Diisopropylethylamine → HCID 178472675, compound

HRID 454334Notes

Reaction equation

HRID 454334 reaction equation
OC(C1N=CC(C2N=C3[N:17]([C@H:22]4[CH2:27][CH2:26][C@H:25]([O:28][CH3:29])[CH2:24][CH2:23]4)C(=O)CNC3=NC=2)=CC=1)(C)C.Br[C:31]1[C:32]([NH:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N:33][CH:34]=[C:35]([Br:37])[N:36]=1.Cl.CO[C@H]1CC[C@H](N)CC1.CCN(C(C)C)C(C)C>[Cl-].[Na+].O.C(OCC)(=O)C.CN1C(=O)CCC1>[Br:37][C:35]1[N:36]=[C:31]([NH:17][C@H:22]2[CH2:27][CH2:26][C@H:25]([O:28][CH3:29])[CH2:24][CH2:23]2)[C:32]([NH:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N:33][CH:34]=1

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 57550751Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetateHCID 178496591HCID 178496591, compoundHCID 178496611HCID 178496611, compound

Product 1

HCID 178472675HCID 178472675, compoundYield 41%

Reagents, catalysts & solvents 3

HCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
127 °C

Procedure

7-(6-(2-Hydroxypropan-2-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (alternate approach). Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (1 equiv) and trans-4-methoxycyclohexanamine.hydrochloride (1.5 equiv), NMP and DIEA were combined and heated to 127° C. and maintained at that temperature for 18 h. Upon reaction completion, the mixture was cooled to 35° C. over 4 h. The batch was transferred to a mixture of ethyl acetate and 5% brine. The aqueous layer was removed and the organic layer containing the batch was washed successively with 5% brine and water. The organic layer containing the batch was concentrated by vacuum distillation to a low volume, cooled to ambient temperature and the solids were collected by vacuum filtration. The filter cake was washed with MTBE and the product was dried in a vacuum to give 41% yield of ethyl 2-(5-bromo-3-(trans-4-methoxycyclohexylamino)pyrazin-2-ylamino)acetate. A mixture of ethyl 2-(5-bromo-3-(trans-4-methoxycyclohexylamino)pyrazin-2-ylamino)acetate (1 equiv), water and 85% phosphoric acid (3:1) was heated to 80° C. over 1 h. Heating was maintained for 18 h to effect reaction completion. Upon reaction completion, the mixture was cooled to 25° C. and filtered to give a crude product as tan solid. The resulting solids were washed with water, slurried in water and filtered. The filter cake was washed with water until the pH of the filtrate was between 4 and 8. The resulting material was dried under vacuum to give 89% yield of 7-bromo-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. 7-Bromo-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1 equiv), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-(trimethylsilyloxy)propan-2-yl)pyridine (1 equiv), sodium carbonate (3 equiv) and PdCl2(AmPhos)2 (0.003 equiv) were combined in isopropanol and heated at 70° C. for 1.5 h. Standard work-up and purification afforded the protected compound in 93% yield. Deprotection using standard conditions for removal of a trimethylsilyl-group and isolation gave the title compound.

Workup

  1. temperaturemaintained at that temperature for 18 h
  2. customUpon reaction completion
  3. temperaturethe mixture was cooled to 35° C. over 4 h
  4. customThe aqueous layer was removed
  5. additionthe organic layer containing the batch
  6. washwas washed successively with 5% brine and water
  7. additionThe organic layer containing the batch
  8. concentrationwas concentrated by vacuum distillation to a low volume
  9. temperaturecooled to ambient temperature
  10. filtrationthe solids were collected by vacuum filtration
  11. washThe filter cake was washed with MTBE
  12. customthe product was dried in a vacuum

Sources & evidence

ORD record
ord-3fb6bba672c84c0295137e7c5f5e4e88
Source dataset
uspto-grants-2013_07
Patent number
US08492381B2

Reaction notes

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