Phosgene → methyl 4-[({[4-(8-azabicyclo[3.2.1]oct-8-yl)-3-(trifluoromethyl)benzyl]amino}carbonyl)amino]-1H-indazole-1-carboxylate

HRID 586080ノート

反応式

HRID 586080 の反応式
[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]([O:13][CH3:14])=[O:12].[C:15](Cl)(Cl)=[O:16].[CH:19]12[N:26]([C:27]3[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][C:28]=3[C:35]([F:38])([F:37])[F:36])[CH:23]([CH2:24][CH2:25]1)[CH2:22][CH2:21][CH2:20]2>C1(C)C=CC=CC=1.C1COCC1>[CH:23]12[N:26]([C:27]3[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:15]([NH:1][C:2]4[CH:10]=[CH:9][CH:8]=[C:7]5[C:3]=4[CH:4]=[N:5][N:6]5[C:11]([O:13][CH3:14])=[O:12])=[O:16])=[CH:29][C:28]=3[C:35]([F:38])([F:36])[F:37])[CH:19]([CH2:25][CH2:24]1)[CH2:20][CH2:21][CH2:22]2

参加物

6

反応物 3

HCID 6371PhosgeneHCID 22032652methyl 4-amino-1H-indazole-1-carboxylateHCID 223376164-(8-Azabicyclo[3.2.1]oct-8-yl)-3-(trifluoromethyl)benzylamine

生成物 1

HCID 22337659methyl 4-[({[4-(8-azabicyclo[3.2.1]oct-8-yl)-3-(trifluoromethyl)benzyl]amino}carbonyl)amino]-1H-indazole-1-carboxylate

試薬・触媒・溶媒 2

HCID 1140Toluene溶媒2 回HCID 8028Tetrahydrofuran溶媒

実験手順

Methyl 4-amino-1H-indazole-1-carboxylate (1.72 g, 9.00 mmol) in toluene (300 mL) was treated with phosgene in toluene (9.00 mL, approx. 20% w/w) via syringe. The mixture was heated at reflux for 3.5 hours, allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was taken up in diethyl ether and concentrated under reduced pressure. The residue was again taken up in diethyl ether (325 mL) followed by addition of triethylamine (10 mL). The mixture was stirred briefly and then filtered. An aliquot of the filtrate (150 mL, 4.14 mmol) was treated with 4-(8-azabicyclo[3.2.1]oct-8-yl)-3-(trifluoromethyl)benzylamine (1.03 g, 3.62 mmol) in THF (10 mL). After stirring for 2 hours, the mixture was concentrated under reduced pressure to approximately 30 mL and filtered. The filter cake was washed with diethyl ether:hexane (1:1) and dried under reduced pressure to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.43 (s, 1H), 7.80 (d, 1H, J=7.8 Hz), 7.69 (d, 1H, J=8.1 Hz), 7.58 (t, 1H, J=2.0 Hz), 7.47 (m, 2H), 7.14 (d, 1H, J=8.1 Hz), 6.86 (t, 1H, J=5.8 Hz), 4.32 (d, 2H, J=5.8 Hz), 4.03 (s, 3H), 3.72 (m, 2H), 1.93 (m, 2H), 1.88-1.55 (m, 5H), 1.49 (m, 3H); MS (ESI) 502 (M+H)+.

後処理

  1. temperatureThe mixture was heated
  2. temperatureat reflux for 3.5 hours
  3. concentrationconcentrated under reduced pressure
  4. concentrationconcentrated under reduced pressure
  5. additionfollowed by addition of triethylamine (10 mL)
  6. filtrationfiltered
  7. stirringAfter stirring for 2 hours
  8. concentrationthe mixture was concentrated under reduced pressure to approximately 30 mL
  9. filtrationfiltered
  10. washThe filter cake was washed with diethyl ether:hexane (1:1)
  11. customdried under reduced pressure

出典と根拠

ORDレコード
ord-955c85abd71142adbbae56131dd49d52
出典データセット
uspto-grants-2005_08
特許番号
US06933311B2

反応ノート

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