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【结 构 式】 
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【分子编号】21991 【品名】2-Methoxyphenacyl bromide; 2-bromo-1-(4-methoxyphenyl)-1-ethanone 【CA登记号】2632-13-5 |
【 分 子 式 】C9H9BrO2 【 分 子 量 】229.07326 【元素组成】C 47.19% H 3.96% Br 34.88% O 13.97% |
合成路线1
该中间体在本合成路线中的序号：(II)The bromination of labeled 4'-methoxyacetophenone (I) with CuBr2 gives 4'-methoxyphenacyl bromide (II), which is reduced with NaBH4, yielding the carbinol (III). The protection of (III) with DHP affords the tetrahydropyranyl ether (IV), which is condensed with 2-(2-chloro-3,4-dimethoxyphenyl)ethylamine (V) and acidified to provide the aminoalcohol (VI). The cyclization of (VI) with MsOH and trifluoroacetic acid furnishes labeled 6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (VII), which is finally demethylated with BBr3 and MsOH.
| 【1】 Hieble, J.P.; Wilson III, J.W.; Weinstock, J.; The chemistry and pharmacology of 3-benzazepines derivatives. Drugs Fut 1985, 10, 8, 645. |
| 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) | 11041 | 4-Methoxyacetophenone; 1-(4-Methoxyphenyl)-1-ethanone | 100-06-1 | C9H10O2 | 详情 | 详情 |
| (I) | 44616 | 1-(4-methoxyphenyl)-1-ethanone | C9H10O2 | 详情 | 详情 | |
| (II) | 21991 | 2-Methoxyphenacyl bromide; 2-bromo-1-(4-methoxyphenyl)-1-ethanone | 2632-13-5 | C9H9BrO2 | 详情 | 详情 |
| (II) | 44617 | 2-bromo-1-(4-methoxyphenyl)-1-ethanone | C9H9BrO2 | 详情 | 详情 | |
| (III) | 44053 | 2-bromo-1-(4-methoxyphenyl)-1-ethanol | C9H11BrO2 | 详情 | 详情 | |
| (III) | 44618 | 2-bromo-1-(4-methoxyphenyl)-1-ethanol | C9H11BrO2 | 详情 | 详情 | |
| (IV) | 44054 | 2-bromo-1-(4-methoxyphenyl)ethyl tetrahydro-2H-pyran-2-yl ether; 2-[2-bromo-1-(4-methoxyphenyl)ethoxy]tetrahydro-2H-pyran | C14H19BrO3 | 详情 | 详情 | |
| (IV) | 44619 | 2-bromo-1-(4-methoxyphenyl)ethyl tetrahydro-2H-pyran-2-yl ether; 2-[2-bromo-1-(4-methoxyphenyl)ethoxy]tetrahydro-2H-pyran | C14H19BrO3 | 详情 | 详情 | |
| (V) | 42037 | 2-chloro-3,4-dimethoxyphenethylamine; 2-(2-chloro-3,4-dimethoxyphenyl)-1-ethanamine | 67287-36-9 | C10H14ClNO2 | 详情 | 详情 |
| (VI) | 31702 | 2-[(2-chloro-3,4-dimethoxyphenethyl)amino]-1-(4-methoxyphenyl)-1-ethanol | C19H24ClNO4 | 详情 | 详情 | |
| (VI) | 44620 | 2-[(2-chloro-3,4-dimethoxyphenethyl)amino]-1-(4-methoxyphenyl)-1-ethanol | C19H24ClNO4 | 详情 | 详情 | |
| (VII) | 31704 | 4-(6-chloro-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl)phenyl methyl ether; 6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine | C19H22ClNO3 | 详情 | 详情 | |
| (VII) | 44621 | 6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine; 4-(6-chloro-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl)phenyl methyl ether | C19H22ClNO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Alkylation of 3-methoxybenzenethiol (I) with 4'-methoxyphenacyl bromide (II) afforded sulfide (III). Cyclization of (III) with concomitant rearrangement in the presence of polyphosphoric acid produced a mixture of regioisomers (IV) and (V) that were separated by their different solubility in acetone. Then, Friedel-Crafts acylation of the desired insoluble isomer (IV) with 3,4,5-trimethoxybenzoyl chloride (VI) in the presence of AlCl3 provided the title ketone, which was separated from some demethylated byproduct by means of silica gel chromatography.
| 【1】 Lee, B.; et al.; Hepatocyte gene therapy in a large animal: A neonatal bovine model of citrullinemia. Proc Natl Acad Sci USA 1999, 96, 7, 3981. |
| 【2】 Jones, C.D.; et al.; Antiestrogens. 2. Structure-activity studies in a series of 3-aroyl-2-arylbenzo[b]thiophene derivatives leading to [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl] [4-[2-(1-piperidinyl)ethoxy]-phenyl]methanone hydrochloride (LY156758), a remarkably effec. J Med Chem 1984, 27, 8, 1057. |
| 【3】 Carlson, D.G.; Cullinan, G.J.; Fahey, K.J.; Jackson, W.T.; Roehm, N.W.; Spaethe, S.M. (Eli Lilly and Company); Novel benzothiophene cpds. and methods. EP 0732331; JP 1999501932; WO 9628156 . |
| 【4】 Pinney, K.G. (Baylor University); Anti-mitotic agents which inhibit tubulin polymerization. US 5886025 . |
| 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) | 25756 | 3-methoxybenzenethiol | 15570-12-4 | C7H8OS | 详情 | 详情 |
| (II) | 21991 | 2-Methoxyphenacyl bromide; 2-bromo-1-(4-methoxyphenyl)-1-ethanone | 2632-13-5 | C9H9BrO2 | 详情 | 详情 |
| (III) | 25757 | 1-(4-methoxyphenyl)-2-[(3-methoxyphenyl)sulfanyl]-1-ethanone | C16H16O3S | 详情 | 详情 | |
| (IV) | 10121 | 4-(6-Methoxy-1-benzothiophen-2-yl)phenyl methyl ether; 6-Methoxy-2-(4-methoxyphenyl)-1-benzothiophene | 63675-74-1 | C16H14O2S | 详情 | 详情 |
| (V) | 25758 | 4-(4-methoxy-1-benzothiophen-2-yl)phenyl methyl ether | C16H14O2S | 详情 | 详情 | |
| (VI) | 13571 | 3,4,5Ttrimethoxybenzoyl chloride | 4521-61-3 | C10H11ClO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The cyclization of 3-methoxythiophenol (I) with 4-methoxyphenacyl bromide (II) by means of KOH in ethanol gives 2-(4-methoxyphenyl)-6-methoxybenzothiophene (III), which is treated with pyridinium hydrochloride at 220 C to yield 2-(4-hydroxyphenyl)-6-hydroxybenzothiophene (IV). The protection of the hydroxy groups of (IV) by reaction with 4-chlorophenacyl bromide (V) and K2CO3 - 18-crown 6 in refluxing ether affords the bis p-chlorophenacyloxy derivative (VI), which by a Friedel-Kraft's reaction with 4-(2-pyrrolidinoethoxy)benzoyl chloride (VII) by means of AlCl3 in refluxing dichloroethane is converted into 2-[4-(4-chlorophenacyloxy)phenyl]-3-[4-(2-pyrrolidinoethoxy)benzoyl]-6-(4-chlorophenacyloxy)benzothiophene (VIII). Finally, this compound is deprotected by treatment with Zn and acetic acid.
| 【1】 Jones, C.D.; Suarez, T.; 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents. DE 2647907; ES 452694; ES 452695; FR 2329271; GB 1570610; JP 52053851; US 4133814 . |
| 【2】 Jones, C.D.; Suarez, T.; 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents. DE 2647907; ES 452694; ES 452695; FR 2329271; GB 1570610; JP 52053851; US 4133814 . |
| 【3】 Blancafort, P.; Castañer, J.; Serradell, M.N.; LY-117018. Drugs Fut 1982, 7, 2, 112. |
| 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) | 25756 | 3-methoxybenzenethiol | 15570-12-4 | C7H8OS | 详情 | 详情 |
| (II) | 21991 | 2-Methoxyphenacyl bromide; 2-bromo-1-(4-methoxyphenyl)-1-ethanone | 2632-13-5 | C9H9BrO2 | 详情 | 详情 |
| (III) | 10121 | 4-(6-Methoxy-1-benzothiophen-2-yl)phenyl methyl ether; 6-Methoxy-2-(4-methoxyphenyl)-1-benzothiophene | 63675-74-1 | C16H14O2S | 详情 | 详情 |
| (IV) | 36414 | 2-(4-hydroxyphenyl)-1-benzothiophen-6-ol | C14H10O2S | 详情 | 详情 | |
| (V) | 16720 | 2-bromo-1-(4-chlorophenyl)-1-ethanone; 2-Bromo-4'-chloroacetophenone | 536-38-9 | C8H6BrClO | 详情 | 详情 |
| (VI) | 36415 | 1-(4-chlorophenyl)-2-(4-[6-[2-(4-chlorophenyl)-2-oxoethoxy]-1-benzothiophen-2-yl]phenoxy)-1-ethanone | C30H20Cl2O4S | 详情 | 详情 | |
| (VII) | 36416 | 4-[2-(1-pyrrolidinyl)ethoxy]benzoyl chloride | C13H16ClNO2 | 详情 | 详情 | |
| (VIII) | 36417 | 1-(4-chlorophenyl)-2-[(2-[4-[2-(4-chlorophenyl)-2-oxoethoxy]phenyl]-3-[4-[2-(1-pyrrolidinyl)ethoxy]benzoyl]-1-benzothiophen-6-yl)oxy]-1-ethanone | C43H35Cl2NO6S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The cyclization of 4-methoxyphenacyl bromide (I) with 2-amidinoacetic acid ethyl ester (II) by means of sodium ethoxide in ethanol gives 2-amino-5-(4-methoxyphenyl)-1H-pyrrole-3-carboxylic acid ethyl ester (III), which is cyclized with formamide in DMF at 150 C to yield the pyrrolopyrimidine (IV). The reaction of the OH group of (IV) with POCl3 at 150 C affords the corresponding chloro derivative (V), which is condensed with 1(R)-phenylethylamine (VI) in refluxing butanol to provide the adduct (VII). Finally, this compound is demethylated by means of BBr3 in dichloromethane to furnish the target pyrrolopyrimidine.
| 【1】 Traxler, P.; Bold, G.; Brill, W.K.-D.; Frei, J. (Novartis AG); Pyrrolopyrimidines and processes for the preparation thereof. EP 0836605; JP 1999508570; US 6140332; WO 9702266 . |
| 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) | 21991 | 2-Methoxyphenacyl bromide; 2-bromo-1-(4-methoxyphenyl)-1-ethanone | 2632-13-5 | C9H9BrO2 | 详情 | 详情 |
| (II) | 54308 | ethyl 3-amino-3-iminopropanoate | 50551-10-5 | C5H10N2O2 | 详情 | 详情 |
| (III) | 54309 | ethyl 2-amino-5-(4-methoxyphenyl)-1H-pyrrole-3-carboxylate | n/a | C14H16N2O3 | 详情 | 详情 |
| (IV) | 54310 | 6-(4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol | n/a | C13H11N3O2 | 详情 | 详情 |
| (V) | 54311 | 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl methyl ether; 4-chloro-6-(4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine | n/a | C13H10ClN3O | 详情 | 详情 |
| (VI) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (VII) | 54312 | N-[6-(4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N-[(1R)-1-phenylethyl]amine; 6-(4-methoxyphenyl)-N-[(1R)-1-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine | n/a | C21H20N4O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)2-Cyanophenol (I) was condensed with 2-bromo-4'-methoxyacetophenone (II) in the presence of K2CO3 in acetone to give aminobenzofuran (III). This was acylated with trifluoroacetic anhydride, and the resulting trifluoroacetamide (IV) was alkylated with 2,5-dimethoxybenzyl chloride (V) under phase-transfer conditions to afford monobenzylated compound (VI). The benzofuro[3,2-b]pyridine nucleus was formed by acylation of the secondary amine group of (VI) with ethyl malonyl chloride (VII) to give (VIII) followed by an intramolecular Knoevenagel condensation over silica gel in refluxing CH2Cl2 to give (IX). Alkaline hydrolysis of the ester function of (IX) then provided the corresponding carboxylic acid.
| 【1】 Mederski, W.K.R.; Wilm, C.; Schmitges, C.-J.; Oswald, M.; Dorsch, D.; Christadler, M.; Benzofuro[3,2-b]pyridines as mixed ETA/ETB and selective ETB endothelin receptor antagonists. Bioorg Med Chem Lett 1999, 9, 4, 619. |
| 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) | 21990 | 2-hydroxybenzonitrile | 611-20-1 | C7H5NO | 详情 | 详情 |
| (II) | 21991 | 2-Methoxyphenacyl bromide; 2-bromo-1-(4-methoxyphenyl)-1-ethanone | 2632-13-5 | C9H9BrO2 | 详情 | 详情 |
| (III) | 21992 | (3-amino-1-benzofuran-2-yl)(4-methoxyphenyl)methanone | C16H13NO3 | 详情 | 详情 | |
| (IV) | 21993 | 2,2,2-trifluoro-N-[2-(4-methoxybenzoyl)-1-benzofuran-3-yl]acetamide | C18H12F3NO4 | 详情 | 详情 | |
| (V) | 21994 | 2-(chloromethyl)-4-methoxyphenyl methyl ether; 2-(chloromethyl)-1,4-dimethoxybenzene | 3840-27-5 | C9H11ClO2 | 详情 | 详情 |
| (VI) | 21995 | [3-[(2,5-dimethoxybenzyl)amino]-1-benzofuran-2-yl](4-methoxyphenyl)methanone | C25H23NO5 | 详情 | 详情 | |
| (VII) | 13188 | ethyl 3-chloro-3-oxopropanoate; 2-Ethoxycarbonylacetyl chloride; Ethyl malonyl chloride | 36239-09-5 | C5H7ClO3 | 详情 | 详情 |
| (VIII) | 21997 | ethyl 3-[(2,5-dimethoxybenzyl)[2-(4-methoxybenzoyl)-1-benzofuran-3-yl]amino]-3-oxopropanoate | C30H29NO8 | 详情 | 详情 | |
| (IX) | 21998 | ethyl 1-(2,5-dimethoxybenzyl)-4-(4-methoxyphenyl)-2-oxo-1,2-dihydro[1]benzofuro[3,2-b]pyridine-3-carboxylate | C30H27NO7 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)Thiazolidinedione (III) was prepared by condensation of chloroacetic acid (I) with thiourea (II). Alkylation of the potassium salt of (III) with 4-methoxyphenacyl bromide (IV) furnished the 3-phenacyl thiazolidinedione (V). Finally, aldol condensation of (V) with flavone-6-carboxaldehyde (VI) in the presence of NaOAc in HOAc provided the title compound.
| 【1】 Altanlar, N.; Ayhan-Killergil, G.; Synthesis of 3-substituted phenacyl-5-[2-phenyl-4H-4-oxo-1-benzopyran-6-yl(methylenyl]thiazolidine-2,4-diones and evaluation of their antimicrobial activity. Arzneim-Forsch Drug Res 2000, 50, 2, 154. |
| 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) | 11847 | 2-Chloroacetic acid; Chloroacetic Acid | 79-11-8 | C2H3ClO2 | 详情 | 详情 |
| (II) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (III) | 10883 | 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione | 2295-31-0 | C3H3NO2S | 详情 | 详情 |
| (IV) | 21991 | 2-Methoxyphenacyl bromide; 2-bromo-1-(4-methoxyphenyl)-1-ethanone | 2632-13-5 | C9H9BrO2 | 详情 | 详情 |
| (V) | 50131 | 3-[2-(4-methoxyphenyl)-2-oxoethyl]-1,3-thiazolidine-2,4-dione | C12H11NO4S | 详情 | 详情 | |
| (VI) | 50132 | 4-oxo-2-phenyl-4H-chromene-6-carbaldehyde | C16H10O3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)The title compound has been prepared by two related procedures. Alkylation of 2-propylpyridine (I) with 4-methoxyphenacyl bromide (II) in refluxing acetone gave the pyridinum salt (III), which was further cyclized to the indolizine (IV) using aqueous NaHCO3. Condensation of (IV) with dimethyl acetylenedicarboxylate (V), followed by oxidation with 2,3-dichloro-5,6-dicyanoquinone furnished the tricyclic system (VI). Hydrolysis of the diester of (VI) and subsequent decarboxylation of the resulting diacid (VII) produced the methoxy derivative (VIII). Finally, demethylation of (VIII) using AlCl3 and ethanethiol gave rise to the title phenol compound.
| 【1】 Christiansen, L.B.; Kanstrup, A.; Jacobsen, P.; Jorgensen, A.S.; Bury, P.S. (Novo Nordisk A/S); Pyrrolo[2,1,5-cd]indolizine derivs. useful in the prevention or treatment of estrogen related diseases or syndromes. EP 0986560; US 6075036; WO 9855482 . |
| 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) | 39281 | 2-propylpyridine | 622-39-9 | C8H11N | 详情 | 详情 |
| (II) | 21991 | 2-Methoxyphenacyl bromide; 2-bromo-1-(4-methoxyphenyl)-1-ethanone | 2632-13-5 | C9H9BrO2 | 详情 | 详情 |
| (III) | 39282 | 1-[2-(4-methoxyphenyl)-2-oxoethyl]-2-propylpyridinium bromide | C17H20BrNO2 | 详情 | 详情 | |
| (IV) | 39283 | 4-(1-ethyl-2-indolizinyl)phenyl methyl ether; 1-ethyl-2-(4-methoxyphenyl)indolizine | C17H17NO | 详情 | 详情 | |
| (V) | 24551 | Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester | 762-42-5 | C6H6O4 | 详情 | 详情 |
| (VI) | 39284 | dimethyl 4-ethyl-3-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylate | C23H21NO5 | 详情 | 详情 | |
| (VII) | 39285 | 4-ethyl-3-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylic acid | C21H17NO5 | 详情 | 详情 | |
| (VIII) | 39286 | 1-ethyl-2-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine; 4-(1-ethylpyrrolo[2,1,5-cd]indolizin-2-yl)phenyl methyl ether | C19H17NO | 详情 | 详情 |