|
【结 构 式】 
|
【分子编号】35983 【品名】m-bromoanisole; 1-Bromo-3-methoxybenzene; 3-Bromoanisole; 3-Bromophenyl methyl ether 【CA登记号】2398-37-0 |
【 分 子 式 】C7H7BrO 【 分 子 量 】187.03598 【元素组成】C 44.95% H 3.77% Br 42.72% O 8.55% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of 3-bromoanisole (I) with magnesium in THF gives 3-methoxyphenylmagnesium bromide (II), which is condensed with 3-bromopyridine (III) in THF by means of dichlorobis(triphenylphosphine)nickel yielding 3-(3-pyridinyl)anisole (IV). The alkylation of (IV) with propylbromide (A) in acetone at 110 C (under pressure) affords N-propyl-3-(3-methoxyphenyl)pyridinium bromide (V), which is reduced with H2 over Pt in methanol to give 1-propyl-3-(3-methoxyphenyl)piperidine (VI). Finally, this compound is demethylated by treatment with refluxing aqueous 48% HBr. The reduction of (IV) with H2 over Pt in methanol gives 3-(3-methoxyphenyl)piperidine (VII), which is acylated and reduced simultaneously with propionic acid (B) and NaBH4 in refluxing benzene to yield (VI), already obtained.
| 【1】 Arvidsson, F.L.E.; et al.; EP 0030526 . |
| 【2】 Sanchez, D.; Nilsson, J.L.G.; Hacksell, U.; Lindberg, P.; Carlsson, A.; Arvidsson, L.E.; Svensson, U.; Hjorth, S.; Wikstroem, H.; 3-Phenylpiperidines. Central dopamine-autoreceptor stimulating activity. J Med Chem 1981, 24, 12, 1475-82. |
| 【3】 Serradell, M.N.; Nohria, V.; Castaner, J.; Blancafort, P.; 3-PPP. Drugs Fut 1983, 8, 1, 27. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 19502 | Propyl bromide; 1-Bromopropane | 106-94-5 | C3H7Br | 详情 | 详情 |
| (B) | 20178 | propionic acid | 79-09-4 | C3H6O2 | 详情 | 详情 |
| (I) | 35983 | m-bromoanisole; 1-Bromo-3-methoxybenzene; 3-Bromoanisole; 3-Bromophenyl methyl ether | 2398-37-0 | C7H7BrO | 详情 | 详情 |
| (II) | 35984 | bromo(3-methoxyphenyl)magnesium | 36282-40-3 | C7H7BrMgO | 详情 | 详情 |
| (III) | 13265 | 3-Bromopyridine | 626-55-1 | C5H4BrN | 详情 | 详情 |
| (IV) | 35985 | 3-(3-methoxyphenyl)pyridine; methyl 3-(3-pyridinyl)phenyl ether | C12H11NO | 详情 | 详情 | |
| (V) | 35986 | 3-(3-methoxyphenyl)-1-propylpyridinium bromide | C15H18BrNO | 详情 | 详情 | |
| (VI) | 35987 | 3-(3-methoxyphenyl)-1-propylpiperidine; methyl 3-(1-propyl-3-piperidinyl)phenyl ether | C15H23NO | 详情 | 详情 | |
| (VII) | 35988 | 3-(3-methoxyphenyl)piperidine; methyl 3-(3-piperidinyl)phenyl ether | C12H17NO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Reaction of 3-bromoanisole (I) with Mg turnings in refluxing THF provides Grignard reagent (II), which is converted into tramadol base (VI) by treatment with Mannich base (III) (obtained in turn via Mannich reaction of cyclohexanone (IV) with dimethylamine hydrochloride and formaldehyde). Alternatively, the transformation of (II) into (VI) can be performed by first treatment of (II) with additive TDA-1 (tris(2-(2-methoxyethoxy)ethylamine) to form complex (V), followed by addition of Mannich base (III). Alternatively, the additive used can be replaced by the following reagents: 1-methylimidazole, diglyme, 4-methylmorpholine, diazabicyclo(5.4.0)undec-7-ene, triethylamine, N,N,N',N',N''-pentamethyldiethylenetriamine, pyridine, 1,2-dimethylimidazole, 1-methylpyrrolidine, 1,4-dimethylpiperazine, pyrazine, S-(-)-nicotine, 1-methylpyrrole, 4-methoxypyridine, quinoline, 1,5-diazabicyclo(4.3.0)non-5-ene, 1-benzylimidazole or 1-butylimidazole. Once tramadol base (VI) is obtained, treatment with HCl in acetonitrile or isopropanol allows formation of the corresponding hydrochloride salt as an isomeric mixture of the trans/cis forms (VII). The desired isomer cis-(XII) can be obtained by many different routes: (a) recrystallization of (VII) from acetonitrile. (b) recrystallization of (VII) from dioxane/H2O. (c) recrystallization of (VII) from isopropanol. (d) heating of the mixture (VI) with p-toluenesulfonic acid or phosphoric acid or formic acid, followed by a recrystallization process. (e) treatment of (VII) with acetic anhydride in DMF, followed by crystallization from isopropanol. (f) treatment of (VII) with thionyl chloride in chlorobenzene, followed by crystallization from isopropanol. (g) treatment of (VII) with trifluoroacetic acid and sodium azide, followed by basification with K2CO3 and final recrystallization from isopropanol. (h) formation of tramadol hydrate (VIII) by treatment with water in diisopropyl ether, followed by hydrochloride formation with HCl. (i) formation of tramadol hydrobromide (IX) by treatment with hydrobromic acid, filtration of the solid obtained, obtaining of the free base by treatment with NaOH (5) and final conversion into the hydrochloride form by means of HCl. (j) formation of tramadol hydroiodide (X) by treatment with hydroiodic acid, filtration of the solid obtained and final conversion into the hydrochloride form by means of HCl.
| 【1】 Cherkez, S.; Lerman, O.; Tennenbaum, M.; Avner, H.; Kunyevski, T.; Process for the purification of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol and its salts. US 5414129 . |
| 【2】 Flick, K.; Frankus, E. (Grunenthal GmbH); 1-(m-Substd. phenyl)-2-aminomethyl cyclohexanols. US 3652589 . |
| 【3】 Cabri, W.; Magrone, D.; Process for the separation of the (RR,SS)-2-(dimethylamino)methyl-1-(3-methoxyphenyl)cyclohexanol isomer from the (RS,SR) isomer by selective precipitation. EP 0940385 . |
| 【4】 Lerman, O.; Kaspi, J.; Brenner, D.; Process for the purification of (RR,SS)-2-dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol hydrochloride. EP 0831082 . |
| 【5】 Mitchell, M.; Archer, N.; Hurley, B.; Ogden, H.; Purification of tramadol. WO 9936389 . |
| 【6】 Anderson, K.E.; Preparation and purification process for 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol and its salts. US 5877351 . |
| 【7】 Mitchell, M.; Archer, N.; Ogden, H.; Cairns, S.; Purification of tramadol. WO 9936390 . |
| 【8】 Jarvi, E.T.; Grayson, N.A.; Halvachs, R.E. (Mallinckrodt Medical Inc.); An improved synthesis and purification of (R*,R*)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol hydrochloride. WO 9961405 . |
| 【9】 Gal, E.; Lerman, O.; Tennenbaum, M.; Kaspi, J.; Process for the purification of (RR,SS)-2-dimethylaminomethyl-(1-(3-methoxyphenyl)cyclohexanol and its salts. EP 0778262 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIa), (VIII), (IX) | 53884 | (1R,2R)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol | n/a | C16H25NO2 | 详情 | 详情 |
| (VIIb) | 53886 | (1R,2S)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol | n/a | C16H25NO2 | 详情 | 详情 |
| (I) | 35983 | m-bromoanisole; 1-Bromo-3-methoxybenzene; 3-Bromoanisole; 3-Bromophenyl methyl ether | 2398-37-0 | C7H7BrO | 详情 | 详情 |
| (II) | 35984 | bromo(3-methoxyphenyl)magnesium | 36282-40-3 | C7H7BrMgO | 详情 | 详情 |
| (III) | 53883 | 2-(Dimethylaminoethyl)-1-cyclohexanone | n/a | C9H17NO | 详情 | 详情 |
| (IV) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
| (V) | 53882 | n/a | C18H32BrMgNO7 | 详情 | 详情 | |
| (VI) | 53885 | Tramadol | 22204-88-2 | C16H25NO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XI)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4
该中间体在本合成路线中的序号：(II)Protected piperidone (I) is condensed with methoxybromobenzene (II) via Grignard reaction by means of Mg and catalytic iodine in refluxing THF, and the resulting alcohol is then dehydrated with refluxing HCl in dioxane to afford compound (III). Hydrogenation of tetrahydropyridine (III) over Pd/C in EtOH yields piperidine derivative (IV), which is then demethylated with aqueous HBr to provide phenol (V). Condensation of (V) with 4-fluorobenzoyl chloride (VI) by means of NaOH in iPrOH/MeOH/H2O furnishes N-benzoylpiperidine derivative (VII), which is converted into the desired product by reaction with ethyl 2-bromo-2-methylpropanoate (VIII) by means of K2CO3 followed by hydrolysis with NaOH in H2O/MeOH/dioxane.
| 【1】 Komoto, T.; et al.; Preparation of new fibrates with piperidine ring and the pharmacological activity. 20th Symp Med Chem (Dec 6 2000, Tokyo) 2000, Abst 2P-06. |
| 【2】 Komoto, T.; et al.; New strong fibrates with piperidine moiety. Chem Pharm Bull 2000, 48, 12, 1978. |
| 【3】 Komoto, T.; Hirota, H.; Sato, S.; Othsuka, M.; Koya, H.; Mizuno, H.; Kuraishi, T. (SSP Co., Ltd.); Arylamide derivs.. EP 0607536; JP 1995053517; US 5411972 . |
| 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) | 15720 | 1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one | 3612-20-2 | C12H15NO | 详情 | 详情 |
| (II) | 35983 | m-bromoanisole; 1-Bromo-3-methoxybenzene; 3-Bromoanisole; 3-Bromophenyl methyl ether | 2398-37-0 | C7H7BrO | 详情 | 详情 |
| (III) | 47137 | 1-benzyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine; 3-(1-benzyl-1,2,3,6-tetrahydro-4-pyridinyl)phenyl methyl ether | C19H21NO | 详情 | 详情 | |
| (IV) | 47138 | 4-(3-methoxyphenyl)piperidine; methyl 3-(4-piperidinyl)phenyl ether | C12H17NO | 详情 | 详情 | |
| (V) | 47139 | 3-(4-piperidinyl)phenol | C11H15NO | 详情 | 详情 | |
| (VI) | 17263 | 4-fluorobenzoyl chloride | 403-43-0 | C7H4ClFO | 详情 | 详情 |
| (VII) | 47140 | (4-fluorophenyl)[4-(3-hydroxyphenyl)-1-piperidinyl]methanone | C18H18FNO2 | 详情 | 详情 | |
| (VIII) | 39799 | ethyl 2-bromo-2-methylpropanoate | 600-00-0 | C6H11BrO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The condensation of 2,3-dimethylphenol (I) with 3-bromoanisole (II) by means of K2CO3 and CuO in pyridine gives the diaryl ether (III), which is demethylated by means of HBr in refluxing acetic acid to yield the phenol (IV). The condensation of (IV) with 4,4,4-trifluorobutylsulfonyl chloride (V) by means of t-BuOK in THF affords the sulfonate (VI), which is brominated by means of NBS in refluxing CCl4 to provide the bis(bromomethyl)compound (VII). The cyclization of (VII) with dimethyl malonate (VIII) by means of K2CO3 in refluxing butanone furnishes the indane-dicarboxylate (IX), which is hydrolyzed and monodecarboxylated by means of HBr in refluxing acetic acid/water to give the indane-carboxylic acid (X). The reduction of the CO2H group of (X) by means of BH3/Me2S in THF yields the racemic hydroxymethyl derivative (XI), which is finally submitted to optical resolution by means of chiral preparative HPLC over Chiracel OD to provide the target (R)-enantiomer.
| 【1】 Dressel, J.; Matzke, M.; Mittendorf, J.; De Vry, J.-M.V.; Mauler, F.; Friedl, A.; Horvath, E.; Keldenich, J.; Franz, J.; Spreyer, P.; Vöhringer, V.; Rock, M.-H.; Schumacher, J. (Bayer AG); Novel aryl sulphonamide amino acid esters and analogues. CA 2341028; DE 19837627; EP 1105371; US 6545050; WO 0010968 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 60555 | 4,4,4-trifluorobutyl methanesulfonate | C5H9F3O3S | 详情 | 详情 | |
| (A) | 60556 | 4,4,4-trifluoro-1-butanol | C4H7F3O | 详情 | 详情 | |
| (I) | 40074 | 2,3-dimethylphenol | 526-75-0 | C8H10O | 详情 | 详情 |
| (II) | 35983 | m-bromoanisole; 1-Bromo-3-methoxybenzene; 3-Bromoanisole; 3-Bromophenyl methyl ether | 2398-37-0 | C7H7BrO | 详情 | 详情 |
| (III) | 60552 | 3-(2,3-dimethylphenoxy)phenyl methyl ether; 1-(3-methoxyphenoxy)-2,3-dimethylbenzene | C15H16O2 | 详情 | 详情 | |
| (IV) | 60553 | 3-(2,3-dimethylphenoxy)phenol | C14H14O2 | 详情 | 详情 | |
| (V) | 26779 | 1-butanesulfonyl chloride | 2386-60-9 | C4H9ClO2S | 详情 | 详情 |
| (VI) | 60557 | 3-(2,3-dimethylphenoxy)phenyl 4,4,4-trifluoro-1-butanesulfonate | C18H19F3O4S | 详情 | 详情 | |
| (VII) | 60558 | 3-[2,3-bis(bromomethyl)phenoxy]phenyl 4,4,4-trifluoro-1-butanesulfonate | C18H17Br2F3O4S | 详情 | 详情 | |
| (VIII) | 19373 | dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester | 108-59-8 | C5H8O4 | 详情 | 详情 |
| (IX) | 60559 | dimethyl 4-(3-{[(4,4,4-trifluorobutyl)sulfonyl]oxy}phenoxy)-1,3-dihydro-2H-indene-2,2-dicarboxylate | C23H23F3O8S | 详情 | 详情 | |
| (X) | 60560 | 4-(3-{[(4,4,4-trifluorobutyl)sulfonyl]oxy}phenoxy)-2-indanecarboxylic acid | C20H19F3O6S | 详情 | 详情 | |
| (XI) | 60551 | 3-{[2-(hydroxymethyl)-2,3-dihydro-1H-inden-4-yl]oxy}phenyl 4,4,4-trifluoro-1-butanesulfonate | C20H21F3O5S | 详情 | 详情 | |
| (C) | 60554 | 4,4,4-trifluoro-1-butanesulfenyl cyanide | C5H6F3NS | 详情 | 详情 |