Acetic Acid → HCID 86762536, compound

HRID 1622948Notes

Reaction equation

FC1C=C(F)C=CC=1C[NH:10][C:11]([C:13]1[C:14](=[O:37])[C:15]([OH:36])=[C:16]2[C:33](=[O:34])[N:20]3[C@@H:21]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:22][CH2:23][N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[C@@H:19]3[CH2:18][N:17]2[CH:35]=1)=[O:12].N[C@@H:39]([CH2:47][CH:48]([CH3:50])[CH3:49])[CH2:40][CH2:41]NCC(C)C.C(O)(=O)C.[Cl:55]CCl>>[ClH:55].[ClH:55].[NH2:20][C@@H:21]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:22][CH2:23][NH:24][CH2:25][CH:26]([CH3:27])[CH3:28].[O:34]=[C:33]1[N:20]2[CH2:21][CH2:22][CH2:23][NH:24][CH:19]2[CH2:18][N:17]2[CH:35]=[C:13]([C:11]([NH2:10])=[O:12])[C:14](=[O:37])[C:15]([O:36][CH2:50][C:48]3[CH:47]=[CH:39][CH:40]=[CH:41][CH:49]=3)=[C:16]12

Participants

Reactant 4

HCID 176Acetic Acid

HCID 6344Dichloromethane

HCID 54713618HCID 54713618, compound

HCID 86637254HCID 86637254, compound

Product 2

HCID 86664880HCID 86664880, compound

HCID 86762536HCID 86762536, compoundYield 66%

Procedure

[(3S)-3-Amino-5-methylhexyl](2-methylpropyl)amine dihydrochloride was prepared in a similar manner as described in example Z-32. 1H NMR (400 MHz, CDCl3/CD3OD) δ 0.87 (d, J=6.4 Hz, 6H), 0.97 (d, J=6.8 Hz, 6H), 1.34-1.41 (m, 1H), 1.45-1.52 (m, 1H), 1.58-1.66 (m, 1H), 2.01-2.13 (m, 2H), 2.72-2.73 (m, 2H), 3.03-3.06 (m, 2H), 3.29 (m, 2H), 8.07 (br, <1H), 8.71 (br, <1H). b) (4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-1,4-bis(2-methylpropyl)-6,8-dioxo 1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide. The title compound was made in two steps using a similar process to that described in example Z-2. 16a (80 mg, 0.17 mmol) and free based [(3S)-3-amino-5-methylhexyl](2-methylpropyl)amine (117 mg, 0.63 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4S,12aS)—N-[(2,4-difluorophenyl)methyl]methylpropyl)-6,8-dioxo-7-[(phenyl methyl)oxy]-1,2,3,4,6,8,12,12a octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (68 mg, 66%) as a film. This material was hydrogenated in a second step as described in example Z-2 to give (4S,12aS)—N-[(2,4-difluorophenyl)methyl]-7-hydroxy-1,4-bis(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (56 mg, 97%) as an off-white solid, 1H NMR (400 MHz, CDCl3) δ 0.74 (d, J=6.4 Hz, 3H), 0.84 (d, J=6.4 Hz, 3H), 0.97-1.00 (m, 6H), 1.37-1.83 (m, 5H), 2.03-2.12 (m, 2H), 2.21-2.28 (m, 1H), 2.77 (m, 1H), 2.90-2.93 (m, 1H), 4.19-4.40 (m, 3H), 4.59-4.70 (m, 2H), 4.96-4.97 (m, 1H), 6.77-6.83 (m, 2H), 7.33-7.39 (m, 1H), 8.28 (s, 1H), 10.47 (s, 1H), 12.59 (br, 1H); ES+ MS: 517 (M+1).

Sources & evidence

ORD record: ord-8bb4e780eb3744a09969e419aceac36e
Source dataset: uspto-grants-2014_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08778943B2

Reaction notes

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