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【结 构 式】 
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【分子编号】18543 【品名】4-[(1H-1,2,3-benzotriazol-1-yloxy)carbonyl]-2-chloro-5-methoxyphenylamine; 4-[(1H-1,2,3-benzotriazol-1-yloxy)carbonyl]-2-chloro-5-methoxyaniline 【CA登记号】 |
【 分 子 式 】C14H11ClN4O3 【 分 子 量 】318.7192 【元素组成】C 52.76% H 3.48% Cl 11.12% N 17.58% O 15.06% |
合成路线1
该中间体在本合成路线中的序号：(XVI)The intermediate amine (XIV) was prepared by several synthetic routes. Condensation of methylene cyclohexane (I) with chlorosulfonyl isocyanate produced b-lactam (II). Treatment of (II) with H2SO4 in boiling MeOH gave ester (III), and subsequent reductive alkylation with formaldehyde and formic acid afforded dimethylamino compound (IV). Ester reduction with LiAlH4 in THF provided alcohol (V), which was condensed with phthalimide (VI) under Mitsunobu conditions to yield N-alkylated phthalimide (VII). Then, phthalimide hydrolysis with methylamine in MeOH provided amine (XIV). Alternatively, cyclohexylideneacetate (VIII) was treated with methanolic NH3 at 140 C in a sealed tube to give aminoacetamide (IX). This compound could also be obtained by heating b-lactam (II) with aqueous ammonia at 150 C. Subsequent alkylation of (IX) with iodomethane provided dimethylamino compound (X), which was reduced with vitride in refluxing toluene to give (XIV). Starting from cyclohexylideneacetonitrile (XI), treatment with NH3 at 100 C in a sealed tube gave aminonitrile (XII). This nitrile could also be prepared by dehydration of amide (X) with POCl3. Reductive alkylation of the primary amine of (XII) with HCHO in the presence of NaBH3CN gave dimethylamino nitrile (XIII). Then, hydrogenation of nitrile (XIII) in the presence of PtO2 provided amine (XIV). Finally, condensation of amine (XIV) with 1-benzotriazolyl ester (XVI), obtained by treatment of benzoic acid (XV) with 1-hydroxybenzotriazole and DCC, gave the title benzamide.
| 【1】 Suzuki, T.; Imanishi, N.; Itahana, H.; Watanuki, S.; Miyata, K.; Ohta, M.; Nakahara, H.; Yamagiwa, Y.; Mase, T.; Novel 5-hydroxytryptamine 4 (5-HT4) receptor agonists. Synthesis and gastroprokinetic activity of 4-amino-N-[2-(1-aminocycloalkan-1-yl)ethyl]-5-chloro-2-methoxybenzamides. Chem Pharm Bull 1998, 46, 7, 1116. |
| 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) | 18528 | 1-methylenecyclohexane | 1192-37-6 | C7H12 | 详情 | 详情 |
| (II) | 18529 | 1-azaspiro[3.5]nonan-2-one | C8H13NO | 详情 | 详情 | |
| (III) | 18530 | methyl 2-(1-aminocyclohexyl)acetate | C9H17NO2 | 详情 | 详情 | |
| (IV) | 18531 | methyl 2-[1-(dimethylamino)cyclohexyl]acetate | C11H21NO2 | 详情 | 详情 | |
| (V) | 18532 | 2-[1-(dimethylamino)cyclohexyl]-1-ethanol | C10H21NO | 详情 | 详情 | |
| (VI) | 12376 | Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione | 85-41-6 | C8H5NO2 | 详情 | 详情 |
| (VII) | 18534 | 2-[2-[1-(dimethylamino)cyclohexyl]ethyl]-1H-isoindole-1,3(2H)-dione | C18H24N2O2 | 详情 | 详情 | |
| (VIII) | 18535 | ethyl 2-cyclohexylideneacetate | C10H16O2 | 详情 | 详情 | |
| (IX) | 18536 | 2-(1-aminocyclohexyl)acetamide | C8H16N2O | 详情 | 详情 | |
| (X) | 18537 | 2-[1-(dimethylamino)cyclohexyl]acetamide | C10H20N2O | 详情 | 详情 | |
| (XI) | 18538 | 2-cyclohexylideneacetonitrile | C8H11N | 详情 | 详情 | |
| (XII) | 18539 | 2-(1-aminocyclohexyl)acetonitrile | C8H14N2 | 详情 | 详情 | |
| (XIII) | 18540 | 2-[1-(dimethylamino)cyclohexyl]acetonitrile | C10H18N2 | 详情 | 详情 | |
| (XIV) | 18541 | 1-(2-aminoethyl)-N,N-dimethylcyclohexanamine; N-[1-(2-aminoethyl)cyclohexyl]-N,N-dimethylamine | C10H22N2 | 详情 | 详情 | |
| (XV) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |
| (XVI) | 18543 | 4-[(1H-1,2,3-benzotriazol-1-yloxy)carbonyl]-2-chloro-5-methoxyphenylamine; 4-[(1H-1,2,3-benzotriazol-1-yloxy)carbonyl]-2-chloro-5-methoxyaniline | C14H11ClN4O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Benzamide (II) was prepared by treatment of the benzotriazolyl ester (I) with ammonium hydroxide in DMF. Dehydration of amide (II) with phosphorus oxychloride gave rise to nitrile (III), and subsequent addition of hydroxylamine to the cyano group of (III) furnished the N-hydroxybenzamidine (IV). Cyclization of (IV) with methyl 2-piperidineacetate (V) in the presence of NaH produced the oxadiazole compound (VI). Racemic (VI) was resolved employing L-ditoluoyltartaric acid, and the desired (S)-enantiomer was finally converted to the corresponding hydrochloride salt.
| 【1】 Suzuki, T.; Iwaoka, K.; Imanishi, N.; Nagakura, Y.; Miyata, K.; Nakahara, H.; Ohta, M.; Mase, T.; Synthesis of the selective 5-hydroxytryptamine 4 (5-HT4) receptor agonist (+)-(S)-2-chloro-5-methoxy-4-[5-(2-piperidylmethyl)-1,2,4-oxadiazol-3-yl]aniline. Chem Pharm Bull 1999, 47, 1, 120. |
| 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) | 18543 | 4-[(1H-1,2,3-benzotriazol-1-yloxy)carbonyl]-2-chloro-5-methoxyphenylamine; 4-[(1H-1,2,3-benzotriazol-1-yloxy)carbonyl]-2-chloro-5-methoxyaniline | C14H11ClN4O3 | 详情 | 详情 | |
| (II) | 51327 | 4-amino-5-chloro-2-methoxybenzamide | C8H9ClN2O2 | 详情 | 详情 | |
| (III) | 51328 | 4-amino-5-chloro-2-methoxybenzonitrile | C8H7ClN2O | 详情 | 详情 | |
| (IV) | 51329 | 4-amino-5-chloro-N'-hydroxy-2-methoxybenzenecarboximidamide | C8H10ClN3O2 | 详情 | 详情 | |
| (V) | 40753 | methyl 2-(2-piperidinyl)acetate | C8H15NO2 | 详情 | 详情 | |
| (VI) | 51330 | 2-chloro-5-methoxy-4-[5-(2-piperidinylmethyl)-1,2,4-oxadiazol-3-yl]aniline; 2-chloro-5-methoxy-4-[5-(2-piperidinylmethyl)-1,2,4-oxadiazol-3-yl]phenylamine | C15H19ClN4O2 | 详情 | 详情 |