Carbon Dioxide → 3,4,5,6-Tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid

HRID 23431ノート

反応式

HRID 23431 の反応式
[Li]C(C)(C)C.Br[C:7]1[C:16]2[C:15]3[N:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH2:13][CH2:12][CH2:11][C:10]=2[NH:9][N:8]=1.[C:21](=[O:23])=[O:22]>CCCCC.C1COCC1>[C:7]1([C:21]([OH:23])=[O:22])[C:16]2[C:15]3[N:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH2:13][CH2:12][CH2:11][C:10]=2[NH:9][N:8]=1

参加物

6

反応物 3

HCID 280Carbon DioxideHCID 121330681-Bromo-3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azuleneHCID 178418306HCID 178418306、化合物

生成物 1

HCID 121330693,4,5,6-Tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid

試薬・触媒・溶媒 2

HCID 8003Pentane溶媒HCID 8028Tetrahydrofuran溶媒

実験手順

7.8 mL of 1.7 M of t-BuLi in pentane is added dropwise under argon to a stirred solution of 1-bromo-3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene (1.4 g) in 75 mL of anhydrous THF at −78° C. After addition, dry carbon dioxide is bubbled into the mixture at the same temperature for 2 hours. The reaction mixture is allowed to warm to room temperature, quenched with 1N HCl solution, and diluted with water. The mixture is basified with 1N NaOH to pH 8-9, and then extracted with EtOAc. The aqueous layer is then acidified with HOAc to pH 4-5 and extracted with CH2Cl2 eight times. The combined extracts are washed with water, dried, and concentrated to give 3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid as a tan solid. 1H NMR(DMSO): 1.95(m, 2H), 2.96(m, 2H), 3.07(t, 2H), 7.45(m,1H), 7.97(d,1H), 8.52(d, 2H). LR-MS: MW 229.23, Found: 230.2(M+1). Step 6: A mixture of 3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid (80 mg), 1-(3-azetidin-1-yl-propyl)-1H-pyrazol-3-ylamine (68 mg), EDCI(85 mg) and DMAP(55 mg) in 10 mL of 1,2-dichloroethane is refluxed overnight, cooled and diluted with CH2Cl2. The mixture is washed with aqueous NaHCO3 solution, water, dried over Na2SO4 and concentrated under vacuum. Purification on a silica gel plate, eluting with 10% MeOH in CH2Cl2 yields 12 mg of 3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid [1-(3-azetidin-1-yl-propyl)-1H-pyrazol-3-yl]-amide as a colorless foam. 1H NMR (CDCl3): 2.01-2.31(m, 6H), 2.67-2.92(m, 8H), 3.63(m, 2H), 4.17(t, 2H), 6.65(d, 1H), 7.23(m, 1H), 7.33(d, 1H), 7.65(d, 1H), 8.62(d, 1H), 14.13(bs, 1H). LR-MS: MW 391.48, Found: 392.2 (M+1).

後処理

  1. customis bubbled into the mixture at the same temperature for 2 hours
  2. customquenched with 1N HCl solution
  3. additiondiluted with water
  4. extractionextracted with EtOAc
  5. extractionextracted with CH2Cl2 eight times
  6. washThe combined extracts are washed with water
  7. customdried
  8. concentrationconcentrated

出典と根拠

ORDレコード
ord-8cb546064d2d461481674853f13a939f
出典データセット
uspto-grants-2005_02
特許番号
US06852730B2

反応ノート

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