(S)-(-)-Tyrosine; (S)-2-Amino-3-(4-hydroxyphenyl)propionic acid; 3-(4-Hydroxyphenyl)-L-alanine; L-(-)-Tyrosine; L-3-(4-Hydroxyphenyl)alanine; L-4-Hydroxy-17O-phenylalanine; L-beta-(p-Hydroxyphenyl)alanine; L-Hydroxy Phenyl Alanine; L-tyrosine -Drug Synthesis Database

【结构式】

【分子编号】48794

【品名】(S)-(-)-Tyrosine; (S)-2-Amino-3-(4-hydroxyphenyl)propionic acid; 3-(4-Hydroxyphenyl)-L-alanine; L-(-)-Tyrosine; L-3-(4-Hydroxyphenyl)alanine; L-4-Hydroxy-17O-phenylalanine; L-beta-(p-Hydroxyphenyl)alanine; L-Hydroxy Phenyl Alanine; L-tyrosine

【CA登记号】60-18-4

【分子式】C₉H₁₁NO₃

【分子量】181.19128

【元素组成】C 59.66% H 6.12% N 7.73% O 26.49%

与该中间体有关的原料药合成路线共 4 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1

该中间体在本合成路线中的序号：(XXVII)

In a variation of this process, L-tyrosine (XXVII) was initially protected as the bis-O-silylated derivative (XXVIII) employing N,O-bis(trimethylsilyl) trifluoroacetamide. Acylation of (XXVIII) with butanesulfonyl chloride (XIV), followed by hydrolysis of the silyl groups, gave rise to N-butanesulfonyl tyrosine (XXIX). The phenolic hydroxyl of (XXIX) was then alkylated by 4-(4-pyridinyl)butyl chloride (XXII) to produce ether (XXVI). Finally, hydrogenation of the pyridine ring furnished the target piperidine derivative, which was isolated as the corresponding hydrochloride salt.

参考文献中间体

合成目标

【1】 Chung, J.Y.L.; Zhao, D.; Hughes, D.L. (Merck & Co., Inc.); Process for preparing fibrinogen receptor antagonists. WO 9316995 .
【2】 Chung, J.Y.L.; Zhao, D.; Hughes, D.L.; Grabowski, E.E.; A practical synthesis of fibrinogen receptor antagonist MK-383 - Selective functionalization of (S)-tyrosine. Tetrahedron 1993, 49, 26, 5767.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIV)	26779	1-butanesulfonyl chloride	2386-60-9	C₄H₉ClO₂S	详情	详情
(XXII)	59551	4-(4-chlorobutyl)pyridine		C₉H₁₂ClN	详情	详情
(XXVI)	59554	(2S)-2-[(butylsulfonyl)amino]-3-{4-[4-(4-pyridinyl)butoxy]phenyl}propanoic acid		C₂₂H₃₀N₂O₅S	详情	详情
(XXVII)	48794	(S)-(-)-Tyrosine; (S)-2-Amino-3-(4-hydroxyphenyl)propionic acid; 3-(4-Hydroxyphenyl)-L-alanine; L-(-)-Tyrosine; L-3-(4-Hydroxyphenyl)alanine; L-4-Hydroxy-17O-phenylalanine; L-beta-(p-Hydroxyphenyl)alanine; L-Hydroxy Phenyl Alanine; L-tyrosine	60-18-4	C₉H₁₁NO₃	详情	详情
(XXVIII)	59555	trimethylsilyl (2S)-2-amino-3-{4-[(trimethylsilyl)oxy]phenyl}propanoate		C₁₅H₂₇NO₃Si₂	详情	详情
(XXIX)	59556	(2S)-2-[(butylsulfonyl)amino]-3-(4-hydroxyphenyl)propanoic acid		C₁₃H₁₉NO₅S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The reaction of L-tyrosine (I) with methyl chloroformate (II) by means of NaOH in water gives the carbamate (III), which is methylated at the remaining phenol and carboxylic groups with dimethyl sulfate and K2CO3 in refluxing acetone to yield the 4-O-methyl tyrosine derivative (IV). The hydrolysis of the methyl ester of (IV) with NaOH in dioxane/water, followed by reaction with O-methylhydroxylamine by means of DCC and HOBT, affords the methyl hydroxamate (V). The cyclization of (V) by means of bis(trifluoroacetoxy)iodobenzene in dichloromethane/methanol provides the spirodienone (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate to give the saturated ketone (VII). The protection of the ketonic group of (VII) with ethyleneglycol and PPTS yields the cyclic ketal (VIII), which is reduced with LiAlH4 in THF to afford the methoxyamine (IX). The protection of the N-methylamine of (IX) with benzyl chloroformate and TEA provides the carbamate (X), which is treated with Zn in acetic acid in order to cleave the N-methoxyamine group and yield the spiropyrrolidine (XI). The alkylation of the pyrrolidine NH with benzyl chloroformate (XII) and K2CO3 in warm acetonitrile affords the adduct (XIII), which is treated with H2 over Pd/C in methanol in order to remove the benzyl and benzyloxycarbonyl protecting groups, providing the amino acid (XIV). The cyclization of (XIV) by means of DPPA and NaHCO3 in DMF/dichloromethane gives the tetracyclic compound (XV), which is condensed with 4-(prenyloxy)benzaldehyde (XVI) by means of LDA in THF yielding the aldol condensation product (XVII).

参考文献中间体

合成目标

【1】 Basak, A.; Wardrop, D.J.; N-methoxy-N-acylnitrenium ions: Application to the formal synthesis of (-)-TAN1251A. Org Lett 2001, 3, 7, 1053.

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)	48794	(S)-(-)-Tyrosine; (S)-2-Amino-3-(4-hydroxyphenyl)propionic acid; 3-(4-Hydroxyphenyl)-L-alanine; L-(-)-Tyrosine; L-3-(4-Hydroxyphenyl)alanine; L-4-Hydroxy-17O-phenylalanine; L-beta-(p-Hydroxyphenyl)alanine; L-Hydroxy Phenyl Alanine; L-tyrosine	60-18-4	C₉H₁₁NO₃	详情	详情
(II)	16993	methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate	79-22-1	C₂H₃ClO₂	详情	详情
(III)	48795	(2S)-3-(4-hydroxyphenyl)-2-[(methoxycarbonyl)amino]propionic acid		C₁₁H₁₃NO₅	详情	详情
(IV)	48796	methyl (2S)-2-[(methoxycarbonyl)amino]-3-(4-methoxyphenyl)propanoate		C₁₃H₁₇NO₅	详情	详情
(V)	48797	methyl (1S)-2-(methoxyamino)-1-(4-methoxybenzyl)-2-oxoethylcarbamate		C₁₃H₁₈N₂O₅	详情	详情
(VI)	48798	methyl (3S)-1-methoxy-2,8-dioxo-1-azaspiro[4.5]deca-6,9-dien-3-ylcarbamate		C₁₂H₁₄N₂O₅	详情	详情
(VII)	48799	methyl (3S)-1-methoxy-2,8-dioxo-1-azaspiro[4.5]dec-3-ylcarbamate		C₁₂H₁₈N₂O₅	详情	详情
(VIII)	48800	methyl (11S)-9-methoxy-10-oxo-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-11-ylcarbamate		C₁₄H₂₂N₂O₆	详情	详情
(IX)	48801	(11S)-9-methoxy-N-methyl-1,4-dioxa-9-azadispiro[4.2.4.2]tetradecan-11-amine; N-[(11S)-9-methoxy-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-11-yl]-N-methylamine		C₁₃H₂₄N₂O₃	详情	详情
(X)	48802	benzyl (11S)-9-methoxy-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-11-yl(methyl)carbamate		C₂₁H₃₀N₂O₅	详情	详情
(XI)	48803	benzyl (11S)-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-11-yl(methyl)carbamate		C₂₀H₂₈N₂O₄	详情	详情
(XII)	12869	benzyl 2-bromoacetate	5437-45-6	C₉H₉BrO₂	详情	详情
(XIII)	48804	benzyl 2-[(11S)-11-[[(benzyloxy)carbonyl](methyl)amino]-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]acetate		C₂₉H₃₆N₂O₆	详情	详情
(XIV)	48805	2-[(11S)-11-(methylamino)-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]acetic acid		C₁₄H₂₄N₂O₄	详情	详情
(XV)	48806			C₁₄H₂₂N₂O₃	详情	详情
(XVI)	19019	4-[(3-methyl-2-butenyl)oxy]benzaldehyde		C₁₂H₁₄O₂	详情	详情
(XVII)	19020	(1R,4S)-4-[1-Hydroxy-1-[4-(3-methyl-2-butenyloxy)phenyl]methyl]-2-methyldispiro[2,5-diazabicyclo[3,2,1]octane-6,1'-cyclohexane-4',2''-[1,3]-dioxolan]-3-one		C₂₆H₃₆N₂O₅	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

The borinated tyrosine intermediate (VII) has been obtained as follows: The esterification of L-tyrosine (I) with SOCl2 and methanol gives the methyl ester (II), which is N-protected with Cbz-Cl and K2CO3 to yield the carbamate (III). The O-protection of (III) with benzyl bromide and Cs2CO3 affords the benzyl ether (IV), which is iodinated with I2 and Ag2SO4 to provide the 3-iodotyrosine derivative (V). Finally, the borylation of (V) by means of pinacolatodiborane (VI) catalyzed by PdCl2[bis(diphenylphosphanyl)ferrocene] (PdCl2(dppf)) gives rise to the target tyrosine intermediate (VII).

参考文献中间体

合成目标

【1】 Lin, S.N.; Danishefsky, S.J.; The total synthesis of proteasome inhibitors TMC-95A and TMC-95B: Discovery of a new method to generate cis-propenyl amides. Angew Chem. Int Ed 2002, 41, 3, 512.

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)	48794	(S)-(-)-Tyrosine; (S)-2-Amino-3-(4-hydroxyphenyl)propionic acid; 3-(4-Hydroxyphenyl)-L-alanine; L-(-)-Tyrosine; L-3-(4-Hydroxyphenyl)alanine; L-4-Hydroxy-17O-phenylalanine; L-beta-(p-Hydroxyphenyl)alanine; L-Hydroxy Phenyl Alanine; L-tyrosine	60-18-4	C₉H₁₁NO₃	详情	详情
(II)	21431	methyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate	1080-06-4	C₁₀H₁₃NO₃	详情	详情
(III)	53339	methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-hydroxyphenyl)propanoate	n/a	C₁₈H₁₉NO₅	详情	详情
(IV)	53340	methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[4-(benzyloxy)phenyl]propanoate	n/a	C₂₅H₂₅NO₅	详情	详情
(V)	53341	methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[4-(benzyloxy)-3-iodophenyl]propanoate	n/a	C₂₅H₂₄INO₅	详情	详情
(VI)	53342	4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-1,3,2-dioxaborolane; Bis(pinacolato)diboron; Diboron pinacol ester	73183-34-3	C₁₂H₂₄B₂O₄	详情	详情
(VII)	53343	methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[4-(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate	n/a	C₃₁H₃₆BNO₇	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

参考文献中间体

合成目标

【1】 Lin, S.N.; Danishefsky, S.J.; The total synthesis of proteasome inhibitors TMC-95A and TMC-95B: Discovery of a new method to generate cis-propenyl amides. Angew Chem. Int Ed 2002, 41, 3, 512.

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)	48794	(S)-(-)-Tyrosine; (S)-2-Amino-3-(4-hydroxyphenyl)propionic acid; 3-(4-Hydroxyphenyl)-L-alanine; L-(-)-Tyrosine; L-3-(4-Hydroxyphenyl)alanine; L-4-Hydroxy-17O-phenylalanine; L-beta-(p-Hydroxyphenyl)alanine; L-Hydroxy Phenyl Alanine; L-tyrosine	60-18-4	C₉H₁₁NO₃	详情	详情
(II)	21431	methyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate	1080-06-4	C₁₀H₁₃NO₃	详情	详情
(III)	53339	methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-hydroxyphenyl)propanoate	n/a	C₁₈H₁₉NO₅	详情	详情
(IV)	53340	methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[4-(benzyloxy)phenyl]propanoate	n/a	C₂₅H₂₅NO₅	详情	详情
(V)	53341	methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[4-(benzyloxy)-3-iodophenyl]propanoate	n/a	C₂₅H₂₄INO₅	详情	详情
(VI)	53342	4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-1,3,2-dioxaborolane; Bis(pinacolato)diboron; Diboron pinacol ester	73183-34-3	C₁₂H₂₄B₂O₄	详情	详情
(VII)	53343	methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[4-(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate	n/a	C₃₁H₃₆BNO₇	详情	详情

Extended Information