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【结 构 式】 
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【分子编号】31397 【品名】3-azetidinol 【CA登记号】 |
【 分 子 式 】C3H7NO 【 分 子 量 】73.09472 【元素组成】C 49.3% H 9.65% N 19.16% O 21.89% |
合成路线1
该中间体在本合成路线中的序号：(IV)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：(XII)Reaction of 2,3,5,6-tetrafluoropyridine (I) with benzylamine (II) in refluxing acetonitrile gives 2-(benzyl-amino)-3,5,6-trifluoropyridine (III), which is debenzylated with H2 over Pd/C in methanol to yield 3,5,6-trifluoropyridine-2-amine (IV). Reaction of amine (IV) with 4-methoxybenzylamine (V) in N-methylpyrrolidone at 140 C affords 3,5-difluoro-6-(4-methoxybenzylamino)pyridine-2-amine (VI), which is cyclized with 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylic acid ethyl ester (VII) obtained by condensation of 2-(3-chloro-2,4,5-trifluorobenzoyl)acetic acid ethyl ester (VIII) with triethyl orthoformate (IX) by means of acetic anhydride in hot DMF in the presence of K2CO3 to provide the N-protected aminoquinolone derivative (X). Reaction of quinolone (X) with HCl in refluxing acetic acid gives 4-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (XI), which is finally condensed with 3-hydroxyazetidine (XII) by means of N-methylpyrrolidine in refluxing acetonitrile.
| 【2】 Yazaki, A.; Niino, Y.; Ohshita, Y.; Hirao, Y.; Amano, H.; Hayashi, N.; Kuramoto, Y. (Wakunaga Pharmaceutical Co., Ltd.); Novel pyridonecarboxylic acid derivs. or their salts and antibacterial agent comprising the same as the active ingredient. EP 0911327; EP 0992501; JP 1999322715; JP 2000136191; US 5998436; US 6133284; WO 9711068 . |
| 【1】 Mealy, N.E.; Castaner, J.; ABT-492. Drugs Fut 2002, 27, 11, 1033. |
| 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) | 56640 | 2,3,5,6-Tetrafluoropyridine | 2875-18-5 | C5HF4N | 详情 | 详情 |
| (II) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (III) | 56641 | N-benzyl-3,5,6-trifluoro-2-pyridinamine; N-benzyl-N-(3,5,6-trifluoro-2-pyridinyl)amine | C12H9F3N2 | 详情 | 详情 | |
| (IV) | 56642 | 3,5,6-trifluoro-2-pyridinamine; 3,5,6-trifluoro-2-pyridinylamine | C5H3F3N2 | 详情 | 详情 | |
| (V) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (VI) | 56643 | N-(6-amino-3,5-difluoro-2-pyridinyl)-N-(4-methoxybenzyl)amine; 3,5-difluoro-N~2~-(4-methoxybenzyl)-2,6-pyridinediamine | C13H13F2N3O | 详情 | 详情 | |
| (VII) | 11682 | ethyl (Z)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxy-2-propenoate | C14H12ClF3O4 | 详情 | 详情 | |
| (VIII) | 11681 | ethyl 3-(3-chloro-2,4,5-trifluorophenyl)-3-oxopropanoate | 101987-86-4 | C11H8ClF3O3 | 详情 | 详情 |
| (IX) | 21304 | Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether | 122-51-0 | C7H16O3 | 详情 | 详情 |
| (X) | 56644 | ethyl 8-chloro-1-{3,5-difluoro-6-[(4-methoxybenzyl)amino]-2-pyridinyl}-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C25H18ClF4N3O4 | 详情 | 详情 | |
| (XI) | 56645 | 1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C15H6ClF4N3O3 | 详情 | 详情 | |
| (XII) | 31397 | 3-azetidinol | C3H7NO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XII)Reaction of 2,3,5,6-tetrafluoropyridine (I) with ammonia in formamide gives the 2-aminopyridine derivative (IV), which is condensed with tert-butylamine (XIII) in N-methylpyrrolidone to yield 6-(tert-butylamino)-3,5-di- fluoropyridine-2-amine (XIV). Condensation of amine (XIV) with 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylic acid ethyl ester (VII) gives the adduct (XV), which is cyclized by means of K2CO3 in DMF to afford the quinolone derivative (XVI). Treatment of quinolone (XVI) with HCl in AcOH produces simultaneous ester hydrolysis and tert-butyl group removal, providing 4-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (XI). Finally, this compound is condensed with 3-hydroxyazetidine (XII) by means of N-methylpyrrolidine in DMF.
| 【2】 Ohshita, Y.; Kuramoto, Y.; Niino, Y.; Yazaki, A.; Structure-activity relationships of fluoroquinolones containing various heteroaromatics at N-1; WQ-3034/ABT-492 and its derivatives. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-544. |
| 【1】 Mealy, N.E.; Castaner, J.; ABT-492. Drugs Fut 2002, 27, 11, 1033. |
| 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) | 56640 | 2,3,5,6-Tetrafluoropyridine | 2875-18-5 | C5HF4N | 详情 | 详情 |
| (IV) | 56642 | 3,5,6-trifluoro-2-pyridinamine; 3,5,6-trifluoro-2-pyridinylamine | C5H3F3N2 | 详情 | 详情 | |
| (VII) | 11682 | ethyl (Z)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxy-2-propenoate | C14H12ClF3O4 | 详情 | 详情 | |
| (XI) | 56645 | 1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C15H6ClF4N3O3 | 详情 | 详情 | |
| (XII) | 31397 | 3-azetidinol | C3H7NO | 详情 | 详情 | |
| (XIII) | 17895 | 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine | 75-64-9 | C4H11N | 详情 | 详情 |
| (XIV) | 56646 | N~2~-(tert-butyl)-3,5-difluoro-2,6-pyridinediamine; N-(6-amino-3,5-difluoro-2-pyridinyl)-N-(tert-butyl)amine | C9H13F2N3 | 详情 | 详情 | |
| (XV) | 56647 | ethyl (Z)-3-{[6-(tert-butylamino)-3,5-difluoro-2-pyridinyl]amino}-2-(3-chloro-2,4,5-trifluorobenzoyl)-2-propenoate | C21H19ClF5N3O3 | 详情 | 详情 | |
| (XVI) | 56648 | ethyl 1-[6-(tert-butylamino)-3,5-difluoro-2-pyridinyl]-8-chloro-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C21H18ClF4N3O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)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5
该中间体在本合成路线中的序号：(IV)The deprotection of the benzyloxypyrimidine derivative (I) by treatment wit TFA and thioanisole gives the hydroxypyrimidine (II), which is treated with hot POCl3, yielding the corresponding chloro derivative (III). Finally, the target compound is obtained by condensation of (III) with 3-hydroxyazetidine (IV) in refluxing ethanol. The azetidine (IV) is obtained by deprotection of 1-benzhydryl-3-hydroxyazetidine (V) by hydrogenation with H2 over Pd/C in ethanol/water.
| 【1】 Naito, H.; Ohsuki, S.; Ejima, A.; Makino, C.; Ohki, H. (Daiichi Pharmaceutical Co., Ltd.); Pyrazole derivs. and salts thereof. EP 1103551; JP 2000169475; WO 0005230 . |
| 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) | 50359 | 4-(benzyloxy)-6-(4-[(E)-3-[4-(3,5-difluorophenyl)-1-piperazinyl]-1-propenyl]-5-methyl-1H-pyrazol-1-yl)-2-pyrimidinamine; 4-(benzyloxy)-6-(4-[(E)-3-[4-(3,5-difluorophenyl)-1-piperazinyl]-1-propenyl]-5-methyl-1H-pyrazol-1-yl)-2-pyrimidinylamine | C28H29F2N7O | 详情 | 详情 | |
| (II) | 50360 | 2-amino-6-(4-[(E)-3-[4-(3,5-difluorophenyl)-1-piperazinyl]-1-propenyl]-5-methyl-1H-pyrazol-1-yl)-4-pyrimidinol | C21H23F2N7O | 详情 | 详情 | |
| (III) | 50361 | 4-chloro-6-(4-[(E)-3-[4-(3,5-difluorophenyl)-1-piperazinyl]-1-propenyl]-5-methyl-1H-pyrazol-1-yl)-2-pyrimidinamine; 4-chloro-6-(4-[(E)-3-[4-(3,5-difluorophenyl)-1-piperazinyl]-1-propenyl]-5-methyl-1H-pyrazol-1-yl)-2-pyrimidinylamine | C21H22ClF2N7 | 详情 | 详情 | |
| (IV) | 31397 | 3-azetidinol | C3H7NO | 详情 | 详情 | |
| (V) | 12592 | 1-Benzhydryl-3-azetidinol; 1-Benzhydryl-3-hydroxyazetidine；1-benzhydrylazetidin-3-ol | 18621-17-5 | C16H17NO | 详情 | 详情 |