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

HRID 80689노트

반응식

HRID 80689 반응식
[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](O)=[O:35])[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][CH:45]([CH2:48][C:49]1[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=1)[C:46]#[N:47].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[CH2:17][CH2:16][CH:15]([CH2:20][CH2:19]1)[CH2:14][N:13]1[C:32](=[O:33])[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([C:34](=[O:35])[NH:44][CH:45]([C:46]#[N:47])[CH2:48][C:49]3[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=3)[N:11]=[C:12]21)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1

참가 물질

8

반응물 5

HCID 8471TriethylamineHCID 65578Oxalyl chlorideHCID 516892Sodium BicarbonateHCID 671165772-Amino-3-(4-fluorophenyl)propanenitrile hydrochlorideHCID 679603133-(Benzyloxy)-10-(((benzyloxy)carbonyl)amino)-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylic acid

생성물 1

HCID 117616854Benzyl(3-(benzyloxy)-2-((1-cyano-2-(4-fluorophenyl)ethyl)carbamoyl)-4-oxo-6,7,8,9-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl)carbamate수율 62%

시약·촉매·용매 2

HCID 6228Dimethylformamide촉매HCID 6344Dichloromethane용매2회

실험 절차

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 (180 mg, 0.368 mmol) in CH2Cl2 (2 mL) was added oxalyl chloride (0.051 mL, 0.588 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 (2 mL) and added to a stirred solution of 2-amino-3-(4-fluorophenyl)propanenitrile HCl (81 mg, 0.404 mmol) and triethylamine (0.205 mL, 1.471 mmol) in CH2Cl2 (2 mL) and the resulting solution was stirred at room temperature. After 16 h at room temperature, 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 (145 mg, 62% yield) as a light yellow solid. 1H NMR (500 MHz, CDCl3) δ: 7.82 (brs, 1H), 7.28-7.49 (m, 10H), 7.06-7.17 (m, 2H), 6.96 (t, 2H, J=8.39 Hz), 6.63 (brs, 1H), 5.27-5.40 (m, 2H), 5.00-5.14 (m, 2H), 4.07-4.14 (m, 3H), 2.77-2.92 (m, 2H), 2.64-2.78 (m, 2H), 2.49 (brs, 1H), 1.87-2.02 (m, 4H), 1.63-1.75 (m, 2H). LCMS (M+H)=636.19.

후처리

  1. concentrationthe mixture was concentrated under reduced pressure
  2. additionThe crude acid chloride was then diluted with dichloromethane (2 mL)
  3. stirringthe resulting solution was stirred at room temperature
  4. waitAfter 16 h at room temperature
  5. extractionextracted with dichloromethane (50 mL×3)
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customto give a yellow oil
  10. customThe crude product was then purified by silica gel chromatography (50-100% EtOAc/hexane)

출처 및 근거

ORD 기록
ord-2f713fab5a1d4e5998f97bd49de9c23a
출처 데이터셋
uspto-grants-2014_09
특허 번호
US08846659B2

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