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Name Tramadol hydrochloride;TRK-091;CG-315E;K-315;U-26225A;NS-315;Tradonal Retard;Ultram;Tramal;Contramal;Ralivia FlashDose;Limadol;Tramundin Retard;Tramadol Flashtab;Zamadol SR;Ralivia;Zydol
Chemical Name (±)-cis-2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol hydrochloride
CAS 36282-47-0
Related CAS 148229-79-2 ((-)-enantiomer), 148229-78-1 ((+)-enantiomer), 22204-88-2 (deleted CAS), 27203-92-5 (f
Formula C16H26ClNO2
Structure
Formula Weight 299.84412
Stage 上市-1977
Company Grünenthal (Originator), Nang Kuang Pharmaceutical (Not Determined), Angelini (Marketer), Aventis Pharma (Marketer), Biovail (Marketer), Esteve (Marketer), Formenti (Marketer), Nippon Shinyaku (Licensee), Ortho-McNeil (Licensee), Pfizer (Licensee), Biovai
Activity/Mechanism ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Opioid Analgesics, 5-HT Reuptake Inhibitors, mu-Opioid Agonists, Norepinephrine Reuptake Inhibitors
Syn. Route 1
Route 1
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.
List of intermediates No.
(2r,3s)-1,1,1-trifluoro-4-methyl-3-nitro-2-pentanol (iv)
methyl (3ar,4s,11bs)-4-[(2s)-2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-3-[(1r)-1-(1-naphthyl)ethyl]-2,3,3a,4,5,7-hexahydro-1h-pyrrolo[2,3-d]carbazole-6-carboxylate (i)
methyl (3ar,4s,11bs)-4-[(2r)-2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-3-[(1r)-1-(1-naphthyl)ethyl]-2,3,3a,4,5,7-hexahydro-1h-pyrrolo[2,3-d]carbazole-6-carboxylate (ii)
Reference 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 .
Reference 2:
    flick, k.; frankus, e. (grunenthal gmbh); 1-(m-substd. phenyl)-2-aminomethyl cyclohexanols. us 3652589 .
Reference 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 .
Reference 4:
    lerman, o.; kaspi, j.; brenner, d.; process for the purification of (rr,ss)-2-dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol hydrochloride. ep 0831082 .
Reference 5:
    mitchell, m.; archer, n.; hurley, b.; ogden, h.; purification of tramadol. wo 9936389 .
Reference 6:
    anderson, k.e.; preparation and purification process for 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol and its salts. us 5877351 .
Reference 7:
    mitchell, m.; archer, n.; ogden, h.; cairns, s.; purification of tramadol. wo 9936390 .
Reference 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 .
Reference 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 .

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名盐酸曲马多;英文名Tramadol hydrochloride;TRK-091;CG-315E;K-315;U-26225A;NS-315;Tradonal Retard;Ultram;Tramal;Contramal;Ralivia FlashDose;Limadol;Tramundin Retard;Tramadol Flashtab;Zamadol SR;Ralivia;Zydol;CAS[36282-47-0]

 
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