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【结 构 式】

【分子编号】53882

【品名】 

【CA登记号】n/a

【 分 子 式 】C18H32BrMgNO7

【 分 子 量 】478.66362

【元素组成】C 45.17% H 6.74% Br 16.69% Mg 5.08% N 2.93% O 23.4%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(V)

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
Extended Information