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WO2000066579A1 - Methodes de preparation de derives de piperidylmethylpyridine - Google Patents

Methodes de preparation de derives de piperidylmethylpyridine Download PDF

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Publication number
WO2000066579A1
WO2000066579A1 PCT/JP2000/002755 JP0002755W WO0066579A1 WO 2000066579 A1 WO2000066579 A1 WO 2000066579A1 JP 0002755 W JP0002755 W JP 0002755W WO 0066579 A1 WO0066579 A1 WO 0066579A1
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Prior art keywords
group
salt
represented
compound
general formula
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PCT/JP2000/002755
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English (en)
Japanese (ja)
Inventor
Takayuki Nemoto
Masashi Kawasaki
Takahiro Itoh
Toshiaki Mase
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Banyu Pharmaceutical Co., Ltd.
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Priority to AU43147/00A priority Critical patent/AU4314700A/en
Publication of WO2000066579A1 publication Critical patent/WO2000066579A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to an industrial method for producing a compound useful as a therapeutic or preventive drug for various respiratory diseases, urological diseases or digestive diseases in the field of medicine, for example. Furthermore, the present invention relates to intermediates useful in various chemical industries and methods for producing the intermediates. Background art
  • a series of fluorinated 1,4-disubstituted piperidine derivatives containing a compound represented by the following formula [I] disclosed in International Publication No. W098Z055641 is a highly selective muscarinic compound. It has M3 receptor antagonistic activity and is extremely useful as a therapeutic or preventive agent for various respiratory, urinary or digestive disorders.
  • Boc is a tert-butoxycarbonyl group
  • DMF is a dimethylformamide
  • Et is an ethyl group
  • Ms is a methylsulfonyl group
  • t-Bu is a tert-butyl group
  • TEA is triethyl.
  • An object of the present invention is to provide a compound of the formula [I] useful as a therapeutic or prophylactic agent for various respiratory diseases, urinary diseases or digestive diseases in the field of medicine.
  • R 1 represents an amino group which may be protected.
  • R 2 represents an amino group which may be substituted.
  • R 1 is as defined above. Or a salt thereof, and then, if necessary, removing the protecting group for the amino group represented by R 1 and the substituent on the amino group represented by R 2 of the compound [V] or a salt thereof.
  • the present invention relates to a method for producing a compound represented by the formula [I] or a salt thereof. Also, the present invention provides a novel compound useful as a production intermediate of the target compound [I] in the production process, that is, a compound represented by the general formula [IV] or a salt thereof, and a compound represented by the general formula [V] It relates to a compound or a salt thereof. Further, the present invention
  • the present invention relates to a method for producing a useful intermediate in the production method of the present invention shown in (a) to (c).
  • X and R 1 are as defined above. Or a salt thereof; and then reacting the general formula [IV] or a salt thereof with an aminating agent;
  • R 1 and R 2 are as defined above.
  • R 1 is as defined above.
  • a piperidine derivative or a salt thereof represented by the general formula [IV] [Wherein, X and R 1 are as defined above. Or a salt thereof, and then reacting the compound [IV] or a salt thereof with an aminating agent to obtain a compound of the general formula [V]
  • R 1 and R 2 are as defined above. Or a salt thereof, and then removing the protecting group for the amino group represented by R 1 and the substituent on the amino group represented by R 2 of the compound [V] or a salt thereof. Characteristic, Formula [VI] II] or a salt thereof.
  • the present invention relates to a novel compound 41 (t- 1 ) in which R 1 is a t-butoxycarbonylamino group among the compounds represented by the formula [III], which are one of the raw materials of the production method of the present invention.
  • R 1 is a t-butoxycarbonylamino group among the compounds represented by the formula [III]
  • halogen atom means a chlorine atom, a bromine atom, a fluorine atom or an iodine atom, and among them, a chlorine atom, a bromine atom or an iodine atom is preferable, and a bromine atom is more preferable.
  • protected amino group means an amino group protected by a known amino group-protecting group.
  • the amino group-protecting group include a benzyl group, a P-methoxybenzyl group and a p-methoxybenzyl group.
  • An aralkyl group such as a nitrobenzyl group or a benzylhydryl group; a lower alkenyl group such as a formyl group, an acetyl group or a propionyl group; an aryl alkanol group such as a phenylacetyl group or a phenoxyacetyl group; A lower alkoxy group such as a methoxycarbonyl group, an ethoxycarbonyl group, an isobutoxycarbonyl group or a t-butoxycarbonyl group; An alkenyloxycarbonyl group such as a 2-propenyloxycarbonyl group; an aralkyloxycarbonyl group such as a benzyloxycarbonyl group or a p-dimethoxybenzyloxycarbonyl group; a trimethylsilyl group or the like. Examples thereof include lower alkylsilyl groups such as t-butylsilyl group and the like, and particularly
  • aminoating agent is a compound that can directly introduce an amino group into a compound to be aminated in one step, or after the reaction with a compound to be aminated, substitution on the amino group derived from the aminating agent.
  • the compound is not particularly limited as long as it can introduce an amino group by two steps of removing the group and converting it to an amino group. For example, the following formula:
  • MM 2 and M 3 may be the same or different, a hydrogen atom or an alkali metal atom, n is 1 or 2, Ra and R b may be the same or different, and a hydrogen atom ,
  • An aryl group, a benzyl group, a p-nitrobenzyl group, a p-methoxybenzyl group, a phenyl group or a formula: — Si (R la ) (R 2 a ) R 3 a (R la , R 2a fine R 3 a may be the same or different, a group represented by.) represents an alkyl group or an off Eniru group having 1 to 4 carbon atoms, R e and R d rather it may also be the same or different
  • alkali metal atom examples include a lithium atom, a sodium atom, a lithium atom, a cesium atom, and the like.
  • alkyl group having 1 to 4 carbon atoms examples include straight-chain or branched such as methyl group, ethyl group, propyl group, isopropyl group, butyl group and t-butyl group. Alkyl group, and among them, a methyl group and the like are preferable.
  • alkyl group having 1 to 10 carbon atoms in addition to the above alkyl groups,
  • Examples thereof include linear or branched alkyl groups such as isobutyl group, sec-butyl group, pentyl group, hexyl group, and heptyl group. Among them, propyl group, butyl group and benzyl group are preferable. It is.
  • aminating agent represented by are ammonia, arylamine, lithium arylamide, sodium arylamide, potassium arylamide, cesium arylamide, diarylamine, lithium diarylamide, sodium diarylamide, potassium diarylamide , Cesium diarylamide, dibenzylamine, lithium dibenzylamide, sodium dibenzylamide, potassium dibenzylamide, cesium dibenzylamide, benzylamine, lithium benzylamide, sodium benzylamide, potassium benzylamide, cesium benzylamide, P-methoxy Benzylamine, lithium amide, sodium amide, potassium amide, cesium amide, bis (trimethylsilyl) amine, lithium bis (Trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide or cesium bis (trimethylsilyl) amide, among which arylamine, bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide
  • aminating agent represented by are, for example, 2-iminopropane, 3-iminopentane, 4-iminoheptane, 5-iminononane, 1-phenylamino, Tan, 1-phenyl-11-iminopropane, benzophenoneimine, 1,4-phenyl-11-imiminobotan, iminocyclopropane, iminocyclobutane, iminocyclohexene, iminocyclohexane, iminocyclohepane, etc.
  • benzophenonyimine or arylamine is preferred.
  • benzophenone imine and the like are suitable.
  • the “salt” of the compound represented by the formula [III], [IV], [V] or [VI] means, for example, an acid addition salt at a basic nitrogen atom present in each compound.
  • Addition salts include inorganic salts such as, for example, hydrochloride, sulfate, nitrate, phosphate or perchlorate; for example, acetate, maleate, fumarate, succinate, tartrate, citrate Or organic carboxylate such as ascorbate; or organic sulfonic acid salt such as methanesulfonate, isethionate, benzenesulfonate or p-toluenesulfonate.
  • the inert solvent examples include alcohols such as methanol or ethanol; ethers such as jet ether, methyl t-butyl ether, tetrahydrofuran or dioxane; aromatic hydrocarbons such as benzene or toluene. Or a mixed solvent thereof, and particularly, methanol, ethanol, tetrahydrofuran, toluene or the like is preferable.
  • examples of the reducing agent include sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, diisobutylaluminum hydride or triacetoxyborohydride.
  • examples thereof include metal hydride complexes such as sodium, among which sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like are preferable.
  • the amount of the reducing agent to be used is generally about 1 mol to excess mol, preferably about 1 mol to 10 mol, per 1 mol of the pyridine derivative represented by the general formula [II].
  • the reaction temperature is usually about 130 to about 200, preferably about 0 t: about 100, and the reaction time is usually about instant to about 7 days, preferably about instant to 2 days. About 4 hours.
  • examples of the catalyst include palladium-carbon catalyst and Raney nickel catalyst.
  • the hydrogen pressure in the catalytic reduction reaction is usually preferably about normal pressure to about 2 atm.
  • the amount of the catalyst used is usually about 110 to 1 to 1 weight of the starting compound [II].
  • the amount is about twice, preferably about 1Z100 to 1/10 times.
  • the reaction temperature is usually about ⁇ 30: about 50, preferably about 0 to room temperature (room temperature means about 10 to 35, the same applies hereinafter).
  • the time is usually from instant to about 7 days, preferably from instant to about 24 hours.
  • This reaction can also be performed under weakly acidic conditions in which a Schiff base is easily formed.
  • Acids that can be used for pH adjustment therefor include, for example, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid and the like.
  • a pyridine derivative represented by the general formula [II] or a salt thereof and a piperidine derivative represented by the general formula [III] are not reacted in the presence of a reducing agent or under catalytic reduction.
  • a reducing agent or under catalytic reduction it is also possible to react the salt with a salt thereof to form an imine in advance, and then subject the imine to a reduction reaction.
  • the compound or a salt thereof can be purified or subjected to a reaction in the next step without purification.
  • reaction of the compound represented by the formula or a salt thereof with the aminating agent is usually carried out in an amount of about 1 mol to an excess of the aminating agent per 1 mol of the compound represented by the general formula [IV] or a salt thereof.
  • the reaction is carried out in an inert solvent which does not adversely influence the reaction, using about 1 to 2 moles, preferably about 1 to 2 moles.
  • the inert solvent examples include ethers such as getyl ether, methyl tert-butyl ether, tetrahydrofuran or dioxane; hydrocarbons such as pentane, hexane, heptane, benzene, toluene or xylene; or Examples thereof include a mixed solvent thereof, and particularly preferred are benzene, tetrahydrofuran and toluene.
  • the reaction temperature is usually about 0 to about 200, preferably room temperature to about 150.
  • the reaction time is usually about instant to about 7 days, preferably about instant to about 24 hours.
  • aminating agent used in this reaction is represented by the following formula:
  • reaction is preferably performed in the presence of a catalyst.
  • Ac is an acetyl group
  • Me is a methyl group
  • Ph is a phenyl group
  • C 6 H 5 Me is an o—, m—, p-tolylyl group
  • C 5 H 4 is a 2,4-cycloalkyl group. Shows Pentagen 11-yl. And the like, among which the following formula:
  • the amount of the catalyst to be used is generally about 1.0 mol or less, preferably about 0.2 mol or less, per 1 mol of the compound represented by the general formula [IV] or a salt thereof.
  • a ligand may be added in an amount of about 2.0 mol to about 1.0 mol% or less based on the catalyst used.
  • the ligand include triphenylphosphine and the following formula: :
  • a base may be added to facilitate the reaction.
  • the base include potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, cesium carbonate, potassium carbonate, sodium carbonate, and hydrogenated hydrogen.
  • examples thereof include sodium, potassium hydride, sodium hydroxide, cesium hydroxide, triethylamine and diisopropylethylamine. Among them, potassium t-butoxide, sodium t-butoxide and the like are preferable.
  • the amount of the base to be used is generally about 1.0 mol to 2.0 mol, preferably about 1.0 mol to 1.5 mol, per 1 mol of the compound represented by the general formula [IV] or a salt thereof. It is about a mole.
  • R 1 and R 2 are as defined above.
  • a salt thereof can be purified and isolated according to a conventional method.
  • the aminating agent has the following formula:
  • the optionally substituted amino group of R 2 in the compound represented by the general formula [V] is an arylamino group
  • the optionally substituted amino group of R 2 in the compound represented by the general formula [V] is represented by the following formula:
  • R cl and R dl both represent a phenyl group.
  • the compound represented by the general formula [V] is preferably a compound having the group.
  • the compound represented by the general formula [V] or a salt thereof is purified according to a conventional method, or without purification, if desired, and if desired, a protecting group for an amino group represented by R 1 and a protecting group represented by R 2 By appropriately performing the removal reaction of the substituent on the amino group, the formula [VI]
  • the removal of the protecting group for the amino group represented by R 1 in the compound represented by the general formula [V] or a salt thereof can be carried out by a method known per se, for example, a protective group-in-one organic synthesis (P For example, according to the method described in TW Green (TW Greene), John Wiley & Sons, Inc. (1981) or a method analogous thereto, for example, acid or base can be used. It can be carried out by solvolysis, chemical reduction using a metal hydride complex or catalytic reduction using a palladium-carbon catalyst or Raney nickel catalyst.
  • solvolysis with an acid it is usually in a solvent such as methylene chloride, anisol, tetrahydrofuran, dioxane, isopropyl acetate, methanol or ethanol, or a mixed solvent thereof with water.
  • a solvent such as methylene chloride, anisol, tetrahydrofuran, dioxane, isopropyl acetate, methanol or ethanol, or a mixed solvent thereof with water.
  • a solvent such as methylene chloride, anisol, tetrahydrofuran, dioxane, isopropyl acetate, methanol or ethanol, or a mixed solvent thereof with water.
  • a solvent such as methylene chloride, anisol, tetrahydrofuran, dioxane, isopropyl acetate, methanol or ethanol, or a mixed solvent thereof with water.
  • solvolysis with a base for example, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, isopropyl acetate or dioxane, or in a mixed solvent thereof with water, for example, lithium hydroxide, sodium hydroxide Alkali metal hydroxides such as triturium or hydroxylating lime, or alkali metal carbonates such as sodium bicarbonate, potassium bicarbonate, sodium carbonate or lithium bicarbonate, preferably from about -20 to about It can be carried out by operating at a temperature in the range of about 80 to about 10 minutes to 24 hours.
  • a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, isopropyl acetate or dioxane
  • water for example, lithium hydroxide, sodium hydroxide Alkali metal hydroxides such as triturium or hydroxylating lime, or alkali metal carbonates such as sodium bicarbonate, potassium bicarbonate,
  • catalytic reduction usually in a solvent such as methanol, ethanol, water or acetic acid, or in a mixed solvent thereof, for example, palladium-carbon catalyst, palladium hydroxide, Raney nickel or platinum oxide using a catalyst like, favored by properly about 1 to about 20 kgZcm 2 about hydrogen reduction, preferably to catalytic reduction about 10 minutes to 24 hours at a temperature in the range of from about 0 to about 4 about 0 More can be done.
  • a solvent such as methanol, ethanol, water or acetic acid
  • a mixed solvent thereof for example, palladium-carbon catalyst, palladium hydroxide, Raney nickel or platinum oxide using a catalyst like, favored by properly about 1 to about 20 kgZcm 2 about hydrogen reduction, preferably to catalytic reduction about 10 minutes to 24 hours at a temperature in the range of from about 0 to about 4 about 0 More can be done.
  • the reaction for removing the substituent on the amino group represented by R 2 can be carried out according to the same method as the above-described reaction for removing the protecting group for the amino group, or a method analogous thereto.
  • Examples of such a method include, in addition to Saul Jaime-Figueroa, Tetrahe dron Letters, Vol. 39, pp. 1313— 1 p. 316 (1998) or Florence Garo Helion (F 1 orence Garo—He 1 ion), as well as Journal of Organic Chemistry 58 Vol. 6109-1 61 13 (1993).
  • reaction for removing the protecting group for the amino group represented by R 1 and the reaction for removing the substituent on the amino group represented by R 2 can be carried out simultaneously or separately.
  • the reaction for obtaining the final target compound [I] is performed when the compound of the formula [V] or the formula [VI] is condensed with the compound of the formula [VII] to form an amide bond and R 2 is a substituted amino group. Is carried out by removing a substituent. This reaction may be performed according to a method known per se.
  • the compound of the formula [VI] obtained by the production method of the present invention can be prepared according to the method described in International Publication W098 / 05641 according to the highly selective muscarinic M3 receptor antagonistic activity disclosed in the publication. It can lead to a fluorine-containing 1,4-disubstituted piperidine derivative which is extremely useful as an agent for treating or preventing various respiratory diseases, urological diseases or digestive diseases.
  • the reaction with the carboxylic acid represented by the formula or a salt or a reactive derivative thereof is usually carried out by reacting the compound represented by the formula [VI] with respect to 1 mol of the carboxylic acid represented by the formula [VII] or 1 mol thereof.
  • the “salt” of a carboxylic acid represented by the formula [VII] means a base addition salt at a carboxyl group, for example, an alkaline metal salt such as a sodium salt or a magnesium salt; Alkaline earth metal salts such as salts; ammonium salts; for example, trimethylamine salts, triethylamine salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, proethanol salts or N, N'— Organic amine salts such as dibenzylethylenediamine salt are exemplified.
  • an alkaline metal salt such as a sodium salt or a magnesium salt
  • Alkaline earth metal salts such as salts
  • ammonium salts for example, trimethylamine salts, triethylamine salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, proethanol salts or N, N'— Organic amine salts
  • reactive derivative J of the carboxylic acid represented by the formula [V I I]
  • a mixed acid anhydride, an active ester or an active amide is used.
  • a carboxylic acid represented by the formula [VII] or a salt thereof for example, N, N'-dicyclohexylcarposimide, 1-ethyl-3- (3-dimethylaminopropyl) carposimide
  • a condensing agent such as diphenylphosphoryl azide, dipyridyl disulfide-triphenylphosphine, preferably 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide.
  • the amount of the condensing agent to be used is not strictly limited, but is usually represented by the formula [V I I
  • the reaction is usually performed in an inert solvent.
  • the inert solvent include dimethyl ether, tetrahydrofuran, N, N-dimethylformamide, dioxane, benzene, toluene, toluene, methylene chloride, and methylene chloride. Examples thereof include form, carbon tetrachloride, dichloroethane, and trichloroethylene, and a mixture of these solvents.
  • dimethyl ether, tetrahydrofuran, N, N-dimethylformamide, dioxane, and the like are preferable.
  • the reaction temperature is usually not about -70 and is the boiling point of the solvent used in the reaction, preferably about -20 to about 100.
  • the reaction time is generally about 5 minutes to 7 days, preferably about 10 minutes to 24 hours.
  • the above reaction can be performed in the presence of a base to smoothly advance the reaction.
  • Examples of the base include aliphatic tertiary amines such as triethylamine and diisopropylethylamine; and aromatic amines such as pyridine, 4-dimethylaminopyridine and quinoline. Among them, 4-dimethylaminopyridine Are preferred.
  • the amount of the base used is about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of the carboxylic acid represented by the formula [VII] or a salt or a reactive derivative thereof. It can be.
  • the mixed acid anhydride of the carboxylic acid of the formula [VII] can be obtained by converting a carboxylic acid of the formula [VII] according to a conventional method, for example, an alkyl carbonate such as ethyl ethyl carbonate; or an aliphatic carboxylic acid such as acetyl chloride or pivaloyl chloride. It can be obtained by reacting with acid chloride or the like.
  • the active ester of the carboxylic acid of the formula [VII] can be prepared by converting the carboxylic acid of the formula [VII] according to a conventional method, for example, N, N'-dicyclohexylcarbodiimide, 1-ethyl 3- (3-dimethylaminopropyl) carbodiimide
  • a hydrochloride or diphenyl condensing agent for example, N-hydroxysuccinimide, N-hydroxyphenyl N-hydroxy compounds such as tallimide or 1-hydroxybenzotriazole; phenol compounds such as 412 trophenol, 2,4-dinitrophenol, 2,4,5-trichlorophenol or pentachlorophenol And the like.
  • An active amide of a carboxylic acid of the formula [VII] can be prepared by converting a carboxylic acid of the formula [VII] according to a conventional method, for example, 1,1, '-l-ponyldiimidazole or 1,1'-carbonylbis (2-methylimidazole) or the like. And can be obtained by reacting
  • the compounds of the formulas [I], [IV], [V] or [VI] obtained by the above-mentioned production steps can be prepared by a method known per se, for example, column chromatography using silica gel, an adsorption resin, etc., liquid chromatography, Purification and isolation can be carried out using a conventional separation and purification method such as chromatography, thin-layer chromatography, solvent extraction or recrystallization / reprecipitation alone or in an appropriate combination.
  • the production intermediate can be used as a raw material in the next step without separation and purification.
  • the compound of the formula [I], [VI], [IV] or [V] obtained by the above-mentioned method can be converted into a pharmaceutically acceptable salt by a conventional method. Conversion to can also be performed according to a conventional method.
  • the pyridine derivative represented by the general formula [II] is exemplified by, for example: E. Parks, et al., Jana ⁇ l ⁇ o in Inorganic 'Chemistry (. ic Chemistry), Volume 10, pp. 2472-2478 (1971), D. Kai (Cai) et al., Tetrahedr on Lettsers, Volume 37, 2537 — 2540 (1996); and MA Peters (Peters on), et al., Journal of Organic 'Chemistry', 62, 8237. — 8 Manufactured and available by the method described on page 239 (1997).
  • the piperidine derivative represented by the general formula [III] or a salt thereof can be produced and obtained, for example, by the method described in JP-A-11-1472.
  • a novel substance 4- (t-butoxycarbonylamino) piperidine acetate in which R 1 is a t-butoxycarbonylamino group in the general formula [III] is commercially available 1-benzyl-14-aminobiperidine.
  • 1-benzyl-4-aminopiperidine can be prepared under a nitrogen atmosphere, for example, in an inert solvent such as methanol, ethanol, or tetrahydrofuran, for example, di-t-butyl dicarbonate or t-butoxycarbonyloxy.
  • the reaction is carried out at about 0 to room temperature, preferably about 0: 1 to 20 at about 0.5 to 2 hours using about 1 to 1 mole of a reagent such as amine.
  • a reagent such as amine.
  • the amino group can be protected by a t-butoxycarponyl group.
  • a catalyst such as palladium carbon or palladium hydroxide carbon is used in an amount of about 1% to 5% by weight based on the weight of 1-benzyl-4- (t-butoxycarbonylamino) piperidine.
  • Debenzylation can be carried out by reacting at about room temperature to about 4 O for about 5 hours to about 10 hours using about weight%.
  • 4- (t-butoxycarbonylamino) piperidineacetate was subjected to a method known per se, for example, a conventional separation and purification method such as solvent extraction or recrystallization / reprecipitation alone or as appropriate. It can be used in combination for purification and isolation.
  • 4- (t-Butoxycarbonylamino) piperidine acetate is a stable crystal, so it is easy to handle and does not require pH adjustment when used as a raw material in the next step.
  • debenzylation which is a process for producing 4- (t-butoxycarbonylamino) piperidine acetate
  • the reaction of debenzylation is completed in a shorter time than in the absence of acetic acid. Therefore, 4- (t-butoxycarbonylamino) piperidine acetate can be produced in high yield, and the generation of by-products is small.
  • the obtained reaction solution was filtered, and the cake collected by filtration was washed with methanol (20 OmL of methanol). The filtrate and the washing solution were combined, and concentrated to about 0.6 L under reduced pressure. Isopropyl acetate (2.0 L) was added to the obtained concentrated solution, and the mixture was concentrated under reduced pressure to about 1.3 L, and left at room temperature for 1 hour to crystallize. The crystals were collected by filtration, washed with isopropyl acetate (20 OmL), and then dried overnight under reduced pressure at room temperature and under a nitrogen stream. The title compound (258 g, 94.3%) was obtained as white crystals (258 g, 94.3%).
  • a toluene solution (3 L) containing 6-promo 2-forimylpyridine (721 g) obtained in Reference Example 2 was mixed at room temperature with 4- (t-butoxycarbonylamino) piperidine (1,060 g, 4. The mixture was added to a suspension consisting of 07mo1) and furan (3.5 L) in tetrahide mouth, and stirred at 15 to 20 for 1 hour. To the resulting solution was added a solution consisting of sodium triacetoxyborohydride (907 g, 4.07 mo 1) and dimethyl sulfoxide (3 L) at 15 to 20 over 4 hours. Stir for 5 hours.
  • reaction solution a solution composed of phthalic anhydride (115 g, 0.776 mol) and dimethyl sulfoxide (0.5 L), and the mixture was stirred at 15 to 20 for 0.5 hour. did.
  • the obtained reaction solution was cooled to 10, then 1N-sodium hydroxide (8 L) was added while keeping the temperature at 25 or less, and the temperature was brought to room temperature.
  • the organic layer was separated, washed with 20% by weight saline (4 L), concentrated at 60 to about 1.2 L under reduced pressure at 60, and n-heptane (12 L) was added at 70 over 1 hour. The mixture was cooled to room temperature for 1 hour, and left at 0 for 2 hours to complete crystallization.
  • Isopropyl acetate was added to the concentrate obtained in Example 4 to dilute to 1 L. This solution was poured into a 5% aqueous solution of citrate and stirred vigorously at room temperature for 40 minutes. The aqueous layer was separated, washed with isopropyl acetate (500 mL), and vigorously stirred with isopropyl acetate (1 L) and 5N aqueous sodium hydroxide at room temperature for 20 minutes. The organic layer was separated, washed with 7% saline (200 mL), and dried over anhydrous sodium sulfate. The solution was treated with activated carbon and filtered through celite. The filtrate is concentrated under reduced pressure to about 300 mL, and seeds are added. While stirring.
  • Methyl t-butyl ether (2 OmL) was added dropwise, and the mixture was stirred for 14 hours.
  • the crystals were collected by filtration, washed with a mixture of methanol and methyl t-butyl ether (1: 2, 15 mL), and dried under reduced pressure to obtain the title compound (3.55 g) in a yield of 98.4%.
  • the reaction solution was concentrated under reduced pressure, and the obtained residue was neutralized with a saturated sodium hydrogen carbonate solution and then extracted with ether.
  • the obtained ether layer was washed with saturated saline, then dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure.
  • the obtained residue was subjected to silica gel force chromatography (250 g, Co-gel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), black form: methanol: 28% ammonia (100: 1: 0 ⁇ 100: 5: 0.5)) to give the product (7.9 g) in a yield of 72.0%.
  • the obtained product was identified as the title compound because it was consistent with that of the compound of Example 20 described in International Publication No. WO 98/05641.
  • n-Butyllithium (1.5 mL of a 5.7 M hexane solution, 435 mmo 1) was added to tetrahedrofuran (250 mL), and 2,6-dibromopyridine (100 g, 422 mmo) was added to the mixture.
  • a solution prepared by dissolving 1) in tetrahydrofuran (650 mL) was maintained at ⁇ 70 below, and added dropwise over 43 minutes. The mixture was further stirred at 173 for 20 minutes.
  • N, N-Dimethylformamide (98 mL, 1266 mmo 1) was added dropwise to the reaction solution over 25 minutes while maintaining the following at -70, and the mixture was further stirred for 20 minutes.
  • n-Butyllithium (1.63 M hexane solution, 1230 g, 2.97 mol) was charged into a 20 L flask under a nitrogen atmosphere, and cooled to 110.
  • n-butylmagnesium chloride (713 g of a 2.00 M solution in tetrahydrofuran, 1.48 mol) was added dropwise over 20 minutes while keeping the pressure between 1 t and 0.
  • a solution of 2,6-dibromopyridine (1000 g, 4.22mo1) in toluene (7.5L) was maintained at -5 while maintaining the internal temperature. The mixture was added dropwise over time, and further stirred for 4 hours.
  • a compound useful as a therapeutic or prophylactic agent for various respiratory diseases, urinary diseases or digestive diseases in the field of medicine is produced in fewer steps and in a higher yield. can do.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne une méthode de préparation du composé de la formule (I) ou des sels dudit composé. La méthode consiste à provoquer une réaction en plaçant un composé de la formule générale (II) ou un sel dudit composé au contact d'un composé de la formule générale (III) ou d'un sel dudit composé, dans des conditions de réduction, pour obtenir un composé de la formule générale (IV) ou un sel dudit composé. La méthode consiste ensuite à provoquer une réaction en plaçant ce dernier composé ou son sel au contact d'un agent d'amination pour obtenir un composé de la formule générale (V) ou un sel dudit composé; à éliminer, si besoin est, le composé de la formule (V) ou son sel du groupe protecteur amino de R1 et du substituant amino de R2 pour obtenir un composé (VI) ou un sel dudit composé; à condenser le composé (V) ou son sel ou le composé (VI) ou son sel avec le composé (VII) et à éliminer le substituant amino de R2 si R2 est amino-substitué. L'invention concerne en outre l'utilisation d'intermédiaires des composés (IV) et (V) et des méthodes de préparation desdits intermédiaires. R1 est amino éventuellement protégé, R2 est amino éventuellement substitué et X est halogéno.
PCT/JP2000/002755 1999-04-28 2000-04-26 Methodes de preparation de derives de piperidylmethylpyridine WO2000066579A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU43147/00A AU4314700A (en) 1999-04-28 2000-04-26 Processes for the preparation of piperidylmethylpyridine derivatives

Applications Claiming Priority (2)

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JP11/123157 1999-04-28
JP12315799 1999-04-28

Publications (1)

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WO2000066579A1 true WO2000066579A1 (fr) 2000-11-09

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014514268A (ja) * 2011-03-08 2014-06-19 ジーイー・ヘルスケア・リミテッド Ｐｅｔ前駆体の製造

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996012718A1 (fr) * 1994-10-20 1996-05-02 Pierre Fabre Medicament NOVEL SUBSTITUTED 2-[1-(φ-PHENOXYALKYLPIPERIDIN-4-YL)AMINOMETHYLEN]-2H-BENZOFURAN-3-ONES, PREPARATION THEREOF AND THERAPEUTICAL APPLICATIONS
WO1997005134A1 (fr) * 1995-07-26 1997-02-13 Pierre Fabre Medicament Composes heterocycliques pour le traitement de l'ischemie myocardique
WO1997013766A1 (fr) * 1995-10-13 1997-04-17 Banyu Pharmaceutical Co., Ltd. Derives heteroaromatiques substitues
JPH09295981A (ja) * 1995-11-09 1997-11-18 Japan Tobacco Inc 縮合ヘテロ５員環アゼピン誘導体及びその医薬用途
WO1998005641A1 (fr) * 1996-08-01 1998-02-12 Banyu Pharmaceutical Co., Ltd. Derives de piperidine fluores a disubstitution en position 1,4

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996012718A1 (fr) * 1994-10-20 1996-05-02 Pierre Fabre Medicament NOVEL SUBSTITUTED 2-[1-(φ-PHENOXYALKYLPIPERIDIN-4-YL)AMINOMETHYLEN]-2H-BENZOFURAN-3-ONES, PREPARATION THEREOF AND THERAPEUTICAL APPLICATIONS
WO1997005134A1 (fr) * 1995-07-26 1997-02-13 Pierre Fabre Medicament Composes heterocycliques pour le traitement de l'ischemie myocardique
WO1997013766A1 (fr) * 1995-10-13 1997-04-17 Banyu Pharmaceutical Co., Ltd. Derives heteroaromatiques substitues
JPH09295981A (ja) * 1995-11-09 1997-11-18 Japan Tobacco Inc 縮合ヘテロ５員環アゼピン誘導体及びその医薬用途
WO1998005641A1 (fr) * 1996-08-01 1998-02-12 Banyu Pharmaceutical Co., Ltd. Derives de piperidine fluores a disubstitution en position 1,4

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014514268A (ja) * 2011-03-08 2014-06-19 ジーイー・ヘルスケア・リミテッド Ｐｅｔ前駆体の製造
US9242924B2 (en) 2011-03-08 2016-01-26 Ge Healthcare Limited Preparation of a 1-amino-3-hydroxy-cyclobutane-1-carboxylic acid derivative

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