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【结 构 式】 
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【分子编号】13625 【品名】2-[(3-Methoxyphenyl)sulfanyl]benzoic acid 【CA登记号】 |
【 分 子 式 】C14H12O3S 【 分 子 量 】260.31348 【元素组成】C 64.6% H 4.65% O 18.44% S 12.32% |
合成路线1
该中间体在本合成路线中的序号：(I)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：(XII)The iodination of 2-hydroxybenzaldehyde (I) with iodine chloride in dichloromethane gives 2-hydroxy-5-iodobenzaldehyde (II), which is protected with Mem-Cl by means of NaH and 1,3-dimethylperhydropyrimidin-2-one (DMPU) in THF yielding the ether derivative (III). The reduction of (III) with NaBH4 in THF affords the benzyl alcohol (IV), which is brominated with NBS and triphenylphosphine in THF to give the benzyl bromide (V). The condensation of (V) with the protected aminopyrrolidinone (VI) by means of NaH and DMPU in THF yields the benzylpyrrolidinone (VII), which is treated with Zn(CN)2 and palladium tetrakis(triphenylphosphine) in DMF to provide the benzonitrile (VIII). The deprotection of (VIII) with HCl gas in ethyl acetate gives the primary amine (IX), which is sulfonated with 5-(3-pyridyl)thiophene-2-sulfonyl chloride (X) in pyridine yielding the sulfonamide (XI). Finally, this compound is treated first with HCl gas in ethanol, and then with NH3 in methanol to convert the cyano group of (XI) into the amidino group of the target compound. The intermediate sulfonyl chloride (X) has been obtained as follows: The condensation of 3-bromopyridine (XII) with 2-bromothiophene (XIII) by means of Mg and NiCl2 in refluxing ethyl ether gives 2-(3-pyridyl)thiophene (XIV), which is chlorosulfonated by means of BuLi, SO2 and SO2Cl2 in THF to yield intermediate (X).
| 【1】 McGarry, D.G.; Choi-Sledeski, Y.M.; Green, D.M.; et al.; Sulfonamidopyrrolidinone factor Xa inhibitors: Potency and selectivity enhancements via P-1 and P-2 optimization. J Med Chem 1999, 42, 18, 3572. |
| 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) | 31671 | 2-hydroxy-5-iodobenzaldehyde | C7H5IO2 | 详情 | 详情 | |
| (III) | 31672 | 5-iodo-2-[(2-methoxyethoxy)methoxy]benzaldehyde; 5-iodo-2-[(2-methoxyethoxy)methoxy]benzaldehyde | C11H13IO4 | 详情 | 详情 | |
| (IV) | 31673 | [5-iodo-2-[(2-methoxyethoxy)methoxy]phenyl]methanol | C11H15IO4 | 详情 | 详情 | |
| (V) | 31674 | 2-[[2-(bromomethyl)-4-iodophenoxy]methoxy]ethyl methyl ether; 2-(bromomethyl)-4-iodo-1-[(2-methoxyethoxy)methoxy]benzene | C11H14BrIO3 | 详情 | 详情 | |
| (VI) | 29492 | tert-butyl (3S)-2-oxopyrrolidinylcarbamate | C9H16N2O3 | 详情 | 详情 | |
| (VII) | 31675 | tert-butyl (3S)-1-[5-iodo-2-[(2-methoxyethoxy)methoxy]benzyl]-2-oxopyrrolidinylcarbamate | C20H29IN2O6 | 详情 | 详情 | |
| (VIII) | 31676 | tert-butyl (3S)-1-[5-cyano-2-[(2-methoxyethoxy)methoxy]benzyl]-2-oxopyrrolidinylcarbamate | C21H29N3O6 | 详情 | 详情 | |
| (IX) | 31677 | 3-[[(3S)-3-amino-2-oxopyrrolidinyl]methyl]-4-hydroxybenzonitrile | C12H13N3O2 | 详情 | 详情 | |
| (X) | 31678 | 5-(3-pyridinyl)-2-thiophenesulfonyl chloride | C9H6ClNO2S2 | 详情 | 详情 | |
| (XI) | 31679 | N-[(3S)-1-(5-cyano-2-hydroxybenzyl)-2-oxopyrrolidinyl]-5-(3-pyridinyl)-2-thiophenesulfonamide | C21H18N4O4S2 | 详情 | 详情 | |
| (XII) | 13625 | 2-[(3-Methoxyphenyl)sulfanyl]benzoic acid | C14H12O3S | 详情 | 详情 | |
| (XIII) | 13681 | 2-Bromothiophene | 1003-09-4 | C4H3BrS | 详情 | 详情 |
| (XIV) | 31680 | 3-(2-thienyl)pyridine | C9H7NS | 详情 | 详情 |