WO1997009983A1 - Derives de piperidine et leurs procedes de production - Google Patents

Derives de piperidine et leurs procedes de production Download PDF

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WO1997009983A1
WO1997009983A1 PCT/US1996/013905 US9613905W WO9709983A1 WO 1997009983 A1 WO1997009983 A1 WO 1997009983A1 US 9613905 W US9613905 W US 9613905W WO 9709983 A1 WO9709983 A1 WO 9709983A1
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formula
substantially pure
compound
process according
piperidine derivative
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PCT/US1996/013905
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Thomas E. D'ambra
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Albany Molecular Research, Inc.
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Priority to AU71045/96A priority Critical patent/AU7104596A/en
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    • 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
    • C07D211/36—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4

Definitions

  • the present invention relates to piperidine derivatives and processes for their production.
  • Terfenadine 1 -(p-tert-buty lpheny l)-4-[4 ' -( ⁇ -hydroxydipheny lmethyl)- 1 ' - piperidinyl] -butanol is a non-sedating anti-histamine. It is reported to be a specific H2- receptor antagonist that is also devoid of any anticholingeric, anti-serotoninergic, and anti-adrenergic effects both in vitro and in vivo. See D. McTavish, K.L. Goa, M. Ferrill, Drugs. 1990, 39, 552; CR. Kingsolving, N.L. Monroe, A.A. Carr, Pharmacologist. 1973, 15, 221; J.K.
  • terfenadine Side effects reported with terfenadine are cardiac arrhythmias (ventricular tachyarrhythmias, torsades de points, ventricular fibrillation), sedation, GI distress, dry mouth, constipation and/or diarrhea.
  • cardiac arrhythmias which are related to terfenadine 's ability to prolong the cardiac QT interval, and are only reported in patients administered terfenadine with liver disease or who also take the antifungal drug ketoconazole or the antibiotic erythromycin.
  • the FDA in 1992, required terfenadine to include a warning label.
  • OTC formulations of terfenadine are purportedly being developed, the potentially serious side effects seen in some patients will be a significant obstacle for regulatory approval.
  • terfenadine Since cardiac side effects of terfenadine have been reported in patients with impaired liver function, as well as in patients also taking antibiotics known to suppress hepatic enzyme function, it was speculated that the cardiac side effects were due to accumulation of terfenadine and not due to accumulation of terfenadine carboxylic acid metabolite. Patch clamp studies in isolated feline ventricular myocytes support the contention that terfenadine, and not the carboxylic acid metabolite, is responsible for cardiac side effects. At a concentration of 1 ⁇ M, terfenadine caused a greater than 90% inhibition of the delayed rectifier potassium current.
  • terfenadine carboxylic acid metabolite had no significant effect on the potassium current in this assay (See R.L. Woosley, Y. Chen, J.P. Frieman, and R.A. Gillis, JAMA 1993, 269, 1532). Since inhibition of ion transport has been linked to cardiac abnormalities such as arrhythmias, these results indicate that terfenadine carboxylic acid is likely not liable to cause cardiac arrhythmias, at dose levels at which there is a distinct risk of such a side effect being caused by terfenadine itself.
  • Carebastine 4-[4-[4-(diphenylmethoxy)-l-piperidinyl]-l-oxobutyl]- ⁇ , ⁇ - dimethylphenylacetic acid, is the carboxylic acid metabolite of ebastine, l-(p-tert- butylphenyl)-4-[4'-( ⁇ -diphenylmethoxy)-l '-piperidinyl] -butanol. Both compounds possess potent selective histamine Hi — receptor blocking and calcium antagonist properties and should prove useful in the treatment of a variety of respiratory, allergic, and cardiovascular disease states. As with terfenadine and its carboxylic acid metabolite, it is expected that carebastine would possess an improved safety margin over ebastine, because the polar carboxylic acid function of carebastine mitigates any effect on ion transport.
  • these compounds relax bronchial and vascular smooth muscle in vitro and in vivo and inhibit the constrictor influence of noradrenaline, potassium ions, and various other agonist drugs.
  • the compounds also inhibit responses of intestinal and tracheal preparations to histamine, acetylcholine, and barium chloride and block the bronchoconstriction induced by histamine aerosol in guinea-pigs in doses less than
  • U.S. Patent No. 4,254,130 indicates ⁇ -haloalkyl substituted phenyl ketones, wherein Z is hydrogen, are prepared by reacting an appropriate straight or branched lower alkyl C . ester of ⁇ - ⁇ -dimethylphenylacetic acid with a compound of the following formula:
  • the yield of the desired para isomer is about 2% .
  • the meta isomer is present in an amount of up to 5% in admixture with the desired para product. Accordingly, although the recrystallization steps in the Carr terfenadine mtabolite patents are effective in removing some of the theoretically-present meta isomer, there remains a quantity of that impurity in the desired para-containing product stream which is inseparable. Consequently, it has not been possible to obtain either of the regioisomers in each mixture in substantially pure form.
  • the present invention relates to substantially pure piperidine derivative compounds of the formulae:
  • R3 is —COOH or -COOR4
  • R4 is an alkyl with 1 to 6 carbon atoms
  • A, B, and D are the substiments of their rings, each of which may be different or the same, and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy, or other substiments
  • the present invention relates to substantially pure piperidine derivative compounds of the formulae:
  • R 3 is -COOH or -COOR4
  • R4 is an alkyl with 1 to 6 carbon atoms
  • A, B, and D are the substiments of their rings, each of which may be different or the same, and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy, or other substiments;
  • Rd are straight or branched alkyl groups, including methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, and n-hexyl groups.
  • Illustrative examples of compounds of the present invention are as follows: 4- [4- [4-(dipheny Imethoxy )- 1 -piperidinyl] - 1 -hydroxybutyl] - ⁇ , ⁇ - dimethylbenzeneacetic acid;
  • both diphenyl groups from the piperidine compound may be alkyl (e.g., methyl) substimted at the position para to the methylene, such as compounds of the formulae:
  • This invention also includes pharmaceutically acceptable salts in the form of inorganic or organic acid or base addition salts of the above compounds.
  • Suitable inorganic acis are, for example, hydrochloric, hydrobromic, sulfuric, and phosphoric acids.
  • Suitable organic acids include carboxylic acids, such as, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, cyclamic, ascorbic, maleic, hydroxymaleic, dihydroxymaleic, benzoic, phenylacetic, 4- aminobenzoic, anthranillic, cinnamic, salicyclic, 4-aminosalicyclic, 2-phenoxybenzoic, 2-acetoxybenzoic, and mandelic acid.
  • Non-toxic salts of the compounds of the above-identified formulas formed with inorganic and organic bases include, for example, those alkali metals, such as, sodium, potassium, and lithium, alkaline earth metals, for example, calcium and magnesium, light metals of group IIIA, for example, aluminum, organic amines, such as, primary, secondary, or tertiary amines, for example, cyclohexylamine, ethylamine, pyridine, methy laminoethanol, and piperazine.
  • These salts are prepared by conventional means, for example, by treating the piperidine derivative compounds of the formulae:
  • the invention further includes substantially pure piperidine derivative compounds having purity from about 98% to 100% and containing, by weight, from 0 to about 2% of one or more impurities, each of which, preferably, is present in a quantity from 0 to about 1 % .
  • the substantially pure piperidine derivative compounds preferably have purity from about 99% to 100% and contain, by weight, from 0 to about 1 % of one or more impurities, with each impurity present in a quantity from 0 to about 0.5 % .
  • the piperidine derivative compounds of the present invention can be utilized as the biologically active components in pharmaceutical compositions.
  • the compounds of this invention are useful as antihistamines, antiallergy agents, and bronchodilators. They may be administered alone or with suitable pharmaceutical carriers, and can be in solid or liquid form such as, tablets, capsules, powders, solutions, suspensions or emulsions.
  • the compounds of this invention can be administered orally, parenterally, for example, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation or by application to mucous membranes, such as, that of the nose, throat and bronchial tubes.
  • mucous membranes such as, that of the nose, throat and bronchial tubes.
  • Such application to mucous membranes can be achieved with an aerosol spray containing small particles of a compound of this invention in a spray or dry powder form.
  • the quantity of the compound of the present invention administered will vary depending on the patient and the mode of administration and can be any effective amount.
  • the quantity of the compound administered may vary over a wide range to provide in a unit dosage an effective amount of from about 0.01 to 20 mg/kg of body weight of the patient per day to achieve the desired effect.
  • the desired antihistamine, antiallergy, and bronchodilator effects can be obtained by consumption of a unit dosage form such as a tablet containing 1 to 50 mg of the compound of the present invention taken 1 to 4 times daily.
  • the solid unit dosage forms can be of the conventional type.
  • the solid form can be a capsule, such as an ordinary gelatin type containing the compound of the present invention and a carrier, for example, lubricants and inert fillers such as, lactose, sucrose, or cornstarch.
  • these compounds are tableted with conventional tablet bases such as lactose, sucrose, or cornstarch in combination with binders like acacia, cornstarch, or gelatin, disintegrating agents such as, cornstarch, potato starch, or alginic acid, and a lubricant like stearic acid or magnesium stearate.
  • the compounds of this invention may also be administered in injectable dosages by solution or suspension of the compounds of the present invention in a physiologically acceptable diluent with a pharmaceutical carrier.
  • a pharmaceutical carrier include sterile liquids such as water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants.
  • Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil.
  • water, saline, aqueous dextrose and related sugar solution, and glycols such as, propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions.
  • the compounds of this invention in solution or suspension may be packaged in a pressurized aerosol container together with suitable propellants, for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants.
  • suitable propellants for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants.
  • the compounds of the present invention also may be administered in a non-pressurized form such as in a nebulizer or atomizer.
  • the compounds of the present invention can be used to treat warm blooded animals, birds, and mammals.
  • Examples of such beings include humans, cats, dogs, horses, sheep, cows, pigs, lambs, rats, mice, and guinea pigs.
  • the piperidine derivative compounds of the present invention are prepared by providing a substantially pure regioisomer of the following formula:
  • the resulting piperidine derivative compounds with a keto group can be converted by reduction to the above-described piperidine compounds with a hydroxyl group.
  • the substantially pure regioisomer is formed by initially acylating a starting compound of the formula:
  • R5 is — OR , — N(R6)2, and — SR , and R is an alkyl with 1 to 6 carbons,
  • X is a halogen
  • Such conditions include those conventionally utilized in a Friedel-Crafts acylation reaction catalyzed by, for example, AICI3.
  • the reaction is carried out in a solvent such as, carbon disulfide, methylene chloride, tetrachloroethane, or nitrobenzene with carbon disulfide being the preferred solvent.
  • the reaction is carried out for a time period of 1/2 to 12 hours, preferably 3 to 5 hours, at a temperamre of 0 to 25 °C.
  • the first mixmre of regioisomers can be treated with an inorganic base, such as, sodium hydroxide or potassium hydroxide, in an aqueous lower alcohol solvent.
  • suitable solvents include aqueous methanol, ethanol, isopropanol, or n-butanol solutions.
  • Hydrolysis is carried out at reflux temperamres of the solvent for 1/2 to 12 hours.
  • X + is a Lewis Acid
  • Such crystallization is carried out by fractional crystallization techniques known in the art. Generally, such procedures involve dissolving the second mixmre of regioisomers in a solvent containing a salt at temperamres of 20 °C to the reflux temperamre of the solvent. The resulting solution is then slowly cooled to temperamres of -20° to 25 °C.
  • Suitable solvents for fractional crystallization include: alcohol solvents, like methanol, ethanol, isopropyl alcohol, and n-butanol; ketone solvents, such as acetone or methyl ethyl ketone; ester-containing solvents, like ethyl acetate or isopropyl acetate; ethereal solvents such as tetrahydrofuran; acetonitrile; and dimethylformamide. Ethyl acetate is preferred.
  • Suitable salts for fractional crystallization are those where X + is an alkali metal salt, like sodium and potassium salts, or, more preferably, ammonium salts of the form NRyRgRo, where R7, Rg, and R9 are hydrogen or a straight or branched alkyl of 1 to 6 carbon atoms which may be substituted at any position with a phenyl ring or a substimted phenyl ring.
  • the ammonium salt can also be cinchonidine. quinine, quinidine, quinuclidine, brucine, thebaine, or cinchonine. Of these salt complexes, cinchonidine is preferred.
  • the substantially pure regioisomer salt is then isolated by filtration and converted to the substantially pure regioisomer of the formula:
  • the substantially pure regioisomer is produced by acylating a starting compound of the formula:
  • R 3 is —COOH, —COOalkyl, — CON(alkyl) 2 , — COSalkyl where the alkyl moieties have 1 to 6 carbon atoms and are straight or branched;
  • Xi is a halogen, trialkyl tin, trialkyl borate, triflate, or substiments useful in organometallic coupling reactions, including lithium or magnesium compounds derived from bromine or iodine, with any alkyl groups having 1 to 4 carbon atoms and being straight or branched,
  • X2 is a halogen; an alkali metal oxide; an amine having the formula -NR14R15, wnere Rl4 and R15 are the same or different and are selected from the group consisting of hydrogen and an alkyl moiety having 1 to 6 carbon atoms; or a cyclic amine having the formula:
  • acylation reaction is carried out in a suitable solvent in the presence of an appropriate catalyst for about 1 to 120 hours and at temperamres of about -78°C to the reflux temperamre of the solvent.
  • suitable solvents for acylation include: hydrocarbon solvents, such as benzene, toluene, xylene, or cyclohexane; halogenated hydrocarbons, such as chlorobenzene, dichloroethane, methylene chloride, chloroform, or carbon tetrachloride; carbon disulfide; dimethylformamide; ethereal solvents, like tetrahydrofuran and diethylether; or dioxane.
  • catalysts may be utilized when A is hydrogen. Suitable catalysts include palladium catalysts, like palladium chloride, palladium acetate, tetrakis(triphenylphosphine) palladium(O), dichlorobis(triphenylphosphine palladium(II), or benzy lchlorobis(triphenylphosphine)palladium(II); or nickel-phosphine catalysts. Acylation may also be carried out in the presence of added lithium chloride or triphenylphosphine. The latter acylation reaction is known in the art as organometallic cross-coupling reactions and are conducted by the general procedures of D. Milstein, et al. , T. Org.
  • Acylation is carried out with an acylation agent such as a cyclopropylcarboxylic acid halide, an alkali metal cyclopropylcarboxylic acid salt, or a cyclopropylcarboxylic acid amide.
  • an acylation agent such as a cyclopropylcarboxylic acid halide, an alkali metal cyclopropylcarboxylic acid salt, or a cyclopropylcarboxylic acid amide.
  • the amide can be an N-unsubstituted amide, such as cyclopropylcarboxylic acid amide; an N-monosubstituted amide, such as N-methyl cyclopropylcarboxylic acid amide, N-ethyl cyclopropylcarboxylic acid amide, N-propyl cyclopropylcarboxylic acid amide, and N-hexyl cyclopropylcarboxylic acid amide; or an N,N-disubstimted amide.
  • N-unsubstituted amide such as cyclopropylcarboxylic acid amide
  • an N-monosubstituted amide such as N-methyl cyclopropylcarboxylic acid amide, N-ethyl cyclopropylcarboxylic acid amide, N-propyl cyclopropylcarboxylic acid amide, and N-hexyl cyclopropylcarbox
  • Suitable N,N-disubstituted amides include N, N-dimethyl cyclopropylcarboxylic acid amide, N-methyl-N-ethyl cyclopropylcarboxylic acid amide, N-methyl-N-propyl cyclopropylcarboxylic acid amide, N-methyl-N-hexyl cyclopropylcarboxylic acid amide, N,N-diethyl cyclopropylcarboxylic acid amide, N- ethyl-N-propyl cyclopropylcarboxylic acid amide, N-ethyl-N-hexyl cyclopropylcarboxylic acid amide, N,N-dipropyl cyclopropylcarboxylic acid amide, N- propyl-N-hexyl cyclopropylcarboxylic acid amide, and N,N-dihexyl cyclopropylcarboxy
  • m is 2, 3, 4, or 5.
  • examples of such compounds include N,N-ethylene cyclopropylcarboxylic acid amide, N,N-propylene cyclopropylcarboxylic acid amide,
  • N,N-butylene cyclopropylcarboxylic acid amide N,N-pentylene cyclopropylcarboxylic acid amide.
  • Suitable cyclopropylcarboxylic acid halides include cyclopropylcarboxylic acid chloride, cyclopropylcarboxylic acid bromide, and cyclopropylcarboxylic acid iodide.
  • alkali metal salt of cyclopropylcarboxylic acid is employed as the acylating agent
  • suitable alkali metals include lithium, sodium, and potassium.
  • the substantially pure regioisomer is produced by acylating a starting compound of the formula:
  • R5 is -OR fj , -N(R&)2, and -SR fj , and R is an alkyl with 1 to 6 carbon atoms
  • acylation is carried out by a Friedel-Crafts reaction, as described above in Process One for Producing Substantially Pure Regioisomers.
  • the substantially pure regioisomer salt is recovered by fractional crystallization, isolation, and converting, as described above with reference to Process
  • the substantially pure regioisomer can be halogenated under conditions effective to form a first intermediate compound of the formula:
  • X3 is a halogen.
  • Suitable halogens include chlorine, bromine, and iodine.
  • Suitable conditions for carrying out such halogenating include reacting the substantially pure regioisomer with a halogen nucleophile and a Lewis Acid.
  • the ring opening reaction is carried out in a suitable solvent, optionally in the presence of a catalytic amount of base for about 0.5 to 24 hours and a temperamre of about -40 degrees C to the reflux temperamre of the solvent.
  • Suitable halogen nucleophiles include sodium iodide, sodium bromide, potassium iodide, potassium bromide, cesium iodide, cesium bromide, trimethylsilyl iodide, manganese iodide, cerium iodide, magnesium bromide, magnesium iodide, magnesium carbonate, calcium bromide, and calcium iodide.
  • Suitable Lewis Acids include silicon compounds such as trimethylsilyl chloride and trimethylsilyl iodide; aluminum compounds such as aluminum chloride, trimethyl aluminum, diethyl aluminum chloride, ethyl aluminum dichloride, and diethyl aluminum cyanide; magnesium salts; and boron salts.
  • Suitable solvents for the ring opening reaction include hydrocarbon solvents, such as, benzene, toluene, xylene, or cyclohexane; ethereal solvents such as ether, tetrahydrofuran, dioxane, or dimethoxyethane; or halogenated hydrocarbons, such as, chlorobenzene, methylene chloride, carbon tetrachloride, chloroform, or dichloroethane.
  • hydrocarbon solvents such as, benzene, toluene, xylene, or cyclohexane
  • ethereal solvents such as ether, tetrahydrofuran, dioxane, or dimethoxyethane
  • halogenated hydrocarbons such as, chlorobenzene, methylene chloride, carbon tetrachloride, chloroform, or dichloroethane.
  • the acid group of the first intermediate compound can be esterified by techniques well know to those skilled in the art, such as by evaporating an alcoholic solution of the acid and a mineral acid, such as a methanolic, ethanolic, propanolic, or butanolic solution of hydrochloric, hydrobromic, or hydro iodic acid, to dryness to form an ester having the formula:
  • the first intermediate compound can be reacted with a piperidine compound of the formula:
  • This alkylation reaction is carried out in a suitable solvent preferably in the presence of a base and, optionally, in the presence of a catalytic amount of potassium iodide for about 4 to 120 hours at a temperamre of about 70 °C to the reflux temperamre of the solvent.
  • suitable solvents for the alkylation reaction include alcohol solvents, such as, methanol, ethanol, isopropyl alcohol, or n-butanol; ketone solvents, such as, methyl isobutyl ketone; hydrocarbon solvents, such as, benzene, toluene, or xylene; halogenated hydrocarbons, such as, chlorobenzene or methylene chloride; or dimethylformamide.
  • Suitable bases for the alkylation reaction include inorganic bases, for example, sodium bicarbonate, potassium carbonate, or potassium bicarbonate or organic bases, such as a trialkylamine, for example, triethylamine or pyridine, or an excess of the piperidine compound can be used.
  • inorganic bases for example, sodium bicarbonate, potassium carbonate, or potassium bicarbonate or organic bases, such as a trialkylamine, for example, triethylamine or pyridine, or an excess of the piperidine compound can be used.
  • Piperidine derivative compounds of the present invention can also be prepared by the following alternative alkylation procedure. Subsequent to halogenation, the first intermediate compound having the formula
  • N-substimted hydroxypiperidine having the formula:
  • the reaction is preferably carried out in an inert organic solvent, for example, toluene, xylene, dioxan, methyl isobutyl ketone, or N, N-dimethylformamide, at a temperamre between 80° and 140°C in the presence of an acid-binding agent such as an alkali metal carbonate or bicarbonate.
  • an acid-binding agent such as an alkali metal carbonate or bicarbonate.
  • the diphenylmonohalomethane can be prepared by the methods known in the art, for example, by reaction of the corresponding diphenylmethanol with a phosphorous or thionyl chloride or bromide in an inert organic solvent. This alternative alkylation method is preferred when R3 in the first intermediate compound is — COOH.
  • the alkylation reaction can be followed by base hydrolysis to convert R3 substiments that are — COOalkyl groups to — COOH groups.
  • base hydrolysis involves treatment of the substantially pure piperidine derivative with an inorganic base, such as, sodium hydroxide in an aqueous lower alcohol solvent, such as, aqueous methanol, ethanol, isopropyl alcohol, or n-butanol at reflux temperamre for about 1/2 hour to 12 hours.
  • Piperidine compounds are prepared by condensation of an appropriately substimted diphenylmonohalomethane, such as diphenylchloromethane, diphenylbromomethane, and di(p-tolyl)chloromethane, with a l-alkoxycarbonyl-4- hydroxypiperidine in a suitable solvent, such as toluene, xylene, dioxan, methyl isobutylketone, or N, N-dimethylformamide.
  • a suitable solvent such as toluene, xylene, dioxan, methyl isobutylketone, or N, N-dimethylformamide.
  • the reaction is conducted at a temperamre between 80°C and 140°C and in the presence of a base, such as an alkali metal carbonate or bicarbonate.
  • hydrolysis with alkali metal hydroxide in an organic solvent, such as ethanol or isopropanol at the boiling point of the solvent, yields the
  • This alkylation reaction is carried out in a suitable solvent preferably in the presence of a base and optionally in the presence of a Lewis Acid such as magnesium, cesium, or calcium salts or trimethylsilyl chloride or in the presence of a catalytic amount of potassium iodide for about 4 to 120 hours at a temperamre of about 70°C to the reflux temperamre of the solvent.
  • a Lewis Acid such as magnesium, cesium, or calcium salts or trimethylsilyl chloride
  • a catalytic amount of potassium iodide for about 4 to 120 hours at a temperamre of about 70°C to the reflux temperamre of the solvent.
  • Suitable solvents for the alkylation reaction include alcohol solvents, such as, methanol, ethanol, isopropyl alcohol, or n-butanol; ketone solvents, such as, methyl isobutyl ketone; hydrocarbon solvents, such as, benzene, toluene, or xylene; and halogenated hydrocarbons, such as, chlorobenzene or methylene chloride; or dimethylformamide.
  • alcohol solvents such as, methanol, ethanol, isopropyl alcohol, or n-butanol
  • ketone solvents such as, methyl isobutyl ketone
  • hydrocarbon solvents such as, benzene, toluene, or xylene
  • halogenated hydrocarbons such as, chlorobenzene or methylene chloride; or dimethylformamide.
  • Suitable bases of the alkylation reaction include inorganic bases, for example, sodium bicarbonate, potassium carbonate, or potassium bicarbonate or organic bases, such as, a trialkylamine, for example, triethylamine or pyridine, or an excess of a compound of the piperidine compound may be used.
  • inorganic bases for example, sodium bicarbonate, potassium carbonate, or potassium bicarbonate or organic bases, such as, a trialkylamine, for example, triethylamine or pyridine, or an excess of a compound of the piperidine compound may be used.
  • the process of the present invention is useful in producing substantially pure piperidine derivatives with either a keto group or a hydroxyl group.
  • Derivatives with keto groups can be converted to similar compounds with hydroxyl groups by reduction reactions which are well known in the art.
  • Reduction can be carried out with sodium borohydride or potassium borohydride in lower alcohol solvents, such as, methanol, ethanol, isopropyl alcohol, or n-butanol.
  • suitable solvents are ethers, for example, diethyl ether, tetrahydrofuran, or dioxane.
  • Catalytic reduction may also be employed using, for example, Raney nickel, palladium, platinum, or rhodium catalysts in lower alcohol solvents, such as, methanol, ethanol, isopropyl alcohol, or n-butanol or acetic acid or their aqueous mixmres, or by the use of aluminum isopropoxide in isopropyl alcohol.
  • Reduction using sodium borohydride is generally preferred over catalytic reduction when forming carboxylic acids or esters.
  • the starting material is an ester
  • lithium aluminum hydride is the preferred reducing agent, while diborane is preferred when starting with an acid.
  • base hydrolysis can be used to produce a carboxylic acid.
  • Such procedures are well known and generally involve treatment with an inorganic base, such as, sodium hydroxide or potassium hydroxide, in an aqueous lower alcoholic solvent, such as aqueous methanol, ethanol, isopropyl alcohol, or n-butanol.
  • Base hydrolysis is carried out at about the solvent reflux temperamre for about 1/2 hour to 12 hours.
  • a mixmre of 4-(cyclopropyl-oxo-methyl)- ⁇ , ⁇ -dimethylphenylacetic acid (40 grams, 0.14 mole), prepared in accordance with Example 2, concentrated hydrochloric acid (150 mL) and 1,4-dioxane (150 mL) were brought to reflux for 20 hours. After cooling, the reaction mixmre was extracted three times with ethyl acetate. The organics were washed with brine, dried over MgSO 4 , concentrated by rotary evaporation, and purified by column chromatography using silica gel, eluting with 80:20:5 hexanes/ethyl acetate/acetic acid.
  • Example 9 Esterification of 4-[4-[4-Diphenylmethoxy-l-piperidinyI]-l- hydroxybutyl]- ⁇ , ⁇ -dimethylphenylacetic acid
  • 4-[4-[4-diphenylmethoxy-l-piperidinyl]-l- hydroxybutyl]- ⁇ , ⁇ -dimethylphenylacetic acid 7.4 grams, 14.8 mole
  • CH 2 C1 2 was added CH 2 N 2 in ether (prepared from 16.1 grams of N -methyl -N-nitrosotoluene-p-sulphonamide and 3.7 grams of KOH in H 2 O (5mL), EtOH (20mL), and ether (20 mL) at O°C).

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Abstract

Dérivés de pipéridine sensiblement purs de formule (I) ou (II), dans lesquelles R3 est -COOH ou -COOR4; R4 possède de 1 à 6 atomes de carbone, A, B et D sont les substituants de leurs cycles, chacun d'entre eux pouvant être différent ou identique, et sont choisis dans le groupe constitué d'hydrogène, d'halogène, d'alkyle, d'hydroxy, d'alcoxy ou d'autres substances. Un procédé de préparation desdits composés de dérivés de pipéridine sous une forme sensiblement pure est également décrit.
PCT/US1996/013905 1995-09-12 1996-08-30 Derives de piperidine et leurs procedes de production WO1997009983A1 (fr)

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US6281212B1 (en) 1996-07-12 2001-08-28 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6288083B1 (en) 1998-09-04 2001-09-11 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US7498443B2 (en) * 2004-09-17 2009-03-03 Albany Molecular Research, Inc. Process for production of carebastine
CN114890994A (zh) * 2022-05-12 2022-08-12 成都施贝康生物医药科技有限公司 一种组胺受体拮抗剂及其制备
WO2023213182A1 (fr) * 2022-05-06 2023-11-09 成都施贝康生物医药科技有限公司 Sel de carebastine et son utilisation

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WO1995000480A1 (fr) * 1993-06-25 1995-01-05 Merrell Pharmaceuticals Inc. Nouveaux intermediaires utilises dans la preparation de derives de piperidine 4-diphenylmethyl/diphenylmethoxy antihistaminiques

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US3878217A (en) * 1972-01-28 1975-04-15 Richardson Merrell Inc Alpha-aryl-4-substituted piperidinoalkanol derivatives
WO1995000480A1 (fr) * 1993-06-25 1995-01-05 Merrell Pharmaceuticals Inc. Nouveaux intermediaires utilises dans la preparation de derives de piperidine 4-diphenylmethyl/diphenylmethoxy antihistaminiques

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6281212B1 (en) 1996-07-12 2001-08-28 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6288083B1 (en) 1998-09-04 2001-09-11 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6288084B1 (en) 1998-09-04 2001-09-11 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US7498443B2 (en) * 2004-09-17 2009-03-03 Albany Molecular Research, Inc. Process for production of carebastine
US8067604B2 (en) 2004-09-17 2011-11-29 Albany Molecular Research, Inc. Process for production of carebastine
WO2023213182A1 (fr) * 2022-05-06 2023-11-09 成都施贝康生物医药科技有限公司 Sel de carebastine et son utilisation
CN114890994A (zh) * 2022-05-12 2022-08-12 成都施贝康生物医药科技有限公司 一种组胺受体拮抗剂及其制备
CN114890994B (zh) * 2022-05-12 2024-08-02 成都施贝康生物医药科技有限公司 一种组胺受体拮抗剂及其制备

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