2,4,5-trichlorophenol -Drug Synthesis Database

【结构式】

【分子编号】16126

【品名】2,4,5-trichlorophenol

【CA登记号】95-95-4

【分子式】C₆H₃Cl₃O

【分子量】197.44732

【元素组成】C 36.5% H 1.53% Cl 53.87% O 8.1%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：

The synthesis of GYKI-14766 is as follows: N2-tert-Butoxycarbonyl-L-arginine (I) was converted to the N6-benzyloxycarbonyl derivative (II). Treatment of (II) with isobutoxycarbonyl chloride and N-methylmorpholine gave the aminolactam (III). Dicyclohexylcarbodiimide-mediated esterification of N-benzyloxycarbonyl-D-phenylalanine (IV) with 2,4,5-trichlorophenol gave the active ester (V), which was coupled with L-proline to the dipeptide (VI). Methylation with iodomethane afforded the N-methyl derivative isolated as the cyclohexylamine salt (VII). The fragments (III) and (VII) were coupled via the mixed anhydride of (VII), generated as in the case of (II), giving the tripeptide lactam (VIII). Reduction with lithium aluminum hydride at low temperature converted (VIII) to the aldehyde (IX), which was finally deprotected to the end product.

参考文献中间体

合成目标

【1】 Nogradi, M.; GYKI-14766. Drugs Fut 1992, 17, 12, 1087.
【2】 Széll, E.; Bagdy, D.; Bajusz, S.; et al.; Highly active and selective anticoagulants: D-Phe-Pro-Arg-H, a free tripeptide aldehyde prone to spontaneous inactivation and its stable N-methyl derivative, D-MePhe-Pro-Arg-H. J Med Chem 1990, 33, 6, 1729-35.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	16126	2,4,5-trichlorophenol	95-95-4	C₆H₃Cl₃O	详情	详情
(I)	14073	(2S)-5-[[Amino(imino)methyl]amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid	13726-76-6	C₁₁H₂₂N₄O₄	详情	详情
(II)	14074	(2S)-5-[(Amino[[(benzyloxy)carbonyl]imino]methyl)amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid		C₁₉H₂₈N₄O₆	详情	详情
(III)	14075	tert-butyl N-[(3S)-1-(amino[[(benzyloxy)carbonyl]imino]methyl)-2-oxotetrahydro-3(2H)-pyridinyl]carbamate		C₁₉H₂₆N₄O₅	详情	详情
(IV)	14076	(2R)-3-Phenyl-2-[[(2-phenylacetyl)oxy]amino]propionic acid		C₁₇H₁₇NO₄	详情	详情
(V)	14077	2,4,5-trichlorophenyl (2R)-3-phenyl-2-[[(2-phenylacetyl)oxy]amino]propanoate		C₂₃H₁₈Cl₃NO₄	详情	详情
(VI)	14078	(2S)-1-((2R)-3-Phenyl-2-[[(2-phenylacetyl)oxy]amino]propanoyl)tetrahydro-1H-pyrrole-2-carboxylic acid		C₂₂H₂₄N₂O₅	详情	详情
(VII)	14079	(2R)-1-((2S)-2-[[(Cyclohexylamino)oxy]carbonyl]pyrrolidinyl)-2-[methyl[(2-phenylacetyl)oxy]amino]-3-phenyl-1-propanone		C₂₉H₃₇N₃O₅	详情	详情
(VIII)	14080	tert-butyl (1R)-2-((2S)-2-[[((3S)-1-[amino[(tert-butoxycarbonyl)imino]methyl]-2-oxopiperidinyl)amino]carbonyl]pyrrolidinyl)-1-benzyl-2-oxoethyl(methyl)carbamate		C₃₁H₄₆N₆O₇	详情	详情
(IX)	14081	tert-butyl (E)-amino[((4S)-4-[[((2S)-1-[(2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-phenylpropanoyl]pyrrolidinyl)carbonyl]amino]-5-oxopentyl)amino]methylidenecarbamate		C₃₁H₄₈N₆O₇	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IX)

A new synthesis of LY-303366 has been reported: The enzymatic hydrolysis of echinocandin B (I) with Actinoplanes utahensis provides the corresponding cyclic peptide (II), which is then reacylated with the active ester 4''-(pentyloxy)-p-terphenyl-4-carboxylic acid 2,4,5-trichlorophenyl ester (III) in DMF. The active ester (III) is obtained as follows: 4-Bromo-4'-(pentyloxy)biphenyl (IV) is treated with sec-butyllithium and triisopropyl borate in THF/cyclohexane, yielding (after hydrolysis with HCl) 4'-(pentyloxy)biphenyl-4-boronic acid (V), which is condensed with methyl 4-iodobenzoate (VI) by means of palladium tetrakis(triphenylphosphine) and K2CO3 in refluxing toluene, giving 4''-(pentyloxy)-p-terphenyl-4-carboxylic acid methyl ester (VII). The hydrolysis of (VII) with NaOH in refluxing dioxane containing 2N NaOH affords the corresponding free acid (VIII), which is finally converted to the active ester (III) by esterification with 2,4,5-trichlorophenol (IX) by means of dicyclohexylcarbodiimide (DCC) in DMF.

参考文献中间体

合成目标

【1】 LaGrandeur, L.; Turner, W.W.; Debono, M.; et al.; Semisynthetic chemical modification of the antifungal lipopeptidechinocandin B (ECB): Structure-activity studies of the lipophilic and geometric parameters of polyarylated acyl analogs of ECB. J Med Chem 1995, 38, 17, 3271.

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)	16120	(9Z,12Z)-N-[(2R,6S,9S,11R,12R,14aS,15S,16S,20S,23S,25aS)-23-[(1S,2S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-2,11,12,15-tetrahydroxy-6,20-bis[(1R)-1-hydroxyethyl]-16-methyl-5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipyrrolo[2,1-c:2,1-l][1,4,7,10,13,16]hexaazacyclohenicosin-9-yl]-9,12-octadecadienamide		C₅₂H₈₁N₇O₁₆	详情	详情
(II)	16118	(2R,6S,9S,11R,12R,14aS,15S,16S,20S,23S,25aS)-9-amino-23-[(1S,2S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-2,11,12,15-tetrahydroxy-6,20-bis[(1R)-1-hydroxyethyl]-16-methylhexadecahydro-1H-dipyrrolo[2,1-c:2,1-l][1,4,7,10,13,16]hexaazacyclohenicosine-5,8,14,19,22,25(9H,25aH)-hexone		C₃₄H₅₁N₇O₁₅	详情	详情
(III)	16119	4''-(Pentyloxy)-p-terphenyl-4-carboxylic acid 2,4,5-trichlorophenyl ester		C₃₀H₂₅Cl₃O₃	详情	详情
(IV)	16121	4-bromo-4'-(pentyloxy)-1,1'-biphenyl; 4'-bromo[1,1'-biphenyl]-4-yl pentyl ether		C₁₇H₁₉BrO	详情	详情
(V)	16122	4'-(Pentyloxy)biphenyl-4-ylboronic acid		C₁₇H₂₁BO₄	详情	详情
(VI)	16123	methyl 4-iodobenzoate	619-44-3	C₈H₇IO₂	详情	详情
(VII)	16124	4''-Pentyloxy-p-terphenyl-4-carboxylic acid methyl ester		C₂₅H₂₆O₃	详情	详情
(VIII)	16125	4''-(Pentyloxy)-p-terphenyl-4-carboxylic acid		C₂₄H₂₄O₃	详情	详情
(IX)	16126	2,4,5-trichlorophenol	95-95-4	C₆H₃Cl₃O	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 reaction of 2,4,5-trichlorophenol (I) with 1,3-dibromopropane (II) by means of refluxing 25% aqueous NaOH gives 3-(2,4,5-trichlorophenoxy)propyl bromide (III), which is condensed with benzhydroxamic acid (IV) by means of NaOH in refluxing methanol yielding 3-(2,4,5-trichlorophenoxy)propyl benzhydroxamate (V). The hydrolysis of (V) with HCl in refluxing methanol affords 3-(2,4,5-trichlorophenoxy)propyloxyamine (VI), which is then condensed with dicyandiamide (VII) in refluxing ethanol to give 3'-(2,4,5-trichlorophenoxy)propyloxydiguanide (VIII). Finally, this compound is cyclized with acetone (IX) by means of HCl.

参考文献中间体

合成目标

【1】 Castañer, J.; Thorpe, P.J.; Blancafort, P.; Serradell, M.N.; BRL-6231. Drugs Fut 1982, 7, 10, 724.
【2】 Mamalis, P.; Outred, D.I. (SmithKline Beecham plc); Di-hydro triazine derivatives and processes for their manufacture. DE 1957769; ES 373657; FR 2023866; GB 1270831 .

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)	16126	2,4,5-trichlorophenol	95-95-4	C₆H₃Cl₃O	详情	详情
(II)	12581	1,3-Dibromopropane	109-64-8	C₃H₆Br₂	详情	详情
(III)	37140	1-(3-bromopropoxy)-2,4,5-trichlorobenzene; 3-bromopropyl 2,4,5-trichlorophenyl ether		C₉H₈BrCl₃O	详情	详情
(IV)	37141	N-hydroxybenzenecarboximidic acid		C₇H₇NO₂	详情	详情
(V)	37142	N-[3-(2,4,5-trichlorophenoxy)propoxy]benzenecarboximidic acid		C₁₆H₁₄Cl₃NO₃	详情	详情
(VI)	37143	O-[3-(2,4,5-trichlorophenoxy)propyl]hydroxylamine; 1-[3-(aminooxy)propoxy]-2,4,5-trichlorobenzene		C₉H₁₀Cl₃NO₂	详情	详情
(VII)	23611	N-cyanoguanidine	461-58-5	C₂H₄N₄	详情	详情
(VIII)	37144	1-[3-([[[[amino(imino)methyl]amino](imino)methyl]amino]oxy)propoxy]-2,4,5-trichlorobenzene		C₁₁H₁₄Cl₃N₅O₂	详情	详情
(IX)	23199	2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether	67-64-1	C₃H₆O	详情	详情

Extended Information