Reacción #47339

Ecuación de reacción

N,N-diisopropylethylamine

(L)-leucine methyl ester hydrochloride

N,N-diisopropylethylamine

4-bromo-3-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-but-2-enoic acid ethyl ester

→

(S)-4-methyl-2-[2-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid methyl ester

Rendimiento 15.2%

Disolventes

acetonitrile

acetonitrile

acetonitrile

Condiciones de reacción

Tratamiento posterior

1. 1
   workup.ADDITIONAfter addition
2. 2
   TemperaturaAt this time, the reaction was cooled to 25° C.
3. 3
   Temperaturaheated to 80° C
4. 4
   OtroUpon reaching 80° C.
5. 5
   workup.ADDITIONAfter the addition
6. 6
   Temperaturathe reaction mixture was heated to 100° C. where it
7. 7
   workup.STIRRINGstirred overnight
8. 8
   TemperaturaAt this time, the reaction mixture was cooled to 25° C.
9. 9
   Concentraciónconcentrated in vacuo
10. 10
    workup.ADDITIONThe residue was diluted with dichloromethane (100 mL)
11. 11
    Lavadowas washed with a 2N aqueous hydrochloric acid solution (1×100 mL)
12. 12
    Secadoa saturated aqueous sodium bicarbonate solution (1×100 mL), a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate
13. 13
    Filtraciónfiltered
14. 14
    Lavadorinsed with dichloromethane
15. 15
    Concentraciónconcentrated in vacuo
16. 16
    OtroPurification by Analogix flash chromatography (40 g, 15-50% ethyl acetate/hexanes)

Procedimiento

A mixture of (L)-leucine methyl ester hydrochloride (0.38 g, 2.09 mmol) in acetonitrile (4.4 mL) was treated with N,N-diisopropylethylamine (0.33 mL, 2.02 mmol). After addition was complete, the mixture was stirred at 60° C. for 1.3 h. At this time, the reaction was cooled to 25° C., treated with N,N-diisopropylethylamine (0.33 mL, 2.02 mmol) and acetonitrile (4.4 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of 4-bromo-3-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-but-2-enoic acid ethyl ester (639 mg, 1.88 mmol) in acetonitrile (4.4 mL). After the addition was complete, the reaction mixture was heated to 100° C. where it stirred overnight. At this time, the reaction mixture was cooled to 25° C. and concentrated in vacuo. The residue was diluted with dichloromethane (100 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 15-50% ethyl acetate/hexanes) afforded impure (S)-4-methyl-2-[2-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid methyl ester (102 mg, 15%) as an orange/red oil. The material was used without further purification.

Fuente