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With N-chloro-succinimide In tetrahydrofuran; dichloromethane at 90℃; for 2.5 h; Microwave irradiation
To a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (2.0 g, 10.64 mmol) indichloromethane/tetrahydrofuran (DCM/THF) (15 mL/6 mL) was added NCS (1 .70g, 12.76mmol). The mixture was heated to 90 °C under microwave irradiation for 2.5 hr. The solvent was removed in vacuo and the crude product was purified by flash column chromatography using a9:1 v/v Hexane:Ethyl acetate to afford the title compound (2.2 g, 93percent yield) as a white crystalline solid. MS m/z 223.48 [M+1].
93.4%
With N-chloro-succinimide In N,N-dimethyl-formamide at 20℃; for 24 h;
2,4-dicUoro-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 26.6 mmol) and N- cWorosuccinimide (5.3 g, 39.9 mmol) were dissolved in N,N-dimethylformamide (50.0 mL) and then stirred at room temperature for 24 hours. The organic layer was isolated, treated with magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was isolated by column chromatography to obtain a title compound (5.5 g, yield: 93.4percent). H NMR (500MHz, CD3OD) δ 7.54(s, 1H)
63.37%
With N-chloro-succinimide In tetrahydrofuran; dichloromethane at 25 - 90℃; for 2.5 h; Microwave irradiation
To a mixture of 2,4-dicholo-7H-pyrrolof2,3- djpyrimidine (1 g, 5.32 mmol) in THF (3 mL) and DCM ( 12 mL) was added NCS (852 mg, 6.38 mmol) in one portion at 25°C. The mixture was stirred under microwave at 90 °C for 2.5 h. LC/MS showed the reaction was completed. Two new peaks were shown on LC/MS and 74percent of desired (M+Ff" = 221 .9) was detected. The mixture was added to brine and extracted with DCM. The organics were dried over anhydrous Na^SO, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 50: 1-5 : 1), to yield the desired product as a yellow? solid (750 mg, 63.37percent). MI R (400 MHz, CDC13): δ 10,70 (s„ 1 H) 8.16 (s, 1 H) 4.14 (s, 3 H).
55%
With N-chloro-succinimide In N,N-dimethyl-formamide at 20℃; for 48 h;
Example 14: Synthesis of Compound XIII-12; Step 1: Synthesis of 2,4,5-trichloro-7H-pyrrolo[2,3-d]pyrimidine (2); 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine ( 1 , 2 g, 10.6 mmol) was dissolved in DMF ( 10 mL), NCS (2.13 g, 15.9 mmol) was added and stirred at RT for 48 h. Ice was added to the reaction mixture, scratched the solid, filtered and dried to afford 2,4,5-trichloro-7H-pyrrolo[2,3-d]pyrimidine (2, 1.29 g, 55percent). NMR (400 MHz, DMSO): δ 13.15 (s, 1 H, D20 exchangeable), 7.95 (s, I H).
Reference：
[1] Chemistry - A European Journal, 2015, vol. 21, # 34, p. 11976 - 11979
[2] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 5, p. 584 - 589
[3] Patent: WO2016/130920, 2016, A2, . Location in patent: Page/Page column 115
[4] Patent: WO2018/4306, 2018, A1, . Location in patent: Page/Page column 127
[5] Organic Letters, 2016, vol. 18, # 9, p. 1976 - 1979
[6] Journal of the American Chemical Society, 2014, vol. 136, # 19, p. 6908 - 6911
[7] Patent: WO2017/87905, 2017, A1, . Location in patent: Page/Page column 170
[8] Patent: WO2011/140338, 2011, A1, . Location in patent: Page/Page column 75
[9] Helvetica Chimica Acta, 2008, vol. 91, # 6, p. 1083 - 1105
[10] Patent: US2010/204221, 2010, A1, . Location in patent: Page/Page column 18
Multi-step reaction with 4 steps
1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C
1.2: 3 h / 20 °C
2.1: methanol / 1 h / 70 °C
3.1: potassium carbonate; tris-(dibenzylideneacetone)dipalladium(0); XPhos / iso-butanol / 6 h / 90 °C / Inert atmosphere
4.1: trifluoroacetic acid / dichloromethane / 3 h / 50 °C
4.2: 6 h
Multi-step reaction with 3 steps
1: sodium hydride; N,N-dimethyl-formamide / water / 3.83 h / 0 - 20 °C
2: methanol / 1 h / 20 - 70 °C
3: XPhos; tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate / iso-butanol / 6 h / 90 °C
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