FR-115906, FK-906

Chemical Name: N-Methyl-N-[2(S)-[N-methyl-N-[2-[N-methyl-N-(4-morpholinylcarbonyl)amino]ethyl]carbamoyloxy]-3-phenylpropionyl]-L-histidine 1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexylamide hydrochloride
CAS No. 124151-25-3
项目整合开发状态: Phase II
项目研究机构: Fujisawa (Originator)
合成路线:By condensation of 2(S)-[N-methyl-N-[2-[N-methyl-N-(morpholinocarbonyl)amino]ethyl]carbamoyloxy]-3-phenylpropanoic acid (I) with protected Nalpha-methyl-L-histidine 1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexylamide (II) by means of oxalyl chloride and DMF in dichloromethane.The starting compounds (I) and (II) are obtained as follows:1) The reaction of morpholinocarbonyl chloride (III) with N-(tert-butoxycarbonyl)-N,N'-dimethylethylenediamine (IV) by means of triethylamine in dichloromethane gives the monoacylated diamine (V),which is deprotected with trifluoroacetic acid to yield N,N'-dimethyl-N-(morpholinocarbonyl)ethylenediamine (VI).The condensation of (VI) with 2(S)-hydroxy-3-phenylpropanoic acid benzyl ester (VII) by means of trichloromethyl chloroformate in refluxing THF affords 2(S)-[N-methyl-N-[2-[N-methyl-N-(morpholinocarbonyl)amino]ethyl]carbamoyloxy]propanoic acid benzyl ester (VIII),which is finally debenzylated by hydrogenation with H2 over Pd/C to give (I).2) The Grignard reaction of tert-butoxycarbonyl-(3-cyclohexyl)-L-alaninal (IX) with 3-methylbutylmagnesium bromide (X) in THF gives 2(S)-(tert-butoxycarbonylamino)-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (XI),which is deprotected with trifluoroacetic acid to yield the free amine derivative (XII).The condensation of (XII) with Nalpha-(tert-butoxycarbonyl)-Nalpha-methyl-Ntau-tosyl-L-histidine (XIII) by means of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide (CDI) in dichloromethane affords the corresponding histidinamide (XIV),which is deprotected with trifluoroacetic acid to afford (II).