Preparation method of baricitinib

A baricitinib and intermediate technology, applied in the field of drug synthesis, can solve problems such as product loss and shorten reaction steps, and achieve the effects of low cost, easy availability of raw materials, and convenient operation

Active Publication Date: 2017-09-19
NANJING YOKO PHARMA +2
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  • Abstract
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Problems solved by technology

[0014] This process directly carries out Michael addition reaction with ethanesulfonyl-substituted azetidine starting material 10, so that intermediate 11 does not need to carry out amino protection and subsequent deprotection in Suzuki coupling reaction, shortening the reaction steps, but boron The separation of the acid ester intermediate 11 uses column chromatography, and the boric acid ester may be adsorbed due to partial hydrolysis into boric acid, resulting in a certain loss of product

Method used

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  • Preparation method of baricitinib

Examples

Experimental program
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Effect test

Embodiment 1

[0034] Preparation of 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (III)

[0035] 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (II, 15.00g, 0.098mol) was dissolved in 400mL THF, then potassium tert-butoxide (13.70g, 0.122mol) was added, and the reaction mixture was kept at room temperature Stir for 20 min. When the reaction exotherms, use an ice-water bath to assist cooling, add benzenesulfonyl chloride (15.6 mL, 0.122 mol) dropwise to the mixed solution, and stir for 3 hours after dropping. The reaction was stopped. After removing part of the solvent under reduced pressure, the reaction solution was slowly poured into 600mL ice-water mixture and stirred for 30 min. A large amount of solid was washed out. After filtration, it was vacuum dried to obtain a white solid, namely 4-chloro-7-(phenylsulfonyl)- 7H-pyrrolo[2,3-d]pyrimidine (25.64 g, yield 89.1%). MS m / z 294[M+1] + ; 1 H-NMR(400M,CDCl 3 ) δ: 8.78 (s, 1H), 8.22 (d, 2H), 7.65 (t, 1H), 7.57-7.55 (t, 1H), 6.73-6.72 (d, 1H) ...

Embodiment 2

[0037] Preparation of 7-(phenylsulfonyl)-4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (V)

[0038] At room temperature, 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (III, 10.00g, 0.034mol), water (50mL) and potassium carbonate (14.12g, 0.102mol) was added to a 500mL reaction flask, and then 4-pyrazoleboronic acid pinacol ester (IV, 7.93g, 0.041mol), DMF (100mL) and Pd (PPh 3 ) 4 (0.59 g, 0.511 mmol). The reaction mixture was heated to 80-85°C, and then kept warm and stirred for 4 hours. The reaction was monitored by TLC. After the reaction was complete, add 500 mL of ice-water mixture to the reaction flask and stir for 20 min. The solid was precipitated. After filtration, the crude product was dried. Then the crude product was dissolved by heating with 50 mL of isopropanol. Allow to cool to precipitate a solid, filter, and dry in vacuo to obtain a white solid, namely 7-(phenylsulfonyl)-4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (9.40g, The yield is 85.0%). M...

Embodiment 3

[0040] 3-(cyanomethyl)-3-(4-(7-benzenesulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1Hpyrazol-1-yl)aza Preparation of tert-butyl cyclobutane-1-carboxylate (VII)

[0041] At room temperature, add DMF (100mL), 7-(benzenesulfonyl)-4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (V , 9.40g, 0.029mol) and tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (VI, 6.20g, 0.032mol), stir and mix well, then add DBU dropwise to the reaction system (0.221g, 1.452mmol), continue to stir at room temperature for 14 hours. When the reaction was complete, the reaction mixture was quenched with water (150 mL) and acetonitrile (100 mL), the resulting mixture was stirred at room temperature for 30 min, filtered, and the solid was collected and washed with acetonitrile-water mixture (2:3v / v, 20mL×2). Dry under vacuum at 40-45℃ to obtain white solid, namely 3-(cyanomethyl)-3-(4-(7-benzenesulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) -1H pyrazol-1-yl)azetidine-1-carboxylic acid tert-butyl ester (13.86 g,...

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Abstract

The invention discloses a preparation method of baricitinib. The method comprises the following steps: performing a substitution reaction on 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (II) serving as a raw material and benzene sulfonyl chloride in the presence of an alkali to obtain an intermediate III; then, performing a Suzuki coupling reaction on the intermediate III and 4-pyrazole-4-boronic acid pinacol ester in the presence of a palladium catalytic system and an alkali to obtain an intermediate V; then performing a Michael addition reaction on the intermediate V and 3-(cyanomethylene)azetidine-1-tert-butyl formate in the presence of a catalyst to obtain an intermediate VII; then removing Boc protection from the intermediate VII under the action of hydrochloric acid to obtain an intermediate VIII; then performing a sulfoamidate reaction on the intermediate VIII and ethyl sulfonyl chloride in an organic solvent in the presence of an alkali to obtain an intermediate IX; lastly, removing benzenesulfonyl protection from the intermediate IX under the action of tetramethylammonium fluoride or tetrabutylammonium fluoride or a trihydrate of the tetramethylammonium fluoride or the tetrabutylammonium fluoride to obtain baricitinib (I). Compared with the prior art, the method has the advantages of adoption of readily-available raw materials, low cost, high product yield and easiness for industrial production.

Description

Technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for preparing pyrrolopyrimidine JAK inhibitor drug baritinib and its intermediate compound. Background technique [0002] Baricitinib (Olumiant, 1) is a selective JAK1 and JAK2 inhibitor jointly developed by Eli Lilly and its partner Incyte, which can inhibit a variety of inflammatory cytokines such as IL-6 and IL-23 Intracellular signaling, chemical name 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1-yl ]-3-azetidine acetonitrile, its structural formula is as shown in formula (I). This product has been approved by the European Union in 2017 for the treatment of moderate to severe rheumatoid arthritis, and adults who do not respond to or are intolerant to current rheumatoid arthritis drugs. It can be used as a single drug or with a wide range of Used together with methotrexate. [0003] [0004] The methods disclosed in the prior art for preparing bariti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 张峰车晓明黄晓静朱素华薛峪泉
Owner NANJING YOKO PHARMA
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