Pyridine → HCID 67331493, compound

HRID 1672367Notes

Reaction equation

HRID 1672367 reaction equation
N1C=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7]([O:11][C:12](=[O:30])[NH:13][CH2:14][CH2:15][S:16]([C:19]1[C:20]2[CH:21]=[CH:22][N:23]=[CH:24][C:25]=2[CH:26]=[C:27](Cl)[CH:28]=1)(=[O:18])=[O:17])([CH3:10])([CH3:9])[CH3:8].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[C:40]([O-:43])([O-])=[O:41].[K+].[K+]>O.C(O)C>[C:7]([O:11][C:12](=[O:30])[NH:13][CH2:14][CH2:15][S:16]([C:19]1[C:20]2[CH:21]=[CH:22][N:23]=[CH:24][C:25]=2[CH:26]=[C:27]([C:34]2[CH:35]=[CH:36][C:31]([O:41][CH:40]3[CH2:5][CH2:4][CH2:3][CH2:2][O:43]3)=[CH:32][CH:33]=2)[CH:28]=1)(=[O:18])=[O:17])([CH3:10])([CH3:9])[CH3:8]

Participants

7

Reactant 4

HCID 1049PyridineHCID 11430Potassium CarbonateHCID 66827Phenylboronic AcidHCID 67331522HCID 67331522, compound

Product 1

HCID 67331493HCID 67331493, compoundYield 64.36%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 962WaterSolvent2×

Conditions

Temperature
78 °C

Procedure

The 60 L reactor is charged with PEPPSI™ (Pyridine-Enhanced Precatalyst Preparation Stabilization and Initiation; 51.0 g; 74.9 mmoles), [2-(7-Chloro-isoquinoline-5-sulfonyl)-ethyl]-carbamic acid tert-butyl ester (1.383 kg; 3.729 moles), phenyl boronic acid (895 g; 4.03 moles), K2CO3 (1.039 kg; 7.518 moles), and ethanol (15 L) under a nitrogen purge. Initially 12 L of ethanol is added to the reactor and the remaining 3 L was used to rinse in the other charges. The reaction is warmed to reflux (78° C.). HPLC indicates a complete reaction after ½ hour. The reaction is cooled to 59° C. using the Huber® circulator. Water (8.7 L) is added to the reaction over 18 minutes. The temperature is decreased from 59° C. to 42° C. during the water addition. The reaction is cooled using the Huber® circulator from 42° C. to 0° C. over 1 hour. The slurry is held at 0° C. for 1 hour. The solid is filtered using a polypropylene pad and washed with 1:1 ethanol:water (3.7 L; chilled). The solid is dried on the filter overnight. The solid is then dried in vacuo at 60° C. for 22 hours. The dry weight of the solid is 2.171 kg. The Pd level in the crude (2-{7-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-isoquinoline-5-sulfonyl}-ethyl)-carbamic acid tert-butyl ester is 2196 mcg/g and the solid contains 6.9% water by KF. A 50 L bottom outlet flask is charged with dichloromethane (4 L). The crude (2-{7-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-isoquinoline-5-sulfonyl}-ethyl)-carbamic acid tert-butyl ester is charged to the 50 L flask and rinsed in with dichloromethane (1 L). Na2SO4 (1.9 kg) is charged and rinsed in with dichloromethane (0.1 L). Darco G-60® (3.8 kg) is charged to a 20 L Büchi flask and slurried in dichloromethane (12 L). This slurry is transferred to the 50 L flask and rinsed in with dichloromethane (4.9 L). The mixture is stirred for 2 hrs at ambient temperature. A 50 cm stainless steel filter is fitted with a polypropylene pad and charged with Hyflo Super Cel® (1.7 kg). The Hyflo Super Cel® pad is rinsed with dichloromethane (2 L). The contents of the 50 L flask are filtered onto the Hyflo Super Cel® pad. The flask and filter cake are rinsed with dichloromethane (22 L). The filtrate is charged to the 60 L reactor through a 0.45 micron cartridge filter. The contents of the reactor are warmed and concentrated by distillation under slight vacuum (˜640 mm Hg). Approximately 33 L of distillate is collected over 2 hrs at 35-37° C. Ethanol (10 L) is added. The vacuum is adjusted slowly down to 280 mm Hg while continuing the distillation. Once the vacuum is reached, the temperature is increased to maintain the distillation. Once the volume in the reactor reaches ˜10 L, ethanol (6.5 L) is added at such a rate to maintain the volume in the reactor while distilling out solvent. The distillation is stopped once all the ethanol is added. The final volume is ˜10 L. The temperature at the end of the distillation is 56° C. The slurry that forms during the solvent exchange is cooled to 20° C. and held overnight. The slurry is filtered. The solid is washed with 1:1 ethanol:water (1.8 L). The wet cake weight is 1.878 kg. The solid is dried in vacuo at 50° C. to give 1.2306 kg (64.36% yield) (2-{7-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-isoquinoline-5-sulfonyl}-ethyl)-carbamic acid tert-butyl ester. Mass Spectrum (LCMS) m/z=513.62) (M+H).

Workup

  1. custompurge
  2. additionInitially 12 L of ethanol is added to the reactor
  3. washto rinse in the other charges
  4. temperatureThe reaction is warmed
  5. customa complete reaction after ½ hour
  6. temperatureThe reaction is cooled to 59° C.
  7. temperatureThe reaction is cooled
  8. customfrom 42° C. to 0° C.
  9. customover 1 hour
  10. filtrationThe solid is filtered
  11. washwashed with 1:1 ethanol
  12. customThe solid is dried on the filter overnight
  13. customThe solid is then dried in vacuo at 60° C. for 22 hours
  14. additionA 50 L bottom outlet flask is charged with dichloromethane (4 L)
  15. additionThe crude (2-{7-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-isoquinoline-5-sulfonyl}-ethyl)-carbamic acid tert-butyl ester is charged to the 50 L flask
  16. washrinsed in with dichloromethane (1 L)
  17. additionNa2SO4 (1.9 kg) is charged
  18. washrinsed in with dichloromethane (0.1 L)
  19. additionDarco G-60® (3.8 kg) is charged to a 20 L Büchi flask
  20. washrinsed in with dichloromethane (4.9 L)
  21. filtrationA 50 cm stainless steel filter
  22. customis fitted with a polypropylene pad
  23. additioncharged with Hyflo Super Cel® (1.7 kg)
  24. washThe Hyflo Super Cel® pad is rinsed with dichloromethane (2 L)
  25. filtrationThe contents of the 50 L flask are filtered onto the Hyflo Super Cel® pad
  26. filtrationThe flask and filter cake
  27. washare rinsed with dichloromethane (22 L)
  28. additionThe filtrate is charged to the 60 L reactor through a 0.45 micron cartridge
  29. filtrationfilter
  30. temperatureThe contents of the reactor are warmed
  31. concentrationconcentrated by distillation under slight vacuum (˜640 mm Hg)
  32. distillationApproximately 33 L of distillate is collected over 2 hrs at 35-37° C
  33. additionEthanol (10 L) is added
  34. distillationthe distillation
  35. temperaturethe temperature is increased
  36. temperatureto maintain
  37. distillationthe distillation
  38. additionis added at such a rate
  39. temperatureto maintain the volume in the reactor
  40. distillationwhile distilling out solvent
  41. distillationThe distillation
  42. additionis added
  43. distillationThe temperature at the end of the distillation
  44. customis 56° C
  45. temperatureis cooled to 20° C.
  46. waitheld overnight
  47. filtrationThe slurry is filtered
  48. washThe solid is washed with 1:1 ethanol
  49. customThe solid is dried in vacuo at 50° C.

Sources & evidence

ORD record
ord-309ee5d6929847a289029b72fa1da3af
Source dataset
uspto-grants-2011_08
Patent number
US07998977B2

Reaction notes

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