Hydrochloric Acid → Duloxetine Hydrochloride

HRID 222785

反応式

HRID 222785 の反応式
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]

参加物

9

反応物 4

HCID 313Hydrochloric Acid2 回HCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 9818212(S)-(+)-N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine

生成物 1

HCID 60834Duloxetine Hydrochloride

試薬・触媒・溶媒 4

HCID 962Water溶媒HCID 1140Toluene溶媒HCID 6569Methyl Ethyl Ketone溶媒HCID 15891Phenyl chloroformate溶媒

反応条件

温度
80 °C

実験手順

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).

後処理

  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

出典と根拠

ORDレコード
ord-a48316fc15d44563b090938720a1f479
出典データセット
uspto-grants-2012_06
特許番号
US08207356B2

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