Dimethylamine → N-(4-Fluorobenzyl)-10-((((3R)-3-fluoro-1-pyrrolidinyl)(oxo)acetyl)(methyl)amino)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide

HRID 1093142Notes

Reaction equation

HRID 1093142 reaction equation
[F:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7](=[O:40])[C:8]([N:10]([CH3:39])[C:11]23[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]2)[CH2:14][N:13]2[C:20](=[O:38])[C:21]([O:29]C(C4C=CC=CC=4)=O)=[C:22]([C:24]([O:26]CC)=O)[N:23]=[C:12]32)=[O:9])[CH2:3]1.CNC.CO.[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][NH2:54])=[CH:49][CH:48]=1.C(N(CC)CC)C>C(O)C>[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][NH:54][C:24]([C:22]2[N:23]=[C:12]3[C:11]4([N:10]([C:8](=[O:9])[C:7]([N:4]5[CH2:5][CH2:6][C@@H:2]([F:1])[CH2:3]5)=[O:40])[CH3:39])[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19]4)[CH2:14][N:13]3[C:20](=[O:38])[C:21]=2[OH:29])=[O:26])=[CH:49][CH:48]=1

Participants

7

Reactant 5

HCID 674DimethylamineHCID 887MethanolHCID 8471TriethylamineHCID 673264-FluorobenzylamineHCID 66588806Ethyl 10-((((3R)-3-fluoro-1-pyrrolidinyl)(oxo)acetyl)(methyl)amino)-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate

Product 1

HCID 57905313N-(4-Fluorobenzyl)-10-((((3R)-3-fluoro-1-pyrrolidinyl)(oxo)acetyl)(methyl)amino)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamideYield 51%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
90 °C

Procedure

To a mixture of ethyl 10-((((3R)-3-fluoro-1-pyrrolidinyl)(oxo)acetyl)(methyl)amino)-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylat (35 mg, 0.063 mmol) in ethanol (2 mL) was added 2M dimethylamine in methanol (0.063 mL, 0.126 mmol) and the resulting mixture was heated at 50° C. for 1 h. (4-Fluorophenyl)methanamine (0.036 mL, 0.316 mmol) followed by triethylamine (0.044 mL, 0.316 mmol) were added and the mixture heated at 90° C. for 18 h. The reaction mixture was then cooled, concentrated and purified by preparative HPLC to afford the title compound (17 mg, 51% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ: 11.96 (1 H, brs), 9.45 (1 H, brs), 7.34-7.40 (2H, m), 6.97 (2 H, t, J=8.70 Hz), 5.32-5.39 (0.5 H, m), 5.20-5.29 (0.5 H, m), 4.76-4.86 (1 H, m), 4.56-4.67 (1 H, m), 4.40-4.52 (1 H, m), 3.86-3.93 (0.5 H, m), 3.74-3.82 (0.5 H, m), 3.34-3.71 (6 H, m), 3.03 (1.2 H, s), 3.02 (1.8 H, s), 2.49 (1 H, brs), 2.29-2.41 (1 H, m), 1.99-2.09 (4 H, m), 1.76-1.83 (2 H, m), 1.44-1.51 (1 H, m). LCMS (M+H)=530.61. HPLC purity: >95%.

Workup

  1. additionwere added
  2. temperatureThe reaction mixture was then cooled
  3. concentrationconcentrated
  4. custompurified by preparative HPLC

Sources & evidence

ORD record
ord-515a6599e9f2478d9a0779d39ab46bcb
Source dataset
uspto-grants-2012_03
Patent number
US08129398B2

Reaction notes

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