Triethylamine → N'-(2-((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 1093128Notes

Reaction equation

HRID 1093128 reaction equation
[NH2:1][C:2]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][N:4]1[C:11](=[O:27])[C:12]([OH:26])=[C:13]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[O:16])[N:14]=[C:3]21.C[CH2:29][N:30](CC)[CH2:31]C.Cl[C:36](=[O:41])[C:37](OC)=[O:38].CNC.CO>C(Cl)Cl.CCO>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][NH:17][C:15]([C:13]2[N:14]=[C:3]3[C:2]4([NH:1][C:36](=[O:41])[C:37]([N:30]([CH3:31])[CH3:29])=[O:38])[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]4)[CH2:5][N:4]3[C:11](=[O:27])[C:12]=2[OH:26])=[O:16])=[CH:24][CH:23]=1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 79846Methyl chloroglyoxylateHCID 22497844Dimethylamine methanolHCID 5790475010-Amino-N-(4-fluorobenzyl)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide

Product 1

HCID 54747155N'-(2-((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 14.2%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 6344DichloromethaneSolvent

Procedure

To a stirred solution of 10-amino-N-(4-fluorobenzyl)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (50 mg, 0.134 mmol) in CH2Cl2 (2 mL) at 0° C. was added Et3N (0.094 mL, 0.671 mmol) followed by methyl 2-chloro-2-oxoacetate (0.1 mL, 0.671 mmol) and the resulting mixture was stirred at room temperature. After 16 h, the reaction mixture was concentrated to give crude product which was dissolved in EtOH (2 mL), treated with 2M dimethylamine/methanol (0.7 mL) and heated in a sealed tube at 85° C. for 2 h, cooled and purified by preparative HPLC to afford the title compound as a light yellow solid (9 mg, 13% yield). 1H NMR (500 MHz, CDCl3) δ: 12.00 (s, 1H), 8.60 (s, 1H), 8.17 (s, 1H), 7.36 (dd, 2H, J=8.55 and 5.49 Hz), 7.00-7.04 (m, 2 Hz), 4.54 (d, 2H, J=6.1 Hz), 4.16 (d, 2H, J=3.66 Hz), 3.28 (s, 3H), 2.91 (s, 3H), 2.50-2.56 (m, 3H), 2.06-2.10 (m, 2H), 1.92-1.99 (m, 2H), 1.70-1.74 (m, 2H). LCMS (M+H)=472.37. HPLC purity: >95%.

Workup

  1. concentrationthe reaction mixture was concentrated
  2. customto give crude product which
  3. temperatureheated in a sealed tube at 85° C. for 2 h
  4. temperaturecooled
  5. custompurified by preparative HPLC

Sources & evidence

ORD record
ord-f1fcb2da34804947b50b94c85b496ebc
Source dataset
uspto-grants-2012_03
Patent number
US08129398B2

Reaction notes

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