SK278422B6 - The production of tramadol of hydrogenchloride - Google Patents
The production of tramadol of hydrogenchloride Download PDFInfo
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- SK278422B6 SK278422B6 SK435-94A SK43594A SK278422B6 SK 278422 B6 SK278422 B6 SK 278422B6 SK 43594 A SK43594 A SK 43594A SK 278422 B6 SK278422 B6 SK 278422B6
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- tramadol
- dioxane
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- tramadol hydrochloride
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- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 title claims abstract description 19
- 229960004380 tramadol Drugs 0.000 title claims abstract description 15
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 title claims abstract description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title claims abstract description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 title claims abstract description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 title claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 title abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000002425 crystallisation Methods 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 3
- 239000002904 solvent Substances 0.000 claims abstract description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- PPKXEPBICJTCRU-XMZRARIVSA-N (R,R)-tramadol hydrochloride Chemical compound Cl.COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 PPKXEPBICJTCRU-XMZRARIVSA-N 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- PPKXEPBICJTCRU-DMLYUBSXSA-N (1r,2s)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexan-1-ol;hydrochloride Chemical compound Cl.COC1=CC=CC([C@]2(O)[C@@H](CCCC2)CN(C)C)=C1 PPKXEPBICJTCRU-DMLYUBSXSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 229960003107 tramadol hydrochloride Drugs 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 7
- -1 methanol Chemical compound 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 238000009835 boiling Methods 0.000 claims description 6
- 239000002037 dichloromethane fraction Substances 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 238000004821 distillation Methods 0.000 claims description 5
- 238000001704 evaporation Methods 0.000 claims description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 4
- PLDWAJLZAAHOGG-UHFFFAOYSA-N 1-bromo-3-methoxybenzene Chemical compound COC1=CC=CC(Br)=C1 PLDWAJLZAAHOGG-UHFFFAOYSA-N 0.000 claims description 3
- 238000003747 Grignard reaction Methods 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 230000008020 evaporation Effects 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 235000019270 ammonium chloride Nutrition 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- FKUUDDGRDRPAQQ-UHFFFAOYSA-M magnesium;methoxybenzene;bromide Chemical compound [Mg+2].[Br-].COC1=CC=C[C-]=C1 FKUUDDGRDRPAQQ-UHFFFAOYSA-M 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- SVYOXGBINYWSDQ-UHFFFAOYSA-N 1,4-dioxane;ethanol Chemical compound CCO.C1COCCO1 SVYOXGBINYWSDQ-UHFFFAOYSA-N 0.000 claims 1
- LBKGSNPSDIYPBE-UHFFFAOYSA-N 2-[(dimethylamino)methyl]cyclohexan-1-ol Chemical compound CN(C)CC1CCCCC1O LBKGSNPSDIYPBE-UHFFFAOYSA-N 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 3
- 239000004084 narcotic analgesic agent Substances 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 abstract 1
- 239000013078 crystal Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 230000000202 analgesic effect Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- QDHLEFBSGUGHCL-UHFFFAOYSA-N 2-[(dimethylamino)methyl]cyclohexan-1-one Chemical compound CN(C)CC1CCCCC1=O QDHLEFBSGUGHCL-UHFFFAOYSA-N 0.000 description 2
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical class OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000006277 sulfonation reaction Methods 0.000 description 2
- TVYLLZQTGLZFBW-HOCLYGCPSA-N (1r,2s)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexan-1-ol Chemical compound COC1=CC=CC([C@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-HOCLYGCPSA-N 0.000 description 1
- UIJPWDSKPZLJAN-UHFFFAOYSA-N 2-(1,4-dioxan-2-yl)ethanol Chemical compound OCCC1COCCO1 UIJPWDSKPZLJAN-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- FLZHDAQGOVPEQW-UHFFFAOYSA-N COC1=CC=CC([Mg])=C1 Chemical compound COC1=CC=CC([Mg])=C1 FLZHDAQGOVPEQW-UHFFFAOYSA-N 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 159000000032 aromatic acids Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000001427 coherent effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000008379 phenol ethers Chemical class 0.000 description 1
- 238000011176 pooling Methods 0.000 description 1
- 238000011425 standardization method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Vynález je z oblasti farmaceutickej chémie. Týka sa výroby narkotického analgetika tramadol hydrogénchloridu CAS No 27203-92-5.The invention is in the field of pharmaceutical chemistry. It concerns the manufacture of the narcotic analgesic tramadol hydrochloride CAS No 27203-92-5.
Doterajší stav technikyBACKGROUND OF THE INVENTION
Analgetický účinok alkylaminocykloalkanolmi substituovaných fenoléterov, hlavne však l-(3-alkoxyfenyl)-2-dialkylaminometylcyklohexanolov je známy už z brit. pat. 997.399 (1965, Grúnenthal Chemie), CAS 63, 9871, 1965. Pozornosť sa venuje hlavne trans-izomérom týchto látok pre dobrú analgetickú účinnosť, biologickú dostupnosť a nízku toxicitu. Výsledky farmakologických a klinických skúšok v US pat. 3. 830. 934 (1974, Grúnenthal Chemie) a v Arzneimittel Forschung 28, 109, (1978) ukázali na výhodnosť tramadolu hydrogénchloridu pre nízku hladinu toxicity a vysokú analgetickú aktivitu.The analgesic effect of alkylaminocycloalkanol-substituted phenol ethers, in particular 1- (3-alkoxyphenyl) -2-dialkylaminomethylcyclohexanols, is already known from brit. pat. 997.399 (1965, Grünenthal Chemie), CAS 63, 9871, 1965. Attention is paid in particular to the trans-isomers of these compounds for good analgesic efficacy, bioavailability and low toxicity. The results of pharmacological and clinical trials in US Pat. 3,830,934 (1974, Grünenthal Chemie) and in Arzneimittel Forschung 28, 109, (1978) have shown the advantage of tramadol hydrochloride for low toxicity and high analgesic activity.
Z týchto spisov je známy postup prípravy hydrogénchloridov l-(3-alkoxyfenyl)-2-dialkylaminometyl cyklohexanolov, tiež tramadol hydrogénchloridu. Pri postupe sa Grignardovou reakciou 3-metoxyfenyl-magneziumbromidu, pripraveného reakciou horčíka s 3-brómanizolom v tetrahydrofuráne, s 2-dimetylaminometyl cyklohexanónom v tetrahydrofuráne s následnou hydrolýzou adičného medziproduktu vodným roztokom chloridu amónneho získa 2-dimetylaminometyl-l-(3-metoxyfenyl)-l-cyklohexanol, ako zmes prevažne trans- izoméru tramadolu, čo je 2-(e)-dimetylaminometyl-l-(e)-(3-metoxyfenyl)-l-(a)-cyklohexanol a cis- tramadolu, 2-(a)-dimetylaminometyl-1 -(e)-(3-metoxyfenyl)-1 -(a)-cyklohexanol.From these publications, a process for preparing 1- (3-alkoxyphenyl) -2-dialkylaminomethyl cyclohexanols, also tramadol hydrochloride, is known. In the process, Grignard reaction of 3-methoxyphenyl-magnesium bromide, prepared by reacting magnesium with 3-bromoanisole in tetrahydrofuran, with 2-dimethylaminomethyl cyclohexanone in tetrahydrofuran followed by hydrolysis of the intermediate intermediate with ammonium chloride aqueous solution gives 2-dimethyphenylmethyl 3-dimethylaminomethyl) 1-cyclohexanol, as a mixture of the predominantly trans-isomer of tramadol which is 2- (e) -dimethylaminomethyl-1- (e) - (3-methoxyphenyl) -1- (a) -cyclohexanol and cis-tramadol, 2- (a 1-Dimethylaminomethyl-1- (e) - (3-methoxyphenyl) -1- (a) -cyclohexanol.
Z teórie Grignardových syntéz je známe (Methoden der organischen Chemie, Houben-Weyl XIII/2a, 289, 302)a platí to i v tomto prípade, že zníženie teploty pri adícii preferuje vznik trans-izoméru.It is known from the theory of Grignard syntheses (Methoden der organischen Chemie, Houben-Weyl XIII / 2a, 289, 302), and in this case too, the reduction of the temperature at the addition favored the formation of the trans-isomer.
Uskutočnením adície pri teplote v intervale 0 až -10°C podľa US pat. 3. 652. 589 (1972, Grúnenthal Chemie) sa získa tramadol vo výťažku 78,6 % s pomerom izomérov trans-/cis- 90 : 10. V ďalšom postupe reaguje tramadol s plynným chlorovodíkom v éteri alebo v sústave etanol éter (US pat. 3. 830. 394, 1974, Arzneimittel Forschung 28, 108, 1978).By carrying out the addition at a temperature in the range of 0 to -10 ° C according to US Pat. 3. 652. 589 (1972, Grunenthal Chemie) gives tramadol in a yield of 78.6% with a trans- / cis- 90: 10 isomer ratio. In a further process, tramadol is reacted with hydrogen chloride gas in ether or in ethanol ether (US Pat. 3,830,394, 1974, Arzneimittel Forschung 28, 108 (1978).
Získa sa zmesová soľ izomérov v pevnom stave. Na rozdelenie solí izomérov sa výhodne používa ich rozdielna rozpustnosť vo vlhkom dioxáne pri teplote varu sústavy.A mixed salt of the isomers in the solid state is obtained. Preferably, different solubility in wet dioxane at the boiling point of the system is used to separate the isomer salts.
Soľ cis- izoméru sa takmer úplne rozpúšťa s časťou soli trans- izoméru do dioxánu. Pevný rafinát predstavuje takmer čistý trans- tramadol hydrogénchlorid. Z dioxánového extraktu po ochladení kryštalizuje zmesová soľ obohatená o cis- tramadol hydrogénchlorid, podľa známych poznatkov predstavuje asi 40 hmotn. % z pôvodnej soli na čistenie a obsahuje asi 25 až 30 hmotn. % cis-izoméru soli. Pre efektívnosť postupu sa aj táto zmesová frakcia ďalej separuje. Suspendovaním zmesovej soli v dichlórmetáne sa rozpúšťa trans- izomér úplne do dichlórmetánu a cis- izomér soli zostáva nerozpustený a v pevnom stave sa odfiltruje. Extrakt sa spracuje odparením dichlórmetánu a následnou kryštalizáciou sa získa dichlórmetánová frakcia trans- tramadol hydrogénchloridu.The cis-isomer salt is almost completely dissolved with part of the trans-isomer salt into dioxane. The solid raffinate is almost pure trans-tramadol hydrogen chloride. The mixed salt enriched in cis-tramadol hydrochloride crystallizes from the dioxane extract upon cooling; % of the original salt for purification and contains about 25 to 30 wt. % cis-isomer of the salt. For the efficiency of the process, this mixed fraction is further separated. By suspending the mixed salt in dichloromethane, the trans-isomer dissolves completely into dichloromethane and the cis-isomer of the salt remains undissolved and filtered off in the solid state. The extract was worked up by evaporation of dichloromethane and subsequent crystallization to give the dichloromethane fraction of trans-tramadol hydrochloride.
Z uvedenej schémy postupu je zrejmá zložitosť a technická náročnosť uskutočnenia postupu. Nevýhodným sa ukazuje, že postupom vznikajú dve frakcie transtramadol hydrogénchloridu, ktoré nie sú koherentné pôvodom, ale z dostupných zdrojov nie je známy spôsob ich spájania s cieľom zjednocovať šarže. Navyše sa prakticky ukazuje, že spôsob dioxánovej ex5 trakcie cis- izoméru soli je vysoko selektívny, ale požadovaná účinnosť sa dosahuje len v úzko ohraničenej oblasti parametrov procesu, čo vo výrobných podmienkach nie je vždy možné procesnými prostriedkami zabezpečiť.The complexity and technical difficulty of carrying out the procedure is evident from the flow chart. It is disadvantageous that the process results in two fractions of transtramadol hydrochloride, which are not coherent in origin, but from the available sources it is not known how to combine them to unify batches. In addition, it has practically been shown that the method of dioxane ex5 traction of the cis-isomer of the salt is highly selective, but the desired efficiency is only achieved within a narrowly defined range of process parameters, which is not always possible under process conditions.
Týka sa to reprodukovaného pomeru izomérov na čistenie, počiatočnej vlhkosti dioxánu, teploty extrahovanej zmesi a teploty zmesi pri filtrácii. Výsledkom týchto vplyvov je neúčinné oddelenie cis- izoméru v produkte a postup je potrebné opakovať.This refers to the reproduced ratio of the isomers to be purified, the initial moisture content of dioxane, the temperature of the extracted mixture, and the temperature of the mixture during filtration. These effects result in ineffective separation of the cis-isomer in the product and the procedure needs to be repeated.
Podobne je to i s obsahom cis- izoméru v dichlórmetánovej frakcii, kde opakovaním postupu podľa vynálezu nedosahuje sa odstránenie cis- izoméru a frakciu trans- izoméru soli je potrebné prečistiť.The same is true for the cis-isomer content of the dichloromethane fraction, where by repeating the process of the invention the cis-isomer removal is not achieved and the fraction of the trans-isomer of the salt needs to be purified.
Technicky nevýhodným sa tiež ukazuje známa fi20 nalizácia rafinátu z dioxánového čistenia odparením dioxánu z pevnej soli.The known flux of raffinate from dioxane purification by evaporation of dioxane from the solid salt also proves to be technically disadvantageous.
Prakticky sa ukazuje náročné dosiahnuť zvyčajnými podmienkami vákuového sušenia požadovanú hladinu zostatkového dioxánu v produkte, požadova25 nú liekopismi, pre jeho toxicitu.In practice, it has proved difficult to achieve the desired level of residual dioxane in the product required by the pharmacopoeias by the usual vacuum drying conditions due to its toxicity.
Uvedené ťažkosti pri priemyselnej realizácii je možné odstrániť postupom podľa vynálezu.These difficulties in industrial implementation can be overcome by the process of the invention.
Podstata vynálezuSUMMARY OF THE INVENTION
Na prípravu tramadol hydrogénchloridu podľa vynálezu sa používa známy postup prípravy tramadolu Grignardovou reakciou 3-metoxyfenylmagnézium35 bromidu z kovového horčíka a 3-brómanizolu v tetrahydrofuráne, s 2-dimetylaminometylcyklohexanónom v tetrahydrofuráne a s následnou hydrolýzou adičného produktu vodným roztokom chloridu amónneho. Premenou tramadolu s chlorovodíkom v 40 etanole a éteri sa pripraví surová soľ tramadolu s obsahom asi 10 až 15 % cis- izoméru tramadol hydrogénchloridu, separuje sa extrakciou vriacim vlhkým dioxánom s obsahom vody v dioxáne do 1 % izoláciou zmesovej soli z dioxánového extraktu s obsahom 45 25 až 30 % cis- izoméru soli, jej suspendovaním v dichlórmetáne, odfiltrovaním nerozpusteného cisizoméru a izolovaním frakcie trans- izoméru rozpusteného v dichlórmetáne odparením rozpúšťadla a kryštalizáciou prídavkom acetónu. Postup je výz50 načný tým, že frakcie trans- izoméru tramadolu, pevný rafinát z dioxánovej extrakcie zmesovej surovej soli a dichlórmetánová frakcia sa kryštalizujú z alkoholu ako je metanol, výhodne etanol a ďalšie alifatické alkoholy s počtom uhlíkov 3 až 6 a sústav alkoho55 lov s počtom uhlíkov 1 až 6 a ďalších organických rozpúšťadiel ako sú ketóny, výhodne acetón, étery ako dietyléter, estery alifatických a aromatických kyselín a alkoholov, a amidy ako alkylamidy nižších karboxylových kyselín ako dimetylformamid.For the preparation of tramadol hydrochloride according to the invention, the known process for the preparation of tramadol by the Grignard reaction of 3-methoxyphenylmagnesium 35 bromide from magnesium metal and 3-bromoanisole in tetrahydrofuran, with 2-dimethylaminomethylcyclohexanone in tetrahydrofuran and subsequent hydrolysis of the amine addition product with aqueous solution. By converting tramadol with hydrogen chloride in 40 ethanol and ether, a crude tramadol salt containing about 10-15% of the cis-isomer of tramadol hydrochloride is prepared, separated by extraction with boiling wet dioxane containing up to 1% water in dioxane by isolating the mixed salt from the dioxane extract containing 45%. 25 to 30% of the cis-isomer of the salt, suspending it in dichloromethane, filtering off the undissolved cis-isomer and isolating the fraction of the trans-isomer dissolved in dichloromethane by evaporating the solvent and crystallizing by addition of acetone. The process is characterized in that the fraction of the trans-isomer of tramadol, the solid raffinate from the dioxane extraction of the mixed crude salt and the dichloromethane fraction are crystallized from an alcohol such as methanol, preferably ethanol and other aliphatic alcohols having carbon numbers of 3-6. carbons 1 to 6 and other organic solvents such as ketones, preferably acetone, ethers such as diethyl ether, esters of aliphatic and aromatic acids and alcohols, and amides such as lower carboxylic acid alkyl amides such as dimethylformamide.
Postup je význačný i tým, že frakcie trans- tramadolu hydrogénchloridu sa kryštalizujú zvlášť a spájajú sa vyhovujúce po kryštalizácii ako v predchádzajúcom postupe.The process is also characterized in that the fractions of trans-tramadol hydrochloride are crystallized separately and combined satisfactorily after crystallization as in the previous process.
Postup je ďalej význačný tým, že na kryštalizáciu sa použije frakcia tramadolu hydrogénchloridu znečistená dioxánom minimálne 5 %, surový tramadol hydrogénchlorid sa rozpusti v etanole v pomere soľ, etanol v intervale 1 : 2 až 10, destiláciou zmesi dioxán etanol sa oddestiluje dioxán, a soľ sa kryštalizuje zo zvyšku ako v predchádzajúcom postupe.The process is further characterized in that a fraction of tramadol hydrogen chloride contaminated with dioxane of at least 5% is used for crystallization, the crude tramadol hydrogen chloride is dissolved in ethanol in a ratio of salt, ethanol in the range of 1: 2 to 10, distilling dioxane ethanol distills dioxane, and is crystallized from the residue as in the previous procedure.
Postupom podľa vynálezu sa dosahuje integrácia šarže tým, že zabezpečuje spájanie frakcií z čistenia do vyhovujúcej šarže. Postup je ďalej výhodný tým, že umožňuje finalizovať aj nevyhovujúce frakcie trans- izoméru ešte s obsahom cis- izoméru do 2 % a s obsahom dioxánu minimálne 5 % a postupom podľa vynálezu sa pripraví vyhovujúca substancia s predpísaným obsahom cis-izoméru menej ako 0,3 % a obsahom dioxánu menej ako 0,3 %, a obsahom dioxánu menej ako 1 ppm.The process according to the invention achieves batch integration by ensuring the pooling of the fractions from the purification into a suitable batch. The process is further advantageous in that it is also possible to finalize non-compliant fractions of the trans-isomer with a cis-isomer content of up to 2% and a dioxane content of at least 5% and a suitable substance with a prescribed cis-isomer content of less than 0.3%. and a dioxane content of less than 0.3%, and a dioxane content of less than 1 ppm.
Postup je ďalej výhodný tým, že jednoduchšie dosahuje požadovanú kvalitu a efektívny výťažok produktu.The process is further advantageous in that it more readily achieves the desired quality and efficient product yield.
Spôsoby výroby podľa vynálezu sú ilustrované nasledovnými príkladmi uskutočnenia, ktoré ho však v žiadnom prípade neohraničujú.The production methods according to the invention are illustrated by the following non-limiting examples.
Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION
Príklad 1Example 1
Do 500 ml banky sa pridá 80 g rafinovaného trans- tramadol hydrogénchloridu z dioxánovej extrakcie s obsahom 95 % trans- izoméru /HPLC, metódou externej normalizácie/, 1,1 % cis- tramadol hydrogénchlorid /HPLC/, 1,0 % dioxánu /GLC, metódou head space/, a 42 g dichlórmetánovej frakcie trans- tramadol hydrogénchloridu s obsahom 96 % trans- tramadol hydrogénchloridu a 1,8 % cis- izoméru tramadol hydrogénchloridu. K soli sa pridá 200 ml 99,8 % liehu a zmes sa za miešania počas 30 minút zahrieva na teplotu 35 až 40°C do roztoku.To a 500 ml flask was added 80 g of refined trans-tramadol hydrochloride from dioxane extraction containing 95% trans-isomer (HPLC, external standardization method), 1.1% cis-tramadol hydrochloride (HPLC), 1.0% dioxane (GLC). , and 42 g of the dichloromethane fraction of trans-tramadol hydrochloride containing 96% trans-tramadol hydrochloride and 1.8% of the cis-isomer of tramadol hydrochloride. 200 ml of 99.8% alcohol are added to the salt, and the mixture is heated to 35-40 ° C until stirring for 30 minutes.
Roztok sa filtruje cez sklenú fritu do 1,5 1 sulfonačnej banky. K roztoku sa počas miešania pri teplote asi 35 až 37°C pridá 20 ml acetónu a cez prikvapkávací lievik 100 až 120 ml dietyléteru do tvorby krátkodobého zákalu. Zmes sa mieša pri teplote miestnosti na kryštalizáciu počas 60 minút, keď už dochádza k vylučovaniu kryštalickej látky. Zmes sa počas miešania ochladí na teplotu 0 až -5°C a izotermicky mieša počas 5 hodín. Kryštalická soľ sa odfiltruje, na filtri premyje 90 ml roztoku z 80 ml dietyléteru a 10 ml acetónu, prenesie do sušiarne a suší sa pri teplote do 95°C a zníženom tlaku 6 kPa počas 6 hodín do konštantnej hmotnosti kryštálu. Získa sa 84 g 1. kry-štálu tramadol hydrogénchloridu s obsahom 99,8 % /titračne, kyselina chloristá/, teplota topenia 182°C, s obsahom cis- izoméru asi 0,1 % /HPLC, metódou ext. normalizácie/.The solution is filtered through a glass frit into a 1.5 L sulfonation flask. While stirring at about 35-37 ° C, 20 mL of acetone was added to the solution, and 100-120 mL of diethyl ether was added via a dropping funnel to form a short turbidity. The mixture was stirred at room temperature for crystallization for 60 minutes, when crystallization had already occurred. The mixture is cooled to 0-5 ° C with stirring and isothermally stirred for 5 hours. The crystalline salt is filtered off, washed on a filter with 90 ml of a solution of 80 ml of diethyl ether and 10 ml of acetone, transferred to an oven and dried at a temperature up to 95 ° C and reduced pressure of 6 kPa for 6 hours to constant crystal weight. 84 g of the first crystal of tramadol hydrochloride with a content of 99.8% (titration, perchloric acid), melting point 182 [deg.] C., with a cis -isomer content of about 0.1% (HPLC), ext. standardization /.
Materské lúhy sa spájajú spolu s premývacím roztokom a s celkovým objemom asi 460 ml sa skoncentrujú oddestilovanim dietyléteru s objemom asi 160 ml, asi 40 až 60 ml acetónovej frakcie a asi 120 ml liehovej frakcie. Horúci zvyšok sa filtruje s aktívnym uhlím a kremelinou. Filtrát sa zberá do 1,5 1 sulfonačnej banky, k roztoku sa cez prikvapkávací lievik pridá postupne 10 ml acetónu a asi 60 ml dietyléteru, zmes sa mieša na kryštalizáciu pri izbovej teplote. Postupom ako v predchádzajúcej časti sa získa ešte 30 g 2. kryštálu vyhovujúcej kvality, ktorý sa spája s 1. kryštálom.The mother liquors are combined with the wash solution and concentrated to a total volume of about 460 ml by distilling off diethyl ether of about 160 ml, about 40 to 60 ml of the acetone fraction and about 120 ml of the alcohol fraction. The hot residue is filtered with activated carbon and diatomaceous earth. The filtrate is collected in a 1.5 L sulfonation flask, 10 ml of acetone and about 60 ml of diethyl ether are added successively through a dropping funnel, and the mixture is stirred for crystallization at room temperature. As in the previous section, 30 g of a second crystal of satisfactory quality are obtained, which is combined with the first crystal.
Príklad 2 g surového tramadolu hydrogénchloridu, rafinátu z dioxánovej extrakcie s obsahom dioxánu 5 %, s obsahom trans- tramadol hydrogénchloridu 92 % /HPLC metódou externej normalizácie/ a s obsahom 1,5 % cis- tramadol hydrogénchloridu sa počas miešania rozpustí v 200 ml 99,8 % liehu v sklenej banke s miešadlom a destilačným chladičom.Example 2 g of crude tramadol hydrogen chloride, a raffinate from dioxane extraction with a dioxane content of 5%, a trans-tramadol hydrochloride content of 92% (by external standardization HPLC) and a content of cis-tramadol hydrochloride of 1.5%, is dissolved in 200 ml of 8% alcohol in a glass flask with stirrer and distillation condenser.
Obsah banky sa zahreje počas miešania do varu zmesi, pričom sa pomaly začína oddestilovávať etanol. Účinnosť oddelenia dioxánu sa sleduje stanovením dioxánu v destiláte plynovou chromatografiou metódou vnútornej normalizácie. Oddestiluje sa asi 150 ml liehu. V prípade pozitívneho testu na dioxán sa pridá ďalších 150 ml čerstvého liehu a destilácia sa opakuje do negatívneho dioxänového testu, čo predstavuje medzu stanoviteľnosti dioxánu v etanole 3. 10'3 hmotn. %.The contents of the flask are heated to the boiling point of the mixture while stirring, and ethanol is slowly distilled off. The efficiency of the dioxane separation is monitored by determination of dioxane in the distillate by gas chromatography by internal standardization. About 150 ml of alcohol is distilled off. In the case of a positive dioxane test, an additional 150 ml of fresh alcohol is added and the distillation is repeated for the negative dioxane test, which represents the limit of determination of dioxane in ethanol 3 . %.
Destilačný zvyšok sa za miešania počas 30 minút ochladí na teplotu 0 až -5°C, zmes sa mieša izotermicky počas 30 minút. Kryštalická soľ sa odsaje pri zníženom tlaku. Kryštál sa premyje 200 ml éteru a suší sa pri teplote 95°C pri zníženom tlaku 6 kPa. Získa sa 42,5 g trans- tramadol hydrogénchloridu s obsahom 99,7 %, obsah cis- tramadol hydrogénchlorid menej ako 0,3 % /HPLC/.The distillation residue was cooled to 0-5 ° C with stirring over 30 minutes, and the mixture was stirred isothermally for 30 minutes. The crystalline salt is suctioned off under reduced pressure. The crystal is washed with 200 ml of ether and dried at 95 ° C under reduced pressure of 6 kPa. 42.5 g of trans-tramadol hydrochloride are obtained with a content of 99.7%, the content of cis-tramadol hydrochloride of less than 0.3% (HPLC).
Claims (3)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SK435-94A SK278422B6 (en) | 1994-04-15 | 1994-04-15 | The production of tramadol of hydrogenchloride |
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| Application Number | Priority Date | Filing Date | Title |
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| SK435-94A SK278422B6 (en) | 1994-04-15 | 1994-04-15 | The production of tramadol of hydrogenchloride |
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| SK43594A3 SK43594A3 (en) | 1995-11-08 |
| SK278422B6 true SK278422B6 (en) | 1997-05-07 |
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| SK435-94A SK278422B6 (en) | 1994-04-15 | 1994-04-15 | The production of tramadol of hydrogenchloride |
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