合成路线1
该中间体在本合成路线中的序号:
(XI) 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
该中间体在本合成路线中的序号:
(XI) 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).
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
该中间体在本合成路线中的序号:
(XI) 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).
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
该中间体在本合成路线中的序号:
(XI) 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
|
合成路线5
该中间体在本合成路线中的序号:
(XI) 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6
该中间体在本合成路线中的序号:
(XI) 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).
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7
该中间体在本合成路线中的序号:
(XI) 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).
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8
该中间体在本合成路线中的序号:
(XI) 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.
【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
|