6-[3-(trimethylsilyl)propyl]-2H-naphtho[1,8-cd]isothiazole-1,1(2H)-dione; 6-[2-[(trimethylsilyl)oxy]ethyl]-2H-naphtho[1,8-cd]isothiazole-1,1(2H)-dione -Drug Synthesis Database

【结构式】

【分子编号】23835

【品名】6-[3-(trimethylsilyl)propyl]-2H-naphtho[1,8-cd]isothiazole-1,1(2H)-dione; 6-[2-[(trimethylsilyl)oxy]ethyl]-2H-naphtho[1,8-cd]isothiazole-1,1(2H)-dione

【CA登记号】

【分子式】C₁₅H₁₉NO₃SSi

【分子量】321.4723

【元素组成】C 56.04% H 5.96% N 4.36% O 14.93% S 9.97% Si 8.74%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VIIIa)

Chlorosulfonylation of 1-methylnaphthalene (I) produced the sulfonyl chloride (II), which was converted to sulfonamide (III) upon treatment with diethylamine. Nitration of (III) produced nitro compound (IV), which was reductively cyclized to the naphthosultam (V). Carboxylation at the methyl group of (V) by means of CO2 and LDA afforded carboxylic acid (VI), and further reduction of (VI) with NaBH4 and BF3-Et2O gave alcohol (VII). Silylation of (VII) with either N,O-bistrimethylsilylacetamide or triethylsilyl chloride and imidazole produced the respective silyl ethers (VIIa) and (VIIb).

参考文献中间体

合成目标

【1】 Wilkening, R.R.; Wildonger, K.J.; Ratcliffe, R.W.; et al.; Synthesis and evaluation of anti-MRSA 1beta-methyl-2-(naphthosultamyl) methyl-carbapenems: Discovery of L-786,392. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-32.
【2】 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.
【3】 Wilkening, R.R.; Ratcliffe, R.W.; Blizzard, T.A. (Merck & Co., Inc.); Carbapenem antibacterial cpds., compsns. containing such cpds. and methods of treatment. EP 0906313; JP 1999508279; US 5756725; WO 9740048 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIIIa)	23835	6-[3-(trimethylsilyl)propyl]-2H-naphtho[1,8-cd]isothiazole-1,1(2H)-dione; 6-[2-[(trimethylsilyl)oxy]ethyl]-2H-naphtho[1,8-cd]isothiazole-1,1(2H)-dione		C₁₅H₁₉NO₃SSi	详情	详情
(VIIIb)	30125	6-[2-[(triethylsilyl)oxy]ethyl]-2H-naphtho[1,8-cd]isothiazole-1,1(2H)-dione		C₁₈H₂₅NO₃SSi	详情	详情
(I)	30117	1-methylnaphthalene	90-12-0	C₁₁H₁₀	详情	详情
(II)	30118	4-methyl-1-naphthalenesulfonyl chloride		C₁₁H₉ClO₂S	详情	详情
(III)	30119	N,N-diethyl-4-methyl-1-naphthalenesulfonamide		C₁₅H₁₉NO₂S	详情	详情
(IV)	30120	N,N-diethyl-4-methyl-8-nitro-1-naphthalenesulfonamide		C₁₅H₁₈N₂O₄S	详情	详情
(V)	30121	6-methyl-2H-naphtho[1,8-cd]isothiazole-1,1(2H)-dione		C₁₁H₉NO₂S	详情	详情
(VI)	30122	2-(1,1-dioxo-1,2-dihydro-2H-naphtho[1,8-cd]isothiazol-6-yl)acetic acid		C₁₂H₉NO₄S	详情	详情
(VII)	30123	6-(2-hydroxyethyl)-2H-naphtho[1,8-cd]isothiazole-1,1(2H)-dione		C₁₂H₁₁NO₃S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIIIa)

Mitsunobu coupling of hydroxymethyl carbapenem (XXX) with protected sultam (VIIIa) produced adduct (XLIII), which was desilylated with trifluoromethanesulfonic acid to give alcohol (XLIV). Conversion of (XLIV) to the corresponding triflate, followed by condensation with 1-carbamoylmethyl-4-aza-1-azoniabicyclo[2.2.2]octane trifluoromethanesulfonate (XLV) furnished bisam-monium salt (XLVI). Finally, cleavage of the allyl groups of (XLVI) in the presence of Pd catalyst yielded the title compound.

参考文献中间体

合成目标

【1】 Morgan, J.D.; Wilkenning, R.R.; Santorelli, G.M.; Parker, D.L. Jr.; Hammond, M.L.; Wildonger, K.J.; Ratcliffe, R.W.; Blizzard, T.A.; Waddell, S.T.; Synthesis and properties of 2-(naphthosultamyl)met. Bioorg Med Chem Lett 1999, 9, 5, 679.
【2】 Wilkening, R.R.; Ratcliffe, R.W.; Blizzard, T.A. (Merck & Co., Inc.); Carbapenem antibacterial cpds., compsns. containing such cpds. and methods of treatment. EP 0906313; JP 1999508279; US 5756725; WO 9740048 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VIIIa)	23835	6-[3-(trimethylsilyl)propyl]-2H-naphtho[1,8-cd]isothiazole-1,1(2H)-dione; 6-[2-[(trimethylsilyl)oxy]ethyl]-2H-naphtho[1,8-cd]isothiazole-1,1(2H)-dione	C₁₅H₁₉NO₃SSi	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
(XLIII)	30155	allyl (4S,5R,6S)-6-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-3-[[1,1-dioxo-6-[3-(trimethylsilyl)propyl]-2H-naphtho[1,8-cd]isothiazol-2(1H)-yl]methyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₃₄H₄₂N₂O₈SSi	详情	详情
(XLIV)	23837	allyl (4S,5R,6S)-6-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-3-[[6-(2-hydroxyethyl)-1,1-dioxo-2H-naphtho[1,8-cd]isothiazol-2(1H)-yl]methyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₃₀H₃₂N₂O₉S	详情	详情
(XLV)	30156	1-(2-amino-2-oxoethyl)-4-aza-1-azoniabicyclo[2.2.2]octane trifluoromethanesulfonate	C₉H₁₆F₃N₃O₄S	详情	详情
(XLVI)	30157	1-[2-(2-[[(4S,5R,6S)-2-[(allyloxy)carbonyl]-6-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]methyl]-1,1-dioxo-1,2-dihydro-2H-naphtho[1,8-cd]isothiazol-6-yl)ethyl]-4-(2-amino-2-oxoethyl)-1,4-diazonia	C₄₀H₄₇F₆N₅O₁₅S₃	详情	详情

Extended Information