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【结 构 式】 
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【药物名称】AG-5473 【化学名称】4-Cyclopentyl-13-[2-oxo-2-(3,4,5-trimethoxyphenyl)acetyl]-4,7,13-triazatricyclo[7.3.1.0(2,7)]tridec-2-ene-5,8-dione 【CA登记号】255910-29-3 【 分 子 式 】C26H31N3O7 【 分 子 量 】497.55287 |
【开发单位】Agouron (Originator) 【药理作用】Cognition Disorders, Treatment of, NEUROLOGIC DRUGS, Neurotrophic Agents, Peptidylprolyl Isomerase Inhibitors |
合成路线1
Pyridine-2,6-dicarboxylic acid (I) was hydrogenated to the corresponding piperidine, which was subsequently protected as the N-benzyloxycarbonyl derivative (II). The dicarboxylic acid (II) was converted into the cyclic anhydride (III) upon heating with Ac2O. Anhydride (III) was then dissolved in MeOH to produce the mono ester (IV). The electrochemical oxidation of acid (IV) in methanol gave rise to the methoxypiperidine (V). The methoxy group of (V) was then displaced by allyl trimethylsilane (VI) in the presence of TiCl4 to furnish the allyl piperidine (VII), which was further oxidized to diol (VIII) employing OsO4 and N-methylmorpholine-N-oxide. Then, oxidative cleavage of diol (VIII) by means of NaIO4 gave aldehyde (IX). After aldehyde (IX) ketalization with trimethyl orthoformate, basic hydrolysis of the methyl ester group provided carboxylic acid (X). This was activated as the mixed anhydride with isobutyl chloroformate and then treated with ammonia to afford amide (XI). The cyclization of the ketal amide (XI) upon treatment with pyridinium p-toluenesulfonate gave rise to the bicyclic derivative (XII). Upon bromination of (XII) in the presence of NaOMe, the bicyclic compound (XII) rearranged to the ketal lactam (XIII). Alkylation of the lactam nitrogen of (XIII) with ethyl bromoacetate and NaH produced ester (XIV), which was then hydrolyzed to the carboxylic acid (XV).
| 【1】 Tada, H.; Kalish, V.; Kato, S.; Villafranca, J.E.; Tatlock, J.H.; Linton, M.A.; Kawakami, H. (Agouron Pharmaceuticals, Inc.); Cpds., compsns., and methods for stimulating neuronal growth and elongation. WO 0004020 . |
| 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) | 43290 | 2,6-pyridinedicarboxylic acid | 499-83-2 | C7H5NO4 | 详情 | 详情 |
| (II) | 43291 | 1-[(benzyloxy)carbonyl]-2,6-piperidinedicarboxylic acid | C15H17NO6 | 详情 | 详情 | |
| (III) | 43292 | benzyl 2,4-dioxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate | C15H15NO5 | 详情 | 详情 | |
| (IV) | 43293 | 1-[(benzyloxy)carbonyl]-6-(methoxycarbonyl)-2-piperidinecarboxylic acid | C16H19NO6 | 详情 | 详情 | |
| (V) | 43294 | 1-benzyl 2-methyl 6-methoxy-1,2-piperidinedicarboxylate | C16H21NO5 | 详情 | 详情 | |
| (VI) | 15775 | Allyltrimethylsilane; allyl(trimethyl)silane | 762-72-1 | C6H14Si | 详情 | 详情 |
| (VII) | 43295 | 1-benzyl 2-methyl (2S,6R)-6-allyl-1,2-piperidinedicarboxylate | C18H23NO4 | 详情 | 详情 | |
| (VIII) | 43296 | 1-benzyl 2-methyl (2S,6R)-6-(2,3-dihydroxypropyl)-1,2-piperidinedicarboxylate | C18H25NO6 | 详情 | 详情 | |
| (IX) | 43297 | 1-benzyl 2-methyl (2S,6R)-6-(2-oxoethyl)-1,2-piperidinedicarboxylate | C17H21NO5 | 详情 | 详情 | |
| (X) | 43298 | (2S,6R)-1-[(benzyloxy)carbonyl]-6-(2,2-dimethoxyethyl)-2-piperidinecarboxylic acid | C18H25NO6 | 详情 | 详情 | |
| (XI) | 43299 | benzyl (2S,6R)-2-(aminocarbonyl)-6-(2,2-dimethoxyethyl)-1-piperidinecarboxylate | C18H26N2O5 | 详情 | 详情 | |
| (XII) | 43300 | benzyl 2-oxo-3,10-diazabicyclo[4.3.1]dec-4-ene-10-carboxylate | C16H18N2O3 | 详情 | 详情 | |
| (XIII) | 43301 | benzyl 2-(dimethoxymethyl)-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate | C18H24N2O5 | 详情 | 详情 | |
| (XIV) | 43302 | benzyl 2-(dimethoxymethyl)-3-(2-ethoxy-2-oxoethyl)-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate | C22H30N2O7 | 详情 | 详情 | |
| (XV) | 43303 | 2-[9-[(benzyloxy)carbonyl]-2-(dimethoxymethyl)-4-oxo-3,9-diazabicyclo[3.3.1]non-3-yl]acetic acid | C20H26N2O7 | 详情 | 详情 |
合成路线2
Carboxylic acid (XV) was coupled with cyclopentylamine (XVI) using EDC and HOBt to produce amide (XVII), which was cyclized to the fused pyrazinone derivative (XVIII) by treatment with pyridinium p-toluenesulfonate in toluene. The benzyloxycarbonyl group of (XVIII) was then removed by catalytic hydrogenation to give amine (XIX). This was finally coupled with (3,4,5-trimethoxyphenyl)glyoxylic acid (XX) to yield the title amide.
| 【1】 Reich, S.; Guo, C.X.; Villafranca, E.; Showalter, R.; Dong, L.; A concise synthesis of AG5473/5507 utilizing N-acyliminium ion chemistry. Tetrahedron Lett 2000, 41, 28, 5307. |
| 【2】 Tada, H.; Kalish, V.; Kato, S.; Villafranca, J.E.; Tatlock, J.H.; Linton, M.A.; Kawakami, H. (Agouron Pharmaceuticals, Inc.); Cpds., compsns., and methods for stimulating neuronal growth and elongation. WO 0004020 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XV) | 43303 | 2-[9-[(benzyloxy)carbonyl]-2-(dimethoxymethyl)-4-oxo-3,9-diazabicyclo[3.3.1]non-3-yl]acetic acid | C20H26N2O7 | 详情 | 详情 | |
| (XVI) | 28850 | cyclopentanamine | 1003-03-8 | C5H11N | 详情 | 详情 |
| (XVII) | 43313 | benzyl 3-[2-(cyclopentylamino)-2-oxoethyl]-2-(dimethoxymethyl)-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate | C25H35N3O6 | 详情 | 详情 | |
| (XVIII) | 43314 | benzyl 4-cyclopentyl-5,8-dioxo-4,7,13-triazatricyclo[7.3.1.0(2,7)]tridec-2-ene-13-carboxylate | C23H27N3O4 | 详情 | 详情 | |
| (XIX) | 43315 | 4-cyclopentyl-4,7,13-triazatricyclo[7.3.1.0(2,7)]tridec-2-ene-5,8-dione | C15H21N3O2 | 详情 | 详情 | |
| (XX) | 30046 | 2-oxo-2-(3,4,5-trimethoxyphenyl)acetic acid | C11H12O6 | 详情 | 详情 |
合成路线3
The synthesis of the intermediate carboxylic acid (XV) has been reported by an alternative procedure. The cyclic anhydride (III) was condensed with glycine ethyl ester (XXI) in refluxing Ac2O, yielding the cyclic imide (XXII). Reduction of the imide (XXII) with NaBH4 produced the aminal (XXIII), which was subsequently converted to the more reactive acetoxyamide (XXIV). Boron trifluoride-catalyzed addition of propargyl trimethylsilane (XXV) to the acetoxyamide (XXIV) gave rise to allene (XXVI). This underwent smooth ozonolysis to the aldehyde (XXVII). After protection of the aldehyde (XXVII) as the dimethyl acetal (XIV), hydrolysis of the ethyl ester group gave the intermediate carboxylic acid (XV).
| 【1】 Reich, S.; Guo, C.X.; Villafranca, E.; Showalter, R.; Dong, L.; A concise synthesis of AG5473/5507 utilizing N-acyliminium ion chemistry. Tetrahedron Lett 2000, 41, 28, 5307. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 43292 | benzyl 2,4-dioxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate | C15H15NO5 | 详情 | 详情 | |
| (XIV) | 43302 | benzyl 2-(dimethoxymethyl)-3-(2-ethoxy-2-oxoethyl)-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate | C22H30N2O7 | 详情 | 详情 | |
| (XV) | 43303 | 2-[9-[(benzyloxy)carbonyl]-2-(dimethoxymethyl)-4-oxo-3,9-diazabicyclo[3.3.1]non-3-yl]acetic acid | C20H26N2O7 | 详情 | 详情 | |
| (XXI) | 10309 | ethyl 2-aminoacetate; Glycine ethyl ester | 459-73-4 | C4H9NO2 | 详情 | 详情 |
| (XXII) | 43307 | benzyl 3-(2-ethoxy-2-oxoethyl)-2,4-dioxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate | C19H22N2O6 | 详情 | 详情 | |
| (XXIII) | 43308 | benzyl 3-(2-ethoxy-2-oxoethyl)-2-hydroxy-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate | C19H24N2O6 | 详情 | 详情 | |
| (XXIV) | 43309 | benzyl 2-(acetoxy)-3-(2-ethoxy-2-oxoethyl)-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate | C21H26N2O7 | 详情 | 详情 | |
| (XXV) | 43310 | trimethyl(2-propynyl)silane | 13361-64-3 | C6H12Si | 详情 | 详情 |
| (XXVI) | 43311 | benzyl 3-(2-ethoxy-2-oxoethyl)-2-oxo-4-(1,2-propadienyl)-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate | C22H26N2O5 | 详情 | 详情 | |
| (XXVII) | 43312 | benzyl 3-(2-ethoxy-2-oxoethyl)-2-formyl-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate | C20H24N2O6 | 详情 | 详情 |