Ethyl 2-(tributylstannyl)acetate → 5-Chloro-4-ethoxycarbonylmethyl-2-methyl-indole-1-carboxylic acid methyl ester

HRID 1161886

반응식

HRID 1161886 반응식
[CH3:1][O:2][C:3]([N:5]1[C:13]2[C:8](=[C:9](Br)[C:10]([Cl:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:16])=[O:4].[CH2:17]([O:19][C:20](=[O:35])[CH2:21][Sn](CCCC)(CCCC)CCCC)[CH3:18]>CN(C=O)C.[Br-].[Zn+2].[Br-].CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][O:2][C:3]([N:5]1[C:13]2[C:8](=[C:9]([CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:35])[C:10]([Cl:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:16])=[O:4]

참가 물질

6

반응물 2

HCID 10894129Ethyl 2-(tributylstannyl)acetateHCID 668201134-Bromo-5-chloro-2-methyl-indole-1-carboxylic acid methyl ester

생성물 1

HCID 668201565-Chloro-4-ethoxycarbonylmethyl-2-methyl-indole-1-carboxylic acid methyl ester

시약·촉매·용매 3

HCID 10421208Zinc bromide촉매HCID 178424406HCID 178424406, 화합물촉매HCID 6228Dimethylformamide용매

반응 조건

온도
80 °C

실험 절차

4-Bromo-5-chloro-2-methyl-indole-1-carboxylic acid methyl ester (1.99 g, 6.57 mmol) and tributylstannanyl-acetic acid ethyl ester (3.22 g, 8.55 mmol) are dissolved in dry DMF (55 ml) under an atmosphere of argon. Zinc(II) bromide (1.92 g, 8.55 mmol) and dichlorobis(tri-o-tolylphosphin)palladium (0) (1.03 g, 1.31 mmol) are added. The reaction mixture is heated to 80° C. for 18 hours. TLC analysis indicates complete consumption of the starting material. The reaction mixture is cooled to RT and poured on a saturated aqueous solution of NH4Cl. After addition of EtOAc (30 ml), the mixture is filtered through a pad of Celite. The organic layer is washed with saturated aq. NaCl solution, dried over Na2SO4 and concentrated. The residue is purified by FCC (hexane/EtOAc 4:1) to yield the desired compound, still contaminated with tin residues. The mixture is dissolved in a 1:1 mixture of 1 M NaOH/EtOAc (200 ml in total) and stirred at RT for 18 hours. The organic layer is separated, washed once with concentrated aqueous NaCl solution, and then dried over Na2SO4. Concentration yields a solid residue which is purified by FCC (hexane/EtOac 4:1) to afford the desired compound, still slightly contaminated. A further round of purification with an automated preparative HPLC system (Gilson HPLC, Xterra 5 mikron, gradient 10% to 100% MeCN in H2O, 30 min) affords the pure title compound. 1H NMR (DMSO, 400 MHz) δ 1.20 (t, J=6.6 Hz, 3H), 2.59 (s, 3H), 4.01 (s, 2H), 4.03 (s, 3H), 4.11 (q, J=6.6 Hz, 2H), 6.68 (s, 1H), 7.32 (d, J=9 Hz, 1H), 7.96 (d, J=9 Hz, 1H); ES-MS: 332.1 [M+Na]+.

후처리

  1. customconsumption of the starting material
  2. temperatureThe reaction mixture is cooled to RT
  3. additionpoured on a saturated aqueous solution of NH4Cl
  4. additionAfter addition of EtOAc (30 ml)
  5. filtrationthe mixture is filtered through a pad of Celite
  6. washThe organic layer is washed with saturated aq. NaCl solution
  7. dry with materialdried over Na2SO4
  8. concentrationconcentrated
  9. customThe residue is purified by FCC (hexane/EtOAc 4:1)

출처 및 근거

ORD 기록
ord-fdd65aca26144bd6822a623573325522
출처 데이터셋
uspto-grants-2010_10
특허 번호
US07820672B2

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