Nolpitantium besilate, SR-140333B, SR-140333A(chloride), SR-140333(cation)

1-[2-[3-(3,4-二氯苯基)-1-[2-(3-异丙氧基苯基)乙酰]哌啶-3(S)-酰基]-4-苯基-1-偶氮二环[2.2.2]辛烷苯磺酸盐 1-[2-[(3S)-3-(3,4-二氯苯基)-1-[2-[3-(1-甲基乙氧基)苯基]乙酰基]-3-哌啶基]乙基]-4-苯基-1-氮杂双环[2.2.2]氯化辛烷 1-Azonia双环[2.2.2]辛烷,1-[2-[(3S)-3-(3,4-二氯苯基)-1-[2-[3-[3-(1-甲基苯氧基)苯基]乙酰]-3-哌啶基]-4-苯基-Chemical Name: 1-[2-[3-(3,4-Dichlorophenyl)-1-[2-(3-isopropoxyphenyl)acetyl]piperidin-3(S)-yl]ethyl]-4-phenyl-1-azoniabicyclo[2.2.2]octane benzenesulfonate
CAS No. 155418-06-7, 153050-21-6 (cation), 155418-05-6 (chloride)
项目整合开发状态: Phase II
项目研究机构: Sanofi-Aventis (Originator)
合成路线:Alkylation of 3,4-dichlorophenylacetonitrile (I) with 2-(tetrahydropyranyloxy)ethyl bromide (II) in the presence of NaH in THF afforded nitrile (III).This was further alkylated with ethyl 3-bromopropionate (IV) using LDA to produce the cyano ester adduct (V).Catalytic hydrogenation of the cyano group of (V) in the presence of Raney-nickel,with concomitant intramolecular cyclization of the intermediate amino ester,gave rise to the piperidinone (VI).This was further reduced to piperidine (VII) using LiAlH4 in THF.After acidic deprotection of the tetrahydropyranyl group of (VII),the racemic amine was resolved by means of tartaric acid to furnish the desired enantiomer (VIII).Acylation of piperidine (VIII) with 3-isopropoxyphenylacetic acid (IX) employing BOP as the coupling reagent yielded amide (X).Conversion of (X) to the mesylate (XI) was carried out by treatment with methanesulfonyl chloride and Et3N.Then,N-alkylation of 4-phenylquinuclidine (XII) with mesylate (XI) produced the corresponding ammonium salt,which was finally subjected to anion exchange of the mesylate for a chloride group by treatment with HCl.