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【结 构 式】 
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【分子编号】30029 【品名】(2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propionic acid 【CA登记号】 |
【 分 子 式 】C14H27NO4Si 【 分 子 量 】301.45822 【元素组成】C 55.78% H 9.03% N 4.65% O 21.23% Si 9.32% |
合成路线1
该中间体在本合成路线中的序号：(I)A short-step synthesis of CS-834 has been described: The condensation of azetidinone (I) with pyrrolidinone (II) by means of CDI gives the thioester (III), which is desilylated with BF3/Et2O to the alcohol (IV). In order to have a more labile protecting group, alcohol (IV) is resilylated with TMS-Cl (or TES-Cl) and triethylamine affording the silyl ether (V), which is protected again at the pyrrolidine nitrogen with TES-Cl, affording the disilylated azetidinone (VI). The condensation of (VI) with the oxalyl chloride (VII) by means of triethylamine in dichloromethane gives the expected oxalylazetidinone (VIII), which is treated with diethyl ethylphosphonite in toluene yielding the ylide (IX). This compound, without isolation, is cyclized in refluxing mesitylene to afford the protected carbapenem intermediate (X), which is finally desilylated with HCl in acetonitrile. The cyclization of azetidinone (VIII) to carbapenem (X) can also be performed with triethyl phosphite instead of diethyl ethylphosphonite. The oxalyl chloride (VII) is obtained by monoesterification of oxalic acid (XI) with pivaloyloxymethyl iodide (XII) by means of triethylamine yielding monoester (XIII), which is finally converted to intermediate (VII) by treatment with oxalyl chloride in dichloromethane.
| 【1】 Oida, S.; Mori, M.; A short-step synthesis of orally active carbapenem antibiotic CS-834. Chem Pharm Bull 2000, 48, 1, 126. |
| 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 | |
| (II) | 17192 | (4R)-4-sulfanyltetrahydro-2H-pyrrol-2-one | 157429-42-0 | C4H7NOS | 详情 | 详情 |
| (III) | 33402 | S-[(3R)-5-oxopyrrolidinyl] (2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propanethioate | C18H32N2O4SSi | 详情 | 详情 | |
| (IV) | 33403 | S-[(3R)-5-oxopyrrolidinyl] (2R)-2-[(2S,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]propanethioate | C12H18N2O4S | 详情 | 详情 | |
| (V) | 33404 | S-[(3R)-5-oxopyrrolidinyl] (2R)-2-((2S,3S)-4-oxo-3-[(1R)-1-[(trimethylsilyl)oxy]ethyl]azetidinyl)propanethioate | C15H26N2O4SSi | 详情 | 详情 | |
| (VI) | 33405 | S-[(3R)-5-oxo-1-(triethylsilyl)pyrrolidinyl] (2R)-2-((2S,3S)-4-oxo-3-[(1R)-1-[(trimethylsilyl)oxy]ethyl]azetidinyl)propanethioate | C21H40N2O4SSi2 | 详情 | 详情 | |
| (VII) | 17199 | [(2-chloro-2-oxoacetyl)oxy]methyl pivalate | C8H11ClO5 | 详情 | 详情 | |
| (VIII) | 33406 | [[2-((2S,3S)-2-((1R)-1-methyl-2-oxo-2-[[(3R)-5-oxo-1-(triethylsilyl)pyrrolidinyl]sulfanyl]ethyl)-4-oxo-3-[(1R)-1-[(trimethylsilyl)oxy]ethyl]azetidinyl)-2-oxoacetyl]oxy]methyl pivalate | C29H50N2O9SSi2 | 详情 | 详情 | |
| (IX) | 33407 | [[2-[diethoxy(ethyl)phosphoranylidene]-2-((2S,3S)-2-((1R)-1-methyl-2-oxo-2-[[(3R)-5-oxo-1-(triethylsilyl)pyrrolidinyl]sulfanyl]ethyl)-4-oxo-3-[(1R)-1-[(trimethylsilyl)oxy]ethyl]azetidinyl)acetyl]oxy]methyl pivalate | C35H65N2O10PSSi2 | 详情 | 详情 | |
| (X) | 33408 | [(2,2-dimethylpropanoyl)oxy]methyl (4R,5S,6S)-4-methyl-7-oxo-3-[[(3R)-5-oxo-1-(triethylsilyl)pyrrolidinyl]sulfanyl]-6-[(1R)-1-[(trimethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C29H50N2O7SSi2 | 详情 | 详情 | |
| (XI) | 15713 | Oxalic acid | 144-62-7 | C2H2O4 | 详情 | 详情 |
| (XII) | 11159 | iodomethyl pivalate | C6H11IO2 | 详情 | 详情 | |
| (XIII) | 33409 | 2-[[(2,2-dimethylpropanoyl)oxy]methoxy]-2-oxoacetic acid | C8H12O6 | 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 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).
| 【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3
该中间体在本合成路线中的序号：(I)Azetidinepropanoic acid derivative (I) was converted to the mixed anhydride with isobutyl chloroformate and then coupled with N,O-dimethylhydroxylamine to afford the N-methoxyamide (II). This was treated with 2-thiazolylmagnesium bromide (III) to give thiazolyl ketone (IV). Condensation of (IV) with allyl glyoxylate hydrate (V) produced adduct (VI). Further reaction of (VI) with SOCl2 and then with triphenylphosphine gave the corresponding phosphorane, which cyclized in boiling anisole to generate the carbapenem (VII). After N-methylation at the thiazole ring of (VII) with methyl triflate, the thiazolium salt (VIII) was reduced with NaBH4 and subsequently hydrolyzed to aldehyde (IX) in the presence of HgCl2. Addition of isopropylmagnesium bromide to (IX) at -78 C, followed by desilylation with tetra-butylammonium fluoride yielded diol (X). Then, palladium-catalyzed deprotection of the allyl ester of (X) in the presence of sodium 2-ethylhexanoate provided the sodium carboxylate salt (XI). Finally, reaction of (XI) with 1-iodoethyl isopropyl carbonate (XII) in cold DMF produced the target ester.
| 【1】 Pyun, D.K.; Lee, J.S.; Kim, J.H.; Lee, C.H.; KR-21012, a new carbapenem: I. Synthesis and structure-activity relationships of beta-methyl-2-(alpha-functionalized) carbapenems. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-46. |
| 【2】 Lee, C.H.; Lee, D.H.; Kim, K.S.; Kim, J.H.; Kim, Y.S.; Jun, Y.S.; Lim, S.S.; Bae, E.M.; Kim, B.J. (Korea Research Institute of Chemical Technology); beta-Methylcarbapenem derivs., process for the preparation thereof and pharmaceutical compsn. comprising same. EP 1019405; JP 1999500750; US 5869477; WO 9720844 . |
| 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 | |
| (II) | 30030 | (2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-N-methoxy-N-methylpropanamide | C16H32N2O4Si | 详情 | 详情 | |
| (III) | 30031 | bromo(1,3-thiazol-2-yl)magnesium | C3H2BrMgNS | 详情 | 详情 | |
| (IV) | 30032 | (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-1-methyl-2-oxo-2-(1,3-thiazol-2-yl)ethyl]-2-azetidinone | C17H28N2O3SSi | 详情 | 详情 | |
| (V) | 30033 | allyl 2,2-dihydroxyacetate | C5H8O4 | 详情 | 详情 | |
| (VI) | 30034 | allyl 2-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-[(1R)-1-methyl-2-oxo-2-(1,3-thiazol-2-yl)ethyl]-4-oxoazetidinyl]-2-hydroxyacetate | C22H34N2O6SSi | 详情 | 详情 | |
| (VII) | 30035 | allyl (4S,5R,6S)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-methyl-7-oxo-3-(1,3-thiazol-2-yl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C22H32N2O4SSi | 详情 | 详情 | |
| (VIII) | 30036 | 2-[(4S,5R,6S)-2-[(allyloxy)carbonyl]-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]-3-methyl-1,3-thiazol-3-ium trifluoromethanesulfonate | C24H35F3N2O7S2Si | 详情 | 详情 | |
| (IX) | 30037 | allyl (4S,5R,6S)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-formyl-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C20H31NO5Si | 详情 | 详情 | |
| (X) | 30038 | allyl (4S,5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[(1R)-1-hydroxy-2-methylpropyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C17H25NO5 | 详情 | 详情 | |
| (XI) | 30039 | sodium (4S,5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[(1R)-1-hydroxy-2-methylpropyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C14H20NNaO5 | 详情 | 详情 | |
| (XII) | 15685 | 1-iodoethyl isopropyl carbonate | C6H11IO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Azetidineacetic acid derivative (I) was activated with 1,1'-carbonyldiimidazole and then condensed with p-nitrobenzyl malonate magnesium salt (II) to afford ketoester (III). Desilylation of (III) with methanolic HCl then gave alcohol (IV). Dodecylbenzenesulfonyl azide (VI) was prepared by treatment of sulfonyl chloride (V) with NaN3. Reaction of (IV) with sulfonyl azide (VI) provided diazo ester (VII). Ring closure of (VII) in the presence of rhodium diacetate in hot cyclohexane, followed by condensation with diphenylphosphoric chloride furnished carbapenem phosphate (VIII).
| 【1】 Lin, Y.-I.; Bitha, P.; Sakya, S.; Strohmeyer, T.W.; Bush, K. (American Cyanamid Co.); Novel 2-thiosubstd. carbapenems. CA 2118961; EP 0617036; JP 1994321948; US 5602118 . |
| 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 | |
| (II) | 33039 | magnesium 2-(4-nitrobenzyl)malonate | C10H7MgNO6 | 详情 | 详情 | |
| (III) | 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 | |
| (IV) | 22573 | 4-nitrobenzyl 4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate | C17H20N2O7 | 详情 | 详情 | |
| (V) | 33041 | 4-dodecylbenzenesulfonyl chloride | C18H29ClO2S | 详情 | 详情 | |
| (VI) | 33042 | 4-dodecylbenzenesulfonyl azide | C18H29N3O2S | 详情 | 详情 | |
| (VII) | 30150 | (3S,4R)-3-((1R)-1-Hydroxyethyl)-4[(1R)-1-methyl-3-diazo-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]azetidin-2-one | 137391-68-5 | C17H18N4O7 | 详情 | 详情 |
| (VIII) | 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5
该中间体在本合成路线中的序号：(XXXI)Azetidinepropanoic acid (XXXI) was converted to methoxyamide (XXXII) and then treated with trimethylsilylmethyllithium to give silyl ketone (XXXIII). After conversion of (XXXIII) to bromoketone (XXXIV), displacement by an acetate group afforded acetoxymethyl ketone (XXXV). A similar route as above produced phosphorane (XXXVI), which was then cyclized to the carbapenem (XXXVII).
| 【1】 Yasuda, N.; et al.; Preparation of anti-MRS carbapenem L-786,392. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-31. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXI) | 30029 | (2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propionic acid | C14H27NO4Si | 详情 | 详情 | |
| (XXXII) | 30030 | (2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-N-methoxy-N-methylpropanamide | C16H32N2O4Si | 详情 | 详情 | |
| (XXXIII) | 30145 | (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-1-methyl-2-oxo-3-(trimethylsilyl)propyl]-2-azetidinone | C18H37NO3Si2 | 详情 | 详情 | |
| (XXXIV) | 30146 | (3S,4R)-4-[(1R)-3-bromo-1-methyl-2-oxopropyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-azetidinone | C15H28BrNO3Si | 详情 | 详情 | |
| (XXXV) | 30147 | (3R)-3-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-2-oxobutyl acetate | C17H31NO5Si | 详情 | 详情 | |
| (XXXVI) | 30148 | (3R)-3-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1-[3-(4-nitrobenzyloxy)-2-oxo-1-(triphenylphosphoranylidene)propyl]-4-oxoazetidinyl]-2-oxobutyl acetate | C44H51N2O9PSi | 详情 | 详情 | |
| (XXXVII) | 30149 | 4-nitrobenzyl (4S,5R,6S)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-(hydroxymethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C24H34N2O7Si | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)Azetidinepropanoic acid derivative (I) was converted to the mixed anhydride with isobutyl chloroformate and then coupled with N,O-dimethylhydroxylamine to afford the N-methoxyamide (II). This was treated with 2-thiazolylmagnesium bromide (III) to give thiazolyl ketone (IV). Condensation of (IV) with allyl glyoxylate hydrate (V) produced adduct (VI). Further reaction of (VI) with SOCl2 and then with triphenylphosphine gave the corresponding phosphorane, which cyclized in boiling anisole to generate the carbapenem (VII). After N-methylation at the thiazole ring of (VII) with methyl triflate, the thiazolium salt (VIII) was reduced with NaBH4 and subsequently hydrolyzed to aldehyde (IX) in the presence of HgCl2. Addition of isopropylmagnesium bromide to (IX) at -78 C, followed by desilylation with tetra-butylammonium fluoride yielded diol (X). Finally, palladium-catalyzed deprotection of the allyl ester of (X) in the presence of sodium 2-ethylhexanoate provided the title sodium carboxylate salt.
| 【1】 Pyun, D.K.; Lee, J.S.; Kim, J.H.; Lee, C.H.; KR-21012, a new carbapenem: I. Synthesis and structure-activity relationships of beta-methyl-2-(alpha-functionalized) carbapenems. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-46. |
| 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 | |
| (II) | 30030 | (2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-N-methoxy-N-methylpropanamide | C16H32N2O4Si | 详情 | 详情 | |
| (III) | 30031 | bromo(1,3-thiazol-2-yl)magnesium | C3H2BrMgNS | 详情 | 详情 | |
| (IV) | 30032 | (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-1-methyl-2-oxo-2-(1,3-thiazol-2-yl)ethyl]-2-azetidinone | C17H28N2O3SSi | 详情 | 详情 | |
| (V) | 30033 | allyl 2,2-dihydroxyacetate | C5H8O4 | 详情 | 详情 | |
| (VI) | 30034 | allyl 2-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-[(1R)-1-methyl-2-oxo-2-(1,3-thiazol-2-yl)ethyl]-4-oxoazetidinyl]-2-hydroxyacetate | C22H34N2O6SSi | 详情 | 详情 | |
| (VII) | 30035 | allyl (4S,5R,6S)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-methyl-7-oxo-3-(1,3-thiazol-2-yl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C22H32N2O4SSi | 详情 | 详情 | |
| (VIII) | 30036 | 2-[(4S,5R,6S)-2-[(allyloxy)carbonyl]-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]-3-methyl-1,3-thiazol-3-ium trifluoromethanesulfonate | C24H35F3N2O7S2Si | 详情 | 详情 | |
| (IX) | 30037 | allyl (4S,5R,6S)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-formyl-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C20H31NO5Si | 详情 | 详情 | |
| (X) | 30038 | allyl (4S,5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[(1R)-1-hydroxy-2-methylpropyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C17H25NO5 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XXII)An alternative procedure for the preparation of the carbapenem system was based on the desulfurative ring contraction of a 1-aza-3-thiabicyclo[4.2.0]octane. The required diethyl (mercaptomethyl)malonate (XXI) was prepared by condensation of diethyl malonate (XVIII) with paraformaldehyde to give methylene malonate (XIX). Conjugate addition of thioacetic acid to (XIX) afforded thioester (XX) and subsequent acid hydrolysis yielded the desired mercaptomethyl derivative (XXI). Coupling of (XXI) with azetidinonepropionic acid (XXII) via activation with CDI generated thioester (XXIII). Oxalic acid chloride isobutyryloxymethyl ester (XXV) was obtained from isobutyryl chloride (XXIV) by condensation with paraformaldehyde, followed by reaction of the resulting chloromethylbutyrate with monobenzyl oxalate tetrabutylammonium salt, hydrogenolysis of the benzyl group and chlorination with oxalyl chloride. Coupling of this acid chloride (XXV) with azetidinone (XXIII) gave imide (XXVI), which was reduced to the hydroxy derivative (XXVII) with Zn and AcOH. After chlorination of (XXVII) with SOCl2 and pyridine, cleavage of the methylenemalonate group, followed by cyclization in the presence of Et3N gave rise to the bicyclic system (XXIX).
| 【1】 Horikawa, H.; Iwasaki, T.; Kondo, K. (Tanabe Seiyaku Co., Ltd.); Process for preparing beta-lactam deriv. and synthetic intermediate thereof. EP 0559533 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIII) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (XIX) | 37725 | diethyl 2-methylenemalonate | C8H12O4 | 详情 | 详情 | |
| (XX) | 37726 | diethyl 2-[(acetylsulfanyl)methyl]malonate | C10H16O5S | 详情 | 详情 | |
| (XXI) | 37727 | diethyl 2-(sulfanylmethyl)malonate | C8H14O4S | 详情 | 详情 | |
| (XXII) | 30029 | (2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propionic acid | C14H27NO4Si | 详情 | 详情 | |
| (XXIII) | 37728 | diethyl 2-[([(2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propanoyl]sulfanyl)methyl]malonate | C22H39NO7SSi | 详情 | 详情 | |
| (XXIV) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |
| (XXV) | 37729 | [(2-chloro-2-oxoacetyl)oxy]methyl 2-methylpropanoate | C7H9ClO5 | 详情 | 详情 | |
| (XXVI) | 37730 | diethyl 2-[([(2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1-(2-[[(3-methylbutanoyl)oxy]methoxy]-2-oxoacetyl)-4-oxoazetidinyl]propanoyl]sulfanyl)methyl]malonate | C30H49NO12SSi | 详情 | 详情 | |
| (XXVII) | 37731 | diethyl 2-[([(2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1-(1-hydroxy-2-[[(3-methylbutanoyl)oxy]methoxy]-2-oxoethyl)-4-oxoazetidinyl]propanoyl]sulfanyl)methyl]malonate | C30H51NO12SSi | 详情 | 详情 | |
| (XXVIII) | 37732 | diethyl 2-[([(2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1-(1-chloro-2-[[(3-methylbutanoyl)oxy]methoxy]-2-oxoethyl)-4-oxoazetidinyl]propanoyl]sulfanyl)methyl]malonate | C30H50ClNO11SSi | 详情 | 详情 | |
| (XXIX) | 37733 | (isobutyryloxy)methyl (5R,6S,7S)-7-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-5-methyl-4,8-dioxo-3-thia-1-azabicyclo[4.2.0]octane-2-carboxylate | C21H35NO7SSi | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XXXV)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.
| 【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 |