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【结 构 式】

【分子编号】12076

【品名】4-Piperidinol; 4-Hydroxypiperidine

【CA登记号】5382-16-1

【 分 子 式 】C5H11NO

【 分 子 量 】101.14848

【元素组成】C 59.37% H 10.96% N 13.85% O 15.82%
与该中间体有关的原料药合成路线共 20 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20

合成路线1

该中间体在本合成路线中的序号：(III)

The reaction of 4-chloro-1-(4-fluorophenyl)-1-butanone (I) with ethylene glycol and p-toluenesulfonic acid in refluxing benzene gives the corresponding ethyleneketal (II), which is condensed with 4-hydroxypiperidine (III) by means of K2CO3 in hot DMF yielding 1-(4-fluorophenyl)-4-(4-hydroxypiperidin-1-yl)-1-butanone ethyleneketal (IV). The Oppenauer oxidation of (IV) with 9-fluorenone and potassium tert-butoxide in hot benzene affords the piperidinone (V), which is condensed with 4-bromo-N-(trimethylsilyl)aniline (VI) by means of BuLi in hot hexane to give 4-[4-(4-aminophenyl)-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)-1-butanone (VII). Finally, this compound is treated with CuBr2 and NO in THF.

参考文献 中间体
合成目标
【1】 Vincent, S.H.; et al.; Synthesis of [82Br]bromperidol and preliminary tissue distribution studies in the rat. J Med Chem 1980, 23, 1, 75.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(I) 35864 4-chloro-1-(4-fluorophenyl)-1-butanone 3874-54-2 C10H10ClFO 详情 详情
(II) 28203 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane 3308-94-9 C12H14ClFO2 详情 详情
(III) 12076 4-Piperidinol; 4-Hydroxypiperidine 5382-16-1 C5H11NO 详情 详情
(IV) 35865 1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-piperidinol C17H24FNO3 详情 详情
(V) 35866 1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-piperidinone C17H22FNO3 详情 详情
(VI) 35867 N-(4-bromophenyl)(trimethyl)silanamine; N-(4-bromophenyl)-N-(trimethylsilyl)amine C9H14BrNSi 详情 详情
(VII) 35868 4-[4-(4-aminophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone C21H25FN2O2 详情 详情
(VIII) 22531 4-Bromoaniline; 4-Bromophenylamine 106-40-1 C6H6BrN 详情 详情
(IX) 35869 　 C6H5Br2MgN 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 reaction of 4-chloro-1-(4-fluorophenyl)-1-butanone (I) with ethylene glycol and p-toluenesulfonic acid in refluxing benzene gives the corresponding ethylene-ketal (II), which is condensed with 4-hydroxypiperidine (III) by means of K2CO3 in hot DMF yielding 1-(4-fluorophenyl)-4-(4-hydroxypiperidin-1-yl)-1-butanone ethyle-neketal (IV). The Oppenauer oxidation of (IV) with 9-fluorenone and potassium tert-butoxide in hot benzene affords the piperidinone (V), which is condensed with 4-bromo-N-(trimethylsilyl)aniline (VI) by means of BuLi in hot hexane to give 4-[4-(4-aminophenyl)-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)-1-butanone (VII). Finally, this compound is treated with Cu82Br2 and NO in THF.

参考文献 中间体
合成目标
【1】 Vincent, S.H.; et al.; Synthesis of [82Br]bromperidol and preliminary tissue distribution studies in the rat. J Med Chem 1980, 23, 1, 75.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(I) 35864 4-chloro-1-(4-fluorophenyl)-1-butanone 3874-54-2 C10H10ClFO 详情 详情
(II) 28203 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane 3308-94-9 C12H14ClFO2 详情 详情
(III) 12076 4-Piperidinol; 4-Hydroxypiperidine 5382-16-1 C5H11NO 详情 详情
(IV) 35865 1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-piperidinol C17H24FNO3 详情 详情
(V) 35866 1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-piperidinone C17H22FNO3 详情 详情
(VI) 35867 N-(4-bromophenyl)(trimethyl)silanamine; N-(4-bromophenyl)-N-(trimethylsilyl)amine C9H14BrNSi 详情 详情
(VII) 35868 4-[4-(4-aminophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone C21H25FN2O2 详情 详情
(VIII) 22531 4-Bromoaniline; 4-Bromophenylamine 106-40-1 C6H6BrN 详情 详情
(IX) 35869 　 C6H5Br2MgN 详情 详情

合成路线3

该中间体在本合成路线中的序号：(II)

3-(4-Hydroxypiperidino)-6-(2-chlorophenyl)pyridazine (CM-40907) is synthesized from 3-chloro-6-(2-chlorophenyl)pyridazine (I) in boiling 1-butanol (A) with an excess of 4-hydroxypiperidine (II).

参考文献 中间体
合成目标
【1】 Chambon, J.P.; Brodin, R.; Biziere, K.; Hallot, A.; Roncucci, R.; Brochard, J.; Heaulme, M.; CM 40907: A structurally novel anticonvulsant in mice, rats and baboons. J Pharmacol Exp Ther 1985, 233, 3, 836-844.
【2】 Loscher, W.; CM-40907. Drugs Fut 1985, 10, 11, 903.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 29766 butanol; n-butanol; 1-butanol 71-36-3 C4H10O 详情 详情
(I) 29765 3-chloro-6-(2-chlorophenyl)pyridazine C10H6Cl2N2 详情 详情
(II) 12076 4-Piperidinol; 4-Hydroxypiperidine 5382-16-1 C5H11NO 详情 详情

合成路线4

该中间体在本合成路线中的序号：(II)

The reaction of 3-chloro-6-(2,4-dicliorophenyl)-pyridazine (I) with 4 hydroxypiperidine (I) in refluxing n-butano and heating gives 6-(2,4-dichlorophenyl)-3-(4 hydroxypiperidino)pyridazine.

参考文献 中间体
合成目标
【1】 Dubois, M.; SR-41378. Drugs Fut 1986, 11, 4, 286.
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) 24032 3-Chloro-6-(2,4-dichlorophenyl)pyridazine C10H5Cl3N2 详情 详情
(II) 12076 4-Piperidinol; 4-Hydroxypiperidine 5382-16-1 C5H11NO 详情 详情

合成路线5

该中间体在本合成路线中的序号：

The bromination of 5-fluoro-2-methylquinoline (I) with Br2 and Ag2SO4 in H2SO4 or with Br2 and AlCl3 gives 5-bromo-6-fluoro-2-methylquinoline (II), which is reduced with H2 over PtO2 in acetic acid, yielding 5-bromo-6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (III). The cyclization of (III) with diethyl ethoxymethylenemalonate (IV) and polyphosphoric acid (PPA) at 150 C affords 8-bromo-9-fluoro-5-methyl-1-oxo-6,7-dihydro-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (V), which is finally condensed with 4-hydroxypiperidine (VI) by heating at 160 C in HMPT.

参考文献 中间体
合成目标
【1】 Kano, M.; Nakagawa, K.; Ishikawa, H.; Uno, T. (Otsuka Pharmaceutical Co., Ltd.); Antibacterial agents. JP 1983090511 .
【2】 Bernauer, K.; Borgulya, J.; Bruderer, H.; Da Prada, M.; Zurcher, G. (F. Hoffmann-La Roche AG); 3,5-Disubstituted pyrocatechol derivs. EP 0237929; US 5389653; US 5476875 .
【3】 Ishikawa, H.; Tabusa, F.; Miyamoto, H.; Kano, M.; Ueda, H.; Tamaoka, H.; Nakagawa, K.; Synthesis of substituted 6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acids. Chem Pharm Bull 1989, 37, 8, 2103-8.
【4】 Prous, J.; Castaner, J.; OPC-7251. Drugs Fut 1990, 15, 7, 685.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12076 4-Piperidinol; 4-Hydroxypiperidine 5382-16-1 C5H11NO 详情 详情
(I) 10869 6-Fluoro-2-methylquinoline 1128-61-6 C10H8FN 详情 详情
(II) 10870 5-Bromo-6-fluoro-2-methylquinoline C10H7BrFN 详情 详情
(III) 10871 5-Bromo-6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline C10H11BrFN 详情 详情
(IV) 10872 diethyl 2-[(E)-ethoxymethylidene]succinate C11H18O5 详情 详情
(V) 10873 8-Bromo-9-fluoro-5-methyl-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid C14H11BrFNO3 详情 详情

合成路线6

该中间体在本合成路线中的序号：(V)

Synthesis of intermediate (X): 4-Hydroxypiperidine (V) is protected with ethyl chloroformate to give (VI), which is then condensed with bromodiphenylmethane in the presence of sodium carbonate yielding (VII). AIkali hydrolysis of (VII) gives (VIII), which is then treated with N-(2-bromoethyl)phthalimide to yield (IX). (IX) is then deprotected by a treatment of 80% hydrazine hydrate, producing (X).

参考文献 中间体
合成目标
【1】 Tasaka, K.; TMK-688. Drugs Fut 1988, 13, 12, 1056.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
37025 2-(2-bromoethyl)-1H-isoindole-1,3(2H)-dione 574-98-1 C10H8BrNO2 详情 详情
(IIb) 12079 Bromodiphenylmethane; 1-[Bromo(phenyl)methyl]benzene; Benzhydrylbromide 776-74-9 C13H11Br 详情 详情
(V) 12076 4-Piperidinol; 4-Hydroxypiperidine 5382-16-1 C5H11NO 详情 详情
(VI) 22709 ethyl 4-hydroxy-1-piperidinecarboxylate C8H15NO3 详情 详情
(VII) 12080 ethyl 4-(benzhydryloxy)tetrahydro-1(2H)-pyridinecarboxylate C21H25NO3 详情 详情
(VIII) 12081 4-(Benzhydryloxy)piperidine; Benzhydryl 4-piperidinyl ether C18H21NO 详情 详情
(IX) 22713 2-[2-[4-(benzhydryloxy)-1-piperidinyl]ethyl]-1H-isoindole-1,3(2H)-dione C28H28N2O3 详情 详情
(X) 22707 2-[4-(benzhydryloxy)-1-piperidinyl]ethylamine; 2-[4-(benzhydryloxy)-1-piperidinyl]-1-ethanamine C20H26N2O 详情 详情

合成路线7

该中间体在本合成路线中的序号：(I)

This compound can be obtained by two related routes: 1) Condensation of 4-hydroxypiperidine (I) with p-tert-butyl-omega-chlorobutyrophenone (II) in hot methyl isobutyl ketone in presence of sodium bicarbonate gives 1-[3-(4-tert-butylbenzoyl)propyl]-4-hydroxypiperidine (III), which reacts with diphenylmethyl bromide (IV) in methyl isobutyl ketone to give ebastine. 2) 4-Diphenylmethoxypiperidine (VI), obtained by alkaline hydrolysis of 1-ethoxycarbonyl-4-diphenyl-methoxypiperidine (V) was reacted with p-tert-butyl-omega-chlorobutyrophenone (II) to give ebastine.

参考文献 中间体
合成目标
【1】 Spickett, R.G.W.; Moragues, J.; Prieto, J.; Vega, A. (Fordonal S.A.); Piperidine derivs. EP 0134124B; US 4550116 .
【2】 Moragues, J.; Roberts, D.J.; EBASTINE. Drugs Fut 1990, 15, 7, 674.
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) 12076 4-Piperidinol; 4-Hydroxypiperidine 5382-16-1 C5H11NO 详情 详情
(II) 12077 4-Chloro-1-[4-(1,1-dimethylethyl)phenyl]-1-butanone; 1-[4-(tert-Butyl)phenyl]-4-chloro-1-butanone; 4'-tert-Butyl-4-chlorobutyrophenone 43076-61-5 C14H19ClO 详情 详情
(III) 12078 1-[4-(tert-Butyl)phenyl]-4-(4-hydroxypiperidino)-1-butanone C19H29NO2 详情 详情
(IV) 12079 Bromodiphenylmethane; 1-[Bromo(phenyl)methyl]benzene; Benzhydrylbromide 776-74-9 C13H11Br 详情 详情
(V) 12080 ethyl 4-(benzhydryloxy)tetrahydro-1(2H)-pyridinecarboxylate C21H25NO3 详情 详情
(VI) 12081 4-(Benzhydryloxy)piperidine; Benzhydryl 4-piperidinyl ether C18H21NO 详情 详情

合成路线8

该中间体在本合成路线中的序号：(VI)

The racemic form of E-5880 is prepared as follows: The esterification of 2-methoxy-1,3-propanediol (I) with phenyl chlorocarbonate (II) in pyridine gives the diester (III), which is treated with 2-(aminomethyl)pyridine (IV) in refluxing chloroform, yielding the carbamate (V). The reaction of (V) with 4-hydroxypiperidine (VI) in refluxing chloroform affords the dicarbamate (VII), which by treatment with octadecyl isocyanate (VIII) gives the tricarbamate (X). Alternatively, (X) can be obtained by treatment of (VIII) with carbonate (II), yielding the intermediate (IX), which by treatment with octadecylamine (XI) at 100 C affords (X). The acylation of (X) with 2-methoxybenzoyl chloride (XII) in pyridine gives the precursor (XIII), which is finally treated with ethyl iodide in excess at reflux temperature and submitted to an ion exchange resin (Amberlite IRA-410 Cl- type). The optically active (R)-enantiomer is synthesized starting from L-mannitol.

参考文献 中间体
合成目标
【1】 Okano, K.; Asano, O.; Shimomura, N.; Kawahara, T.; Abe, S.; Miyazawa, S.; Miyamoto, M.; Yoshimura, H.; Harada, K.; Nagaoka, J.; Kawata, T.; Yoshimura, T.; Suzuki, H.; Souda, S.; Machida, Y.; Katayama, K.; Yamatsu, I. (Eisai Co., Ltd.); Glycerin deriv. and its pharmacological use. AU 8937213; EP 0353474; JP 1990131467; JP 1996231508; US 5037827; US 5273985; US 5476863; US 5476864 .
【2】 Okano, K.; Shimomura, N.; Asano, O.; et al.; Okano, K., Asano, O., Shimomura, N. et al. Structure-activity relationships of platelet activating factor (PAF) antagonists. 198th ACS Natl Meet (Sept 10-15, Miami Beach) 1989, Abst MEDI 55.
【3】 Prous, J.; Castaner, J.; E-5880. Drugs Fut 1992, 17, 12, 1082.
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) 13579 2-Methoxy-1,3-propanediol C4H10O3 详情 详情
(II) 13580 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate 1885-14-9 C7H5ClO2 详情 详情
(III) 13581 2-methoxy-3-[(phenoxycarbonyl)oxy]propyl phenyl carbonate C18H18O7 详情 详情
(IV) 13582 2-Pyridinylmethanamine; 2-Pyridinylmethylamine; 2-(Aminomethyl)pyridine 3731-51-9 C6H8N2 详情 详情
(V) 13583 (5-oxo-6-phenyl-1,4-dioxan-2-yl)methyl 2-pyridinylmethylcarbamate C18H18N2O5 详情 详情
(VI) 12076 4-Piperidinol; 4-Hydroxypiperidine 5382-16-1 C5H11NO 详情 详情
(VII) 13585 2-methoxy-3-([[(2-pyridinylmethyl)amino]carbonyl]oxy)propyl 4-hydroxy-1-piperidinecarboxylate C17H25N3O6 详情 详情
(VIII) 13586 1-Isocyanatooctadecane; octadecyl isocyanate 112-96-9 C19H37NO 详情 详情
(IX) 13587 2-methoxy-3-([[(2-pyridinylmethyl)amino]carbonyl]oxy)propyl 4-[(phenoxycarbonyl)oxy]-1-piperidinecarboxylate C24H29N3O8 详情 详情
(X) 13588 2-methoxy-3-([[(2-pyridinylmethyl)amino]carbonyl]oxy)propyl 4-[[(octadecylamino)carbonyl]oxy]-1-piperidinecarboxylate C36H62N4O7 详情 详情
(XI) 13589 1-Aminooctadecane; Octadecylamine; 1-Octadecanamine 124-30-1 C18H39N 详情 详情
(XII) 13590 2-Methoxybenzoyl chloride; o-Anisoyl chloride; 2-Anisoyl chloride 21615-34-9 C8H7ClO2 详情 详情
(XIII) 13591 2-methoxy-3-([[(2-methoxybenzoyl)(2-pyridinylmethyl)amino]carbonyl]oxy)propyl 4-[[(octadecylamino)carbonyl]oxy]-1-piperidinecarboxylate C44H68N4O9 详情 详情

合成路线9

该中间体在本合成路线中的序号：(IV)

Reaction of theophylline (I) with 1,3-dibromopropane (II) in DMF in the presence of triethylamine afforded the bromo intermediate (III)) in 77% yield. Reaction of (III) with 4-hydroxypiperidine (IV) in DMF in the presence of sodium bicarbonate afforded the unsubstituted hydroxypiperidinyl intermediate (V) in 31% yield which was subsequently alkylated with diphenylmethylbromide (VI) to afford Wy-49,051 in 29% yield.

参考文献 中间体
合成目标
【1】 Abou-Gharbia, M.A.; Nielsen, S.T.; Webb, M.B. (American Home Products Corp.); Histamine H1-antagonists. EP 0271192; GB 2196963; JP 1988152381; US 4716166 .
【2】 Abou-Gharbia, M.; Wy-49,051. Drugs Fut 1990, 15, 2, 137.
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) 63786 1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione C7H8N4O2 详情 详情
(II) 12581 1,3-Dibromopropane 109-64-8 C3H6Br2 详情 详情
(III) 13592 7-(3-Bromopropyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione C10H13BrN4O2 详情 详情
(IV) 12076 4-Piperidinol; 4-Hydroxypiperidine 5382-16-1 C5H11NO 详情 详情
(V) 13593 7-[3-(4-Hydroxy-1-piperidinyl)propyl]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione C15H23N5O3 详情 详情
(VI) 12079 Bromodiphenylmethane; 1-[Bromo(phenyl)methyl]benzene; Benzhydrylbromide 776-74-9 C13H11Br 详情 详情
(VII) 63787 7-{3-[4-(benzhydryloxy)-1-piperidinyl]propyl}-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione C28H33N5O3 详情 详情

合成路线10

该中间体在本合成路线中的序号：(I)

The acylation of 4-hydroxypiperidine (I) with benzyl chloroformate (II) by means of triethylamine in dichloromethane gives 4-hydroxypiperidine-1-carboxylic acid benzyl ester (III), which is condensed with tert-butyl bromoacetate (IV) by means of tetrabutylammonium hydrogensulfate and NaOH in toluene/water, affording 2-[1-(benzyloxycarbonyl)piperidin-4-yloxy]acetic acid tert-butyl ester (V). The deprotection of (V) by hydrogenation with H2 over Pd/C in ethanol gives the piperidine (VI), which is condensed with N-(benzyloxycarbonyl)-4-O-tert-butyl-L-tyrosine (VII) by means of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-methylmorpholine (NMM) in dichloromethane, yielding the expected condensation product (VIII). The deprotection of the amino group of (VIII) by hydrogenation as before affords (IX), which is N-acylated with 4-amidinobenzoyl chloride (X), prepared by reaction of 4-amidinobenzoic acid (XI) with SOCl2, giving the bis-tert-butylated product (XII). Finally, this compound is deprotected by means of trifluoroacetic acid in dichloromethane.

参考文献 中间体
合成目标
【1】 Weller, T.; Hadvary, P.; Trzeciak, A.; Knopp, D.; Steiner, B.; Edenhofer, A.; Muller, M.; Hurzeler, M.; Alig, L.; Low molecular weight, non-peptide fibrinogen receptor antagonists. J Med Chem 1992, 35, 23, 4393.
【2】 Castaner, J.; Merlos, M.; Cases, A.; Rabasseda, X.; Lamifiban. Drugs Fut 1999, 24, 3, 261.
【3】 Alig, L.; Hadvary, P.; Huzeler, M.; Muller, M.; Steiner, B.; Weller, T. (F. Hoffmann-La Roche AG); N-acyl-alpha-aminoacids derivs.. EP 0505868; JP 1993148204; US 5378712; US 5545658; US 5658928; US 5670515; US 5747522 .
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) 12076 4-Piperidinol; 4-Hydroxypiperidine 5382-16-1 C5H11NO 详情 详情
(II) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(III) 19284 benzyl 4-hydroxy-1-piperidinecarboxylate C13H17NO3 详情 详情
(IV) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(V) 19286 benzyl 4-[2-(tert-butoxy)-2-oxoethoxy]-1-piperidinecarboxylate C19H27NO5 详情 详情
(VI) 19287 tert-butyl 2-(4-piperidinyloxy)acetate C11H21NO3 详情 详情
(VII) 22478 (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[4-(tert-butoxy)phenyl]propionic acid C21H25NO5 详情 详情
(VIII) 22479 tert-butyl 2-[(1-[(2S)-2-[[(benzyloxy)carbonyl]amino]-3-[4-(tert-butoxy)phenyl]propanoyl]-4-piperidinyl)oxy]acetate C32H44N2O7 详情 详情
(IX) 22480 tert-butyl 2-[(1-[(2S)-2-amino-3-[4-(tert-butoxy)phenyl]propanoyl]-4-piperidinyl)oxy]acetate C24H38N2O5 详情 详情
(X) 22481 4-[amino(imino)methyl]benzoyl chloride C8H7ClN2O 详情 详情
(XI) 22482 4-Amidinobenzic acid; 4-[amino(imino)methyl]benzoic acid 15535-95-2 C8H8N2O2 详情 详情
(XII) 22483 tert-butyl 2-[(1-[(2S)-2-([4-[amino(imino)methyl]benzoyl]amino)-3-[4-(tert-butoxy)phenyl]propanoyl]-4-piperidinyl)oxy]acetate C32H44N4O6 详情 详情

合成路线11

该中间体在本合成路线中的序号：

The key intermediate (VI) is synthesized through the condensation of 5-methylnicotinic acid (VIII) with 4-hydroxypiperidine by means of DCC in DMF to give amide (IX), followed by reduction with POCl3 and NaBH4 to give the amino alcohol (X), which is treated with SOCl2.

参考文献 中间体
合成目标
【1】 Carceller, E.; Jiménez, P.J.; Salas, J. (J. Uriach & Cia., SA); Process for the preparation of 8-chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine. ES 9602107 .
【2】 García-Rafanell, J.; Rupatadine Fumarate. Drugs Fut 1996, 21, 10, 1032.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12076 4-Piperidinol; 4-Hydroxypiperidine 5382-16-1 C5H11NO 详情 详情
(VI) 16505 4-chloro-1-[(5-methyl-3-pyridinyl)methyl]piperidine C12H17ClN2 详情 详情
(VIII) 16507 5-methylnicotinic acid 3222-49-9 C7H7NO2 详情 详情
(IX) 16508 (4-hydroxypiperidino)(5-methyl-3-pyridinyl)methanone C12H16N2O2 详情 详情
(X) 16509 1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinol C12H18N2O 详情 详情

合成路线12

该中间体在本合成路线中的序号：(VII)

2) The reaction of 4-hydroxypiperidine (VII) with benzyl chloroformate (VIII) by means of triethylamine in dichloromethane gives the expected benzyloxycarbonyl derivative (IX), which is condensed with tert-butyl 2-bromoacetate (X) by means of tetrabutylammonium bisulfate and NaOH, yielding 2-[1-(benzyloxycarbonyl)piperidin-4-yloxy]acetic acid tert-butyl ester (XI). The deprotection of (XI) as ususal affords 2-(4-piperidinyloxy)acetic acid tert-butyl ester (XII), which is condensed with N-(benzyloxycarbonyl)-L-alanine (XIII) by means of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-methyl-morpholine (NMM) in dichloromethane to yield the acylated piperidine (XIV). The deprotection of (XIV) as usual affords compound (XV), which is acylated at the free amino group with 4-cyanobenzoyl chloride (V) and tetrabutylammonium bisulfate to give 2-[1-[N-(4-cyanobenzoyl)-L-alanyl]piperidin-4-yloxy]acetic acid tert-butyl ester (XVI). The reaction of the cyano group of (XVI) with hydroxylamine affords compound (XVII) with a hydroxyamidino substituent. Finally, the tert-butyl ester group of (XVII) is converted in ethyl ester by hydrolysis with hot fomic acid to the corresponding acetic acid (XVIII) and subsequent esterification with ethanol/H2SO4.

参考文献 中间体
合成目标
【1】 Alig, L.; Beresini, M.; Weller, T.; et al.; Orally active fibrinogen receptor antagonists. 2. Amidoximes as prodrugs of amidines. J Med Chem 1996, 39, 16, 3139.
【2】 Weller, T.; Hadvary, P.; Trzeciak, A.; Knopp, D.; Steiner, B.; Edenhofer, A.; Muller, M.; Hurzeler, M.; Alig, L.; Low molecular weight, non-peptide fibrinogen receptor antagonists. J Med Chem 1992, 35, 23, 4393.
【3】 Castañer, J.; Graul, A.; Merlos, M.; Sibrafiban . Drugs Fut 1998, 23, 12, 1297.
【4】 Alig, L.; Hadvary, P.; Hurzeler Muller, M.; Muller, M.; Steiner, B.; Weller, T. (F. Hoffmann-La Roche AG); Acetic acid derivs. as medicaments. EP 0656348; JP 1995196592; US 5726185 .
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) 19280 4-cyanobenzoyl chloride 6068-72-0 C8H4ClNO 详情 详情
(VII) 12076 4-Piperidinol; 4-Hydroxypiperidine 5382-16-1 C5H11NO 详情 详情
(VIII) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(IX) 19284 benzyl 4-hydroxy-1-piperidinecarboxylate C13H17NO3 详情 详情
(X) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(XI) 19286 benzyl 4-[2-(tert-butoxy)-2-oxoethoxy]-1-piperidinecarboxylate C19H27NO5 详情 详情
(XII) 19287 tert-butyl 2-(4-piperidinyloxy)acetate C11H21NO3 详情 详情
(XIII) 61209 CBZ-L-Alanine; (2S)-2-[[(Benzyloxy)carbonyl]amino]propionic acid; N-((Phenylmethoxy)carbonyl)-alanine; Carbobenzyloxy-L-alanine C11H13NO4 详情 详情
(XIV) 19289 tert-butyl 2-[[1-((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)-4-piperidinyl]oxy]acetate C22H32N2O6 详情 详情
(XV) 19290 tert-butyl 2-([1-[(2S)-2-aminopropanoyl]-4-piperidinyl]oxy)acetate C14H26N2O4 详情 详情
(XVI) 19291 tert-butyl 2-[(1-[(2S)-2-[(4-cyanobenzoyl)amino]propanoyl]-4-piperidinyl)oxy]acetate C22H29N3O5 详情 详情
(XVII) 19292 tert-butyl 2-([1-[(2S)-2-([4-[amino(hydroxyimino)methyl]benzoyl]amino)propanoyl]-4-piperidinyl]oxy)acetate C22H32N4O6 详情 详情
(XVIII) 19293 2-([1-[(2S)-2-([4-[amino(hydroxyimino)methyl]benzoyl]amino)propanoyl]-4-piperidinyl]oxy)acetic acid C18H24N4O6 详情 详情

合成路线13

该中间体在本合成路线中的序号：(II)

The reaction of N-(tert-butoxycarbonyl)-L-4-fluorophenylalanine (I) with 4-hydroxypiperidine (II) by means of triethylamine, EDC and HOBT in dichloromethane gives the expected piperidide (III), which is deprotected with with HCl in dioxane to afford (IV) with a free amino group that is condensed with 5-chloro-1H-indole-2-carboxylic acid (V) by means of triethylamine, EDC and HOBT as before.

参考文献 中间体
合成目标
【1】 Hoover, D.J.; et al.; Indole-2-carboxamide inhibitors of human liver glycogen phosphorylase. J Med Chem 1998, 41, 16, 2934.
【2】 Hulin, B.; Hoover, D.J.; Treadway, J.L.; Martin, W.H.; Phillips, D. (Pfizer Inc.); Substd. N-(indole-2-carbonyl)-glycinamides and derivs. as glycogen phosphorylase inhibitors. EP 0832065; WO 9639384 .
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) 25929 (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-fluorophenyl)propionic acid C14H18FNO4 详情 详情
(II) 12076 4-Piperidinol; 4-Hydroxypiperidine 5382-16-1 C5H11NO 详情 详情
(III) 25930 tert-butyl (1S)-1-(4-fluorobenzyl)-2-(4-hydroxy-1-piperidinyl)-2-oxoethylcarbamate C19H27FN2O4 详情 详情
(IV) 25931 (2S)-2-amino-3-(4-fluorophenyl)-1-(4-hydroxy-1-piperidinyl)-1-propanone C14H19FN2O2 详情 详情
(V) 25932 5-Chloroindole-2-carboxylic acid; 5-Chloro-1H-indole-2-carboxylic acid 10517-21-2 C9H6ClNO2 详情 详情

合成路线14

该中间体在本合成路线中的序号：(IX)

5-Bromovaleryl chloride (VI) was reduced to aldehyde (VII) by means of lithium tri-tert-butoxyaluminumhydride at -78 C and subsequently converted into the dimethyl acetal (VIII) with H2SO4 in methanol (1). Alkylation of 4-hydroxypiperidine (IX) with bromoacetal (VIII) gave adduct (X). This was subjected to Fisher indolization with the hydrazine (V), yielding indole (XI). The piperidine hydroxyl group was then oxidized to the corresponding ketone (XII) using sulfur trioxide-pyridine complex in DMSO.

参考文献 中间体
合成目标
【1】 Matassa, V.G.; Pengilley, R.R.; Russell, M.G.N.; et al.; 3-[3-(Piperidin-1-yl)propyl]indoles as highly selective h5-HT1D receptor agonists. J Med Chem 1999, 42, 24, 4981.
【2】 Baker, R.; Bourrain, S.; Castro Pineiro, J.L.; Chambers, M.S.; Guiblin, A.R.; Hobbs, S.C.; Jelley, R.A.; Madin, A.; Matassa, V.G.; Reeve, A.J.; Russell, M.G.N.; Showell, G.A.; Sternfeld, F.; Street, L.J.; Van Niel, M.B. (Merck Sharp & Dohme Ltd.); Azetidine, pyrrolidine and piperidine derivs.. EP 0804434; JP 1998503768; US 5854268; WO 9604274 .
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) 25647 4-(4-hydrazinophenyl)-4H-1,2,4-triazole C8H9N5 详情 详情
(VI) 39700 5-bromopentanoyl chloride 4509-90-4 C5H8BrClO 详情 详情
(VII) 43094 5-bromopentanal C5H9BrO 详情 详情
(VIII) 25645 5-bromo-1-methoxypentyl methyl ether; 5-bromo-1,1-dimethoxypentane C7H15BrO2 详情 详情
(IX) 12076 4-Piperidinol; 4-Hydroxypiperidine 5382-16-1 C5H11NO 详情 详情
(X) 43095 1-(5,5-dimethoxypentyl)-4-piperidinol C12H25NO3 详情 详情
(XI) 43096 1-[3-[5-(4H-1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl]-4-piperidinol C18H23N5O 详情 详情
(XII) 43097 1-[3-[5-(4H-1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl]-4-piperidinone C18H21N5O 详情 详情

合成路线15

该中间体在本合成路线中的序号：(VII)

The reaction of 4-aminophthalimide (I) with NaNO2/HCl and then with CuCl/KCN gives 4-cyanophthalimide (II), which is treated with hydrazone in ethanol, yielding 6-cyanophthalazine-2,3(1H,4H)-dione (III). The reaction of (III) with refluxing POCl3 affords 1,4-dichlorophthalazine-6-carbonitrile (IV), which is condensed with 3-chloro-4-methoxybenzylamine (V) by means of TEA in THF to provide the secondary amine (VI). Finally, this compound is condensed with 4-hydroxypiperidine (VII) by means of DIEA in N-methyl-2-pyrrolidone to furnish the target phthalazine.

参考文献 中间体
合成目标
【1】 Watanabe, N.; Kabasawa, Y.; Takase, Y.; Ozaki, F.; Ishibashi, K.; Miyazaki, K.; Matsukura, M.; Souda, S.; Miyake, K.; Ishihara, H.; Kodama, K.; Adachi, H. (Eisai Co., Ltd.); Fused pyridazine cpd.. EP 0722936; JP 1996225541; US 6218392; WO 9605176 .
【2】 Takase, Y.; Adachi, H.; Watanabe, N.; et al.; 4-(3-Chloro-4-methoxybenzyl)aminophthalazines: Synthesis and inhibitory activity toward phosphodiesterase 5. J Med Chem 2000, 43, 13, 2523.
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) 51974 5-amino-1H-isoindole-1,3(2H)-dione C8H6N2O2 详情 详情
(II) 51975 1,3-dioxo-5-isoindolinecarbonitrile C9H4N2O2 详情 详情
(III) 51976 1,4-dioxo-1,2,3,4-tetrahydro-6-phthalazinecarbonitrile C9H5N3O2 详情 详情
(IV) 51977 1,4-dichloro-6-phthalazinecarbonitrile C9H3Cl2N3 详情 详情
(V) 51978 (3-chloro-4-methoxyphenyl)methanamine; 3-chloro-4-methoxybenzylamine C8H10ClNO 详情 详情
(VI) 51979 1-chloro-4-[(3-chloro-4-methoxybenzyl)amino]-6-phthalazinecarbonitrile C17H12Cl2N4O 详情 详情
(VII) 12076 4-Piperidinol; 4-Hydroxypiperidine 5382-16-1 C5H11NO 详情 详情

合成路线16

该中间体在本合成路线中的序号：(II)

The condensation of the commercially available (Amersham) 14C-labeled 1-chloro-4-(3-chloro-4-methoxybenzylamino)phthalazine-6-carbonitrile (I) with 4-hydroxypiperidine (II) by means of K2CO3 and N-methyl-2-pyrrolidinone at 170 C yields the target phthalazine derivative.

参考文献 中间体
合成目标
【1】 Watanabe, N.; et al.; Synthesis of 14C-labeled E4010. J Label Compd Radiopharm 2001, 44, 12, 843.
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) 51979 1-chloro-4-[(3-chloro-4-methoxybenzyl)amino]-6-phthalazinecarbonitrile C17H12Cl2N4O 详情 详情
(I) 51980 1-chloro-4-[(3-chloro-4-methoxybenzyl)amino]-6-phthalazinecarbonitrile C17H12Cl2N4O 详情 详情
(II) 12076 4-Piperidinol; 4-Hydroxypiperidine 5382-16-1 C5H11NO 详情 详情

合成路线17

该中间体在本合成路线中的序号：(I)

4-Hydroxypiperidine (I) was protected as the tert-butyl carbamate (II) upon treatment with (Boc)2O. Subsequent Mitsunobu coupling of (II) with diphenyl disulfide using tributylphosphine and diethyl azodicarboxylate afforded thioether (III). Acid deprotection of the Boc group of (III), followed by nitrosation of the resulting amine (IV) gave N-nitrosopiperidine (V). Further reduction of (V) with LiAlH4 yielded hydrazine (VI). Condensation of (VI) with dichloropurine derivative (VII) produced piperidinyladenosine (VIII). Debenzoylation of the tribenzoate ester (VIII) with methanolic ammonia gave (IX). Then, chlorination at position 5' with concomitant formation of the 2',3' cyclic sulfite (X) by reaction with thionyl chloride and pyridine was followed by sulfite hydrolysis with methanolic ammonia to yield the title compound.

参考文献 中间体
合成目标
【1】 Lau, J.; Judge, M.E.; Sheardown, M.J.; Petersen, H.; Shalmi, M.; Knutsen, L.J.S.; Hansen, A.J.; Thomsen, C.; Weis, J.U.; N-substituted adenosines as novel neuroprotective A1 agonists with diminished hypotensive effects. J Med Chem 1999, 42, 18, 3463.
【2】 Lau, J.; Knutsen, L.J.S. (Novo Nordisk A/S); Chemical cpds., their preparation and use. EP 0719275; JP 1999511436; US 5589467; WO 9507921 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
17473 diphenyl disulfide; 1-(phenyldisulfanyl)benzene; diphenyldisulfide 882-33-7 C12H10S2 详情 详情
(I) 12076 4-Piperidinol; 4-Hydroxypiperidine 5382-16-1 C5H11NO 详情 详情
(II) 18625 tert-butyl 4-hydroxy-1-piperidinecarboxylate C10H19NO3 详情 详情
(III) 32561 tert-butyl 4-(phenylsulfanyl)-1-piperidinecarboxylate C16H23NO2S 详情 详情
(IV) 32562 4-(phenylsulfanyl)piperidine; phenyl 4-piperidinyl sulfide C11H15NS 详情 详情
(V) 32563 1-nitroso-4-piperidinyl phenyl sulfide; 1-nitroso-4-(phenylsulfanyl)piperidine C11H14N2OS 详情 详情
(VI) 32564 4-(phenylsulfanyl)-1-piperidinamine; 4-(phenylsulfanyl)-1-piperidinylamine C11H16N2S 详情 详情
(VII) 32565 (2R,3R,4R,5R)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]-5-(2,6-dichloro-9H-purin-9-yl)tetrahydro-3-furanyl benzoate C31H22Cl2N4O7 详情 详情
(VIII) 32568 [(2R,3R,4R,5R)-3,4-bis(benzoyloxy)-5-(2-chloro-6-[[4-(phenylsulfanyl)-1-piperidinyl]amino]-9H-purin-9-yl)tetrahydro-2-furanyl]methyl benzoate C42H37ClN6O7S 详情 详情
(IX) 32566 (2R,3R,4S,5R)-2-(2-chloro-6-[[4-(phenylsulfanyl)-1-piperidinyl]amino]-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol C21H25ClN6O4S 详情 详情
(X) 32567 (3aR,4S,6R,6aR)-4-(chloromethyl)-6-(2-chloro-6-[[4-(phenylsulfanyl)-1-piperidinyl]amino]-9H-purin-9-yl)tetrahydro-2lambda(4)-furo[3,4-d][1,3,2]dioxathiol-2-one C21H22Cl2N6O4S2 详情 详情

合成路线18

该中间体在本合成路线中的序号：(I)

Condensation of 4-hydroxypiperidine (I) with methyl 3,4-difluorobenzoate (II) in DMSO yields derivative (III), which is first mesylated with methanesulfonyl chloride (MsCl) and Et3N in CH2Cl2 and then subjected to reaction with NaN3 in DMF to provide azido derivative (IV). Hydrogenation of (IV) over Pd/C in HOAc/H2O/dioxane affords amino derivative (V), which is then condensed with 2-bromopyrimidine (VI) in DMSO in the presence of DIEA, yielding derivative (VII). Methyl ester group of (VII) is then subjected to saponification by means of aqueous NaOH in THF/MeOH, and the resulting carboxylic acid is coupled to diaminopropionate derivative (VIII) in DMF by means of EDC, HOBt and N-methylmorpholine (NMM) to furnish amide (IX). Hydrolysis of the t-butyl ester group of (IX) by treatment with TFA in CH2Cl2 affords carboxylic acid (X), which is finally hydrogenated over Pd/C in dioxane/H2O to give the target compound.

参考文献 中间体
合成目标
【1】 Ajito, K.; Katano, K.; Kubota, D.; Ishikawa, M.; Murakami, S.; Hachisu, M.; Yamamoto, M. (Meiji Seika Kaisha, Ltd.); Aminopiperidine derivs. as integrin alphavbeta3 antagonists. EP 1074543; WO 9952872 .
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) 12076 4-Piperidinol; 4-Hydroxypiperidine 5382-16-1 C5H11NO 详情 详情
(II) 45450 methyl 3,4-difluorobenzoate 369-25-5 C8H6F2O2 详情 详情
(III) 45451 methyl 3-fluoro-4-(4-hydroxy-1-piperidinyl)benzoate 107-82-4 C13H16FNO3 详情 详情
(IV) 45452 methyl 4-(4-azido-1-piperidinyl)-3-fluorobenzoate C13H15FN4O2 详情 详情
(V) 45453 methyl 4-(4-amino-1-piperidinyl)-3-fluorobenzoate C13H17FN2O2 详情 详情
(VI) 45454 2-bromopyrimidine 4595-60-2 C4H3BrN2 详情 详情
(VII) 45455 methyl 3-fluoro-4-[4-(2-pyrimidinylamino)-1-piperidinyl]benzoate C17H19FN4O2 详情 详情
(VIII) 31423 tert-butyl (2S)-3-amino-2-[(phenylsulfonyl)amino]propanoate C13H20N2O4S 详情 详情
(IX) 45456 tert-butyl (2S)-3-([3-fluoro-4-[4-(2-pyrimidinylamino)-1-piperidinyl]benzoyl]amino)-2-[(phenylsulfonyl)amino]propanoate C29H35FN6O5S 详情 详情
(X) 45457 (2S)-3-([3-fluoro-4-[4-(2-pyrimidinylamino)-1-piperidinyl]benzoyl]amino)-2-[(phenylsulfonyl)amino]propionic acid C25H27FN6O5S 详情 详情

合成路线19

该中间体在本合成路线中的序号：(I)

4-Hydroxypiperidine (I) was protected as the N-Boc derivative (II), which was then condensed with 1,2-difluoro-4-nitrobenzene (III) in the presence of potassium tert-butoxide, yielding ether (IV). Reduction of the nitro group of (IV) by transfer hydrogenation, followed by treatment of the resulting aniline (V) with benzyl chloroformate, afforded carbamate (VI). After deprotonation of the carbamate group of (VI) with n-butyllithium, reaction with (R)-glycidyl butyrate (VII) generated the chiral oxazolidinone (VIII). Conversion of (VIII) to mesylate (IX) and subsequent displacement with NaN3 provided azide (X). This was reduced to the corresponding amine, which was acetylated with Ac2O to furnish amide (XI). Cleavage of the Boc protecting group of (XI) with trifluoroacetic acid gave piperidine (XII). This was finally acylated with benzyloxyacetyl chloride (XIII) to provide the title amide.

参考文献 中间体
合成目标
【2】 Boggs, C.M.; et al.; Novel piperidinyloxy-oxazolidinone antimicrobial agents: Effects of position, fluorine substitution, and ring-size on in vitro antimicrobial activity. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 98.
【3】 Boggs, C.; Nelson, E.; Weidner-Wells, M.; Hlasta, D. (Ortho-McNeil Pharmaceutical, Inc.); Piperidinyloxy and pyrrolidinyloxyphenyl oxazolidinones as antibacterials. WO 0146164 .
【1】 Hilliard, J.J.; Montenegro, D.A.; Nelson, E.A.; Goldschmidt, R.M.; Boggs, C.M.; Weidner-Wells, M.A.; Wira, E.; Hlasta, D.J.; Melton, J.; Foleno, B.D.; Bush, K.; Piperidinyloxy substituted oxazolidinones as antibacterial agents. Diversification of the N-substituent. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1828.
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) 12076 4-Piperidinol; 4-Hydroxypiperidine 5382-16-1 C5H11NO 详情 详情
(II) 18625 tert-butyl 4-hydroxy-1-piperidinecarboxylate C10H19NO3 详情 详情
(III) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(IV) 45645 tert-butyl 4-(2-fluoro-4-nitrophenoxy)-1-piperidinecarboxylate C16H21FN2O5 详情 详情
(V) 45646 tert-butyl 4-(4-amino-2-fluorophenoxy)-1-piperidinecarboxylate 654-01-3 C16H23FN2O3 详情 详情
(VI) 45647 tert-butyl 4-(4-[[(benzyloxy)carbonyl]amino]-2-fluorophenoxy)-1-piperidinecarboxylate C24H29FN2O5 详情 详情
(VII) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(VIII) 45648 tert-butyl 4-[2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenoxy]-1-piperidinecarboxylate C20H27FN2O6 详情 详情
(IX) 45649 tert-butyl 4-[2-fluoro-4-((5R)-5-[[(methylsulfonyl)oxy]methyl]-2-oxo-1,3-oxazolidin-3-yl)phenoxy]-1-piperidinecarboxylate 22888-70-6 C21H29FN2O8S 详情 详情
(X) 45650 tert-butyl 4-[4-[(5R)-5-(azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenoxy]-1-piperidinecarboxylate C20H26FN5O5 详情 详情
(XI) 45651 tert-butyl 4-(4-[(5S)-5-[(acetamido)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenoxy)-1-piperidinecarboxylate C22H30FN3O6 详情 详情
(XII) 45652 N-([(5S)-3-[3-fluoro-4-(4-piperidinyloxy)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl)acetamide 2642-63-9 C17H22FN3O4 详情 详情
(XIII) 10493 2-(Benzyloxy)acetyl chloride; Benzyloxyacetyl chloride 19810-31-2 C9H9ClO2 详情 详情

合成路线20

该中间体在本合成路线中的序号：(I)

4-Hydroxypiperidine (I) was protected as the N-Boc derivative (II), which was then condensed with 1,2-difluoro-4-nitrobenzene (III) in the presence of potassium tert-butoxide, yielding ether (IV). Reduction of the nitro group of (IV) by transfer hydrogenation, followed by treatment of the resulting aniline (V) with benzyl chloroformate, afforded carbamate (VI). After deprotonation of the carbamate group of (VI) with n-butyllithium, reaction with (R)-glycidyl butyrate (VII) generated the chiral oxazolidinone (VIII). Conversion of (VIII) to mesylate (IX) and subsequent displacement with NaN3 provided azide (X). This was reduced to the corresponding amine, which was acetylated with Ac2O to furnish amide (XI). Cleavage of the Boc protecting group of (XI) with trifluoroacetic acid, followed by acylation of the resulting piperidine with benzyloxyacetyl chloride, provided amide (XII). Finally, hydrogenolysis of the O-benzyl group of (XII) by transfer hydrogenation in the presence of ammonium formate and Pd/C yielded the title hydroxyacetamide.

参考文献 中间体
合成目标
【1】 Weidner-Wells, M.A.; et al.; Novel piperidinyloxy oxazolidinone antibacterial agents. Diversification of the N-substituent. Bioorg Med Chem 2002, 10, 7, 2345.
【3】 Boggs, C.M.; et al.; Novel piperidinyloxy-oxazolidinone antimicrobial agents: Effects of position, fluorine substitution, and ring-size on in vitro antimicrobial activity. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 98.
【4】 Boggs, C.; Nelson, E.; Weidner-Wells, M.; Hlasta, D. (Ortho-McNeil Pharmaceutical, Inc.); Piperidinyloxy and pyrrolidinyloxyphenyl oxazolidinones as antibacterials. WO 0146164 .
【2】 Hilliard, J.J.; Montenegro, D.A.; Nelson, E.A.; Goldschmidt, R.M.; Boggs, C.M.; Weidner-Wells, M.A.; Wira, E.; Hlasta, D.J.; Melton, J.; Foleno, B.D.; Bush, K.; Piperidinyloxy substituted oxazolidinones as antibacterial agents. Diversification of the N-substituent. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1828.
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) 12076 4-Piperidinol; 4-Hydroxypiperidine 5382-16-1 C5H11NO 详情 详情
(II) 18625 tert-butyl 4-hydroxy-1-piperidinecarboxylate C10H19NO3 详情 详情
(III) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(IV) 45645 tert-butyl 4-(2-fluoro-4-nitrophenoxy)-1-piperidinecarboxylate C16H21FN2O5 详情 详情
(V) 45646 tert-butyl 4-(4-amino-2-fluorophenoxy)-1-piperidinecarboxylate 654-01-3 C16H23FN2O3 详情 详情
(VI) 45647 tert-butyl 4-(4-[[(benzyloxy)carbonyl]amino]-2-fluorophenoxy)-1-piperidinecarboxylate C24H29FN2O5 详情 详情
(VII) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(VIII) 45648 tert-butyl 4-[2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenoxy]-1-piperidinecarboxylate C20H27FN2O6 详情 详情
(IX) 45649 tert-butyl 4-[2-fluoro-4-((5R)-5-[[(methylsulfonyl)oxy]methyl]-2-oxo-1,3-oxazolidin-3-yl)phenoxy]-1-piperidinecarboxylate 22888-70-6 C21H29FN2O8S 详情 详情
(X) 45650 tert-butyl 4-[4-[(5R)-5-(azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenoxy]-1-piperidinecarboxylate C20H26FN5O5 详情 详情
(XI) 45651 tert-butyl 4-(4-[(5S)-5-[(acetamido)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenoxy)-1-piperidinecarboxylate C22H30FN3O6 详情 详情
(XII) 45653 benzyl 4-(4-[(5S)-5-[(acetamido)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenoxy)-1-piperidinecarboxylate C25H28FN3O6 详情 详情
Extended Information