WO2006013399A1 - Intermediaires pharmaceutiques et procede de preparation de ceux-ci - Google Patents

Intermediaires pharmaceutiques et procede de preparation de ceux-ci Download PDF

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WO2006013399A1
WO2006013399A1 PCT/HU2005/000067 HU2005000067W WO2006013399A1 WO 2006013399 A1 WO2006013399 A1 WO 2006013399A1 HU 2005000067 W HU2005000067 W HU 2005000067W WO 2006013399 A1 WO2006013399 A1 WO 2006013399A1
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ethyl
phenyl
methyl
hydrogen
chloro
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PCT/HU2005/000067
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English (en)
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József Barkóczy
István LING
József BÁLINT
Gabriella Egri
Violetta Kiss
Elemér Fogassy
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EGIS Gyógyszergyár Rt.
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Priority claimed from HU0401267A external-priority patent/HU0401267D0/hu
Priority claimed from HU0500622A external-priority patent/HUP0500622A3/hu
Application filed by EGIS Gyógyszergyár Rt. filed Critical EGIS Gyógyszergyár Rt.
Publication of WO2006013399A1 publication Critical patent/WO2006013399A1/fr

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    • 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
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C07C215/38—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/31—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by at least three rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/40—Halogenated unsaturated alcohols
    • C07C33/46—Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/62—Halogen-containing esters
    • C07C69/63—Halogen-containing esters of saturated acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/80—Phthalic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/54—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
    • C12P41/004—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of alcohol- or thiol groups in the enantiomers or the inverse reaction
    • 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

Definitions

  • the present invention relates to new pharmaceutical intermediates and a process for the preparation thereof.
  • Optically active aryl-isopropanols are important pharmaceutical intermediates. According to DE 2832604 steroid compounds are prepared in a stereoselective synthesis by using the corresponding enantiomeric aryl-isopropanol derivatives. In /. Am. Chem. Soc. (1995), 777, 12358-12359 the synthesis of talampanel is described; the key intermediate is also an enantiomeric aryl-isopropanol derivative. According to Bull. Soc. Chim. 130, 450-458 (1993) for the formation of the amino group of suitable stereo chemistry of (S)- phenfluramine as starting material an optically active aryl- isopropanol derivative is used.
  • Racemic aryl-isopropanols of the general Formula I of the present invention are known compounds.
  • the new racemic aryl-isopropanols of the general Formula I of the present invention are known compounds.
  • the new racemic aryl-isopropanols of the general Formula I of the present invention are known compounds.
  • the new racemic aryl-isopropanols of the general Formula I of the present invention are known compounds.
  • the new racemic aryl-isopropanols of the general Formula II of the present invention are known compounds.
  • the new racemic aryl-isopropanols of the general Formula I of the present invention are known compounds.
  • the new racemic aryl-isopropanols of the general Formula I of the present invention are known compounds.
  • the new racemic aryl-isopropanols of the general Formula II of the present invention are known compounds.
  • optically active aryl-isopropanols can be prepared by chemical or biochemical or enzyme catalyzed reactions.
  • optically active alcohol is prepared by reacting the lithium salt obtained by the reaction of optically active propylene oxide and 3-trifluoromethyl-bromo-benzene by using butyl-lithium at -78 0 C.
  • this process is not quite suitable for industrial scale manufacture because of the reactant and the extreme reaction conditions are used.
  • racemic alcohols are separated by means of enzyme catalyzed reaction of racemic O-acylated l-phenyl-2-propanol derivatives. Said enzymatic hydrolysis is carried out for a weak in a very diluted solution and the mixture of ester-alcohols obtained is separated by preparative thin-layer chromatography. The optically active l-phenyl-2-propanol obtained is converted into the corresponding optically active semiester without isolation.
  • racemic l-benzo[l,3]dioxol-5-yl-propane-2- ol into the enantiomers is described in Tetrahedron Asymmetry 14 333-337 (2003).
  • the essence of said process is that racemic aryl-isopropanol is acylated in the presence of a suitable lipase enzyme.
  • a (+)-rotating alcohol and a (-)-rotating acylated product are obtained.
  • acylating agent vinyl acetate is used in a hexane solution.
  • the acylated product and the alcohol used can be separated only by means of chromatography.
  • optically active acylated aryl- isopropanol derivative obtained in the reaction and the optically active aryl-isopropanol being still present in the reaction mixture have very similar solubility properties. Additionally, compounds of this type are generally oily substances having low melting point. This obvious separation method is, however, unsuitable for industrial scale manufacture.
  • the object of the present invention is the development of new enantiomeric aryl-isopropanol derivatives which enable the enantioselective synthesis of numerous new pharmaceutical active ingredients. It is a further object of the present invention to elaborate a process which eliminate the drawbacks of the methods described in prior art, can be performed in a reaction mixture of reasonable concentration, requires a relatively short reaction time, can be performed on industrial scale and provides an easy separation of the antipode forms of the process.
  • R 3 is hydrogen
  • R 1 and R 2 independently from each other stand for hydrogen, Ci -4 -alkyl, C 1-4 -alkoxy, aryloxy, aralkoxy, trifluoromethyl, cyano or halogen; or R and R together form methylenedioxy; with the proviso that at least one of symbols R 1 and R 2 is other than hydrogen; with the proviso that if R 1 and R 2 stand for alkoxy, one of said substituents is attached to position 2 of the phenyl ring; with the further proviso that if R 1 and R 2 together form methylenedioxy, said group together with the phenyl ring form l-benzo[l,3]dioxol-4-yl; or if one of symbols R 1 and R is cyano is attached to position 2, the other group is other than hydrogen or methoxy attached to position 3; or if one of symbols of R 1 and R 2 is hydrogen, the other is different from methoxy attached to position 2 or 3; or the chiral carbon
  • R is hydrogen
  • R and R independently from each other stand for hydrogen, Ci -4 -alkyl, Q ⁇ -alkoxy, aryloxy, aralkoxy, trifluoromethyl, cyano or halogen; or R 1 and R 2 together form methylenedioxy; with the proviso that at least one of symbols R 1 and R 2 is other than hydrogen; with the further proviso that if R 1 and R 2 are Ci -4 -alkoxy, one of said alkoxy groups is attached to position 2 of the phenyl
  • R 3 is Ci_ 4 -acyl
  • R 1 and R 2 independently from each other represent hydrogen, C 1-4 -alkyl, C 1-4 -alkoxy, aryloxy, aralkoxy, trifluoromethyl, cyano or halogen; or R 1 and R 2 together form methylenedioxy; with the proviso that at least one of symbols R 1 and R 2 is other than hydrogen; with the further proviso that if R 3 is acetyl and at least one of symbols of R and R is hydrogen, the substituent attached to position 4 of the phenyl ring is other than methoxy; or the chiral carbon atom is of ⁇ -configuration and
  • R 3 is Ci. 4 -acyl
  • R 1 and R 2 independently from each other stand for hydrogen, Ci_ 4 -alkyl, Ci_ 4 -alkoxy, aryloxy, aralkoxy, trifluoromethyl, cyano or halogen; or R 1 and R 2 together form methylenedioxy; with the proviso that at least one of symbols R 1 and R 2 is other than hydrogen; with the further proviso that if R 3 is acetyl and R 1 and R 2 together form methylenedioxy, said group together with the phenyl ring form l-benzo[l,3]dioxol-4-yl; or R 3 is acyl in which the group R 5 binds said acyl group with a further carboxy group; wherein
  • R 5 stands for substituted or unsubstituted alkenyl or aryl; with the proviso that if R 3 stands for phthalyl, one of symbols R 1 and R 2 represents methoxy attached to position 3 of the phenyl ring and the other is different from hydrogen or methoxy attached to position 4 of the phenyl ring; and salts of said racemic or optically active enantiomers formed with optically active bases with the exception of salts formed with optically active brucine as base and compounds of the general Formula I in which R 3 is phthalyl, one of symbols R 1 and R 2 is methoxy attached to position to 3 of the phenyl ring and the other is hydrogen or methoxy attached to position 4 of the phenyl ring.
  • R 1 and R 2 independently from each other stands for hydrogen, C ⁇ -alkyl, C 1 _ 4 -alkoxy, aryloxy, aralkoxy, trifluoromethyl, cyano or halogen; or R 1 and R 2 together form methylenedioxy
  • R 1 and R 2 independently from each other stands for hydrogen, C ⁇ -alkyl, C 1 _ 4 -alkoxy, aryloxy, aralkoxy, trifluoromethyl, cyano or halogen; or R 1 and R 2 together form methylenedioxy
  • R 1 and R 2 independently from each other stands for hydrogen, C 1-4 -alkyl, C 1-4 -alkoxy, aryloxy, aralkoxy, trifluoromethyl, cyano or halogen; or R 1 and R together form methylenedioxy
  • R 1 and R 2 independently from each other stands for hydrogen, C 1-4 -alkyl, C 1-4 -alkoxy, aryloxy, aralkoxy, trifluoromethyl, cyano or halogen; or R 1 and R together form methylenedioxy
  • R 1 and R 2 independently from each other stands for hydrogen, C 1-4 -alkyl, C 1-4 -alkoxy, aryloxy, aralkoxy, trifluoromethyl, cyano or halogen; or R 1 and R together form methylenedioxy
  • R 4 is C 1-4 - alkyl; R 1 and R 2 independently from each other stands for hydrogen, C 1-4 -alkyl, C 1-4 -alkoxy, aryloxy, aralkoxy, trifluoromethyl, cyano or halogen; or R 1 and R 2 together form methylenedioxy) converting the dicarboxylic acid derivative of the general Formula
  • R stands for alkyl, branched chain alkyl, alkenyl or aryl; R 1 and R 2 independently from each other stands for hydrogen, C 1-4 -alkyl, C 1-4 -alkoxy,. aralkoxy, trifluoromethyl, cyano or halogen; or R and R together form methylenedioxy
  • R stands for alkyl, branched chain alkyl, alkenyl or aryl; R 1 and R 2 independently from each other stands for hydrogen, C 1-4 -alkyl, C 1-4 -alkoxy,. aralkoxy, trifluoromethyl, cyano or halogen; or R and R together form methylenedioxy
  • into a salt by using an aqueous base in the presence of a water- insoluble solvent; thereafter separating the aqueous phase which contains the dicarboxylic acid derivative of the general Formula I/D from the organic phase which contains the acylated enantiomeric derivative of the general Formula I/C; thereafter
  • the present invention is based on the recognition that the separation of two enantiomers of aryl-isopropanols is high enantioselectivity can be carried out by using simple conventional extraction method of pharmaceutical industry by forming derivatives of the two enantiomers, one of said enantiomers being water-soluble and the other being soluble in water-immiscible solvents.
  • acylating the (+)-enantiomer aryl-isopropanol of the general Formula I/B with a dicarboxylic acid anhydride a semiester-semiacidic form beside the other enantiomer, namely the acylated derivative of the general Formula I/C.
  • the semiester-semiacid formed from the dextrorotatory enantiomer can be separated from the acylated derivative of the laevorotatory enantiomer by means of an alkaline aqueous and organic solvent extraction.
  • the salt formed from the semiester-semiacid of the general Formula I/D goes into the aqueous phase, whereby the acylated derivative of the general Formula I/C remains in the organic phase.
  • the phases are than worked up in a manner known per se.
  • the enantiomer-pure semiester-semiacid of the general Formula I/D is recovered from the aqueous phase.
  • On hydrolysing said compound one of the enantiomeric alcohols of the general Formula I/B is obtained, while the other enantiomeric alcohol is formed by subjecting the enantiomer of the general Formula I/C obtained from the organic phase to hydrolysis.
  • the aryl-isopropanol of the general Formula I/B having non-satisfactory optical purity is acylated with a dicarboxylic acid dihydrate in a manner known per se to yield the semiester-semiacid of the general Formula I/D; from said compound a salt is formed with an optically active base, the diastereomic salt is subjected to recrystallization and thereby a salt having the desired optical purity is obtained.
  • the semiester-semiacid of the general Formula I/D of satisfactory optical purity is set free from said salt and hydrolysis of the latter compound gives an aryl-isopropanol of the general Formula IfB having high optical purity.
  • the enzyme catalyzed reaction according to the present invention is carried out by using a lipase enzyme in an acylating solvent or a mixture of said acylating solvent and a further solvent.
  • acylating solvent preferably vinyl acetate or vinyl butylate, particularly vinyl acetate can be used.
  • One may also proceed by performing the reaction in a solvent of said acylating solvent formed with another solvent, or in the presence of a suitable solvent solution.
  • ether-type solvents particularly diethyl ether
  • saturated hydrocarbons preferably hexane or heptane
  • Acylation can also be performed in the presence of a phosphate buffer (pH 7.5).
  • lipase enzyme preferably Pseudomonas fhiorescens, Pseudomonas cepacia, Candida cylindracea, Candida antarctica or Mucor miehei lipase, particularly Pseudomonas cepacia lipase, particularly advantageously Amano® PS-C can be used.
  • the enzymatic reaction can be carried out at a temperature between 10-60 0 C, particularly 20-40 0 C, most advantageously at room
  • the reaction time is generally 4-72 hours, preferably 6-48 hours, the most advantageously 6-30 hours.
  • the mixture of the acylated compound of the general Formula I/C and the derivative of the general Formula I/B can be separated by formation of chemical derivatives.
  • a semiester-semiacid of the general Formula I/D is formed, whereby the acylated enantiomer of the general Formula I/C remains unchanged.
  • dicarboxylic acid derivative one can use derivatives of dicarboxylic acid containing alkyl, branched chain alkyl, substituted alkyl, alkenyl, substituted alkenyl or aryl groups, preferably derivatives of maleic acid, succinic acid or phthalic acid.
  • dicarboxylic acid anhydrates It is preferably to use dicarboxylic acid anhydrates.
  • Acylation of the compounds of the general Formula I/B can be carried out preferably in an inert solvent.
  • reaction medium preferably chlorinated hydrocarbon, acetonitrile, tetrahydrofurane, particularly dichloromethane can be used.
  • a catalyst preferably an organic base, particularly triethyl amine or diethyl amino-pyridine.
  • the semiester- semiacid derivative of the general Formula I/D is converted into a salt by using an aqueous base.
  • an alkali metal or an alkaline earth metal hydroxide, hydrogen carbonate or carbonate solution or suspension, particularly an alkali carbonate solution, most advantageously sodium carbonate solution can be used.
  • a two-phase reaction mixture is formed after the salt formation, whereby the organic phase contains the compound of the general Formula I/C and the aqueous phase contains the salt of the semiester-semiacid derivative of the general Formula I/D.
  • the two phases are separated and worked up by methods known per se. One may proceed by drying and evaporating the organic phase and, if necessary, purifying the compound of the general Formula I/C by distillation in vacuo.
  • the aqueous phase can be acidified and on adding a water non- miscible solvent, the organic acid solution of the semiester- semiacid of the general Formula I/D is obtained.
  • optically active organic amines can be used, e.g. (2 ⁇ -(+)-l-phenyl-ethyl-amine, ($-(-)- 1-phenyl- ethyl-amine, (+)-dehydroabiethyl-amine, quinine, (-)-l-(4- nitrophenyl)-2-amine- 1,3 -propanediol or ($-(+)-2-benzyl- amino-1-butanol.
  • Resolution is carried out in an organic solvent.
  • a dipolar aprotic solvent, ether- type solvent preferably ethyl acetate, acetone, diisopropyl ether, diethyl ether or a mixture of said solvents can be used.
  • the corresponding semiester-semiacid of the general Formula I/D is set free from the diastereomeric salt by using an aqueous acid which is then recovered from the reaction mixture by extraction. On evaporating the extract the semiester-semiacid of the general Formula I/D is obtained which is subjected to hydrolysis.
  • the reaction mixture of said hydrolysis step results in the optically pure aryl isopropanol of the general Formula IfB which can be purified by distillation, if necessary.
  • (+)- 1 -(4-fluoro-phenyl)-2-propanol (+)- 1 -(4-fluoro-phenyl)-2-propanol.
  • the essence of the present invention is the combination of an enzymatic route on the one hand and a chemical derivative- formation on the other.
  • the present invention provides a unique, completely unknown route for the separation of two enantiomers which is suitable for an industrial scale resolution.
  • optically pure derivatives can be separated by a simple method by using a conventional liquid-liquid extraction method
  • the enantioselective activity of the reaction can be influenced by choosing the reaction conditions, reaction time, temperature and the type of the lipase enzyme;
  • the enantiomer purity of the product obtained can be further improved with a significantly smaller reactant and apparatus need than the resolution of the complete amount of the racemic aryl-isopropanol;
  • the non-desired enantiomer pure antipode can be converted into the desired enantiomer by methods known from prior art in a simple way.
  • the present invention provides a new industrial scale process for the preparation of partially known and partially new optically active aryl-isopropanols.
  • Pseudomonas cepacia lipase To a solution of 35.00 g (194.23 mmoles) of 1- benzo[1.3]dioxol-5-yl-2-propanol in 175 ml of vinyl-acetate 10.50 g of Ps eudomonas cepacia lipase (Amano® PS-C) bond to a carrier are added. The mixture is stirred at room temperature for 6 hours, filtered, the enzyme is washed 4 times in 10 ml of vinyl-acetate each and the filtrate is evaporated in vacuo.
  • the reaction mixture gradually warms up, while its colour turns into dark brown.
  • the reaction mixture is heated to boiling for 5 minutes, cooled and washed once with 100 ml, once with 15 ml of 1.5 molar hydrochloric acid and twice with 15 ml of water each.
  • the dichloro-methane phase is extracted once with 125 ml and twice with 15 ml of a 1 molar sodium carbonate solution.
  • the aqueous layers are united and washed 3 times with 15 ml of dichloro-methane each.
  • the aqueous phase contains the sodium salt of (+)-2-(l- benzo[l .3]dioxol-5-yl)-l-methyl-ethyl-hydrogen-maleate.
  • the dichloro-methane phases are united, dried over sodium sulfate and the solvent is removed in vacuo. Thus 21.60 g (97.19
  • the reaction mixture gradually warms up, whereby its colour turns dark brown.
  • the reaction mixture is heated to boiling for 5 minutes, cooled, washed once with 10 ml, once with 3 ml of 1.5 molar hydrochloric acid and twice with 3 ml of water each.
  • the dichloro-methane layer is extracted once with 12.5 ml and twice with 3 ml of a 1 molar sodium-carbonate solution each.
  • the aqueous layers are united and washed 3 times with 3 ml of dichloro-methane each.
  • the aqueous phase contains the sodium salt of a (+)-2-(l- benzo[1.3]dioxol-5-yl)-l-methyl-ethyl-hydrogen-maleate.
  • the dichloro-methane are united, dried over sodium sulfate and the solvent is removed in vacuo. Thus 2.62 g (11.79 mmoles, yield 121.4 %) of (-)-2-(l-benzo[1.3]dioxol-5-yl)-l-methyl- ethyl-acetate are obtained.
  • the crystals are dissolved in 20 ml of hot ethyl-acetate and allowed to crystallize at room temperature for an hour.
  • the reaction mixture is heated to boiling for 5 minutes, then cooled, washed once in 100 ml and once with 10 ml of 1.5 molar hydrochloric acid and twice with 15 ml of water each.
  • the dichloro-methane phase is extracted once with 100 ml and twice with 5 ml of a 1 molar sodium-carbonate solution each.
  • the aqueous layers are united and washed 3 times with 15 ml of dichloro-methane each.
  • the reaction mixture warms up gradually and its colour turns dark brown.
  • the reaction mixture is heated to boiling for 5 minutes, cooled, washed once with 100 ml and once with 15 ml of 1.5 molar hydrochloric acid twice with 15 ml of water each.
  • the dichloro-methane phase is extracted once with 115 ml and twice with 15 ml of a 1 molar sodium carbonate solution.
  • the aqueous layers are united and washed 3 times with 15 ml of dichloro-methane each.
  • the aqueous phase contains the sodium salt of (+)-2-(4-chloro-phenyl)-l-methyl-ethyl- hydrogen-maleate.
  • the dichloro-methane phases are united, dried over sodium sulfate and the solvent is distilled off in vacuo.
  • 29.08 g (136.74 mmoles, 155.6 %) of (-)-l-(3- chloro-phenyl)-2-propil-acetate are obtained in the form of a yellow oil.
  • the crystals are dissolved in 10 ml of hot acetone. The solution is allowed to crystallize at 10 0 C for 10 hours. The crystals are filtered, washed twice with 5 ml of ethyl-acetate each and dried. Thus 3.85 g (9.82 mmoles, 27.1%) of white crystalline ( ⁇ ) -( ' - y ) -l-phenyl-ethyl-ammonium-[(-)-2-(4-chloro-phenyl)-l- methyl-ethyl-succinate] are obtained.
  • the reaction mixture gradually warms up, while its colour turns dark brown.
  • the reaction mixture is heated to boiling for 5 minutes, cooled, washed once with 100 ml and once with 10 ml of 1.5 molar hydrochloric acid and twice with 15 ml of water each.
  • a dichloro-methane layer is extracted once with 100 ml and twice with 5 ml of 1 molar sodium carbonate solution each.
  • the aqueous layers are united and washed 3 times with 15 ml of dichloro-methane each. [The aqueous
  • phase contains the sodium salt of the maleic acid semiester of (+)-l-(3,4-dichloro-phenyl)-2-propanol.]
  • the dichloro- methane layers are united, dried over sodium sulfate and the solvent is removed in vacuo.
  • 23.24 g (94.04 mmoles, 110.2 %) of (-)-2-(3,4-dichloro-phenyl)-l-methyl-ethyl-acetate are obtained in the form of a yellow oil.
  • the reaction mixture gradually warms up and its colour turns dark brown.
  • the reaction mixture is heated to boiling for 5 minutes, cooled, washed once with 85 ml and once with 10 ml of a 1.5 molar hydrochloric acid and twice with 15 ml of water.
  • the dichloro- methane phases are extracted once with 100 ml and twice with 5 ml of a 1 molar sodium carbonate solution.
  • the aqueous layers are united and washed 3 times with 15 ml of dichloro- methane each.
  • the aqueous phase contains the sodium salt of (+)-2-(3 ⁇ bromo-4-methoxy-phenyl)- 1 -methyl-ethyl-hydrogen- maleate.
  • the dichloro-methane phases are united, washed over sodium sulfate and the solvent is distilled off in vacuo.
  • 23.54 g (81.98 mmoles, 114.8 %) of (-)-2-(3-bromo-4- methoxy-phenyl)-l -methyl-ethyl-acetate are obtained in the form of a yellow oil.
  • the reaction mixture is heated to boiling for 5 minutes, cooled, washed once with 45 ml and once with 10 ml of 1.5 molar hydrochloric acid and twice with 10 ml of water each.
  • the dichloro-methane layer is extracted once with 20 ml and twice with 5 ml of 1 molar sodium carbonate solution each.
  • the aqueous layers are united and washed 3 times with 10 ml of dichloro-methane each.
  • the aqueous phase contains the sodium salt of (+)-2-(4- fluor-phenyl)-l-methyl-ethyl-hydrogen-maleate.]
  • the dichloro- methane phases are united, dried over sodium sulfate and the solvent is distilled off in vacuo.

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Abstract

L’invention concerne des dérivés d’isopropanol de formule générale (I) sous forme d’énantiomères purs et dans certains cas de nouveaux dérivés racémiques, et un procédé de préparation de ceux-ci. Les composés partiellement nouveaux et partiellement connus de formule générale (I) sont des intermédiaires pharmaceutiques utiles. La définition de substituants des symboles R1, R2 et R3 est telle qu’exposée dans la spécification du brevet.
PCT/HU2005/000067 2004-06-23 2005-06-23 Intermediaires pharmaceutiques et procede de preparation de ceux-ci WO2006013399A1 (fr)

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HU0401267A HU0401267D0 (en) 2004-06-23 2004-06-23 New intermediates and process for producing them
HUP0401267 2004-06-23
HUP0500622 2005-06-22
HU0500622A HUP0500622A3 (en) 2005-06-22 2005-06-22 New intermediates and process for producing them

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2258696A1 (fr) * 2009-05-14 2010-12-08 ENDURA S.p.A. Procédé pour l'obtention de 3-(Benzo[1,3]dioxol-5-yl)-2-methylpropanal enrichi en énantiomères
CN106478588A (zh) * 2016-09-04 2017-03-08 王际菊 一种手性1‑胡椒基‑2‑丙醇及其异构体制备方法

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2258696A1 (fr) * 2009-05-14 2010-12-08 ENDURA S.p.A. Procédé pour l'obtention de 3-(Benzo[1,3]dioxol-5-yl)-2-methylpropanal enrichi en énantiomères
CN106478588A (zh) * 2016-09-04 2017-03-08 王际菊 一种手性1‑胡椒基‑2‑丙醇及其异构体制备方法

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