Synthesis of the 7H-Pyrrolo[2,3-d]pyriMidin-4-aMine,N-Methyl-N-[(3R,4R)-4-Methyl-1-(phenylMethyl)-3-piperidinyl]-

General Description

7H-Pyrrolo[2,3-d]pyriMidin-4-aMine,N-Methyl-N-[(3R,4R)-4-Methyl-1-(phenylMethyl)-3-piperidinyl]-, as a heterocyclic derivatives, is synthetic hydrazine. It can be used as the most critical intermediate of tolfortib citrate directly affects the quality of the final product, taufi citrate. For example, the previous research has described that this intermediate can be used to synthetize the tofacitinib aspartate.[1]

Figure1 7H-Pyrrolo[2,3-d]pyriMidin-4-aMine, N-Methyl-N-[(3R,4R)-4-Methyl-1-(phenylMethyl)-3-piperidinyl]- powder

Preparation

The first method:The raw materials 4-chloro-7H-pyrrolo[2,3-D]pyrimidine (compound 1,76.78g, 0.5mol), p-toluenesulfonyl chloride (106.76g, 0.56mol) and 450mL acetone were added to the reaction flask respectively, 240 mL of 2.5 mol/L sodium hydroxide solution was slowly added dropwise, and the reaction was carried out at room temperature for 4 to 5 hours, followed by TLC until the reaction was complete. 300mL of water was added to the reaction solution, a large amount of solid was precipitated, filtered, the filter cake was washed with acetone-water (v/v=1:4), and then dried under reduced pressure to obtain 137.6g of off-white solids, namely 4-chloro-7-p-toluene Sulfonyl-7H-pyrrolo[2,3-D]pyrimidine (compound 2), yield 93.7%. In the reaction flask, respectively add compound 2 (135.12g, 0.46mol) and (3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine (compound 3) (87.34g, 0.4 mol), potassium carbonate (387g, 2.8mol) and tetrahydrofuran-water mixed solution (v/v=4:1) 1000mL, heated under reflux for 8~10 hours, followed by TLC until the reaction was complete. After removing most of the solvent by rotary evaporation, ethyl acetate and water were added to the residual liquid for extraction, the organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was regenerated. After crystallization, 217.89 g of white solid, N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7-p-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (compound 4), yield 85.5%.compound 4 (76.45g, 0.3mol), potassium hydroxide (33.66g, 0.6mol) and 1300mL methanol were added to the reaction flask, heated to 40~50℃, reacted for 3~4 hours, followed by TLC to the reaction completely. After removing most of the solvent by rotary evaporation, ethyl acetate and water were added to the residual liquid for extraction, the organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 93.28g of light gray The brown solid is 7H-Pyrrolo[2,3-d]pyriMidin-4-aMine,N-Methyl-N-[(3R,4R)-4-Methyl-1-(phenylMethyl)-3-piperidinyl]-, the yield was 92.7%.[2]

The second method:1 to 3 parts of 4-chloro-7-p-toluenesulfonylpyrrolo[2,3-d]pyrimidine, 0.4 to 2 parts of 1-benzyl-4-methyl-3-methyl are weighed by weight ratio Aminopiperidine dihydrochloride, 0.2 to 2 parts of potassium carbonate, 0.1 to 1.0 part of sodium hydroxide, 6 to 15 parts of n-butanol, reserved;4-Chloro-7-p-toluenesulfonylpyrrolo[2,3-d]pyrimidine,1-benzyl-4-methyl-3-methylaminopiperidine dihydrochloride, potassium carbonate and water are sequentially added to In the reaction vessel, the mixture is heated to 70-90℃, the reaction is kept for 0.5 to 2 h, then lowered to room temperature, filtered, washed with ethanol, and dried under reduced pressure to give a white solid;The white solid, sodium hydroxide and n-butanol are sequentially added to the reaction vessel, heated to 80-100℃, cooled to room temperature, purified water is added, extracted with dichloromethane, and the organic phase is separated, repeated 2 to 4 times, and combined. The organic phase;The organic phase of step 3) is washed with water, and then anhydrous with anhydrous magnesium sulfate added to the organic phase to give N-[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-N-a dichloromethane extract of methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;The methylene chloride extract obtained in the step 4) is concentrated and dried to obtain an oily substance. The organic solvent is added to the oil at a weight ratio of 1. to 5, and the oil is solidified by stirring at room temperature, and then heated to reflux to dissolve and then decolorized with activated carbon. Filtration at a temperature of 75-85℃to obtain a clear filtrate;The filtrate is uniformly stirred by cooling and stirring, and the precipitated crystals are collected by filtration at 20 to 30℃, and the solvent is removed under reduced pressure at a temperature of 40 to 50℃ to obtain a white crystal, that is, 7H-Pyrrolo[2,3-d]pyriMidin-4-aMine,N-Methyl-N-[(3R,4R)-4-Methyl-1-(phenylMethyl)-3-piperidinyl]- crystal, the yield of the crystal is 91 to 96%, purity ≥ 99.9%.[3]

Reference

[1]Avirneni, Srirama Krishna.NovelTofacitinib addition salts and process for the preparation thereof[P].WO2018172821.2015.12.31.

[2]Qian X, Ding Q,et al. Preparation method of tofacitinib as JAK inhibitor with high yield[P].CN 114685515.2022.07.01.

[3]Chen L,Liu J.Process for preparation of crystalline Tasocitinib intermediate[P].CN 105153166.2015.12.16.

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