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【结 构 式】 
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【分子编号】15585 【品名】allyl 2-chloro-2-oxoacetate 【CA登记号】 |
【 分 子 式 】C5H5ClO3 【 分 子 量 】148.5456 【元素组成】C 40.43% H 3.39% Cl 23.87% O 32.31% |
合成路线1
该中间体在本合成路线中的序号：(XII)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).
| 【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：(VI)Substitution with sodium [N-(allyloxycarbonyl)amino]thioacetate of the tert-butylsulfonyl group of the (3S,4R)-azetidinone (I) (obtained in several steps from L threonine), with overall retention of configuration at C-4, gives the azetidinone (II), wnich is converted with allyloxalyl chloride to the oxamide (III). Cyclization of (III) with triethylphosphite yields the (5R,6S,1'R)-allyl-2-(allyloxycarbonylaminomethyl)-6-(1'-allyloxycarbonyloxyethyl)penem-3-carboxylate (IV), which is deprotected to yield crystalline CGP-31608.
| 【1】 Gregg, C.; Tioutiounnik, N.; Dempsey, W.; Revankar, S.; Helv Chim Acta 1986, 69, 1576. |
| 【2】 Cozens, R.M.; Lang, M.; CGP-31608. Drugs Fut 1988, 13, 1, 19. |
| 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) | 21563 | allyl (1R)-1-[(2R,3S)-2-(tert-butylsulfonyl)-4-oxoazetidinyl]ethyl carbonate | C13H21NO6S | 详情 | 详情 | |
| (II) | 21564 | S-[(2R,3S)-3-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-4-oxoazetidinyl] 2-[[(allyloxy)carbonyl]amino]ethanethioate | C15H20N2O7S | 详情 | 详情 | |
| (III) | 21565 | allyl 2-[(2R,3S)-2-[(2-[[(allyloxy)carbonyl]amino]acetyl)sulfanyl]-3-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-4-oxoazetidinyl]-2-oxoacetate | C20H24N2O10S | 详情 | 详情 | |
| (IV) | 21566 | allyl (5R,6S)-3-([[(allyloxy)carbonyl]amino]methyl)-6-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C20H24N2O8S | 详情 | 详情 | |
| (V) | 21567 | sodium 2-[[(allyloxy)carbonyl]amino]ethanethioate | C6H8NNaO3S | 详情 | 详情 | |
| (VI) | 15585 | allyl 2-chloro-2-oxoacetate | C5H5ClO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)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4
该中间体在本合成路线中的序号：(IX)The reaction of N-(tert-butoxycarbonyl)-L-serine methyl ester (I) with hydrazine gives the corresponding hydrazide (II), which is acylated with trifluorothioacetic acid S-ethyl ester (III), yielding the diacylated hydrazine (IV). The cyclization of (IV) by means of DEAD and PPh3 affords the pyrazolidinone (V), which is deacylated with NaOH to furnish 4(S)-(tert-butoxycarbonyl)pyrazolidin-3-one (VI). The condensation of (VI) with vinylphosphonate (VII) gives the adduct (VIII), which is cyclized with the oxalyl monoester chloride (IX) by means of DIEA, yielding the pyrazolopyrazole (X). Finally, this compound is deprotected in acid medium and acylated with thiazole derivative (XI) by means of a Pd(0) catalyst to furnish the target compound.
| 【1】 Ternansky, R.J.; Draheim, S.E.; The synthesis of bicyclic pyrazolidinone antibacterial agents. 30th Nat Org Symp (Vancouver) 1987. |
| 【2】 Jungheim, L.N.; Holmes, R.E. (Eli Lilly and Company); Substd. diazolidinones. US 4826993 . |
| 【3】 Jungheim, L.N.; Ternansky, R.J.; Holmes, R.E.; BICYCLIC PYRAZOLIDINONE ANTIBACTERIAL AGENTS. Drugs Fut 1990, 15, 2, 149. |
| 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) | 43221 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoate | 2766-43-0 | C9H17NO5 | 详情 | 详情 |
| (II) | 43222 | tert-butyl (1S)-2-hydrazino-1-(hydroxymethyl)-2-oxoethylcarbamate | C8H17N3O4 | 详情 | 详情 | |
| (III) | 43223 | S-ethyl 2,2,2-trifluoroethanethioate | 383-64-2 | C4H5F3OS | 详情 | 详情 |
| (IV) | 43224 | tert-butyl (1S)-1-(hydroxymethyl)-2-oxo-2-[2-(2,2,2-trifluoroacetyl)hydrazino]ethylcarbamate | C10H16F3N3O5 | 详情 | 详情 | |
| (V) | 43225 | tert-butyl (4S)-3-oxo-1-(2,2,2-trifluoroacetyl)pyrazolidinylcarbamate | C10H14F3N3O4 | 详情 | 详情 | |
| (VI) | 43226 | tert-butyl (4S)-3-oxopyrazolidinylcarbamate | C8H15N3O3 | 详情 | 详情 | |
| (VII) | 43227 | diethyl 1-cyanovinylphosphonate | C7H12NO3P | 详情 | 详情 | |
| (VIII) | 43228 | diethyl 2-[(4S)-4-[(tert-butoxycarbonyl)amino]-3-oxopyrazolidinyl]-1-cyanoethylphosphonate | C15H27N4O6P | 详情 | 详情 | |
| (IX) | 15585 | allyl 2-chloro-2-oxoacetate | C5H5ClO3 | 详情 | 详情 | |
| (X) | 43229 | allyl (6S)-6-[(tert-butoxycarbonyl)amino]-2-cyano-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-3-carboxylate | C16H20N4O5 | 详情 | 详情 | |
| (XI) | 24316 | 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl chloride | C6H6ClN3O2S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IX)The reaction of N-(tert-butoxycarbonyl)-L-serine methyl ester (I) with hydrazine gives the corresponding hydrazide (II), which is acylated with trifluorothioacetic acid S-ethyl ester (III), yielding the diacylated hydrazine (IV). The cyclization of (IV) by means of DEAD and PPh3 affords the pyrazolidinone (V), which is deacylated with NaOH to furnish 4(S)-(tert-butoxycarbonyl)pyrazolidin-3-one (VI). The condensation of (VI) with vinylphosphonate (VII) gives the adduct (VIII), which is cyclized with the oxalyl monoester chloride (IX) by means of DIEA, yielding the pyrazolopyrazole (X). Finally, this compound is deprotected in acid medium and acylated with thiazole derivative (XI) by means of a Pd(0) catalyst to furnish the target compound.
| 【1】 Ternansky, R.J.; Draheim, S.E.; The synthesis of bicyclic pyrazolidinone antibacterial agents. 30th Nat Org Symp (Vancouver) 1987. |
| 【2】 Jungheim, L.N.; Holmes, R.E. (Eli Lilly and Company); Substd. diazolidinones. US 4826993 . |
| 【3】 Jungheim, L.N.; Ternansky, R.J.; Holmes, R.E.; BICYCLIC PYRAZOLIDINONE ANTIBACTERIAL AGENTS. Drugs Fut 1990, 15, 2, 149. |
| 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) | 43221 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoate | 2766-43-0 | C9H17NO5 | 详情 | 详情 |
| (II) | 43222 | tert-butyl (1S)-2-hydrazino-1-(hydroxymethyl)-2-oxoethylcarbamate | C8H17N3O4 | 详情 | 详情 | |
| (III) | 43223 | S-ethyl 2,2,2-trifluoroethanethioate | 383-64-2 | C4H5F3OS | 详情 | 详情 |
| (IV) | 43224 | tert-butyl (1S)-1-(hydroxymethyl)-2-oxo-2-[2-(2,2,2-trifluoroacetyl)hydrazino]ethylcarbamate | C10H16F3N3O5 | 详情 | 详情 | |
| (V) | 43225 | tert-butyl (4S)-3-oxo-1-(2,2,2-trifluoroacetyl)pyrazolidinylcarbamate | C10H14F3N3O4 | 详情 | 详情 | |
| (VI) | 43226 | tert-butyl (4S)-3-oxopyrazolidinylcarbamate | C8H15N3O3 | 详情 | 详情 | |
| (VII) | 43230 | diethyl 1-(methylsulfonyl)vinylphosphonate | C7H15O5PS | 详情 | 详情 | |
| (VIII) | 43231 | diethyl 2-[(4S)-4-[(tert-butoxycarbonyl)amino]-3-oxopyrazolidinyl]-1-(methylsulfonyl)ethylphosphonate | C15H30N3O8PS | 详情 | 详情 | |
| (IX) | 15585 | allyl 2-chloro-2-oxoacetate | C5H5ClO3 | 详情 | 详情 | |
| (X) | 43232 | allyl (6S)-6-[(tert-butoxycarbonyl)amino]-2-(methylsulfonyl)-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-3-carboxylate | C16H23N3O7S | 详情 | 详情 | |
| (XI) | 24316 | 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl chloride | C6H6ClN3O2S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XXVI)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.
| 【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7
该中间体在本合成路线中的序号：(V)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).
| 【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8
该中间体在本合成路线中的序号：(XVI)Alternatively, faropenem allyl ester (XIII) can also be prepared by cyclization of compound (XII) in refluxing benzene to yield silylated penem allyl ester (XV), which is then deprotected with either tetrabutylammonium fluoride in AcOH or triethylamine tris(hydrogen fluoride) in methyl isobutyl ketone or toluene. Penem (XV) can also be synthesized by several related ways: a) By coupling of azetidinone (VI) with allyl oxalyl chloride (XVI) in CH2Cl2 by means of Et3N, followed by intramolecular Wittig cyclization by means of triethyl phosphite in refluxing xylene. b) Substitution of phenyl sulfonyl group of azetidinone (VIII) by tritylmercaptan by means of NaOH in acetone/water provides tritylsulfanyl-azetidinone (II), which is condensed with allyl oxalyl chloride (XVI) by means of DIEA in CH2Cl2 to give the oxalyl amide (XVII). Compound (XVII) is then treated with AgNO3 and pyridine in acetonitrile to provide the silver mercaptide (XVIII), which is acylated with tetrahydrofuran-2(R)-carbonyl chloride (IV) in acetonitrile to afford the penem precursor (XIX). Finally, compound (XV) is obtained by intramolecular Wittig cyclization of (XX) with P(OEt)3 in refluxing xylene.
| 【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】 Rabasseda, X.; Sorbera, L.A.; del Fresno, M.; Castaner, J.; Faropenem daloxate. Drugs Fut 2002, 27, 3, 223. |
| 【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.; Kanebo, A.; Kaku, T.; Nakatsuka, T. (Nippon Soda Co., Ltd.; Suntory Ltd.); Method of desilylating silylether cpds.. EP 0612749 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 52161 | (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-(tritylsulfanyl)-2-azetidinone | C30H37NO2SSi | 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 | |
| (VIII) | 52164 | (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-(phenylsulfonyl)-2-azetidinone | C17H27NO4SSi | 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 | |
| (XV) | 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 | |
| (XVI) | 15585 | allyl 2-chloro-2-oxoacetate | C5H5ClO3 | 详情 | 详情 | |
| (XVII) | 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 | |
| (XVIII) | 52168 | C16H26AgNO5SSi | 详情 | 详情 | ||
| (XIX) | 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9
该中间体在本合成路线中的序号：(V)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).
| 【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：(XI)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.
| 【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11
该中间体在本合成路线中的序号：(IX)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.
| 【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 |