Carbamate → N-((3S)-4-(allyloxy)-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-2-(6-(trifluoromethyl)quinazolin-4-ylamino)acetamide

HRID 564415노트

반응식

HRID 564415 반응식
[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][NH:7][C:6]2=O.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.Cl.[NH2:24][CH2:25][C:26]([NH2:28])=[O:27].[C:29](N)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=CC=1.FC(F)(F)C1C=[C:42](C=CC=1)[C:43]([NH:45][CH2:46][C:47]([OH:49])=O)=O.C(=O)([O-])N.[CH2:59]1[CH2:69]CN2C(=NCCC2)C[CH2:60]1>ClC(Cl)C.C(#N)C.C1(C)C=CC=CC=1>[CH2:69]([O:49][CH:47]1[CH2:46][N:45]([CH:35]2[CH2:30][CH2:29][O:36][CH2:33][CH2:34]2)[CH2:43][C@@H:42]1[NH:28][C:26](=[O:27])[CH2:25][NH:24][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1)[CH:59]=[CH2:60]

참가 물질

11

반응물 7

HCID 276CarbamateHCID 2331BenzamideHCID 24819Phosphorus pentachloride2회HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 2777432((3-(Trifluoromethyl)benzoyl)amino)acetic acidHCID 203793052-Aminoacetamide-bis-hydrochloride saltHCID 1357451556-(Trifluoromethyl)quinazolin-4(1H)-one

생성물 1

HCID 57814147N-((3S)-4-(allyloxy)-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-2-(6-(trifluoromethyl)quinazolin-4-ylamino)acetamide수율 18%

시약·촉매·용매 3

HCID 1140Toluene용매HCID 6342Acetonitrile용매HCID 63651,1-Dichloroethane용매

실험 절차

A solution of 6-(trifluoromethyl)quinazolin-4(3H)-one (84 mg, 0.39 mmol, prepared according to WO2005021500A), PCl5 (106 mg, 0.507 mmol) in dichloroethane was sealed in a microwave-safe tube and was microwaved for 3000 seconds reaching an internal temperature of 170° C. An additional portion of PCl5 (25 mg) was added and the mixture was again microwaved for 3000 seconds reaching an internal temperature of 170° C. The mixture was transferred to a flask, toluene was added, then was concentrated. The resulting 4-chloro-6-trifluoromethyl)quinazoline (used without further purification) was dissolved in acetonitrile (2 mL) and was added to a 0° C. cooled mixture of rel-N-[(3R,4R)-4-<allyloxy)-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]-2-aminoacetamide-bis-hydrochloride salt (139 mg, 0.309 mmol, prepared in similar fashion to rel-N-(2-{[(3R,4R)-4-(allyloxy)-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-trifluoromethyl)benzamide, substituting [(tert-butoxycarbonyl)amino]acetic acid for {[3-(trifluoromethyl)benzoyl]amino}acetic acid and the resulting tert-butyl rel-(2-{[(3R,4R)-4-allyloxy)-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)carbamate was deprotected under standard HCl/dioxane conditions), DBU (0.292 mL, 1.95 mmol) and acetonitrile (3.5 mL). The mixture was warmed to RT and after 150 min. was quenched with K2CO3 (1M solution) and EtOAc. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography (15% MeOH, 1% NH4OH in EtOAc) to afford the title compound (34 mg, 18%) as a white solid. 1H-NMR (DMSO-d6) δ−1.66 (m, 2M), 2.12 (m, 1H), 2.30 (m, 1H), 2.42 (m, 1H), 2.81 (m, 2H), 3.23 (m, 2H), 3.78 (m, 4H), 4.00 (m, 3H), 4.11 (m, 3H), 5.08 (d, 1H), 5.18 (d, 1H), 5.79 (m, 1H), 7.87 (d, 1H), 8.04 (d, 1H), 8.26 (d, 1H), 8.51 (s, 1H), 8.78 (s, 1H), 9.01 (m, 1H). MS m/z=480 (M+1).

후처리

  1. customwas microwaved for 3000 seconds
  2. customan internal temperature of 170° C
  3. customthe mixture was again microwaved for 3000 seconds
  4. customan internal temperature of 170° C
  5. customThe mixture was transferred to a flask
  6. concentrationwas concentrated
  7. dissolutionThe resulting 4-chloro-6-trifluoromethyl)quinazoline (used without further purification) was dissolved in acetonitrile (2 mL)
  8. additionwas added to a 0° C.
  9. temperaturecooled
  10. customwas quenched with K2CO3 (1M solution) and EtOAc
  11. customThe organic layer was separated
  12. dry with materialdried over Na2SO4
  13. filtrationfiltered
  14. concentrationconcentrated

출처 및 근거

ORD 기록
ord-8972f54274b848b2a2fca84b9213d183
출처 데이터셋
uspto-grants-2011_11
특허 번호
US08067457B2

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