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Preparation method of key intermediate of JAK3 enzyme inhibitor

A technology of inhibitors and intermediates, applied in the field of medicine, can solve the problems of high cost, low yield, unsuitable for large-scale production, etc., and achieve the effects of mild reaction conditions, high reaction controllability, and good industrial application prospects

Pending Publication Date: 2021-07-16
JIANGSU ALICORN PHARMATECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The method of obtaining chiral pure key intermediates in the patent route is to separate by chiral chromatography, and only the enantiomeric mixture containing the target can be obtained, the yield is low, the cost is high, and it is not suitable for large-scale production

Method used

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  • Preparation method of key intermediate of JAK3 enzyme inhibitor
  • Preparation method of key intermediate of JAK3 enzyme inhibitor
  • Preparation method of key intermediate of JAK3 enzyme inhibitor

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Embodiment Construction

[0032] The present invention is specifically described below by the examples, it is necessary to point out again that the following examples are only used to further illustrate the present invention, and cannot be interpreted as limiting the protection scope of the present invention

[0033] Synthesis of (6-methylpyridin-3-yl) tert-butyl carbamate (3)

[0034]

[0035] In a 1000ml three-necked flask, add 6-picoline-3-amine (80.00g, 739.75mmol, 1.0eq), ethanol (320ml), cool down to 0°C and stir. Add slowly (Boc) 2 O (209.89g, 209.89mol, 1.3eq), added dropwise completely, transferred to room temperature and stirred overnight. TLC monitoring (PE / EA=3:1) showed that the reaction was complete, filtered under reduced pressure, washed the filter cake with a small amount of absolute ethanol, and concentrated the filtrate under reduced pressure to obtain a crude oily product.

[0036] Transfer the crude product to a 2000ml three-necked flask, add ethyl acetate (160ml) and n-hexane...

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Abstract

The invention relates to a preparation method of a key intermediate ((3R,6S)-1-benzyl-6-methyl piperidine-3-amine) of a JAK3 enzyme inhibitor, and particularly relates to a method for preparing the required intermediate by taking 6-methyl piperidine-3-amine as an initial raw material through Boc protection, catalytic hydrogenation, benzyl protection, trifluoroacetic acid Boc de-protection, salt forming and splitting, and dissociation. The salt forming and splitting method comprises the following steps: mixing a racemic mixture containing a compound enantiomer with a structure shown in the formula with a splitting reagent with definite stereo-specificity in a solvent to form a solution, wherein the splitting agent is capable of binding at least one but not all of said enantiomers to form a precipitate containing the at least one the stereo-specific form of enantiomers; and collecting and purifying the precipitate , or collecting a solution containing other enantiomers and recrystallizing the enantiomers contained in the solution. The preparation method has the advantages of cheap and easily available raw materials, mild reaction conditions, high reaction controllability and good industrial application prospect.

Description

technical field [0001] The invention relates to the field of medicine, in particular to the preparation of a key intermediate of a JAK3 enzyme inhibitor (pure enantiomer (3R, 6S)-1-benzyl-6-methylpiperidin-3-amine) method. Background technique [0002] PF-06651600 is a highly selective orally bioavailable Janus kinase 3 (JAK3) inhibitor developed by Pfizer, representing a potential immunomodulatory therapy. Due to its favorable efficacy, safety, and ADME profile, this JAk3-specific covalent inhibitor has been used in the treatment of alopecia areata, rheumatoid arthritis, Crohn's disease, and ulcerative colitis. On September 5, 2018, the FDA granted PF-06651600 "Breakthrough Therapy" designation for the treatment of alopecia areata, backed by positive results from a Phase 2 study. [0003] The preparation method of the compound is disclosed in the patent WO2015 / 083028, wherein the preparation method related to the present invention is as follows: [0004] [0005] The ...

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/56
CPCC07D211/56C07B2200/07Y02P20/55
Inventor 吴心宇陈磊丁杰
Owner JIANGSU ALICORN PHARMATECH CO LTD
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