ethyl 4-(3-bromopropoxy)-3-methyl-1-benzofuran-2-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】52127

【品名】ethyl 4-(3-bromopropoxy)-3-methyl-1-benzofuran-2-carboxylate

【CA登记号】

【分子式】C₁₅H₁₇BrO₄

【分子量】341.20158

【元素组成】C 52.8% H 5.02% Br 23.42% O 18.76%

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：(VIII)

Lithiation of 1,3-bis(O-methoxymethyl)resorcinol (I) by means of n-butyllithium, followed by acylation with acetyl chloride, gave the protected acetophenone (II). Subsequent acid hydrolysis of the methoxymethyl protecting groups furnished diol (III). The 4-hydroxybenzofuran derivative (VI) was prepared by monoalkylation of (III) with ethyl bromoacetate (IV), followed by base-catalyzed cyclization of the resulting keto ester (V). Alkylation of the hydroxybenzofuran (VI) with 1,3-dibromopropane (VII) gave the bromopropyl ether (VIII). This was finally condensed with 3-picolylamine (IX) to produce the title compound.

参考文献中间体

合成目标

【1】 Masubuchi, M.; et al.; Design and synthesis of novel benzofurans as a new class of antifungal agents targeting fungal N-myristoyltransferase. Part 1. Bioorg Med Chem Lett 2001, 11, 14, 1833.
【2】 Fujii, T.; Tsujii, S.; Liu, P.; Ohtsuka, T.; Ebiike, H.; Masubuchi, M.; Aoki, Y.; Kawasaki, K. (F. Hoffmann-La Roche AG); Novel bicyclic cpds.. US 6376491; WO 0037464 .

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)	52123	[3-(methoxymethoxy)phenoxy]methyl methyl ether; 1,3-bis(methoxymethoxy)benzene		C₁₀H₁₄O₄	详情	详情
(II)	52124	1-[2,6-bis(methoxymethoxy)phenyl]-1-ethanone		C₁₂H₁₆O₅	详情	详情
(III)	27511	1-(2,6-dihydroxyphenyl)-1-ethanone	699-83-2	C₈H₈O₃	详情	详情
(IV)	16640	Ethyl 2-bromoacetate; Ethyl bromoacetate	105-36-2	C₄H₇BrO₂	详情	详情
(V)	52125	ethyl 2-(2-acetyl-3-hydroxyphenoxy)acetate		C₁₂H₁₄O₅	详情	详情
(VI)	52126	ethyl 4-hydroxy-3-methyl-1-benzofuran-2-carboxylate		C₁₂H₁₂O₄	详情	详情
(VII)	12581	1,3-Dibromopropane	109-64-8	C₃H₆Br₂	详情	详情
(VIII)	52127	ethyl 4-(3-bromopropoxy)-3-methyl-1-benzofuran-2-carboxylate		C₁₅H₁₇BrO₄	详情	详情
(IX)	18731	3-pyridinylmethanamine; 3-pyridinylmethylamine	3731-52-0	C₆H₈N₂	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 ethyl 4-hydroxy-3-methylbenzofuran-2-carboxylate (I) with 1,3-dibromopropane (II) in the presence of K2CO3 produced the bromopropyl ether (III). Subsequent displacement of the remaining bromine of (III) with 3-picolylamine (IV) furnished the secondary amine (V). The ester group of (V) was then reduced to alcohol (VI) with LiAlH4. Finally, Mitsunobu coupling of alcohol (VI) with 2,4-difluorophenol (VII) in the presence of 1,1'-(azodicarbonyl)dipiperidine and tributylphosphine gave rise to the target difluorophenyl ether.

参考文献中间体

合成目标

【1】 Ebiike, H.; Masubuchi, M.; Liu, P.; Kawasaki, K.,-I.; Morikami, K.; Sogabe, S.; Hayase, M.; Fujii, T.; Sakata, K.; Shindoh, H.; Shiratori, Y.; Aoki, Y.; Ohtsuka, T.; Shimma, N.; Design and synthesis of novel benzofurans as a new class of antifungal agents targeting fungal N-myristoyltransferase. Part 2. Bioorg Med Chem Lett 2002, 12, 4, 607.
【2】 Fujii, T.; Tsujii, S.; Liu, P.; Ohtsuka, T.; Ebiike, H.; Masubuchi, M.; Aoki, Y.; Kawasaki, K. (F. Hoffmann-La Roche AG); Novel bicyclic cpds.. US 6376491; WO 0037464 .

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)	52126	ethyl 4-hydroxy-3-methyl-1-benzofuran-2-carboxylate		C₁₂H₁₂O₄	详情	详情
(II)	12581	1,3-Dibromopropane	109-64-8	C₃H₆Br₂	详情	详情
(III)	52127	ethyl 4-(3-bromopropoxy)-3-methyl-1-benzofuran-2-carboxylate		C₁₅H₁₇BrO₄	详情	详情
(IV)	18731	3-pyridinylmethanamine; 3-pyridinylmethylamine	3731-52-0	C₆H₈N₂	详情	详情
(V)	52875	ethyl 3-methyl-4-{3-[(3-pyridinylmethyl)amino]propoxy}-1-benzofuran-2-carboxylate		C₂₁H₂₄N₂O₄	详情	详情
(VI)	52876	(3-methyl-4-{3-[(3-pyridinylmethyl)amino]propoxy}-1-benzofuran-2-yl)methanol		C₁₉H₂₂N₂O₃	详情	详情
(VII)	21486	2,4-difluorophenol	367-27-1	C₆H₄F₂O	详情	详情

合成路线3

该中间体在本合成路线中的序号：(III)

Condensation of ethyl 4-hydroxy-3-methylbenzofuran-2-carboxylate (I) with 1,3-dibromopropane (II) affords the benzofuran bromopropyl ether (III). Subsequent displacement of bromide (III) with 3-picolylamine (IV) yields amine (V). The ester group of (V) is then reduced with LiAlH4 to furnish alcohol (VI). Finally, Mitsunobu coupling between alcohol (VI) and 2,3,4-trifluorophenol (VII) in the presence of 1,1'-(azodicarbonyl)dipiperidine (ADDP) and tributylphosphine provides the title compound

参考文献中间体

合成目标

【1】 Ebiike, H.; Masubuchi, M.; Kawasaki, K.-I.; et al.; Design and synthesis of novel N-myristoyltransferase inhibitors as antifungal agents. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 56.
【2】 Ebiike, H.; Masubuchi, M.; Liu, P.; Kawasaki, K.,-I.; Morikami, K.; Sogabe, S.; Hayase, M.; Fujii, T.; Sakata, K.; Shindoh, H.; Shiratori, Y.; Aoki, Y.; Ohtsuka, T.; Shimma, N.; Design and synthesis of novel benzofurans as a new class of antifungal agents targeting fungal N-myristoyltransferase. Part 2. Bioorg Med Chem Lett 2002, 12, 4, 607.
【3】 Fujii, T.; Tsujii, S.; Liu, P.; Ohtsuka, T.; Ebiike, H.; Masubuchi, M.; Aoki, Y.; Kawasaki, K. (F. Hoffmann-La Roche AG); Novel bicyclic cpds.. US 6376491; WO 0037464 .

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)	52126	ethyl 4-hydroxy-3-methyl-1-benzofuran-2-carboxylate		C₁₂H₁₂O₄	详情	详情
(II)	12581	1,3-Dibromopropane	109-64-8	C₃H₆Br₂	详情	详情
(III)	52127	ethyl 4-(3-bromopropoxy)-3-methyl-1-benzofuran-2-carboxylate		C₁₅H₁₇BrO₄	详情	详情
(IV)	18731	3-pyridinylmethanamine; 3-pyridinylmethylamine	3731-52-0	C₆H₈N₂	详情	详情
(V)	52875	ethyl 3-methyl-4-{3-[(3-pyridinylmethyl)amino]propoxy}-1-benzofuran-2-carboxylate		C₂₁H₂₄N₂O₄	详情	详情
(VI)	53876	N-(5,6-dimethoxy-2,3-dihydro-1H-inden-2-yl)-N,N-dipropylamine; 5,6-dimethoxy-N,N-dipropyl-2-indanamine	n/a	C₁₇H₂₇NO₂	详情	详情
(VII)	60408	2,3,4-trifluorophenol		C₆H₃F₃O	详情	详情

Extended Information