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Preparation method of tofacitinib citrate

A technology of tofacitinib and citric acid, applied in the field of preparation of tofacitinib citrate, can solve the problems of unsuitability for industrialized production, complicated post-processing, harsh synthesis conditions and the like

Active Publication Date: 2015-01-21
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Ruggeri et al. reported for the first time in their PCT application WO 2007012953 that debenzylation was performed using a 5:1 mixed solvent of isopropanol and water (V / V). Amine is used as base, toluene is used as solvent, heated to 100°C for 24 hours, and the yield is about 60%. After a series of treatments, it is salted to obtain tofacitinib citrate. The synthesis conditions are relatively harsh and are not suitable for industrial production. Therefore, it is developed The new synthesis process of tofacitinib citrate has important application value

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  • Preparation method of tofacitinib citrate

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preparation example Construction

[0043] The third aspect of the present invention provides a preparation method of tofacitinib citrate crystal form A, which includes: using a nitrile solvent or a mixed solvent of a nitrile solvent and water and any solid form of the tofacitinib citrate method Mix Tini, heat to dissolve, cool down to precipitate crystals, and collect crystals.

[0044] The tofacitinib citrate of the present invention can be prepared by any existing disclosed technology, such as the method disclosed in Chinese patent CN 2002823587, and the tofacitinib citrate can be in any solid form, such as The solid tofacitinib citrate prepared by the prior art or the first aspect of the present invention or the amorphous tofacitinib citrate prepared by the second aspect of the present invention.

[0045] When the preparation method of the present invention dissolves tofacitinib citrate with a solvent, the dissolution methods such as stirring, heating, reflux and stirring can be used.

[0046] To obtain a s...

specific Embodiment approach

[0059] The embodiment of the present invention discloses a method for preparing tofacitinib citrate (I). Those skilled in the art can refer to the content of this article to appropriately improve the process parameters to achieve. In particular, it should be pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously make changes or appropriate changes and combinations to the method described herein without departing from the content, spirit and scope of the present invention to realize and apply the technology of the present invention .

[0060] In order to further understand the present invention, the present invention will be described in detail below in conjunction with examples.

Embodiment 1

[0061] Embodiment 1: the synthesis of tofacitinib citrate

[0062] To the reaction vessel was added 10% palladium hydroxide on carbon (0.56g), methanol (20ml), N-methyl-N-{(3R,4R)-1-benzyl-4-methylpiperidine-3- Base}-7H-pyrrole[2,3-d]pyrimidin-4-amine (2.8g) and acetic acid (0.5g), first replaced by nitrogen, then hydrogen (1atm), reacted at 60°C for about 6 hours, and the reaction After completion, directly put DBU (3.8g) and ethyl cyanoacetate (3.7g), and react at room temperature for 6 hours to detect N-methyl-N-{(3R,4R)-1-benzyl-4-methylguanidine The ultraviolet fluorescence point of pyridin-3-yl}-7H-pyrrole[2,3-d]pyrimidin-4-amine disappears, and the treatment is directly put into citric acid (3.5g) and water (18ml) to stir and crystallize at room temperature, and keep warm for 2h After filtering, drying to obtain tofacitinib citrate (total yield 85%), the peak area of ​​high performance liquid phase HPLC is 99.68%.

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Abstract

The invention relates to a method for preparing tofacitinib citrate. The method comprises the following steps: by taking N-methyl-N-((3R, 4R)-1-benzyl-4-methylpiperidine-3-yl)-7H-pyrrolo (2, 3-d) pyrimidin-4-amine as a raw material, performing hydrogenation to remove an amino protecting group, performing amidation reaction and salt-forming reaction and finally drying to obtain tofacitinib citrate. In the preparation process, after-treatment is not required, the separation of a target intermediate is not required, and only reactants need to be added sequentially. The preparation method of tofacitinib citrate provided by the invention has the advantages of simplicity in operation, high yield, mild conditions and the like, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic and pharmaceutical synthesis, and in particular relates to a preparation method of tofacitinib citrate. Background technique [0002] PCT applications WO 2001042246 and WO 2002096909 reported a series of pyrrolo[2,3-d]pyrimidine compounds, among them, tofacitinib citrate, chemical name: 3-[(3R,4R)-4-methyl- 3-[methyl(7H-pyrrole[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropionitrile citrate, its chemical structure is as formula (I ) as shown: [0003] [0004] Tofacitinib citrate is an oral Janus kinase JAK-3 and JAK-1 inhibitor developed by Pfizer. Treatment of adult patients with severely active rheumatoid arthritis (RA). Clinically, tofacitinib can be used alone or in combination with methamphetamine or other slow-acting rheumatic drugs to treat rheumatoid arthritis. [0005] Ruggeri et al. reported for the first time in their PCT application WO 2007012953 that debenzylation was pe...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCY02P20/55C07D487/04C07B2200/13
Inventor 申燕雷鑫彭锦安
Owner SUNSHINE LAKE PHARM CO LTD
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