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Baricitinib intermediate and preparation method thereof and method for preparing baricitinib from the intermediate

A baricitinib and intermediate technology, applied in the field of small molecule drug preparation, can solve the problems of limited industrial production of compounds, complex by-products, numerous reaction routes, etc., and achieves good market application prospects, high product purity, and simple process steps. Effect

Active Publication Date: 2017-11-28
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Analyzing the above synthetic route, there are various reaction routes and complicated by-products greatly limit the industrial production of this compound

Method used

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  • Baricitinib intermediate and preparation method thereof and method for preparing baricitinib from the intermediate
  • Baricitinib intermediate and preparation method thereof and method for preparing baricitinib from the intermediate
  • Baricitinib intermediate and preparation method thereof and method for preparing baricitinib from the intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] (1) Preparation of compound 1

[0067] The preparation of compound 1 is an existing technology, and the method disclosed in the patent application with the international publication number WO 2009 / 114512Al can be referred to. In this example, compound 1 was directly purchased from the company.

[0068] (2) Preparation of compound 2

[0069] The synthetic route is:

[0070]

preparation example 1-1

[0072] Sodium hydride (0.260g, 0.011mol) was dissolved in tetrahydrofuran solvent in a three-necked flask protected by nitrogen, cooled to 0°C, compound 7 (1100ml, 6.72mmol, 1.15equiv) was dissolved in tetrahydrofuran solvent, and slowly added to the previous solution . The mixture was raised to room temperature (25° C.) for 1 hour, then cooled to 0° C., and reacted for 1 hour. Compound 1 (1.0 g, 5.84 mmol) was dissolved in tetrahydrofuran solvent, the above mixture was added slowly, and stirred for 1 hour. Rise to room temperature (25°C) and react overnight (12h). Quenched with cold water, and the solvent tetrahydrofuran was removed by rotary evaporation. Extracted with ethyl acetate, the aqueous layer was separated, and the organic layer was washed with brine. Dry over anhydrous magnesium sulfate, filter, concentrate, and purify by column chromatography to obtain 0.939 g of white solid with a yield of 83%.

[0073] The data of the HNMR of target product compound 2 are as...

preparation example 1-2

[0077] The alkali catalyst sodium hydride was replaced by potassium tert-butoxide, and the other reaction conditions remained unchanged, as in Preparation 1-1, and the yield of the final target compound 2 was 67%.

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Abstract

The invention discloses a baricitinib intermediate and a preparation method thereof, and a method for preparing baricitinib from the intermediate. The structure of the intermediate is disclosed as Formula (5). The preparation method of the intermediate comprises the following steps: carrying out reaction on diethyl cyanomethylphosphate and 1-boc-3-azacyclobutanone under the catalytic action of an alkali to obtain a compound 2 disclosed as Formula (2); removing the Boc group of the compound 2 to obtain a compound 3 disclosed as Formula (3); under alkaline conditions, carrying out reaction on the compound 3 and ethyl sulfonyl chloride to obtain a compound 4 disclosed as Formula (4); and in the presence of 1,8-diazabicyclo[5,4,0]hendecyne-7-ene, carrying out reaction on the compound 4 and pinacone 4-pyrazolylborate to obtain the intermediate. The method for preparing baricitinib from the intermediate comprises the following step: in the presence of a palladium catalyst and cesium fluoride, carrying out Suzuki coupling reaction on the intermediate and 6-chloro-7-deazapurine to obtain the baricitinib. The preparation method of baricitinib has the advantages of accessible raw materials and simple technique, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the preparation of small molecule drugs, in particular to an intermediate of pyrrolopyrimidine JAK inhibitor drug baricitinib, a preparation method thereof and a method for preparing baricitinib from the intermediate. Background technique [0002] Rheumatoid arthritis (RA) is an autoimmune disease characterized by persistent synovitis and progressive bone destruction in multiple joints, the pathogenesis of which has not yet been fully understood. Studies have shown that immune disorders in RA patients are mainly mediated by TNF-α, IL-1, IL-6 and other cytokines, which are activated through specific signaling pathways to exert their biological effects. JAK-STAT signaling pathway (Janus-activited kinase-signal transducer and cativator of transcriptions, JAK-STAT) is one of the important signal transduction pathways, which is widely involved in regulating the pathophysiological process of diseases, especially playing an important ...

Claims

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Application Information

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IPC IPC(8): C07F5/02C07D487/04
CPCC07D487/04C07F5/02
Inventor 吉民许娇娇王鹏王影蔡进
Owner SOUTHEAST UNIV
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