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Method for preparing tofacitinib

A technology of tofacitinib and its compound, which is applied in the field of preparation of tofacitinib, can solve the problems of hindering the domestic industrial production of tofacitinib citrate, unfavorable industrial production, and many by-products formed, so as to achieve low production cost, Ease of purification and simple operation

Active Publication Date: 2015-03-04
SHANDONG WEIFANG PHARMA FACTORY
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Problems solved by technology

[0008] As can be seen from the above preparation routes, these preparation methods all use N-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl]-7-H-pyrrole[2,3-d ] pyrimidine-4-amine is raw material, prepares tofacitinib (Tofacitinib) with cyanoacetate ester compound in basic catalytic condition next step reaction, and the yield of this preparation method of literature report is all lower than 60%, and the reaction time is long , the formation of more by-products requires column chromatography purification, which is not conducive to industrial production; more attention should be paid to the use of N-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl ]-7-H-pyrrole[2,3-d]pyrimidin-4-amine and cyanoacetate compounds one-step reaction to prepare tofacitinib synthetic route has been protected by international and domestic patents, hindering the future citrate Domestic industrial production of Tofacitinib; therefore, it is particularly important to develop new synthetic routes suitable for industrial production and form independent intellectual property rights of enterprises

Method used

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  • Method for preparing tofacitinib
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  • Method for preparing tofacitinib

Examples

Experimental program
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Effect test

Embodiment 1

[0030] The following examples help to understand the present invention, but do not limit the content of the present invention.

[0031] Example 1: 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino] with the structural formula shown in II Preparation of ethyl piperidin-1-yl}-3-oxopropionate

[0032] Add 240ml of anhydrous methanol, 24.5g of compound Ⅰ (0.1mol), 17.62g of diethyl malonate (0.11mol) and 11.1g of triethylamine (0.11mol) into a 500ml four-neck flask, stir and reflux for 9h, thin layer After the reaction was analyzed, methanol was removed under reduced pressure, 50 ml of water was added, extracted with ethyl acetate (120 ml*2), the organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and precipitated under reduced pressure to obtain 30.5 g of compound II. The yield is 85%.

[0033] MS: m / z 360.1 (MH + ); 1 HNMR(600 MHz)(CDCl3):1.05-1.10(3H,m), 1.22-1.31(1H,m), 1.69-1.72(1H,m), 1.87-1.91(1H,m),...

Embodiment 2

[0034] Example 2: 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino] with structural formula III Preparation of piperidin-1-yl}-3-oxopropionamide

[0035] Into a 500ml four-neck flask, add 200ml methanol, 17.97g compound II (0.05mol) and 18.8g 28% ammonia water (0.15mol) in sequence, stir and reflux for 3 hours, after the reaction is completed by TLC analysis, the solvent is removed under reduced pressure, and 50ml of water is added. Extract with methyl chloride (150ml*2), combine the dichloromethane layers, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 14.86g of compound III with a yield of 90%.

[0036] MS: m / z331 (MH + ); 1 HNMR(600MHz)(DMSO):0.99-1.02(3H,d), 1.53-1.82(2H,d), 2.35-2.41(1H,m), 3.16-3.17(1H,d), 3.27-.334(5H ,m), 3.49-3.51(1H,s), 3.66-3.91(2H,m), 5.76(1H,d), 6.55(1H,s), 6.95-7.02(1H,d), 7.13(1H,t ), 7.41-7.48(1H,d), 8.11(1H,m), 11.62-11.64(1H,m).

Embodiment 3

[0037]Example 3: 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino] with structural formula III Preparation of piperidin-1-yl}-3-oxopropionamide

[0038] Add 120ml of anhydrous methanol, 12.25g of compound I (0.05mol), 13.1g (0.1mol) of ethyl 3-amino-3-oxopropionate and 11.4g of DBU (0.075mol) into a 500ml four-necked flask, and stir and reflux for 12h , evaporated the solvent under reduced pressure, added 30ml of water to the residue, extracted with dichloromethane (100ml*2), collected the dichloromethane layer, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and precipitated under reduced pressure to obtain The residue was purified by dichloromethane / anhydrous methanol (10:1) column chromatography to obtain compound III.

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Abstract

The invention belongs to the technical field of medicines, and especially relates to a method for preparing tofacitinib. The method for preparing tofacitinib employs a compound with the structural formula shown as (I), and is characterized in that a compound with the structural formula shown as (III) is prepared from the compound I and a compound with the structural formula shown as (V) or a compound with the structural formula shown as (VI), and the compound III is subjected to a dewatering reaction under the condition of adding a dewatering agent, so that the tofacitinib product with the structural formula shown as (IV) is obtained. Tofacitinib is prepared through two new synthetic routines, the raw materials are cheap and easily obtained, the operation process is simple, the intermediate is easily purified, the total yield is high, the production cost is low, and the method is suitable for industrial amplified production.

Description

(1) Technical field [0001] The invention belongs to the technical field of medicine, in particular to a method for preparing tofacitinib. (2) Background technology [0002] The chemical system name of Tofacitinib (tofacitinib citrate) is 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d ]pyrimidin-4-yl)-piperidin-1-yl]-3-oxo-propionitrile citrate, the structural formula is as figure 1 , a Janus kinase inhibitor developed by Pfizer. On November 6, 2012, the U.S. Food and Drug Administration (FDA) approved the substance as a drug listing for the treatment of moderately to severely active rheumatoid arthritis (RA) that has insufficient response or intolerance to methotrexate therapy. Treatment of adult patients. [0003] Existing literature describes following several processing routes for preparing Tofacitinib: [0004] The earliest document related to the preparation of Tofacitinib is patent WO 2001042246, which refers to US patent US6956041 and Chinese patent ZL0081694...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 赵春涛李金姑杨龙冉东升
Owner SHANDONG WEIFANG PHARMA FACTORY
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