반응 #701546

반응 방정식

phosgene

1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-[2-(4-pyridylamino)-ethylamino]-piperidine

→

1-{1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-piperidyl}-3-(4-pyridyl)-imidazolidin-2-one-dihydrochloride

용매

potassium hydroxide

toluene

toluene

potassium hydroxide

반응 조건

후처리

1. 1
   workup.STIRRINGThe reaction mixture is further stirred for 30 minutes at 10° C and for 20 hours at room temperature
2. 2
   기타The aqueous acid phase is separated
3. 3
   농축concentrated to a volume of approx. 50 ml
4. 4
   추출The emulsion is extracted with four 75 ml portions of methylene chloride
5. 5
   건조The combined methylene chloride phases are dried over sodium sulphate
6. 6
   농축concentrated
7. 7
   기타The residue is chromatographed through a column of 800 g of silica gel using
8. 8
   workup.ADDITIONa 9:1 mixture of methylene chloride and methanol as eluant
9. 9
   농축The acid solution is concentrated under reduced pressure
10. 10
    workup.ADDITIONThe residue is treated with toluene
11. 11
    기타recrystallised from a mixture of methanol and diethyl ether

실험 절차

With stirring, 392 ml of an approx. 20% solution of phosgene in toluene are added dropwise at a reaction temperature of 5° to 10° C in the course of 1 hour to a mixture of 31.5 g of 1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-[2-(4-pyridylamino)-ethylamino]-piperidine in 300 ml of toluene and 126 ml of 3N aqueous potassium hydroxide solution. Thereafter 120 ml of a 6N aqueous potassium hydroxide solution are added dropwise at the same temperature in the course of 30 minutes. The reaction mixture is further stirred for 30 minutes at 10° C and for 20 hours at room temperature. The aqueous acid phase is separated, concentrated to a volume of approx. 50 ml and made alkaline with a concentrated aqueous solution of ammonia. The emulsion is extracted with four 75 ml portions of methylene chloride. The combined methylene chloride phases are dried over sodium sulphate and concentrated. The residue is chromatographed through a column of 800 g of silica gel using a 9:1 mixture of methylene chloride and methanol as eluant. The purified 1-{1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-piperidyl}-3-(4-pyridyl)-imidazolidin-2-one is taken up in methanol and the solution is acidified with methanolic hydrochloric acid. The acid solution is concentrated under reduced pressure. The residue is treated with toluene and recrystallised from a mixture of methanol and diethyl ether to yield the 1-{1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-piperidyl}-3-(4-pyridyl)-imidazolidin-2-one-dihydrochloride in the form of the hemihydrate; m.p. 230°-234° C.

출처