4-nitrobenzyl (4R)-2-diazo-4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate -Drug Synthesis Database

【结构式】

【分子编号】38749

【品名】4-nitrobenzyl (4R)-2-diazo-4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate

【CA登记号】

【分子式】C₁₇H₁₈N₄O₇

【分子量】390.35268

【元素组成】C 52.31% H 4.65% N 14.35% O 28.69%

与该中间体有关的原料药合成路线共 4 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1

该中间体在本合成路线中的序号：(XVII)

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2

该中间体在本合成路线中的序号：(I)

The cyclization of the diazo azetidinone (I) by means of a Rhodium catalyst in dichloromethane gives the -methyl-2-oxocarbapenam derivative (II), which is treated with methanesulfonic anhydride and TEA in dichloromethane yielding the enol triflate (II). The silylation of the OH group of (III) with triethylsilyl triflate and TEA affords the silyl ether (IV), which is condensed with the fluorenone boronic acid (V) by means of KOH and a Pd catalyst giving the adduct (VI) (1). The mesylation of (VI) with MsCl and TEA in dichloromethane, followed by reaction with NaI in acetone yields the iodomethyl compound (VII), which is condensed with 2-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)acetamide triflate (VIII) by means of silver triflate in THF/acetonitrile to afford the protected intermediate (IX). Finally, this compound is deprotected first with HCl in THF/water and then by hydrogenation with H2 over Rh/C. The intermediate 2-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)acetamide triflate (VIII) has been obtained as follows: The condensation of 1,4-diazabicyclo[2.2.2]octane (X) with 2-bromoacetamide (XI) in acetonitrile gives 2-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)acetamide bromide (XII), which is then treated with silver triflate in acetonitrile/methanol to yield (VIII).

参考文献中间体

合成目标

【1】 DiNinno, F.; Laub, J.B.; Greenlee, M.L.; Rouen, G.P.; Hammond, G.G.; Sundelof, J.G.; Hammond, M.L.; Huber, J.L.; Dicationic 2-fluorenylcarbapenems: Potent anti-MRS agents with improved solubility and pharmacokinetic properties. Bioorg Med Chem Lett 1999, 9, 22, 3225.
【2】 Greenlee, M.L.; Dininno, F.P.; Hammond, M.L. (Merck & Co., Inc.); 1-beta-Methyl-carbapenem, compsns. containing same and methods of use. US 5451579; WO 9521841 .

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)	38749	4-nitrobenzyl (4R)-2-diazo-4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate		C₁₇H₁₈N₄O₇	详情	详情
(II)	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
(III)	38750	4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(trifluoromethyl)sulfonyl]oxy]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₁₈H₁₇F₃N₂O₉S	详情	详情
(IV)	38751	4-nitrobenzyl (4R,5R,6S)-4-methyl-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-3-[[(trifluoromethyl)sulfonyl]oxy]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₂₄H₃₁F₃N₂O₉SSi	详情	详情
(V)	38752	7-(hydroxymethyl)-9-oxo-9H-fluoren-3-ylboronic acid		C₁₄H₁₁BO₄	详情	详情
(VI)	38753	4-nitrobenzyl (4S,5R,6S)-3-[7-(hydroxymethyl)-9-oxo-9H-fluoren-3-yl]-4-methyl-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₃₇H₄₀N₂O₈Si	详情	详情
(VII)	38754	4-nitrobenzyl (4S,5R,6S)-3-[7-(iodomethyl)-9-oxo-9H-fluoren-3-yl]-4-methyl-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₃₇H₃₉IN₂O₇Si	详情	详情
(VIII)	30156	1-(2-amino-2-oxoethyl)-4-aza-1-azoniabicyclo[2.2.2]octane trifluoromethanesulfonate		C₉H₁₆F₃N₃O₄S	详情	详情
(IX)	38755	1-(2-amino-2-oxoethyl)-4-[[6-((4S,5R,6S)-4-methyl-2-[[(4-nitrobenzyl)oxy]carbonyl]-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-en-3-yl)-9-oxo-9H-fluoren-2-yl]methyl]-1,4-diazoniabicyclo[2.2.2]octane di(trifluoromethanesulfonate		C₄₇H₅₅F₆N₅O₁₄S₂Si	详情	详情
(X)	28358	1,4-diazabicyclo[2.2.2]octane	280-57-9	C₆H₁₂N₂	详情	详情
(XI)	38747	2-bromoacetamide	683-57-8	C₂H₄BrNO	详情	详情
(XII)	38748	1-(2-amino-2-oxoethyl)-4-aza-1-azoniabicyclo[2.2.2]octane bromide		C₈H₁₆BrN₃O	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

Cyclization of azetidinone (I) by means of catalyst Rh2(OAc)4 in toluol provides carbapenam (II), which is treated with SiO2 in EtOAc to produce epimerization to the alpha-methyl compound (III). Methylation of (III) with diazomethane in dioxane affords carbapenem (IV), which is hydrogenolyzed over Pd/C in EtOAc and finally saponified with KHCO3 in H2O to furnish the desired compound.

参考文献中间体

合成目标

【1】 Weishaupt, R.; Pfaendler, H.R.; Meffert, H.; Synthesis and biological activities of an alpha-methyl and a beta-methyl carbapenem and the corresponding unsubstituted compound. Bioorg Med Chem Lett 2000, 10, 12, 1389.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	38749	4-nitrobenzyl (4R)-2-diazo-4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate	C₁₇H₁₈N₄O₇	详情	详情
(II)	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
(III)	46695	4-nitrobenzyl (4S,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate	C₁₇H₁₈N₂O₇	详情	详情
(IV)	46696	4-nitrobenzyl (4S,5R,6S)-6-[(1R)-1-hydroxyethyl]-3-methoxy-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₁₈H₂₀N₂O₇	详情	详情

合成路线4

该中间体在本合成路线中的序号：(IV)

Imidazothiazole (I) is converted into methylsulfanyl derivative (II) by first reaction with EtMgBr in THF followed by treatment with MeSSO2Me. Lithiation of derivative (II) by means of BuLi in THF/hexane, followed by reaction with tributyltin chloride and LiHMDS, provides tributyltin derivative (III), which is then condensed with carbapenem derivative (VI) by means of Pd(dba)3, P(2-furyl)3 and ZnCl2 in NMP to afford (VII). (Derivative (VI) in turn can be obtained by first cyclization of the diazo compound (IV) by means of ZnBr2 and Rh2Oct4 in MeOAc/THF to provide bicyclic ketoester (V), which is finally treated with triflic anhydride (Tf2O) and DIEA in acetonitrile. The target product is finally obtained by first N-alkylation of the imidazothiazole ring of (VII) with iodoacetamide (VIII) in acetonitrile followed by deprotection of the carboxylic acid by hydrogenation over Pd/C inTHF/H2O.

参考文献中间体

合成目标

【2】 Lynch, J.E.; Liu, T.M.-H.; Volante, R.P. (Merck & Co., Inc.); Process for synthesizing carbapenem intermediates using a rhodium catalyst and Lewis acid. US 5493018 .
【1】 Sakakibara, S.; Takata, T.; Yamamoto, K.; Shitara, E.; Shibasaki, Y.; Shimizu, A.; Komiya, I.; CP5068, a new carbapenem: Synthesis and structure-activity relationships. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1236.

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)	47193	7-iodoimidazo[5,1-b][1,3]thiazole		C₅H₃IN₂S	详情	详情
(II)	47194	7-(methylsulfanyl)imidazo[5,1-b][1,3]thiazole; imidazo[5,1-b][1,3]thiazol-7-yl methyl sulfide		C₆H₆N₂S₂	详情	详情
(III)	47195	7-(methylsulfanyl)-2-(tributylstannyl)imidazo[5,1-b][1,3]thiazole; methyl 2-(tributylstannyl)imidazo[5,1-b][1,3]thiazol-7-yl sulfide		C₁₈H₃₂N₂S₂Sn	详情	详情
(IV)	38749	4-nitrobenzyl (4R)-2-diazo-4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate		C₁₇H₁₈N₄O₇	详情	详情
(V)	22575	4-nitrobenzyl (2R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate		C₁₇H₁₈N₂O₇	详情	详情
(VI)	38750	4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(trifluoromethyl)sulfonyl]oxy]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₁₈H₁₇F₃N₂O₉S	详情	详情
(VII)	47196	4-nitrobenzyl (4S,5R)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[7-(methylsulfanyl)imidazo[5,1-b][1,3]thiazol-2-yl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₂₃H₂₂N₄O₆S₂	详情	详情
(VIII)	47197	2-iodoacetamide	144-48-9	C₂H₄INO	详情	详情

Extended Information