Preparation method for and intermediate of pyrrolo six-membered heteroaromatic ring derivative
a technology of heteroaromatic rings and derivatives, which is applied in the field of preparation of pyrrolo six-membered heteroaromatic rings derivatives, can solve the problems of unfavorable industrial production methods, and achieve the effects of reducing side reactions, reducing product yield and increasing impurities, and reducing side effects
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preparation example 1
ing the starting material the compound of formula (A2) is as follows:
[0114]
[0115]Preparation of 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (2 kg, 12.96 mol) and dichloromethane (40 L) were added to a reaction flask at room temperature, and stirred to dissolve. Triethylamine (3.88 kg, 38.4 mol) and 4-dimethylaminopyridine (157.6 g, 1.28 mol) were added successively, and stirred to dissolve. A solution of p-toluenesulfonyl chloride (2.6 kg, 13.6 mol) in dichloromethane (30 L) was added dropwise at 0° C., followed by stirring at room temperature for 30 minutes. After TLC showed that the reaction was completed, the reaction solution was washed with water (16 L×3). The organic phases were combined, dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated and dried under reduced pressure to obtain the title product (3.9 kg, yield 97.7%).
[0116]MS m / z (ESI): 309.0 [M+1]
[0117]1H-NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.10-8.08 (d, ...
preparation example 2
the compound of formula (B2) was prepared by the known methods disclosed in the Example 1 of WO2008089636A1 (publication date 31 Jul. 2008) and the Example 5 of WO2013091539A1 (publication date 27 Jun. 2013).
[0118]MS m / z (ESI): 241.5 [M+1]
[0119]1H-NMR (400 MHz, CDCl3) δ 3.21 (m, 2H), 2.90-2.83 (m, 3H), 2.47-2.45 (m, 2H), 2.08 (s, 3H), 1.42-1.33 (m, 4H), 1.15 (s, 9H), 0.94 (s, 1H).
preparation example 3
ing the starting material the compound of formula (C) is as follows:
[0120](1) Preparation of 1-(isothiocyanatomethyl)-4-methoxybenzene
[0121]Methoxybenzylamine (14 kg), tetrahydrofuran (50 L) and triethylamine (26.8 kg) were added to a reactor, and stirred to dissolve. A solution of carbon disulfide (7.8 kg) in tetrahydrofuran (5 L) was added dropwise at 10-15° C. After completion of the dropwise addition, a solid was precipitated from the reaction solution, and the reaction was stirred at 10-20° C. for 30 minutes. A solution of p-toluenesulfonyl chloride (20.5 kg) in tetrahydrofuran (50 L) was added dropwise at 10-20° C. After completion of the dropwise addition, the reaction was stirred for 30 minutes. After TLC showed that the reaction was completed, the reaction solution was added with petroleum ether (30 L) and purified water (100 L) to extract, and two phases were separated. The organic phase was washed with dilute hydrochloric acid (40 L) until pH=4-5, and then washed with wat...
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