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【结 构 式】 
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【分子编号】28358 【品名】1,4-diazabicyclo[2.2.2]octane 【CA登记号】280-57-9 |
【 分 子 式 】C6H12N2 【 分 子 量 】112.17476 【元素组成】C 64.24% H 10.78% N 24.97% |
合成路线1
该中间体在本合成路线中的序号：(X)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).
| 【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2
该中间体在本合成路线中的序号：(V)The mesylation of carbapenem (I) with MsCl and TEA in dichloromethane, followed by reaction with NaI in acetone yields the iodomethyl compound (II), which is condensed with 2-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)acetamide triflate (III) by means of silver triflate in THF/acetonitrile to afford the protected intermediate (IV). 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 (III) has been obtained as follows: The condensation of 1,4-diazabicyclo[2.2.2]octane (V) with 2-bromoacetamide (VI) in acetonitrile gives 2-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)acetamide bromide (VII), which is then treated with silver triflate in acetonitrile/methanol to yield (III).
| 【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) | 38629 | 4-nitrobenzyl (5R,6S)-3-[7-(hydroxymethyl)-9-oxo-9H-fluoren-3-yl]-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C36H38N2O8Si | 详情 | 详情 | |
| (II) | 38745 | 4-nitrobenzyl (5R,6S)-3-[7-(iodomethyl)-9-oxo-9H-fluoren-3-yl]-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C36H37IN2O7Si | 详情 | 详情 | |
| (III) | 30156 | 1-(2-amino-2-oxoethyl)-4-aza-1-azoniabicyclo[2.2.2]octane trifluoromethanesulfonate | C9H16F3N3O4S | 详情 | 详情 | |
| (IV) | 38746 | 1-(2-amino-2-oxoethyl)-4-[[6-((5R,6S)-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) | C46H53F6N5O14S2Si | 详情 | 详情 | |
| (V) | 28358 | 1,4-diazabicyclo[2.2.2]octane | 280-57-9 | C6H12N2 | 详情 | 详情 |
| (VI) | 38747 | 2-bromoacetamide | 683-57-8 | C2H4BrNO | 详情 | 详情 |
| (VII) | 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：(XI)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4
该中间体在本合成路线中的序号：(II)The reaction of 2-amino-6-chloropurine (I) with 1,4-diazabicyclo[2.2.2]octane (II) in DMSO gives 1-(2-aminopurin-6-yl)-4-aza-1-azoniabicyclo[2.2.2]octane chloride (II), which is condensed with cyclohexylmethanol (III) by means of NaH in DMSO.
| 【1】 Lembicz, N.K.; et al.; Facilitation of displacements at the 6-position of purines by the use of 1,4-diazabicyclo[2.2.2]octane as leaving group. J Chem Soc - Perkins Trans I 1997, 3, 185. |
| 【2】 Boyle, F.T.; Arris, C.E.; Calvert, A.H.; et al.; Identification of novel purine and pyrimidine cyclin-dependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles. J Med Chem 2000, 43, 15, 2797. |
| 【3】 Boyle, F.T.; Curtin, N.J.; Calvert, A.H.; Jewsbury, P.J.; Endicott, J.A.; Noble, M.E.M.; Griffin, R.J.; Golding, B.T.; Newell, D.R. (University of Newcastle upon Tyne); Cyclin dependent kinase inhibiting purine derivs.. EP 1017394; WO 9902162 . |
| 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) | 11644 | 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine | 10310-21-1 | C5H4ClN5 | 详情 | 详情 |
| (II) | 28358 | 1,4-diazabicyclo[2.2.2]octane | 280-57-9 | C6H12N2 | 详情 | 详情 |
| (III) | 28359 | 1-(2-amino-9H-purin-6-yl)-4-aza-1-azoniabicyclo[2.2.2]octane | C11H16N7 | 详情 | 详情 | |
| (IV) | 28360 | cyclohexylmethanol | 100-49-2 | C7H14O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XIX)Intramolecular cyclization of (XIII) in the presence of potassium tert-butoxide affords a racemic mixture of syn adducts, which can be resolved by chiral chromatography to provide the target (R,R)-isomer (XIV). Methyl ether cleavage in (XIV) employing methanesulfonic acid affords phenol (XV). This is then alkylated with 4-chlorobutanol (XVI) yielding ether (XVII). After conversion of the primary hydroxyl group of (XVII) into mesylate (XVIII), condensation with diazabicyclo[2.2.2]octane produces the title ammonium salt
| 【1】 Manning, R.E.; Tremont, S.J.; Glenn, K.C.; Keller, B.T. (Pharmacia Corp.); Combination therapy for the prophylaxis and treatment of hyperlipidemic conditions and disorders. WO 0168096 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 59715 | 2-butyl-2-({[4-(dimethylamino)-2-(4-methoxybenzyl)phenyl]sulfonyl}methyl)hexanal | C27H39NO4S | 详情 | 详情 | |
| (XIV) | 59717 | (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-1lambda~6~-benzothiepine-1,1-dione | C27H39NO4S | 详情 | 详情 | |
| (XV) | 59718 | (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-1lambda~6~-benzothiepine-1,1-dione | C26H37NO4S | 详情 | 详情 | |
| (XVI) | 22336 | 4-chloro-1-butanol | 928-51-8 | C4H9ClO | 详情 | 详情 |
| (XVII) | 59719 | (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-[4-(4-hydroxybutoxy)phenyl]-2,3,4,5-tetrahydro-1H-1lambda~6~-benzothiepine-1,1-dione | C30H45NO5S | 详情 | 详情 | |
| (XVIII) | 59720 | 4-{4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-1lambda~6~-benzothiepin-5-yl]phenoxy}butyl methanesulfonate | C31H47NO7S2 | 详情 | 详情 | |
| (XIX) | 28358 | 1,4-diazabicyclo[2.2.2]octane | 280-57-9 | C6H12N2 | 详情 | 详情 |