-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】(5R,6S)-2-[6-(2-Aminopyridinium-1-ylmethyl)naphth-2-yl]-6-[1(R)-hydroxyethyl]carbapen-2-em-3-carboxylate inner salt

【CA登记号】

【分子式】C₂₅H₂₃N₃O₄

【分子量】429.47976

【开发单位】Merck & Co. (Originator)

【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Carbapenems

合成路线1 合成路线2

合成路线1

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.

参考文献中间体

【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

合成路线2

Reagent (XI) can be prepared as follows: Reduction of carboxylic acid (IX) with LiAlH4 in Et2O or BH3 in THF followed by alcohol protection with TBDMSCl in CH2Cl2 in the presence of TEA and DMAP yields silyl ether (X). Derivative (X) is finally converted into Grignard reagent (XI) by means of Mg in THF or, alternatively, by treatment with t-BuLi in THF followed by MgBr2 in CH2Cl2 in the presence of TEA.

参考文献中间体

【1】 Greenlee, M.L.; et al.; 2-Naphthylcarbapenems: Broad spectrum antibiotics with enhanced potency against MRSA. Bioorg Med Chem Lett 1999, 9, 19, 2893.
【2】 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
(IX)	42564	6-Bromo-2-naphthoic acid；(6-Bromonaphthalen-2-yl)acetic acid;6-Bromo-2-naphthalenecarboxylic acid	5773-80-8	C₁₁H₇BrO₂	详情	详情
(X)	42565	(6-bromo-2-naphthyl)methyl tert-butyl(dimethyl)silyl ether; [(6-bromo-2-naphthyl)methoxy](tert-butyl)dimethylsilane		C₁₇H₂₃BrOSi	详情	详情
(XI)	42559	bromo[6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-naphthyl]magnesium		C₁₇H₂₃BrMgOSi	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)