ITMI20100924A1 - NEW METHOD OF SYNTHESIS OF THE TWO TAPENTADOL ENANTIOMERIC FORMS - Google Patents
NEW METHOD OF SYNTHESIS OF THE TWO TAPENTADOL ENANTIOMERIC FORMS Download PDFInfo
- Publication number
- ITMI20100924A1 ITMI20100924A1 IT000924A ITMI20100924A ITMI20100924A1 IT MI20100924 A1 ITMI20100924 A1 IT MI20100924A1 IT 000924 A IT000924 A IT 000924A IT MI20100924 A ITMI20100924 A IT MI20100924A IT MI20100924 A1 ITMI20100924 A1 IT MI20100924A1
- Authority
- IT
- Italy
- Prior art keywords
- dimethylamino
- phenol
- ethyl
- methylpropyl
- methyl
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 21
- KWTWDQCKEHXFFR-SMDDNHRTSA-N tapentadol Chemical compound CN(C)C[C@H](C)[C@@H](CC)C1=CC=CC(O)=C1 KWTWDQCKEHXFFR-SMDDNHRTSA-N 0.000 title claims description 19
- 229960005126 tapentadol Drugs 0.000 title claims description 11
- 230000015572 biosynthetic process Effects 0.000 title description 7
- 238000003786 synthesis reaction Methods 0.000 title description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 19
- 150000001875 compounds Chemical class 0.000 claims description 15
- 230000008569 process Effects 0.000 claims description 15
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- -1 3-hydroxy-3'-dimethylamino-2'-methylpropiophenone Chemical compound 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- SMDGVPQREIZILS-UHFFFAOYSA-N $l^{1}-oxidanylmethylbenzene Chemical compound [O]CC1=CC=CC=C1 SMDGVPQREIZILS-UHFFFAOYSA-N 0.000 claims description 6
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- 150000001298 alcohols Chemical class 0.000 claims description 5
- 150000002576 ketones Chemical class 0.000 claims description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 4
- 230000003213 activating effect Effects 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 238000001640 fractional crystallisation Methods 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 238000011084 recovery Methods 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- NJSYYJGNHXRFAW-SMDDNHRTSA-N 3-[(3R,4R)-5-(dimethylamino)-4-methylpent-1-en-3-yl]phenol Chemical compound C1=C(C=CC=C1O)[C@@H]([C@@H](C)CN(C)C)C=C NJSYYJGNHXRFAW-SMDDNHRTSA-N 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- 150000004794 vinyl magnesium halides Chemical class 0.000 claims description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 2
- 239000012670 alkaline solution Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- RMGJCSHZTFKPNO-UHFFFAOYSA-M magnesium;ethene;bromide Chemical compound [Mg+2].[Br-].[CH-]=C RMGJCSHZTFKPNO-UHFFFAOYSA-M 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 230000009466 transformation Effects 0.000 claims description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 2
- KWTWDQCKEHXFFR-RISCZKNCSA-N 3-[(2s,3s)-1-(dimethylamino)-2-methylpentan-3-yl]phenol Chemical compound CN(C)C[C@@H](C)[C@H](CC)C1=CC=CC(O)=C1 KWTWDQCKEHXFFR-RISCZKNCSA-N 0.000 claims 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims 1
- IJMWREDHKRHWQI-UHFFFAOYSA-M magnesium;ethene;chloride Chemical compound [Mg+2].[Cl-].[CH-]=C IJMWREDHKRHWQI-UHFFFAOYSA-M 0.000 claims 1
- 235000019441 ethanol Nutrition 0.000 description 10
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- PQCFUZMQHVIOSM-UHFFFAOYSA-N 3-hydroxy-1-phenylpropan-1-one Chemical compound OCCC(=O)C1=CC=CC=C1 PQCFUZMQHVIOSM-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 125000002524 organometallic group Chemical group 0.000 description 3
- ZELFLGGRLLOERW-UHFFFAOYSA-N 3-[1-(dimethylamino)-2-methylpentan-3-yl]phenol;hydrochloride Chemical compound Cl.CN(C)CC(C)C(CC)C1=CC=CC(O)=C1 ZELFLGGRLLOERW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 238000006683 Mannich reaction Methods 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- INLLPKCGLOXCIV-UHFFFAOYSA-N bromoethene Chemical compound BrC=C INLLPKCGLOXCIV-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- MNOJRWOWILAHAV-UHFFFAOYSA-N 3-bromophenol Chemical compound OC1=CC=CC(Br)=C1 MNOJRWOWILAHAV-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 101100043727 Caenorhabditis elegans syx-2 gene Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 101100535673 Drosophila melanogaster Syn gene Proteins 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- DSWICQDUYHOEPQ-UHFFFAOYSA-N [Mg]C=C Chemical compound [Mg]C=C DSWICQDUYHOEPQ-UHFFFAOYSA-N 0.000 description 1
- 150000001336 alkenes Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- WURBFLDFSFBTLW-UHFFFAOYSA-N benzil Chemical group C=1C=CC=CC=1C(=O)C(=O)C1=CC=CC=C1 WURBFLDFSFBTLW-UHFFFAOYSA-N 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 238000004061 bleaching Methods 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 229910010277 boron hydride Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 238000006392 deoxygenation reaction Methods 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000010956 selective crystallization Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
- C07C215/54—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Description
Descrizione del brevetto per invenzione industriale avente per titolo: Description of the patent for industrial invention entitled:
“NUOVO METODO DI SINTESI DELLE DUE FORME ENANTIOMERICHE DEL TAPENTADOL” "NEW METHOD OF SYNTHESIS OF THE TWO ENANTIOMERIC FORMS OF TAPENTADOL"
La presente invenzione riguarda un nuovo metodo per la preparazione delle due forme enantiomeriche [(IR, 2R) o (1S,2S)] del Tapentadol a partire da 3-idrossi-3<,>-dimetilammino-2’-metilpropiofenone in forma racema. Un ulteriore oggetto dell’ invenzione è il nuovo intermedio 3-(3-(dimetilammino)-l-idrossi-2-metil-l-vinilpropil)fenolo. The present invention relates to a new method for the preparation of the two enantiomeric forms [(IR, 2R) or (1S, 2S)] of Tapentadol starting from 3-hydroxy-3 <,> - dimethylamino-2'-methylpropiophenone in racemic form . A further object of the invention is the new intermediate 3- (3- (dimethylamino) -1-hydroxy-2-methyl-1-vinylpropyl) phenol.
Stato della tecnica State of the art
Il Tapentadol è un nuovo agente terapeutico con azione antidolorifica recentemente entrato in commercio costituito dal cloridrato delTenantiomero R,R del prodotto 1, chimicamente corrispondente a 3-[(lR,2R)-3-(dimetilammino)-l-etil-2-metilpropil] -fenolo (EP-A-0,693,475 e WO 2004/108658). La caratterizzazione farmacologica del prodotto è descritta da T.M. Tzschentke et al, The J. of Pharmacol. and Exp. Therapeutics, 323(1), 265-276, 2007. Ci sono essenzialmente due vie di accesso al prodotto 1. Il primo utilizza come materiale di partenza Laminino chetone 3, costruito da dietil chetone, formaldeide e dimetil ammina in una reazione di Mannich. Questo materiale è utilizzato come racemo per dare, attraverso l’addizione di un organometallico derivato da una forma protetta del 3-bromo fenolo, lo scheletro del Tapentadol 4. Successivamente, si rimuove l’ossidrile terziario in posizione benzilica 3 attraverso l’azione di un idruro di boro su un derivato attivato e si idrolizza infine l’etere metilico con HBr per dare (+/-) Tapentadol. L’addizione sul gruppo carbonilico dell’ammino chetone 3 dell’ organometallico derivato dal 3 -bromo fenolo protetto all’ossidrile dà il diastereoisomero ariti, ma nel passaggio successivo di rimozione della funzione ossigenata si ha inversione di configurazione, così da ottenere il diastereoisomero desiderato syn. La separazione dei due enantiomeri viene praticata per via fisica attraverso HPLC preparativa su colonna chirale. Il procedimento è poco pratico a causa di questa ultima operazione il cui sviluppo su larga scala è molto costoso. Tapentadol is a new therapeutic agent with pain relieving action recently entered on the market consisting of the hydrochloride of the R, R tenant of product 1, chemically corresponding to 3 - [(1R, 2R) -3- (dimethylamino) -l-ethyl-2-methylpropyl ] -phenol (EP-A-0,693,475 and WO 2004/108658). The pharmacological characterization of the product is described by T.M. Tzschentke et al, The J. of Pharmacol. and Exp. Therapeutics, 323 (1), 265-276, 2007. There are essentially two routes of access to the product 1. The first uses Laminino Ketone 3 as the starting material, built from diethyl ketone, formaldehyde and dimethyl amine in a reaction by Mannich. This material is used as a raceme to give, through the addition of an organometallic derived from a protected form of 3-bromine phenol, the skeleton of Tapentadol 4. Subsequently, the tertiary hydroxyl in the benzyl position 3 is removed through the action of a boron hydride on an activated derivative and methyl ether is finally hydrolyzed with HBr to give (+/-) Tapentadol. The addition on the carbonyl group of the amino ketone 3 of the organometallic derived from the 3 -bromo phenol protected to the hydroxyl gives the diastereomer ariti, but in the next step of removing the oxygenated function there is an inversion of configuration, so as to obtain the desired diastereomer syn. The separation of the two enantiomers is practiced physically through preparative HPLC on a chiral column. The process is impractical due to this last operation, which is very expensive to develop on a large scale.
1 R = H 3 4 R = CH3o CH2C6H52 R = CH3o CH2C6H55 R = H 1 R = H 3 4 R = CH3o CH2C6H52 R = CH3o CH2C6H55 R = H
Pertanto, sono apparsi nuovi brevetti di sintesi di 1 che utilizzano forme otticamente attive deirammino chetone 6 in cui l’ossigeno sull’anello aromatico è protetto generalmente come etere metilico o benzilico (WO 2008/012046 e WO 2008/012047). Questi materiali in forma racema sono sintetizzati con una reazione di Mannich a partire da forme protette del 3-idrossi-propiofenone, dimetil ammina e formaldeide. Successivamente si procede alla separazione degli enantiomeri attraverso cristallizzazione frazionata dei sali con l’acido L-(+)-dibenzoil tartarico. L’ammino chetone 6 otticamente attivo viene recuperato dal sale attraverso spostamento con una base. Le condizioni di questa operazione sono molto controllate per il pericolo che l’ammino chetone che porta uno stereocentro in posizione a racemizzi. Successivamente, in entrambi i brevetti si costruisce lo scheletro del Tapentadol attraverso l’addizione di un organometallico C-2, tipicamente bromuro di etil magnesio. In questo modo si arriva allo stesso intermedio 4 con stereochimica relativa ariti rivendicato nel brevetto originale. A questo punto si differenziano le vie attraverso le quali viene rimosso l’ossidrile benzilico terziario con procedimenti che portino ad un prodotto con stereochimica syn. Pertanto, nel metodo descritto in WO 2008/012047 si procede alla disidratazione di 4 in condizioni acide controllate che generano prevalentemente una miscela di alcheni ZJE in posizione γ rispetto al gruppo dimetil amminico. L’idrogenazione di questa miscela di prodotti insaturi viene in parte controllata dal centro stereogenico in a al gruppo dimetil amminico, ottenendo una miscela di prodotti in cui prevale il diastereoisomero syn 2. Nello stadio finale, nel caso in cui il gruppo protettore dell’ossigeno sia il metile, si procede alla demetilazione per ebollizione con HBr concentrato. Infine, con vari trattamenti acido/base si ottiene il cloridrato desiderato 1 in forma otticamente attiva. In questo procedimento si ha, tuttavia, un non completo controllo della stereochimica nell’idrogenazione, tale da rendere necessaria la cristallizzazione del cloridrato di 2 per separare nelle acque madri il diastereoisomero indesiderato anti. Therefore, new 1 synthesis patents have appeared that use optically active forms of amino ketone 6 in which the oxygen on the aromatic ring is generally protected as methyl or benzyl ether (WO 2008/012046 and WO 2008/012047). These racemic materials are synthesized with a Mannich reaction starting from protected forms of 3-hydroxy-propiophenone, dimethyl amine and formaldehyde. Subsequently, the enantiomers are separated through fractional crystallization of the salts with L - (+) - dibenzoyl tartaric acid. The optically active amino ketone 6 is recovered from the salt through displacement with a base. The conditions of this operation are very controlled due to the danger that the amino ketone that brings a stereocenter into a racemizing position. Subsequently, in both patents the Tapentadol skeleton is built through the addition of a C-2 organometallic, typically ethyl magnesium bromide. In this way we arrive at the same intermediate 4 with relative stereochemistry arites claimed in the original patent. At this point, the pathways through which the tertiary benzyl hydroxyl is removed with procedures that lead to a product with syn stereochemistry are differentiated. Therefore, in the method described in WO 2008/012047 dehydration of 4 is carried out under controlled acid conditions which mainly generate a mixture of ZJE alkenes in position γ with respect to the dimethyl amine group. The hydrogenation of this mixture of unsaturated products is partly controlled by the stereogenic center in a to the dimethyl amino group, obtaining a mixture of products in which the syn 2 diastereomer prevails. In the final stage, in the event that the oxygen protecting group both methyl, demethylation is carried out by boiling with concentrated HBr. Finally, with various acid / base treatments, the desired hydrochloride 1 is obtained in optically active form. In this process, however, there is an incomplete control of the stereochemistry in hydrogenation, such as to make it necessary to crystallize the 2 hydrochloride to separate the unwanted anti diastereomer in the mother liquors.
6 R = CH3o CH2C6H5 6 R = CH3o CH2C6H5
7 R = H 7 R = H
In WO 2008/012046 si preferisce come prodotto di partenza l’ammino chetone 6 otticamente attivo in cui R = benzile. Per addizione di bromuro di etil magnesio si ha quindi 4 che è trasformato in 1 attraverso due operazione eseguite in sequenza. Nella prima si attiva l’ossigeno benzilico attraverso la formazione di un estere fra cui quello con l’acido trifluoroacetico e quindi si idrogena in presenza di catalizzatori metallici. In questo trattamento si ha sia la rimozione dell’ossigeno benzilico con inversione di configurazione, sia la liberazione del fenolo a dare appunto 1. In WO 2008/012046 the optically active amino ketone 6 in which R = benzyl is preferred as the starting product. By adding ethyl magnesium bromide there is therefore 4 which is transformed into 1 through two operations carried out in sequence. In the first, benzyl oxygen is activated through the formation of an ester including that with trifluoroacetic acid and then hydrogenates in the presence of metal catalysts. In this treatment there is both the removal of benzyl oxygen with inversion of configuration, and the release of phenol to give precisely 1.
I processi descritti in questi due brevetti rappresentano vie di accesso a 1 enantiomericamente puro più praticabili di quella originaria basata sulla separazione HPLC. Tuttavia non sono prive di inconvenienti. Il primo, comune alle due procedure, è costituito dalla attitudine a racemizzare dei prodotti 6 durante il trattamento basico necessario per il loro recupero dai sali con l’acido otticamente puro usato come agente risolvente. Siccome nei passaggi successivi non c’è l’occasione di ottenere derivati cristallini che siano purificabili per cristallizzazione selettiva da solventi opportuni si ottengono campioni di Tapentadol 1 dotati di purezza enantiomerica non adeguata. Il secondo inconveniente riguarda la sintesi di 1 da 6 otticamente attivo avente come gruppo protettore l’etere metilico. Infatti, l’idrolisi di questo gruppo protettore alla fine della sequenza porta ad un prodotto 1 leggermente colorato di rosa dovute a tracce di bromo presente nell’acido bromidrico commerciale impiegato per l’idrolisi, le quali bromurano l’anello fenolico. La decolorazione eseguita, ad esempio, con carbone è poco efficiente e genera, comunque, perdita di prodotto. The processes described in these two patents represent more practicable access routes to enantiomerically pure 1 than the original one based on HPLC separation. However, they are not without drawbacks. The first, common to the two procedures, consists of the ability to racemize the products 6 during the basic treatment necessary for their recovery from the salts with the optically pure acid used as a resolving agent. Since in the following steps there is no opportunity to obtain crystalline derivatives that can be purified by selective crystallization from suitable solvents, samples of Tapentadol 1 are obtained with inadequate enantiomeric purity. The second drawback concerns the synthesis of optically active 1 from 6 having methyl ether as a protecting group. In fact, the hydrolysis of this protecting group at the end of the sequence leads to a slightly pink colored product 1 due to traces of bromine present in the commercial hydrobromic acid used for hydrolysis, which bromide the phenolic ring. The bleaching performed, for example, with carbon is not very efficient and generates, however, product loss.
Descrizione dell’invenzione Description of the invention
Si è ora sorprendentemente trovato, e costituisce un oggetto della presente invenzione, che se al posto dell’ amino chetone risolto 6 si usa come prodotto di partenza l’analogo non protetto 3-idrossi-3’-dimetilammino-2’-metilpropiofenone 7 in forma racema si può realizzare una sintesi della forma enantiomerica desiderata del Tapentadol 1 priva degli inconvenienti dei processi finora rivendicati. It has now surprisingly been found, and constitutes an object of the present invention, that if instead of the resolved amino ketone 6 the unprotected analog 3-hydroxy-3'-dimethylamino-2'-methylpropiophenone 7 is used as starting product in racemic form it is possible to carry out a synthesis of the desired enantiomeric form of Tapentadol 1 without the drawbacks of the processes claimed up to now.
Due sono gli elementi migliorativi del processo. Il primo è costituito dalla sostituzione del bromuro di etil magnesio con il bromuro di vinil magnesio quale fonte dell’unità C-2 che addizionata a 7 permette di costruire lo scheletro di carbonio di 1. Questa operazione porta al prodotto 3-(3-(dimetilammino)-l-idrossi-2-metil-l-vinilpropil)fenolo 8 in forma racema. There are two elements to improve the process. The first consists of the replacement of ethyl magnesium bromide with vinyl magnesium bromide as the source of the C-2 unit which, added to 7, allows to build the carbon skeleton of 1. This operation leads to the product 3- (3- ( dimethylamino) -1-hydroxy-2-methyl-1-vinylpropyl) phenol 8 in racemic form.
Ci sono due vantaggi nell’uso di 8 come intermedio. Il primo è costituito dal fatto che 8 dà sali con gli acidi D-(-) e L-(+)-dibenzoil tartarici. Detti sali sono ottenibili in forma diastereoisomericamente pura, con marcata differenza di solubilità fra i due diastereoisomeri, mediante cristallizzazione caldo-freddo da solventi tipo alcooli inferiori (per esempio, metilico, etilico, isopropilico) e esteri (acetato di etile) o miscele di questo sia con gli alcooli che con chetoni tipo acetone o omologhi superiori quale, ad esempio, 2-butanone. Da questi sali il prodotto 8 nelle due forme enantiomeriche, a seconda dell’acido risolvente usato, si separa senza pericoli di racemizzazione mediante trattamento con basi acquose e non più con dietil ammina in etere come prescritto per il recupero di 6 dai suoi sali (come indicato nei due brevetti sopra discussi). Per di più, la cristallizzazione dei sali da alcool etilico fornisce un materiale altamente cristallino, con piccoli cristalli facilmente filtrabili, a differenza dei sali di 6 che cristallizzano da acetone in forma molto voluminosa difficilmente filtrabile. There are two advantages of using 8 as an intermediate. The first is constituted by the fact that 8 gives salts with the D - (-) and L - (+) - dibenzoyl tartaric acids. Said salts can be obtained in pure diastereoisomer form, with marked difference in solubility between the two diastereoisomers, by means of hot-cold crystallization from solvents such as lower alcohols (for example, methyl, ethyl, isopropyl) and esters (ethyl acetate) or mixtures thereof. both with alcohols and with ketones such as acetone or higher homologs such as, for example, 2-butanone. From these salts the product 8 in the two enantiomeric forms, depending on the resolving acid used, separates without risk of racemization by treatment with aqueous bases and no longer with diethyl amine in ether as prescribed for the recovery of 6 from its salts (such as indicated in the two patents discussed above). Furthermore, the crystallization of salts from ethyl alcohol provides a highly crystalline material, with small easily filterable crystals, unlike 6 salts which crystallize from acetone in a very voluminous form that is difficult to filter.
Questo primo elemento migliorativo sopra descritto riguarda l’aspetto fisico del nuovo processo. C’è tuttavia nell’uso di 8 come intermedio chiave un secondo vantaggio in termini di reattività chimica. Infatti, quando, in un’unica operazione, si sottopone 8 a deossigenazione in posizione benzilica e a saturazione del doppio legame, a dare direttamente 1 attraverso il trattamento di un estere attivante con idrogeno e catalizzatori, si sperimenta che la prima operazione è particolarmente veloce, come atteso per la rimozione di un ossigeno benzilico che si trova anche in posizione allilica, cioè adiacente al frammento vinilico di 8. This first improvement element described above concerns the physical aspect of the new process. However, there is a second advantage in terms of chemical reactivity in the use of 8 as a key intermediate. In fact, when, in a single operation, 8 is subjected to deoxygenation in the benzyl position and to saturation of the double bond, to give 1 directly through the treatment of an activating ester with hydrogen and catalysts, it is experienced that the first operation is particularly fast, as expected for the removal of a benzyl oxygen which is also in the allyl position, i.e. adjacent to the vinyl fragment of 8.
Pertanto, la nuova via di sintesi delle forme enantio- e diastereoisomericamente pure di 1 oggetto della presente invenzione è basata sull’impiego dell’ammino chetone fenolico 7, ottenibile in forma racema, per esempio, per reazione di Mannich da 3-idrossi propiofenone, dimetilammina e formaldeide, e comprende i seguenti passaggi: Therefore, the new synthesis route of the enantio- and diastereoisomerically pure forms of the object of the present invention is based on the use of the phenolic amino ketone 7, obtainable in racemic form, for example, by Mannich reaction from 3-hydroxy propiophenone, dimethylamine and formaldehyde, and includes the following steps:
a) addizione di un alogenuro (preferibilmente bromuro o cloruro) di vinil magnesio al prodotto racemo 7 a dare il composto 8 che contiene tutti gli atomi di carbonio del Tapentadol 1. L’addizione dell’ alogenuro di vinil magnesio a 7 procede a dare un unico diastereoisomero del composto 8. La reazione viene condotta in solvente etereo, preferibilmente tetraidrofurano; b) separazione dei due enantiomeri dell’ addotto 8 attraverso cristallizzazione frazionata, ad esempio da etanolo, o altri solventi utili allo scopo, dei sali con gli acidi L-(+) o D-(-)-dibenzoil tartarici; a) addition of a halide (preferably bromide or chloride) of vinyl magnesium to the racemic product 7 to give compound 8 which contains all the carbon atoms of Tapentadol 1. The addition of vinyl magnesium halide to 7 proceeds to give a single diastereomer of compound 8. The reaction is carried out in ethereal solvent, preferably tetrahydrofuran; b) separation of the two enantiomers of adduct 8 through fractional crystallization, for example from ethanol, or other solvents useful for the purpose, of the salts with L - (+) or D - (-) - dibenzoyl tartaric acids;
c) trattamento con basi acquose del sale di 8 ottenuto in b) e recupero della base enantiomericamente pura 8 mediante estrazione con solvente immiscibile con acqua dalla soluzione acquosa alcalina del sale; c) treatment with aqueous bases of the salt of 8 obtained in b) and recovery of the enantiomerically pure base 8 by extraction with a water-immiscible solvent from the aqueous alkaline solution of the salt;
d) trasformazione della base enantiomericamente pura 8 ottenuta in c) in un estere attivante l’ossigeno benzilico, per trattamento, ad esempio, con anidride trifluoroacetica; d) transformation of the enantiomerically pure base 8 obtained in c) into an ester activating benzyl oxygen, by treatment, for example, with trifluoroacetic anhydride;
e) conversione dell’estere attivato di 8 ottenuto in d) nella forma enantiomericamente pura del Tapentadol 1 per trattamento con idrogeno e catalizzatori, ad esempio Pd/C, in solvente inerte. e) conversion of the activated ester of 8 obtained in d) into the enantiomerically pure form of Tapentadol 1 by treatment with hydrogen and catalysts, for example Pd / C, in an inert solvent.
Il composto 8 è nuovo è costituisce anch’esso un oggetto della presente invenzione. Compound 8 is new and also constitutes an object of the present invention.
Costituiscono ulteriori aspetti dell’invenzione i sali diastereoisomerici del composto 8 con l’acido L-(+)-dibenzoil tartarico o D-(-)-dibenzoil tartarico e un composto di formula 8 scelto tra 3-[(lR,2R)-3-(dimetilammino)-2-metil-l-vinilpropil]fenolo e 3-[(lS,2S)-3-(dimetilammino)-2-metil-lvinilpropil]fenolo. Further aspects of the invention are the diastereoisomeric salts of compound 8 with L - (+) - dibenzoyl tartaric acid or D - (-) - dibenzoyl tartaric acid and a compound of formula 8 selected from 3 - [(1R, 2R) - 3- (dimethylamino) -2-methyl-1-vinylpropyl] phenol and 3 - [(1S, 2S) -3- (dimethylamino) -2-methyl-vinylpropyl] phenol.
Un ulteriore aspetto dell’ invenzione è rappresentato dall’uso del composto 7, dei sali diastereoisomerici del composto 8 con l’acido L-(+)-dibenzoil tartarico o D-(-)-dibenzoil tartarico e di un composto di formula 8 scelto tra 3-[(lR,2R)-3-(dimetilammino)-2-metil- 1 -vinilpropil]fenolo e 3 -[( 1 S,2S)-3-(dimetilammino)-2-metil-l-vinilpropil] fenolo per la preparazione delle forme enantiomericamente e diastereoisomericamente pure del composto di formula 1. A further aspect of the invention is represented by the use of compound 7, of the diastereoisomeric salts of compound 8 with L - (+) - dibenzoyl tartaric acid or D - (-) - dibenzoyl tartaric acid and of a compound of formula 8 selected between 3 - [(1R, 2R) -3- (dimethylamino) -2-methyl- 1-vinylpropyl] phenol and 3 - [(1 S, 2S) -3- (dimethylamino) -2-methyl-1-vinylpropyl] phenol for the preparation of the enantiomerically and diastereomerically pure forms of the compound of formula 1.
L’invenzione viene ora ulteriormente illustrata tramite i seguenti esempi. The invention is now further illustrated through the following examples.
Esempio 1 Example 1
Una miscela costituita da 3-idrossipropiofenone, dimetil ammina cloridrato, para formaldeide in rapporto ponderale 15/8/4 è fatta bollire in etanolo per 24 h in presenza di quantità catalitiche di HC1 concentrato. A fine reazione si concentra a piccolo volume, si diluisce con acqua e dalla soluzione acida si estrae con solvente il 3-idrossipropiofenone non reagito. Successivamente si basifica con bicarbonato a freddo e si estrae con solvente Laminino chetone 7 ottenuto come olio chiaro con resa dell’ 80%. A mixture consisting of 3-hydroxypropiophenone, dimethyl amine hydrochloride, para formaldehyde in weight ratio 15/8/4 is boiled in ethanol for 24 h in the presence of catalytic quantities of concentrated HCl. At the end of the reaction it is concentrated to a small volume, diluted with water and the unreacted 3-hydroxypropiophenone is extracted from the acid solution with a solvent. It is then basified with cold bicarbonate and extracted with a solvent Laminino ketone 7 obtained as a light oil with a yield of 80%.
Esempio 2 Example 2
Si prepara il reagente di Grignard in THF del bromuro di vinile addizionando al magnesio in trucioli usato in eccesso la soluzione al 15% di bromuro di vinile in THF. A questa soluzione si addiziona l’ammino chetone 7, in ragione di 1 mole di ammino chetone per 3 moli di reagente di Grignard. Dopo 3 h a ricadere si raffredda e si spegne la reazione con soluzione fredda di cloruro d’ammonio. Si addiziona acetato di etile e si separano le fasi. Si estrae per tre volte con acetato di etile. La fase organica lavata e seccata è evaporata a dare un olio giallino costituito da 8 con resa del 90%. The Grignard reagent in THF of vinyl bromide is prepared by adding the 15% solution of vinyl bromide in THF to the excess magnesium in chips. The amino ketone 7 is added to this solution, at the rate of 1 mole of amino ketone per 3 moles of Grignard's reagent. After 3 h under reflux, the reaction is cooled and the reaction with a cold ammonium chloride solution is quenched. Ethyl acetate is added and the phases are separated. It is extracted three times with ethyl acetate. The washed and dried organic phase is evaporated to give a yellowish oil consisting of 8 with a yield of 90%.
Esempio 3 Example 3
Il prodotto 8 è sciolto in 3-4 volumi di etanolo a caldo e trattato su bagnomaria con una soluzione concentrata in etanolo dell’acido risolvente dibenzoil tartarico in rapporto molare 1: 1. Si fa bollire la soluzione per 30 min e quindi si lascia a sé per una notte a temperatura ambiente. Si raccolgono i cristalli per filtrazione e si ricristallizzano da etanolo bollente. Due cristallizzazioni sono di solito sufficienti per ottenere un prodotto enantiomericamente puro. Product 8 is dissolved in 3-4 volumes of hot ethanol and treated on a water bath with a solution concentrated in ethanol of the resolving acid dibenzoyl tartaric in a 1: 1 molar ratio. The solution is boiled for 30 min and then left to stand itself overnight at room temperature. The crystals are collected by filtration and recrystallized from boiling ethanol. Two crystallizations are usually sufficient to obtain an enantiomerically pure product.
Esempio 4 Example 4
Il sale di 8 con l’acido dibenzoil tartarico ottenuto nell’esempio 3 è trattato con 4-5 voi di acqua e sotto agitazione in sistema bifasico con acetato di etile o cloruro di metilene si tratta con una soluzione satura di bicarbonato di sodio a basicità. Si separano le fasi e si estrae ancora la fase acquosa. Per evaporazione della fase organica seccata si ottiene un olio che lasciato a sé solidifica. Questo materiale è sciolto in 3-4 voi di THF ed è addizionato a freddo di 3 volte in peso di anidride trifluoroacetica. Si porta a temperatura ambiente e quindi si riscalda a leggero riflusso per 3 h. Si raffredda, si aggiungono 10 voi di acetato di etile e si evapora sotto vuoto a piccolo volume. Si aggiunge ancora acetato di etile e si idrogena a 3-4 atm a temperatura ambiente in presenza di Pd/C 10%. Dopo una notte si filtra e si tira a secco. L’olio così ottenuto è sciolto in poco etanolo e la soluzione è addizionata a NaOH 10% in acqua. Si scalda per 2 h a 40-50°C e quindi si acidifica cautamente a freddo. La soluzione acida è portata a pH basico per aggiunta di una soluzione satura di bicarbonato di sodio. Si estrae 5 volte con acetato di etile, controllando l’effettiva efficacia dell’estrazione. La fase organica è seccata ed evaporata a dare un olio che solidifica spontaneamente, costituito da 3-[3-(dimetilammino)-l-etil-2-metilpropil]fenolo (base libera) in forma enantiomericamente pura. Questo materiale è trattato con eccesso di HC1 gassoso in etanolo e, dopo 10 min si evapora a secchezza. Il residuo ben seccato sotto vuoto è costituito da un solido biancastro che si cristallizza da isopropanolo a dare il 3-[3-(dimetilammino)-l-etil-2-metilpropil]fenolo sotto forma di cloridrato, in forma enantiomericamente pura. Utilizzando nell’esempio 3 come agente risolvente l’acido D-(-)-dibenzoil tartarico si ottiene 3-[3-(dimetilammino)-l-etil-2-metilpropil]fenolo cloridrato con [α]°20+20,6 ° (c 1, MEOH), mentre dall’acido L-(+)-dibenzoil tartarico si ottiene 3-[3-(dimetilammino)-l-etil-2-metilpropil]fenolo cloridrato con [α]°20- 23 (c 1, MeOH). The salt of 8 with the dibenzoyl tartaric acid obtained in example 3 is treated with 4-5 volume of water and under stirring in a biphasic system with ethyl acetate or methylene chloride and treated with a saturated solution of basic sodium bicarbonate . The phases are separated and the aqueous phase is extracted again. By evaporation of the dried organic phase, an oil is obtained which, left to itself, solidifies. This material is dissolved in 3-4 volts of THF and is cold added with 3 times by weight of trifluoroacetic anhydride. The mixture is brought to room temperature and then heated at slight reflux for 3 h. It is cooled, 10 volts of ethyl acetate are added and evaporated under vacuum to a small volume. Ethyl acetate is added again and hydrogenated at 3-4 atm at room temperature in the presence of 10% Pd / C. After one night it is filtered and dried. The oil thus obtained is dissolved in a little ethanol and the solution is added to 10% NaOH in water. It is heated for 2 hours at 40-50 ° C and then acidified carefully when cold. The acid solution is brought to basic pH by adding a saturated solution of sodium bicarbonate. It is extracted 5 times with ethyl acetate, checking the effective effectiveness of the extraction. The organic phase is dried and evaporated to give an oil which solidifies spontaneously, consisting of 3- [3- (dimethylamino) -1-ethyl-2-methylpropyl] phenol (free base) in an enantiomerically pure form. This material is treated with an excess of gaseous HCl in ethanol and after 10 min it evaporates to dryness. The well dried residue under vacuum consists of a whitish solid which crystallizes from isopropanol to give 3- [3- (dimethylamino) -1-ethyl-2-methylpropyl] phenol in the form of hydrochloride, in an enantiomerically pure form. Using in Example 3 the D - (-) - dibenzoyl tartaric acid as resolving agent we obtain 3- [3- (dimethylamino) -1-ethyl-2-methylpropyl] phenol hydrochloride with [α] ° 20 + 20.6 ° (c 1, MEOH), while from L - (+) - dibenzoyl tartaric acid we obtain 3- [3- (dimethylamino) -1-ethyl-2-methylpropyl] phenol hydrochloride with [α] ° 20- 23 ( c 1, MeOH).
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6248737B1 (en) * | 1994-07-23 | 2001-06-19 | Gruenenthal Gmbh | 1-phenyl-3-dimethylaminopropane compounds with a pharmacological effects |
US20060194988A1 (en) * | 2003-06-06 | 2006-08-31 | Gruenenthal Gmbh | Process for the preparation of substitued 3-aryl-butylamine compounds |
WO2008012047A1 (en) * | 2006-07-24 | 2008-01-31 | Grünenthal GmbH | Process for the preparation of (1r,2r)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol |
US20080269524A1 (en) * | 2005-05-27 | 2008-10-30 | Gruenenthal Gmbh | Separation of Stereoisomeric N,N-Dialkylamino-2Alkyl-3-Hydroxy-3-Phenylalkanes |
US20090326271A1 (en) * | 2006-07-24 | 2009-12-31 | Gruenenthal Gmbh | Preparation of 3-[(1R,2R)-3-(Dimethylamino)-1Ethyl-2-Methylpropyl]phenol |
-
2010
- 2010-05-21 IT IT000924A patent/ITMI20100924A1/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6248737B1 (en) * | 1994-07-23 | 2001-06-19 | Gruenenthal Gmbh | 1-phenyl-3-dimethylaminopropane compounds with a pharmacological effects |
US20060194988A1 (en) * | 2003-06-06 | 2006-08-31 | Gruenenthal Gmbh | Process for the preparation of substitued 3-aryl-butylamine compounds |
US20080269524A1 (en) * | 2005-05-27 | 2008-10-30 | Gruenenthal Gmbh | Separation of Stereoisomeric N,N-Dialkylamino-2Alkyl-3-Hydroxy-3-Phenylalkanes |
WO2008012047A1 (en) * | 2006-07-24 | 2008-01-31 | Grünenthal GmbH | Process for the preparation of (1r,2r)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol |
US20090326271A1 (en) * | 2006-07-24 | 2009-12-31 | Gruenenthal Gmbh | Preparation of 3-[(1R,2R)-3-(Dimethylamino)-1Ethyl-2-Methylpropyl]phenol |
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