Triethylamine → benzyl(3-(benzyloxy)-2-((3-(4-fluorophenyl)-2-oxopropyl)carbamoyl)-4-oxo-6,7,8,9-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl)carbamate

HRID 80691Notes

Reaction equation

HRID 80691 reaction equation
[CH2:1]([O:8][C:9]1[C:32](=[O:33])[N:13]2[CH2:14][CH:15]3[CH2:20][CH2:19][C:18]([NH:21][C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])([C:12]2=[N:11][C:10]=1[C:34]([OH:36])=O)[CH2:17][CH2:16]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:44][CH2:45][C:46](=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[CH2:25]([O:24][C:22](=[O:23])[NH:21][C:18]12[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]1)[CH2:14][N:13]1[C:32](=[O:33])[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([C:34](=[O:36])[NH:44][CH2:45][C:46](=[O:55])[CH2:47][C:48]3[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=3)[N:11]=[C:12]21)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1

Participants

8

Reactant 5

HCID 8471TriethylamineHCID 65578Oxalyl chlorideHCID 516892Sodium BicarbonateHCID 132906742-Propanone, 1-amino-3-(4-fluorophenyl)-, hydrochloride (1:1)HCID 67960313HCID 67960313, compound

Product 1

HCID 71100903benzyl(3-(benzyloxy)-2-((3-(4-fluorophenyl)-2-oxopropyl)carbamoyl)-4-oxo-6,7,8,9-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl)carbamateYield 77%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent2×

Procedure

To a solution of 3-(benzyloxy)-10-(((benzyloxy)carbonyl)amino)-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylic acid, Intermediate 4 (400 mg, 0.817 mmol) in CH2Cl2 (8 mL) was added oxalyl chloride (0.114 mL, 1.307 mmol) followed by 1 drop of DMF. After stirring for 2 h, the mixture was concentrated under reduced pressure. The crude acid chloride was then diluted with dichloromethane (5 mL)) and added to a stirred solution of 1-amino-3-(4-fluorophenyl)propan-2-one HCl (183 mg, 0.899 mmol) and triethylamine (0.456 mL, 3.27 mmol) in CH2Cl2 (8.00 mL) and the resulting solution stirred at room temperature. After 16 h the reaction mixture was poured into sat. NaHCO3 and extracted with dichloromethane (50 mL×3), dried (Na2SO4), filtered and concentrated to give a yellow oil. The crude product was then purified by silica gel chromatography (50-100% EtOAc/hexane) to afford the title compound (400 mg, 0.626 mmol, 77% yield) as a light yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.99 (1H, br. s.), 7.49 (2H, d, J=5.80 Hz), 7.28-7.37 (8H, m), 7.15 (2H, dd, J=8.55, 5.49 Hz), 7.01-7.04 (2H, m), 6.79 (1H, br. s.), 5.32 (2H, s), 5.06 (2H, s), 4.17 (2H, d, J=4.88 Hz), 4.12 (2H, d, J=3.66 Hz), 3.69 (2H, s), 2.67-2.78 (2H, m), 2.47 (1H, br. s.), 1.89-2.01 (4H, m), 1.64-1.72 (2H, m). LCMS (M+H)=640.04.

Workup

  1. concentrationthe mixture was concentrated under reduced pressure
  2. additionThe crude acid chloride was then diluted with dichloromethane (5 mL)) and
  3. stirringthe resulting solution stirred at room temperature
  4. extractionextracted with dichloromethane (50 mL×3)
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto give a yellow oil
  9. customThe crude product was then purified by silica gel chromatography (50-100% EtOAc/hexane)

Sources & evidence

ORD record
ord-730facc2e5cc470a999e5e1633875660
Source dataset
uspto-grants-2014_09
Patent number
US08846659B2

Reaction notes

Loading…