Carbon Dioxide → 1-Chloroisoquinoline-6-sulfonyl chloride

A 1 L round bottom flask was charged with 6-bromo-1-chloro-isoquinoline (10.1 g, 41.6 mmol) and diethyl ether (416 mL) and THF (41.6 mL, 41.6 mmol) to give a light yellow solution. The flask was cooled in a dry ice and acetone bath for 20 min, then 2.5 M n-butyllithium in hexanes (18.3 mL, 43.6 mmol) was added dropwise over 5 min to give a dark solution. After 10 min, LC/MS of an aliquot in MeOH showed conversion of 6-bromo-1-chloro-isoquinoline to mainly 1-chloroisoquinoline. Sulfur dioxide (g) was condensed into the reaction mixture from a lecture bottle (warmed by a warm water bath to make sure there was a positive pressure of SO2(g) which was monitored by an oil bubbler) using a needle for 15 min to give a yellow suspension. After 20 min, LC/MS of an aliquot in MeOH showed consumption of 6-bromo-1-chloro-isoquinoline to 1-chloroisoquinoline-6-sulfinic acid. The chlorination step should be performed at −78° C. Solid n-chlorosuccinimide (5.55 g, 41.6 mmol) was added in three portions at −78° C. The cold bath was removed and the mixture was warmed to room temperature. After 2 hours, 1.2 g of NCS and 100 mL of THF were added at room temperature. After stirring for another 30 min at room temperature, LC/MS of an aliquot in MeOH showed mainly sulfonyl chloride product. After another 30 min, the solid was filtered with an aid of 100 mL of THF. The yellow filtrate was concentrated and placed under vacuum overnight to afford a yellow solid. The next day, the solid was triturated with i-PrOH (30 mL) at room temperature, filtered quickly (left on the frit for less than 3 min), and dried under a vacuum to give a beige solid. The filtrate was concentrated, absorbed onto a plug of silica gel, and purified by chromatography through a silica gel column (120 g), eluting with a gradient of 0% to 20% EtOAc in heptane, to provide a second batch. MS (ESI): 262 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 7.82 (d, J=5.2 Hz, 1H), 8.23 (dd, J=9.00, 1.96 Hz, 1H), 8.53 (d, J=5.67 Hz, 1H), 8.58-8.65 (m, 2H).

1. customto give a light yellow solution
2. customto give a dark solution
3. customcondensed into the reaction mixture from a lecture bottle (
4. temperaturewarmed by a warm water bath
5. customfor 15 min
6. customto give a yellow suspension
7. waitAfter 20 min
8. customconsumption of 6-bromo-1-chloro-isoquinoline to 1-chloroisoquinoline-6-sulfinic acid
9. customshould be performed at −78° C
10. customThe cold bath was removed
11. waitAfter 2 hours
12. addition1.2 g of NCS and 100 mL of THF were added at room temperature
13. waitAfter another 30 min
14. filtrationthe solid was filtered with an aid of 100 mL of THF
15. concentrationThe yellow filtrate was concentrated
16. customplaced under vacuum overnight
17. customto afford a yellow solid
18. customThe next day, the solid was triturated with i-PrOH (30 mL) at room temperature
19. filtrationfiltered quickly (
20. waitleft on the frit for less than 3 min), and
21. customdried under a vacuum
22. customto give a beige solid
23. concentrationThe filtrate was concentrated
24. customabsorbed onto a plug of silica gel
25. custompurified by chromatography through a silica gel column (120 g)
26. washeluting with a gradient of 0% to 20% EtOAc in heptane
27. customto provide a second batch

ORD 기록

ord-cf4e6741996c4764b96dbb0a23b57dc6

출처 데이터셋

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US09012443B2