Hydrochloric Acid → Duloxetine Hydrochloride

HRID 222785

반응식

HRID 222785 반응식
C(N(C(C)C)CC)(C)C.[CH3:10][N:11](C)[CH2:12][CH2:13][C@H:14]([O:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1.[ClH:32].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C1(OC(Cl)=O)C=CC=CC=1.C(C(C)=O)C.O>[CH3:10][NH:11][CH2:12][CH2:13][C@H:14]([O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=12)[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1.[ClH:32]

참가 물질

9

반응물 4

HCID 313Hydrochloric Acid2회HCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 9818212(S)-(+)-N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine

생성물 1

HCID 60834Duloxetine Hydrochloride

시약·촉매·용매 4

HCID 962Water용매HCID 1140Toluene용매HCID 6569Methyl Ethyl Ketone용매HCID 15891Phenyl chloroformate용매

반응 조건

온도
80 °C

실험 절차

Diisopropylethylamine (210 ml) is added to a solution of (S)—N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)-propanamine (311 g; 99.6% ee) in toluene (1200 ml) and phenylchloroformate (150 ml) is then added at 60° C. After two hours of stirring at 80° C., the mixture is cooled down, shaken with a diluted solution of hydrochloric acid, water and a 2% solution of sodium hydrogencarbonate. The organic phase is dried with sodium sulfate and evaporated. The evaporation residue is dissolved in ethanol (300 ml) and a 5M solution of potassium hydroxide (400 ml) is added drop-wise under reflux. After two hours of refluxing, the mixture is evaporated to half the volume, diluted with water (1000 ml) and extracted with toluene (300 ml). The organic phase is dried with sodium sulfate and evaporated. The evaporation residue is dissolved in ethylmethylketone (300 ml) and concentrated HCl (1 mole), diluted with ethylmethylketone (300 ml), is added drop-wise at 0° C.; then the mixture is stirred for two hours. The precipitated crystals are then sucked off. Yield: 250 g (75%), m.p.: 167-169° C. Recrystallization from ethylmethylketone affords colorless crystalline duloxetine hydrochloride, m.p. 170.5-171.5° C. Optical purity: 99.9% ee (CE), chemical purity: 99.9% (HPLC).

후처리

  1. additionis then added at 60° C
  2. temperaturethe mixture is cooled down
  3. dry with materialThe organic phase is dried with sodium sulfate
  4. customevaporated
  5. dissolutionThe evaporation residue is dissolved in ethanol (300 ml)
  6. additiona 5M solution of potassium hydroxide (400 ml) is added drop-wise
  7. temperatureunder reflux
  8. temperatureAfter two hours of refluxing
  9. customthe mixture is evaporated to half the volume
  10. additiondiluted with water (1000 ml)
  11. extractionextracted with toluene (300 ml)
  12. dry with materialThe organic phase is dried with sodium sulfate
  13. customevaporated
  14. dissolutionThe evaporation residue is dissolved in ethylmethylketone (300 ml)
  15. additionis added drop-wise at 0° C.
  16. stirringthen the mixture is stirred for two hours
  17. customRecrystallization from ethylmethylketone

출처 및 근거

ORD 기록
ord-a48316fc15d44563b090938720a1f479
출처 데이터셋
uspto-grants-2012_06
특허 번호
US08207356B2

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