Diethyl chlorophosphate → 8-Bromo-6-(2-fluorophenyl)-4-methyl-4h-2,5,10b-triaza-benzo [e]azulene-3-carboxylic acid ethyl ester

HRID 75257

反応式

HRID 75257 の反応式
[Br:1][C:2]1[CH:21]=[CH:20][C:5]2[NH:6][C:7](=O)[CH:8]([CH3:18])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.[H-].[Na+].P(Cl)(OCC)(OCC)=O.[N+:33]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])#[C-:34].[H-].[Na+].C1COCC1>C1COCC1>[CH2:39]([O:38][C:36]([C:35]1[N:33]=[CH:34][N:6]2[C:7]=1[CH:8]([CH3:18])[N:9]=[C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])[C:4]1[CH:3]=[C:2]([Br:1])[CH:21]=[CH:20][C:5]2=1)=[O:37])[CH3:40]

参加物

7

反応物 5

HCID 13139Diethyl chlorophosphateHCID 24758Sodium hydride2 回HCID 533707Ethyl isocyanoacetateHCID 23694757NaH THFHCID 685254147-Bromo-5-(2-fluoro-phenyl)-3-methyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one

生成物 1

HCID 685269648-Bromo-6-(2-fluorophenyl)-4-methyl-4h-2,5,10b-triaza-benzo [e]azulene-3-carboxylic acid ethyl ester

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒2 回

反応条件

温度
-10 °C

実験手順

7-Bromo-5-(2-fluorophenyl)-3-methyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one 117 (3.78 g, 10.88 mmol) was suspended in dry THF (150 mL) and cooled to −10° C. Sodium hydride (60% dispersion in mineral oil, 0.52 g, 13.07 mol) was added into the suspension in one portion. The reaction mixture was allowed to stir and then warm to rt over a 3 h period. The reaction mixture was again cooled to −10° C. and diethyl chlorophosphate (2.65 mL, 17.42 mmol) was added. The cooling bath was then removed and stirring continued for 3 h. During this time, sodium hydride (60% dispersion in mineral oil, 0.61 g, 15.24 mmol) was suspended in dry THF (60 mL) at −10° C. in another flask. Ethyl isocyanoacetate (1.43 ml, 13.07 mnol) was added to the NaH/THF suspension and this mixture allowed to stir for 3 h. After 3 h the first flask was cooled to −30° C. with a cooling bath and the mixture in the second reaction flask was added to the first flask via a cannula. The reaction mixture was allowed to stir for 24 h, after which it was cooled to 0° C. with an ice-water bath and slowly quenched with acetic acid (5 mL). Water was then added to the reaction mixture and this was extracted with EtOAc. The EtOAc layers were combined, washed with aq NaHCO3, brine and dried (Na2SO4). After removal of the solvent under reduced pressure, the solid was purified by flash chromatography (silica gel, EtOAc:hexane: gradient elution 1:2, 1:1, 2:1). The ethyl ester 118 was a white solid (1.82 g, 38%). mp 190-192° C.; IR (KBr, cm−1) 3316, 2925, 1693, 1621, 1485, 1448, 1371; 1H NMR (CDCl3) δ 7.92 (s, 1 H), 7.72 (dd, J=8.5, 1.5 Hz, 1 H), 7.6 (t, J=6.9 Hz, 1 H), 7.48 (d, J=8.5 Hz, 1 H), 7.42-7.49 (m, 2 H), 7.23-7.29 (m, 1 H), 7.05 (t, J=9.3 Hz, 1 H), 6.71 (q, J=7.3 Hz, 1 H), 4.41 (m, 2 H), 1.42 (t, J=7.1 Hz, 3 H), 1.29 (d, J=7.2, 3 H). MS (EI) m/e (relative intensity) 442 (M+, 5), 428 (7), 381 (58), 355 (100), 303 (37); [α]26D=10.6 (c 0.53, EtOAc).

後処理

  1. temperaturewarm to rt over a 3 h period
  2. temperatureThe reaction mixture was again cooled to −10° C.
  3. customThe cooling bath was then removed
  4. stirringstirring
  5. stirringto stir for 3 h
  6. temperatureAfter 3 h the first flask was cooled to −30° C. with a cooling bath
  7. additionthe mixture in the second reaction flask was added to the first flask via a cannula
  8. stirringto stir for 24 h
  9. temperatureafter which it was cooled to 0° C. with an ice-water bath
  10. customslowly quenched with acetic acid (5 mL)
  11. additionWater was then added to the reaction mixture
  12. extractionthis was extracted with EtOAc
  13. washwashed with aq NaHCO3, brine
  14. dry with materialdried (Na2SO4)
  15. customAfter removal of the solvent under reduced pressure
  16. customthe solid was purified by flash chromatography (silica gel, EtOAc:hexane: gradient elution 1:2, 1:1, 2:1)

出典と根拠

ORDレコード
ord-5f780b0595ab4d838a73161f5a1e2fa7
出典データセット
uspto-grants-2014_09
特許番号
US08835424B2

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