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【结 构 式】 
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【分子编号】19286 【品名】benzyl 4-[2-(tert-butoxy)-2-oxoethoxy]-1-piperidinecarboxylate 【CA登记号】 |
【 分 子 式 】C19H27NO5 【 分 子 量 】349.42712 【元素组成】C 65.31% H 7.79% N 4.01% O 22.89% |
合成路线1
该中间体在本合成路线中的序号：(V)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.
| 【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2
该中间体在本合成路线中的序号：(XI)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.
| 【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. |
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【3】
Castañer, J.; Graul, A.; Merlos, M.; Sibrafiban |
| 【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 |