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【结 构 式】

【分子编号】22482

【品名】4-Amidinobenzic acid; 4-[amino(imino)methyl]benzoic acid

【CA登记号】15535-95-2

【 分 子 式 】C8H8N2O2

【 分 子 量 】164.1638

【元素组成】C 58.53% H 4.91% N 17.06% O 19.49%

与该中间体有关的原料药合成路线共 4 条

合成路线1

该中间体在本合成路线中的序号:(XI)

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:(XVI)

The intermediate 4-(tert-butoxycarbonylamindino)benzoic acid (XII) has been obtained as follows: Comerciaally available 4-amidinobenzamide (XV) is hydrolyzed with aqueous HCl to give 4-amidinobenzoic acid (XVI), which is then treated with tert-butoxycarbonyl anhydride and N,O-bis(trimethylsilyl)acetamide in dichloromethane to afford the target intermediate (XII).

1 Ikeda, Y.; Ueki, Y.; Kishimoto, H.; Nishihara, T.; Kamikawa, Y. (Sumitomo Pharmaceuticals Co., Ltd.); 2,3-Diaminopropionic acid deriv.. US 5707994; US 6048854; WO 9511228 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XII) 26622 4-[[(tert-butoxycarbonyl)amino](imino)methyl]benzoic acid C13H16N2O4 详情 详情
(XV) 26625 4-[amino(imino)methyl]benzamide 59855-11-7 C8H9N3O 详情 详情
(XVI) 22482 4-Amidinobenzic acid; 4-[amino(imino)methyl]benzoic acid 15535-95-2 C8H8N2O2 详情 详情

合成路线3

该中间体在本合成路线中的序号:(II)

Title compound was obtained by coupling the sulfonylprolylpiperazine derivative (I) with 4-amidinobenzoic acid (II) in the presence of EDC and HOBt in DMF, followed by conversion to the dihydrochloride salt.

1 Dodey, P.; Bondoux, M.; Houziaux, P.; Barth, M.; Ou, K. (Laboratoires Fournier SA); N-Benzenesulphonyl-L-proline derivs. as bradykinin B2 agonists. EP 0925295; US 6071917; WO 9803503 .
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) 26768 [(2S)-1-[(2,4-dichloro-3-[[(2,4-dimethyl-8-quinolinyl)oxy]methyl]phenyl)sulfonyl]pyrrolidinyl](1-piperazinyl)methanone C27H30Cl2N4O4S 详情 详情
(II) 22482 4-Amidinobenzic acid; 4-[amino(imino)methyl]benzoic acid 15535-95-2 C8H8N2O2 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 synthesized by condensation of amidino benzoic acid (I) with primary amine (II) using EDC and HOAt.

1 Dodey, P.; Bondoux, M.; Ou, K.; Barth, M.; Houziaux, P. (Fournier Industrie et Santé); Novel N-benzenesulphonyl-L-proline derivs., method for preparing and therapeutic use. EP 0944618; US 6063791; WO 9824783 .
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) 22482 4-Amidinobenzic acid; 4-[amino(imino)methyl]benzoic acid 15535-95-2 C8H8N2O2 详情 详情
(II) 37922 (2S)-N-(3-aminopropyl)-1-[(2,4-dichloro-3-[[(2,4-dimethyl-8-quinolinyl)oxy]methyl]phenyl)sulfonyl]-2-pyrrolidinecarboxamide C26H30Cl2N4O4S 详情 详情
Extended Information