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【结 构 式】 
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【分子编号】30123 【品名】6-(2-hydroxyethyl)-2H-naphtho[1,8-cd]isothiazole-1,1(2H)-dione 【CA登记号】 |
【 分 子 式 】C12H11NO3S 【 分 子 量 】249.29028 【元素组成】C 57.82% H 4.45% N 5.62% O 19.25% S 12.86% |
合成路线1
该中间体在本合成路线中的序号：(VII)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).
| 【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：(VII)An alternative procedure starting from 2-(1-naphthyl)ethyl acetate (IX) consisted of sulfonation, followed by treatment of the resulting sulfonate salt (X) with SOCl2 and DMF to yield sulfonyl chloride (XI). Nitration of (XI) at -20 C produced a mixture of nitro derivatives, from which the major isomer (XII) was isolated by crystallization. Subsequent reaction of (XII) with methanolic ammo-nia gave nitro sulfonamide (XIII), which was cyclized in the presence of Cs2CO3 to afford the naphthosultam (VII).
| 【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. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 30123 | 6-(2-hydroxyethyl)-2H-naphtho[1,8-cd]isothiazole-1,1(2H)-dione | C12H11NO3S | 详情 | 详情 | |
| (IX) | 30126 | 2-(1-naphthyl)ethyl acetate | C14H14O2 | 详情 | 详情 | |
| (X) | 30127 | potassium 4-[2-(acetoxy)ethyl]-1-naphthalenesulfonate | C14H13KO5S | 详情 | 详情 | |
| (XI) | 30128 | 2-[4-(chlorosulfonyl)-1-naphthyl]ethyl acetate | C14H13ClO4S | 详情 | 详情 | |
| (XII) | 30129 | 2-[4-(chlorosulfonyl)-5-nitro-1-naphthyl]ethyl acetate | C14H12ClNO6S | 详情 | 详情 | |
| (XIII) | 30130 | 4-(2-hydroxyethyl)-8-nitro-1-naphthalenesulfonyl chloride | C12H10ClNO5S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)Sulfonation of methyl naphthylacetate (XIV) gave sulfonate (XV), which was nitrated at -20 C to produce (XVI) as the major isomer. Reduction of the nitro group of (XVI) employing iron and H2SO4 yielded aminosulfonate (XVII), which was cyclized by means of POCl3 to give sultam (XVIII). The ester group of (XVIII) was finally reduced to alcohol (VII) with LiAlH4.
| 【1】 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 |
|---|---|---|---|---|---|---|
| (VII) | 30123 | 6-(2-hydroxyethyl)-2H-naphtho[1,8-cd]isothiazole-1,1(2H)-dione | C12H11NO3S | 详情 | 详情 | |
| (XIV) | 30131 | methyl 2-(1-naphthyl)acetate | 2876-78-0 | C13H12O2 | 详情 | 详情 |
| (XV) | 30132 | potassium 4-(2-methoxy-2-oxoethyl)-1-naphthalenesulfonate | C13H11KO5S | 详情 | 详情 | |
| (XVI) | 30133 | 4-(2-methoxy-2-oxoethyl)-8-nitro-1-naphthalenesulfonic acid | C13H11NO7S | 详情 | 详情 | |
| (XVII) | 30134 | sodium 8-amino-4-(2-methoxy-2-oxoethyl)-1-naphthalenesulfonate | C13H12NNaO5S | 详情 | 详情 | |
| (XVIII) | 30135 | methyl 2-(1,1-dioxo-1,2-dihydro-2H-naphtho[1,8-cd]isothiazol-6-yl)acetate | C13H11NO4S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VIII)The chlorosulfonation of 1-methylnaphthalene (I) with chlorosulfonic acid gives 4-methylnaphthalen-1-ylsulfonyl chloride (II), which is nitrated with nitric and sulfuric acids yielding the 8-nitro derivative (III). The reaction of (III) with benzylamine and K2CO3 affords the corresponding sulfonamide (IV), which is cyclized by hydrogenation with formic and Pd/C giving the methylnaphthosultam (VI). The reaction of (VI) with lithium diisopropylamide (LDA) and CO2 yields the carboxymethyl derivative (VII), which is reduced with NaBH4 and BF3 ethearate affording the 2-hydroxyethyl derivative (VIII). Finally, this compound is condensed with 1-(2-amino-2-oxoethyl)-4-aza-1-azoniabicyclo[2.2.2]octane trifluoromethanesulfonate (IX) by means of trifluromethanesulfonic anhydride in acetonitrile to provide the desired naphthosultam intermediate (X). Compound (XI) is obtained by condensation of quinuclidine (XI) with chloroacetamide (XII) by means of sodium trilfluoromethanesulfonate in refluxing acetonitrile. Alternatively, 4-methylnaphthalen-1-ylsulfonyl chloride (II) can be condensed with diethylamine giving the corresponding sulfonamide (XIII), which is nitrated with nitric and sulfuric acids yielding the 8-nitro derivative (XIV). Finally, this compound is cyclized to the previously reported naphthosultam (VI) by hydrogenation with H2 or potassium formate over Pd/C.
| 【1】 Miller, R.A.; et al.; A practical an efficient preparation of the releasable naphthosultan side chain of a novel anti -MRSA carbapenem. J Org Chem 2000, 65, 5, 1399. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 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) | 35501 | 4-methyl-8-nitro-1-naphthalenesulfonyl chloride | C11H8ClNO4S | 详情 | 详情 | |
| (IV) | 35500 | N-benzyl-4-methyl-8-nitro-1-naphthalenesulfonamide | C18H16N2O4S | 详情 | 详情 | |
| (V) | 35503 | 2-benzyl-6-methyl-2H-naphtho[1,8-cd]isothiazole-1,1(2H)-dione | C18H15NO2S | 详情 | 详情 | |
| (VI) | 30121 | 6-methyl-2H-naphtho[1,8-cd]isothiazole-1,1(2H)-dione | C11H9NO2S | 详情 | 详情 | |
| (VII) | 30122 | 2-(1,1-dioxo-1,2-dihydro-2H-naphtho[1,8-cd]isothiazol-6-yl)acetic acid | C12H9NO4S | 详情 | 详情 | |
| (VIII) | 30123 | 6-(2-hydroxyethyl)-2H-naphtho[1,8-cd]isothiazole-1,1(2H)-dione | C12H11NO3S | 详情 | 详情 | |
| (IX) | 30156 | 1-(2-amino-2-oxoethyl)-4-aza-1-azoniabicyclo[2.2.2]octane trifluoromethanesulfonate | C9H16F3N3O4S | 详情 | 详情 | |
| (X) | 35505 | 1-(2-amino-2-oxoethyl)-4-[2-(1,1-dioxo-1,2-dihydro-2H-naphtho[1,8-cd]isothiazol-6-yl)ethyl]-1,4-diazoniabicyclo[2.2.2]octane di(trifluoromethanesulfonate) | C22H26F6N4O9S3 | 详情 | 详情 | |
| (XI) | 28358 | 1,4-diazabicyclo[2.2.2]octane | 280-57-9 | C6H12N2 | 详情 | 详情 |
| (XII) | 28964 | 2-chloroacetamide | 79-07-2 | C2H4ClNO | 详情 | 详情 |
| (XIII) | 35502 | 4-methyl-N,N-dipropyl-1-naphthalenesulfonamide | C17H23NO2S | 详情 | 详情 | |
| (XIV) | 35499 | 4-methyl-8-nitro-N,N-dipropyl-1-naphthalenesulfonamide | C17H22N2O4S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(III)Several improvements is the synthesis of 258849 have been developed: The reaction of stannatrane chloride (I) with Et2Zn and CH2I2 in HF gives iodomethylstannatrane (II), which is condensed with the naphthosultam (III) (intermediate (VII) in previous synthesis of 258849, scheme 25884901a) by means of K2CO3 in DMF yielding the stannatrane derivative (IV). The reaction of (IV) with Tf2O and lutidine in dichloromethane affords the corresponding ester (V), which is condensed with 1-(carbamoylmethyl)-4-aza-1-azoniabicyclo[2.2.2]octane trifluoromethanesulfonate (VI) (intermediate (XLV) in scheme 25884901g) giving the stannatrane derivative (VII). The condensation of intermediate (VII) with carbapenem triflate (VIII) (intermediate (XLI) in scheme 25884901f) by means of a Pd catalyst in acetonitrile provides the protected carbapenem derivative (IX) (intermediate (II) in scheme 25884902a). Finally, this compound is deprotected first with HCl to eliminate the silyl group and then with H2 over Pd/C to eliminate the p-nitrobenzyl group.
| 【1】 Jensen, M.S.; et al.; Synthesis of an anti-methicillin-resistant Staphylococcus aureus (MRSA) carbapenem via stannatrane-mediated Stille coupling. Org Lett 2000, 2, 8, 1081. |
| 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) | 36871 | 5-chloro-1-aza-5-stannabicyclo[3.3.3]undecane | C9H18ClNSn | 详情 | 详情 | |
| (II) | 36872 | 5-(iodomethyl)-1-aza-5-stannabicyclo[3.3.3]undecane | C10H20INSn | 详情 | 详情 | |
| (III) | 30123 | 6-(2-hydroxyethyl)-2H-naphtho[1,8-cd]isothiazole-1,1(2H)-dione | C12H11NO3S | 详情 | 详情 | |
| (IV) | 36873 | 2-(1-aza-5-stannabicyclo[3.3.3]undec-5-ylmethyl)-6-(2-hydroxyethyl)-2H-naphtho[1,8-cd]isothiazole-1,1(2H)-dione | C22H30N2O3SSn | 详情 | 详情 | |
| (V) | 36874 | 2-[2-(1-aza-5-stannabicyclo[3.3.3]undec-5-ylmethyl)-1,1-dioxo-1,2-dihydro-2H-naphtho[1,8-cd]isothiazol-6-yl]ethyl trifluoromethanesulfonate | C23H29F3N2O5S2Sn | 详情 | 详情 | |
| (VI) | 30156 | 1-(2-amino-2-oxoethyl)-4-aza-1-azoniabicyclo[2.2.2]octane trifluoromethanesulfonate | C9H16F3N3O4S | 详情 | 详情 | |
| (VII) | 36875 | 1-(2-amino-2-oxoethyl)-4-[2-[2-(1-aza-5-stannabicyclo[3.3.3]undec-5-ylmethyl)-1,1-dioxo-1,2-dihydro-2H-naphtho[1,8-cd]isothiazol-6-yl]ethyl]-1,4-diazoniabicyclo[2.2.2]octane | C30H45N5O3SSn | 详情 | 详情 | |
| (VIII) | 30153 | (4R,5R,6S)-4-methyl-2-[2-(4-nitrobenzyloxy)acetyl]-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-en-3-yl trifluoromethanesulfonate | C24H31F3N2O9SSi | 详情 | 详情 | |
| (IX) | 30160 | 1-(2-amino-2-oxoethyl)-4-(2-[2-[((4S,5R,6S)-4-methyl-2-[2-(4-nitrobenzyloxy)acetyl]-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-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)-1,4-diazonia | C46H58F6N6O15S3Si | 详情 | 详情 |