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Cesium carbonate → 6-chloro-5-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3 (4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide

HRID 523294
ノート
印刷プレビュー

反応式

HRID 523294 の反応式
Br[C:2]1[C:14]([Cl:15])=[CH:13][C:12]([C:16]([NH2:18])=[O:17])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][C@H:7]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:8][C:9]=1[NH:10]2.[F:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]([CH3:34])[C:31](=[O:35])[N:30]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38](B3OC(C)(C)C(C)(C)O3)[C:37]=1[CH3:51])[C:29]2=[O:52].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:15][C:14]1[C:2]([C:38]2[CH:39]=[CH:40][CH:41]=[C:36]([N:30]3[C:29](=[O:52])[C:28]4[C:33](=[C:24]([F:23])[CH:25]=[CH:26][CH:27]=4)[N:32]([CH3:34])[C:31]3=[O:35])[C:37]=2[CH3:51])=[C:3]2[C:11](=[C:12]([C:16]([NH2:18])=[O:17])[CH:13]=1)[NH:10][C:9]1[CH2:8][C@@H:7]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:6][CH2:5][C:4]2=1
参加物反応条件実験手順後処理出典と根拠反応ノート

参加物

8

反応物 3

HCID 10796Cesium carbonateHCID 117761028(S)-5-bromo-6-chloro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide2 回HCID 1239796828-Fluoro-1-methyl-3-[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]quinazoline-2,4-dione2 回

生成物 1

HCID 865806916-chloro-5-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3 (4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide
収率 50%

試薬・触媒・溶媒 4

HCID 178418807HCID 178418807、化合物触媒HCID 962Water溶媒HCID 8028Tetrahydrofuran溶媒HCID 8857Ethyl Acetate溶媒

反応条件

温度
50 °C

実験手順

A mixture of (S)-5-bromo-6-chloro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide [Intermediate 31] (100 mg, 0.259 mmol), 8-fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 2] (112 mg, 0.272 mmol), Cs2CO3 (169 mg, 0.519 mmol) and PdCl2(dppf) DCM adduct (16.9 mg, 0.021 mmol) in THF (4.3 mL) and water (1.1 mL) was heated at 50° C. for 17.5 h. The cooled mixture was diluted with EtOAc, washed sequentially with water and brine, dried and concentrated. The residue was purified by column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (gradient from 50-80%). The impure product was further purified by preparative HPLC to give 6-chloro-5-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (mixture of four atropisomers) (76 mg, 50% yield). Mass spectrum m/z 589 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.13 (br. s., 1H), 7.94 (d, J=7.9 Hz, 1H), 7.76-7.68 (m, 2H), 7.46 (br. s., 1H), 7.40-7.28 (m, 3H), 7.22-7.16 (m, 1H), 4.21-4.13 (m, 1H), 3.77-3.64 (m, 3H), 2.95-2.82 (m, 1H), 2.40 (d, J=16.3 Hz, 1H), 1.94-1.70 (m, 3H), 1.70-1.61 (m, 3H), 1.58-1.48 (m, 1H), 1.16-1.02 (m, 7H).

後処理

  1. washwashed sequentially with water and brine
  2. customdried
  3. concentrationconcentrated
  4. customThe residue was purified by column chromatography on silica gel (24 g)
  5. washeluting with EtOAc-hexanes (gradient from 50-80%)
  6. customThe impure product was further purified by preparative HPLC

出典と根拠

ORDレコード
ord-ef47fb92d3404ad5b06f1cdb09d7f74b
出典データセット
uspto-grants-2016_05
DOI
10.6084/m9.figshare.5104873.v1
特許番号
US09334290B2

反応ノート

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