A new synthetic method of JAK inhibitor baricitinib and its intermediate

A technology for baricitinib and a synthesis method, applied in the field of medicine and chemical industry, can solve the problems of expensive 3-hydroxyazetidine starting material, unsatisfactory product yield and purity, poor acetonitrile stability, etc. Route efficiency and atom economy, simplified separation and purification process, simple operation effect

Active Publication Date: 2019-06-11
HANGZHOU CHEMINSPIRE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] But this route 3-hydroxyazetidine starting material is still more expensive, when we repeat this route, find its key intermediate 1-(ethylsulfonyl)-3-[4-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]-3-azetidine acetonitrile has poor stability, resulting in difficulties in separation and purification, and in the following It is easy to deteriorate in the Suzuki coupling reaction, so that the yield and purity of the final product are not particularly ideal

Method used

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  • A new synthetic method of JAK inhibitor baricitinib and its intermediate
  • A new synthetic method of JAK inhibitor baricitinib and its intermediate
  • A new synthetic method of JAK inhibitor baricitinib and its intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1: N-(3-chloro-2-hydroxypropyl)ethanesulfonamide

[0048]

[0049] Add 1-amino-3-chloropropyl-2-ol hydrochloride (14.60g, 100mmol), tetrahydrofuran (73mL), water (73mL) into a three-necked flask, stir to dissolve and cool to 0~5℃, add hydrogen phosphate Dipotassium (34.84g, 200mmol), stir for 5 minutes and then add ethyl sulfonyl chloride (13.50g, 105mmol) dropwise. After the addition, warm up to room temperature and react for 3-4 hours. At the end of the reaction, add 73mL of 0.5mol / L dilute hydrochloric acid to quench Reaction, stirring and liquid separation, the aqueous phase was extracted twice with 35 mL ethyl acetate, the combined organic phase was washed once with saturated brine (73 mL), dried over anhydrous sodium sulfate, and concentrated to obtain N-(3-chloro-2-hydroxypropyl) The crude product of ethyl sulfonamide is directly applied to the next reaction (GC purity is about 92%).

[0050] ESI m / z=202.1(M+H) + , 1 H NMR(400MHz, CDCl 3 )δ5.10-4.95(m,1H), 4....

Embodiment 2

[0052] Example 2: 1-(Ethylsulfonyl)azidine-3-ol

[0053]

[0054] Add N-(3-chloro-2-hydroxypropyl)ethanesulfonamide (prepared from Example 1) and N,N-dimethylformamide (100mL) into a three-necked flask, stir to dissolve, and cool to 0~5℃. Potassium tert-butoxide (11.22g, 100mmol) was added, after the addition, kept at 0~5℃ and stirred for 15~20 minutes, then warmed to room temperature and reacted for 3-4 hours. Add 1mol / L dilute hydrochloric acid 100mL to quench the reaction, stir and separate. The aqueous phase was extracted twice with 50 mL ethyl acetate, and the combined organic phases were washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain crude 1-(ethylsulfonyl)azidine-3-ol directly Throw into the next reaction (GC purity about 86%). ESI m / z=166.3(M+H) + .

[0055] In Example 2, the alkaline substance potassium tert-butoxide can be sodium hydride, sodium tert-butoxide, lithium diisopropylamide, lithium hexamethyldisilaz...

Embodiment 3

[0056] Example 3: 1-(Ethylsulfonyl)azidine-3-one

[0057]

[0058] A three-necked flask was charged with 1-(ethylsulfonyl)azidine-3-ol (prepared from Example 2), sodium bromide (10.29g, 100mmol), sodium bicarbonate (12.6g, 150mmol), dichloromethane (83mL) and water (123mL), stir well and then cool to -5~0℃, add TEMPO (312mg, 2mmol), add 10% sodium hypochlorite solution (81.9g, 110mmol) dropwise after the addition, the reaction is over and liquid separation, water The phase was extracted with dichloromethane (83mL) once again, the combined organic phase was washed with sodium bisulfite solution (5%, 42mL) once, washed with saturated brine once (83mL), dried over sodium sulfate, and concentrated to obtain 1-( The crude ethylsulfonyl)azidine-3-one (GC purity about 83%) was directly used in the next reaction. ESI m / z=164.0(M+H) +

[0059] The additives sodium bromide and sodium bicarbonate in Example 3 can be replaced by one or more combinations of triethylamine, diisopropylethylamin...

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Abstract

The present invention provides a new synthesis method of a baricitinib compound 11. According to the present invention, by using a compound 1 as a staring raw material, the amino group is protected by directly using ethanesulfonyl chloride, and direct cyclization is directly performed by using the effect of an alkali to obtain a key intermediate compound 3 so as to avoid the use of other protection groups and substantially improve the route efficiency and the atomic economy; during the compound 5 preparation, a Wittig reaction is performed by using triphenylphosphine acetonitrile so as to avoid the use of strong alkali and improve the reaction yield; the completely-new neopentyl glycol borate derivative compound 8 has good stability and good crystallinity so as to simplify the separation and purification process; and the route is simple to operate and has the high yield, the purity of the obtained product is high, and the synthesis method is suitable for amplification production. The formulas 1-11 are defined in the specification.

Description

Technical field [0001] The invention belongs to the field of medicine and chemical industry, and specifically relates to a new intermediate for rheumatoid arthritis drug baritinib, a method for synthesizing the same, and a method for preparing baritinib by using the intermediate. Background technique [0002] Baricitinib is a selective oral JAK1 / JAK2 inhibitor jointly developed by Eli Lilly and Incyte Pharmaceuticals. It can inhibit the intracellular signal transduction of a variety of inflammatory cytokines such as IL-6 and IL-23. , Used to treat autoimmune diseases and related inflammations, such as rheumatoid arthritis, psoriasis and diabetic nephropathy. EMA has approved baricitinib as a single agent or in combination with methotrexate on February 13, 2017 for the treatment of one or more disease-modifying anti-rheumatic drugs (DMARD) to relieve inadequate or intolerant moderate to severe activities Treatment of adult patients with rheumatoid arthritis (RA). [0003] The chem...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F5/02C07D487/04
CPCY02P20/55
Inventor 郑旭春张一平吴怡华
Owner HANGZHOU CHEMINSPIRE TECH CO LTD
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