Water → tert-butyl 8-carbamoyl-6-chloro-7-(3-cyanophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

HRID 589869

Reaction equation

HRID 589869 reaction equation
Br[C:2]1[C:3]([C:19](=[O:21])[NH2:20])=[C:4]2[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:6][N:5]2[C:17]=1[Cl:18].[C:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)#[N:23].O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[C:19]([C:3]1[C:2]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([C:22]#[N:23])[CH:29]=2)=[C:17]([Cl:18])[N:5]2[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C:4]=12)(=[O:21])[NH2:20]

Participants

8

Reactant 4

HCID 962WaterHCID 10796Cesium carbonateHCID 27343253-Cyanophenylboronic acidHCID 66585083tert-butyl 7-bromo-8-carbamoyl-6-chloro-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

Product 1

HCID 66584843tert-butyl 8-carbamoyl-6-chloro-7-(3-cyanophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylateYield 53.5%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
100 °C

Procedure

To a solution under nitrogen of 6.50 g (17.2 mmol) of tert-butyl 7-bromo-8-carbamoyl-6-chloro-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in 200 ml of tetrahydrofuran are added 2.52 g (17.2 mmol) of 3-cyanophenylboronic acid (CAS 150255-96-2), 10 ml of water, 16.8 g (52.4 mmol) of caesium carbonate and 1.68 g (2.06 mmol) of a complex of 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) and dichloromethane (PdCl2(dppf).CH2Cl2—CAS 95464-05-4). The mixture is stirred for 6 hours at 100° C. and then for 15 hours at 80° C., then cooled to room temperature and filtered through Celite™. The Celite is rinsed with 200 ml of ethyl acetate and 30 ml of water are added to the combined filtrates. The organic phase is separated out by settling, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained is chromatographed on a column of silica gel, eluting with a mixture of 2 to 50% ethyl acetate in dichloromethane, to give 3.69 g of tert-butyl 8-carbamoyl-6-chloro-7-(3-cyanophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in the form of a white solid after recrystallization from ethyl acetate and drying at 60° C. under reduced pressure.

Workup

  1. waitfor 15 hours at 80° C.
  2. temperaturecooled to room temperature
  3. filtrationfiltered through Celite™
  4. washThe Celite is rinsed with 200 ml of ethyl acetate and 30 ml of water
  5. additionare added to the combined filtrates
  6. customThe organic phase is separated out
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customThe residue obtained
  11. customis chromatographed on a column of silica gel
  12. washeluting with a mixture of 2 to 50% ethyl acetate in dichloromethane

Sources & evidence

ORD record
ord-13170ad184914cfabac933b17516cdaa
Source dataset
uspto-grants-2016_01
Patent number
US09233965B2

Linked notes

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