Benzofuran-2-carboxylic acid; 1-benzofuran-2-carboxylic acid -Drug Synthesis Database

【结构式】

【分子编号】38339

【品名】Benzofuran-2-carboxylic acid; 1-benzofuran-2-carboxylic acid

【CA登记号】496-41-3

【分子式】C₉H₆O₃

【分子量】162.14484

【元素组成】C 66.67% H 3.73% O 29.6%

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：(IX)

The intermediate 1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine (VIII) has been obtained by three different ways: 1) The cyclization of 2-hdroxybenzaldehyde (I) with ethyl 2-bromoacetate (II) by means of K2CO3 in DMF gives ethyl benzofuran-2-carboxylate (III), which is reduced with LiAlH4 in refluxing THF to the carbinol (IV). The reaction of (IV) with acetone cyanohydrin (V), PPh3 and DEAD yields the acetonitrile (VI), which is reduced with H2 over Raney-Ni to afford the ethylamine (VII). Finally, this compound is cyclized with formaldehyde in refluxing water to provide the desired intermediate (VIII). 2) The intermediate ethyl benzofuran-2-carboxylate (III), is hydrolyzed with NaOH to the corresponding free acid (IX), which is decarboxylated with Cu at 240 C in quinoline to yield benzofuran (X). The reaction of (X) with oxirane (XI) by means of n-BuLi in ethyl ether affords 2-(2-benzofuryl)ethanol (XII), which is treated first with MsCl and TEA, and then with NaI in refluxing acetone to provide the 2-(2-iodoethyl)benzofuran (XIII). The reaction of (XIII) with hexamethylenetetramine (HMT) gives the adduct (XIV), which is finally cyclized to the target intermediate (VIII) by means of HCl in refluxing ethanol. 3) The target intermediate (VIII) can also be obtained by cyclization of O-phenylhydroxylamine (XV) with 4-piperidone (XVI) in refluxing isopropanol. Finally, intermediate (VIII) is condensed with 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidine (XVII) by means of Na2CO3 and KI in a refluxing organic solvent such as 4-methyl-2-pentanone.

参考文献中间体

合成目标

【1】 Bischoff, F.P.; Kennis, L.E.J.; Mertens, C.J.; et al.; New 2-substituted 1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine having highly active and potent central alpha2-antagonistic activity as potential antidepressants. Bioorg Med Chem Lett 2000, 10, 1, 71.
【2】 Bischoff, F.P.; Kennis, L.E.J.; Love, C.J. (Janssen Pharmaceutica NV); 1,2,3,4-Tetrahydro-benzofuro[3,2-c]pyridine derivs.. EP 1019408; JP 2000505115; WO 9845297 .

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)	21351	2-Hydroxybenzaldehyde;Salicylic aldehyde；2-Formylphenol;salicylaldehyde	90-02-8	C₇H₆O₂	详情	详情
(II)	16640	Ethyl 2-bromoacetate; Ethyl bromoacetate	105-36-2	C₄H₇BrO₂	详情	详情
(III)	38334	ethyl 1-benzofuran-2-carboxylate		C₁₁H₁₀O₃	详情	详情
(IV)	38335	1-benzofuran-2-ylmethanol		C₉H₈O₂	详情	详情
(V)	18029	Acetone cyanohydrin; 2-Hydroxy-2-methylpropanenitrile; 2-Hydroxy-2-methylpropionitrile; 2-Hydroxyisobutyronitrile; 2-Methyllactonitrile; alpha-Hydroxyisobutyronitrile	75-86-5	C₄H₇NO	详情	详情
(VI)	38336	2-(1-benzofuran-2-yl)acetonitrile		C₁₀H₇NO	详情	详情
(VII)	38337	2-(1-benzofuran-2-yl)-1-ethanamine; 2-(1-benzofuran-2-yl)ethylamine		C₁₀H₁₁NO	详情	详情
(VIII)	38338	1,2,3,4-tetrahydro[1]benzofuro[3,2-c]pyridine		C₁₁H₁₁NO	详情	详情
(IX)	38339	Benzofuran-2-carboxylic acid; 1-benzofuran-2-carboxylic acid	496-41-3	C₉H₆O₃	详情	详情
(X)	38340	1-benzofuran	271-89-6	C₈H₆O	详情	详情
(XI)	10393	Oxirane; Ethylene oxide	75-21-8	C₂H₄O	详情	详情
(XII)	38341	2-(1-benzofuran-2-yl)-1-ethanol		C₁₀H₁₀O₂	详情	详情
(XIII)	38342	2-(2-iodoethyl)-1-benzofuran		C₁₀H₉IO	详情	详情
(XIV)	38343	1-[2-(1-benzofuran-2-yl)ethyl]-3,5-diaza-1-azoniatricyclo[3.3.1.1(3,7)]decane iodide		C₁₇H₂₂IN₃O	详情	详情
(XV)	25770	1-(aminooxy)benzene; O-phenylhydroxylamine		C₆H₇NO	详情	详情
(XVI)	27115	4-piperidinone	40064-34-4	C₅H₉NO	详情	详情
(XVII)	38344	3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one		C₁₁H₁₁ClN₂O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

Condensation of 4-fluorobenzenesulfonyl chloride (I) with anthranilic acid derivative (II) by means of pyridine yields sulfonamide derivative (III), which is then N-alkylated by reaction with benzyl bromide (IV) by means of NaH in DMF to furnish compound (V). Saponification of the methyl ester group of (V) by treatment with NaOH in refluxing MeOH affords carboxylic acid (VI) (1), which is then converted into compound (X) by condensation with hydroxy derivative (IX) by means of NaH in DMF. (In turn, compound (IX) can be obtained by coupling of 2-benzofurancarboxylic acid (VII) with ethanolamine (VIII) by means of HOBt/EDC and NMM in DMF. Finally, the target product is obtained by derivatization of the carboxylic acid moiety of (X) with hydroxylamine hydrochloride by means of HOBt/EDC and Et3N in DMF.

参考文献中间体

合成目标

【2】 Gu, Y.; Nelson, F.C.; Zask, A.; Du, M.T.; Levin, J.I.; Venkatesan, M. (American Cyanamid Co.); Preparation and use of orthosulfonamido aryl hydroxamic acids as matrix metalloproteinase and TACE inhibitors. US 5929097 .
【1】 Levin, J.I.; Nilakantan, R.; Mobilio, D.; Chen, J.M.; Nelson, F.C.; Powers, R.; Moy, F.J.; Zask, A.; Structure-based design of a novel, potent, and selective inhibitor for MMP-13 utilizing NMR spectroscopy and computer-aided molecular design. J Am Chem Soc 2000, 122, 40, 9648.

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)	12292	4-Fluorobenzenesulfonyl chloride	349-88-2	C₆H₄ClFO₂S	详情	详情
(II)	47141	methyl 2-amino-3,5-dimethylbenzoate		C₁₀H₁₃NO₂	详情	详情
(III)	47142	methyl 2-[[(4-fluorophenyl)sulfonyl]amino]-3,5-dimethylbenzoate		C₁₆H₁₆FNO₄S	详情	详情
(IV)	12912	1-(Bromomethyl)benzene; Alpha-bromotoluene	100-39-0	C₇H₇Br	详情	详情
(V)	47143	methyl 2-[benzyl[(4-fluorophenyl)sulfonyl]amino]-3,5-dimethylbenzoate		C₂₃H₂₂FNO₄S	详情	详情
(VI)	47144	2-[benzyl[(4-fluorophenyl)sulfonyl]amino]-3,5-dimethylbenzoic acid		C₂₂H₂₀FNO₄S	详情	详情
(VII)	38339	Benzofuran-2-carboxylic acid; 1-benzofuran-2-carboxylic acid	496-41-3	C₉H₆O₃	详情	详情
(VIII)	10259	Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol	141-43-5	C₂H₇NO	详情	详情
(IX)	47145	N-(2-hydroxyethyl)-1-benzofuran-2-carboxamide		C₁₁H₁₁NO₃	详情	详情
(X)	47146	2-[[(4-[2-[(1-benzofuran-2-ylcarbonyl)amino]ethoxy]phenyl)sulfonyl](benzyl)amino]-3,5-dimethylbenzoic acid		C₃₃H₃₀N₂O₇S	详情	详情

Extended Information