methyl 3,5-dihydroxybenzoate -Drug Synthesis Database

【结构式】

【分子编号】25155

【品名】methyl 3,5-dihydroxybenzoate

【CA登记号】2150-44-9

【分子式】C₈H₈O₄

【分子量】168.14912

【元素组成】C 57.14% H 4.8% O 38.06%

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)

Alkylation of methyl 3,5-dihydroxybenzoate (I) with benzyl bromide in the presence of NaH gave dibenzyl ether (II). Subsequent basic hydrolysis of the ester function of (II) provided carboxylic acid (III). This was protected as the oxazoline (VI) via conversion into acid chloride with SOCl2, followed by coupling with 2-amino-2-methyl-1-propanol (IV), and then cyclization of the hydroxy amide (V) with SOCl2. After lithiation of (VI) with n-BuLi at -78 C, the 2-benzyl substituent was introduced by treatment with benzyl bromide to afford (VII). Quaternization of (VII) with boiling CH3I provided iminium salt (VIII), which was reduced with NaBH4 and then hydrolyzed to aldehyde (IX). Hydantoin (X) was then prepared from (IX) under Bucherer-Bergs conditions in the presence of KCN and (NH4)2CO3. Finally, hydrogenolytic cleavage of the O-benzyl groups, of (X) yielded (XI), which by basic hydrolysis of the hydantoin ring provided the title amino acid.

参考文献中间体

合成目标

【1】 Baker, S.R.; et al.; Synthesis and pharmacological evaluation of benzamides as selective 5-HT4 receptor agonists. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abs P 270.
【2】 Baker, S.R.; Clark, B.P.; Goldsworthy, J.; Harris, J.R. (Eli Lilly and Company); Derivs. of phenylglycine and use thereof as pharmaceuticals. EP 0807621; JP 1998067723; US 5863947 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	12912	1-(Bromomethyl)benzene; Alpha-bromotoluene	100-39-0	C₇H₇Br	详情	详情
(I)	25155	methyl 3,5-dihydroxybenzoate	2150-44-9	C₈H₈O₄	详情	详情
(II)	25156	methyl 3,5-bis(benzyloxy)benzoate		C₂₂H₂₀O₄	详情	详情
(III)	25157	3,5-bis(benzyloxy)benzoic acid	28917-43-3	C₂₁H₁₈O₄	详情	详情
(IV)	21513	2-amino-2-methyl-1-propanol；Karl Fischer;2-Amino-2-methyl-propan-1-ol；2-amino-2-methyl-1-propanol	124-68-5	C₄H₁₁NO	详情	详情
(V)	25158	3,5-bis(benzyloxy)-N-(2-hydroxy-1,1-dimethylethyl)benzamide		C₂₅H₂₇NO₄	详情	详情
(VI)	25159	benzyl 3-(benzyloxy)-5-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl ether		C₂₅H₂₅NO₃	详情	详情
(VII)	25160	2-[2-benzyl-3,5-bis(benzyloxy)phenyl]-4,4-dimethyl-4,5-dihydro-1,3-oxazole		C₃₂H₃₁NO₃	详情	详情
(VIII)	25161	2-[2-benzyl-3,5-bis(benzyloxy)phenyl]-3,4,4-trimethyl-4,5-dihydro-1,3-oxazol-3-ium iodide		C₃₃H₃₄INO₃	详情	详情
(IX)	25162	2-benzyl-3,5-bis(benzyloxy)benzaldehyde		C₂₈H₂₄O₃	详情	详情
(X)	25163	5-[2-benzyl-3,5-bis(benzyloxy)phenyl]-2,4-imidazolidinedione		C₃₀H₂₆N₂O₄	详情	详情
(XI)	25164	5-(2-benzyl-3,5-dihydroxyphenyl)-2,4-imidazolidinedione		C₁₆H₁₄N₂O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Condensation of methyl 3,5-dihydroxybenzoate (I) with 3-chloro-3-methyl-1-butyne (II) in the presence of CuI, followed by thermal cyclization at 75 C, gives rise to a mixture of two regioisomeric chromenes (III) and (IV). After chromatographic separation, the desired isomer (III) is reduced with LiAlH4 to provide alcohol (V). Copper-catalyzed coupling of the phenolic chromene (V) with sodium 2-iodobenzoate (VI) leads to the diaryl ether (VII), which is further cyclized to the pyranoxanthenone (VIII) in the presence of trifluoroacetic anhydride. After basic hydrolysis of the trifluoroacetate ester (VIII), the resultant alcohol (IX) is converted to mesylate (X) by treatment with methanesulfonyl chloride and triethylamine. Finally, displacement of the mesylate group of (X) with N,N-diethyl ethylenediamine (XI) furnishes the title compound.

参考文献中间体

合成目标

【1】 Kolokythas, G.; et al.; Design and synthesis of some new pyranoxanthenone aminoderivatives with cytotoxic activity. Bioorg Med Chem Lett 2002, 12, 11, 1443.

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)	25155	methyl 3,5-dihydroxybenzoate	2150-44-9	C₈H₈O₄	详情	详情
(II)	22416	3-chloro-3-methyl-1-butyne	1111-97-3	C₅H₇Cl	详情	详情
(III)	57036	methyl 7-hydroxy-2,2-dimethyl-2H-chromene-5-carboxylate		C₁₃H₁₄O₄	详情	详情
(IV)	57037	methyl 5-hydroxy-2,2-dimethyl-2H-chromene-7-carboxylate		C₁₃H₁₄O₄	详情	详情
(V)	57039	5-(hydroxymethyl)-2,2-dimethyl-2H-chromen-7-ol		C₁₂H₁₄O₃	详情	详情
(VI)	57038	sodium 2-iodobenzoate		C₇H₄INaO₂	详情	详情
(VII)	57040	2-{[5-(hydroxymethyl)-2,2-dimethyl-2H-chromen-7-yl]oxy}benzoic acid		C₁₉H₁₈O₅	详情	详情
(VIII)	57041	(2,2-dimethyl-6-oxo-2H,6H-pyrano[3,2-b]xanthen-5-yl)methyl 2,2,2-trifluoroacetate		C₂₁H₁₅F₃O₅	详情	详情
(IX)	57042	5-(hydroxymethyl)-2,2-dimethyl-2H,6H-pyrano[3,2-b]xanthen-6-one		C₁₉H₁₆O₄	详情	详情
(X)	57043	(2,2-dimethyl-6-oxo-2H,6H-pyrano[3,2-b]xanthen-5-yl)methyl methanesulfonate		C₂₀H₁₈O₆S	详情	详情
(XI)	12420	N-(2-Aminoethyl)-N,N-diethylamine; N,N-Diethylethylene-diamine; N(1),N(1)-Diethyl-1,2-ethanediamine	100-36-7	C₆H₁₆N₂	详情	详情

Extended Information