Diisopropylethylamine → (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

Temperature

60 °C

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.

1. additionAfter addition
2. temperatureAt this time, the reaction was cooled to 25° C.
3. temperatureheated to 80° C
4. customUpon reaching 80° C.
5. additionAfter the addition
6. temperaturethe reaction mixture was heated to 100° C. where it
7. stirringstirred overnight
8. temperatureAt this time, the reaction mixture was cooled to 25° C.
9. concentrationconcentrated in vacuo
10. additionThe residue was diluted with dichloromethane (100 mL)
11. washwas washed with a 2N aqueous hydrochloric acid solution (1×100 mL)
12. dry with materiala saturated aqueous sodium bicarbonate solution (1×100 mL), a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate
13. filtrationfiltered
14. washrinsed with dichloromethane
15. concentrationconcentrated in vacuo
16. customPurification by Analogix flash chromatography (40 g, 15-50% ethyl acetate/hexanes)

ORD record

ord-2248e3f99b4649e6b873ef138c91cbe8

Source dataset

uspto-grants-2010_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07741327B2