VULM 411

Chemical Name: [3-(2-Cyclohexylphenoxy)-2-hydroxypropyl]isopropyl dimethyl ammonium chloride
项目整合开发状态: Biological Testing
项目研究机构: Res. Inst. Drugs (Originator)
合成路线:Reaction of 1-isopropylamino-3-(3-cyclohexylphenoxy)-2-propanol (I) (exaprolol) with formaldehyde and formic acid affords the N-methyl derivative (II),which is subsequently quaternized by methyliodide.The iodide (III) is then converted to the chloride on an anex column.

合成路线:The intermediate phosphonate (XXI) has been obtained as follows: The reaction of tert-butyl mercaptan (XV) with allyl bromide (XVI) by means of NaOH in ethanol gives the sulfide (XVII),which is oxidized with Oxone in methanol/water to yield the sulfone (XVIII).The bromination of (XVIII) with Br2 in CCl4 followed by dehydrobromination with TEA affords the bromosulfone (XIX),which is finally condensed with tributyl phosphite (XX) by heating at 130 C to provide the target intermediate phosphonate (XXI).The silylation of the known diol (XXII) (obtained by degradation of vitamin D2) with Tes-OTf and lutidine gives the bis silyl ether (XXIII),which is submitted to a Swern oxidation ((COCl)2),yielding the carbaldehyde (XXIV).The Wadsworth-Emmons condensation of aldehyde (XXIV) with the intermediate phosphonate (XXI) by means of tBu-OLi affords the diinsaturated sulfone (XXV),which is desilylated with HF in THF to provide the alcohol (XXVI).The oxidation of (XXVI) with TPAP and NMO furnishes the ketone (XXVII),which is submitted to a Wittig-Horner condensation with the intermediate phosphine oxide (XIV) by means of PhLi,giving the silylated precursor (XXVIII).Finally,this compound is desilylated with HF in ethanol to afford the target vitamin D3 analogue.