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【结 构 式】 
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【分子编号】38335 【品名】1-benzofuran-2-ylmethanol 【CA登记号】 |
【 分 子 式 】C9H8O2 【 分 子 量 】148.16132 【元素组成】C 72.96% H 5.44% O 21.6% |
合成路线1
该中间体在本合成路线中的序号：(X)Condensation of alpha-methyl tryptophan methyl ester (I) with benzylchloroformate (II) in the presence of Et3N in THF yields urethane (III), which is hydrolyzed with LiOH in THF/MeOH/H2O and then activated with DCCI and pentafluorophenol (IV) to furnish ester (V). Treatment of (V) with alpha-methyl-benzylamine (VI) gives derivative (VII), which is then debenzylated by hydrogenation over Pd(OH)2 in EtOH to afford (VIII). Finally, amine (VIII) reacts in DMF with DMAP and carbonate (IX), which has been previously prepared from 2-benzofuranylmethanol (X), 4-nitrophenylchloroformate (XI) and pyridine in CH2Cl2.
| 【1】 Boyle, S.; et al.; Rational design of high affinity tachykinin NK1 receptor antagonists. Bioorg Med Chem 1994, 2, 5, 357. |
| 【2】 Horwell, D.C.; Howson, W.; Rees, D.C.; Roberts, E.; Pritchard, M.C. (Pfizer Inc.); Tachykinin antagonists. EP 0655055; EP 1000930; US 5594022; WO 9404494 . |
| 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) | 44166 | methyl (2R)-2-amino-3-(1H-indol-3-yl)-2-methylpropanoate | C13H16N2O2 | 详情 | 详情 | |
| (II) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (III) | 44167 | methyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropanoate | C21H22N2O4 | 详情 | 详情 | |
| (IV) | 22662 | 2,3,4,5,6-pentafluorophenol | 771-61-9 | C6HF5O | 详情 | 详情 |
| (V) | 44168 | 2,3,4,5,6-pentafluorophenyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropanoate | C26H19F5N2O4 | 详情 | 详情 | |
| (VI) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
| (VII) | 44169 | benzyl (1R)-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[[(1S)-1-phenylethyl]amino]ethylcarbamate | C28H29N3O3 | 详情 | 详情 | |
| (VIII) | 44170 | (2R)-2-amino-3-(1H-indol-3-yl)-2-methyl-N-[(1S)-1-phenylethyl]propanamide | C20H23N3O | 详情 | 详情 | |
| (IX) | 44171 | 1-benzofuran-2-ylmethyl 4-nitrophenyl carbonate | C16H11NO6 | 详情 | 详情 | |
| (X) | 38335 | 1-benzofuran-2-ylmethanol | C9H8O2 | 详情 | 详情 | |
| (XI) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)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.
| 【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3
该中间体在本合成路线中的序号：(V)Treatment of salicylaldehyde (I) with methyl chloroacetate (II) in DMF in the presence of potassium carbonate provides methyl o-formylphenoxyacetate (III), which is converted into methyl 2-benzofuranecarboxylate (IV) by reaction with DBU in toluene. Reduction of (IV) by means of LiAlH4 in ether yields hydroxy derivative (V), which then reacts with SOCl2 in ether/DMF to furnish chloro derivative (VI). Treatment of (VI) with NaCN in DMSO affords cyano derivative (VII), which is converted into 2-benzofuraneacetic acid (VIII) by treatment with NaOH in boiling water. Esterification of (VIII) by treatment with HCl in refluxing MeOH affords methyl acetate derivative (IX), which is condensed with p-anisoyl chloride (X) by means of SnCl4 in 1,2-dichloroethane to yield compound (XI). Treatment of (XI) with aluminum powder and iodine crystals (to generate AlI3) in refluxing benzene gives acetic acid derivative (XII), which is iodinated with iodine and K2CO3 in H2O to give derivative (XIII). Esterification of (XIII) by means of iPrOH and H2SO4 provides isopropyl acetate derivative (XIV), which is finally converted into the desired product by reaction with diethylaminoethyl chloride (XV) in NaOH and CH2Cl2 in the presence of benzyltriethylammonium chloride.
| 【1】 Druzgala, P. (ARYx Therapeutics, Inc.); Benzoylbenzofurane derivs. for treatment of cardiac arrhythmia. EP 0703910; JP 1996511546; US 5364880; WO 9429289 . |
| 【2】 Druzgala, P. (ARYx Therapeutics, Inc.); Cpd. for treatment of cardiac arrhythmia, synthesis, and methods of use. US 5849788 . |
| 【3】 Druzgala, P. (ARYx Therapeutics, Inc.); Cpd. for treatment of cardiac arrhythmia, synthesis, and methods of use. US 6130240 . |
| 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) | 10257 | methyl 2-chloroacetate; methyl chloroacetate | 96-34-4 | C3H5ClO2 | 详情 | 详情 |
| (III) | 49708 | methyl 2-(2-formylphenoxy)acetate | C10H10O4 | 详情 | 详情 | |
| (IV) | 49709 | methyl 1-benzofuran-2-carboxylate | C10H8O3 | 详情 | 详情 | |
| (V) | 38335 | 1-benzofuran-2-ylmethanol | C9H8O2 | 详情 | 详情 | |
| (VI) | 49710 | 2-(chloromethyl)-1-benzofuran | C9H7ClO | 详情 | 详情 | |
| (VII) | 38336 | 2-(1-benzofuran-2-yl)acetonitrile | C10H7NO | 详情 | 详情 | |
| (VIII) | 49711 | 2-(1-benzofuran-2-yl)acetic acid | C10H8O3 | 详情 | 详情 | |
| (IX) | 49712 | methyl 2-(1-benzofuran-2-yl)acetate | C11H10O3 | 详情 | 详情 | |
| (X) | 22671 | 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride | 100-07-2 | C8H7ClO2 | 详情 | 详情 |
| (XI) | 49713 | methyl 2-[3-(4-methoxybenzoyl)-1-benzofuran-2-yl]acetate | C19H16O5 | 详情 | 详情 | |
| (XII) | 49714 | 2-[3-(4-hydroxybenzoyl)-1-benzofuran-2-yl]acetic acid | C17H12O5 | 详情 | 详情 | |
| (XIII) | 49715 | 2-[3-(4-hydroxy-3,5-diiodobenzoyl)-1-benzofuran-2-yl]acetic acid | C17H10I2O5 | 详情 | 详情 | |
| (XIV) | 49716 | isopropyl 2-[3-(4-hydroxy-3,5-diiodobenzoyl)-1-benzofuran-2-yl]acetate | C20H16I2O5 | 详情 | 详情 | |
| (XV) | 16194 | 2-chloro-N,N-diethyl-1-ethanamine; N-(2-chloroethyl)-N,N-diethylamine | 100-35-6 | C6H14ClN | 详情 | 详情 |