A kind of related substance of tofacitinib and preparation method and application thereof
A technology of tofacitinib and related substances, which is applied in the field of medicinal chemistry, can solve problems such as insufficient research on process impurities, and achieve the effects of high purity, good stability, and simple synthesis process
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[0053] 3) Residual ammonia in sodium cyanide generates iminodiacetic acid and remains in nitrile acetic acid with N-alkylation reaction of chloroacetic acid in the preparation process of nitrile acetic acid;
[0054] 4) The iminodiacetic acid remaining in nitrile acetic acid is condensed with TF-M7 in the N-nitrile acetylation reaction of TF-M7 to form this impurity, which is named N,N'-diacetyl{(3R,4R) -4-Methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}imine.
[0055] Possible build routes are as follows:
[0056]
[0057] The inventors searched databases such as CAS (Scifinder), Reaxy, TLC (Pharmaceutical Standards) and literature on systematic quality research of Tofacitinib (J.Pharm.Biomed.Anal., 143(2017):17-25; Der Pharma Chemica, 2014, 6 (2): 11-19) after all do not find the research report of this compound, therefore confirm that it is a new compound.
[0058] Although the impurity is produced at a low level during the condensation reaction, ...
Embodiment 1
[0082] (1) Preparation of 2,2'-tert-butoxycarbonimino-diacetate methyl ester
[0083] Add iminodiacetic acid (1.33g), methanol (30ml) and methanesulfonic acid (0.3g) into a reaction flask, heat to reflux and stir to react for 7-8 hours, concentrate under reduced pressure to remove solvent; add sodium carbonate solution to neutralize To pH 6~7, extract with dichloromethane (2*20ml), separate liquids, take the organic phase, dry and cool down to 0~5°C, add triethylamine (0.5g), slowly drop di-tert-butyl dicarbonate Ester (3.3g, 1.5eq), then continue to stir and react at 25-35°C for 3-5 hours, and concentrate under reduced pressure to remove the solvent to obtain an oily substance.
[0084] (2) Preparation of 2,2'-tert-butoxycarbonimino-diacetic acid
[0085] Take the oily matter obtained in step (1), add tetrahydrofuran (30ml) and stir and mix well, after cooling to -10°C, slowly add lithium hydroxide aqueous solution (14ml, 5%), stir and react for 1 to 2 hours, add sodium chlo...
Embodiment 2
[0090] (1) Preparation of 2,2'-benzyloxycarbonimino-ethyl diacetate
[0091] Add iminodiacetic acid (0.66g), ethanol (30ml) and p-toluenesulfonic acid (0.2g) into the reaction flask, heat to reflux and stir for 5-6 hours, concentrate under reduced pressure to remove the solvent; add to the sodium carbonate solution Mix to pH 6~7, extract with dichloromethane (2*20ml), separate the layers, take the organic phase, dry it and cool it down to 0~5°C, add N,N-diisopropylethylamine (1.0g), Slowly add benzyl chloroformate (1.1g, 1.3eq) dropwise, then continue to stir the reaction at 30-40°C for 3-4 hours, concentrate under reduced pressure to remove the solvent, and obtain an oily substance.
[0092] (2) Preparation of 2,2'-benzyloxycarbonimino-diacetic acid
[0093] Take the oily product obtained in step (1), add 1,4-dioxane (30ml) and stir to mix evenly. After cooling down to -5°C, slowly add potassium hydroxide aqueous solution (20ml, 5%), and stir for 1-2 hour, add sodium chlori...
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