Triethylamine → n-{4-Fluoro-2-(methylcarbamoyl)benzyl}-3-benzyloxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide

HRID 1726608Notes

Reaction equation

HRID 1726608 reaction equation
[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH:13]([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:21]([OH:23])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:31][CH2:32][C:33]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:34]=1[C:35]([NH:37][CH3:38])=[O:36].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCl.C(OCC)(=O)C>[F:43][C:40]1[CH:41]=[CH:42][C:33]([CH2:32][NH:31][C:21]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:15][O:14][CH:13]3[CH3:20])=[O:23])=[C:34]([C:35](=[O:36])[NH:37][CH3:38])[CH:39]=1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 2724699PyBOPHCID 210698142-(Aminomethyl)-5-fluoro-n-methylbenzamide trifluoroacetate saltHCID 210698603-Benzyloxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylic acid

Product 1

HCID 21070023n-{4-Fluoro-2-(methylcarbamoyl)benzyl}-3-benzyloxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamideYield 100.2%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of intermediate 27, 3-benzyloxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylic acid (0.172 g, 0.54 mmol) and intermediate 39, 2-(aminomethyl)-5-fluoro-N-methylbenzamide trifluoroacetate salt (0.177 g, 0.60 mmol) in dichloromethane (10 ml) was treated at 22° C. with triethylamine (0.17 ml, 1.22 mmol) followed by benzotriazole-1-yloxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PYBOP) (0.340 g, 0.65 mmol). After 3 h, the reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine then dried over anhydrous magnesium sulfate. Evaporation of the solvent followed by chromatography of the residue on silica gel (elution gradient ethyl acetate 50-100% in toluene) gave 0.260 g (100% yield) of the title amide as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.70 (3H, d, J=6.6 Hz, CH3), 3.01 (3H, d, J=4.7 Hz, NCH3), 3.89 (2H, m, CH2), 4.14 (1H, m, CH), 4.29 (1H, m, CH), 4.53 (2H, d, J=6.7 Hz, NCH2), 4.69 (1H, q, J=6.6 Hz, OCH), 5.35 (2H, s, OCH2), 6.69 (1H, broad q, NH), 7.09 (1H, m, aromatic), 7.16 (1H, m, aromatic), 7.32 (3H, m, aromatics), 7.42 (1H, m, aromatic), 7.47 (2H, m, aromatics), 8.61 (1H, broad t, NH). HRMS (ESI+) calculated for C25H26FN4O5 [M+H+]: 481.1887: found: 481.1884.

Workup

  1. washwashed with saturated sodium bicarbonate and brine
  2. dry with materialthen dried over anhydrous magnesium sulfate
  3. customEvaporation of the solvent

Sources & evidence

ORD record
ord-ba0e19fef9a94ef980ba860e9dd97775
Source dataset
uspto-grants-2009_02
Patent number
US07491819B1

Reaction notes

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