Triethylamine → (R)-2-tert-butyl 8-methyl 1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2,8 (1H)-dicarboxylate

HRID 1051813노트

반응식

HRID 1051813 반응식
[NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:4][C:3]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:18]([CH:29]([CH3:31])[CH3:30])[C:17]1=O.CCN(CC)CC.[Si](Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH:29]([C@H:18]1[N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:20][CH2:21][N:16]2[C:3]3[CH:4]=[C:5]([S:12]([CH3:15])(=[O:13])=[O:14])[C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:7][C:2]=3[N:1]=[C:17]12)([CH3:30])[CH3:31]

참가 물질

6

반응물 4

HCID 8471TriethylamineHCID 24816Silicon tetrachlorideHCID 516892Sodium BicarbonateHCID 89827925(R)-tert-butyl 4-(2-amino-4-(methoxycarbonyl)-5-(methylsulfonyl)phenyl)-2-isopropyl-3-oxopiperazine-1-carboxylate

생성물 1

HCID 89815749(R)-2-tert-butyl 8-methyl 1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2,8 (1H)-dicarboxylate수율 55%

시약·촉매·용매 1

HCID 6344Dichloromethane용매

실험 절차

To a 1 L round-bottom flask containing (R)-tert-butyl 4-(2-amino-4-(methoxycarbonyl)-5-(methylsulfonyl)phenyl)-2-isopropyl-3-oxopiperazine-1-carboxylate (25 g, 0.0532 mol) in dichloromethane (500 mL) were added Et3N (64.5 g, 0.638 mol, 12 eq.) and SiCl4 (27.1 g, 0.160 mol, 3 eq.). The mixture was stirred at rt overnight. The mixture was added dropwise to aq. NaHCO3 solution (54.1 g in 1 L of water, 0.644 mol, 12.1 eq.) at 0° C. slowly and adjusted to pH=8. The mixture was filtered and the aqueous layer was extracted with dichloromethane (3×600 mL). The combined organic layers were washed with brine, and then dried over anhydrous Na2SO4. The mixture was filtered and concentrated under vacuum to give the residue. The residue was purified by column chromatography on silica gel eluting with petroleum ether: EtOAc 2:1 to give (R)-2-tert-butyl 8-methyl 1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2,8(1H)-dicarboxylate (13.2 g, 55% yield) as a pale yellow solid. Analytical chiral HPLC: tR=9.03 min in 15 min chromatography (Method: OD-3_3_5_40_2.5 ML). LC-MS MS (ESI) m/z 452.2 [M+H]+. 1H NMR (CD3OD 400 MHz): δ 8.31 (s, 1H), 8.01 (s, 1H), 5.30-5.18 (m, 1H), 4.70-4.52 (m, 1H), 4.47 (dd, J=3.2 and 12.4 Hz, 1H), 4.18 (dt, J=5.2 and 11.6 Hz, 1H), 3.98 (s, 3H), 3.70-3.52 (m, 1H), 3.44 (s, 3H), 2.50-2.38 (m, 1H), 1.53 (s, 9H), 1.25 (d, J=6.8 Hz, 3H), 1.06 (d, J=6.8 Hz, 3H).

후처리

  1. filtrationThe mixture was filtered
  2. extractionthe aqueous layer was extracted with dichloromethane (3×600 mL)
  3. washThe combined organic layers were washed with brine
  4. dry with materialdried over anhydrous Na2SO4
  5. filtrationThe mixture was filtered
  6. concentrationconcentrated under vacuum
  7. customto give the residue
  8. customThe residue was purified by column chromatography on silica gel eluting with petroleum ether: EtOAc 2:1

출처 및 근거

ORD 기록
ord-f8d8cb6dff134713bd7f00aed42e7ca5
출처 데이터셋
uspto-grants-2016_07
특허 번호
US09388190B2

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