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【结 构 式】 
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【分子编号】52162 【品名】 【CA登记号】 |
【 分 子 式 】C11H22AgNO2SSi 【 分 子 量 】368.32092 【元素组成】C 35.87% H 6.02% Ag 29.29% N 3.8% O 8.69% S 8.71% Si 7.63% |
合成路线1
该中间体在本合成路线中的序号：(III)Treatment of the silylated azetidinone (I) with tritylmercaptan affords the tritylsulfanyl-azetidinone (II), which is converted into the silver salt (III) by reaction with AgNO3. Compound (III) is coupled with tetrahydrofuran-2(R)-carbonyl chloride (IV) -- obtained by treatment of carboxylic acid (V) with thionyl chloride -- providing the azetidinone thioester (VI). Coupling of azetidinone (VI) with allyl oxalyl chloride (VII) in CH2Cl2 by means of Et3N, followed by intramolecular Wittig cyclization by means of triethyl phosphite in refluxing xylene, affords penem (VIII). Alternatively, compound (VIII) can also be obtained as follows: Substitution of phenyl sulfonyl group of azetidinone (X) by tritylmercaptan by means of NaOH in acetone/water provides tritylsulfanyl-azetidinone (XI), which is condensed with allyl oxalyl chloride (VII) by means of DIEA in CH2Cl2 to give the oxalyl amide (XII). Compound (XII) is then treated with AgNO3 and pyridine in acetonitrile, providing the silver mercaptide (XIII), which is acylated with tetrahydrofuran-2(R)-carbonyl chloride (IV) in acetonitrile to afford the penem precursor (XIV). Penem (VIII) is obtained by intramolecular Wittig cyclization of (XIV) with P(OEt)3 in refluxing xylene. Finally, faropenem sodium can be obtained by removal of the tbdms protecting group of (VIII) by means of either Et3N tris(hydrogen fluoride) in ethyl acetate or tetrabutylammonium fluoride (TBAF) and HOAc in THF to give compound (IX). This is followed by allyl ester group removal of (IX), which can be performed under several different conditions: i) triphenylphosphine, sodium 2-ethylhexanoate and palladium tetrakis(triphenylphosphine); ii) palladium tetrakis(triphenylphosphine) and sodium 4-(methoxycarbonyl)-5,5-dimethylcyclohexane-1,3-dione enolate in several different solvents such as methyl acetate, ethyl acetate, tetrahydrofuran, dioxane, sec-butanol, acetonitrile, acetone, 2-butanone, 1,2-dichloroethane, chlorobenzene, toluene or ethylene glycol dimethyl ether; iii) triphenylphosphine and palladium tetrakis(triphenylphosphine) with sodium propionate, sodium acetate or sodium lactate in tetrahydrofuran or acetone; or iv) palladium acetate in the presence of P(OBu)3 and sodium propionate in THF.
| 【1】 Nakatsuka, T.; Tanaka, R.; Noguchi, T.; Ishiguro, M.; Iwata, H.; Nishino, T.; Nishihara, T.; Maeda, Y.; Studies on penem antibiotics. I. Synthesis and in vitro activity of novel 2-chiral substituted penems. J Antibiot 1988, 41, 11, 1685. |
| 【2】 Oyama, Y.; Imajo, S.; Tanaka, R.; Matsuki, S.; Ishiguro, M.; Structure-activity relationships of penem antibiotics: Crystallographic structures and implications for their antimicrobial activities. Bioorg Med Chem 1997, 5, 7, 1389. |
| 【3】 Jin, J.; Han, H.-N.; Liu, J.; Synthesis of the key intermediate of faropenem: (3S,4R)-3-[(R)-1-tert-Butyldimethylsilyloxyethyl]-4-[(R)-tetrahydrofuranoylthio]-2-azetidinone. J Shenyang Pharm Univ 2001, 18, 1, 20. |
| 【4】 Ishiguro, M.; Iwata, H.; Nakatsuka, T. (Suntory Ltd.); Penem cpds. AU 8654460; EP 0199446; JP 1994128267; US 4997829 . |
| 【5】 Ishiguro, M.; Iwata, H.; Nakatsuka, T.; Nakajima, M.; Yamada, Y.; Doi, J.; Fujimaru, M. (Suntory Ltd.); Processes for removing allyl groups. EP 0410727 . |
| 【6】 Ishiguro, M.; Yamada, Y.; Kimura, Y.; Imai, K. (Nippon Soda Co., Ltd.; Suntory Ltd.); Methods for removing allyl groups. JP 1992041489 . |
| 【7】 Matsunaga, K.; Shimanuki, K. (Nippon Soda Co., Ltd.; Suntory Ltd.); Removal method of allyl group. JP 1994321952 . |
| 【8】 Ishiguro, M.; Kanebo, A.; Kaku, T.; Nakatsuka, T. (Nippon Soda Co., Ltd.; Suntory Ltd.); Method of desilylating silylether cpds.. EP 0612749 . |
| 【9】 Fukami, H.; Shima, K.; Nakatsuka, T.; Iwata, H.; Yoshida, T.; Mizukawa, Y.; Shibata, M.; Sekiuchi, K.; Iwanami, T. (Suntory Ltd.); Preparation method of penem derivs.. JP 1994192270 . |
| 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) | 11687 | (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate | C13H25NO4Si | 详情 | 详情 | |
| (II) | 52161 | (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-(tritylsulfanyl)-2-azetidinone | C30H37NO2SSi | 详情 | 详情 | |
| (III) | 52162 | C11H22AgNO2SSi | 详情 | 详情 | ||
| (IV) | 11696 | (2R)Tetrahydro-2-furancarbonyl chloride | C5H7ClO2 | 详情 | 详情 | |
| (V) | 52163 | (2R)-Tetrahydro-2-furancarboxylic acid; (2R)-2-Tetrahydrofuroic acid | 87392-05-0 | C5H8O3 | 详情 | 详情 |
| (VI) | 11689 | S-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl] (2R)tetrahydro-2-furancarbothioate | C16H29NO4SSi | 详情 | 详情 | |
| (VII) | 15585 | allyl 2-chloro-2-oxoacetate | C5H5ClO3 | 详情 | 详情 | |
| (VIII) | 11697 | allyl (5R,6S)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-7-oxo-3-[(2R)tetrahydro-2-furanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C21H33NO5SSi | 详情 | 详情 | |
| (IX) | 11694 | allyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(2R)tetrahydro-2-furanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C15H19NO5S | 详情 | 详情 | |
| (X) | 52164 | (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-(phenylsulfonyl)-2-azetidinone | C17H27NO4SSi | 详情 | 详情 | |
| (XI) | 52161 | (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-(tritylsulfanyl)-2-azetidinone | C30H37NO2SSi | 详情 | 详情 | |
| (XII) | 52169 | allyl 2-[(3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-oxo-4-(tritylsulfanyl)azetidinyl]-2-oxoacetate | C35H41NO5SSi | 详情 | 详情 | |
| (XIII) | 52168 | C16H26AgNO5SSi | 详情 | 详情 | ||
| (XIV) | 52167 | allyl 2-((3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-oxo-4-[[(2R)tetrahydro-2-furanylcarbonyl]sulfanyl]azetidinyl)-2-oxoacetate | C21H33NO7SSi | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)Treatment of the silylated azetidinone (I) with tritylmercaptan affords the tritylsulfanylazetidinone (II), which by reaction with AgNO3 is converted into the silver salt (III). Compound (III) is coupled with tetrahydrofuran-2(R)-carbonyl chloride (IV) obtained by treatment of carboxylic acid (V) with thionyl chloride to provide the azetidinone thioester (VI). Alternatively, compound (VI) can be obtained by condensation of tetrahydrofuran-2(R)-thiocarboxylic S-acid (VII) obtained by treatment of carboxylic acid (V) with hydrogen sulfide with silylated azetidinones (I) or (VIII) by means of NaOH in THF/water. Condensation of azetidinone thioester (VI) with allyl glyoxylate (IX) in refluxing benzene gives the hydroxy ester (X), which is treated with SOCl2 to yield the chloro ester (XI). Reaction of compound (XI) with triphenylphosphine and lutidine in hot THF provides the phosphoranylidene derivative (XII), which is converted into (5R,6S)-6-[1(R)-hydroxyethyl]-2-[2(R)-tetrahydrofuryl]penem-3-carboxylic acid allyl ester, faropenem allyl ester (XIII) by removal of the silyl protecting group with tetrabutylammonium fluoride, followed by cyclization in refluxing toluene. Compound (XII) can also be obtained by condensation of the silver salt of protected azetidinone (XIV) with tetrahydrofuran-2(R)-carbonyl chloride (V).
| 【1】 Jin, J.; Han, H.-N.; Liu, J.; Synthesis of the key intermediate of faropenem: (3S,4R)-3-[(R)-1-tert-Butyldimethylsilyloxyethyl]-4-[(R)-tetrahydrofuranoylthio]-2-azetidinone. J Shenyang Pharm Univ 2001, 18, 1, 20. |
| 【2】 Rabasseda, X.; Sorbera, L.A.; del Fresno, M.; Castaner, J.; Faropenem daloxate. Drugs Fut 2002, 27, 3, 223. |
| 【3】 Ishiguro, M.; Iwata, H.; Nakatsuka, T. (Suntory Ltd.); Penem cpds. AU 8654460; EP 0199446; JP 1994128267; US 4997829 . |
| 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) | 11687 | (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate | C13H25NO4Si | 详情 | 详情 | |
| (II) | 52161 | (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-(tritylsulfanyl)-2-azetidinone | C30H37NO2SSi | 详情 | 详情 | |
| (III) | 52162 | C11H22AgNO2SSi | 详情 | 详情 | ||
| (IV) | 11696 | (2R)Tetrahydro-2-furancarbonyl chloride | C5H7ClO2 | 详情 | 详情 | |
| (V) | 52163 | (2R)-Tetrahydro-2-furancarboxylic acid; (2R)-2-Tetrahydrofuroic acid | 87392-05-0 | C5H8O3 | 详情 | 详情 |
| (VI) | 11689 | S-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl] (2R)tetrahydro-2-furancarbothioate | C16H29NO4SSi | 详情 | 详情 | |
| (VII) | 11688 | (2R)Tetrahydro-2-furancarbothioic S-acid | C5H8O2S | 详情 | 详情 | |
| (VIII) | 52164 | (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-(phenylsulfonyl)-2-azetidinone | C17H27NO4SSi | 详情 | 详情 | |
| (IX) | 30139 | allyl 2-oxoacetate | C5H6O3 | 详情 | 详情 | |
| (X) | 11690 | allyl 2-((3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-oxo-4-[[(2R)tetrahydro-2-furanylcarbonyl]sulfanyl]azetanyl)-2-hydroxyacetate | C21H35NO7SSi | 详情 | 详情 | |
| (XI) | 11691 | allyl 2-((3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-oxo-4-[[(2R)tetrahydro-2-furanylcarbonyl]sulfanyl]azetanyl)-2-chloroacetate | C21H34ClNO6SSi | 详情 | 详情 | |
| (XII) | 52165 | allyl 2-((3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-oxo-4-[[(2R)tetrahydro-2-furanylcarbonyl]sulfanyl]azetidinyl)-2-(triphenylphosphoranylidene)acetate | C39H48NO6PSSi | 详情 | 详情 | |
| (XIII) | 11694 | allyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(2R)tetrahydro-2-furanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C15H19NO5S | 详情 | 详情 | |
| (XIV) | 52166 | C34H41AgNO4PSSi | 详情 | 详情 |