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Novel synthetic method for baricitinib and intermediate thereof

A baricitinib and synthetic method technology, applied in the field of medicine and chemical industry, can solve the problems of high operation risk, high process cost and low efficiency, and achieve the effects of shortening the reaction steps, high product purity and high yield

Active Publication Date: 2017-03-15
HANGZHOU CHEMINSPIRE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] This route prepares key intermediate 2-[1-(ethylsulfonyl)-3-azetidinylidene] acetonitrile steps are longer, and the price of diethyl cyanomethyl phosphate used is higher, resulting in high cost of this fragment ; Subsequent reactions need to use sodium hydride when using 2-(trimethylsilyl) ethoxymethyl protection, and the process amplification operation is dangerous; and it is necessary to remove 2-(trimethylsilyl) ethoxymethyl protecting Two-step reaction, low efficiency, high process cost

Method used

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  • Novel synthetic method for baricitinib and intermediate thereof
  • Novel synthetic method for baricitinib and intermediate thereof
  • Novel synthetic method for baricitinib and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052]

[0053] Add compound 1 (10.75g, 100mmol) and dichloromethane (86mL) into a three-necked flask, stir evenly, cool to 0-5°C, add diisopropylethylamine (38.77g, 300mmol), stir for 5-5°C after adding For 10 minutes, add ethylsulfonyl chloride solution (15.43g, 120mmol, dissolved in 21mL of dichloromethane) dropwise, and after the dropping, warm up to room temperature and react for 3-4 hours, add 108mL of 0.5mol / L dilute hydrochloric acid to quench the reaction, stir and divide liquid, and the aqueous phase was extracted twice with 43 mL of dichloromethane, and the combined organic phase was washed once with saturated brine (108 mL), dried over sodium sulfate, concentrated and separated by column chromatography with petroleum ether ethyl acetate mixed solvent to obtain compound 2 (14.20 g ,87%).

[0054] ESI m / z=164.1(M+1), 1 H NMR (300MHz, CDCl3): δ4.08(d, J=2.4Hz, 2H), 3.94(d, J=2.6Hz, 2H), 3.35-3.10(m, 2H), 1.40-1.20(m, 3H )ppm.

[0055] The base diisopropylethylam...

Embodiment 2

[0057]

[0058] Add compound formula 2 (16.32g, 100mmol), cyanoacetic acid (17.01g, 200mmol) and toluene (82mL) into the three-necked flask, stir evenly, add piperidine (17.03g, 200mmol), after the addition, heat up to reflux reaction 16 -24 hours, after the reaction is completed, cool to room temperature and add 326 mL of 0.5 mol / L dilute hydrochloric acid to quench the reaction, separate the layers, extract the aqueous phase with ethyl acetate (163 mL) once, combine the organic phases and wash with saturated brine twice (163 mL), After drying over sodium sulfate and concentrating, compound 3 (15.08 g, 81%) was obtained by column chromatography with a mixed solvent of petroleum ether and ethyl acetate. ESI m / z=187.2(M+1), 1 HNMR (DMSO-d6, 400MHz) δ5.45 (t, J = 2.4Hz, 1H), 4.79 (t, J = 2.8Hz, 2H), 4.72 (t, J = 2.4Hz, 2H), 3.10-2.90 ( m,2H), 1.52-1.25(m,3H).

[0059] In embodiment 2, additive pyridine can be replaced by piperidine, acetic acid or ammonium acetate; solvent ...

Embodiment 3

[0061]

[0062] Add 3 (18.62g, 100mmol), 4-iodo-pyrazole 4a (19.40g, 100mmol) and acetonitrile (93mLmL) into the three-necked flask, stir well and then add DBU (15.20g, 100mmol), heat up to 35~ React overnight at 40°C. Part of the acetonitrile was spun off at the end of the reaction, the reaction was quenched by adding 0.5mol / L dilute hydrochloric acid (186mL), the aqueous phase was extracted three times with ethyl acetate (93mL), the combined organic phases were washed twice with saturated brine (93mL), dried over sodium sulfate, After concentration, compound 5a (29.66 g, 78%) was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether. ESI m / z=381.1(M+1), 1 HNMR(DMSO-d6,400MHz)δ8.10(s,1H),7.62(s,1H),4.40(d,J=8.0Hz,2H),4.24(d,J=8.4Hz,2H),3.63( s,2H), 3.34-3.15(m,2H), 1.44-1.24(m,3H)ppm.

[0063] In Example 3, 4-iodo-pyrazole can be replaced by 4-chloro-pyrazole, and the basic substance 1,8-diazabicyclo[5.4.0]undec-7-ene can be diisopr...

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Abstract

The invention discloses a novel intermediate compound 5 of baricitinib. The compound 5 has stable properties, which is favorable for separation and purification. The invention also discloses a preparation method for the compound 5 and two schemes for preparing baricitinib from the baricitinib. The two schemes are simple in operation, shortened in reaction steps, high in yield and product purity and suitable for enlarged production. The compound 5 has a structural formula as defined in the specification. In the formula, X represents halogen, e.g., chlorine, bromine or iodine.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a new synthesis method of the rheumatoid arthritis drug baricitinib and its intermediate. Background technique [0002] Baricitinib is a selective oral JAK1 / JAK2 inhibitor developed jointly 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, etc. In a study involving more than 1,300 patients, Eli Lilly and Incyte's daily dose of baricitinib significantly improved RA symptoms compared with placebo after 12 weeks, meeting the primary endpoint. For two common clinical indicators of RA, the drug has also been proved to be superior to adalimumab (Humira), and has achieved the secondary goal of the study. The results of recent clinical studies have shown that the efficacy is significan...

Claims

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Application Information

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IPC IPC(8): C07D403/04C07D487/04C07D205/06
CPCC07D205/06C07D403/04C07D487/04
Inventor 郑旭春张一平吴怡华
Owner HANGZHOU CHEMINSPIRE TECH CO LTD
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