Triethylamine → 3-[2-((3-(Benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenyl]prop-2-ynyl methanesulfonate

HRID 1788207Notes

Reaction equation

HRID 1788207 reaction equation
[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([C:33]#[C:34][CH2:35][OH:36])[CH:3]=1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl.C(OCC)(=O)C>[CH3:44][S:45]([O:36][CH2:35][C:34]#[C:33][C:4]1[CH:3]=[C:2]([F:1])[CH:32]=[CH:31][C:5]=1[CH2:6][NH:7][C:8]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:28])[C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:30])[CH3:29])=[O:9])(=[O:47])=[O:46]

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 31297Methanesulfonyl chlorideHCID 21070008N-(4-Fluoro-2-(3-hydroxyprop-1-ynyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide

Product 1

HCID 210698463-[2-((3-(Benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenyl]prop-2-ynyl methanesulfonateYield 75.5%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of intermediate 182, N-(4-fluoro-2-(3-hydroxyprop-1-ynyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.280 g, 0.57 mmol) and triethylamine (0.12 ml, 0.86 mmol) in dichloromethane (5 ml) was cooled to 0° C., treated drop wise with methanesulfonyl chloride (0.050 ml, 0.64 mmol) and then stirred for 30 min. The reaction mixture was then diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Chromatography of the residue on silica gel (elution gradient of ethyl acetate in hexane) gave 0.245 g (75% yield) of the title material as a white solid. 1 HNMR 400 MHz (CDCl3) δ ppm: 1.65 (6H, s, 2×CH3), 3.10 (3H, s, SCH3), 4.05 (4H, m, 2×CH2), 4.67 (2H, d, J=6.1 Hz, NCH2), 5.03 (2H, s, CH2), 5.29 (2H, s, OCH2), 7.07 (1H, m, aromatic), 7.18 (1H,dd, J=2.5 Hz and J=9.1 Hz, aromatic), 7.32-7.36 (3H, m, aromatics), 7.38 (1H,dd, J=5.5 Hz and J=8.6 Hz, aromatic), 7.49-7.51 (2H, m, aromatics), 7.77 (1H, broad t, NH). MS (ESI+) m/e 570 [M+H+].

Workup

  1. washwashed with saturated sodium bicarbonate, brine
  2. dry with materialdried over anhydrous magnesium sulfate
  3. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-5f7f0c3b522a423c8e89db380a0e6ed4
Source dataset
uspto-grants-2009_03
Patent number
US07511037B2

Reaction notes

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