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

【结构式】

【分子编号】39328

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

【CA登记号】

【分子式】C₁₇H₁₇NO₅

【分子量】315.32572

【元素组成】C 64.75% H 5.43% N 4.44% O 25.37%

与该中间体有关的原料药合成路线共 7 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1

该中间体在本合成路线中的序号：(IV)

Protection of the carboxyl group of Boc-L-threonine (I) with [2-(chloromethoxy)ethyl]trimethylsilane (SEM-Cl) (II) by means of Li2CO3 affords protected threonine (III). Separately, Z-L-tyrosine (IV) is treated with dimethyl sulfate and KOH in THF with tetrabutylammonium hydrogen sulfate as a catalyst to furnish N,O-dimethyl-L-tyrosine (V), which is then converted into secondary amine (VI) by coupling with protected threonine (III) either by means of 2,4,6-trichlorobenzoyl chloride in THF and DMAP in benzene or with isopropenyl chloroformate, Et3N and DMAP, followed by elimination of the carbobenzyloxy group by hydrogenation over Pd/C. Coupling of Z-L-leucine (IX) to L-proline methyl ester (X) by means of DCC, HOBt and NMM in CH2Cl2, followed by hydrolysis with LiOH, affords Z-leucylproline (VII), which is then coupled to amine (VI) by means of BOPCl and Et3N in CH2Cl2, and then subjected to deprotection with hydrofluoric acid in acetonitrile affording intermediate (VIII).

参考文献中间体

合成目标

【1】 Li, W.-R.; et al.; Total synthesis and structural investigations of didemnins A, B, and C. J Am Chem Soc 1990, 112, 21, 7659.

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)	50745	N-BOC-L-threonine; Boc-Threonine; N-tert-Butoxycarbonyl-L-threonine; N-(tert-Butoxycarbonyl)-L-threonine; BOC-L-Threonine	2592-18-9	C₉H₁₇NO₅	详情	详情
(II)	27243	[2-(chloromethoxy)ethyl](trimethyl)silane	76513-69-4	C₆H₁₅ClOSi	详情	详情
(III)	50746	[2-(trimethylsilyl)ethoxy]methyl (2S,3R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxybutanoate		C₁₅H₃₁NO₆Si	详情	详情
(IV)	39328	(2S)-2-[[(benzyloxy)carbonyl]amino]-3-(4-hydroxyphenyl)propionic acid		C₁₇H₁₇NO₅	详情	详情
(V)	50747	(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propionic acid		C₁₉H₂₁NO₅	详情	详情
(VI)	50748	(2S,3R)-2-[(tert-butoxycarbonyl)amino]-3-[[(2S)-3-(4-methoxyphenyl)-2-(methylamino)propanoyl]oxy]butyric acid		C₂₀H₃₀N₂O₇	详情	详情
(VII)	50749	(2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoyl)-2-pyrrolidinecarboxylic acid		C₁₉H₂₆N₂O₅	详情	详情
(VIII)	50750	(2S,3R)-3-[[(2S)-2-[[[(2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoyl)pyrrolidinyl]carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy]-2-[(tert-butoxycarbonyl)amino]butyric acid		C₃₉H₅₄N₄O₁₁	详情	详情
(IX)	22838	(2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoic acid		C₁₄H₁₉NO₄	详情	详情
(X)	29552	methyl (2S)-2-pyrrolidinecarboxylate	2133-40-6	C₆H₁₁NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XVI)

参考文献中间体

合成目标

【1】 Hamada, Y.; Shioiri, T.; Anti-tumor active cyclic peptide derived from marine organism: Synthesis, conformation and bioactivity. Kagaku Zokan 1990, 118, 31.
【2】 Harris, B.D.; et al.; Synthetic studies of didemnins. II. Approaches to statine diastereomers. Tetrahedron Lett 1987, 28, 25, 2837.
【3】 Hamada, Y.; et al.; Efficient total synthesis of didemnins A and B. J Am Chem Soc 1989, 111, 2, 669.

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)	50775	(2R,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid		C₁₁H₂₁NO₄	详情	详情
(II)	44205	(2-ethoxy-2-oxoethyl)lithium		C₄H₇LiO₂	详情	详情
(III)	50776	ethyl (4R,5S)-4-[(tert-butoxycarbonyl)amino]-5-methyl-3-oxoheptanoate		C₁₅H₂₇NO₅	详情	详情
(IV)	50777	tert-butyl (1R,2S)-1-formyl-2-methylbutylcarbamate		C₁₁H₂₁NO₃	详情	详情
(V)	50778	ethyl (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-methylheptanoate		C₁₅H₂₉NO₅	详情	详情
(VI)	50779	2,2,2-trichloro-1-ethanol		C₂H₃Cl₃O	详情	详情
(VII)	50780	2,2,2-trichloroethyl (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-methylheptanoate		C₁₅H₂₆Cl₃NO₅	详情	详情
(VIII)	50781	2,2,2-trichloroethyl (3S,4R,5S)-4-amino-3-hydroxy-5-methylheptanoate		C₁₀H₁₈Cl₃NO₃	详情	详情
(IX)	50782	(2S,3R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]butyric acid		C₁₆H₂₃NO₅	详情	详情
(X)	50783	2,2,2-trichloroethyl (3S,4R,5S)-4-[[(2S,3R)-2-amino-3-(benzyloxy)butanoyl]amino]-3-hydroxy-5-methylheptanoate		C₂₁H₃₁Cl₃N₂O₅	详情	详情
(XI)	50788	(2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoic acid		C₁₂H₂₃NO₄	详情	详情
(XII)	31819	(2R)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid	16937-99-8	C₁₁H₂₁NO₄	详情	详情
(XIII)	50787	2,2,2-trichloroethyl (6R,9S,12R,13S)-9-[(1R)-1-(benzyloxy)ethyl]-13-[[tert-butyl(dimethyl)silyl]oxy]-6-isobutyl-2,2,5-trimethyl-12-[(1S)-1-methylpropyl]-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate		C₃₉H₆₆Cl₃N₃O₈Si	详情	详情
(XIV)	50784	2,2,2-trichloroethyl (6R,9S,12R,13S)-13-[[tert-butyl(dimethyl)silyl]oxy]-9-[(1R)-1-hydroxyethyl]-6-isobutyl-2,2,5-trimethyl-12-[(1S)-1-methylpropyl]-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate		C₃₂H₆₀Cl₃N₃O₈Si	详情	详情
(XV)	50747	(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propionic acid		C₁₉H₂₁NO₅	详情	详情
(XVI)	39328	(2S)-2-[[(benzyloxy)carbonyl]amino]-3-(4-hydroxyphenyl)propionic acid		C₁₇H₁₇NO₅	详情	详情
(XVII)	50785	2,2,2-trichloroethyl (5S,8R,9S,12R,13S)-13-[[tert-butyl(dimethyl)silyl]oxy]-5-(4-methoxybenzyl)-4,8-dimethyl-9-[[(2R)-4-methyl-2-(methylamino)pentanoyl]amino]-12-[(1S)-1-methylpropyl]-3,6,10-trioxo-1-phenyl-2,7-dioxa-4,11-diazapentadecan-15-oate		C₄₆H₇₁Cl₃N₄O₁₀Si	详情	详情
(XVIII)	50786	(5S,8R,9S,12R,13S)-13-[[tert-butyl(dimethyl)silyl]oxy]-5-(4-methoxybenzyl)-4,8-dimethyl-9-[[(2R)-4-methyl-2-(methylamino)pentanoyl]amino]-12-[(1S)-1-methylpropyl]-3,6,10-trioxo-1-phenyl-2,7-dioxa-4,11-diazapentadecan-15-oic acid		C₄₄H₇₀N₄O₁₀Si	详情	详情

合成路线3

该中间体在本合成路线中的序号：(X)

4-Pyridineacetic acid (I) was hydrogenated to the corresponding piperidine (II) in the presence of PtO2. After protection of (II) as the N-Boc derivative (III), reduction of its carboxylate group with borane in THF provided alcohol (IV). Subsequent Swern oxidation of alcohol (IV) furnished aldehyde (V). This was then subjected to a Wittig condensation with carbomethoxytriphenylphosphorane to yield the unsaturated ester (VI), which was further hydrogenated to (VII) in the presence of Pd/C. After saponification of the methyl ester function of (VII), the resultant carboxylic acid was reduced to alcohol (VIII) by means of borane in THF. Conversion of alcohol (VIII) into the alkyl bromide (IX) was accomplished by treatment with carbon tetrabromide and triphenylphosphine. Then, alkylation of the phenolic hydroxyl of N-Cbz-L-tyrosine (X) with bromide (IX) in the presence of NaH in DMF afforded adduct (XI).

参考文献中间体

合成目标

【1】 Egbertson, M.S.; Laswell, W.L.; Hartman, G.D.; Duggan, M.E.; Halczenko, W. (Merck & Co., Inc.); Novel sulfonamide fibrinogen receptor antagonists. EP 0478363; EP 0743302; JP 1992288051; US 5292756 .
【2】 Egbertson, M.S.; Hartman, G.D.; Halczenko, W.; Laswell, W.L.; Duggan, M.E. (Merck & Co., Inc.); Novel sulfonamide fibrinogen receptor antagonists. WO 9319046 .
【3】 Egbertson, M.S.; Chang, C.T.C.; Duggan, M.E.; et al.; Non-peptide fibrinogen receptor antagonists. 2. Optimization of a tyrosine template as a mimic for Arg-Gly-Asp. J Med Chem 1994, 37, 16, 2537.

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)	17883	2-(4-pyridinyl)acetic acid	28356-58-3	C₇H₇NO₂	详情	详情
(II)	45854	2-(4-piperidinyl)acetic acid; 4-piperidinylacetic acid	51052-78-9	C₇H₁₃NO₂	详情	详情
(III)	19346	1-Boc-piperidin-4-ylacetic acid; 2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetic acid	157688-46-5	C₁₂H₂₁NO₄	详情	详情
(IV)	43453	tert-butyl 4-(2-hydroxyethyl)-1-piperidinecarboxylate		C₁₂H₂₃NO₃	详情	详情
(V)	59541	tert-butyl 4-(2-oxoethyl)-1-piperidinecarboxylate		C₁₂H₂₁NO₃	详情	详情
(VI)	45855	tert-butyl 4-[(E)-4-methoxy-4-oxo-2-butenyl]-1-piperidinecarboxylate		C₁₅H₂₅NO₄	详情	详情
(VII)	45856	tert-butyl 4-(4-methoxy-4-oxobutyl)-1-piperidinecarboxylate		C₁₅H₂₇NO₄	详情	详情
(VIII)	59542	tert-butyl 4-(4-hydroxybutyl)-1-piperidinecarboxylate		C₁₄H₂₇NO₃	详情	详情
(IX)	59543	tert-butyl 4-(4-bromobutyl)-1-piperidinecarboxylate		C₁₄H₂₆BrNO₂	详情	详情
(X)	39328	(2S)-2-[[(benzyloxy)carbonyl]amino]-3-(4-hydroxyphenyl)propionic acid		C₁₇H₁₇NO₅	详情	详情
(XI)	59544	(2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-{4-[1-(tert-butoxycarbonyl)-4-piperidinyl]butoxy}phenyl)propanoic acid		C₃₁H₄₂N₂O₇	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 modified tyrosine building block (II) was prepared by alkylation of N-Cbz-L-tyrosine (I) at both the phenolic OH and the NH groups employing dimethyl sulfate under phase-transfer conditions. N-Boc-L-Threonine benzyl ether (III) was converted to the corresponding (triethylsilyl)ethoxymethyl ester, and the O-benzyl group was subsequently removed by catalytic hydrogenolysis to afford (IV). Coupling between the tyrosine (II) and threonine (IV) derivatives using DCC and DMAP gave rise to the protected didepsipeptide (V). The SEM protecting group was then cleaved by means of HF in acetonitrile, yielding intermediate (VI)

参考文献中间体

合成目标

【1】 Jou, G.; Gonzalez, I.; Albericio, F.; Lloyd-Williams, P.; Giralt, E.; Total synthesis of dehydrodidemnin B. Use of uronium and phosphonium salt coupling reagents in peptide synthesis in solution. J Org Chem 1997, 62, 2, 354.
【2】 Giralt Lledo, E.; Albericio Palomera, F.; Lloyd-Williams, P.; Gonzalez Valcarcel, I.; Jou Prat, G.; Gomez Gonzalez, A.; Manzanares Secades, I. (PharmaMar, SA); Process for the preparation of didemnine A. ES 2102322 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	39328	(2S)-2-[[(benzyloxy)carbonyl]amino]-3-(4-hydroxyphenyl)propionic acid	C₁₇H₁₇NO₅	详情	详情
(II)	50747	(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propionic acid	C₁₉H₂₁NO₅	详情	详情
(III)	50782	(2S,3R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]butyric acid	C₁₆H₂₃NO₅	详情	详情
(IV)	50746	[2-(trimethylsilyl)ethoxy]methyl (2S,3R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxybutanoate	C₁₅H₃₁NO₆Si	详情	详情
(V)	62532	[2-(trimethylsilyl)ethoxy]methyl (2S,3R)-3-{[(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy}-2-[(tert-butoxycarbonyl)amino]butanoate	C₃₄H₅₀N₂O₁₀Si	详情	详情
(VI)	52709	(2S,3R)-3-{[(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy}-2-[(tert-butoxycarbonyl)amino]butanoic acid	C₂₈H₃₆N₂O₉	详情	详情

合成路线5

该中间体在本合成路线中的序号：(XII)

N-Cbz-D-Alanine (VIII) is activated as the mixed anhydride (IX) and subsequently coupled to the dipeptide amide (VII), producing (X). Deprotection of the N-Cbz group of tripeptide (X) by hydrogenolysis over Pd/C yields (XI). The mixed anhydride (XIII) (prepared from N-Cbz-L-tyrosine (XII) and isobutyl chloroformate) is then coupled to tripeptide (XI), producing (XIV). Finally, removal of the N-Cbz group of (XIV) by catalytic hydrogenolysis furnishes the title compound.

参考文献中间体

合成目标

【1】 Franzen, H. (AstraZeneca plc); Process for the preparation of a tetrapeptide. WO 9947548 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VII)	61044	(2S)-2-amino-N-[(1S)-2-amino-1-benzyl-2-oxoethyl]-3-(4-fluorophenyl)propanamide	C₁₈H₂₀FN₃O₂	详情	详情
(VIII)	61209	CBZ-L-Alanine; (2S)-2-[[(Benzyloxy)carbonyl]amino]propionic acid; N-((Phenylmethoxy)carbonyl)-alanine; Carbobenzyloxy-L-alanine	C₁₁H₁₃NO₄	详情	详情
(IX)	61210		C₁₆H₂₁NO₆	详情	详情
(X)	61211	benzyl (1R)-2-{[(1S)-2-{[(1S)-2-amino-1-benzyl-2-oxoethyl]amino}-1-(4-fluorobenzyl)-2-oxoethyl]amino}-1-methyl-2-oxoethylcarbamate	C₂₉H₃₁FN₄O₅	详情	详情
(XI)	61045	(2S)-N-[(1S)-2-amino-1-benzyl-2-oxoethyl]-2-{[(2R)-2-aminopropanoyl]amino}-3-(4-fluorophenyl)propanamide	C₂₁H₂₅FN₄O₃	详情	详情
(XII)	39328	(2S)-2-[[(benzyloxy)carbonyl]amino]-3-(4-hydroxyphenyl)propionic acid	C₁₇H₁₇NO₅	详情	详情
(XIII)	61212		C₂₂H₂₅NO₇	详情	详情
(XIV)	61213	(1R)-2-{[(1S)-2-{[(1S)-2-amino-1-benzyl-2-oxoethyl]amino}-1-(4-fluorobenzyl)-2-oxoethyl]amino}-1-methyl-2-oxoethyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-hydroxyphenyl)propanoate	C₃₈H₃₉FN₄O₈	详情	详情

合成路线6

该中间体在本合成路线中的序号：(I)

In an alternative procedure, N-Cbz-L-tyrosine (I) is condensed with D-alanine methyl ester (II), either employing TBTU as the coupling reagent or via previous activation as the mixed anhydride with isobutyl chloroformate, to produce dipeptide (III). After alkaline hydrolysis of the methyl ester function of (III), the resultant carboxylic acid (IV) is coupled to dipeptide amide (V) yielding the protected tetrapeptide (VI). Finally, deprotection of (VI) is carried out by catalytic hydrogenolysis over Pd/C.

参考文献中间体

合成目标

【1】 Franzen, H.M.; Bessidskaia, G.; Abedi, V.; Nilsson, A.; Nilsson, M.; Olsson, L.; Frakefamide, an analgesic tetrapeptide: Development of a pilot-plant-scale process. Org Process Res Dev 2002, 6, 6, 788.
【2】 Nilsson, M.; Ellburg, M.; Franzen, H. (AstraZeneca AB); A process for the preparation of H-Tyr-D-Ala-Phe(F)-Phe-NH2. EP 1212350; JP 2003509437; WO 0119849 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	39328	(2S)-2-[[(benzyloxy)carbonyl]amino]-3-(4-hydroxyphenyl)propionic acid	C₁₇H₁₇NO₅	详情	详情
(II)	20694	methyl (2S)-2-aminopropanoate	C₄H₉NO₂	详情	详情
(III)	61214	methyl (2R)-2-{[(2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-hydroxyphenyl)propanoyl]amino}propanoate	C₂₁H₂₄N₂O₆	详情	详情
(IV)	61215	(2R)-2-{[(2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-hydroxyphenyl)propanoyl]amino}propanoic acid	C₂₀H₂₂N₂O₆	详情	详情
(V)	61044	(2S)-2-amino-N-[(1S)-2-amino-1-benzyl-2-oxoethyl]-3-(4-fluorophenyl)propanamide	C₁₈H₂₀FN₃O₂	详情	详情
(VI)	61216	benzyl (1S)-2-[((1R)-2-{[(1S)-2-{[(1S)-2-amino-1-benzyl-2-oxoethyl]amino}-1-(4-fluorobenzyl)-2-oxoethyl]amino}-1-methyl-2-oxoethyl)amino]-1-(4-hydroxybenzyl)-2-oxoethylcarbamate	C₃₈H₄₀FN₅O₇	详情	详情

合成路线7

该中间体在本合成路线中的序号：(I)

Coupling of N-Cbz-tyrosine (I) with n-pentylamine (II) afforded amide (III). Subsequent alkylation of the phenol group of (III) with diethyl chloromalonate (IV) gave phenoxy malonate (V). Hydrogenolytical deprotection of the N-Cbz group of (V) provided the corresponding amine, which was isolated as the hydrochloride salt (VI). Conversion of (VI) to isocyanate (VII) was effected by treatment with diphosgene in the presence of Proton Sponge(r). Addition of phenylalanine ethyl ester (VIII) to isocyanate (VII) furnished urea (IX). Finally, the ethyl ester groups of (IX) were saponified with LiOH to yield the title compound.

参考文献中间体

合成目标

【1】 Bleasdale, J.; May, P.D.; Schostarez, H.J.; Barf, T.; Larsen, S.D.; Liljebris, C. (Pharmacia Corp.); Inhibitors of protein tyrosine phosphatase. WO 9911606 .

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)	39328	(2S)-2-[[(benzyloxy)carbonyl]amino]-3-(4-hydroxyphenyl)propionic acid		C₁₇H₁₇NO₅	详情	详情
(II)	15764	amylamine; 1-pentanamine; pentylamine	110-58-7	C₅H₁₃N	详情	详情
(III)	39329	benzyl (1S)-1-(4-hydroxybenzyl)-2-oxo-2-(pentylamino)ethylcarbamate		C₂₂H₂₈N₂O₄	详情	详情
(IV)	39330	diethyl 2-chloromalonate	14064-10-9	C₇H₁₁ClO₄	详情	详情
(V)	39331	diethyl 2-[4-[(2S)-2-[[(benzyloxy)carbonyl]amino]-3-oxo-3-(pentylamino)propyl]phenoxy]malonate		C₂₉H₃₈N₂O₈	详情	详情
(VI)	39332	diethyl 2-[4-[(2S)-2-amino-3-oxo-3-(pentylamino)propyl]phenoxy]malonate		C₂₁H₃₂N₂O₆	详情	详情
(VII)	39333	diethyl 2-[4-[(2S)-2-isocyanato-3-oxo-3-(pentylamino)propyl]phenoxy]malonate		C₂₂H₃₀N₂O₇	详情	详情
(VIII)	32593	ethyl (2S)-2-amino-3-phenylpropanoate		C₁₁H₁₅NO₂	详情	详情
(IX)	39334	diethyl 2-[4-[(2S)-2-[([[(1S)-1-benzyl-2-ethoxy-2-oxoethyl]amino]carbonyl)amino]-3-oxo-3-(pentylamino)propyl]phenoxy]malonate		C₃₃H₄₅N₃O₉	详情	详情

Extended Information