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【结 构 式】

【分子编号】31401

【品名】N-(2-chloroethyl)-3-hydroxy-1-azetidinecarbothioamide

【CA登记号】

【 分 子 式 】C6H11ClN2OS

【 分 子 量 】194.68492

【元素组成】C 37.02% H 5.7% Cl 18.21% N 14.39% O 8.22% S 16.47%
与该中间体有关的原料药合成路线共 2 条
合成路线1合成路线2

合成路线1

该中间体在本合成路线中的序号：(VIII)

Halogenation of allylamine (I) with either bromine or sulfuryl chloride produced the corresponding (halomethyl)aziridines (II). Subsequent treatment of (II) with n-butyllithium at -78 C yielded 1-azabicyclobutane (III). Opening of the bicyclic system of (III) with formic acid followed by acid hydrolysis provided 3-hydroxyazetidine (IV). This was condensed with 2-(methylsulfanyl)thiazoline (V) to give thiazolinylazetidine (VI). Alternatively, 3-hydroxyazetidine (IV) was condensed with 2-chloroethyl isothiocyanate (VII) to give the intermediate thiourea (VIII), which cyclized to the thiazoline (VI). Conversion of the hydroxyl group of (VI) into the thioacetate (IX) was carried out by either coupling with thioacetic acid under Mitsunobu conditions or by conversion to mesylate (X) followed by displacement with potassium thioacetate. The required thiol (XI) was then obtained from (IX) by basic hydrolysis of the thioacetate ester.

参考文献 中间体
合成目标
【1】 Satoh, C.; Mihira, A.; Yamamoto, S.; Hayashi, K.; Kitamura, M.; Tamai, S.; Abe, T.; Kumagai, T.; Hikida, M.; L-084, a new oral carbapenem: Synthesis and structure-activity relationships of C2-substituted 1beta-methylcarbapenems. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-64.
【2】 Abe, T.; Isoda, T.; Sato, C.; Mihira, A.; Tamai, S.; Kumagai, T. (Lederle (Japan), Ltd.); 2-(1-(1,3-Thiazolin-2-yl)azetidin-3-yl)thio-carbapenem derivs.. EP 0632039; EP 0717042; JP 1996053453; US 5534510; US 5659043; US 5783703 .
【3】 Abe, T.; Kumagai, T. (Lederle (Japan), Ltd.); Carbapenem-3-carboxylic acid ester derivs.. EP 0808315; JP 1999504039; US 5886172; WO 9721712 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12893 Ethanethioic S-acid C2H4OS 详情 详情
17190 potassium ethanethioate 10387-40-3 C2H3KOS 详情 详情
(IIa) 31394 2-(chloromethyl)aziridine C3H6ClN 详情 详情
(IIb) 31395 2-(bromomethyl)aziridine C3H6BrN 详情 详情
(I) 13672 Allylamine; 2-Propen-1-amine 107-11-9 C3H7N 详情 详情
(III) 31396 1-azabicyclo[1.1.0]butane C3H5N 详情 详情
(IV) 31397 3-azetidinol C3H7NO 详情 详情
(V) 31398 2-(methylsulfanyl)-4,5-dihydro-1,3-thiazole; 4,5-dihydro-1,3-thiazol-2-yl methyl sulfide 19975-56-5 C4H7NS2 详情 详情
(VI) 31399 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinol C6H10N2OS 详情 详情
(VII) 31400 2-chloroethyl isothiocyanate; 1-chloro-2-isothiocyanatoethane 6099-88-3 C3H4ClNS 详情 详情
(VIII) 31401 N-(2-chloroethyl)-3-hydroxy-1-azetidinecarbothioamide C6H11ClN2OS 详情 详情
(IX) 31402 S-[1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinyl] ethanethioate C8H12N2OS2 详情 详情
(X) 31403 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinyl methanesulfonate C7H12N2O3S2 详情 详情
(XI) 31404 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinylhydrosulfide; 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinethiol 179337-57-6 C6H10N2S2 详情 详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

Halogenation of allylamine (I) with either bromine or sulfuryl chloride produced the corresponding (halomethyl)aziridines (II). Subsequent treatment of (II) with n-butyllithium at -78 C yielded 1-azabicyclobutane (III). Opening of the bicyclic system of (III) with formic acid followed by acid hydrolysis provided 3-hydroxyazetidine (IV). This was condensed with 2-(methylsulfanyl)thiazoline (V) to give thiazolinylazetidine (VI). Alternatively, 3-hydroxyazetidine (IV) was condensed with 2-chloroethyl isothiocyanate (VII) to give the intermediate thiourea (VIII), which cyclized to the thiazoline (VI). Conversion of the hydroxyl group of (VI) into the thioacetate (IX) was carried out by either coupling with thioacetic acid under Mitsunobu conditions or by conversion to mesylate (X) followed by displacement with potassium thioacetate. The required thiol (XI) was then obtained from (IX) by basic hydrolysis of the thioacetate ester.

参考文献 中间体
合成目标
【1】 Satoh, C.; Mihira, A.; Yamamoto, S.; Hayashi, K.; Kitamura, M.; Tamai, S.; Abe, T.; Kumagai, T.; Hikida, M.; L-084, a new oral carbapenem: Synthesis and structure-activity relationships of C2-substituted 1beta-methylcarbapenems. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-64.
【2】 Abe, T.; Isoda, T.; Sato, C.; Mihira, A.; Tamai, S.; Kumagai, T. (Lederle (Japan), Ltd.); 2-(1-(1,3-Thiazolin-2-yl)azetidin-3-yl)thio-carbapenem derivs.. EP 0632039; EP 0717042; JP 1996053453; US 5534510; US 5659043; US 5783703 .
【3】 Abe, T.; Kumagai, T. (Lederle (Japan), Ltd.); Carbapenem-3-carboxylic acid ester derivs.. EP 0808315; JP 1999504039; US 5886172; WO 9721712 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12893 Ethanethioic S-acid C2H4OS 详情 详情
17190 potassium ethanethioate 10387-40-3 C2H3KOS 详情 详情
(IIa) 31394 2-(chloromethyl)aziridine C3H6ClN 详情 详情
(IIb) 31395 2-(bromomethyl)aziridine C3H6BrN 详情 详情
(I) 13672 Allylamine; 2-Propen-1-amine 107-11-9 C3H7N 详情 详情
(III) 31396 1-azabicyclo[1.1.0]butane C3H5N 详情 详情
(IV) 31397 3-azetidinol C3H7NO 详情 详情
(V) 31398 2-(methylsulfanyl)-4,5-dihydro-1,3-thiazole; 4,5-dihydro-1,3-thiazol-2-yl methyl sulfide 19975-56-5 C4H7NS2 详情 详情
(VI) 31399 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinol C6H10N2OS 详情 详情
(VII) 31400 2-chloroethyl isothiocyanate; 1-chloro-2-isothiocyanatoethane 6099-88-3 C3H4ClNS 详情 详情
(VIII) 31401 N-(2-chloroethyl)-3-hydroxy-1-azetidinecarbothioamide C6H11ClN2OS 详情 详情
(IX) 31402 S-[1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinyl] ethanethioate C8H12N2OS2 详情 详情
(X) 31403 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinyl methanesulfonate C7H12N2O3S2 详情 详情
(XI) 31404 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinylhydrosulfide; 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinethiol 179337-57-6 C6H10N2S2 详情 详情
Extended Information