Acetic Acid → HCID 66594547, compound

HRID 1622946Notes

Reaction equation

HRID 1622946 reaction equation
[CH:1]1([N:5]2[CH2:10][CH2:9][C@H:8]([CH3:11])[N:7]3[C:12](=[O:34])[C:13]4[N:14]([CH:16]=[C:17]([C:22]([NH:24][CH2:25][C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=5[F:33])=[O:23])[C:18](=[O:21])[C:19]=4[OH:20])[CH2:15][C@@H:6]23)[CH2:4][CH2:3][CH2:2]1.N[C@@H](C)CCN[CH:40]1[CH2:43][CH2:42][CH2:41]1.[C:45](O)(=O)[CH3:46].[Cl:49][CH2:50]Cl>>[ClH:49].[ClH:49].[NH2:7][C@@H:8]([CH3:11])[CH2:9][CH2:10][NH:5][CH:1]1[CH2:4][CH2:3][CH2:2]1.[CH:1]1([N:5]2[CH2:10][CH2:9][C@H:8]([CH3:11])[N:7]3[C:12](=[O:34])[C:13]4[N:14]([CH:16]=[C:17]([C:22]([NH:24][CH2:25][C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=5[F:33])=[O:23])[C:18](=[O:21])[C:19]=4[OH:20])[CH2:15][C@@H:6]23)[CH2:2][CH2:3][CH2:4]1.[CH:1]1([N:5]2[CH2:10][CH2:9][C@H:8]([CH3:11])[N:7]3[C:12](=[O:34])[C:13]4[N:14]([CH:16]=[C:17]([C:22]([NH:24][CH2:25][C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=5[F:33])=[O:23])[C:18](=[O:21])[C:19]=4[O:20][CH2:50][C:40]4[CH:43]=[CH:42][CH:41]=[CH:46][CH:45]=4)[CH2:15][C@@H:6]23)[CH2:2][CH2:3][CH2:4]1

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 6344DichloromethaneHCID 54713616HCID 54713616, compoundHCID 66594127HCID 66594127, compound

Product 3

HCID 54713616HCID 54713616, compoundHCID 66594547HCID 66594547, compoundYield 70%HCID 66594664HCID 66594664, compound

Procedure

[(3S)-3-Aminobutyl]cyclobutylamine dihydrochloride was prepared in a similar manner as described in example Z-47, 1H NMR (400 MHz, CDCl3/CD3OD) δ 1.23 (d, J=6.4 Hz, 3H), 1.69-2.26 (m, 8H), 2.83 (m, 2H), 3.31-3.33 (m, 1H), 3.55 (m, 1H), 8.08 (br, <1H), 9.07 (br, <1H). b) (4S,12aS)-1Cyclobutyl-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-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-aminobutyl]cyclobutylamine (96 mg, 0.68 mural) were reacted in dichloromethane (2 in L) with acetic acid to give (4S,12aS)-1-cyclobutyl-N-[(2,4-difluorophenyl)methyl]-4-methyl-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 (68 mg, 70%) as a film. This material was hydrogenated in a second step as described in example Z-2 to give (4S,12aS)-1-cyclobutyl-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (57 mg, 100%) as an off-white solid, 1H NMR (4.00 MHz, CDCl3) δ 1.31 (d, J=6.8 Hz, 3H), 1.46-1.70 (m, 4H), 1.91-2.12 (m, 4H), 2.52 (m, 1H), 2.90-2.93 (m, 1H), 3.06 (m, 1H), 4.16-4.29 (m, 3H), 4.57-4.66 (m, 2H), 4.99-5.05 (m, 1H), 6.75-6.82 (m, 2H), 7.32-7.38 (m, 1H), 8.20 (s, 1H), 10.44 (s, 1H), 12.51 (s, 1H); ES+ MS: 473 (M+1).

Sources & evidence

ORD record
ord-3b8a3e85caa644a79283e91d3aab125c
Source dataset
uspto-grants-2014_07
Patent number
US08778943B2

Reaction notes

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