Potassium Carbonate → HCID 70819173, compound

HRID 575905Notes

Reaction equation

HRID 575905 reaction equation
[C:1]([O:5][C:6]([N:8]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:9]1[C:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][CH:22]=3)[CH:17]=2)=[N:11][C:12](Br)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:55][C:56]([C:60]1[CH:65]=[C:64](B2OC(C)(C)C(C)(C)O2)[CH:63]=[CH:62][N:61]=1)([CH3:59])[C:57]#[N:58]>C1(C)C=CC=CC=1.O>[C:1]([O:5][C:6]([N:8]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:9]1[C:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][CH:22]=3)[CH:17]=2)=[N:11][C:12]([C:64]2[CH:63]=[CH:62][N:61]=[C:60]([C:56]([C:57]#[N:58])([CH3:59])[CH3:55])[CH:65]=2)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 70819311HCID 70819311, compoundHCID 86680727tert-butyl (5-bromo-3-(3-(4-(((tert-butoxycarbonyl)(tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-yl)(tert-butoxycarbonyl)carbamate

Product 1

HCID 70819173HCID 70819173, compoundYield 68.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 1140TolueneSolvent2×

Conditions

Temperature
70 °C

Procedure

A mixture of tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-bromo-pyrazin-2-yl]isoxazol-3-yl]phenyl]methyl]-N-tetrahydropyran-4-yl-carbamate (110.0 g, 151 mmol), K2CO3 (41.6 g, 301 mmol), and 2-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]propanenitrile (41.0 g, 151 mmol) in toluene (770 mL) and water (220 mL) is stirred and degassed with N2 for 30 min. at 20° C. The catalyst Pd(dtbpf)Cl2 (1.96 g, 3.01 mmol) is added and the mixture is degassed for an additional 10 min. The mixture is heated at 70° C. until the reaction is complete. The mixture is cooled to ambient temperature, diluted with water (220 mL), and filtered through a bed of Celite. The organic phase is concentrated to remove most of the solvent. The concentrate is diluted with i-PrOH (550 mL). The resultant suspension is stirred for at least 1 h and then the solid is collected by filtration to afford a tan powder. The solid is dissolved in toluene (990 mL) and stirred with Biotage MP-TMT resin (18.6 g) for 2 h at ambient temperature. The resin is removed by filtration. The filtrate is concentrated then diluted with i-PrOH (550 mL) and then re-concentrated. Add i-PrOH (550 mL) and stir for 1 h at ambient temperature. Cool the suspension to 5° C. and collect the solid by filtration then dry to afford tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-[2-(1-cyano-1-methyl-ethyl)-4-pyridyl]pyrazin-2-yl]isoxazol-3-yl]phenyl]methyl]-N-tetrahydropyran-4-yl-carbamate (Compound I-1) (81.9 g; 68%, yield, 98.7 area % purity by HPLC) as a cream-colored powder.

Workup

  1. customdegassed with N2 for 30 min. at 20° C
  2. customthe mixture is degassed for an additional 10 min
  3. temperatureThe mixture is cooled to ambient temperature
  4. additiondiluted with water (220 mL)
  5. filtrationfiltered through a bed of Celite
  6. concentrationThe organic phase is concentrated
  7. customto remove most of the solvent
  8. additionThe concentrate is diluted with i-PrOH (550 mL)
  9. stirringThe resultant suspension is stirred for at least 1 h
  10. filtrationthe solid is collected by filtration
  11. customto afford a tan powder
  12. customThe resin is removed by filtration
  13. concentrationThe filtrate is concentrated
  14. additionthen diluted with i-PrOH (550 mL)
  15. concentrationre-concentrated
  16. stirringAdd i-PrOH (550 mL) and stir for 1 h at ambient temperature
  17. temperatureCool the suspension to 5° C.
  18. customcollect the solid
  19. filtrationby filtration
  20. customthen dry

Sources & evidence

ORD record
ord-b418b66c45ca42a2bbf74e0ace9108a7
Source dataset
uspto-grants-2015_05
Patent number
US09035053B2

Reaction notes

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