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【结 构 式】 
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【分子编号】12419 【品名】4-Amino-5-chloro-2-methoxybenzoic acid 【CA登记号】7206-70-4 |
【 分 子 式 】C8H8ClNO3 【 分 子 量 】201.60916 【元素组成】C 47.66% H 4% Cl 17.58% N 6.95% O 23.81% |
合成路线1
该中间体在本合成路线中的序号：(X)The condensation of 3-(4-fluorophenoxy)propionic acid (I) with 4-piperidone (II) by means of pivaloyl chloride and TEA in refluxing toluene gives the amide (III), which is submitted to oxidation with diacetoxyiodobenzene and KOH in methanol, yielding the hydroxy-dimethoxyketal (IV). The methylation of the OH group of (IV) with Me-I and Ag2O in DMF affords the corresponding methoxy compound (V), which is hydrolyzed with HOAc to provide the methoxypiperidone (VI). The reaction of (VI) with O-benzylhydroxylamine (VII) and pyridine in refluxing toluene gives the oxime (VIII), which is diastereoselectively reduced with BH3 in THF, yielding the cis-isomer (IX). Finally, this amine is condensed with 4-amino-5-chloro-2-methoxybenzoic acid (X) by means of ethyl chloroformate, TEA and HOBt in DMF to afford the target amide.
| 【1】 Cossy, J.; et al.; A short synthesis of cisapride: A gastrointestinal stimulant derived from cis-4-amino-3-methoxypiperidine. Tetrahedron Lett 2001, 42, 33, 5713. |
| 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) | 39121 | 3-(4-fluorophenoxy)propionic acid | 2967-70-6 | C9H9FO3 | 详情 | 详情 |
| (II) | 27115 | 4-piperidinone | 40064-34-4 | C5H9NO | 详情 | 详情 |
| (III) | 49549 | 1-[3-(4-fluorophenoxy)propanoyl]-4-piperidinone | C14H16FNO3 | 详情 | 详情 | |
| (IV) | 49550 | 3-(4-fluorophenoxy)-1-(3-hydroxy-4,4-dimethoxy-1-piperidinyl)-1-propanone | C16H22FNO5 | 详情 | 详情 | |
| (V) | 49551 | 3-(4-fluorophenoxy)-1-(3,4,4-trimethoxy-1-piperidinyl)-1-propanone | C17H24FNO5 | 详情 | 详情 | |
| (VI) | 49552 | C15H18FNO4 | 详情 | 详情 | ||
| (VII) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (VIII) | 49553 | 1-[3-(4-fluorophenoxy)propanoyl]-3-methoxy-4-piperidinone O-benzyloxime | C22H25FN2O4 | 详情 | 详情 | |
| (IX) | 49554 | (3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinamine; (3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidinylamine | C15H23FN2O2 | 详情 | 详情 | |
| (X) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)The reductive amination of 1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidin-4-one (I) with benzylamine by hydrogenation with H2 over Pd/C, followed by crystallization of the HCl or HNO3 salts, gives cis-1-[3-(4-fluorophenyl)propyl]-3-methoxypiperidine-4-amine (II). This compound is condensed with 4-amino-5-chloro-2-methoxybenzoic acid (III) by means of ethyl chloroformate, TEA and HOBt to afford the target amide.
| 【1】 Moens, L.J.R.; Rey, M.; De Knaep, A.G.M. (Janssen Pharmaceutica NV); Synthesis of cisapride. WO 9816511 . |
| 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) | 49555 | 1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinone | C15H20FNO3 | 详情 | 详情 | |
| (II) | 49554 | (3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinamine; (3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidinylamine | C15H23FN2O2 | 详情 | 详情 | |
| (III) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIV)This compound has been obtained by two related ways: 1. The reaction of 1-benzyl-3-bromopiperidin-4-one (I) with sodium methoxide in methanol gives the intermediate epoxide, which in the reaction medium yields 1-benzyl-3-hydroxypiperidin-4-one dimethylacetal (III). The hydrogenation of (III) with H2 over Pd/C in methanol affords 3-hydroxypiperidin-4-one dimethylacetal (IV), which is condensed with ethyl chloroformate (V) by means of NaOH in THF to provide 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylic acid ethyl ester (VI), which is methylated with methyl iodide and NaH in DMF to give the 3,4,4-trimethoxy compound (VII). The hydrolysis of the acetal group of (VII) by means of H2SO4 in refluxing water yields the piperidinone (VIII), which by reductocondensation with benzylamine and H2 over Pd/C in methanol affords the cis- 4-(benzylamino)-3-methoxypiperidine-1-carboxylic acid ethyl ester (IX). The decarboxylation of (IX) by means of KOH in refluxing isopropanol provides the cis-4-(benzyloxy)-3-methoxypiperidine (X), which is alkylated with 3-(4-fluorophenoxy)propyl chloride (XI) by means of TEA in DMF, giving the N-substituted piperidine (XII). The deprotection of the amino group of (XII) by hydrogenation with H2 over Pd/C in methanol yields the 4-aminopiperidine (XIII), which is finally condensed with 4-amino-5-chloro-2-methoxybenzoic acid (XIV) by means of ethyl chloroformate and TEA in chloroform to obtain the target carboxamide. 2. The debenzylation of the cis- 4-(benzylamino)-3-methoxypiperidine-1-carboxylic acid ethyl ester (IX) with H2 over Pd/C in methanol gives the cis-4-amino-3-methoxypiperidine-1-carboxylic acid ethyl ester (XV), which is condensed with 4-amino-5-chloro-2-methoxybenzoic acid (XIV) by means of ethyl chloroformate and TEA in chloroform to yield the corresponding amide (XVI). The decarboxylation of (XVI) with KOH in refluxing isopropanol affords (XVII), with a free NH group that is alkylated with 3-(4-fluorophenoxy)propyl chloride (XI) by means of TEA in DMF to obtain the target carboxamide.
| 【1】 Van Daele, G.H.P.; et al.; Synthesis of cisapride, a gastrointestinal stimulant derived from cis-4-amino-3-methoxypiperidine. Drug Dev Res 1986, 8, 225. |
| 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) | 49566 | 1-benzyl-3-bromo-4-piperidinone | C12H14BrNO | 详情 | 详情 | |
| (II) | 49567 | 3-benzyl-6-methoxy-7-oxa-3-azabicyclo[4.1.0]heptane; 3-benzyl-7-oxa-3-azabicyclo[4.1.0]hept-6-yl methyl ether | C13H17NO2 | 详情 | 详情 | |
| (III) | 49568 | 1-benzyl-4,4-dimethoxy-3-piperidinol | C14H21NO3 | 详情 | 详情 | |
| (IV) | 49557 | 4,4-dimethoxy-3-piperidinol | C7H15NO3 | 详情 | 详情 | |
| (V) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |
| (VI) | 49556 | ethyl 3-hydroxy-4,4-dimethoxy-1-piperidinecarboxylate | C10H19NO5 | 详情 | 详情 | |
| (VII) | 49569 | ethyl 3,4,4-trimethoxy-1-piperidinecarboxylate | C11H21NO5 | 详情 | 详情 | |
| (VIII) | 49570 | ethyl 3-methoxy-4-oxo-1-piperidinecarboxylate | C9H15NO4 | 详情 | 详情 | |
| (IX) | 49571 | ethyl (3S,4R)-4-(benzylamino)-3-methoxy-1-piperidinecarboxylate | C16H24N2O3 | 详情 | 详情 | |
| (X) | 49572 | (3S,4R)-N-benzyl-3-methoxy-4-piperidinamine; N-benzyl-N-[(3S,4R)-3-methoxypiperidinyl]amine | C13H20N2O | 详情 | 详情 | |
| (XI) | 30524 | 3-chloropropyl 4-fluorophenyl ether; 1-(3-chloropropoxy)-4-fluorobenzene; 1-(4-Fluorophenoxy)-3-chloropropane | 1716-42-3 | C9H10ClFO | 详情 | 详情 |
| (XII) | 49573 | (3S,4R)-N-benzyl-1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinamine; N-benzyl-N-[(3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidinyl]amine | C22H29FN2O2 | 详情 | 详情 | |
| (XIII) | 49574 | ethyl (3S,4R)-4-amino-3-methoxy-1-piperidinecarboxylate | C9H18N2O3 | 详情 | 详情 | |
| (XIV) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |
| (XV) | 49574 | ethyl (3S,4R)-4-amino-3-methoxy-1-piperidinecarboxylate | C9H18N2O3 | 详情 | 详情 | |
| (XVI) | 49575 | ethyl (3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinecarboxylate | C17H24ClN3O5 | 详情 | 详情 | |
| (XVII) | 49576 | 4-amino-5-chloro-2-methoxy-N-[(3S,4R)-3-methoxypiperidinyl]benzamide | C14H20ClN3O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The title compound has been obtained by condensation of 4-amino-5-chloro-2-methoxybenzoic acid (I) with cis-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidine-4-amine (II) by means of DCC in dichloromethane or PCl3 in benzene.
| 【1】 Izquierdo Sanjose, M.; Martin Escudero, U.; Process for obtaining a 4-amino-5-chloro-2-methoxybenzoic acid deriv.. ES 2002640 . |
| 【2】 Alonso Cires, L.; Process for the preparation of substd. benzamides. ES 8605768 . |
合成路线5
该中间体在本合成路线中的序号：(I)The reaction of 4-amino-5-chloro-2-methoxybenzoic acid (I) with benzyl chloride (II) and NaHCO3 in refluxing water gives the N-benzyl protected compound (III), which is condensed with cis-4-amino-3-methoxypiperidine-1-carboxylic acid ethyl ester (IV) by means of methyl chloroformate and TEA in dichloromethane to yield the benzamide (V). The deprotection of (V) with KOH in refluxing isopropanol affords compound (VI) with a free piperidinic NH group that is acylated with 3-(4-fluorophenoxy)propyl chloride (VII) by means of Na2CO3 in refluxing methylisobutylketone to provide the protected adduct (VIII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in hot methanol to give the target compound. Alternatively, the piperidine derivative (VI) is treated with p-toluenesulfonic acid in refluxing toluene and then debenzylated and simultaneously reductocondensed with 3-(4-fluorophenoxy)propionaldehyde (IX) by means of H2 over Pd/C in methanol to give the target compound.
| 【1】 Gutierrez Fuentes, L.G.; Process for the preparation of benzamides. ES 2019047 . |
| 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) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |
| (II) | 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 |
| (III) | 49580 | 4-(benzylamino)-5-chloro-2-methoxybenzoic acid | C15H14ClNO3 | 详情 | 详情 | |
| (IV) | 19574 | (4-carboxybutyl)(triphenyl)phosphonium chloride | C23H24ClO2P | 详情 | 详情 | |
| (V) | 19581 | trans-4-Aminocyclohexanol；trans-4-Amino-1-cyclohexanol;trans-4-Amino-1-cyclohexanol; | 27489-62-9 | C6H13NO | 详情 | 详情 |
| (VI) | 49582 | 4-(benzylamino)-5-chloro-2-methoxy-N-[(3S,4R)-3-methoxypiperidinyl]benzamide | C21H26ClN3O3 | 详情 | 详情 | |
| (VII) | 30524 | 3-chloropropyl 4-fluorophenyl ether; 1-(3-chloropropoxy)-4-fluorobenzene; 1-(4-Fluorophenoxy)-3-chloropropane | 1716-42-3 | C9H10ClFO | 详情 | 详情 |
| (VIII) | 49583 | 4-(benzylamino)-5-chloro-N-[(3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidinyl]-2-methoxybenzamide | C30H35ClFN3O4 | 详情 | 详情 | |
| (IX) | 49584 | 3-(4-fluorophenoxy)propanal | C9H9FO2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VII)The bromination of 4-oxopiperidine-1-carboxylic acid ethyl ester (I) with Br2 in chloroform gives 3-bromo-4-oxopiperidine-1-carboxylic acid ethyl ester (II), which is treated with NaOMe in methanol to yield 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylic acid ethyl ester (III). The methylation of (III) with NaH and MeI in DMF affords 3,4,4-trimethoxypiperidine-1-carboxylic acid ethyl ester (IV), which is hydrolyzed with refluxing 1% aq. H2SO4 to provide 3-methoxy-4-oxopiperidine-1-carboxylic acid ethyl ester (V). The reductocondensation of (V) with benzylamine and H2 over Pd/C in methanol in the presence of thiophene gives cis-4-amino-3-methoxypiperidine-1-carboxylic acid ethyl ester (VI), which is condensed with 4-amino-5-chloro-2-methoxybenzoic acid (VII) by means of ethyl chloroformate and TEA in chloroform to yield the benzamide (VIII). The hydrolysis of the carbamate group of (VIII) with KOH in refluxing isopropanol affords the free piperidine derivative (IX), which is finally condensed with 3-(4-fluorophenoxy)propyl chloride (X) by means of TEA and KI in hot DMF to provide the target, cisapride.
| 【1】 Van Daele, G. (Janssen Pharmaceutica NV); Novel N-(3-hydroxy-4-piperidinyl)benzamide derivs.. US 4962115 . |
| 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) | 13486 | Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone | 29976-53-2 | C8H13NO3 | 详情 | 详情 |
| (II) | 53112 | ethyl 3-bromo-4-oxo-1-piperidinecarboxylate | 95629-02-0 | C8H12BrNO3 | 详情 | 详情 |
| (III) | 49556 | ethyl 3-hydroxy-4,4-dimethoxy-1-piperidinecarboxylate | C10H19NO5 | 详情 | 详情 | |
| (IV) | 49569 | ethyl 3,4,4-trimethoxy-1-piperidinecarboxylate | C11H21NO5 | 详情 | 详情 | |
| (V) | 49570 | ethyl 3-methoxy-4-oxo-1-piperidinecarboxylate | C9H15NO4 | 详情 | 详情 | |
| (VI) | 49574 | ethyl (3S,4R)-4-amino-3-methoxy-1-piperidinecarboxylate | C9H18N2O3 | 详情 | 详情 | |
| (VII) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |
| (VIII) | 49575 | ethyl (3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinecarboxylate | C17H24ClN3O5 | 详情 | 详情 | |
| (IX) | 49576 | 4-amino-5-chloro-2-methoxy-N-[(3S,4R)-3-methoxypiperidinyl]benzamide | C14H20ClN3O3 | 详情 | 详情 | |
| (X) | 30524 | 3-chloropropyl 4-fluorophenyl ether; 1-(3-chloropropoxy)-4-fluorobenzene; 1-(4-Fluorophenoxy)-3-chloropropane | 1716-42-3 | C9H10ClFO | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)The condensation of 4-amino-5-chloro-2-methoxybenzoic acid (I) with 3-methoxypyridine-4-amine (II) by means of ethyl chloroformate and DEA in chloroform gives the corresponding amide (III), which is condensed with 3-(4-fluorophenoxy)propyl chloride (IV) by means of phenol in hot toluene to yield the pyridinium chloride (V). Finally, this compound is hydrogenated with H2 over PtO2/C in ethanol containing NaHCO3 to afford the target cisapride.
| 【1】 Van Daele, G.H.P. (Janssen Pharmaceutica NV); ES 2007259 . |
| 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) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |
| (II) | 53287 | 3-methoxy-4-pyridinylamine; 3-methoxy-4-pyridinamine | n/a | C6H8N2O | 详情 | 详情 |
| (III) | 53288 | 4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-pyridinyl)benzamide | n/a | C14H14ClN3O3 | 详情 | 详情 |
| (IV) | 30524 | 3-chloropropyl 4-fluorophenyl ether; 1-(3-chloropropoxy)-4-fluorobenzene; 1-(4-Fluorophenoxy)-3-chloropropane | 1716-42-3 | C9H10ClFO | 详情 | 详情 |
| (V) | 53289 | 4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-[3-(4-fluorophenoxy)propyl]-3-methoxypyridinium chloride | n/a | C23H24Cl2FN3O4 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(D)Dazopride can be prepared by the condensation of the 1,2-diethyl-4-aminopyrazolidine (VIII) with either 4-amino-5-chloro-2-methoxybenzoic acid in the presence of phosphorus trichloride-pyridine or the corresponding mixed anhydride (IX).
| 【1】 Munson, H.R. Jr.; Cale, A.D. Jr, Lo, Y.S.; Lunsford, C.D.; Synthetic and pharmacological properties of N-(1,2-dialkyl-4-pyrazolidinyl)benzamides - Selective gastric prokinetic agents. 187th ACS Natl Meet (April 8-13, St. Louis) 1984, 7, 9, 650. |
| 【2】 Cale, A.D.Jr.; Lunsfod, C.D. (A.H. Robins Co. Inc.); N-(4-Pyrazolidinyl)benzamides and their amino precursors. US 4207327 . |
| 【3】 Cale, A. Jr.; Dazopride succinate. Drugs Fut 1985, 10, 7, 553. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (E) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |
| (D) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |
| (VIII) | 27385 | 1,2-diethyl-4-pyrazolidinamine | 70180-92-6 | C7H17N3 | 详情 | 详情 |
| (IX) | 27388 | 4-Amino-5-chloro-2-methoxybenzoic acid ethoxycarbonyl anhydride | C11H12ClNO5 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(V)A new synthesis for [14C]-labeled batanopride has been described: The starting material is 4-amino-2-hydroxybenzoic acid labeled with [14C] at the carboxy group (I). The methylation of (I) in the usual way gives 4-amino-2-methoxybenzoic acid methyl ester (II), which is treated with acetic anhydride to yield the corresponding acetamido derivative (III). Chlorination of (III) with Cl2 in acetic acid affords 4-acetamido-5-chloro-2-methoxybenzoic acid methyl ester (IV), which is hydrolyzed with aqueous NaOH to 4-amino-5-chloro-2-methoxybenzoic acid (V). The condensation of (V) with 2-(diethylamino)ethylamine (VI) by means of triethylamine and isobutyl chloroformate in THF gives the corresponding amide (VII), which is demethylated with sodium ethanethiolate in DMF to yield the phenolate (VIII). The condensation of (VIII) with 3-chloro-2-butanone (IX) in DMF affords batanopride free base (X), which is finally treated with HCl in acetone - water.
| 【1】 Standridge, R.T.; Swigor, J.E.; Synthesis of 4-amino-5-chloro-N[2-(diethylamino)ethyl]-2-[(butan-2-on-3-yl)oxy]-[carbonyl-C-14]benzamide hydrochloride (C-14-batanopride). J Label Compd Radiopharm 1991, 29, 9, 983. |
| 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) | 12415 | 4-Aminosalicylic Acid; 4-Amino-2-hydroxybenzoic acid | 65-49-6 | C7H7NO3 | 详情 | 详情 |
| (I) | 45126 | 4-amino-2-hydroxybenzoic acid | C7H7NO3 | 详情 | 详情 | |
| (II) | 12416 | methyl 4-amino-2-methoxybenzoate | 27492-84-8 | C9H11NO3 | 详情 | 详情 |
| (II) | 45127 | methyl 4-amino-2-methoxybenzoate | C9H11NO3 | 详情 | 详情 | |
| (III) | 12417 | methyl 4-(acetamido)-2-methoxybenzoate; Methyl 4-acetamido-2-methoxybenzoate | 4093-28-1 | C11H13NO4 | 详情 | 详情 |
| (III) | 45128 | methyl 4-(acetamido)-2-methoxybenzoate | C11H13NO4 | 详情 | 详情 | |
| (IV) | 12418 | 4-Acetamido-5-chloro-2-methoxy methyl benzoate; methyl 4-(acetamido)-5-chloro-2-methoxybenzoate; Methyl 4-acetamido-5-chloro-2-methoxybenzoate; 4-Acetamido-5-chloro-2-methoxybenzoic acid methyl ester; 4-Acetamido-5-chloro-o-anisic acid methyl ester | 4093-31-6 | C11H12ClNO4 | 详情 | 详情 |
| (IV) | 45129 | methyl 4-(acetamido)-5-chloro-2-methoxybenzoate | C11H12ClNO4 | 详情 | 详情 | |
| (V) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |
| (V) | 45130 | 4-amino-5-chloro-2-methoxybenzoic acid | C8H8ClNO3 | 详情 | 详情 | |
| (VI) | 12420 | N-(2-Aminoethyl)-N,N-diethylamine; N,N-Diethylethylene-diamine; N(1),N(1)-Diethyl-1,2-ethanediamine | 100-36-7 | C6H16N2 | 详情 | 详情 |
| (VII) | 12421 | 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide | 364-62-5 | C14H22ClN3O2 | 详情 | 详情 |
| (VII) | 45131 | 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide | C14H22ClN3O2 | 详情 | 详情 | |
| (VIII) | 12422 | sodium 5-amino-4-chloro-2-([[2-(diethylamino)ethyl]amino]carbonyl)benzenolate | C13H19ClN3NaO2 | 详情 | 详情 | |
| (VIII) | 45132 | sodium 5-amino-4-chloro-2-([[2-(diethylamino)ethyl]amino]carbonyl)benzenolate | C13H19ClN3NaO2 | 详情 | 详情 | |
| (IX) | 12423 | 3-Chloro-2-butanone | 4091-39-8 | C4H7ClO | 详情 | 详情 |
| (X) | 12424 | 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(1-methyl-2-oxopropoxy)benzamide | C17H26ClN3O3 | 详情 | 详情 | |
| (X) | 45133 | 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(1-methyl-2-oxopropoxy)benzamide | C17H26ClN3O3 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(XVIII)The Diels-Alder condensation of the fumaric acid (S)-methyl lactate ester (I) with cyclopentadiene (II) gives the norbornene derivative (III), which is submitted to saponification with LiOH and iodolactonization with KI and I2 yielding the iodolactone (IV). The reaction of (IV) with SOCl2 and then with ammonia affords the amide (V). The Hofmann-type rearrangement of (V) by means of hydroxytosyloxy iodobenzene (HTIB) gives the primary amine (VI), which is treated with TsCl and pyridine to yield the sulfonamide (VII). The iodolactone ring is then cleaved with Zn/AcOH affording the norbornene-carboxylic acid (VIII), which is submitted to ozonolysis with O3 to give the dialdehyde (IX). The reduction of (IX) with NaBH4 provides the diol (X), which is cyclized in acidic medium to lactone (XI). The reaction of (XI) with ammonia affords the amide (XII), which is reduced with BH3 to the primary amine (XIII). The protection of (XIII) with 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (Boc-ON) gives the carbamate (XIV), which is treated with Ts-Cl to yield the ditosylate (XV). The cyclization of (XV) by means of TFA affords the azanoradamantane sulfonamide (XVI), which is treated with calcium in liquid ammonia to obtain thee corresponding primary amine (XVII). Finally, this compound is condensed with 4-amino-5-chloro-2-methoxybenzoic acid (XVIII) by means of carbonyldiimidazole (CDI) in DMF.
| 【1】 Becker, D.P.; et al.; Enantioselective synthesis of dual 5-HT4/5-HT3 serotonergic azanoradamantane SC-52491. Tetrahedron 1999, 55, 40, 11787. |
| 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) | 32307 | bis[(1S)-2-ethoxy-1-methyl-2-oxoethyl] (E)-2-butenedioate | C14H20O8 | 详情 | 详情 | |
| (II) | 11183 | 1,3-Cyclopentadiene | C5H6 | 详情 | 详情 | |
| (III) | 32308 | bis[(1S)-2-ethoxy-1-methyl-2-oxoethyl] (2R,3R)bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate | C19H26O8 | 详情 | 详情 | |
| (IV) | 32309 | (2S,3S,6R,9S)-2-iodo-5-oxo-4-oxatricyclo[4.2.1.0(3,7)]nonane-9-carboxylic acid | C9H9IO4 | 详情 | 详情 | |
| (V) | 32310 | (2S,3S,6R,9S)-2-iodo-5-oxo-4-oxatricyclo[4.2.1.0(3,7)]nonane-9-carboxamide | C9H10INO3 | 详情 | 详情 | |
| (VI) | 32311 | (2S,3S,6R,9S)-9-amino-2-iodo-4-oxatricyclo[4.2.1.0(3,7)]nonan-5-one | C8H10INO2 | 详情 | 详情 | |
| (VII) | 32312 | N-[(2S,3S,6R,9S)-2-iodo-5-oxo-4-oxatricyclo[4.2.1.0(3,7)]non-9-yl]-4-methylbenzenesulfonamide | C15H16INO4S | 详情 | 详情 | |
| (VIII) | 32313 | (2R,3R)-3-[[(4-methylphenyl)sulfonyl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid | C15H17NO4S | 详情 | 详情 | |
| (IX) | 32314 | (1R,2R,3S,5R)-3,5-diformyl-2-[[(4-methylphenyl)sulfonyl]amino]cyclopentanecarboxylic acid | C15H17NO6S | 详情 | 详情 | |
| (X) | 32315 | (1R,2R,3S,5R)-3,5-bis(hydroxymethyl)-2-[[(4-methylphenyl)sulfonyl]amino]cyclopentanecarboxylic acid | C15H21NO6S | 详情 | 详情 | |
| (XI) | 32316 | N-[(3aR,4R,5S,6aR)-5-(hydroxymethyl)-3-oxohexahydro-2H-cyclopenta[b]furan-4-yl]-4-methylbenzenesulfonamide | C15H19NO5S | 详情 | 详情 | |
| (XII) | 32317 | (1R,2R,3S,5R)-3,5-bis(hydroxymethyl)-2-[[(4-methylphenyl)sulfonyl]amino]cyclopentanecarboxamide | C15H22N2O5S | 详情 | 详情 | |
| (XIII) | 32318 | N-[(1S,2S,3R,5S)-2-(aminomethyl)-3,5-bis(hydroxymethyl)cyclopentyl]-4-methylbenzenesulfonamide | C15H24N2O4S | 详情 | 详情 | |
| (XIV) | 32319 | tert-butyl ((1S,2S,3S,5R)-3,5-bis(hydroxymethyl)-2-[[(4-methylphenyl)sulfonyl]amino]cyclopentyl)methylcarbamate | C20H32N2O6S | 详情 | 详情 | |
| (XV) | 32320 | [(1S,2S,3S,4R)-3-[[(tert-butoxycarbonyl)amino]methyl]-2-[[(4-methylphenyl)sulfonyl]amino]-4-([[(4-methylphenyl)sulfonyl]oxy]methyl)cyclopentyl]methyl 4-methylbenzenesulfonate | C34H44N2O10S3 | 详情 | 详情 | |
| (XVI) | 32321 | N-[(3S,4S,5R,7R)-1-azatricyclo[3.3.1.0(3,7)]non-4-yl]-4-methylbenzenesulfonamide | C15H20N2O2S | 详情 | 详情 | |
| (XVII) | 32322 | (3S,4S,5R,7R)-1-azatricyclo[3.3.1.0(3,7)]nonan-4-amine; (3S,4S,5R,7R)-1-azatricyclo[3.3.1.0(3,7)]non-4-ylamine | C8H14N2 | 详情 | 详情 | |
| (XVIII) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(XV)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12
该中间体在本合成路线中的序号：(I)Reaction of 4-amino-5-chloro-2-methoxybenzoic acid (I) with 1,2-dibromoethane in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene afforded bromoethyl ester (II). This was then condensed with a mixture of cis and trans 3,5-dimethylpiperidines (III), and the resulting mixture of amines was finally separated by column chromatogaphy to provide the target cis compound.
| 【1】 Sicsic, S.; Soulier, J.-L.; Yang, D.; et al.; New esters of 4-amino-5-chloro-2-methoxybenzoic acid as potent agonists and antagonists for 5-HT4 receptors. J Med Chem 1997, 40, 4, 608. |
| 【2】 Langlois, M.; Guzzi, U.; Cecchi, R.; Croci, T. (Midy SpA); Esters of 4-amino-5-chloro-2-methoxybenzoic acid, process for their preparation and pharmaceutical compsns. containing them. EP 0683161 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 | |
| (I) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |
| (II) | 26533 | 2-bromoethyl 4-amino-5-chloro-2-methoxybenzoate | C10H11BrClNO3 | 详情 | 详情 | |
| (III) | 26534 | 3,5-dimethylpiperidine | 35794-11-7 | C7H15N | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(V)4-(Aminomethyl)piperidine (I) was protected as the benzylideneimine (III) by condensation with benzaldehyde (II). Further acylation of (III) at the secondary amino group by treatment with di-tert--butyl dicarbonate gave, after acid hydrolysis of the imine, the N-Boc-piperidine (IV). The benzoic acid derivative (V) was activated as the mixed anhydride by treatment with ethyl chloroformate and triethylamine, and subsequently condensed with amine (IV) to provide the corresponding amide (VI). Then, the N-tert-butoxycarbonyl group was eliminated with HCl to give the piperidine (VII), which was finally alkylated with halide (VIII) in the presence of K2CO3 in DMF to furnish the title compound.
| 【1】 Baker, S.R.; et al.; Synthesis and pharmacological evaluation of benzamides as selective 5-HT4 receptor agonists. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abs P 270. |
| 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) | 19349 | 4-piperidinylmethylamine; 4-piperidinylmethanamine; 4-(Aminomethyl)piperidine | 7144-05-0 | C6H14N2 | 详情 | 详情 |
| (II) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (III) | 19351 | N-[(E)-benzylidene]-N-(4-piperidinylmethyl)amine; N-[(E)-benzylidene](4-piperidinyl)methanamine | C13H18N2 | 详情 | 详情 | |
| (IV) | 19352 | 4-Aminomethyl-1-N-Boc-piperidine; tert-butyl 4-(aminomethyl)-1-piperidinecarboxylate | 144222-22-0 | C11H22N2O2 | 详情 | 详情 |
| (V) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |
| (VI) | 19354 | tert-butyl 4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]-1-piperidinecarboxylate | C19H28ClN3O4 | 详情 | 详情 | |
| (VII) | 19355 | 4-amino-5-chloro-2-methoxy-N-(4-piperidinylmethyl)benzamide | C14H20ClN3O2 | 详情 | 详情 | |
| (VIII) | 19356 | benzyl 4-chlorobutyl sulfone; benzyl(4-chlorobutyl)dioxo-lambda(6)-sulfane | 14633-43-3 | C11H15ClO2S | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(VI)4-(Aminomethyl)piperidine (I) was protected as the benzylideneimine (III) by condensation with benzaldehyde (II). Further acylation of (III) at the secondary amino group by treatment with di-tert--butyl dicarbonate gave, after acid hydrolysis of the imine, the N-Boc-piperidine (IV). The benzoic acid derivative (V) was activated as the mixed anhydride by treatment with ethyl chloroformate and triethylamine, and subsequently condensed with amine (IV) to provide the corresponding amide (VI). Then, the N-tert-butoxycarbonyl group was eliminated with HCl to give the piperidine (VII), which was finally alkylated with halide (VIII) in the presence of K2CO3 in DMF to furnish the title compound).
| 【1】 Baker, S.R.; et al.; Synthesis and pharmacological evaluation of benzamides as selective 5-HT4 receptor agonists. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abs P 270. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
| (A) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (I) | 19349 | 4-piperidinylmethylamine; 4-piperidinylmethanamine; 4-(Aminomethyl)piperidine | 7144-05-0 | C6H14N2 | 详情 | 详情 |
| (II) | 19351 | N-[(E)-benzylidene]-N-(4-piperidinylmethyl)amine; N-[(E)-benzylidene](4-piperidinyl)methanamine | C13H18N2 | 详情 | 详情 | |
| (III) | 21110 | benzylhydrosulfide; phenylmethanethiol | 100-53-8 | C7H8S | 详情 | 详情 |
| (IV) | 21111 | benzyl(3-chloropropyl)dioxo-lambda(6)-sulfane; benzyl 3-chloropropyl sulfone | C10H13ClO2S | 详情 | 详情 | |
| (V) | 21112 | [1-[3-(benzylsulfonyl)propyl]-4-piperidinyl]methylamine; [1-[3-(benzylsulfonyl)propyl]-4-piperidinyl]methanamine | C16H26N2O2S | 详情 | 详情 | |
| (VI) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(I)The condensation of 4-amino-5-chloro-2-methoxybenzoic acid (I) with 4-amino-1-(triphenylmethyl)piperidine (II) by means of ethyl chloroformate and triethylamine in THF gives the corresponding amide (III), which is deprotected with HCl in actone yielding 4-amino-5-chloro-2-methoxy-N-(4-piperidyl)benzamide (IV). The condensation of (IV) with ethyl bromoacetate (V) by means of K2CO3 in DMF affords the substituted acetate (VI), which is finally saponified with NaOH in methanol.
| 【1】 Ito, Y.; Kato, H.; Yasuda, S.; Iwasaki, N.; Nishino, H.; Takeshita, M. (Hokuriku Seiyaku Co., Ltd.); Benzamide deriv.. EP 0640601; US 5395832; US 5500422; WO 9214705 . |
| 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) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |
| (II) | 19955 | 1-trityl-4-piperidinylamine; 1-trityl-4-piperidinamine | C24H26N2 | 详情 | 详情 | |
| (III) | 19956 | 4-amino-5-chloro-2-methoxy-N-(1-trityl-4-piperidinyl)benzamide | C32H32ClN3O2 | 详情 | 详情 | |
| (IV) | 19957 | 4-amino-5-chloro-2-methoxy-N-(4-piperidinyl)benzamide | C13H18ClN3O2 | 详情 | 详情 | |
| (V) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (VI) | 19959 | ethyl 2-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidinyl]acetate | C17H24ClN3O4 | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：(I)4-Amino-5-chloro-2-methoxybenzoic acid (I) was converted to the mixed anhydride (II) upon treatment with ethyl chloroformate and Et3N. Subsequent coupling of (II) with 4-amino-1-tritylpiperidine (III) afforded amide (IV). The trityl group of (IV) was then removed by acidic treatment to give piperidine (V). Finally, alkylation of (V) with butyl bromoacetate (VI) furnished the title compound.
| 【1】 Ito, Y.; Kato, H.; Yasuda, S.; Iwasaki, N.; Nishino, H.; Takeshita, M. (Hokuriku Seiyaku Co., Ltd.); Benzamide deriv.. EP 0640601; US 5395832; US 5500422; WO 9214705 . |
| 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) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |
| (II) | 29299 | 4-Amino-5-chloro-2-methoxybenzoic acid methoxycarbonyl anhydride | C10H10ClNO5 | 详情 | 详情 | |
| (III) | 19955 | 1-trityl-4-piperidinylamine; 1-trityl-4-piperidinamine | C24H26N2 | 详情 | 详情 | |
| (IV) | 19956 | 4-amino-5-chloro-2-methoxy-N-(1-trityl-4-piperidinyl)benzamide | C32H32ClN3O2 | 详情 | 详情 | |
| (V) | 19957 | 4-amino-5-chloro-2-methoxy-N-(4-piperidinyl)benzamide | C13H18ClN3O2 | 详情 | 详情 | |
| (VI) | 29300 | butyl 2-bromoacetate | C32H32ClN3O2 | 详情 | 详情 |
合成路线17
该中间体在本合成路线中的序号：(V)The condensation of 4-(tert-butoxycarbonylamino)piperidine (I) with butyl chloroacetate (II) by means of TEA in hot DMF gives butyl 2-[4-(tert-butoxycarbonylamino)piperdin-1-yl]acetate (III), which is deprotected with HCl in isopropanol to yield butyl 2-(4-aminopiperidin-1-yl)acetate (IV). Finally, this compound is condensed with 4-amino-5-chloro-2-methoxybenzoic acid (V) by means of ethyl chloroacetate, TEA and K2CO3 in THF to afford the target benzamide.
| 【1】 Sakaguchi, J.; Kato, H.; Kado, N. (Hokuriku Seiyaku Co., Ltd.); Benzamide derivs. and drugs containing the same. EP 1149832; JP 2000290254; WO 0046201 . |
| 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) | 41601 | tert-butyl 4-piperidinylcarbamate; 4-tert-Boc-aminopiperidine | 73874-95-0 | C10H20N2O2 | 详情 | 详情 |
| (II) | 14595 | n-Butyl Chloroacetate; butyl 2-chloroacetate | 590-02-3 | C6H11ClO2 | 详情 | 详情 |
| (III) | 51930 | butyl 2-[4-[(tert-butoxycarbonyl)amino]-1-piperidinyl]acetate | C16H30N2O4 | 详情 | 详情 | |
| (IV) | 51931 | butyl 2-(4-amino-1-piperidinyl)acetate | C11H22N2O2 | 详情 | 详情 | |
| (V) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |
合成路线18
该中间体在本合成路线中的序号：(I)4-Amino-5-chloro-2-methoxybenzoic acid (I) was coupled to 4-(aminomethyl)-1-[2-(methylsulfonylamino)ethyl]piperidine (II) employing 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride and 1-hydroxybenzotriazole. The resulting compound was then treated with oxalic acid to provide the corresponding oxalate salt.
| 【1】 Kawakita, T.; Haga, K.; Itoh, K.; Ikebe, T.; kanzaki, K.; Sato, N.; Tomozane, H.; Sonda, S.; Kuroita, T.; Synthesis and pharmacological evaluation of carboxamide derivatives as selective serotoninergic 5-HT4 receptor agonists. Eur J Med Chem 1999, 34, 11, 977. |
合成路线19
该中间体在本合成路线中的序号：(X)1-Benzyl-4-(aminomethyl)piperidine (I) was protected at the primary amino group as the Boc derivative (II) and the N-benzyl group was subsequently removed by transfer hydrogenolysis with hydrazine and Pd/C to give piperidine (III). Alkylation of (III) with N-(5-bromopentyl)phthalimide (IV) afforded (V), which was subjected to hydrazinolysis of the phthalimido group, yielding primary amine (VI). Coupling of (VI) with 1-methylindole-3-carboxylic acid (VII) by means of EDC and HOBt gave rise to amide (VIII). The Boc protecting group of (VIII) was then cleaved by acidic treatment to furnish amine (IX). Finally, coupling of (IX) with 4-amino-5-chloro-2-methoxybenzoic acid (X) provided the title benzamide.
| 【1】 Haga, K.; Tomozane, H.; Sato, N.; Kawakita, T.; Itoh, K.; Sonda, S.; Asano, K.; Fujimura, M.; Hakira, H.; Synthesis and pharmacological properties of novel benzamide derivatives acting as ligands to the 5-hydroxytryptamine 4 (5-HT4) receptor. Eur J Med Chem 1999, 34, 12, 1101. |
| 【2】 Kawakita, T.; Hakira, H.; Haga, K.; Murozono, T.; Kuroita, T. (Welfide Corporation); Benzoic acid cpd. and use thereof as medicine. EP 0774460; WO 9526953 . |
| 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) | 37901 | (1-benzyl-4-piperidinyl)methylamine; (1-benzyl-4-piperidinyl)methanamine | C13H20N2 | 详情 | 详情 | |
| (II) | 37902 | tert-butyl (1-benzyl-4-piperidinyl)methylcarbamate | C18H28N2O2 | 详情 | 详情 | |
| (III) | 37903 | tert-butyl 4-piperidinylmethylcarbamate | C11H22N2O2 | 详情 | 详情 | |
| (IV) | 37904 | 2-(5-bromopentyl)-1H-isoindole-1,3(2H)-dione | 954-81-4 | C13H14BrNO2 | 详情 | 详情 |
| (V) | 37905 | tert-butyl [1-[5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentyl]-4-piperidinyl]methylcarbamate | C24H35N3O4 | 详情 | 详情 | |
| (VI) | 37906 | tert-butyl [1-(5-aminopentyl)-4-piperidinyl]methylcarbamate | C16H33N3O2 | 详情 | 详情 | |
| (VII) | 15067 | 1-methyl-1H-indole-3-carboxylic acid; N-Methylindole-3-carboxylic acid | 32387-21-6 | C10H9NO2 | 详情 | 详情 |
| (VIII) | 37907 | tert-butyl [1-(5-[[(1-methyl-1H-indol-3-yl)carbonyl]amino]pentyl)-4-piperidinyl]methylcarbamate | C26H40N4O3 | 详情 | 详情 | |
| (IX) | 37908 | N-[5-[4-(aminomethyl)-1-piperidinyl]pentyl]-1-methyl-1H-indole-3-carboxamide | C21H32N4O | 详情 | 详情 | |
| (X) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |
合成路线20
该中间体在本合成路线中的序号：(VIII)Isonipecotic acid (I) was protected with benzyl chloroformate and the resultant 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid (II) was subsequently converted to the corresponding acid chloride (III) by treatment with SOCl2. Coupling of acid chloride (III) with 4-(tert-butoxycarbonylamino)piperidine (IV) afforded the piperidinyl amide (V), which was further reduced with BH3 to the piperidinylmethyl piperidine (VI). Aminopiperidine (VII), obtained by acidic cleavage of the N-Boc group of (VI), was then coupled with 4-amino-5-chloro-2-methoxybenzoic acid (VIII) to provide amide (IX). Deprotection of the N-benzyloxycarbonyl group was carried out by means of methanesulfonic acid in the presence of anisole to give (X). Acylation of piperidine (X) with the protected aminoacid (XI) yielded amide (XII). Then, selective reduction of the aliphatic amide function, followed by deprotection of the amino group provided the title compound.
| 【1】 Harada, H.; et al.; Novel N-[1-(1-substituted 4-piperidinylmethyl)-4-piperidinyl]benzamides as potent colonic prokinetic agents. Bioorg Med Chem Lett 2002, 12, 6, 967. |
| 【2】 Kato, S.; Yoshida, N.; Harada, H.; Toyotomi, Y.; Morikage, S. (Dainippon Pharmaceutical Co., Ltd.); Benzamido derivs. and medicinal compsns. containing the same. JP 1999001472 . |
| 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) | 17462 | (6S)-6-[(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl]-5,6-dihydro-2H-pyran-2-one | C25H20FNO2 | 详情 | 详情 | |
| (II) | 56082 | Z-Isonipecotic acid | 10314-98-4 | C14H17NO4 | 详情 | 详情 |
| (III) | 35165 | benzyl 4-(chlorocarbonyl)-1-piperidinecarboxylate | C14H16ClNO3 | 详情 | 详情 | |
| (IV) | 41601 | tert-butyl 4-piperidinylcarbamate; 4-tert-Boc-aminopiperidine | 73874-95-0 | C10H20N2O2 | 详情 | 详情 |
| (V) | 56548 | benzyl 4-({4-[(tert-butoxycarbonyl)amino]-1-piperidinyl}carbonyl)-1-piperidinecarboxylate | C24H35N3O5 | 详情 | 详情 | |
| (VI) | 56549 | benzyl 4-({4-[(tert-butoxycarbonyl)amino]-1-piperidinyl}methyl)-1-piperidinecarboxylate | C24H37N3O4 | 详情 | 详情 | |
| (VII) | 56550 | benzyl 4-[(4-amino-1-piperidinyl)methyl]-1-piperidinecarboxylate | C19H29N3O2 | 详情 | 详情 | |
| (VIII) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |
| (IX) | 56551 | benzyl 4-({4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidinyl}methyl)-1-piperidinecarboxylate | C27H35ClN4O4 | 详情 | 详情 | |
| (X) | 56552 | 4-amino-5-chloro-2-methoxy-N-[1-(4-piperidinylmethyl)-4-piperidinyl]benzamide | C19H29ClN4O2 | 详情 | 详情 | |
| (XI) | 56553 | N-Carbobenzoxy-4-amino-n-butyric acid; N-Carbobenzoxy-gamma-aminobutyric acid | 5105-78-2 | C12H15NO4 | 详情 | 详情 |
| (XII) | 56554 | benzyl 4-[4-({4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidinyl}methyl)-1-piperidinyl]-4-oxobutylcarbamate | C31H42ClN5O5 | 详情 | 详情 |