Phenol → (2S)-7-bromo-2-(phenoxymethyl)-2,3-dihydro-1,4-benzodioxine

HRID 965832

반응식

HRID 965832 반응식
[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11][OH:12])[O:7][C:6]=2[CH:13]=1.[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11][O:12][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:7][C:6]=2[CH:13]=1

참가 물질

6

반응물 4

HCID 996PhenolHCID 11776TriphenylphosphineHCID 5462977Diethyl azodicarboxylateHCID 23394142(S)-(7-Bromo-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanol

생성물 1

HCID 69607053(2S)-7-bromo-2-(phenoxymethyl)-2,3-dihydro-1,4-benzodioxine수율 49.1%

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매

반응 조건

온도
0 °C

실험 절차

A mixture of [(2S)-7-bromo-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (2.26 g, 9.20 mmol), phenol (0.87 g, 9.2 mmol), triphenylphosphine (2.42 g, 9.20 mmol) and THF (80 mL) is cooled in a 0° C. bath under N2. Diethylazodicarboxylate (1.50 ml, 9.5 mmol) is added, and the mixture is allowed to warm to rt overnight. The mixture is adsorbed onto SiO2 and chromatographed (Biotage 40S+SIM, (1:19) EtOAc:hexane). The product fractions are pooled and concentrated to afford 1.45 g (49%) of (2S)-7-bromo-2-(phenoxymethyl)-2,3-dihydro-1,4-benzodioxine as a clear oil. A mixture of this oil (14, 0.472 g, 1.47 mmol), (R)-3-aminoquinuclidine (0.557 g, 4.41 mmol), palladium acetate (0.083 g, 0.37 mmol), 1,3-bis(diphenylphosphino)propane (0.153 g, 0.370 mmol), and toluene (20 ml) are stirred under CO (g) in a 97° C. oil bath. The mixture is allowed to cool to rt and after 1.5 h is concentrated. The residue is partitioned between NaOH (aq) and EtOAc. The organic layer is separated, washed with brine, dried (MgSO4), filtered, and concentrated. The residue is chromatographed (Biotage 40 S, (1:10:190) NH4OH—MeOH—CHCl3). The product fractions are pooled and concentrated affording the product as a foam. The foam is taken up in EtOH, treated with fumaric acid (1.0 eq) and water (1 drop), and partially concentrated. Et2O is added and the resulting solid filtered and dried to provide 0.310 g (53%) of Example 11 as a monohydrate solid: 1H NMR (400 MHz, CD3OD) δ 7.49, 7.43, 7.25-7.35, 6.90-7.05, 6.70, 4.55-4.65, 4.45-4.55, 4.35-4.45, 4.20-4.35, 3.75-3.85, 3.20-3.50, 2.30-2.40, 2.15-2.30, 2.00-2.15, 1.85-2.00.

후처리

  1. temperatureto warm to rt overnight
  2. customchromatographed (Biotage 40S+SIM, (1:19) EtOAc:hexane)
  3. concentrationconcentrated

출처 및 근거

ORD 기록
ord-8ad7ba60a21e4baea8cc017ecd4a33e1
출처 데이터셋
uspto-grants-2005_10
특허 번호
US06951868B2

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