(2S)-2-amino-3-[4-(benzyloxy)phenyl]propionic acid -Drug Synthesis Database

【结构式】

【分子编号】26716

【品名】(2S)-2-amino-3-[4-(benzyloxy)phenyl]propionic acid

【CA登记号】16652-64-5

【分子式】C₁₆H₁₇NO₃

【分子量】271.31592

【元素组成】C 70.83% H 6.32% N 5.16% O 17.69%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(I)

The acylation of O-benzyltyrosine (I) with ethyl trifluoroacetate in methanol gives O-benzyl-N-trifluroacetyltyrosine (II), which is condensed with N-(2-aminoethyl)carbamic acid benzyl ester (III) by means of ethyl chloroformate in THF, yielding the tyrosinamide (IV). The deacylation of (IV) by means of NaBH4 in ethanol affords the N-deprotected tyrosinamide (V), which is submitted to hydrogenolysis with H2 over Pd/C in methanol to provide tyrosine 2-aminoethylamide (VI). The reduction of (VI) with diborane gives 3-aza-1-(4-hydroxybenzyl)pentane-1,5-diamine (VII), which is alkylated with bromoacetic acid tert-butyl ester (VIII) and NaHCO3 to yield the 1-(4-hydroxybenzyl)-3-azapentane-1,5-diamine N,N,N'.N'',N''-pentaacetate penta-tert-butyl ester (IX) (1). The alkylation of the OH group of (IX) with ethyl iodide and NaH in THF affords the corresponding ethoxybenzyl derivative (X), which is treated with TFA to provide the pentaacetic acid derivative (XI). Finally, this compound is complexed with Gd2O3 and NaOH in hot water to furnish the target gadolinium complex.

参考文献中间体

合成目标

【1】 Schmitt-Willich, H.; Platzek, J.; Gries, H.; Schuhmann-Giampieri, G.; Vogler, H.; Weinmann, H.-J. (Schering AG); DTPA-complexes derivs., pharmaceutical compsns. containing them, their use and process for their preparation. AU 9058024; DE 3922005; EP 0405704; JP 1991215457; US 5695739; US 6039931 .
【2】 Deutsch, J.; Gries, H.; Klieger, E.; Niedballa, U.; Renneke, F.J.; Conrad, J.; Mützel, W. (Schering AG); Substd. complex-builders, complexes and complex salts, process for their preparation and pharmaceutical compsns. containing them. DE 3710730; WO 8807521 .

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)	26716	(2S)-2-amino-3-[4-(benzyloxy)phenyl]propionic acid	16652-64-5	C₁₆H₁₇NO₃	详情	详情
(II)	53319	(2S)-3-[4-(benzyloxy)phenyl]-2-[(2,2,2-trifluoroacetyl)amino]propanoic acid	n/a	C₁₈H₁₆F₃NO₄	详情	详情
(III)	51002	benzyl 2-aminoethylcarbamate		C₁₀H₁₄N₂O₂	详情	详情
(IV)	53320	benzyl 2-({(2S)-3-[4-(benzyloxy)phenyl]-2-[(2,2,2-trifluoroacetyl)amino]propanoyl}amino)ethylcarbamate	n/a	C₂₈H₂₈F₃N₃O₅	详情	详情
(V)	53321	benzyl 2-({(2S)-2-amino-3-[4-(benzyloxy)phenyl]propanoyl}amino)ethylcarbamate	n/a	C₂₆H₂₉N₃O₄	详情	详情
(VI)	53322	(2S)-2-amino-N-(2-aminoethyl)-3-(4-hydroxyphenyl)propanamide	n/a	C₁₁H₁₇N₃O₂	详情	详情
(VII)	53323	4-{(2S)-2-amino-3-[(2-aminoethyl)amino]propyl}phenol	n/a	C₁₁H₁₉N₃O	详情	详情
(VIII)	17430	2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate	5292-43-3	C₆H₁₁BrO₂	详情	详情
(IX)	53324	tert-butyl (7S)-6,9,12-tris[2-(tert-butoxy)-2-oxoethyl]-7-(4-hydroxybenzyl)-2,2-dimethyl-4-oxo-3-oxa-6,9,12-triazatetradecan-14-oate	n/a	C₄₁H₆₉N₃O₁₁	详情	详情
(X)	53325	tert-butyl (7S)-6,9,12-tris[2-(tert-butoxy)-2-oxoethyl]-7-(4-ethoxybenzyl)-2,2-dimethyl-4-oxo-3-oxa-6,9,12-triazatetradecan-14-oate	n/a	C₄₃H₇₃N₃O₁₁	详情	详情
(XI)	53326	2-([(2S)-2-[bis(carboxymethyl)amino]-3-(4-ethoxyphenyl)propyl]{2-[bis(carboxymethyl)amino]ethyl}amino)acetic acid	n/a	C₂₃H₃₃N₃O₁₁	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

By condensation of N-(perhydroazepin-1-ylcarbonyl)-L-leucine (V) with 4-O-benzyl-L-tyrosine tert-butyl ester (VIII) by means of HOBT and diisopropylethylamine in DMF. The two peptide intermediates (V) and (VIII) have been obtaines a follows: L-Leucine fragment (V): The carbonatation of perhydroazepine (I) with CO2 and pyridine followed by reaction with SOCl2 gives perhydroazepin-1-ylcarbonyl chloride (II), which is condensed with L-leucine benzyl ester (III) yielding the N-acylated leucine ester (IV). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in THF to afford the target intermediate (V). Tyrosine fragment (VIII): By esterification of 4-O-benzyl-L-tyrosine (VI) with isobutylene (VII) by means of sulfuric acid in dioxane.

参考文献中间体

合成目标

【1】 Malone, T.; et al.; Identification and SAR studies of PD 151307, a novel N-type calcium channel blocker. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 122.
【2】 Roth, B.D.; Connor, D.T.; Malone, T.C.; Hamilton, H.W.; Rafferty, M.F.; Hu, L.-Y.; Cody, W.L.; He, J.X.; Nadasdi, L.; Brogley, L.; Urge, L.; Silva, D.F.; Song, Y.; Szoke, B.G.; Booth, R.J.; Lescosky, J. (Neurex Corp.; Pfizer Inc.); Peptidyl calcium channel blockers. US 6423689 .

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)	18672	azepane	111-49-9	C₆H₁₃N	详情	详情
(II)	26713	1-azepanecarbonyl chloride		C₇H₁₂ClNO	详情	详情
(III)	22252	Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate		C₁₃H₁₉NO₂	详情	详情
(IV)	26714	benzyl (2S)-2-[(1-azepanylcarbonyl)amino]-4-methylpentanoate		C₂₀H₃₀N₂O₃	详情	详情
(V)	26715	(2S)-2-[(1-azepanylcarbonyl)amino]-4-methylpentanoic acid		C₁₃H₂₄N₂O₃	详情	详情
(VI)	26716	(2S)-2-amino-3-[4-(benzyloxy)phenyl]propionic acid	16652-64-5	C₁₆H₁₇NO₃	详情	详情
(VII)	15926	2-methyl-1-propene; isobutylene	115-11-7	C₄H₈	详情	详情
(VIII)	26717	tert-butyl (2S)-2-amino-3-[4-(benzyloxy)phenyl]propanoate		C₂₀H₂₅NO₃	详情	详情

Extended Information