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

HRID 564415ノート

反応式

HRID 564415 の反応式
[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]

参加物

11

反応物 7

HCID 276CarbamateHCID 2331BenzamideHCID 24819Phosphorus pentachloride2 回HCID 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

生成物 1

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

試薬・触媒・溶媒 3

HCID 1140Toluene溶媒HCID 6342Acetonitrile溶媒HCID 63651,1-Dichloroethane溶媒

実験手順

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).

後処理

  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

出典と根拠

ORDレコード
ord-8972f54274b848b2a2fca84b9213d183
出典データセット
uspto-grants-2011_11
特許番号
US08067457B2

反応ノート

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