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【结 构 式】 
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【分子编号】25746 【品名】2-(benzyloxy)-5-chloro-3-[4-(methylsulfonyl)phenyl]pyridine; 4-[2-(benzyloxy)-5-chloro-3-pyridinyl]phenyl methyl sulfone 【CA登记号】 |
【 分 子 式 】C19H16ClNO3S 【 分 子 量 】373.85968 【元素组成】C 61.04% H 4.31% Cl 9.48% N 3.75% O 12.84% S 8.58% |
合成路线1
该中间体在本合成路线中的序号：(V)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2
该中间体在本合成路线中的序号：(VI)Synthesis of etoricoxib via dichloropyridine (VIII): a) The bromination of 5-chloro-2-hydroxypyridine (I) with Br2 in acetic acid gives 3-bromo-5-chloro-2-hydroxypyridine (II), which is treated with benzyl bromide and Ag2CO3 in hot benzene to yield benzyl ether (III). Condensation of (III) with 4-(methylsulfanyl)phenylboronic acid (IV) by means of Pd(PPh3)4 and Na2CO3 in refluxing ethanol/benzene affords 2-(benzyloxy)-5-chloro-3-[4-(methylsulfanyl)phenyl]pyridine (V), which is oxidized with OsO4 and sodium sulfite to furnish sulfone (VI). Treatment of (VI) with TFA provides the 2-hydroxypyridine (VII), which is reacted with POCl3 to yield 2,5-dichloro-3-[4-(methylsulfonyl)phenyl]pyridine (VIII). b) Bromination of 2-amino-5-chloropyridine (IX) with Br2 in acetic acid provides 2-amino-3-bromo-5-chloropyridine (X), which is condensed with 4-(methylsulfanyl)phenylboronic acid (IV) by means of Pd(PPh3)4 and Na2CO3 in refluxing ethanol/benzene to give 2-amino-5-chloro-3-[4-(methylsulfanyl)phenyl]pyridine (XI). Oxidation of compound (XI) with OsO4 as before yields sulfone (XII), which is converted into compound (VIII) by treatment first with NaNO2 and HCl and then chlorination with POCl3.
| 【1】 Castañer, R.M.; Silvestre, J.S.; Sorbera, L.A.; Castañer, J.; Etoricoxib. Drugs Fut 2001, 26, 4, 346. |
| 【2】 Friesen, R.W.; Brideau, C.; Chan, C.C.; Charleson, S.; Deschenes, D.; Dube, D.; Ethier, D.; Fortin, R.; Gauthier, J.Y.; Girard, Y.; Gordon, R.; Greig, G.M.; Riendeau, D.; Savoie, C.; Wang, Z.; Wong, E.; Visco, D.; Xu, L.J.; Young, R.N.; 2-Pyridinyl-3-(4-methylsulfonyl)phenylpyridines: Selective and orally active cyclooxygenase-2 inhibitors. Bioorg Med Chem Lett 1998, 8, 19, 2777. |
| 【3】 Dube, D.; Fortin, R.; Friesen, R.; Wang, Z.; Gauthier, J.Y. (Merck Frosst Canada Inc.); Substd. pyridines as selective cyclooxygenase-2 inhibitors. EP 0912518; JP 1999514008; US 5861419; WO 9803484 . |
| 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) | 25742 | 5-chloro-2-pyridinol | 4214-79-3 | C5H4ClNO | 详情 | 详情 |
| (II) | 25743 | 3-bromo-5-chloro-2-pyridinol | C5H3BrClNO | 详情 | 详情 | |
| (III) | 25744 | benzyl 3-bromo-5-chloro-2-pyridinyl ether; 2-(benzyloxy)-3-bromo-5-chloropyridine | C12H9BrClNO | 详情 | 详情 | |
| (IV) | 18561 | 4-(methylsulfanyl)phenylboronic acid | 98546-51-1 | C7H9BO2S | 详情 | 详情 |
| (V) | 25745 | benzyl 5-chloro-3-[4-(methylsulfanyl)phenyl]-2-pyridinyl ether; 2-(benzyloxy)-5-chloro-3-[4-(methylsulfanyl)phenyl]pyridine | C19H16ClNOS | 详情 | 详情 | |
| (VI) | 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 | |
| (VII) | 25747 | 5-chloro-3-[4-(methylsulfonyl)phenyl]-2-pyridinol | C12H10ClNO3S | 详情 | 详情 | |
| (VIII) | 18565 | 2,5-dichloro-3-[4-(methylsulfonyl)phenyl]pyridine; 4-(2,5-dichloro-3-pyridinyl)phenyl methyl sulfone | C12H9Cl2NO2S | 详情 | 详情 | |
| (IX) | 18559 | 5-Chloro-2-pyridinylamine; 5-Chloro-2-pyridinamine; 2-Amino-5-chloropyridine | 1072-98-6 | C5H5ClN2 | 详情 | 详情 |
| (X) | 18560 | 3-bromo-5-chloro-2-pyridinylamine; 3-bromo-5-chloro-2-pyridinamine | C5H4BrClN2 | 详情 | 详情 | |
| (XI) | 18562 | 5-chloro-3-[4-(methylsulfanyl)phenyl]-2-pyridinylamine; 5-chloro-3-[4-(methylsulfanyl)phenyl]-2-pyridinamine | C12H11ClN2S | 详情 | 详情 | |
| (XII) | 18563 | 5-chloro-3-[4-(methylsulfonyl)phenyl]-2-pyridinamine; 5-chloro-3-[4-(methylsulfonyl)phenyl]-2-pyridinylamine | C12H11ClN2O2S | 详情 | 详情 |