Triethylamine → Isotretinoin

HRID 1955363

반응식

HRID 1955363 반응식
O[CH:2]1[O:6][C:5](=[O:7])[CH:4]=[C:3]1[CH3:8].C(N(CC)CC)C.[CH3:16][C:17]([CH:39]=[CH:40][C:41]1[C:46]([CH3:48])([CH3:47])[CH2:45][CH2:44][CH2:43][C:42]=1[CH3:49])=[CH:18][CH2:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl-].[Mg+2].[Cl-]>CCCCCCC.CN(C)C(=O)C>[CH3:49][C:42]1[CH2:43][CH2:44][CH2:45][C:46]([CH3:47])([CH3:48])[C:41]=1/[CH:40]=[CH:39]/[C:17](/[CH3:16])=[CH:18]/[CH:19]=[CH:2]/[C:3](/[CH3:8])=[CH:4]\[C:5]([OH:6])=[O:7]

참가 물질

7

반응물 4

HCID 8471TriethylamineHCID 1153012(5H)-Furanone, 5-hydroxy-4-methyl-HCID 164726[3-Methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienyl] triphenyl phosphoniumHCID 5360315Magnesium Chloride

생성물 1

HCID 5282379Isotretinoin

시약·촉매·용매 2

HCID 8900Heptane용매HCID 31374Dimethylacetamide용매

반응 조건

온도
15 °C

실험 절차

N,N-dimethylacetamide (300 milliliters (mL)) , 5-hydroxy-4-methyl-2[5H]-furanone (26.81 grams (g)), 235 millimoles (mmol), 1.2 equivalents), and triethylamine (164 mL,1.2 moles, 6 equivalents) were added to 107.26 g (197 mmol) of [3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienyl] triphenyl phosphonium salt. The resulting mixture was cooled to 15° C. prior to addition of magnesium chloride (30.03 g, 315 mmol, 1.6 equivalents). The reaction mixture was allowed to stir at room temperature for 17 hours. The reaction solution was washed with 200 mL of heptane. Toluene (100 mL) was added and the solution was acidified with 280 mL of 20% by volume HCl . The aqueous layer was back-extracted three times, each time with 200 mL of a 9:1 heptane:toluene mixture. The combined organic layers were washed with aqueous methanol, water, and then concentrated to give an orange solid. Heptane (250 mL) was added to the crude solid and the slurry was cooled to 0° C. and then filtered. Acetone (200 mL) and heptane (800 mL) were added to the solid and the resulting mixture was stirred at 25° C. Filtration of this slurry provided isotretinoin with >98% purity as a solid. 1H NMR: (300 MHz, CDCl3):δ 1.03(s,6; H), 1.44-1.68(m,4H), 1.72(s,3H), 1.88-2.05(m,2H), 2.0(s,3H), 2.11 (d,3H), 5.67(s,1H), 6.15-6.32(m,3H), 7.03 (dd,1H), 7.76 (d,1H).

후처리

  1. washThe reaction solution was washed with 200 mL of heptane
  2. additionToluene (100 mL) was added
  3. extractionThe aqueous layer was back-extracted three times
  4. washThe combined organic layers were washed with aqueous methanol, water
  5. concentrationconcentrated
  6. customto give an orange solid
  7. temperaturethe slurry was cooled to 0° C.
  8. filtrationfiltered
  9. additionAcetone (200 mL) and heptane (800 mL) were added to the solid
  10. stirringthe resulting mixture was stirred at 25° C
  11. filtrationFiltration of this slurry

출처 및 근거

ORD 기록
ord-4f710e3958934aada8e95763a5a48533
출처 데이터셋
uspto-grants-2000_09
특허 번호
US06124485

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