3-Methyl-2-butenal → (S)-4-Methyl-2-[methyl-(3-methyl-but-2-enyl)-amino]-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide monohydrochloride

(S)-4-Methyl-2-methylamino-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide monohydrochloride (0.25 g, 0.59 mmol, Example 12) and 3-methyl-2-butenal (50 mg, 0.59 mmol, Aldrich, Milwaukee, Wis.) were mixed in CH2Cl2 (10 mL). After stirring at ambient temperature under nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (0.19 g, 0.88 mmol). The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. and 12 hours at ambient temperature. Six milliliters of saturated aqueous NaHCO3 solution was added to the reaction mixture, and the resulting mixture was stirred for 5 minutes. The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organic solution was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was purified by flash chromatography (50% EtOAc in hexanes), the mixed fractions were combined, concentrated in vacuo, and purified by preparative plate (50% EtOAc in hexanes). The desired product isolated from flash chromatography and preparative plate were combined and further purified by preparative plate (5% acetonitrile in chloroform, developed twice). The free amine was dissolved in 5 mL of ethyl ether and treated with ethereal HCl to afford 75 mg (28% over 2 steps) of the pure titled compound as a white foam: mp 55-68° C. APCI-MS m/z 456.9 (MH+).

1. temperaturethe solution was cooled to 0° C. in an ice-water bath
2. customThe resulting reaction mixture
3. stirringwas stirred for, in succession, 30 minutes at 0° C.
4. custom12 hours
5. customat ambient temperature
6. stirringthe resulting mixture was stirred for 5 minutes
7. customThe two layers were separated
8. extractionthe aqueous layer was extracted with CH2Cl2 (2×10 mL)
9. dry with materialThe combined organic solution was dried over Na2SO4
10. concentrationThe solution was concentrated in vacuo
11. customaffording a viscous oil
12. customThe crude product was purified by flash chromatography (50% EtOAc in hexanes)
13. concentrationconcentrated in vacuo
14. custompurified by preparative plate (50% EtOAc in hexanes)

ORD record

ord-cee51c2d073a441a915965dfa453eef2

Source dataset

uspto-grants-2002_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06458781B1