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【结 构 式】

【分子编号】32229

【品名】(2R,6S)-2,6-dimethylpiperidine; cis-2,6-dimethylpiperidine

【CA登记号】

【 分 子 式 】C7H15N

【 分 子 量 】113.20284

【元素组成】C 74.27% H 13.36% N 12.37%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(IV)

The reaction of gamma-chlorobutyrophenone (I) with ethylene glycol (II) by means of p-toluenesulfonic acid in refluxing benzene gives the corresponding ethylene ketal (III), which is condensed with cis-2,6-dimethylpiperidine (IV) by means of Na and heat, and hydrolyzed with concentrated HCl yielding gamma-(cis-2,6-dimethyl-1-piperidyl)butyrophenone (V). Finally, this compound is condensed with 2-bromopyridine (VI) by means of butyllithium in THF.

1 Fleming, R.W. (Pfizer Inc.); Antiarrhythmic (+,-)-cis- alpha [3-(2,6-dimethyl-1-piperidinyl)propyl]-alpha-phenyl-2-pyridinemethanols. US 4112103 .
2 Blancafort, P.; Serradell, M.N.; Castaner, J.; Hillier, K.; Pirmenol hydrochloride. Drugs Fut 1981, 6, 4, 234.
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) 32227 gamma-Chlorobutyrophenone; 4-Chloro-1-phenyl-1-butanone 939-52-6 C10H11ClO 详情 详情
(II) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(III) 32228 2-(3-chloropropyl)-2-phenyl-1,3-dioxolane C12H15ClO2 详情 详情
(IV) 32229 (2R,6S)-2,6-dimethylpiperidine; cis-2,6-dimethylpiperidine C7H15N 详情 详情
(V) 32230 gamma-(cis-2,6-dimethyl-1-piperidyl)butyrophenone; 4-[(2R,6S)-2,6-dimethylpiperidinyl]-1-phenyl-1-butanone; gamma-(cis-2,6-dimethyl-1-piperidyl)butyrophenone C17H25NO 详情 详情
(VI) 29052 2-Bromopyridine;α-bromopyridine;α-bromoazine 109-04-6 C5H4BrN 详情 详情

合成路线2

该中间体在本合成路线中的序号:(IV)

The reaction of dimethylpiperidine (IV) with 3-bromopropanol (VII) in refluxing xylene gives 1-(3-hydroxypropyl)-2,6-cis-dimethylpiperidine (VIII), which by treatment with SOCl2 in refluxing benzene is converted into 1-(3-chloropropyl)-2,6-cis-dimethylpiperidine (IX). Finally, this compound is condensed with 2-benzoylpyridine (X) by means of Li in THF.

1 Fleming, R.W. (Pfizer Inc.); Antiarrhythmic (+,-)-cis- alpha [3-(2,6-dimethyl-1-piperidinyl)propyl]-alpha-phenyl-2-pyridinemethanols. US 4112103 .
2 Blancafort, P.; Serradell, M.N.; Castaner, J.; Hillier, K.; Pirmenol hydrochloride. Drugs Fut 1981, 6, 4, 234.
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) 32229 (2R,6S)-2,6-dimethylpiperidine; cis-2,6-dimethylpiperidine C7H15N 详情 详情
(VII) 12573 3-Bromo-1-propanol; 3-Bromopropanol 627-18-9 C3H7BrO 详情 详情
(VIII) 32231 1-(3-hydroxypropyl)-2,6-cis-dimethylpiperidine; 3-[(2R,6S)-2,6-dimethylpiperidinyl]-1-propanol C10H21NO 详情 详情
(IX) 32232 1-(3-chloropropyl)-2,6-cis-dimethylpiperidine; (2R,6S)-1-(3-chloropropyl)-2,6-dimethylpiperidine C10H20ClN 详情 详情
(X) 32233 2-Benzoylpyridine; Phenyl(2-pyridinyl)methanone 91-02-1 C12H9NO 详情 详情

合成路线3

该中间体在本合成路线中的序号:(IX)

Benzyl ester (VII) was prepared by reaction of N-Boc-L-gamma-methylleucine (VI) with benzyl bromide in the presence of Cs2CO3. Subsequent N-Boc group cleavage in (VII) by means of HCl in dioxane furnished gamma-methylleucine benzyl ester (VIII). Amino ester (VIII) was converted into urea (X) by condensation with 2,6-dimethylpiperidine (IX) either in the presence of carbonyl diimidazole or diphosgene. Then, hydrogenolysis of the benzyl ester group of (X) in the presence of Pd/C led to the N-carbamoyl aminoacid (XI). Coupling of amino acid (XI) with dipeptide (V) in the presence of EDC and HOBt gave the tripeptide derivative (XII). The tert-butyl ester group of (XII) was then cleaved under acidic conditions, and the resultant carboxylic acid was finally converted to the corresponding sodium salt by treatment with NaHCO3.

1 He, J.X.; et al.; An efficient preparation of the pseudopeptide endothelin-B receptor selective antagonist BQ-788. J Org Chem 1995, 60, 25, 8262.
2 Ishikawa, K.; Fukami, T.; Nagase, T.; Mase, T.; Ihara, M.; Yano, M.; Nishikibe, M. (Banyu Pharmaceutical Co., Ltd.); Endothelin antagonistic substance. EP 0555537; JP 1994107680 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 55973 methyl 3-((2R)-2-amino-3-{[(1R)-1-(tert-butoxycarbonyl)pentyl]amino}-3-oxopropyl)-1H-indole-1-carboxylate C23H33N3O5 详情 详情
(VI) 55974 (2S)-2-[(tert-butoxycarbonyl)amino]-4,4-dimethylpentanoic acid C12H23NO4 详情 详情
(VII) 55975 benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-4,4-dimethylpentanoate C19H29NO4 详情 详情
(VIII) 55976 benzyl (2S)-2-amino-4,4-dimethylpentanoate C14H21NO2 详情 详情
(IX) 32229 (2R,6S)-2,6-dimethylpiperidine; cis-2,6-dimethylpiperidine C7H15N 详情 详情
(X) 55977 benzyl (2S)-2-({[(2R,6S)-2,6-dimethylpiperidinyl]carbonyl}amino)-4,4-dimethylpentanoate C22H34N2O3 详情 详情
(XI) 55978 (2S)-2-({[(2R,6S)-2,6-dimethylpiperidinyl]carbonyl}amino)-4,4-dimethylpentanoic acid C15H28N2O3 详情 详情
(XII) 55979 methyl 3-((2R)-3-{[(1R)-1-(tert-butoxycarbonyl)pentyl]amino}-2-{[(2S)-2-({[(2R,6S)-2,6-dimethylpiperidinyl]carbonyl}amino)-4,4-dimethylpentanoyl]amino}-3-oxopropyl)-1H-indole-1-carboxylate C38H59N5O7 详情 详情
Extended Information