapeutic effect on rheumatoid arthritis, ulcerative colitis, psoriasis and other inflammation-related diseases. [0003] The chemical name of tofacitinib is 3-[(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidine -1-yl]-3-oxopropionitrile has a chemical structure shown in formula I: [0004] [0005] The synthetic method report situation about tofacitinib is as follows at present: [0006] 1. The original US patent US6627754 and Chinese patent CN1409712 of this product are reported as follows: ...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 李震周丙阳冷香香
Owner SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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