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【结 构 式】 
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【分子编号】43301 【品名】benzyl 2-(dimethoxymethyl)-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate 【CA登记号】 |
【 分 子 式 】C18H24N2O5 【 分 子 量 】348.39904 【元素组成】C 62.05% H 6.94% N 8.04% O 22.96% |
合成路线1
该中间体在本合成路线中的序号：(XIII)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
该中间体在本合成路线中的序号：(XIII)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 |