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【结 构 式】

【药物名称】Nolpitantium besilate, SR-140333B, SR-140333A(chloride), SR-140333(cation)

【化学名称】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

【CA登记号】155418-06-7, 153050-21-6 (cation), 155418-05-6 (chloride)

【 分 子 式 】C43H50Cl2N2O5S

【 分 子 量 】777.85835

【开发单位】Sanofi-synthélabo (Originator)

【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, GASTROINTESTINAL DRUGS, Inflammatory Bowel Disease, Agents for, Oncolytic Drugs, RESPIRATORY DRUGS, Tachykinin NK1 Antagonists

合成路线1

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.

1 Emonds-Alt, X.; Gueule, P.; Proietto, V.; Van Broeck, D. (Sanofi-Synthelabo); Quaternary basic amides as tachykinines antagonists. EP 0591040; FR 2696178; JP 1998175976; US 5583134; US 5712288 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 26935 2-(3,4-dichlorophenyl)acetonitrile 3218-49-3 C8H5Cl2N 详情 详情
(II) 26934 2-bromoethyl tetrahydro-2H-pyran-2-yl ether C7H13BrO2 详情 详情
(III) 26936 2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butanenitrile C15H17Cl2NO2 详情 详情
(IV) 29132 ethyl 3-bromopropanoate 539-74-2 C5H9BrO2 详情 详情
(V) 59767 ethyl 4-cyano-4-(3,4-dichlorophenyl)-6-(tetrahydro-2H-pyran-2-yloxy)hexanoate C20H25Cl2NO4 详情 详情
(VI) 59768 5-(3,4-dichlorophenyl)-5-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-2-piperidinone C18H23Cl2NO3 详情 详情
(VII) 59769 2-[3-(3,4-dichlorophenyl)-3-piperidinyl]ethyl tetrahydro-2H-pyran-2-yl ether; 3-(3,4-dichlorophenyl)-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]piperidine C18H25Cl2NO2 详情 详情
(VIII) 59770 2-[(3S)-3-(3,4-dichlorophenyl)piperidinyl]-1-ethanol C13H17Cl2NO 详情 详情
(IX) 59771 2-(3-isopropoxyphenyl)acetic acid C11H14O3 详情 详情
(X) 59772 1-[(3S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)piperidinyl]-2-(3-isopropoxyphenyl)-1-ethanone C24H29Cl2NO3 详情 详情
(XI) 59773 2-{(3S)-3-(3,4-dichlorophenyl)-1-[2-(3-isopropoxyphenyl)acetyl]piperidinyl}ethyl methanesulfonate C25H31Cl2NO5S 详情 详情
(XII) 59774 4-phenyl-1-azabicyclo[2.2.2]octane C13H17N 详情 详情
Extended Information