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【结 构 式】

【分子编号】11687

【品名】(2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate

【CA登记号】

【 分 子 式 】C13H25NO4Si

【 分 子 量 】287.43134

【元素组成】C 54.32% H 8.77% N 4.87% O 22.27% Si 9.77%
与该中间体有关的原料药合成路线共 22 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20合成路线21合成路线22

合成路线1

该中间体在本合成路线中的序号：(IX)

The synthetic route from 8-aminopenicillanic acid (6-APA) to title compound is depicted in scheme. Diazotization of 6-APA (I) in the presence of Br2, followed by conventional esterification (MeI), gives the dibromopenicillanate (II), whose magnesium enolate (EtMgBr) is condensed with acetaldehyde to stereoselectively afford the bromohydrin (III). Debromination (Zn/MeOH) gives the trans-penicillanate (VI), which, via a two-step demolition of the thiazolidine ring [Hg(OAc)2, then KMnO4], is converted to the key azetidinone intermediate (IX). Acetate displacement with a suitable rhioacid (prepared trom glycolic acid after silylation of the hydroxy group) yields (XI). N-Oxalylation of the latter, followed by an original phosphite-mediated dicarbonyl coupling, gives the penem (XIV). Selective deblocking of the primary hydroxyl (Bu4NF) and exposure to trichloroacetylisocyanate results in the fully protected precursor (XVI), with is first unmasked in positions 2,8 (Bu4NF) and then in position 3 (Pd(0)-catalyzed deallylation in the presence of Na ethylhexanoate) to afford the sodium salt (FCE-22101).

参考文献 中间体
合成目标
【1】 Riva, F.; FCE-22101. Drugs Fut 1985, 10, 2, 119.
【2】 Franceschi, G.; Foglio, M.; Alpegiani, M.; Battistini, C.; Bedeschi, A.; Perrone, E.; Zarini, F.; Arcamone, F.; Della Bruna, C.; Sanfilippo, A.; Synthesis and biological properties of sodium (5R,6S, 8R)-6alpha-hydroxyethyl-2-carbamoyloxymethyl-2-penem-3-carboxylate (FCE 22101) and its orally absorbed esters FCE 22553 and FCE 22891. J Antibiot 1983, 36, 7, 938-41.
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) 28871 (2S,5R)-6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid C8H12N2O3S 详情 详情
(II) 28872 (2S,5R)-6,6-dibromo-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid C8H9Br2NO3S 详情 详情
(III) 28873 methyl (2S,5R)-6,6-dibromo-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate C9H11Br2NO3S 详情 详情
(IV) 24239 bromo(ethyl)magnesium；ethylmagnesium bromide 925-90-6 C2H5BrMg 详情 详情
(V) 28874 methyl (2S,5R,6S)-6-bromo-6-[(1R)-1-hydroxyethyl]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate C11H16BrNO4S 详情 详情
(VI) 28875 methyl (2S,5R)-6-[(1R)-1-hydroxyethyl]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate C11H17NO4S 详情 详情
(VII) 28876 methyl (2S,5R)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate C17H31NO4SSi 详情 详情
(VIII) 28877 methyl 2-[(2R)-2-(acetoxy)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-3-methyl-2-butenoate C19H33NO6Si 详情 详情
(IX) 11687 (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate C13H25NO4Si 详情 详情
(X) 28878 2-[[tert-butyl(diphenyl)silyl]oxy]ethanethioic S-acid C18H22O2SSi 详情 详情
(XI) 28879 S-[(2R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl] 2-[[tert-butyl(diphenyl)silyl]oxy]ethanethioate C29H43NO4SSi2 详情 详情
(XII) 15585 allyl 2-chloro-2-oxoacetate C5H5ClO3 详情 详情
(XIII) 28880 allyl 2-[(2R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-[(2-[[tert-butyl(diphenyl)silyl]oxy]acetyl)sulfanyl]-4-oxoazetidinyl]-2-oxoacetate C34H47NO7SSi2 详情 详情
(XIV) 28881 allyl (5R)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-([[tert-butyl(diphenyl)silyl]oxy]methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C34H47NO5SSi2 详情 详情
(XV) 28882 allyl (5R)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-(hydroxymethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C18H29NO5SSi 详情 详情
(XVI) 28883 allyl (5R)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-7-oxo-3-[([[(2,2,2-trichloroacetyl)amino]carbonyl]oxy)methyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C21H29Cl3N2O7SSi 详情 详情
(XVII) 28884 allyl (5R)-3-[[(aminocarbonyl)oxy]methyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C13H16N2O6S 详情 详情

合成路线2

该中间体在本合成路线中的序号：(I)

The reaction of 4-acetoxy-3-[(1-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (I) with benzyl-3-pyrrolidinocrotonate (II) gives the enimine ester (III), which is hydrolyzed with HCl to the corresponding ketoester (IV). The cyclization of (IV), through the diazo compound (V) by means of rhodium acetate, yields the bicyclic ketoester (VI). The condensation of (VI) with 1-(4-nitrobenzyloxycarbonyl)-3-mercaptopyrrolidine (VII) affords the protected carbapenem compound (VIII), which is deprotected by hydrogenation with H2 over Pd/C in THF giving 6-(1-hydroxyethyl)-2-(pyrrolidin-3-ylthio)-1-carbapen-2-em-2-carboxylic acid (IX). Finally, this compound is condensed with ethyl acetimidate (X) in a phosphate buffer.

参考文献 中间体
合成目标
【1】 Tanaka, T.; Sugimura, Y.; Miyadera, T.; Hashimoto, T.; Iino, K.; Shibata, T.; Sugawara, S.; Synthesis and in vitro activity of a new carbapenem, RS-533. J Antibiot 1983, 36, 8, 1034.
【2】 Serradell, M.N.; Castaner, J.; RS-533. Drugs Fut 1985, 10, 12, 989.
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) 29845 benzyl (Z)-3-(1-pyrrolidinyl)-2-butenoate C15H19NO2 详情 详情
(III) 29846 benzyl (Z)-4-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-3-(1-pyrrolidinyl)-2-butenoate C26H40N2O4Si 详情 详情
(IV) 29847 benzyl 4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxobutanoate C16H19NO5 详情 详情
(V) 29848 2-Diazo-4-[3(S)-(1(R)-hydroxyethyl)-4-oxoazetidin-2(R)-yl]-3-oxobutyric acid benzyl ester C16H17N3O5 详情 详情
(VI) 29849 benzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate C16H17NO5 详情 详情
(VII) 29850 4-nitrobenzyl (3S)-3-sulfanyl-1-pyrrolidinecarboxylate C12H14N2O4S 详情 详情
(VIII) 29851 benzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[[(3S)-1-(4-nitrobenzyl)pyrrolidinyl]sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C27H29N3O6S 详情 详情
(IX) 29852 (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(3S)pyrrolidinylsulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid C13H18N2O4S 详情 详情
(X) 12831 ethyl ethanimidoate 1000-84-6 C4H9NO 详情 详情

合成路线3

该中间体在本合成路线中的序号：(I)

This compound is prepared by several related ways: 1) The reaction of silylated azetidinone (I) with tetrahydrofuran-2-thiocarboxylic acid (II) by means of NaOH in THF - water gives the azetidinone thioester (III), which is condensed with allyl glyoxylate in refluxing benzene yielding the hydroxyester (IV). The reaction of (IV) with SOCl2 affords the chloroester (V), which by reaction with triphenylphosphine by means of lutidine in hot THF is converted into the phosphoranylidene derivative (VI). The elimination of the silyl protecting group of (VI) with tetrabutylammonium fluoride gives the azetidinone (VII), which is cyclized in refluxing toluene yielding the (5R,6S)-6-[1(R)-hydroxyethyl]-2-[2(R)-tetrahydrofuryl]penem-3-carboxyli c acid allyl ester (VIII). Finally, this compound is hydrolyzed with triphenylphosphine, sodium 2-ethylhexanoate and Pd-tetrakis(triphenylphosphine). 2) The condensation of the silver salt of protected azetidinone (IX) with tetrahydrofuran-2(R)-carbonyl chloride (X) also yields the phosphoranylidene salt (VI). 3) Phosphoranylidene ester (VI) can also be cyclized first in refluxing benzene yielding the silylated penem ester (XI), which is deprotected with tetrabutylammonium fluoride to (VIII). 4) The hydrolysis of allyl ester (VIII) to the final product can also be performed with paladium tetrakis(triphenylphosphine) and sodium 4-(methoxycarbonyl)-5,5-dimethylcyclohexane-1,3-dione enolate in several different solvents such as methyl acetate, ethylacetate, tetrahydrofuran, dioxane, sec-butanol, acetonitrile, acetone, 2-butanone, 1,2-dichloroethane, chlorobenzene, toluene, or ethylene glycol dimethyl ether. 5) The preceding hydrolysis can also be performed with triphenylphosphine and paladium tetrakis(triphenylphosphine) with sodium propionate, sodium acetate or sodium lactate in tetrahydrofuran or acetone.

参考文献 中间体
合成目标
【1】 Ishiguro, M.; Iwata, H.; Nakatsuka, T. (Suntory Ltd.); Penem cpds. AU 8654460; EP 0199446; JP 1994128267; US 4997829 .
【2】 Ishiguro, M.; Iwata, H.; Nakatsuka, T.; Nakajima, M.; Yamada, Y.; Doi, J.; Fujimaru, M. (Suntory Ltd.); Processes for removing allyl groups. EP 0410727 .
【3】 Ishiguro, M.; Yamada, Y.; Kimura, Y.; Imai, K. (Nippon Soda Co., Ltd.; Suntory Ltd.); Methods for removing allyl groups. JP 1992041489 .
【4】 Castaner, J.; Mealy, N.; Prous, J.; SUN-5555. Drugs Fut 1993, 18, 6, 525.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
30139 allyl 2-oxoacetate C5H6O3 详情 详情
(I) 11687 (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate C13H25NO4Si 详情 详情
(I) 52164 (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-(phenylsulfonyl)-2-azetidinone C17H27NO4SSi 详情 详情
(II) 11688 (2R)Tetrahydro-2-furancarbothioic S-acid C5H8O2S 详情 详情
(III) 11689 S-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl] (2R)tetrahydro-2-furancarbothioate C16H29NO4SSi 详情 详情
(IV) 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
(V) 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
(VI) 11692 allyl 2-((3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-oxo-4-[[(2R)tetrahydro-2-furanylcarbonyl]sulfanyl]azetanyl)-2-phosphinideneacetate C21H34NO6PSSi 详情 详情
(VII) 11693 allyl 2-((3S,4R)-3-[(1R)-1-hydroxyethyl]-2-oxo-4-[[(2R)tetrahydro-2-furanylcarbonyl]sulfanyl]azetanyl)-2-phosphinideneacetate C15H20NO6PS 详情 详情
(VIII) 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
(IX) 11695 (3S,4R)-2-[3-(1(R)-Hydroxyethyl)-2-oxo-4-sulfanylazetidin-1-yl]-2-(triphenylphosphanylidene)acetic acid allyl ester C16H27AgNO4PSSi 详情 详情
(X) 11696 (2R)Tetrahydro-2-furancarbonyl chloride C5H7ClO2 详情 详情
(XI) 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

合成路线4

该中间体在本合成路线中的序号：(I)

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.

参考文献 中间体
合成目标
【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5

该中间体在本合成路线中的序号：(XI)

Reaction of 3-(benzyloxy)propionic acid (I) with 4(R)-isopropyl-1,3-thiazolidine-2-thione (II) in the presence of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride and DMAP gives 3-[3-(benzyloxy)propanoyl]-4(R)-isopropyl-1,3-thiazolidine-2-thione (III), which by treatment with tin(II) trifluoromethanesulfonate and excess acetaldehyde affords 3-[(2S,3R)-2-(benzyloxymethyl)-3-hydroxybutanoyl]-4(R)-isopropyl-1,3-thiazolidine-2-thione (IV). Protection of the hydroxy group of (IV) with tert-butyldimethylsilyl chloride in the presence of imidazole yields 3-[(2S,3R)-2-(benzyloxymethyl)-3-(tert-butyldimethylsilyloxy)butanoyl]-4(R)-isopropyl-1,3-thiazolidine-2-thione (V), which is treated with p-anisidine to afford (2S,3R)-2-(benzyloxymethyl)-3-(tert-butyldimethylsilyloxy)-N-(4-methoxyphenyl)butylamide (VI). Deprotection of (VI) by hydrogenation with Pd/C in methanol-acetic acid gives (2S,3R)-3-(tert-butyldimethylsilyloxy)-2-(hydroxymethyl)-N-(4-methoxyphenyl)butylamide (VII), which is mesylated with methanesulfonyl chloride in the presence of triethylamine to yield (2S,3R)-3-(tert-butyldimethylsilyloxy)-2-[(methanesulfonyloxy)methyl]-N-(4-methoxyphenyl)butylamide (VIII). Cyclization of (VIII) with sodium hydride in CH2Cl2-DMF affords 3(S)-[1(R)-(tert-butyldimethylsilyloxy)ethyl]-1-(4-methoxyphenyl) azetidin-2-one (IX), the nitrogen atom of which is deprotected with cerium ammonium nitrate (CAN) in a mixture of acetonitrile-water to yield 3(S)-[1(R)-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (X). Compound (X) is stereoselectively converted to (3S,4R)-3-[1(R)-(tert-butyldimethylsilyloxy)ethyl]-4-acetoxyazetidin-2-one (XI) on treatment with peracetic acid and ruthenium(III) chloride. Compound (XI) and 4(S)-ethyl-3-propionyl-1,3-thiazolidine-2-thione (XII) give, on treatment with tin(II) trifluoromethanesulfonate, (3S,4R)-3-[1(R)-(tert-butyldimethysilyloxy)methyl]-4-[1(R)-[4(S)-ethyl-2-thioxo-1,3-thiazolidin-3-ylcarbonyl]ethyl]azetidin-2-one (XIII) as the major diastereoisomer. Reaction of (XIII) with imidazole in acetonitrile gives (3S,4R)-3-[1(R)-(tert-butyldimethylsilyloxy)ethyl]-4-[1(R)-(imidazol-1-ylcarbonyl)ethyl]azetidin-2-one (XIV), which is treated with Mg(O2CH2CO2PNB)2 in acetonitrile to yield (3S,4R)-3-[1(R)-(tert-butyldimethylsilyloxy)ethyl]-4-[1(R)-methyl-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]azetidin-2-one (XV). Compound (XV) is deprotected with hydrochloric acid in methanol to give (3S,4R)-3-[1(R)-hydroxyethyl]-4-[1(R)-methyl-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]azetidin-2-one (XVI), which on diazotization with dodecylbenzenesulfonyl azide in acetonitrile yields (3S,4R)-4-[3-diazo-1(R)-methyl-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-3-[1(R)-hydroxyethyl]azetidin-2-one (XVII). Treatment of compound (XVII) with rhodium(II) octanoate in ethylacetate gives p-nitrobenzyl (1R,5R,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-oxocarbapenam-3-carboxylate (XVIII), which is reacted with diphenylchlorophosphate and diisopropylethylamine to afford p-nitrobenzyl (1R,5R,6S)-2-[(diphenylphosphono)oxy]-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (XIX).

参考文献 中间体
合成目标
【1】 Kumagai, T.; Matsunaga, H.; Machida, Y.; Nagase, Y.; Hikida, M.; Nagao, Y. (Lederle (Japan), Ltd.); (1R,5S,6S)-2-(Substd. thio)-6-[(R)-1-hydroxy-ethyl]-1-methyl-carbapenem-3-carboxylic-acid derivatives. AU 8814428; EP 0289801; JP 1989025779; US 4925836 .
【2】 Abe, T.; Matsunaga, H.; Kumagai, T.; Nagase, Y. (Lederle (Japan), Ltd.); Method of preparation of carbapenem cpds. JP 1990088578 .
【3】 Rabasseda, X.; Prous, J.; Castaner, J.; Biapenem. Drugs Fut 1994, 19, 7, 631.
【4】 Hayashi, T.; Shimada, O.; Inoue, Y.; Nagao, Y.; Matsunaga, H.; Nagase, Y.; Kumagai, T.; Abe, T.; beta-Lactams. 3. Asymmetric total synthesis of new non-natural 1beta-methylcarbapenems exhibiting strong antimicrobial activities and stability against human renal dehydropeptidase-. J Org Chem 1992, 57, 15, 4243-9.
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) 13189 3-(Benzyloxy)propionic acid C10H12O3 详情 详情
(II) 13190 (4R)-4-Isopropyl-1,3-thiazolidine-2-thione C6H11NS2 详情 详情
(III) 13191 3-(Benzyloxy)-1-[(4R)-4-isopropyl-2-thioxo-1,3-thiazolidin-3-yl]-1-propanone C16H21NO2S2 详情 详情
(IV) 13192 (2S,3R)-2-[(Benzyloxy)methyl]-3-hydroxy-1-[(4R)-4-isopropyl-2-thioxo-1,3-thiazolidin-3-yl]-1-butanone C18H25NO3S2 详情 详情
(V) 13193 (2S,3R)-2-[(Benzyloxy)methyl]-3-[[tert-butyl(dimethyl)silyl]oxy]-1-[(4R)-4-isopropyl-2-thioxo-1,3-thiazolidin-3-yl]-1-butanone C24H39NO3S2Si 详情 详情
(VI) 13194 (2S,3R)-2-[(Benzyloxy)methyl]-3-[[tert-butyl(dimethyl)silyl]oxy]-N-(4-methoxyphenyl)butanamide C25H37NO4Si 详情 详情
(VII) 13195 (2S,3R)-3-[[tert-Butyl(dimethyl)silyl]oxy]-2-(hydroxymethyl)-N-(4-methoxyphenyl)butanamide C18H31NO4Si 详情 详情
(VIII) 13196 (2S,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[(4-methoxyanilino)carbonyl]butyl methanesulfonate C19H33NO6SSi 详情 详情
(IX) 13197 (3S)-3-((1R)-1-[[tert-Butyl(dimethyl)silyl]oxy]ethyl)-1-(4-methoxyphenyl)-2-azetidinone C18H29NO3Si 详情 详情
(X) 13198 (3S)-3-((1R)-1-[[tert-Butyl(dimethyl)silyl]oxy]ethyl)-2-azetidinone C11H23NO2Si 详情 详情
(XI) 11687 (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate C13H25NO4Si 详情 详情
(XII) 13200 1-[(4S)-4-Ethyl-2-thioxo-1,3-thiazolidin-3-yl]-1-propanone C8H13NOS2 详情 详情
(XIII) 13201 (3S,4S)-3-((1R)-1-[[tert-Butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-2-[(4S)-4-ethyl-2-thioxo-1,3-thiazolidin-3-yl]-1-methyl-2-oxoethyl]-2-azetidinone C19H34N2O3S2Si 详情 详情
(XIV) 13202 (3S,4S)-3-((1R)-1-[[tert-Butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-2-(1H-imidazol-1-yl)-1-methyl-2-oxoethyl]-2-azetidinone C17H29N3O3Si 详情 详情
(XV) 33040 4-nitrobenzyl (4R)-4-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-3-oxopentanoate C23H34N2O7Si 详情 详情
(XVI) 22573 4-nitrobenzyl 4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate C17H20N2O7 详情 详情
(XVII) 38749 4-nitrobenzyl (4R)-2-diazo-4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate C17H18N4O7 详情 详情
(XVIII) 37720 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate C17H18N2O7 详情 详情
(XIX) 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

合成路线6

该中间体在本合成路线中的序号：(Ia)

FCE 22891 in the ester prodrug formulation of FCE 22101. Reaction of the latter (sodium salt) with acetoxymethyl bromide (DMF) is the traditional synthetic route to FCE 22891. This route is also the preferred one as long as manufacturing involves both compounds (the reverse process, conversion of FCE 22891 into the parent acid FCE 22101, can be conveniently realized by enzymic hydrolysis catalyzed by porcine liver esterase or lipase A6 from Aspergillus niger). Direct synthesis of FCE 22891 can be performed using two major strategies. The total synthetic approaches start from chiral amino or hydroxy acids (threonine, 3-hydroxybutyric acid) and have (3R,4R)-4-acetoxy-3-[(R)-1-hydroxyethyl]-2-oxo-1H-azetidine (Ia) or its 4-benzoyloxy analogue (Ib), usually protected as the tert-butyldimethylsilyl ethers, as common intermediates. These compounds, in particular (Ia), can also be found on the market (Kaneka). Reaction of either (Ia) or (Ib) with the sodium salt of 2-carbamoyloxyethanethioic acid gives the azetidinone thiolester (II), which is condensed with acetoxymethyl oxalyl chloride. Reductive carbonyl condensation (triethyl phosphite, refluxing toluene) and desilylation (tetrabutylammonium fluoride buffered with acetic acid) affords FCE 22891. The hemisynthetic route utilizes 6-APA as a chiral template. Introduction of the alpha-hydroxyethyl chain on the penam nucleus is satisfactorily achieved by deaminative bromination, metal exchange with EtMgBr, aldol reaction (acetaldehyde, THF, -70 C) and reductive dehalogenation (Zn-AcOH), MeOH, -10 C). During this process, the acetoxymethyl promoiety characterizing the final product is conveniently introduced. According to an original procedure, beta-eliminative ring opening of the thiazolidine ring (AgCl/DBN) and in situ acylation of the intermediate silver mercaptide with carbamoyloxyacetyl chloride affords the key azetidone thioester (VII). Ozonolysis (CH2Cl2, -50 C) and reductive carbonyl condensation completes the sequence, without resorting to protective groups other than trimethylsilyl, which is removed at the end by simple acidic work-up.

参考文献 中间体
合成目标
【1】 Franceschi, G.; Foglio, M.; Alpegiani, M.; Battistini, C.; Bedeschi, A.; Perrone, E.; Zarini, F.; Arcamone, F.; Della Bruna, C.; Sanfilippo, A.; Synthesis and biological properties of sodium (5R,6S, 8R)-6alpha-hydroxyethyl-2-carbamoyloxymethyl-2-penem-3-carboxylate (FCE 22101) and its orally absorbed esters FCE 22553 and FCE 22891. J Antibiot 1983, 36, 7, 938-41.
【2】 Perrone, E.; FCE 22891. Drugs Fut 1991, 16, 4, 313.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
63804 2-[(aminocarbonyl)oxy]ethanethioic S-acid C3H5NO3S 详情 详情
63805 [(2-chloro-2-oxoacetyl)oxy]methyl acetate C5H5ClO5 详情 详情
(Ia) 11687 (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate C13H25NO4Si 详情 详情
(Ib) 13689 (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl benzoate C18H27NO4Si 详情 详情
(IIIa) 13691 (acetoxy)methyl 2-[(2R,3S)-2-([2-[(aminocarbonyl)oxy]acetyl]sulfanyl)-3-(1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-2-oxoacetate C19H30N2O10SSi 详情 详情
(IIIb) 13692 (acetoxy)methyl 2-((2R,3S)-2-([2-[(aminocarbonyl)oxy]acetyl]sulfanyl)-4-oxo-3-[1-[(trimethylsilyl)oxy]ethyl]azetidinyl)-2-oxoacetate C16H24N2O10SSi 详情 详情
(VIa) 13695 (acetoxy)methyl (2S,5R,6S)-6-[(1R)-1-hydroxyethyl]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate C13H19NO6S 详情 详情
(VIb) 13696 (acetoxy)methyl (2S,5R,6S)-3,3-dimethyl-7-oxo-6-[(1R)-1-[(trimethylsilyl)oxy]ethyl]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate C16H27NO6SSi 详情 详情
FCE 22101 63806 sodium 3-{[(aminocarbonyl)oxy]methyl}-6-(1-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C10H11N2NaO6S 详情 详情
(II) 13690 S-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl] 2-[(aminocarbonyl)oxy]ethanethioate C14H26N2O5SSi 详情 详情
(IV) 13693 (acetoxy)methyl (2S,5R)-6,6-dibromo-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate C11H13Br2NO5S 详情 详情
(V) 13694 (acetoxy)methyl (2S,5R,6S)-6-bromo-6-[(1R)-1-hydroxyethyl]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate C13H18BrNO6S 详情 详情
6-APA 32631 (2S,5R,6R)-6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid; (+)-6-Aminopenicillanic acid; 6-APA 551-16-6 C8H12N2O3S 详情 详情
(VII) 13697 (acetoxy)methyl 2-[(2R,3S)-2-([2-[(aminocarbonyl)oxy]acetyl]sulfanyl)-3-[(1R)-1-methyl-2-(trimethylsilyl)ethyl]-4-oxoazetidinyl]-3-methyl-2-butenoate C20H32N2O8SSi 详情 详情

合成路线7

该中间体在本合成路线中的序号：(III)

1) The reaction of 2-methoxycyclohexanone (I) with dialkyl carbonate by means of NaH/KH in THF gives 3-methoxy-2-oxocyclohexanecarboxylic acid allyl ester (II), which is condensed with (3R,4R)-4-acetoxy-3-[1(R)-tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (III) by means of NaH in THF yielding the condensation product (IV) as a mixture of the alpha- and beta-stereoisomers at the methoxy group. The protection of the NH group of (IV) with tert-butyldimethylsilyl (TBS) trifluoromethanesulfonate affords the bis-TBS-protected compound (V), which is stereospecifically decarboxylated with palladium acetate, formic acid and triphenylphosphine to the protected azetidinone (VI) also as alpha- and beta-isomers. The selective desilylation of (VI) with tetrabutylammonium fluoride (TBAF) in acetic acid gives the O-protected azetidinone (VII) also as a mixture, which is epimerized by sequential treatments with lithium diisopropylamide (LDA), with ZnBr2 and finally with diethyl malonate to afford the alpha-(S)-epimer (VIII). The acylation of (VIII) with benzyloxalyl chloride and pyridine in dichloromethane gives the N-benzyloxazyl derivative (IX), which is cyclized by means of triethyl phosphite in refluxing xylene yielding (4S,8S,9R,10S)-10-[1(R)-(tert-butyldimethylsilyloxy)ethyl]-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0(3,8)]undec-2-ene-2-carboxylic acid benzyl ester (X). The desilylation of (X) with TBAF in THF/acetic acid affords (XI) with a 1-hydroxyethyl group, which is hydrogenated with H2 over Pd/C in dioxane in the presence of 3,3,6,9,9-pentamethyl-2,10-diazabicyclo[4.4.0]dec-1-ene (XII) giving the addition salt (XIII). The treatment of (XIII) with potassium 2-ethylhexanoate yields the corresponding potassium salt (XIV) (1), which is finally esterified with 1-chloroethyl cyclohexyl carbonate (XV) by means of benzyltrimethylammonium chloride in DMF.

参考文献 中间体
合成目标
【1】 Owen, M.R.; et al.; Efficiency by design: Optimisation in process research. Org Process Res Dev 2001, 5, 3, 308.
【2】 Ngo, J.; Castaner, J.; Sanfetrinem cilexetil. Drugs Fut 1996, 21, 12, 1238.
【3】 Hanessian, S.; Rozema, M.J.; A highly stereoselective and practical total synthesis of the tricyclic beta-lactam antibiotic GV104326 (4-methoxytrinem). J Am Chem Soc 1996, 118, 41, 9884-91.
【4】 Perboni, A.; Rossi, T.; Gaviraghi, G.; Ursini, A.; Tarzia, G. (Glaxo Wellcome plc); 10(1-Hydroxyethyl-11-oxo-1-azatricyclo[7.2.0.0.3.8]undec-2-ene-2-carboxylic acid esters and a process for preparing thereof. JP 1993502044; US 5587374; WO 9203437 .
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) 15559 2-methoxycyclohexanone 7429-44-9 C7H12O2 详情 详情
(II) 15560 allyl 3-methoxy-2-oxocyclohexanecarboxylate C11H16O4 详情 详情
(III) 11687 (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate C13H25NO4Si 详情 详情
(IV) 15562 allyl 1-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl]-3-methoxy-2-oxocyclohexanecarboxylate C22H37NO6Si 详情 详情
(V) 15563 allyl 1-[(2S,3S)-1-[tert-butyl(dimethyl)silyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-3-methoxy-2-oxocyclohexanecarboxylate C28H51NO6Si2 详情 详情
(VI) 15564 (3S,4R)-1-[tert-butyl(dimethyl)silyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-3-methoxy-2-oxocyclohexyl]-2-azetanone C24H47NO4Si2 详情 详情
(VII) 15565 (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-3-methoxy-2-oxocyclohexyl]-2-azetanone C18H33NO4Si 详情 详情
(VIII) 15566 (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R,3S)-3-methoxy-2-oxocyclohexyl]-2-azetanone C18H33NO4Si 详情 详情
(IX) 15567 benzyl 2-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-[(1R,3S)-3-methoxy-2-oxocyclohexyl]-4-oxoazetidinyl]-2-oxoacetate C27H39NO7Si 详情 详情
(X) 15568 benzyl (1S,5S,8aS,8bR)-1-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-5-methoxy-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate C27H39NO5Si 详情 详情
(XI) 15569 benzyl (1S,5S,8aS,8bR)-1-[(1R)-1-hydroxyethyl]-5-methoxy-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate C21H25NO5 详情 详情
(XII) 15570 2,2,4a,7,7-pentamethyl-1,2,3,4,4a,5,6,7-octahydro[1,8]naphthyridine; 3,3,6,9,9-pentamethyl-2,10-diazabicyclo[4.4.0]dec-1-ene 69340-58-5 C13H24N2 详情 详情
(XIII) 15571 (1S,5S,8aS,8bR)-1-(1(R)-Hydroxyethyl)-5-methoxy-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[3,1-a]isoindole-4-carboxylic acid 2,2,4a,7,7-pentamethyl-2,3,4,4a,5,6,7,8-octahydro-1,8-naphthyridine salt C27H43N3O5 详情 详情
(XIV) 15572 potassium (1S,5S,8aS,8bR)-1-[(1R)-1-hydroxyethyl]-5-methoxy-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate C14H18KNO5 详情 详情
(XV) 15573 1-chloroethyl cyclohexyl carbonate C9H15ClO3 详情 详情

合成路线8

该中间体在本合成路线中的序号：(III)

6) The condensation of 2-methyl-2-cyclohexen-1-one (XXIV) with the previously described azetidinone (III) by means of lithium diisopropylamide in THF, followed by flash chromatography, gives the enantiomerically pure 3-methoxy-3-cyclohexenylazetidinone (XXV), which by reduction with H2 over Pd/C in ethyl acetate followed by chromatography yields the previously described azetidinone (VIII). The cyclization of (VIII) with allyloxyoxalyl chloride (XXVI) by means of K2CO3 in dichloromethane affords (4S,8S,9R,10S)-1-[1(R)-(tert-butyldimethylsilyloxy)ethyl-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0(3,8)]undec-2-ene-2-carboxylic acid allyl ester (XXVII), which is treated with tetrabutylammonium fluoride in THF/acetic acid to eliminate the TBS group giving the 1-hydroxyethyl derivative (XXVIII). Finally, this compound is treated with triphenylphosphine and potassium 2-ethylhexanoate to afford the potassium salt (XIV), already described in Scheme 18359601a.

参考文献 中间体
合成目标
【1】 Owen, M.R.; et al.; Efficiency by design: Optimisation in process research. Org Process Res Dev 2001, 5, 3, 308.
【2】 Tamburini, B.; Perboni, A.; Rossi, T.; Donati, D.; Andreotti, D.; Gaviraghi, G.; Carlesso, R.; Bismara, C. (Glaxo Wellcome plc); 10-(1-Hydroxyethyl)-11-oxo-1-azatricyclo[7.2.0.0.3,8]undec-2-ene-2-carboxylic acid derivs. AU 9162265; EP 0416953; US 5407931 .
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) 11687 (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate C13H25NO4Si 详情 详情
(VIII) 15566 (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R,3S)-3-methoxy-2-oxocyclohexyl]-2-azetanone C18H33NO4Si 详情 详情
(XIV) 15572 potassium (1S,5S,8aS,8bR)-1-[(1R)-1-hydroxyethyl]-5-methoxy-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate C14H18KNO5 详情 详情
(XXIV) 15583 2-methoxy-2-cyclohexen-1-one 23740-37-6 C7H10O2 详情 详情
(XXV) 15584 (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-3-methoxy-2-oxo-3-cyclohexen-1-yl]-2-azetanone C18H31NO4Si 详情 详情
(XXVI) 15585 allyl 2-chloro-2-oxoacetate C5H5ClO3 详情 详情
(XXVII) 15586 allyl (1S,5S,8aS,8bR)-1-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-5-methoxy-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate C23H37NO5Si 详情 详情
(XXVIII) 15587 allyl (1S,5S,8aS,8bR)-1-[(1R)-1-hydroxyethyl]-5-methoxy-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate C17H23NO5 详情 详情

合成路线9

该中间体在本合成路线中的序号：(I)

A new synthesis of sanfetrinem has been published: The condensation of (3S,4R)-4-acetoxy-3-[1(R)-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (I) with 2-methoxy-2-cyclohexen-1-one (II) by means of lithium bis(trimethylsilyl)amide (LHMDA) in THF gives a mixture of diastereomers that are separated by flash chromatography yielding pure enantiomer (III). The hydrogenation of the double bond of (III) with H2 over Pd/C in ethyl acetate affords another mixture of diastereomers that are also separated by flash chromatography giving pure enantiomer (IV). The cyclization of (IV) with allyl acrylate (V) by means of triethylamine yields (4S,8S,9R,10S)-10-[1(R)-hydroxyethyl]-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0(3,8)]undec-2-ene-2-carboxylic acid allyl ester (VI), the silylated allyl ester of sanfetrinem. Finally, this compound is desilylated by treatment with tetrabutylammonium fluoride (TBAF)/acetic acid in THF, and saponified with potassium 2-ethylhexanoate (KEH).

参考文献 中间体
合成目标
【1】 Owen, M.R.; et al.; Efficiency by design: Optimisation in process research. Org Process Res Dev 2001, 5, 3, 308.
【2】 Gaviraghi, G.; Marchioro, C.; Di Modugno, E.; Rossi, T.; Perboni, A.; Andreotti, D.; Donati, D.; Synthesis and antibacterial activity of 4- and 8-methoxy trinems. Bioorg Med Chem Lett 1996, 6, 4, 491.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IIIb) 23856 (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1S)-3-methoxy-2-oxo-3-cyclohexen-1-yl]-2-azetidinone C18H31NO4Si 详情 详情
(I) 11687 (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate C13H25NO4Si 详情 详情
(II) 15583 2-methoxy-2-cyclohexen-1-one 23740-37-6 C7H10O2 详情 详情
(III) 15584 (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-3-methoxy-2-oxo-3-cyclohexen-1-yl]-2-azetanone C18H31NO4Si 详情 详情
(IV) 15566 (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R,3S)-3-methoxy-2-oxocyclohexyl]-2-azetanone C18H33NO4Si 详情 详情
(V) 15585 allyl 2-chloro-2-oxoacetate C5H5ClO3 详情 详情
(VI) 15586 allyl (1S,5S,8aS,8bR)-1-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-5-methoxy-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate C23H37NO5Si 详情 详情

合成路线10

该中间体在本合成路线中的序号：(I)

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).

参考文献 中间体
合成目标
【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

合成路线11

该中间体在本合成路线中的序号：(I)

A new synthesis of sanfetrinem has been puplished: The condensation of (3S,4R)-4-acetoxy-3-[1(R)-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (I) with 2-methoxy-2-cyclohexen-1-one (II) by means of lithium bis(trimethylsilyl)amide (LHMDA) in THF gives a mixture of diastereomers that are separated by flash chromatography yielding pure enantiomer (III). The hydrogenation of the double bond of (III) with H2 over Pd/C in ethyl acetate affords another mixture of diastereomers that are also separated by flash chromatography giving pure enantiomer (IV). The cyclization of (IV) with allyl acrylate (V) by means of triethylamine yields (4S,8S,9R,10S)-10-[1(R)-hydroxyethyl]-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0(3,8)]undec-2-ene-2-carboxylic acid allyl ester (VI), the silylated allyl ester of sanfetrinem. Finally, this compound is desilylated by treatment with tetrabutylammonium fluoride (TBAF)/acetic acid in THF, and saponified with potassium 2-ethylhexanoate (KEH).

参考文献 中间体
合成目标
【1】 Owen, M.R.; et al.; Efficiency by design: Optimisation in process research. Org Process Res Dev 2001, 5, 3, 308.
【2】 Gaviraghi, G.; Marchioro, C.; Di Modugno, E.; Rossi, T.; Perboni, A.; Andreotti, D.; Donati, D.; Synthesis and antibacterial activity of 4- and 8-methoxy trinems. Bioorg Med Chem Lett 1996, 6, 4, 491.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IIIb) 23856 (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1S)-3-methoxy-2-oxo-3-cyclohexen-1-yl]-2-azetidinone C18H31NO4Si 详情 详情
(I) 11687 (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate C13H25NO4Si 详情 详情
(II) 15583 2-methoxy-2-cyclohexen-1-one 23740-37-6 C7H10O2 详情 详情
(III) 15584 (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-3-methoxy-2-oxo-3-cyclohexen-1-yl]-2-azetanone C18H31NO4Si 详情 详情
(IV) 15566 (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R,3S)-3-methoxy-2-oxocyclohexyl]-2-azetanone C18H33NO4Si 详情 详情
(V) 15585 allyl 2-chloro-2-oxoacetate C5H5ClO3 详情 详情
(VI) 15586 allyl (1S,5S,8aS,8bR)-1-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-5-methoxy-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate C23H37NO5Si 详情 详情

合成路线12

该中间体在本合成路线中的序号：(I)

In a related method, the 4-acetoxy-azetidinone (I) is reacted with 2-chlorothioacetic acid (II) in the presence of ZnI2 to give the (chloroacetylthio)azetidinone (III). Nitrogen acylation in (III) by means of allyl oxalyl chloride produces (IV), which undergoes ring closure to the penem (V) in the presence of triethyl phosphite in boiling toluene. Displacement of chloride (V) with sarcosinamide (VI) yields adduct (VII). After desilylation of (VII) to (VIII) by means of tetrabutylammonium fluoride, palladium-catalyzed allyl ester cleavage leads to the title compound.

参考文献 中间体
合成目标
【1】 Arcamone, F.M.; et al.; Synthesis and biological activity of the penem antibiotic MEN 10700 and its orally absorbed ester MEN 11505. J Antibiot 2000, 53, 10, 1086.
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) 58256 2-chloroethanethioic S-acid C2H3ClOS 详情 详情
(III) 58257 S-[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidinyl] 2-chloroethanethioate C13H24ClNO3SSi 详情 详情
(IV) 58258 allyl 2-{(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-[(2-chloroacetyl)sulfanyl]-4-oxoazetidinyl}-2-oxoacetate C18H28ClNO6SSi 详情 详情
(V) 58259 allyl (5R,6S)-6-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(chloromethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C18H28ClNO4SSi 详情 详情
(VI) 54572 2-(methylamino)acetamide C3H8N2O 详情 详情
(VII) 58254 allyl (5R,6S)-3-{[(2-amino-2-oxoethyl)(methyl)amino]methyl}-6-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C21H35N3O5SSi 详情 详情
(VIII) 58255 allyl (5R,6S)-3-{[(2-amino-2-oxoethyl)(methyl)amino]methyl}-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C15H21N3O5S 详情 详情

合成路线13

该中间体在本合成路线中的序号：(XVI)

The reaction of 2-hydroxybenzamide (XI) with cyclohexanone (XII) by means of Ts-OH in toluene gives the spiranic benzoxazine (XIII), which is condensed with 2-bromopropionyl bromide (XIV) by means of pyridine in toluene, yielding the corresponding acylated benzoxazine (XV). The condensation of (XV) with chiral azetidinone (XVI) by means of Zn in refluxing THF affords the adduct (XVII), which is finally hydrolyzed with LiOH and H2O2 to furnish the target azetidinonepropionic acid (I).

参考文献 中间体
合成目标
【1】 Lu, X.; et al.; Process development on (3S,4S)-[(R)-1'((tert-butyldimethylsilyl)oxy)ethyl]-4-[(R)-1-carboxyethyl]-2-azetidinone: 1-beta-methylcarbapanem key intermediate. Org Process Res Dev 2001, 5, 2, 186.
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) 30029 (2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propionic acid C14H27NO4Si 详情 详情
(XI) 14652 salicylamide 65-45-2 C7H7NO2 详情 详情
(XII) 11059 Cyclohexanone 108-94-1 C6H10O 详情 详情
(XIII) 46246 　 C13H15NO2 详情 详情
(XIV) 13127 2-Bromopropionyl bromide; 2-Bromopropanoyl bromide 563-76-8 C3H4Br2O 详情 详情
(XV) 37738 3-(2-Bromo-1-oxopropyl)-spiro[2H-1,3-benzoxazine-2,1'-cyclohexan]-4(3H)-one 158299-05-9 C16H18BrNO3 详情 详情
(XVI) 11687 (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate C13H25NO4Si 详情 详情
(XVII) 46247 　 C27H40N2O5Si 详情 详情

合成路线14

该中间体在本合成路线中的序号：(XIX)

The reaction of 4(R)-hydroxy-L-proline (I) with allyl chloroformate (II) and NaOH gives the protected proline (III), which is esterified with MeOH and sulfuric acid to yield the methyl prolinate (IV). The reaction of (IV) with Ms-Cl and TEA affords the mesylate (V), which is reduced with NaBH4 to provide the prolinol derivative (VI). The Swern oxidation of alcohol (VI) gives the carbaldehyde (VII), which is condensed with the phosphorane (VIII) by means of NaOMe, yielding the acrylate (IX). The reduction of (IX) with DIBAL affords the substituted allyl alcohol (X), which is condensed with phthalimide (XI) by means of PPh3 and DIAD to provide the adduct (XII). The cleavage of the phthalimido group of (XII) with hydrazine gives the amino derivative (XIII), which is treated with Ms-Cl and TEA to yield the sulfonamide (XIV). The reaction of (XIV) with potassium thioacetate affords the acetylsulfanyl pyrrolidine (XV), which is hydrolyzed with HCl to provide the thiol (XVI). The condensation of the thiol (XVI) with the carbapenem derivative (XVII) by means of DIEA gives the protected adduct (XVIII), which is finally treated with Pd(II) and Bu3SnH in order to eliminate the allyl protecting groups. The intermediate carbapenem derivative (XVII) has been obtained from azetidinone (XIX) by known methods as indicated in the scheme.

参考文献 中间体
合成目标
【1】 Kwon, J.W.; Kim, W.B.; Kim, S.H.; Lee, M.G.; DA-1131. Drugs Fut 2001, 26, 11, 1040.
【2】 Shin, H.C.; Kim, J.Y.; Kim, G.W.; Lee, C.W.; Lim, J.I.; Chang, M.S.; Kim, N.S.; Kim, D.S.; Im, W.B.; Rhee, J.K. (Dong-A Pharmaceutical Co., Ltd.); Carbapenem derivs. and processes for preparing the same. WO 9514692 .
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) 14489 (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline 51-35-4 C5H9NO3 详情 详情
(II) 38115 3-[(chlorocarbonyl)oxy]-1-propene 2937-50-0 C4H5ClO2 详情 详情
(III) 47730 (2S,4R)-1-[(allyloxy)carbonyl]-4-hydroxy-2-pyrrolidinecarboxylic acid C9H13NO5 详情 详情
(IV) 42200 1-allyl 2-methyl (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate C10H15NO5 详情 详情
(V) 42201 1-allyl 2-methyl (2S,4R)-4-[(methylsulfonyl)oxy]-1,2-pyrrolidinedicarboxylate C11H17NO7S 详情 详情
(VI) 42202 allyl (2S,4R)-2-(hydroxymethyl)-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C10H17NO6S 详情 详情
(VII) 49446 allyl (2S,4R)-2-formyl-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C10H15NO6S 详情 详情
(VIII) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(IX) 49447 allyl (2S,4R)-2-[(E)-3-methoxy-3-oxo-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C13H19NO7S 详情 详情
(X) 49448 allyl (2S,4R)-2-[(E)-3-hydroxy-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C12H19NO6S 详情 详情
(XI) 12376 Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione 85-41-6 C8H5NO2 详情 详情
(XII) 49449 allyl (2S,4R)-2-[(E)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C20H22N2O7S 详情 详情
(XIII) 49450 allyl (2S,4R)-2-[(E)-3-amino-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C12H20N2O5S 详情 详情
(XIV) 50598 allyl (2S,4R)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C13H22N2O7S2 详情 详情
(XV) 49451 allyl (2S,4S)-4-(acetylsulfanyl)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-1-pyrrolidinecarboxylate C14H22N2O5S2 详情 详情
(XVI) 49452 allyl (2S,4S)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-4-sulfanyl-1-pyrrolidinecarboxylate C12H20N2O4S2 详情 详情
(XVII) 32617 allyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C25H26NO8P 详情 详情
(XVIII) 49454 allyl (4R,5S,6S)-3-[((3S,5S)-1-[(allyloxy)carbonyl]-5-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]pyrrolidinyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C25H35N3O8S2 详情 详情
(XIX) 11687 (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate C13H25NO4Si 详情 详情
(XX) 50599 　 C17H27N3O6Si 详情 详情
(XXI) 16074 Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate 2524-64-3 C12H10ClO3P 详情 详情

合成路线15

该中间体在本合成路线中的序号：(XIX)

Reaction of the acetoxy azetidinone (XIX) with methyl 2-(bromomethyl)butenoate (XX) in the presence of Zn produced adduct (XXI). Reduction of the ester group of (XXI) with DIBAL-H, followed by protection of the resulting allyl alcohol with trityl chloride gave (XXII). Further ozonolysis of (XXII) generated ketone (XXIII). Condensation of (XXIII) with allyl glyoxylate (XXIV) gave hemiaminal (XXV). After treatment of (XXV) with SOCl2, reaction with triphenylphosphine produced phosphorane (XXVI). Acid deprotection of the trityl and silyl groups of (XXVI), followed by acetylation with AcCl gave acetate ester (XXVII). The secondary hydroxyl group of (XXVII) was then protected with allyl chloroformate to afford carbonate (XXVIII). Then, deprotection of the acetate ester of (XXVIII) with methanolic NaOMe gave hydroxy ketone (XXIX). Finally, cyclization between keto and phosphorane groups of (XXIX) in boiling toluene furnished the carbapenem compound (XXX).

参考文献 中间体
合成目标
【1】 Dininno, F.P.; Dykstra, K.D.; Wildonger, K.J.; Blizzard, T.A.; Wilkening, R.R.; Hammond, M.L.; Ratcliffe, R.W.; Cama, L.D.; Synthesis and in vitro evaluation of 1beta-methyl-2-(sulfonamido) methyl-carbapenems: Discovery of a novel PBP2a-binding, anti-MRSA 1,8-naphthosultamyl pharmacophore. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-33.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIX) 11687 (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate C13H25NO4Si 详情 详情
(XX) 30136 methyl (Z)-2-(bromomethyl)-2-butenoate C6H9BrO2 详情 详情
(XXI) 30164 methyl 2-[(1S)-1-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]ethyl]acrylate C17H31NO4Si 详情 详情
(XXII) 30137 (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1S)-1-methyl-2-[(trityloxy)methyl]-2-propenyl]-2-azetidinone C35H45NO3Si 详情 详情
(XXIII) 30138 (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-1-methyl-2-oxo-3-(trityloxy)propyl]-2-azetidinone C34H43NO4Si 详情 详情
(XXIV) 30139 allyl 2-oxoacetate C5H6O3 详情 详情
(XXV) 30140 allyl 2-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-[(1R)-1-methyl-2-oxo-3-(trityloxy)propyl]-4-oxoazetidinyl]-2-hydroxyacetate C39H49NO7Si 详情 详情
(XXVI) 30141 allyl 2-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-[(1R)-1-methyl-2-oxo-3-(trityloxy)propyl]-4-oxoazetidinyl]-2-(triphenylphosphoranylidene)acetate C57H62NO6PSi 详情 详情
(XXVII) 30142 allyl 2-[(2R,3S)-2-[(1R)-3-(acetoxy)-1-methyl-2-oxopropyl]-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-2-(triphenylphosphoranylidene)acetate C34H36NO7P 详情 详情
(XXVIII) 30143 allyl 2-[(2R,3S)-2-[(1R)-3-(acetoxy)-1-methyl-2-oxopropyl]-3-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-4-oxoazetidinyl]-2-(triphenylphosphoranylidene)acetate C38H40NO9P 详情 详情
(XXIX) 30144 allyl 2-[(2R,3S)-3-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-2-[(1R)-3-hydroxy-1-methyl-2-oxopropyl]-4-oxoazetidinyl]-2-(triphenylphosphoranylidene)acetate C36H38NO8P 详情 详情
(XXX) 23834 allyl (4S,5R,6S)-6-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-3-(hydroxymethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C18H23NO7 详情 详情

合成路线16

该中间体在本合成路线中的序号：(I)

The condensation of azetidinone (I) with carbonate (II) by means of TiCl4 and tributylamine in toluene gives the addition product (III), which is desilylated with HCl in aqueous acetonitrile and resilylated again with Tes-Cl and imidazole in toluene/acetonitrile yielding the silyl ether (IV). The condensation of (IV) with the oxalyl derivative (V) by means of pyridine in toluene affords the addition compound (VI), which is cyclized by means of P(OEt)3 in hot heptane giving the carbapenem compound (VII). The condensation of (VII) with naphthosultam (VIII) by means of palladium acetate and P(OBu)3 affords the protected target compound (IX), which is finally desilylated with aqueous Tf-OH, debenzylated with H2 over Pd/C, and treated with sodium benzenesulfonate to obtain the sulfonate salt of the target compound.

参考文献 中间体
合成目标
【1】 Humphrey, G.R.; et al.; Efficient and practical synthesis of a potent anti-MRSA beta-methylcarbapenem containing a releasable side chain. J Am Chem Soc 1999, 121, 49, 11261.
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) 31601 tert-butyl 2-oxobutyl carbonate C9H16O4 详情 详情
(III) 31602 tert-butyl (3R)-3-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-2-oxobutyl carbonate C20H37NO6Si 详情 详情
(IV) 31603 tert-butyl (3R)-2-oxo-3-((2R,3S)-4-oxo-3-[(1R)-1-[(triethylsilyl)oxy]ethyl]azetidinyl)butyl carbonate C20H37NO6Si 详情 详情
(V) 31604 3-(4-nitrobenzyloxy)-2-oxopropanoyl chloride C9H6ClNO5 详情 详情
(VI) 31605 tert-butyl (3R)-3-((2R,3S)-1-[3-(4-nitrobenzyloxy)-2-oxopropanoyl]-4-oxo-3-[(1R)-1-[(triethylsilyl)oxy]ethyl]azetidinyl)-2-oxobutyl carbonate C29H42N2O11Si 详情 详情
(VII) 31606 tert-butyl ((4S,5R,6S)-4-methyl-2-[2-(4-nitrobenzyloxy)acetyl]-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-en-3-yl)methyl carbonate C29H42N2O9Si 详情 详情
(VIII) 31607 1-(2-amino-2-oxoethyl)-4-[2-(1,1-dioxo-1,2-dihydro-2H-naphtho[1,8-cd]isothiazol-6-yl)ethyl]-1,4-diazoniabicyclo[2.2.2]octane di(trifluoromethanesulfonate) C22H26F6N4O9S3 详情 详情
(IX) 31160 1-[(2R,4S,5R)-4-(benzyloxy)-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione C35H32N2O5 详情 详情

合成路线17

该中间体在本合成路线中的序号：(I)

The selective silylation of azetidine (I) with TBDMSCl and Et3N in CH2Cl2 gives the fully silylated azetidine (II), which is condensed with 1-(trimethylsilyloxy) cyclohexene (III) by means of SnCl4 in CH3CN to yield the adduct (IV). The N-silylation of (IV) with TBDMSCl and Et3N in DMF affords the disilylated compound (V), which is condensed with diethyl chlorophosphate by means of LiHMDS in THF providing the phosphate ester (VI). The reaction of (VI) with MCPBA in CH2Cl2 gives the epoxide (VII), which is treated with methylamine and K2CO3 in ethyl acetate to yield the secondary amine (VIII). The acylation of (VIII) with allyl chloroformate (IX) and Et3N in CH2Cl2 affords the carbamate (X), which is cyclized with allyl chlorooxalate (XI) and Et3N in CH2Cl2 providing the tricyclic compound (XII). The desilylation of (XII) with TBAF and HOAc in THF gives the hydroxy diallyl ester (XIII), which is treated with Pd(PPh3)4 and 5,5-dimethylcyclohexane-1,3-dione (DMCHE) to yield the tricyclic aminoacid (XIV). Finally this compound is treated with benzyloxy formimidate (XV) in a pH 8 buffer to afford the target N-methylformamidino compound.

参考文献 中间体
合成目标
【1】 Perboni, A.; Donati, D.; Tarzia, G. (Glaxo Wellcome plc); Antibacterial condensed carbapenems. EP 0502468; EP 0575375; JP 1994505018; US 5426104; WO 9215288; WO 9215586 .
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) 41919 (2R)-1-[tert-butyl(dimethyl)silyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl acetate C19H39NO4Si2 详情 详情
(III) 15574 1-cyclohexen-1-yl trimethylsilyl ether; (1-cyclohexen-1-yloxy)(trimethyl)silane; 1-Cyclohexenyloxytrimethylsilane 6651-36-1 C9H18OSi 详情 详情
(IV) 15575 (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-2-oxocyclohexyl]-2-azetanone C17H31NO3Si 详情 详情
(V) 41920 (4R)-1-[tert-butyl(dimethyl)silyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-2-oxocyclohexyl]-2-azetidinone C23H45NO3Si2 详情 详情
(VI) 41921 (6R)-6-[(2R)-1-[tert-butyl(dimethyl)silyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-1-cyclohexen-1-yl diethyl phosphate C27H54NO6PSi2 详情 详情
(VII) 41922 (2R)-2-[(2R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-7-oxabicyclo[4.1.0]hept-1-yl diethyl phosphate C21H40NO7PSi 详情 详情
(VIII) 41923 (4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R,3S)-3-(methylamino)-2-oxocyclohexyl]-2-azetidinone C18H34N2O3Si 详情 详情
(IX) 38115 3-[(chlorocarbonyl)oxy]-1-propene 2937-50-0 C4H5ClO2 详情 详情
(X) 41924 allyl (1S,3R)-3-[(2R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-2-oxocyclohexyl(methyl)carbamate C22H38N2O5Si 详情 详情
(XI) 15585 allyl 2-chloro-2-oxoacetate C5H5ClO3 详情 详情
(XII) 41925 allyl (5S,8aS,8bR)-5-[[(allyloxy)carbonyl](methyl)amino]-1-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate C27H42N2O6Si 详情 详情
(XIII) 41926 allyl (5S,8aS,8bR)-5-[[(allyloxy)carbonyl](methyl)amino]-1-[(1R)-1-hydroxyethyl]-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate C21H28N2O6 详情 详情
(XIV) 41927 (5S,8aS,8bR)-1-[(1R)-1-hydroxyethyl]-5-(methylamino)-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylic acid C14H20N2O4 详情 详情
(XV) 41928 1-[[amino(imino)methoxy]methyl]benzene C8H10N2O 详情 详情

合成路线18

该中间体在本合成路线中的序号：(I)

The condensation of azetidine (I) with B-2-cyclohexenyl(2-methylcyclohexyl)2 by means of Et2Zn gives the adduct (II), which is epoxidated with Mg monoperphthalic acid (MgPOPH) in CH2Cl2 to yield the epoxide (III). Opening of the epoxide (III) with methylamine and LiClO4 in CH3CN affords the methylamino derivative (IV), which is oxidated with oxalyl chloride and Et3N in DMSO/CH2Cl2 to provide the cyclohexanone derivative (V). The protection of the methylamino group of (V) with benzyl chloroformate (VI) and Et3N in CH2Cl2 gives the carbamate (VII), which is condensed with 9-fluorenyl chlorooxalate (VIII) by means of Et3N in toluene to yield the oxalamic ester (IX). The cyclization of (IX) by means of P(OEt)3 in refluxing toluene affords the tricyclic carboxylate (X), which is desilylated with Bu4NBr and KF in HOAc/THF providing the intermediate (XI). The deprotection of the ester and carbamate groups of (XI) with H2 over Pd/C in i-PrOH/H2O furnishes the tricyclic aminoacid (XII), which is finally treated with benzyloxy formimidate (XIII) over amberlyst IRA68 in CH3CN/H2O to afford the target N-methylformamidino compound.

参考文献 中间体
合成目标
【1】 Biondi, S.; et al.; Highly diastereoselective synthesis of 4-N-methylformamidino trinem (GV129606), a potent antibacterial agent. Tetrahedron 2000, 56, 31, 5649.
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) 15576 (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1S)-2-cyclohexen-1-yl]-2-azetanone C17H31NO2Si 详情 详情
(III) 15577 (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1S,2R,6R)-7-oxabicyclo[4.1.0]hept-2-yl]-2-azetidinone C17H31NO3Si 详情 详情
(IV) 41929 (4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R,2S,3S)-2-hydroxy-3-(methylamino)cyclohexyl]-2-azetidinone C18H36N2O3Si 详情 详情
(V) 41923 (4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R,3S)-3-(methylamino)-2-oxocyclohexyl]-2-azetidinone C18H34N2O3Si 详情 详情
(VI) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(VII) 41930 benzyl (1S,3R)-3-[(2R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-2-oxocyclohexyl(methyl)carbamate C26H40N2O5Si 详情 详情
(VIII) 41931 2-(9H-fluoren-9-yloxy)-2-oxoacetyl chloride C15H9ClO3 详情 详情
(IX) 41932 9H-fluoren-9-yl 2-((2R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-[(1R,3S)-3-[(methoxycarbonyl)(methyl)amino]-2-oxocyclohexyl]-4-oxoazetidinyl)-2-oxoacetate C35H44N2O8Si 详情 详情
(X) 41933 9H-fluoren-9-yl (5S,8aS,8bR)-1-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-5-[(methoxycarbonyl)(methyl)amino]-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate C35H44N2O6Si 详情 详情
(XI) 41934 9H-fluoren-9-yl (5S,8aS,8bR)-1-[(1R)-1-hydroxyethyl]-5-[(methoxycarbonyl)(methyl)amino]-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate C29H30N2O6 详情 详情
(XII) 41927 (5S,8aS,8bR)-1-[(1R)-1-hydroxyethyl]-5-(methylamino)-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylic acid C14H20N2O4 详情 详情
(XIII) 41928 1-[[amino(imino)methoxy]methyl]benzene C8H10N2O 详情 详情

合成路线19

该中间体在本合成路线中的序号：(XXXIII)

A new procedure based on the counterattack stategy was further developed. Azetidinonepropionic acid (XXXV) was available from acetoxy azetidinone (XXXIII) by coupling with benzoxazinone (XXXIV). After protection of (XXXV) with tert-butyldimethylsilyl chloride, alkylation with allyl bromoacetate yielded (XXXVI). DCC-mediated condensation of (XXXVI) with mercaptopyrrolidine (IV) produced thioester (XXXVII). Dieckman-type cyclization of (XXXVII) upon treatment with sodium bis(trimethylsilyl)amide produced carbapenem (XXXVIII) together with mercaptopyrrolidine (XXXIX). Treatment of the crude reaction mixture with chlorotrimethylsilane and subsequent addition of diphenylphosphoryl chloride generated the vinyl phosphate (XL) and the silylated mercaptopyrrolidine (XLI). The counterattack of the thiolate anion, liberated by desilylation of (XLI) with tetrabutylammonium fluoride, to the vinyl phosphate (XL) yielded the desired thioether (XLII). The hydroxyl protective group of (XLII) was removed by treatment with NH4F·HF to give (XLIII), and the allyl ester group of (XLIII) was further cleaved by means of palladium diacetate, producing carboxylic acid (XLIV). Finally, alkylation of the carboxylate group of (XLIV) with iodomethyl isobutyrate (XVI) gave rise to the title compound.

参考文献 中间体
合成目标
【1】 Seki, M.; et al.; Practical synthesis of (R)-4-mercaptopyrrolidine-2-thione from L-aspartic acid.Preparation of a novel orally active 1-beta-methylcarbapenem, TA-949. J Org Chem 2000, 65, 2, 517.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
40728 allyl 2-bromoacetate C5H7BrO2 详情 详情
(IV) 37712 (4R)-4-sulfanyl-2-pyrrolidinethione C4H7NS2 详情 详情
(XVI) 37723 iodomethyl 2-methylpropanoate C5H9IO2 详情 详情
(XXXIII) 11687 (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate C13H25NO4Si 详情 详情
(XXXIV) 37738 3-(2-Bromo-1-oxopropyl)-spiro[2H-1,3-benzoxazine-2,1'-cyclohexan]-4(3H)-one 158299-05-9 C16H18BrNO3 详情 详情
(XXXV) 30029 (2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propionic acid C14H27NO4Si 详情 详情
(XXXVI) 37739 (2R)-2-[(2S,3S)-1-[2-(allyloxy)-2-oxoethyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propionic acid C19H33NO6Si 详情 详情
(XXXVII) 37740 allyl 2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-((1R)-1-methyl-2-oxo-2-[[(3R)-5-thioxopyrrolidinyl]sulfanyl]ethyl)-4-oxoazetidinyl]acetate C23H38N2O5S2Si 详情 详情
(XXXVIII) 37741 　 C19H30NNaO5Si 详情 详情
(XXXIX) 37742 　 C4H5NNa2S2 详情 详情
(XL) 37743 allyl (4R,5R,6S)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-[(diphenoxyphosphoryl)oxy]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C31H40NO8PSi 详情 详情
(XLI) 37744 (4R)-1-(trimethylsilyl)-4-[(trimethylsilyl)sulfanyl]-2-pyrrolidinethione C10H23NS2Si2 详情 详情
(XLII) 37745 allyl (4R,5S,6S)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-methyl-7-oxo-3-[[(3R)-5-thioxopyrrolidinyl]sulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C23H36N2O4S2Si 详情 详情
(XLIII) 37746 allyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3R)-5-thioxopyrrolidinyl]sulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C17H22N2O4S2 详情 详情
(XLIV) 37747 sodium (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3R)-5-thioxopyrrolidinyl]sulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C14H17N2NaO4S2 详情 详情

合成路线20

该中间体在本合成路线中的序号：(I)

The reaction of azetidinone (I) with sodium methyl mercaptan in acetonitrile gives the methylsulfanyl derivative (II), which is alkylated with para-methoxybenzyl 2-iodoacetate (III) by means of BuLi in THF to yield the azetidine-acetic acid derivative (IV). The acylation of (IV) with 5-azido-2,2-dimethylpentanoyl chloride (V) by means of LiHMDS affords the beta-oxopentanoate (VI), which is desilylated by means of TBAF and AcOH in THF to provide the 1-hydroxyethyl-azetidine (VII). The reaction of (VII) with chlorine or methyl sulphenyl chloride furnishes the chloroazetidine (VIII), which, without isolation, is cyclized by means of TEA in THF to give the precursor (IX). Finally, this compound is submitted to hydrogenation with H2 over Pd/C to provide the target aminoacid.

参考文献 中间体
合成目标
【1】 Simpson, I.N.; et al.; Broad-spectrum beta-lactamase inhibitor AM-112: Synthesis and enhancement of the in vitro activity of ceftazidime and piperacillin. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-345.
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) 61726 (3S,4R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-(methylsulfanyl)-2-azetidinone C12H25NO2SSi 详情 详情
(III) 54841 4-nitrobenzyl 2-iodoacetate C9H8INO4 详情 详情
(IV) 54842 4-nitrobenzyl 2-[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(methylsulfanyl)-4-oxoazetidinyl]acetate C21H32N2O6SSi 详情 详情
(V) 61727 5-azido-2,2-dimethylpentanoyl chloride C7H12ClN3O 详情 详情
(VI) 61728 4-nitrobenzyl 7-azido-2-[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(methylsulfanyl)-4-oxoazetidinyl]-4,4-dimethyl-3-oxoheptanoate C28H43N5O7SSi 详情 详情
(VII) 61729 4-nitrobenzyl 7-azido-2-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-2-(methylsulfanyl)-4-oxoazetidinyl]-4,4-dimethyl-3-oxoheptanoate C22H29N5O7S 详情 详情
(VIII) 61730 4-nitrobenzyl 7-azido-2-{(3S)-2-chloro-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl}-4,4-dimethyl-3-oxoheptanoate C21H26ClN5O7 详情 详情
(IX) 61731 4-nitrobenzyl (5R,6R)-3-(5-azido-1,1-dimethylpentyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-4-oxa-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C22H27N5O7 详情 详情

合成路线21

该中间体在本合成路线中的序号：(I)

Azetidinone acetate (I) was treated with sodium methanethiolate to produce thioether (II). Lactam (II) N-alkylation with p-nitrobenzyl iodoacetate (III) furnished the azetidineacetate (IV). The lithium enolate of ester (IV) was subsequently acylated with pivaloyl chloride (V) at low temperature to afford keto ester (VI). The silyl protecting group of (VI) was then removed by treatment with tetrabutylammonium fluoride, yielding alcohol (VII). Chlorination of (VII) with concomitant oxidative cleavage of the methylthio group at -78 C gave rise to the chloroazetidine (VIII). Cyclization of (VIII) to the key oxapenem bicyclic system was accomplished by treatment with triethylamine in cold THF. Chromatographic separation of the resultant mixture of cis/trans bicyclic compounds afforded the desired isomer (IX). After hydrogenolysis of the p-nitrobenzyl ester group of (IX), the resultant carboxylic acid was converted to the required potassium salt by treatment with aqueous potassium bicarbonate.

参考文献 中间体
合成目标
【1】 Pfaendler, H.R.; Weisner, F.; Synthesis and antibacterial activity of 1'R,5R,6R)-2-tert-butyl-6-(1'hydroxyethyl)oxapenem-3-carboxylic acid. Bioorg Med Chem Lett 1993, 3, 11, 2211.
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) 54840 (3S,4R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-(methylsulfanyl)-2-azetidinone C12H25NO2SSi 详情 详情
(III) 54841 4-nitrobenzyl 2-iodoacetate C9H8INO4 详情 详情
(IV) 54842 4-nitrobenzyl 2-[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(methylsulfanyl)-4-oxoazetidinyl]acetate C21H32N2O6SSi 详情 详情
(V) 13597 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride 3282-30-2 C5H9ClO 详情 详情
(VI) 54843 4-nitrobenzyl 2-[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(methylsulfanyl)-4-oxoazetidinyl]-4,4-dimethyl-3-oxopentanoate C26H40N2O7SSi 详情 详情
(VII) 54844 4-nitrobenzyl 2-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-2-(methylsulfanyl)-4-oxoazetidinyl]-4,4-dimethyl-3-oxopentanoate C20H26N2O7S 详情 详情
(VIII) 54845 4-nitrobenzyl 2-{(2R,3S)-2-chloro-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl}-4,4-dimethyl-3-oxopentanoate C19H23ClN2O7 详情 详情
(IX) 54846 4-nitrobenzyl 2-{(2S,3S)-2-chloro-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl}-4,4-dimethyl-3-oxopentanoate C19H23ClN2O7 详情 详情
(X) 54847 4-nitrobenzyl (5R,6R)-3-(tert-butyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-4-oxa-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C19H22N2O7 详情 详情

合成路线22

该中间体在本合成路线中的序号：(VII)

Dynamic kinetic resolution of 3-acetyl-1-benzyl-2-pyrrolidinone (I) by Ru-BINAP catalyzed hydrogenation provides the (hydroxyethyl) pyrrolidinone (II). Subsequent reduction of lactam (II) employing NaBH4-BF3•Et2O affords pyrrolidine (III). After debenzylation of (III) by hydrogenation over Pd/C, the resultant pyrrolidine (IV) is protected as the corresponding N-Alloc derivative (V) upon treatment with allyl chloroformate. Subsequent Swern oxidation of the alcohol function of (V) leads to the optically pure ketone (VI). Treatment of ketone (VI) with Me3SiOTf and Et3N, followed by condensation with the acetoxyazetidinone (VII) affords adduct (VIII). Acylation of azetidinone (VIII) with allyl oxalyl chloride (IX), followed by cyclization of the intermediate oxalimide in the presence of triethyl phosphite, gives rise to the carbapenem system ( X). Desilylation of (X) with tetrabutylammonium fluoride leads to alcohol (XI). Further palladium-catalyzed deprotection of both the Alloc and allyl ester groups of (XI) provides the pyrrolidinyl carbapenem (XII). Finally, introduction of the desired N-methyl formimidoyl group into (XII) is accomplished by treatment with ethyl N-methyl formimidate.

参考文献 中间体
合成目标
【1】 Hattori, K.; et al.; Synthesis and antibacterial evaluation of novel 2-[N-imidoylpyrrolidinyl] carbapenems. Bioorg Med Chem Lett 2002, 12, 3, 383.
【2】 Murata, M.; Chiba, T.; Tsutsumi, H.; Hattori, K.; Kuroda, S.; Ohtake, H.; Shirai, F. (Fujisawa Pharmaceutical Co., Ltd.); 1-Azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid cpds.. EP 0394991; JP 1990300187; US 5102877 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 38115 3-[(chlorocarbonyl)oxy]-1-propene 2937-50-0 C4H5ClO2 详情 详情
(B) 60185 ethyl methyliminoformate C4H9NO 详情 详情
(I) 60175 3-acetyl-1-benzyl-2-pyrrolidinone C13H15NO2 详情 详情
(II) 60176 (3S)-1-benzyl-3-[(1R)-1-hydroxyethyl]-2-pyrrolidinone C13H17NO2 详情 详情
(III) 60177 (1R)-1-[(3R)-1-benzylpyrrolidinyl]-1-ethanol C13H19NO 详情 详情
(IV) 60178 (1R)-1-[(3R)pyrrolidinyl]-1-ethanol C6H13NO 详情 详情
(V) 60179 allyl (3R)-3-[(1R)-1-hydroxyethyl]-1-pyrrolidinecarboxylate C10H17NO3 详情 详情
(VI) 60180 allyl (3R)-3-acetyl-1-pyrrolidinecarboxylate C10H15NO3 详情 详情
(VII) 11687 (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate C13H25NO4Si 详情 详情
(VIII) 60181 allyl (3R)-3-{2-[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidinyl]acetyl}-1-pyrrolidinecarboxylate C21H36N2O5Si 详情 详情
(IX) 15585 allyl 2-chloro-2-oxoacetate C5H5ClO3 详情 详情
(X) 60182 2-propenyl 6-(1-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-7-oxo-3-{1-[(2-propenyloxy)carbonyl]-3-pyrrolidinyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C26H40N2O6Si 详情 详情
(XI) 60183 2-propenyl 6-(1-hydroxyethyl)-7-oxo-3-{1-[(2-propenyloxy)carbonyl]-3-pyrrolidinyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C20H26N2O6 详情 详情
(XII) 60184 6-(1-hydroxyethyl)-7-oxo-3-(3-pyrrolidinyl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid C13H18N2O4 详情 详情
Extended Information