L-796568

N-[4-[2-[2(R)-羟基-2-(3-吡啶基)乙基氨基]苯基]-4-[4-[4-[(三氟甲基)苯基]噻唑-2-酰基]苯磺酰胺二盐酸盐Chemical Name: N-[4-[2-[2(R)-Hydroxy-2-(3-pyridyl)ethylamino]ethyl]phenyl]-4-[4-[4-(trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide dihydrochloride
CAS No. 211031-81-1, 211031-01-5 (free base)
项目整合开发状态: Phase I
项目研究机构: Merck & Co. (Originator)
合成路线:The intermediate sulfonyl chloride (IV) was prepared by condensation of phenyl isocyanate (I) with n-hexylamine (II),followed by chlorosulfonation of the resulting hexyl phenyl urea (III) with ClSO3H at 60 C.

合成路线:Chlorination of 3-acetylpyridine (V) with N-chlorosuccinimide in HCl-AcOH gave (chloroacetyl)pyridine (VI).Subsequent enantioselective reduction of (VI) using (-)-B-chlorodiisopinocampheylborane yielded (R)-chlorohydrin (VII),which was cyclized to pyridyloxirane (VIII) with K2CO3 in boiling acetone.Opening of epoxide (VIII) with 4-aminophenethylamine (IX) produced amino alcohol (X).After protection as the tert-butyl carbamate (XI),coupling with sulfonyl chloride (IV) furnished sulfonamide (XII).Finally,Boc deprotection of (XII) using TFA produced the title compound.

合成路线:Alternatively,reaction of 6-chloronicotinic acid (XIII) with methyllithium-lithium bromide complex gave methyl ketone (XIV).This was brominated by means of dibromobarbituric acid (XV) to produce bromoketone (XVI).Asymmetric reduction of (XVI) with (-)-B-chlorodiisopinocampheylborane provided the (R)-bromohydrin (XVII),which was converted to epoxide (XVIII) with NaOH in aqueous THF.Epoxide (XVIII) opening with 4-nitrophenethylamine (XIX) produced amino alcohol (XX),which by further protection with Boc2O gave carbamate (XXI).Concomitant dechlorination and nitro group reduction in (XXI) by hydrogenation using Raney Nickel as catalyst provided amine (XI).This was finally converted to the target compound by means of sulfonylation and deprotection as above.

合成路线:The chlorination of 3-acetylpyridine (I) with N-chlorosuccinimide (NCS) in acetic acid gives 3-(2-chloroacetyl)pyridine (II),which is reduced with (-)-B-chlorodiisopinocampheylborane [(-)-DIP-Cl] yielding the chiral chloroethanol (III).The epoxidation of (III) with K2CO3 in refluxing acetone affords the chiral epoxide (IV),which is opened with 4-(2-aminoethyl)aniline (V) in refluxing methanol giving the chiral aminoethanol (VI).The protection of the aliphatic amino group of (VI) with di-tert-butyl dicarbonate yields the carbamate (VII),which is finally condensed with the sulfonyl chloride (VIII) by means of pyridine in dichloromethane and deprotected with TFA in the same solvent.

合成路线:The chlorination of 2-acetylpyridine (I) with N-chlorosuccinimide in ethereal HCl gives 2-(chloroacetyl)pyridine (II),which is reduced with (-)-B-chlorodiisopinocampheylborane [(-)-DIP-Cl] in THF yielding (R)-2-chloro-1-(2-pyridyl)ethanol (III).The epoxidation of (III) with K2CO3 in refluxing acetone affords the epoxide (IV),which is condensed with 4-(2-aminoethyl)aniline (V) in refluxing methanol providing (R)-2-[2-(4-aminophenyl)ethylamino]-1-(2-pyridyl)ethanol (VI).The selective protection of the secondary amino group of (VI) with tert-butoxycarbonyl anhydride in THF gives the carbamate (VII) (1),which is condensed with 4-[2-(2-cyclopentylethyl)oxazol-5-yl]phenylsulfonyl chloride (VIII) in pyridine yielding the sulfonamide (IX).Finally,this compound is deprotected with trifluoroacetic acid.

合成路线:3-Acetylpyridine (I) was converted to the hydrochloride salt and then chlorinated with N-chlorosuccinimide to afford (chloroacetyl)pyridine (II).Asymmetric reduction of (II) by means of (-)-B-chlorodiisopinocampheylborane in THF produced the (R)-alcohol (III),which was cyclized to oxirane (IV) upon heating with K2CO3 in acetone.Epoxide (IV) opening with 4-aminophenethyl amine (V) in boiling MeOH gave aminoalcohol (VI).Then,selective protection of the aliphatic amine of (VI) as the tert-butyl carbamate yielded the target intermediate (VII).In a similar procedure,2-chloro-5-acetylpyridine (VIII) was brominated employing dibromobarbituric acid in THF to afford bromide (IX),which was enantioselectively reduced to the (R)-alcohol (X).After cyclization of (X) to epoxide (XI),its opening with 4-nitrophenethyl amine (XII) yielded aminoalcohol (XIII).This was protected as the N-Boc derivative (XIV) and then,hydrogenation of the nitro group of (XIV) with concomitant halogen hydrogenolysis in the presence of Raney Nickel provided an alternative access to intermediate (VII).