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【结 构 式】 
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【分子编号】30139 【品名】allyl 2-oxoacetate 【CA登记号】 |
【 分 子 式 】C5H6O3 【 分 子 量 】114.10084 【元素组成】C 52.63% H 5.3% O 42.07% |
合成路线1
该中间体在本合成路线中的序号：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.
| 【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2
该中间体在本合成路线中的序号：(IX)Treatment of the silylated azetidinone (I) with tritylmercaptan affords the tritylsulfanylazetidinone (II), which by reaction with AgNO3 is converted into the silver salt (III). Compound (III) is coupled with tetrahydrofuran-2(R)-carbonyl chloride (IV) obtained by treatment of carboxylic acid (V) with thionyl chloride to provide the azetidinone thioester (VI). Alternatively, compound (VI) can be obtained by condensation of tetrahydrofuran-2(R)-thiocarboxylic S-acid (VII) obtained by treatment of carboxylic acid (V) with hydrogen sulfide with silylated azetidinones (I) or (VIII) by means of NaOH in THF/water. Condensation of azetidinone thioester (VI) with allyl glyoxylate (IX) in refluxing benzene gives the hydroxy ester (X), which is treated with SOCl2 to yield the chloro ester (XI). Reaction of compound (XI) with triphenylphosphine and lutidine in hot THF provides the phosphoranylidene derivative (XII), which is converted into (5R,6S)-6-[1(R)-hydroxyethyl]-2-[2(R)-tetrahydrofuryl]penem-3-carboxylic acid allyl ester, faropenem allyl ester (XIII) by removal of the silyl protecting group with tetrabutylammonium fluoride, followed by cyclization in refluxing toluene. Compound (XII) can also be obtained by condensation of the silver salt of protected azetidinone (XIV) with tetrahydrofuran-2(R)-carbonyl chloride (V).
| 【1】 Jin, J.; Han, H.-N.; Liu, J.; Synthesis of the key intermediate of faropenem: (3S,4R)-3-[(R)-1-tert-Butyldimethylsilyloxyethyl]-4-[(R)-tetrahydrofuranoylthio]-2-azetidinone. J Shenyang Pharm Univ 2001, 18, 1, 20. |
| 【2】 Rabasseda, X.; Sorbera, L.A.; del Fresno, M.; Castaner, J.; Faropenem daloxate. Drugs Fut 2002, 27, 3, 223. |
| 【3】 Ishiguro, M.; Iwata, H.; Nakatsuka, T. (Suntory Ltd.); Penem cpds. AU 8654460; EP 0199446; JP 1994128267; US 4997829 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 11687 | (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate | C13H25NO4Si | 详情 | 详情 | |
| (II) | 52161 | (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-(tritylsulfanyl)-2-azetidinone | C30H37NO2SSi | 详情 | 详情 | |
| (III) | 52162 | C11H22AgNO2SSi | 详情 | 详情 | ||
| (IV) | 11696 | (2R)Tetrahydro-2-furancarbonyl chloride | C5H7ClO2 | 详情 | 详情 | |
| (V) | 52163 | (2R)-Tetrahydro-2-furancarboxylic acid; (2R)-2-Tetrahydrofuroic acid | 87392-05-0 | C5H8O3 | 详情 | 详情 |
| (VI) | 11689 | S-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl] (2R)tetrahydro-2-furancarbothioate | C16H29NO4SSi | 详情 | 详情 | |
| (VII) | 11688 | (2R)Tetrahydro-2-furancarbothioic S-acid | C5H8O2S | 详情 | 详情 | |
| (VIII) | 52164 | (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-(phenylsulfonyl)-2-azetidinone | C17H27NO4SSi | 详情 | 详情 | |
| (IX) | 30139 | allyl 2-oxoacetate | C5H6O3 | 详情 | 详情 | |
| (X) | 11690 | allyl 2-((3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-oxo-4-[[(2R)tetrahydro-2-furanylcarbonyl]sulfanyl]azetanyl)-2-hydroxyacetate | C21H35NO7SSi | 详情 | 详情 | |
| (XI) | 11691 | allyl 2-((3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-oxo-4-[[(2R)tetrahydro-2-furanylcarbonyl]sulfanyl]azetanyl)-2-chloroacetate | C21H34ClNO6SSi | 详情 | 详情 | |
| (XII) | 52165 | allyl 2-((3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-oxo-4-[[(2R)tetrahydro-2-furanylcarbonyl]sulfanyl]azetidinyl)-2-(triphenylphosphoranylidene)acetate | C39H48NO6PSSi | 详情 | 详情 | |
| (XIII) | 11694 | allyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(2R)tetrahydro-2-furanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C15H19NO5S | 详情 | 详情 | |
| (XIV) | 52166 | C34H41AgNO4PSSi | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXIV)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).
| 【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4
该中间体在本合成路线中的序号：(III)Silylation of carboxylic acid (I) by means of tert-butyldimethylsilyl chloride and imidazole in DMF yields derivative (II), which then reacts with allyl glyoxylate (III) in toluene to afford (IV). Treatment of (IV) with SOCl2 and pyridine in THF provides chloro azetidinone (V), which is then converted into (VI) by means of PPh3 and pyridine or 2,6-lutidine in DMF. Ylide acid (VI) is treated with 2-pyridyl chlorothioformate (VII) and Et3N in CH2Cl2 to give derivative (VIII), which is then condensed with the Grignard reagent (XI) and desilylated by means of H2SO4 in MeOH to provide ketophosphorane (XII). Cyclization of (XII) via an internal Wittig reaction by treatment with refluxing p-xylene gives carbapenem (XIII), which is then converted into the corresponding iodide (XIV) via mesylation with MsCl by means of TEA in dichloromethane followed by Finkelstein reaction with NaI in acetone. Reaction of (XIV) with 2-aminopyridine (XV) in acetonitrile provides pyridinium salt (XVI), whose allyl protecting groups are removed by treatment with Pd(PPh3)4, PPh3 in CH2Cl2/EtOAc, followed by 2-ethylhexanoic acid and potassium 2-ethylhexanoate in EtOAc.
| 【1】 Guthikonda, R.N.; et al.; Structure-activity relationships in the 2-arylcarbapenem series: Synthesis of 1-methyl-2-arylcarbapenems. J Med Chem 1987, 30, 5, 871. |
| 【2】 Greenlee, M.L.; et al.; 2-Naphthylcarbapenems: Broad spectrum antibiotics with enhanced potency against MRSA. Bioorg Med Chem Lett 1999, 9, 19, 2893. |
| 【3】 DiNinno, F.P.; Greenlee, M.L. (Merck & Co., Inc.); 2-Naphthyl-carbapenem antibacterial agents. EP 0466254; JP 1992253980; US 5032587 . |
| 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) | 42552 | 2-[(2R,3S)-3-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-4-oxoazetidinyl]acetic acid | C11H15NO6 | 详情 | 详情 | |
| (II) | 42553 | tert-butyl(dimethyl)silyl 2-[(2R,3S)-3-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-4-oxoazetidinyl]acetate | C17H29NO6Si | 详情 | 详情 | |
| (III) | 30139 | allyl 2-oxoacetate | C5H6O3 | 详情 | 详情 | |
| (IV) | 42554 | allyl 2-[(2R,3S)-3-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-2-(2-[[tert-butyl(dimethyl)silyl]oxy]-2-oxoethyl)-4-oxoazetidinyl]-2-hydroxyacetate | C22H35NO9Si | 详情 | 详情 | |
| (V) | 42555 | 2-[(2R,3S)-3-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-1-[2-(allyloxy)-1-chloro-2-oxoethyl]-4-oxoazetidinyl]acetic acid | C16H20ClNO8 | 详情 | 详情 | |
| (VI) | 42556 | 2-[(2R,3S)-3-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-1-[2-(allyloxy)-2-oxo-1-(triphenylphosphoranylidene)ethyl]-4-oxoazetidinyl]acetic acid | C34H34NO8P | 详情 | 详情 | |
| (VII) | 42557 | 2-[(chlorocarbonyl)sulfanyl]pyridine | C6H4ClNOS | 详情 | 详情 | |
| (VIII) | 42558 | allyl 2-[(3S,4R)-3-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-2-oxo-4-[2-oxo-2-(2-pyridinylsulfanyl)ethyl]azetidinyl]-2-(triphenylphosphoranylidene)acetate | C39H37N2O7PS | 详情 | 详情 | |
| (XI) | 42559 | bromo[6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-naphthyl]magnesium | C17H23BrMgOSi | 详情 | 详情 | |
| (XII) | 42560 | allyl 2-((2R,3S)-3-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-2-[2-[6-(hydroxymethyl)-2-naphthyl]-2-oxoethyl]-4-oxoazetidinyl)-2-(triphenylphosphoranylidene)acetate | C45H42NO8P | 详情 | 详情 | |
| (XIII) | 42561 | allyl (5R,6S)-6-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-3-[6-(hydroxymethyl)-2-naphthyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C27H27NO7 | 详情 | 详情 | |
| (XIV) | 42562 | allyl (5R,6S)-6-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-3-[6-(iodomethyl)-2-naphthyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C27H26INO6 | 详情 | 详情 | |
| (XV) | 11305 | 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine | 504-29-0 | C5H6N2 | 详情 | 详情 |
| (XVI) | 42563 | 1-([6-[(5R,6S)-2-[(allyloxy)carbonyl]-6-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]-2-naphthyl]methyl)-2-aminopyridinium iodide | C32H32IN3O6 | 详情 | 详情 |