Tebipenem pivoxil, L-084, -Drug Synthesis Database

【结构式】

【药物名称】Tebipenem pivoxil, L-084

【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 pivaloyloxymethyl ester

【CA登记号】161715-24-8

【分子式】C₂₂H₃₁N₃O₆S₂

【分子量】497.63687

【开发单位】Wyeth Pharmaceuticals (Originator)

【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Carbapenems

合成路线1 合成路线2 合成路线3 合成路线4

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.

参考文献中间体

【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).

参考文献中间体

【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).

参考文献中间体

【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 carboxylic acid. Finally, treatment of (XVIII) with either iodo or chloromethyl pivalate (XIX) produced the target compound.

参考文献中间体

【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
(XIXa)	11159	iodomethyl pivalate		C₆H₁₁IO₂	详情	详情
(XIXb)	16166	chloromethyl pivalate	18997-19-8	C₆H₁₁ClO₂	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
(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
(XVIII)	31409	(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-carboxylic acid		C₁₆H₂₁N₃O₄S₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)