Reaktion #42554

Reaktionsgleichung

4-methyl morpholine

TFA

3-[(dipropylamino)carbonyl]-5-methylbenzoic acid

CDI

tert-Butyl (1S)-2-(cyclohexyl)-1-[(2S)-oxiran-2-yl]ethylcarbamate

m-ethyl benzylamine

HCl

→

N1-{(1S,2R)-1-(cyclohexylmethyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N3,N3-dipropylisophthalamide hydrochloride

Lösungsmittel

THF

THF

isopropanol

Reaktionsbedingungen

Aufarbeitung

1. 1
   Sonstigethe solvent was removed in vacuo
2. 2
   workup.DISSOLUTIONthe residue was dissolved in ethyl acetate
3. 3
   WaschenIt was washed three times with small portions of 10% HCl
4. 4
   Extraktionthe aqueous phases were back-extracted with ethyl acetate
5. 5
   WaschenThe combined organic phases were washed with 1 N NaHCO3 and brine
6. 6
   Trocknendried over Na2SO4
7. 7
   Einengenconcentrated
8. 8
   workup.DISSOLUTIONThe resulting oil (300 mg) was dissolved in 2 mL of dichloromethane
9. 9
   EinengenIt was concentrated
10. 10
    workup.STIRRINGhad previously been stirred together for 1 h at room temperature
11. 11
    workup.ADDITIONwas added
12. 12
    Temperaturto warm to ambient temperature
13. 13
    SonstigeAfter 3 days the reaction was quenched with 1 N KH2PO4
14. 14
    workup.DISSOLUTIONdissolved in ethyl acetate
15. 15
    WaschenThe organic phase was washed with 1 N KH2PO4, 1 N NaHCO3 (2×) and brine
16. 16
    Trocknendried over Na2SO4
17. 17
    Einengenconcentrated
18. 18
    WaschenChromatography over silica gel, eluting with 4% to 10% methanol (containing 1% NH4OH) in dichloromethane

Vorschrift

tert-Butyl (1S)-2-(cyclohexyl)-1-[(2S)-oxiran-2-yl]ethylcarbamate (225 mg, 0.84 mmol) was refluxed with m-ethyl benzylamine (254 mg, 1.9 mmol) in 5 mL of isopropanol under nitrogen for 1.5 h, the solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. It was washed three times with small portions of 10% HCl, and the aqueous phases were back-extracted with ethyl acetate. The combined organic phases were washed with 1 N NaHCO3 and brine, dried over Na2SO4, and concentrated. The resulting oil (300 mg) was dissolved in 2 mL of dichloromethane and 2 mL of TFA and stirred for 30 min. It was concentrated, and by weight determined to contain 4 eq. of TFA. This was dissolved in 2 mL of dry THF, and 0.4 mL (3.6 mmol) of 4-methyl morpholine was added. This was cooled to −30° C., and a mixture of 3-[(dipropylamino)carbonyl]-5-methylbenzoic acid (238 mg, 0.9 mmol) and CDI (165 mg, 1 mmol) in 3 mL of dry THF, which had previously been stirred together for 1 h at room temperature, was added. The mixture was allowed to warm to ambient temperature. After 3 days the reaction was quenched with 1 N KH2PO4 and dissolved in ethyl acetate. The organic phase was washed with 1 N KH2PO4, 1 N NaHCO3 (2×) and brine, dried over Na2SO4, and concentrated. Chromatography over silica gel, eluting with 4% to 10% methanol (containing 1% NH4OH) in dichloromethane afforded 124 mg (0.21 mmol) of N1-{(1S,2R)-1-(cyclohexylmethyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N3,N3-dipropylisophthalamide hydrochloride (EXAMPLE SP-256) as a white solid after formation of the salt with ethereal HCl: CI MS m/z 550 [M+H]+.

Quelle