Potassium Phosphate, Tribasic → 3-chloro-4-(2-chloro-3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3 (4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide

HRID 523305ノート

反応式

HRID 523305 の反応式
Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[Cl:22].[Cl:23][C:24]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=[CH:26][C:25]=1[N:39]1[C:48](=[O:49])[C:47]2[C:42](=[C:43]([F:50])[CH:44]=[CH:45][CH:46]=2)[NH:41][C:40]1=[O:51].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].C1COCC1>[Cl:22][C:3]1[CH:4]=[C:5]([C:19]([NH2:21])=[O:20])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([N:39]2[C:48](=[O:49])[C:47]4[C:42](=[C:43]([F:50])[CH:44]=[CH:45][CH:46]=4)[NH:41][C:40]2=[O:51])[C:24]=1[Cl:23])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3

参加物

6

反応物 3

HCID 62657Potassium Phosphate, TribasicHCID 1177612874-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide2 回HCID 1235759513-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione2 回

生成物 1

HCID 865810103-chloro-4-(2-chloro-3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3 (4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide収率 18.9%

試薬・触媒・溶媒 2

HCID 178454861HCID 178454861、化合物触媒HCID 8028Tetrahydrofuran溶媒

実験手順

A mixture of 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 3] (103 mg, 0.269 mmol), 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione [Intermediate 42] (140 mg, 0.336 mmol), THF (5 mL), 2 M aqueous K3PO4 (0.504 mL, 1.01 mmol) was bubbled with nitrogen for 15 min. The mixture was treated with 1,1′-bis(di-tert-butylphosphino)ferrocene palladium(II) chloride (17.5 mg, 0.027 mmol) and was stirred at room temperature overnight. The mixture was concentrated, and the residue was partitioned between EtOAc and water. The organic phase was dried and concentrated. The residue was purified by preparative HPLC. The appropriate fractions were treated with saturated aqueous NaHCO3 and concentrated. The aqueous residue was extracted with EtOAc. The organic phase was washed sequentially with water and brine, and dried and concentrated to give 3-chloro-4-(2-chloro-3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) (30 mg, 15% yield). This material was separated by chiral super-critical fluid chromatography as follows: column: CHIRALCEL® OJ-H (3×25 cm, 5 nm); Mobile Phase: CO2-MeOH-MeCN (65:17.5:17.5) at 85 mL/min; sample preparation: 6.8 mg/mL in MeOH—CHCl3 (1:1); injection: 3.0 mL. The first peak eluting from the column provided a single atropisomer of 3-chloro-4-(R)-(2-chloro-3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide. Mass spectrum m/z 573 (M+H—H2O)+. 1H NMR (500 MHz, DMSO-d6) δ 11.63-11.48 (m, 1H), 8.39-8.25 (m, 1H), 8.17-8.12 (m, 1H), 7.99-7.92 (m, 1H), 7.88-7.85 (m, 1H), 7.85-7.81 (m, 1H), 7.81-7.76 (m, 1H), 7.76-7.70 (m, 1H), 7.70-7.62 (m, 2H), 7.57-7.46 (m, 1H), 7.32-7.20 (m, 1H), 7.13-6.99 (m, 1H), 6.77-6.63 (m, 1H), 5.10-4.98 (m, 1H), 1.47-1.45 (m, 6H). 19F NMR (400 MHz, chloroform-d) δ −129.63.

後処理

  1. customwas bubbled with nitrogen for 15 min
  2. concentrationThe mixture was concentrated
  3. customthe residue was partitioned between EtOAc and water
  4. customThe organic phase was dried
  5. concentrationconcentrated
  6. customThe residue was purified by preparative HPLC
  7. additionThe appropriate fractions were treated with saturated aqueous NaHCO3
  8. concentrationconcentrated
  9. extractionThe aqueous residue was extracted with EtOAc
  10. washThe organic phase was washed sequentially with water and brine
  11. customdried
  12. concentrationconcentrated

出典と根拠

ORDレコード
ord-d69b22f8e25e434689c6e298684b8b5f
出典データセット
uspto-grants-2016_05
特許番号
US09334290B2

反応ノート

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