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 80696Notes

Reaction equation

HRID 80696 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 59%

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 (1 g, 2.043 mmol) in CH2Cl2 (20 mL) was added oxalyl chloride (0.286 mL, 3.27 mmol). A few drops of DMF was then added and the mixture stirred at room temperature for 2 h. Solvent was removed under reduced pressure and the crude acid chloride was diluted with dichloromethane (10 mL) and added to a stirred solution of 1-amino-3-(4-fluorophenyl)propan-2-one HCl (0.458 g, 2.247 mmol) and triethylamine (1.139 mL, 8.17 mmol) in CH2Cl2 (20 mL). The resulting solution was stirred at room temperature for 16 h then 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 (770 mg, 1.206 mmol, 59.0% 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. customSolvent was removed under reduced pressure
  2. additionthe crude acid chloride was diluted with dichloromethane (10 mL)
  3. stirringThe resulting solution was stirred at room temperature for 16 h
  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-6c8fa33fad8345589d6fc329537d3f0c
Source dataset
uspto-grants-2014_09
Patent number
US08846659B2

Reaction notes

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