3,5-bis(benzyloxy)benzoic acid -Drug Synthesis Database

【结构式】

【分子编号】25157

【品名】3,5-bis(benzyloxy)benzoic acid

【CA登记号】28917-43-3

【分子式】C₂₁H₁₈O₄

【分子量】334.37152

【元素组成】C 75.43% H 5.43% O 19.14%

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：(II)

The reaction of 3,5-dihydroxybenzoic acid (I) with Bn-Br, K2CO3 and 18-crown-6 in refluxing acetone gives 3,5-bis(benzyloxy)benzoic acid (II), which is reduced with LiAlH4 in ethyl ether to yield the corresponding benzyl alcohol (III). The reaction of (III) with PBr3 in ethyl ether/pyridine affords the benzyl bromide (IV), which is treated with triisopropyl phosphite (V) at 140-150 C to provide the phosphonate (VI). The condensation of (VI) with 4-benzyloxybenzaldehyde (VII) by means of NaOMe in DMF gives (E)-3,4',5-tris(benzyloxy)stilbene (VIII), which is finally debenzylated by treatment with BBr3 in dichloromethane. Alternatively, the synthesis of the target product can be performed by first condensation of 3,5-dimethoxybenzoyl chloride (IX) with 4-acetoxystyrene (X) by means of palladium(II) acetate and Et3N in p-xylene to yield (E)-4-acetoxy-3',5'-dimethoxystilbene (XI), whose acetoxy group is subjected to saponification either with NaOMe or with K2CO3 in THF/H2O/MeOH and whose methoxy groups are cleaved by means of BBr3 in CH2Cl2.

参考文献中间体

合成目标

【1】 Meredith, E.; Andrus, M. (Brigham Young University); Synthesis of resveratrol. WO 0160774 .

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)	16230	resorcylic acid; 3,5-dihydroxybenzoic acid	99-10-5	C₇H₆O₄	详情	详情
(II)	25157	3,5-bis(benzyloxy)benzoic acid	28917-43-3	C₂₁H₁₈O₄	详情	详情
(III)	50091	[3,5-bis(benzyloxy)phenyl]methanol		C₂₁H₂₀O₃	详情	详情
(IV)	50092	1,3-bis(benzyloxy)-5-(bromomethyl)benzene; benzyl 3-(benzyloxy)-5-(bromomethyl)phenyl ether		C₂₁H₁₉BrO₂	详情	详情
(V)	32162	Triisopropyl phosphite	116-17-6	C₉H₂₁O₃P	详情	详情
(VI)	50093	diisopropyl 3,5-bis(benzyloxy)benzylphosphonate		C₂₇H₃₃O₅P	详情	详情
(VII)	29179	4-(Benzyloxy)benzaldehyde	4397-53-9	C₁₄H₁₂O₂	详情	详情
(VIII)	50094	benzyl 3-(benzyloxy)-5-[(E)-2-[4-(benzyloxy)phenyl]ethenyl]phenyl ether; 1,3-bis(benzyloxy)-5-[(E)-2-[4-(benzyloxy)phenyl]ethenyl]benzene		C₃₅H₃₀O₃	详情	详情
(IX)	50095	3,5-Dimethoxybenzoyl chloride	17213-57-9	C₉H₉ClO₃	详情	详情
(X)	27297	4-vinylphenyl acetate	2628-16-2	C₁₀H₁₀O₂	详情	详情
(XI)	50096	4-[(E)-2-(3,5-dimethoxyphenyl)ethenyl]phenyl acetate		C₁₈H₁₈O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

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

Extended Information