IRL-3630

Chemical Name: N1-(Butylsulfonyl)-N2-[N-(3,5-dimethylbenzoyl)-N-methyl-4-(5-isoxazolyl)-D-phenylalanyl]-L-valinamide
CAS No. 189252-56-0 (monoNa salt)
项目整合开发状态: Preclinical
项目研究机构: Novartis (Originator)
合成路线:4'-Methylacetophenone (I) was condensed with boiling dimethylformamide dimethylacetal,and the resulting enaminoketone (II) was cyclized to the isoxazole (III) with hydroxylamine O-sulfonic acid in MeOH.Benzylic bromination of (III) with N-bromosuccinimide in the presence of benzoyl peroxide gave bromomethyl compound (IV).Subsequent alkylation of diphenylmethylene glycine ethyl ester (V) with (IV) under phase-transfer conditions,followed by acid deprotection furnished isoxazolylphenylalanine ethyl ester (VII).This compound was condensed with 3,5-dimethyl benzoic acid (VIII) using EDC and HOBt to give amide (IX).Further N-methylation of (IX) with MeI and NaH yielded (X),which was hydrolyzed with LiOH to the carboxylic acid (XI).

合成路线:1-Butanesulfonyl chloride (XII) was reacted with ammonia in acetonitrile,and the resulting sulfonamide (XIII) was then converted to the N-trimethylsilyl derivative (XIV).This compound was coupled with acid fluoride (XVII),(obtained from Boc-valine (XV) and cyanuric fluoride (XVI)),to provide Boc-valinesulfonamide (XVIII).The Boc group of (XVIII) was then removed by acid treatment to give (XIX).Coupling of this chiral intermediate (XIX) with racemic acid (XI) in a biphasic solvent system,with partial isomerization of acid (XI),furnished the amide (XX) as a 12:1 diastereomeric mixture.The major D,L diastereoisomer was then isolated either by preparative HPLC or by recrystallization from isopropanol.