【结 构 式】 |
【药物名称】Tebipenem, L-036, LJC-11036 【化学名称】(1R,5S,6S)-6-[1(R)-Hydroxyethyl]-1-methyl-2-[1-(2-thiazolin-2-yl)azetidin-3-ylsulfanyl]-1-carba-2-penem-3-carboxylic acid 【CA登记号】161715-21-5 【 分 子 式 】C16H21N3O4S2 【 分 子 量 】383.49147 |
【开发单位】Wyeth Pharmaceuticals (Originator) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Carbapenems |
合成路线1
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.
【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
1-azabicyclobutane (III) was opened with thioacetic acid with concomitant N-acetylation yielding (XII). Further acid hydrolysis of (XII) gave 3-mercaptoazetidine (XIII). Condensation of (XIII) with either 2-(methylthio)thiazoline (V) or 2-chloroethyl isothiocyanate (VII) then produced thiazolinylazetidine (XI).
【1】 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 . |
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 | ||
(III) | 31396 | 1-azabicyclo[1.1.0]butane | C3H5N | 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 |
(VII) | 31400 | 2-chloroethyl isothiocyanate; 1-chloro-2-isothiocyanatoethane | 6099-88-3 | C3H4ClNS | 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 |
(XII) | 31405 | S-(1-acetyl-3-azetidinyl) ethanethioate | C7H11NO2S | 详情 | 详情 | |
(XIII) | 31406 | 3-azetidinylhydrosulfide; 3-azetidinethiol | C3H7NS | 详情 | 详情 |
合成路线3
A further procedure consisted in the opening of 1-azabicyclobutane (III) with 2-mercaptothiazoline (XIV) to give (XV). Subsequent rearrangement of (XV) in the presence of methanesulfonic acid produced thiazolinyl azetidine (XI).
【1】 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 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(III) | 31396 | 1-azabicyclo[1.1.0]butane | C3H5N | 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 |
(XIV) | 28895 | 4,5-dihydro-1,3-thiazol-2-ylhydrosulfide | 96-53-7 | C3H5NS2 | 详情 | 详情 |
(XV) | 31407 | 3-azetidinyl 4,5-dihydro-1,3-thiazol-2-yl sulfide; 2-(3-azetidinylsulfanyl)-4,5-dihydro-1,3-thiazole | C6H10N2S2 | 详情 | 详情 |
合成路线4
Condensation of (phosphoryloxy)carbapenem (XVI) with 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine (XI) gave thioether (XVII). The p-nitrobenzyl ester group of (XVII) was then deprotected with Zn powder to afford the target carboxylic acid.
【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 |
---|---|---|---|---|---|---|
(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 |
(XVI) | 13224 | 4-nitrobenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | 90776-59-3 | C29H27N2O10P | 详情 | 详情 |
(XVII) | 31408 | 4-nitrobenzyl (4R,5S,6S)-3-[[1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C23H26N4O6S2 | 详情 | 详情 |