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【结 构 式】 
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【分子编号】25756 【品名】3-methoxybenzenethiol 【CA登记号】15570-12-4 |
【 分 子 式 】C7H8OS 【 分 子 量 】140.20592 【元素组成】C 59.97% H 5.75% O 11.41% S 22.87% |
合成路线1
该中间体在本合成路线中的序号：(I)The condensation of 3-methoxybenzenethiol (I) with 2,6-dichloro-3-nitrobenzoic acid (II) produced the (arylthio)benzoic acid (III). Intramolecular cyclization of (III) to the thioxanthenone (IV) was effected by treatment with trifluoroacetic anhydride in trifluoroacetic acid. The pentacyclic system (VI) was prepared by condensation of chloroxanthenone (IV) with 2-(diethylamino)ethyl hydrazine (V). Subsequently, the nitro group of (IV) was reduced with H2 in the presence of Pd/C to furnish amine (VII). This was alkylated with 2-bromoethylamine (VIII), yielding the ethylenediamine derivative (IX). The methyl ether group of (IX) was finally cleaved by treatment with boron tribromide.
| 【1】 Showalter, H.D.H.; Werbel, L.M.; Ortwine, D.F.; Eislager, E.F.; Worth, D.F. (Pfizer Inc.); Benzothiopyrano[4,3,2-cd]indazole compsns. and methods for their production. EP 0114002; ES 8600303; ES 8604229; ES 8604230; JP 1994279385; US 4604390 . |
| 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) | 52274 | 2,5-Dichloro-3-nitrobenzoic acid | 88-86-8 | C7H3Cl2NO4 | 详情 | 详情 |
| (III) | 52815 | 6-chloro-2-[(3-methoxyphenyl)sulfanyl]-3-nitrobenzoic acid | C14H10ClNO5S | 详情 | 详情 | |
| (IV) | 52816 | 1-chloro-6-methoxy-4-nitro-9H-thioxanthen-9-one | C14H8ClNO4S | 详情 | 详情 | |
| (V) | 52817 | N,N-diethyl-2-hydrazino-1-ethanamine; N,N-diethyl-N-(2-hydrazinoethyl)amine | C6H17N3 | 详情 | 详情 | |
| (VI) | 52818 | N,N-diethyl-2-(8-methoxy-5-nitro-2H-thiochromeno[4,3,2-cd]indazol-2-yl)-1-ethanamine; N,N-diethyl-N-[2-(8-methoxy-5-nitro-2H-thiochromeno[4,3,2-cd]indazol-2-yl)ethyl]amine | C20H22N4O3S | 详情 | 详情 | |
| (VII) | 52819 | 2-[2-(diethylamino)ethyl]-8-methoxy-2H-thiochromeno[4,3,2-cd]indazol-5-amine; N-[2-(5-amino-8-methoxy-2H-thiochromeno[4,3,2-cd]indazol-2-yl)ethyl]-N,N-diethylamine | C20H24N4OS | 详情 | 详情 | |
| (VIII) | 38475 | 2-bromoethylamine; 2-bromo-1-ethanamine | C2H6BrN | 详情 | 详情 | |
| (IX) | 52820 | N-(2-aminoethyl)-N-{2-[2-(diethylamino)ethyl]-8-methoxy-2H-thiochromeno[4,3,2-cd]indazol-5-yl}amine; N~1~-{2-[2-(diethylamino)ethyl]-8-methoxy-2H-thiochromeno[4,3,2-cd]indazol-5-yl}-1,2-ethanediamine | C22H29N5OS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)The synthesis of moxifetin was described according to the following methods: 1) The first synthesis starts from the acid (I), which is prepared either by reaction of 3-methoxythiophenol (V) with 2-iodobenzoic acid (IX) in boiling aqueous potassium hydroxide in the presence of copper, or by reaction of thiosalicylic acid (X) with 3-bromoanisole (XI) in boiling dimethylformamide in the presence of potassium carbonate and copper. The acid (I) is transformed to the acid chloride (II) by treatment with thionyl chloride in boiling benzene in the presence of a small quantity of dimethylformamide. Treatment of the benzene solution of (II) with dimethylamine (XII) under various conditions results in the amide (III), which is reduced to the amine (IV) either with lithium aluminum hydride in ether or with diborane, generated in situ by reaction of sodium borohydride with boron trifluoride etherate in tetrahydrofuran (this method proceeds via the corresponding amine borane which has to be hydrolyzed with sodium hydroxide in boiling aqueous ethanol). The reaction of (III) with phosphoryl chloride, followed by sodium borohydride in ethanol, also results in the amine (IV). This methoxy compound is demethylated in the final step to the desired compound (V) either by heating with pyridine hydrochloride to 210-220 C, by treatment with boron tribromide in chloroform or by refluxing with hydrobromic acid. 2) A shorter synthesis begins with the aldehyde (VI), obtained by reaction of 3-methoxythiophenol (XIII) with 2-chlorobenzaldehyde (XIV) in dimethylformamide at 90 C in the presence of potassium carbonate. Leuckart reaction of (VI) with dimethylformamide and formic acid at 180 C directly affords the methoxy amine (IV). Even a procedure via intermediates (VII) and (VIII), i.e., without protection of the phenolic hydroxyl, is feasible. Refluxing 3-hydroxythiophenol (XV) with 2-iodobenzoic acid (XVI) in aqueous potassium hydroxide in the presence of copper affords the hydroxy acid (VII) in a reasonable yield. The following reaction with dimethylamine (XII), leading to the hydroxy amide (VIII), proceeds in the presence of the complex of triphenylphosphine and tetrachloromethane. The final reduction of (VIII) to moxifetin (V) is carried out with lithium aluminum hydride in tetrahydrofuran. The moxifetin base is converted by reactions with acids to crystalline salts, viz. hydrobromide and hydrogen maleate.
| 【1】 Nemec, J.; Metysová, J.; Protiva, M.; Bártl, V.; Metys, J.; Neurotropic and psychotropic agents. LXIII. 7-Methoxy-10-(4-methylpiperazino)dibenzo[b,f]thiepin and its 10,11-dihydro derivative. Coll Czech Chem Commun 1973, 38, 2301-6. |
| 【2】 Schneider, B.; Hasek, J.; Jecny, J.; Crystal and molecular structure of 2-dimethylaminomethyl-3'-hydroxydiphenyl sulfide maleate. Coll Czech Chem Commun 1990, 55, 1529-34. |
| 【3】 Jílek, J.; Valchár, M.; Protiva, M.; Metysová, J.; Sindelár, K.; A novel series of potential antidepressants and selective 5-HT uptake inhibitors. XIth Int Symp Med Chem (Sept 2-7, Jerusalem) 1990, 3. |
| 【4】 Pomykacek, J.; Sindelar, K.; Jilek, J.; et al.; Potential antidepressants: 2-(Methoxy- and hydroxy-phenylthio)-benzylamines as selective inhibitors of 5 hydroxytryptamine re-uptake in the brain. Coll Czech Chem Commun 1989, 54, 12, 3294-338. |
| 【5】 Protiva, M.; Moxifetin Hydrogen Maleate. Drugs Fut 1991, 16, 10, 911. |
| 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) | 13625 | 2-[(3-Methoxyphenyl)sulfanyl]benzoic acid | C14H12O3S | 详情 | 详情 | |
| (II) | 13626 | 2-[(3-Methoxyphenyl)sulfanyl]benzoyl chloride | C14H11ClO2S | 详情 | 详情 | |
| (III) | 13627 | 2-[(3-Methoxyphenyl)sulfanyl]-N,N-dimethylbenzamide | C16H17NO2S | 详情 | 详情 | |
| (IV) | 13628 | N-[2-[(3-Methoxyphenyl)sulfanyl]benzyl]-N,N-dimethylamine; [2-[(3-Methoxyphenyl)sulfanyl]phenyl]-N,N-dimethylmethanamine | C16H19NOS | 详情 | 详情 | |
| (V) | 25746 | 2-(benzyloxy)-5-chloro-3-[4-(methylsulfonyl)phenyl]pyridine; 4-[2-(benzyloxy)-5-chloro-3-pyridinyl]phenyl methyl sulfone | C19H16ClNO3S | 详情 | 详情 | |
| (VI) | 13630 | 2-[(3-Methoxyphenyl)sulfanyl]benzaldehyde | C14H12O2S | 详情 | 详情 | |
| (VII) | 13631 | 2-[(3-Hydroxyphenyl)sulfanyl]benzoic acid | C13H10O3S | 详情 | 详情 | |
| (VIII) | 13632 | 2-[(3-Hydroxyphenyl)sulfanyl]-N,N-dimethylbenzamide | C15H15NO2S | 详情 | 详情 | |
| (IX) | 37170 | 2-(10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)-2-(hydroxyimino)acetic acid | C16H14N2O3 | 详情 | 详情 | |
| (X) | 63792 | 2-sulfanylbenzoic acid; thiosalicylic acid | 147-93-3 | C7H6O2S | 详情 | 详情 |
| (XI) | 35983 | m-bromoanisole; 1-Bromo-3-methoxybenzene; 3-Bromoanisole; 3-Bromophenyl methyl ether | 2398-37-0 | C7H7BrO | 详情 | 详情 |
| (XII) | 19443 | N-methylmethanamine; N,N-dimethylamine | 124-40-3 | C2H7N | 详情 | 详情 |
| (XIII) | 25756 | 3-methoxybenzenethiol | 15570-12-4 | C7H8OS | 详情 | 详情 |
| (XIV) | 24114 | 2-chlorobenzaldehyde | 89-98-5 | C7H5ClO | 详情 | 详情 |
| (XV) | 63793 | 3-sulfanylphenol | C6H6OS | 详情 | 详情 | |
| (XVI) | 37160 | 2-iodobenzoic acid | 88-67-5 | C7H5IO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)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4
该中间体在本合成路线中的序号：(I)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 |