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New synthesis methods of JCK inhibitor baricitinib and intermediate thereof

A technology of baricitinib and synthetic methods, applied in the field of medicine and chemical industry, can solve the problems of expensive 3-hydroxyazetidine starting raw materials, unsatisfactory product yield and purity, poor stability of acetonitrile, etc., and achieve improvement The effect of route efficiency and atom economy, simplified separation and purification process, and simple operation

Active Publication Date: 2017-07-14
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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  • New synthesis methods of JCK inhibitor baricitinib and intermediate thereof
  • New synthesis methods of JCK inhibitor baricitinib and intermediate thereof
  • New synthesis methods of JCK inhibitor baricitinib and intermediate thereof

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°C, add hydrogen phosphate Dipotassium (34.84g, 200mmol), after stirring for 5 minutes, add ethylsulfonyl chloride (13.50g, 105mmol) dropwise. After the addition, warm up to room temperature and react for 3-4 hours. After the reaction, add 73mL of 0.5mol / L dilute hydrochloric acid to quench reaction, stirred and separated, the aqueous phase was extracted twice with ethyl acetate 35mL, the combined organic phase was washed once with saturated brine (73mL), dried over anhydrous sodium sulfate, and concentrated to obtain N-(3-chloro-2-hydroxypropane Base) The crude product of ethanesulfonamide was directly put into the next reaction (GC purity about 92%).

[0050] ESI m / z=202.1(M+H) + , 1 H NMR (400MHz, CDCl 3 )δ5.10-4.95(m,1H),4.00-3...

Embodiment 2

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

[0053]

[0054] Add N-(3-chloro-2-hydroxypropyl)ethanesulfonamide (prepared from Example 1) and N,N-dimethylformamide (100 mL) into a three-necked flask, stir to dissolve, cool to 0-5°C, Add potassium tert-butoxide (11.22g, 100mmol), keep stirring at 0-5°C for 15-20 minutes after the addition is complete, then raise the temperature to room temperature and react 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 of ethyl acetate, the combined organic phase was washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain crude 1-(ethylsulfonyl)azidine-3-ol, which was directly Submit 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,...

Embodiment 3

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

[0057]

[0058] Add 1-(ethylsulfonyl)azepin-3-ol (prepared by Example 2), sodium bromide (10.29g, 100mmol), sodium bicarbonate (12.6g, 150mmol), dichloromethane in the three-necked flask (83mL) and water (123mL), stirred evenly and cooled to -5~0℃, added TEMPO (312mg, 2mmol), added dropwise 10% sodium hypochlorite solution (81.9g, 110mmol), after the reaction was completed, the water The phase was extracted with dichloromethane (83mL) once more, the combined organic phase was washed once with sodium bisulfite solution (5%, 42mL), washed once with saturated brine (83mL), dried over sodium sulfate, and concentrated to give 1-( The crude ethylsulfonyl)azepin-3-one (GC purity about 83%) was directly put into the next reaction. ESI m / z=164.0(M+H) +

[0059] Additive sodium bromide and sodium bicarbonate can be replaced by one or more combinations of triethylamine, diisopropylethylamine, sodium acetate, sodium bicarbonate, sodi...

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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 in particular relates to a new intermediate of rheumatoid arthritis drug baricitinib, a synthesis method thereof, and a method for preparing baricitinib by using the intermediate. Background technique [0002] Baricitinib is a selective oral JAK1 / JAK2 inhibitor jointly developed by Eli Lilly and Incyte Pharmaceuticals, which can inhibit the intracellular signaling of various inflammatory cytokines such as IL-6 and IL-23 , for the treatment of 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 moderate to severe activity inadequately responded to or intolerant to one or more disease-modifying antirheumatic drug (DMARD) therapy Treatment of adult patients with rheumatoid arthritis (RA). [0003] Baricitinib chem...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02C07D487/04
CPCY02P20/55C07F5/025C07D487/04
Inventor 郑旭春张一平吴怡华
Owner HANGZHOU CHEMINSPIRE TECH CO LTD
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