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

温度

-30 °C

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]+.

1. customthe solvent was removed in vacuo
2. dissolutionthe residue was dissolved in ethyl acetate
3. washIt was washed three times with small portions of 10% HCl
4. extractionthe aqueous phases were back-extracted with ethyl acetate
5. washThe combined organic phases were washed with 1 N NaHCO3 and brine
6. dry with materialdried over Na2SO4
7. concentrationconcentrated
8. dissolutionThe resulting oil (300 mg) was dissolved in 2 mL of dichloromethane
9. concentrationIt was concentrated
10. stirringhad previously been stirred together for 1 h at room temperature
11. additionwas added
12. temperatureto warm to ambient temperature
13. customAfter 3 days the reaction was quenched with 1 N KH2PO4
14. dissolutiondissolved in ethyl acetate
15. washThe organic phase was washed with 1 N KH2PO4, 1 N NaHCO3 (2×) and brine
16. dry with materialdried over Na2SO4
17. concentrationconcentrated
18. washChromatography over silica gel, eluting with 4% to 10% methanol (containing 1% NH4OH) in dichloromethane

ORDレコード

ord-da8f8fceabc84ff9a2438aecbc1a5fee

出典データセット

uspto-grants-2007_02

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US07176242B2