ES2690177B2 - PROCEDURE FOR THE PREPARATION OF ENANTIOSELECTIVA DE PROFENOS Y FENIDATOS - Google Patents
PROCEDURE FOR THE PREPARATION OF ENANTIOSELECTIVA DE PROFENOS Y FENIDATOS Download PDFInfo
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- ES2690177B2 ES2690177B2 ES201830342A ES201830342A ES2690177B2 ES 2690177 B2 ES2690177 B2 ES 2690177B2 ES 201830342 A ES201830342 A ES 201830342A ES 201830342 A ES201830342 A ES 201830342A ES 2690177 B2 ES2690177 B2 ES 2690177B2
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- epoxysulfone
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- 238000000034 method Methods 0.000 title claims description 26
- 238000002360 preparation method Methods 0.000 title claims description 6
- 239000003054 catalyst Substances 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 238000003786 synthesis reaction Methods 0.000 claims description 18
- 230000015572 biosynthetic process Effects 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 10
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 7
- 229920002554 vinyl polymer Polymers 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 230000003647 oxidation Effects 0.000 claims description 6
- 238000007254 oxidation reaction Methods 0.000 claims description 6
- -1 -SCH2CH2CH3 Chemical group 0.000 claims description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 150000003457 sulfones Chemical class 0.000 claims description 4
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 3
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical group [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 3
- 229910010084 LiAlH4 Inorganic materials 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- QMQBBUPJKANITL-MYXGOWFTSA-N dextropropoxyphene hydrochloride Chemical compound [H+].[Cl-].C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 QMQBBUPJKANITL-MYXGOWFTSA-N 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- 239000012286 potassium permanganate Substances 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 150000002118 epoxides Chemical class 0.000 claims 3
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 13
- 238000003408 phase transfer catalysis Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 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 description 5
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 0 CC1C(CC2)CC(C(*)c3c(cccc4)c4ncc3)[N+]2(*)C1 Chemical compound CC1C(CC2)CC(C(*)c3c(cccc4)c4ncc3)[N+]2(*)C1 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- DUGOZIWVEXMGBE-CHWSQXEVSA-N dexmethylphenidate Chemical compound C([C@@H]1[C@H](C(=O)OC)C=2C=CC=CC=2)CCCN1 DUGOZIWVEXMGBE-CHWSQXEVSA-N 0.000 description 2
- 229960001042 dexmethylphenidate Drugs 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- 239000003444 phase transfer catalyst Substances 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
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- KEAGRYYGYWZVPC-UHFFFAOYSA-N 1-[4-(2-methylpropyl)phenyl]ethanone Chemical compound CC(C)CC1=CC=C(C(C)=O)C=C1 KEAGRYYGYWZVPC-UHFFFAOYSA-N 0.000 description 1
- RALRVIPTUXSBPO-UHFFFAOYSA-N 4-[4-chloro-3-(trifluoromethyl)phenyl]piperidin-4-ol Chemical compound C=1C=C(Cl)C(C(F)(F)F)=CC=1C1(O)CCNCC1 RALRVIPTUXSBPO-UHFFFAOYSA-N 0.000 description 1
- 125000001318 4-trifluoromethylbenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])*)C(F)(F)F 0.000 description 1
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 238000003476 Darzens condensation reaction Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- DUGOZIWVEXMGBE-UHFFFAOYSA-N Methylphenidate Chemical compound C=1C=CC=CC=1C(C(=O)OC)C1CCCCN1 DUGOZIWVEXMGBE-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- QYTDEUPAUMOIOP-UHFFFAOYSA-N TEMPO Chemical group CC1(C)CCCC(C)(C)N1[O] QYTDEUPAUMOIOP-UHFFFAOYSA-N 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- NXAIQSVCXQZNRY-UHFFFAOYSA-N chloromethylsulfonylbenzene Chemical compound ClCS(=O)(=O)C1=CC=CC=C1 NXAIQSVCXQZNRY-UHFFFAOYSA-N 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229940053650 focalin Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- GCSHUYKULREZSJ-UHFFFAOYSA-N phenyl(pyridin-2-yl)methanone Chemical compound C=1C=CC=NC=1C(=O)C1=CC=CC=C1 GCSHUYKULREZSJ-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
Description
DESCRIPCIÓNDESCRIPTION
PROCEDIMIENTO DE PREPARACIÓN ENANTIOSELECTIVA DE PROFENOS Y FENIDATOSPROCEDURE FOR THE PREPARATION OF ENANTIOSELECTIVA DE PROFENOS Y FENIDATOS
Campo de la invenciónField of the invention
La presente invención se encuadra en general en el sector farmacéutico, y en particular se refiere a un procedimiento para la síntesis de fármacos antiinflamatorios, analgésicos y fármacos indicados para el tratamiento del déficit de atención por hiperactividad (ADHD).The present invention is generally framed in the pharmaceutical sector, and in particular it relates to a process for the synthesis of anti-inflammatory drugs, analgesics and drugs indicated for the treatment of attention deficit hyperactivity disorder (ADHD).
Estado de la técnicaState of the art
Los profenos, como el ibuprofeno, y los fenidatos, son fármacos ampliamente comercializados. Sin embargo aunque solamente una de las formas enantioméricas es activa, algunos de los profenos como el ibuprofeno se comercializan como una mezcla de los dos enantiómeros, en otros casos se comercializa únicamente el enantiómero activo. En aquellos casos en que se comercializa la mezcla es porque el enantiómero que no es activo no es tóxico y porque no existen síntesis enantioselectivas industriales efectivas. Por ejemplo se sabe que el enantiómero d-threo del dexmetil fenidato es más activo que el enantiómero l-treo (Pharmacol. Exp. Ther. 1970, 173, 158-165).Profens, such as ibuprofen, and fenidates, are widely marketed drugs. However, although only one of the enantiomeric forms is active, some of the profanes such as ibuprofen are marketed as a mixture of the two enantiomers, in other cases only the active enantiomer is marketed. In those cases in which the mixture is commercialized, it is because the enantiomer that is not active is not toxic and because there are no effective industrial enantioselective syntheses. For example, it is known that the d-threo enantiomer of dexmethylphenidate is more active than the l-threo enantiomer (Pharmacol, Exp, Ther, 1970, 173, 158-165).
Existen publicadas síntesis enantioselectivas de profenos (Tetrahedron: Asymmetry 1992, 3, 163-192; Tetrahedron Letters 1989, 30, 2825-2828; J. Am. Chem. Soc. 1989, 111, 7650-7651; Synlett 1992, 48-50). Sin embargo estas síntesis tienen la limitación de tratarse de síntesis que emplean reactivos sofisticados lo cual dificulta mucho su implantación a nivel industrial.There are published enantioselective syntheses of profenos (Tetrahedron: Asymmetry 1992, 3, 163-192, Tetrahedron Letters 1989, 30, 2825-2828, J. Am. Chem. Soc. 1989, 111, 7650-7651; Synlett 1992, 48-50 ). However, these syntheses have the limitation of being syntheses that use sophisticated reagents, which makes it very difficult to implement them on an industrial level.
Una forma habitual empleada por la industria para la preparación de fármacos en una forma enantiomérica es prepararlo como racemato y después llevar a cabo una resolución. Por ejemplo el dexmetilfenidato (focalin) se prepara por resolución (Int. J. Res. Pharm. L. Sci. 2014, 4, 1066-1069.). Sin embargo la resolución tiene la limitación de que la mitad del producto se pierde.A common way used by the industry for the preparation of drugs in an enantiomeric form is to prepare it as a racemate and then carry out a resolution. For example, dexmethylphenidate (focalin) is prepared by resolution (Int. J. Res. Pharm. L. Sci. 2014, 4, 1066-1069.). However, the resolution has the limitation that half of the product is lost.
Jin-Mo Ku, et al. Asymmetric synthesis of a,p-epoxysulfones via phase-transfer catalytic Darzens reaction. Tetrahedron 63 (2007) 8099-8103, describe el uso de catalizadores de transferencia de fase, PTC (Phase Transfer Catalysis) para preparar epoxisulfonas de forma enantioselectiva. Sin embargo, mediante el procedimiento descrito en este documetno, sólo se obtienen un tipo particular de epoxisulfonas, con una enantioselectividad y rendimiento químico bajos.Jin-Mo Ku, et al. Asymmetric synthesis of a, p-epoxysulfones via phase-transfer catalytic Darzens reaction. Tetrahedron 63 (2007) 8099-8103, describes the use of phase transfer catalysts, PTC (Phase Transfer Catalysis) to prepare epoxysulfones enantioselectively. However, by the procedure described in this document, only one particular type of epoxysulfones is obtained, with an enantioselectivity and chemical yield low.
Existe pues la necesidad de proporcionar un procedimiento para la preparación de profenos y fenidatos de forma enantioselectiva a nivel industrial, que sea sencillo y que solucione los problemas descritos en el estado de la técnica.There is therefore a need to provide a method for the preparation of prophenes and fenidates in an enantioselective manner at industrial level, which is simple and which solves the problems described in the state of the art.
Breve descripción de la invenciónBRIEF DESCRIPTION OF THE INVENTION
La presente invención soluciona los problemas descritos en el estado de la técnica ya que proporciona un procedimiento sencillo para la síntesis enantioselectiva de profenos y fenidatos, mediante unas reacciones químicas basadas en la apertura reductiva de epoxisulfonas ópticamente activas. El procedimiento consta de una primera reacción de síntesis enantioselectiva de epoxisulfonas empleando catalizadores quiral de tipo PTC (catalizador de transferencia de fase (Phase Transfer Catalysis) y una segunda etapa de transformación de las epoxisulfonas en profenos o fenidatos, según cuál sea la epoxisulfona. Por otro lado, al utilizarse pequeñas cantidades de catalizadores tipo PTC, no se generan residuos tóxicos y se obtiene un producto final sin trazas de contaminantes de metales tóxicos, que puede ser usado en la industria farmacéutica.The present invention solves the problems described in the state of the art since it provides a simple procedure for the enantioselective synthesis of prophenes and fenidates, through chemical reactions based on the reductive opening of optically active epoxysulfones. The process consists of a first enantioselective synthesis reaction of epoxysulfones using PTC-type chiral catalysts (Phase Transfer Catalysis) and a second stage of transformation of the epoxysulfones into prophenes or phenytodates, depending on the epoxysulfone. On the other hand, when using small quantities of PTC type catalysts, no toxic residues are generated and a final product without traces of toxic metal contaminants is obtained, which can be used in the pharmaceutical industry.
Así pues en un primer aspecto, la presente invención se refiere a un procedimiento para la preparación enantioselectiva de profenos y fenidatos (de aquí en adelante, procedimiento de la presente invención) que comprende las siguientes etapas:Thus in a first aspect, the present invention relates to a process for the enantioselective preparation of prophenes and fenidates (hereinafter, process of the present invention) comprising the following steps:
a) Síntesis enantioselectiva de una epoxisulfona de fórmula general (I) y/o formas isoméricas de las mismas, mediante la reacción de una cetona de fórmula general (II) y una sulfona de fórmula general (III), en presencia de un catalizador PTC y una base:a) Enantioselective synthesis of an epoxysulfone of general formula (I) and / or isomeric forms thereof, by the reaction of a ketone of general formula (II) and a sulfone of general formula (III), in the presence of a PTC catalyst and a base:
Donde:Where:
Ar1 es seleccionado de entre fenilo, i-butilfenilo y 2-piridilo;Ar 1 is selected from phenyl, i-butylphenyl and 2-pyridyl;
Ar2 es seleccionado de entre fenilo y fenilo sustituido; Ar 2 is selected from phenyl and substituted phenyl;
R1 es seleccionado entre -H, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -NHCH3, -NHCH2CH3, NHCH2CH2CH3, -SCH3, -SCH2CH3,-SCH2CH2CH3, -Cl, -Br, -I y 2-piridilo; R1 is selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -NHCH3, -NHCH2CH3, NHCH2CH2CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -Cl, -Br, -I and 2-pyridyl;
X es seleccionado entre Cl, Br, e I.X is selected from Cl, Br, and I.
En la presente invención y tal y como lo entendería un experto en la materia, por base se refiere a cualquier sustancia que en disolución acuosa aporta iones hidroxilo al medio.In the present invention and as understood by a person skilled in the art, by base refers to any substance that in aqueous solution contributes hydroxyl ions to the medium.
b) reducción de la epoxisulfona de fórmula general (I) obtenida en la etapa a) para obtener el correspondiente aldehído de fórmula general (IV) o alcohol de fórmula general (V):b) reduction of the epoxysulfone of the general formula (I) obtained in step a) to obtain the corresponding aldehyde of the general formula (IV) or alcohol of the general formula (V):
c) oxidación del compuesto obtenido en la etapa b) para dar lugar al profeno de fórmula general (VI) o fenidato de fórmula general (VII):c) oxidation of the compound obtained in step b) to give the prophene of general formula (VI) or fenidate of general formula (VII):
En la presente invención, por formas isoméricas de la epoxisulfona de fórmula general (I) se refiere a cualquiera forma isomérica de la epoxisulfona, en particular, se refiere a cualquiera de las siguientes fórmulas:In the present invention, isomeric forms of the epoxysulfone of the general formula (I) refers to any isomeric form of the epoxysulfone, in particular, it refers to any of the following formulas:
En una realización particular, el catalizador tipo PTC de la etapa a) del procedimiento de la presente invención, es un catalizador PTC de fórmula general (VIII): In a particular embodiment, the PTC catalyst of step a) of the process of the present invention is a PTC catalyst of general formula (VIII):
Donde:Where:
R5 es seleccionado de entre -H, -CH3, -CH2CH3, - CH2CH2CH3, Bn, etilo, alilo y vinilo;R5 is selected from -H, -CH3, -CH2CH3, - CH2CH3 CH2, Bn, ethyl, allyl and vinyl;
R6 es seleccionado de entre -H, -CH3, -CH2CH3, - CH2CH2CH3, Bn, etilo, alilo y vinilo;R6 is selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, Bn, ethyl, allyl and vinyl;
R7 es seleccionado de entre etilo y vinilo;X es seleccionado entre Cl, Br, e I.R7 is selected from ethyl and vinyl, X is selected from Cl, Br, and I.
Más en particular, el catalizador PTC de la etapa a) del procedimiento de la presente invención es seleccionado de entre un catalizador del tipo N-alquil cinchonino, cinchonidinio, quininio y quinidinio.More particularly, the PTC catalyst of step a) of the process of the present invention is selected from a catalyst of the N-alkyl cinchonino, cinchonidinium, quininium and quinidinium type.
En otra realización particular, el agente reductor de la etapa b) del procedimiento de la presente invención es seleccionado de entre NaBH4, LiAlH4, Dibal-H, Zn(BH4)2, BH3, Bu3SnH, LiBH4 y H2 In another particular embodiment, the reducing agent of step b) of the process of the present invention is selected from NaBH4, LiAlH4, Dibal-H, Zn (BH4) 2, BH3, Bu3SnH, LiBH4 and H2
Más en particular, la etapa b) del procedimiento de la presente invención comprende un catalizador metálico, más en particular el catalizador metálico es seleccionado de entre Pd/C y Pt/C.More particularly, step b) of the process of the present invention comprises a metal catalyst, more in particular the metal catalyst is selected from Pd / C and Pt / C.
En otra realización particular, el agente oxidante de la etapa c) del procedimiento de la presente invención es seleccionado de entre NaClO, H2O2 y KMnO4.In another particular embodiment, the oxidizing agent of step c) of the process of the present invention is selected from NaClO, H2O2 and KMnO4.
En una realización particular, la presente invención se refiere a un procedimiento para la síntesis enantioselectiva de profenos de fórmula general (VI) que comprende las siguientes etapas:In a particular embodiment, the present invention relates to a method for the enantioselective synthesis of prophenes of general formula (VI) comprising the following steps:
Donde: Where:
Ar1 es seleccionado de entre fenilo, i-butilfenilo y 2-piridilo;Ar 1 is selected from phenyl, i-butylphenyl and 2-pyridyl;
Ar2 es seleccionado de entre fenilo y fenilo sustituido;Ar2 is selected from phenyl and substituted phenyl;
R1 es seleccionado entre -H, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -NHCH3, -NHCH2CH3, NHCH2CH2CH3, -SCH3, -SCH2CH3,-SCH2CH2CH3, -Cl, -Br e -I;R1 is selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -NHCH3, -NHCH2CH3, NHCH2CH2CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -Cl, -Br and -I ;
X es seleccionado entre Cl, Br, e I.X is selected from Cl, Br, and I.
En otra realización particular, la presente invención se refiere a un procedimiento para la síntesis enantioselectiva de fenidatos de fórmula general (VII) que comprende las siguientes etapas:In another particular embodiment, the present invention relates to a method for the enantioselective synthesis of fenidates of general formula (VII) comprising the following steps:
Donde:Where:
Ar1 es seleccionado de entre fenilo, i-butilfenilo y 2-piridilo;Ar 1 is selected from phenyl, i-butylphenyl and 2-pyridyl;
Ar2 es seleccionado de entre fenilo y fenilo sustituido.Ar2 is selected from phenyl and substituted phenyl.
R1 es seleccionado entre -H, -CH3 , -CH2CH3 , -CH2CH2CH3 , -OCH3 , -OCH2CH3 , -OCH2CH2CH3 -NHCH3, -NHCH2CH3, NHCH2CH2CH3, -SCH3, -SCH2CH3,-SCH2CH2CH3, -Cl, -Br, -I y 2-piridilo; R 1 is selected from -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 -NHCH 3 , -NHCH 2 CH 3 , NHCH 2 CH 2 CH 3 , -SCH 3, -SCH 2 CH 3, -SCH 2 CH 2 CH 3, -Cl, -Br, -I and 2-pyridyl;
X es seleccionado entre Cl, Br, e I.X is selected from Cl, Br, and I.
R4 es seleccionado de entre -H, -CH3, -CH2CH3, Bn, Alilo y Vinilo. En otro aspecto, la presente invención se refiere a un compuesto de fórmula general (VI) ó (VII) obtenido mediante el procedimiento de la presente invención.R4 is selected from -H, -CH3, -CH2CH3, Bn, Allyl and Vinyl. In another aspect, the present invention relates to a compound of general formula (VI) or (VII) obtained by the process of the present invention.
Descripción detallada de la invención.Detailed description of the invention.
Los siguientes ejemplos ilustran realizaciones específicas de la presente invención, pero de ningún modo con carácter limitativo.The following examples illustrate specific embodiments of the present invention, but not by way of limitation.
Ejemplo 1: síntesis de profenosExample 1: synthesis of professes
La acetofenona y la 4-isobutil acetofenona se transformaron en la correspondientes epoxisulfonas como una mezcla de diastereoisómeros los cuales al mismo tiempo son una mezcla de enantiómeros enriquecidos en uno de los dos posibles enantiómeros. La mezcla de epoxisulfonas se transformó en el alcohol primero el cual después se convirtió en el profeno correspondiente por oxidación, tal y como se muestra en el esquema I:Acetophenone and 4-isobutyl acetophenone were converted into the corresponding epoxysulfones as a mixture of diastereoisomers which at the same time are a mixture of enantiomers enriched in one of the two possible enantiomers. The mixture of epoxysulfones was converted to the alcohol first which was then converted to the corresponding profen by oxidation, as shown in Scheme I:
Para ello, se trató una disolución de clorometil fenil sulfona (2 mmol) en dietil éter (6 mL) a temperatura ambiente, con la correspondiente acetofenona (2.4 mmol), el catalizador de transferencia de fase N-(4-trifluoromethylbenzyl)quininium bromide (0.2 mmol) y finalmente con hidróxido de potasio (7.8 mmol). La mezcla resultante se agitó a temperatura ambiente durante 16 horas. Pasado este tiempo, la mezcla de reacción se filtró a través de celite lavando con acetato de etilo, el filtrado se concentró en el rotavapor y el residuo resultante se purificó mediante cromatografía empleando mezclas de hexano-acetato de etilo.For this, a solution of chloromethyl phenyl sulfone (2 mmol) in diethyl ether (6 mL) was treated at room temperature, with the corresponding acetophenone (2.4 mmol), the N- (4-trifluoromethylbenzyl) quininium bromide phase transfer catalyst. (0.2 mmol) and finally with potassium hydroxide (7.8 mmol). The resulting mixture was stirred at room temperature for 16 hours. After this time, the reaction mixture was filtered through celite washing with ethyl acetate, the filtrate was concentrated in the rotary evaporator and the resulting residue was purified by chromatography using mixtures of hexane-ethyl acetate.
A una suspensión de litio aluminio hidruro (0.63 mmol) en tetrahidrofurano recién destilado (3 mL) bajo atmósfera inerte de nitrógeno y enfriado con un baño de hielo se añadió una disolución de la epoxisulfona obtenida anteriormente (0.21 mmol) en tetrahidrofurano (1 mL). La mezcla resultante se agitó a temperatura ambiente durante 16 horas. Después de este tiempo, se añadió acetato de etilo (1 mL) y se agitó durante 15 minutos. A continuación, se añadió acetato de etilo (6 mL) y una disolución 0.1M de HCl (12 mL) y se vertió en un embudo de extracción. La fase acuosa se extrajo con acetato de etilo (3 x 15 mL), los extractos orgánicos se juntaron, se secaron (MgSO4) y se concentraron en el rotavapor. El residuo aceitoso resultante se purificó mediante cromatografía con hexano/acetato de etilo.To a suspension of lithium aluminum hydride (0.63 mmol) in freshly distilled tetrahydrofuran (3 mL) under an inert atmosphere of nitrogen and cooled with an ice bath was added a solution of the epoxysulfone obtained above (0.21 mmol) in tetrahydrofuran (1 mL). . The resulting mixture was stirred at room temperature for 16 hours. After this time, ethyl acetate (1 mL) was added and stirred for 15 minutes. Then, ethyl acetate (6 mL) and 0.1M HCl solution (12 mL) were added and poured into an extraction funnel. The aqueous phase was extracted with ethyl acetate (3 x 15 mL), the organic extracts were combined, dried (MgSO 4) and concentrated in the rotary evaporator. The resulting oily residue was purified by chromatography with hexane / ethyl acetate.
A una disolución del alcohol (0.4 mmol) en acetonitrilo (3 mL) se añadió una disolución de clorito de sodio (1.6 mmol) en agua (0.8 mL), luego 2,2,6,6-tetrametil-1-piperidiniloxi (0.016 mmol), tampón fosfato (0.67 M, 3 mL) y finalmente una disolución de hipoclorito de sodio (5.25%, 21 mL) diluida con agua (0.4 mL). La reacción se monitoreó mediante cromatografía por capa fina y una vez finalizada se enfrió en un baño de hielo y se añadió agua (6 mL), una disolución saturada de bicarbonato de sodio hasta pH 8 y sulfito de sodio (2.8 mmol). Tras agitar la mezcla durante media hora, se añadió acetato de etilo y se agitó quince minutos más. A continuación, la mezcla de reacción se vertió en un embudo de extracción y la fase orgánica se descartó, entonces la fase acuosa se enfrió en un baño de hielo, se llevó a pH 2 y entonces vertió en un embudo de extracción donde se extrajo con acetato de etilo (2 x 3 mL), los extractos orgánicos se juntaron, se secaron (sulfato de sodio), se filtró y se concentró en el rotavapor para dar lugar al correspondiente profeno o fenidato.To a solution of the alcohol (0.4 mmol) in acetonitrile (3 mL) was added a solution of sodium chlorite (1.6 mmol) in water (0.8 mL), then 2,2,6,6-tetramethyl-1-piperidinyloxy (0.016). mmol), phosphate buffer (0.67 M, 3 mL) and finally a solution of sodium hypochlorite (5.25%, 21 mL) diluted with water (0.4 mL). The reaction was monitored by thin layer chromatography and after completion was cooled in an ice bath and water (6 mL), a saturated solution of sodium bicarbonate to pH 8 and sodium sulfite (2.8 mmol) were added. After stirring the mixture for half an hour, ethyl acetate was added and stirred an additional fifteen minutes. Then, the reaction mixture was poured into an extraction funnel and the organic phase was discarded, then the aqueous phase was cooled in an ice bath, brought to pH 2 and then poured into an extraction funnel where it was extracted with ethyl acetate (2 x 3 mL), the organic extracts were combined, dried (sodium sulfate), filtered and concentrated in the rotary evaporator to give the corresponding profene or fenidate.
Ejemplo 2: Síntesis de fenidatosExample 2: Synthesis of fenidates
La fenil piridinil cetona se transformó en la correspondiente epoxisulfona como una mezcla de diastereoisómeros los cuales al mismo tiempo son una mezcla de enantiómeros enriquecidos en uno de los dos posibles enantiómeros. La mezcla de epoxisulfonas se sometió a hidrogenación a elevada presión para dar lugar al correspondiente piperidín alcohol el cual después se convirtió en el fenidato por oxidación, tal y como se muestra en el esquema II:The phenyl pyridinyl ketone was converted into the corresponding epoxysulfone as a mixture of diastereomers which at the same time are a mixture of enantiomers enriched in one of the two possible enantiomers. The mixture of epoxysulfones was subjected to hydrogenation under high pressure to give rise to the corresponding piperidine alcohol which was then converted to the fenidate by oxidation, as shown in Scheme II:
El paso 1 y 3 siguen el mismo procedimiento que los pasos 1 y 3 indicados arriba para la síntesis de profenos.Step 1 and 3 follow the same procedure as steps 1 and 3 indicated above for the synthesis of profens.
A una suspensión del catalizador Pt/C (20 mg) en ácido acético (2 mL) se añadió una disolución de la epoxisulfona (2 mmol) en ácido acético (6 mL) a temperatura ambiente. La mezcla resultante se agitó a temperatura ambiente durante 18 horas bajo atmósfera de hidrógeno. Pasado este tiempo, la mezcla de reacción se trató con una disolución saturada de bicarbonato de sodio con precaución y a continuación se llevó a pH 9 con una disolución acuosa de sosa 2M. Finalmente se vertió en un embudo de extracción donde se extrajo con acetato de etilo (2 x 3 mL), los extractos orgánicos se lavaron con una disolución acuosa de ácido clorhídrico 1M y luego con salmuera, luego se secaron (sulfato de sodio), se filtró y se concentró en el rotavapor para dar lugar al correspondiente alcohol. To a suspension of the catalyst Pt / C (20 mg) in acetic acid (2 mL) was added a solution of the epoxysulfone (2 mmol) in acetic acid (6 mL) at room temperature. The resulting mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere. After this time, the reaction mixture was treated with a saturated solution of sodium bicarbonate with caution and then brought to pH 9 with an aqueous solution of 2M soda. Finally it was poured into an extraction funnel where it was extracted with ethyl acetate (2 x 3 mL), the organic extracts were washed with an aqueous solution of 1M hydrochloric acid and then with brine, then dried (sodium sulfate), filtered and concentrated on the rotavapor to give rise to the corresponding alcohol.
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