Acetic Acid → HCID 66594124, compound

HRID 1622940Notes

Reaction equation

[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:33])[C:15]([OH:32])=[C:16]2[C:29](=[O:30])[N:20]3[C@@H:21]([CH3:28])[CH2:22][CH2:23][N:24]([CH:25]([CH3:27])[CH3:26])[C@@H:19]3[CH2:18][N:17]2[CH:31]=1)=[O:12].N[C@@H:35]([CH3:42])[CH2:36][CH2:37]NC(C)C.[C:43](O)(=O)[CH3:44].[Cl:47][CH2:48]Cl>>[ClH:47].[ClH:47].[NH2:20][C@@H:21]([CH3:28])[CH2:22][CH2:23][NH:24][CH:25]([CH3:27])[CH3:26].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:33])[C:15]([O:32][CH2:48][C:35]2[CH:36]=[CH:37][CH:44]=[CH:43][CH:42]=2)=[C:16]2[C:29](=[O:30])[N:20]3[C@@H:21]([CH3:28])[CH2:22][CH2:23][N:24]([CH:25]([CH3:27])[CH3:26])[C@@H:19]3[CH2:18][N:17]2[CH:31]=1)=[O:12]

Participants

Reactant 4

HCID 176Acetic Acid

HCID 6344Dichloromethane

HCID 54713703HCID 54713703, compound

HCID 86637253HCID 86637253, compound

Product 2

HCID 66594124HCID 66594124, compoundYield 57%

HCID 86664873HCID 86664873, compound

Procedure

[(3S)-3-Aminobutyl](1-methylethyl)amine dihydrochloride was prepared in a similar manner as described in example Z-29, 1H NMR (400 MHz, CDCl3/CD3OD) δ 1.20-1.25 (m, 9H), 1.93-2.02 (m, 2H), 2.92 (m, 2H), 3.20-3.29 (m, 2H), 8.04 (br, <1H), 8.64 (br, <1H). b) (4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-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 (60 mg, 0.13 mmol) and free based [(3S)-3-aminobutyl](1-methylethyl)amine (55 mg, 0.42 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4S,12aS)—N-[(2,4-difluorophenyl)methyl]-4-methyl-1-(1-methylethyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (40 mg, 57%) 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-4-methyl-1-(1-methylethyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (17 mg, 50%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 1.02 (d, J=6.4 Hz, 3H), 1.07 (d, J=6.4 Hz, 3H), 1.33 (d, J=7.2 Hz, 8H), 1.55-1.58 (m, 1H), 1.94-2.03 (m, 1H), 2.70-2.77 (m, 1H), 2.81-2.86 (m, 1H), 3.11-3.18 (m, 1H), 4.17 (dd, J=3.0, 13.8 Hz, 1H), 4.32 (dd, J=3.2, 14.0 Hz, 1H), 4.48 (m, 1H), 4.59-4.69 (m, 2H), 4.97-5.00 (m, 1H), 6.77-6.83 (m, 2H), 7.33-7.39 (m, 1H), 8.28 (s, 1H), 10.50 (m, 1H), 12.55 (s, 1H); ES+ MS: 461 (M+1).

Sources & evidence

ORD record: ord-a4b625790bc940a3900a97136d6ce219
Source dataset: uspto-grants-2014_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08778943B2

Reaction notes

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