Triethylamine → 6-chloro-4-cyclopropyl-4-isobutyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one

HRID 19708노트

반응식

HRID 19708 반응식
[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([CH:19]1[CH2:21][CH2:20]1)O.CCN(CC)CC.O=S(Cl)Cl.[CH2:33]([Mg]Br)[CH:34]([CH3:36])[CH3:35]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([CH:19]1[CH2:21][CH2:20]1)[CH2:33][CH:34]([CH3:36])[CH3:35]

참가 물질

6

반응물 4

HCID 8471TriethylamineHCID 24386Thionyl ChlorideHCID 593465896-chloro-4-cyclopropyl-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-oneHCID 178418816HCID 178418816, 화합물2회

생성물 1

HCID 118569796-chloro-4-cyclopropyl-4-isobutyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one

시약·촉매·용매 1

HCID 1140Toluene용매

실험 절차

To a 0° C. solution of 0.08 g (0.25 mmol) 6-chloro-4-cyclopropyl-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one in 3 mL toluene was added 0.17 mL (1.25 mmol) Et3N and 0.018 mL (0.25 mmol) SOCl2. After 20 min at 0° C. 1 mL (1 mmol, 1M solution in ether) isobutyl magnesium bromide was added and the reaction mixture was stirred 30 minutes before an additional 0.5 mL (0.5 mmol) isobutyl magnesium bromide was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was quenched with 75 mL saturated aqueous NH4Cl solution and extracted with 100 mL EtOAc. The extract was washed with 75 mL brine, dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (1×10 cm silica gel, linear gradient 10-35% EtOAc/hexanes) followed by preparative HPLC (YMC C18 PRO20×150 mm, linear gradient 5-95% CH3CN/H2O 0.05% added TFA, over 30 min) to afford afforded 6-chloro-4-cyclopropyl-4-isobutyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one. 1H NMR (CDCl3, 400 MHz) 8.17 (s, 1H); 7.43 (d, J=2.20 Hz, 1H); 7.15 (dd, J=2.38 and 8.61 Hz, 1H); 6.62 (d, J=8.42 Hz, 1H); 4.50 (dq, J=15.4 and 8.61 Hz, 1H); 3.96 (dq, J=15.4 and 8.60 Hz, 1H); 1.56 (m, 1H); 1.41 (dd, J=14.8 and 5.31 Hz, 1H); 1.23 (dd, J=14.8 and 5.68 Hz, 1H); 0.88 (m, 1H); 0.80 (d, J=6.59 Hz, 3H); 0.78 (m, 1H); 0.69 (m, 2H); 0.55 (d, J=6.59 Hz, 3H). High resolution mass spec (FT/ICR): calc M+H=361.1289, found 361.1283.

후처리

  1. additionwas added
  2. customThe reaction mixture was quenched with 75 mL saturated aqueous NH4Cl solution
  3. extractionextracted with 100 mL EtOAc
  4. washThe extract was washed with 75 mL brine
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customPurification by flash chromatography (1×10 cm silica gel, linear gradient 10-35% EtOAc/hexanes)
  9. additionfollowed by preparative HPLC (YMC C18 PRO20×150 mm, linear gradient 5-95% CH3CN/H2O 0.05% added TFA, over 30 min)
  10. customto afford

출처 및 근거

ORD 기록
ord-3e35d77232c34bffb41778aa2b37b6e3
출처 데이터셋
uspto-grants-2010_06
특허 번호
US07745452B2

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