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【结 构 式】 
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【分子编号】41601 【品名】tert-butyl 4-piperidinylcarbamate; 4-tert-Boc-aminopiperidine 【CA登记号】73874-95-0 |
【 分 子 式 】C10H20N2O2 【 分 子 量 】200.28108 【元素组成】C 59.97% H 10.07% N 13.99% O 15.98% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The alkylation of 4-(tert-butoxycarbonylamino)piperidine (VIII) with (S)-4- methylhexyl methanesulfonate (IX) provided the tertiary amine (X). Cleavage of the Boc protecting group of (X) gave aminopiperidine (XI), which was finally coupled with the chiral hydroxyacid (IV) by means of carbonyl diimidazole.
| 【1】 Tsuchiya, Y.; Nomoto, T.; Ohsawa, H.; Kawakami, K.; Ohwaki, K.; Nishikibe, M. (Banyu Pharmaceutical Co., Ltd.); 1,4-Disubstd. piperidine derivs.. EP 0823423; US 5750540; WO 9633973 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 41601 | tert-butyl 4-piperidinylcarbamate; 4-tert-Boc-aminopiperidine | 73874-95-0 | C10H20N2O2 | 详情 | 详情 |
| (IX) | 41602 | (4S)-4-methylhexyl methanesulfonate | C8H18O3S | 详情 | 详情 | |
| (X) | 41603 | tert-butyl 1-[(4S)-4-methylhexyl]-4-piperidinylcarbamate | C17H34N2O2 | 详情 | 详情 | |
| (XI) | 41604 | 1-[(4S)-4-methylhexyl]-4-piperidinylamine; 1-[(4S)-4-methylhexyl]-4-piperidinamine | C12H26N2 | 详情 | 详情 | |
| (XII) | 31466 | (2R)-2-cyclopentyl-2-hydroxy-2-phenylethanoic acid | C13H16O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)The alkylation of 4-(tert-butoxycarbonylamino)piperidine (VIII) with 5-bromo-2-methyl-2-pentene (IX) provided the tertiary amine (X). Cleavage of the Boc protecting group of (X) gave aminopiperidine (XI), which was finally coupled with the chiral hydroxyacid (IV) by means of carbonyl diimidazole.
| 【1】 Tsuchiya, Y.; Nomoto, T.; Ohsawa, H.; Kawakami, K.; Ohwaki, K.; Nishikibe, M. (Banyu Pharmaceutical Co., Ltd.); 1,4-Disubstd. piperidine derivs.. EP 0823423; US 5750540; WO 9633973 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 31466 | (2R)-2-cyclopentyl-2-hydroxy-2-phenylethanoic acid | C13H16O3 | 详情 | 详情 | |
| (VIII) | 41601 | tert-butyl 4-piperidinylcarbamate; 4-tert-Boc-aminopiperidine | 73874-95-0 | C10H20N2O2 | 详情 | 详情 |
| (IX) | 31462 | 5-bromo-2-methyl-2-pentene | C6H11Br | 详情 | 详情 | |
| (X) | 41607 | tert-butyl 1-(4-methyl-3-pentenyl)-4-piperidinylcarbamate | C16H30N2O2 | 详情 | 详情 | |
| (XII) | 31463 | 1-(4-methyl-3-pentenyl)-4-piperidinamine; 1-(4-methyl-3-pentenyl)-4-piperidinylamine | C11H22N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)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4
该中间体在本合成路线中的序号：(III)A new synthetic route has been reported. 4-Amino-1-benzylpiperidine (I) was protected as the t-butyl carbamate (II) using Boc2O, and the N-benzyl group was subsequently removed by transfer hydrogenolysis, yielding 4-(t-butoxycarbonylamino)piperidine (III). Butyl chloroacetate (V), prepared by treatment of chloroacetyl chloride (IV) with n-butanol, was then condensed with piperidine (III) to afford (VI). After acidic cleavage of the Boc protecting group of (VI), the resultant amino piperidine (VII) was acylated with the mixed anhydride (VIII) to provide the target amide.
| 【1】 Sakaguchi, J.; et al.; An improved synthesis of butyl 4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidineacetate (AU-224). Chem Pharm Bull 2001, 49, 6, 788. |
| 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) | 34808 | 1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine | 50541-93-0 | C12H18N2 | 详情 | 详情 |
| (II) | 56563 | tert-butyl 1-benzyl-4-piperidinylcarbamate | C17H26N2O2 | 详情 | 详情 | |
| (III) | 41601 | tert-butyl 4-piperidinylcarbamate; 4-tert-Boc-aminopiperidine | 73874-95-0 | C10H20N2O2 | 详情 | 详情 |
| (IV) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (V) | 14595 | n-Butyl Chloroacetate; butyl 2-chloroacetate | 590-02-3 | C6H11ClO2 | 详情 | 详情 |
| (VI) | 51930 | butyl 2-[4-[(tert-butoxycarbonyl)amino]-1-piperidinyl]acetate | C16H30N2O4 | 详情 | 详情 | |
| (VII) | 51931 | butyl 2-(4-amino-1-piperidinyl)acetate | C11H22N2O2 | 详情 | 详情 | |
| (VIII) | 29299 | 4-Amino-5-chloro-2-methoxybenzoic acid methoxycarbonyl anhydride | C10H10ClNO5 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(III)Cyclooctanone tosylhydrazone was treated with n-BuLi and subsequently reacted with DMF to afford (II). Compound (III) was prepared from 4-tert-butoxycarbonylpiperidine by reductive alkylation with (II). Deprotection of (III) and condensation with 2,7-dichloroxanthen-9-carboxylic acid (IV) using 1,1'-carbonyldiimidazole (CDI) afforded (V). Compound (V) was quaternarized with iodoethane to provide a quaternary ammonium derivative as a mixture of two isomers (cis and trans) attributed to the 4-substituted piperidinium structure in a ratio of 2:1. Finally, the mixture was separated by silica gel column chromatography to give a major isomer, J-113863.
| 【1】 Naya, A.; et al.; Design, synthesis, and discovery of a novel CCR1 antagonist. J Med Chem 2001, 44, 9, 1429. |
| 【2】 Saeki, T.; Naya, A.; J-113863. Drugs Fut 2001, 26, 2, 121. |
| 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) | 14209 | Cyclooctanone | 502-49-8 | C8H14O | 详情 | 详情 |
| (II) | 37975 | 1-cyclooctene-1-carbaldehyde | C9H14O | 详情 | 详情 | |
| (III) | 41601 | tert-butyl 4-piperidinylcarbamate; 4-tert-Boc-aminopiperidine | 73874-95-0 | C10H20N2O2 | 详情 | 详情 |
| (IV) | 44356 | tert-butyl 1-(1-cycloocten-1-ylmethyl)-4-piperidinylcarbamate | C19H34N2O2 | 详情 | 详情 | |
| (V) | 37972 | 2,7-dichloro-9H-xanthene-9-carboxylic acid | C14H8Cl2O3 | 详情 | 详情 | |
| (VI) | 37976 | 2,7-dichloro-N-[1-(1-cycloocten-1-ylmethyl)-4-piperidinyl]-9H-xanthene-9-carboxamide | C28H32Cl2N2O2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)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 |