Dimethylamine → N'-(2-((3-Cyclopropyl-4-fluorobenzyl)carbamoyl)-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl)-N,N-dimethylethanediamide

HRID 1093131Notes

Reaction equation

HRID 1093131 reaction equation
[CH3:1][N:2]([C:4](=[O:36])[C:5]([NH:7][C:8]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][N:10]1[C:17](=[O:35])[C:18]([O:26]C(C3C=CC=CC=3)=O)=[C:19]([C:21]([O:23]CC)=O)[N:20]=[C:9]21)=[O:6])[CH3:3].CNC.Cl.[CH:41]1([C:44]2[CH:45]=[C:46]([CH2:51][NH2:52])[CH:47]=[CH:48][C:49]=2[F:50])[CH2:43][CH2:42]1.C(N(CC)CC)C>C(O)C>[CH:41]1([C:44]2[CH:45]=[C:46]([CH:47]=[CH:48][C:49]=2[F:50])[CH2:51][NH:52][C:21]([C:19]2[N:20]=[C:9]3[C:8]4([NH:7][C:5](=[O:6])[C:4]([N:2]([CH3:1])[CH3:3])=[O:36])[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16]4)[CH2:11][N:10]3[C:17](=[O:35])[C:18]=2[OH:26])=[O:23])[CH2:42][CH2:43]1

Participants

6

Reactant 4

HCID 674DimethylamineHCID 8471TriethylamineHCID 66588776Ethyl 10-(((dimethylamino)(oxo)acetyl)amino)-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylateHCID 66588843(3-Cyclopropyl-4-fluorophenyl)methanamine hydrochloride

Product 1

HCID 54747154N'-(2-((3-Cyclopropyl-4-fluorobenzyl)carbamoyl)-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl)-N,N-dimethylethanediamideYield 23.5%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
50 °C

Procedure

A suspension of ethyl 10-(((dimethylamino)(oxo)acetyl)amino)-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (0.025 g, 0.050 mmol) and dimethylamine (0.050 mL, 0.101 mmol) (2 M in methanol) in ethanol (1 mL) was stirred at 50° C. for 1 h. Added to the mixture were (3-cyclopropyl-4-fluorophenyl)methanamine hydrochloride salt (0.025 g, 0.126 mmol) and triethylamine (0.070 mL, 0.504 mmol) and the mixture stirred at 90° C. for 5 h. The mixture was cooled to room temperature and concentrated. The brown residue was purified by preparative HPLC: Solvent A=10% ACN/90% H2O/0.1% trifluoroacetic acid; Solvent B=90% ACN/10% H2O/0.1% trifluoroacetic acid; Start % B=0; Final % B=100; Gradient time=20 min; Stop time=23 min; Column=Sunfire 19×100 mm, C18, 5 μm. The resulting purple solid was triturated with hot methanol to give the title compound as a white solid (6.0 mg, 21% yield). 1H NMR (500 MHz, CDCl3) δ: 12.03 (1 H, s), 8.56 (1 H, t, J=5.49 Hz), 8.15 (1 H, s), 7.11-7.20 (1 H, m), 6.85-7.01 (2 H, m),4.49 (2 H, d, J=6.10 Hz), 4.16 (2 H, d, J=3.97 Hz), 3.28 (3 H, s), 2.91 (3 H, s), 2.42-2.65 (3 H, m), 2.01-2.18 (3 H, m), 1.86-2.00 (2 H, m), 1.71 (2 H, ddd, J=13.28, 6.56, 6.41 Hz), 0.90-1.02 (2 H, m), 0.67-0.80 (2 H, m). LCMS (M+H) calcd for C26H31FN5O5: 512.23; found: 512.24.

Workup

  1. additionAdded to the mixture
  2. stirringthe mixture stirred at 90° C. for 5 h
  3. temperatureThe mixture was cooled to room temperature
  4. concentrationconcentrated
  5. customThe brown residue was purified by preparative HPLC
  6. customGradient time=20 min
  7. customtime=23 min
  8. customThe resulting purple solid was triturated with hot methanol

Sources & evidence

ORD record
ord-9f9ccd6bd147444f93ea787bd1b8d993
Source dataset
uspto-grants-2012_03
Patent number
US08129398B2

Reaction notes

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