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Cyanomethylenetributylphosphorane → tert-butyl 7-(3-cyano-4-fluoro-2-methylphenyl)-hexahydro-1H-pyrazino[1,2-d][1,4]oxazepine-2(9H)-carboxylate

HRID 1502084
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HRID 1502084 반응식
[C:1]([C:3]1[C:4]([CH3:29])=[C:5]([CH:10]([OH:28])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[CH2:25][CH2:26]O)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C(C=P(CCCC)(CCCC)CCCC)#N>C1C=CC=CC=1>[C:1]([C:3]1[C:4]([CH3:29])=[C:5]([CH:10]2[CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH:13]3[CH2:25][CH2:26][O:28]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
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HCID 4622928CyanomethylenetributylphosphoraneHCID 89619232Tert-butyl 4-(2-(3-cyano-4-fluoro-2-methylphenyl)-2-hydroxyethyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate

생성물 1

HCID 89618843tert-butyl 7-(3-cyano-4-fluoro-2-methylphenyl)-hexahydro-1H-pyrazino[1,2-d][1,4]oxazepine-2(9H)-carboxylate

시약·촉매·용매 1

HCID 241Benzene용매

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온도
100 °C

실험 절차

tert-Butyl 4-(2-(3-cyano-4-fluoro-2-methylphenyl)-2-hydroxyethyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate (2.61 g, 6.41 mmol) and dissolved in benzene (60 mL) and added cyanomethylene tributyl phosphorane (2.78 g, 11.5 mmol). The mixture was placed into four separate 20 mL microwave tubes then heated at 100° C. overnight. The reaction mixtures were combined, concentrated then purified by MPLC chromatography using a 330 g ISCO Redi-Sep column and 5% acetone-95% DCM solvent system. Under these purification conditions was separated tert-butyl 7-(3-cyano-4-fluoro-2-methylphenyl)-hexahydro-1H-pyrazino[1,2-d][1,4]oxazepine-2(9H)-carboxylate cis diastereomers from the trans diastereomers LC-MS (IE, m/z): 334 [(M-56)+1]+; The cis-diastereomers were further separated to S,R and R,S diastereomers using the following conditions: Chiral IC column: 30×250 mm, 20% MeOH:/CO2, 70 mL/min, 100 bar, 50 mg/ml in MeOH, 35° C., 330 nm: cis-diastereomer A: 1H-NMR (600 MHz, CDCl3) δ ppm 7.88 (dd, J=8.7, 6.2 Hz, 1H), 7.04 (t, J=8.6 Hz, 1H), 4.83 (s, 1H), 4.03 (d, J=12.9 Hz, 1H), 3.86 (t, J=11.3 Hz, 1H), 3.79-3.96 (b, 2H), 2.93 (q, 2H), 2.83 (b, 1H), 2.56-2.63 (m, 4H), 2.53 (s, 3H), 1.78-1.87 (m, 2H), 1.49 (s, 9H).

후처리

  1. customseparate 20 mL microwave tubes
  2. customThe reaction mixtures
  3. concentrationconcentrated
  4. customthen purified by MPLC chromatography
  5. customUnder these purification conditions
  6. customwas separated tert-butyl 7-(3-cyano-4-fluoro-2-methylphenyl)-hexahydro-1H-pyrazino[1,2-d][1,4]oxazepine-2(9H)-carboxylate
  7. customThe cis-diastereomers were further separated to S,R and R,S diastereomers
  8. custom35° C., 330 nm

출처 및 근거

ORD 기록
ord-b1526c19b06c4313bb339892a8781a10
출처 데이터셋
uspto-grants-2015_12
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US09206199B2

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