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WO2001004088A1 - Procede de preparation de derives d'amiline - Google Patents

Procede de preparation de derives d'amiline Download PDF

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Publication number
WO2001004088A1
WO2001004088A1 PCT/JP2000/004588 JP0004588W WO0104088A1 WO 2001004088 A1 WO2001004088 A1 WO 2001004088A1 JP 0004588 W JP0004588 W JP 0004588W WO 0104088 A1 WO0104088 A1 WO 0104088A1
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Prior art keywords
compound represented
general formula
group
compound
alkyl group
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English (en)
Japanese (ja)
Inventor
Hitoshi Shimizu
Nobuaki Kimura
Megumi Ishii
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Chugai Pharmaceutical Co Ltd
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Chugai Pharmaceutical Co Ltd
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Priority to AU58514/00A priority Critical patent/AU5851400A/en
Publication of WO2001004088A1 publication Critical patent/WO2001004088A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/30—Isothioureas
    • C07C335/32—Isothioureas having sulfur atoms of isothiourea groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • 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 a method for producing an aniline derivative (see Background Art).
  • R 4 and R 5 may be the same or different and are each a hydrogen atom, a lower alkyl group, or together form a 3- to 8-membered ring.
  • ⁇ 2 , ⁇ 3 , ⁇ 4 may be the same or different, and each is a lower alkoxy group, a lower alkyl group, a lower alkyl group which may be substituted with a hydrogen atom, a halogen atom, or an aromatic hydrocarbon group.
  • No. 6,906,006, which has a nitric oxide synthase inhibitory action As such therapeutic agent for vascular disorders known to be useful. Methods for producing these compounds are described in the publication and the like.
  • the present invention provides a method for producing an aniline derivative shown below (in the following general formula, X represents a halogen atom.
  • X represents a halogen atom.
  • R 2 represents a lower alkoxy group
  • R 3 represents a lower alkyl group, a lower alkoxy group, or an aromatic hydrocarbon group
  • R 4 and R 5 may be the same or different, and each represents a hydrogen atom or a lower alkyl group.
  • ⁇ ⁇ 2 , ⁇ 3 , ⁇ 4 may be the same or different and each represents a hydrogen atom, a halogen atom, or an aromatic group.
  • ⁇ is an integer of 0 or 1. Indicate the number.
  • a compound represented by the general formula (5) is obtained by subjecting the phthalimide group of this compound to a deprotection reaction.
  • a compound represented by the general formula (2) is obtained by performing a deprotection reaction of a protecting group for an amino group of the compound using a deprotecting agent.
  • the present invention provides a method for producing an aniline derivative shown below (in the following general formula, X represents a halogen atom.
  • 1 ⁇ represents a lower alkyl group.
  • R 2 represents Represents a lower alkoxy group
  • R 3 represents a lower alkyl group, a lower alkoxy group, or an aromatic hydrocarbon group
  • 4 or 5 may be the same or different, and each represents a hydrogen atom
  • Y or Y 2 , ⁇ 3 , ⁇ 4 may be the same or different, and may represent a lower alkyl group or may form a 3- to 8-membered ring together;
  • Indicates metal or DBU ⁇ is an integer of 0 or 1 Indicate the number.
  • the compound represented by the general formula (2) is obtained by performing a deprotection reaction of a protecting group for an amino group of the compound using a deprotecting agent comprising an inorganic acid and an alcohol.
  • the compound represented by the general formula (2) is crystallized by adding an organic solvent without distilling off the inorganic acid and the alcohols.
  • a method for producing an inorganic acid salt is described
  • the present invention also provides a method for producing the aniline derivative shown below (in the following general formula, represents a lower alkyl group.
  • R 2 represents a lower alkoxy group.
  • R 3 represents Represents a lower alkyl group, a lower alkoxy group, or an aromatic hydrocarbon group, and R 4 and R 5 may be the same or different and each represent a hydrogen atom, a lower alkyl group, or ⁇ 2 , ⁇ 3 , and ⁇ 4 may be the same or different and are each substituted with a hydrogen atom, a halogen atom, or an aromatic hydrocarbon group.
  • ⁇ represents an integer of 0 or 1.
  • a compound represented by H-containing H (9) is obtained, and this compound is reacted with a base and water and / or alcohols to obtain a compound represented by the general formula (10).
  • the compound represented by formula (2) is obtained by obtaining a compound represented by formula (1) and performing a deprotection reaction of a protecting group for an amino group of the compound using a deprotecting agent. From the compound represented by the general formula (2)
  • the compound represented by the general formula (2) is crystallized by adding an organic solvent without distilling off the inorganic acid and the alcohol after producing the compound represented by the general formula (2).
  • a method for producing an inorganic acid salt is provided.
  • the present invention also provides a method for producing an aniline derivative shown below.
  • R 2 represents a lower alkoxy group.
  • R 3 represents a lower alkyl group, a lower alkoxy group, or an aromatic hydrocarbon group.
  • R 4 and R 5, which may be the same or different, are each a hydrogen atom, or a lower alkyl group, or, connexion 3 may form a 8-membered ring such together.
  • Y physician Upsilon 2, Upsilon 3 , Upsilon 4 may be the same or different and are each a water atom, a halogen atom, an aromatic hydrocarbon optionally substituted lower an alkoxy group, lower alkyl, which may have a substituent A good cyclic alkyl group having 3 to 6 carbon atoms, or — — 5 ⁇ 6 , wherein ⁇ 5 and ⁇ 6 may be the same or different, and are each a hydrogen atom, a lower alkyl group, or And together form a 3- to 8-membered ring . There ⁇ is an integer of 0 or 1).:
  • the compound represented by the general formula (9) is obtained by reacting this compound with a base, water and Z or an alcohol.
  • a compound represented by the general formula (2) is obtained by performing a deprotection reaction of a protecting group for an amino group of the compound using a deprotecting agent.
  • the compound represented by the general formula (9) is reacted with the compound represented by the general formula (8) to thereby form the compound represented by the general formula (9). Reacting this compound with water and Z or alcohols. Wherein the reaction for obtaining the compound represented by the general formula (10) is carried out in one pot.
  • the present invention also provides a method for producing the aniline derivative shown below (in the following general formula, represents a lower alkyl group.
  • R 2 represents a lower alkoxy group.
  • R 3 represents Represents a lower alkyl group, a lower alkoxy group, or an aromatic hydrocarbon group, and R 4 and R 5 may be the same or different and each represent a hydrogen atom, a lower alkyl group, or ⁇ 2 , ⁇ 3 , and ⁇ 4 may be the same or different and are each substituted with a hydrogen atom, a halogen atom, or an aromatic hydrocarbon group.
  • the atom, lower alkyl group, or together a connexion 3-8 membered ring may form the shape of ⁇ is an integer of 0 or 1).:
  • the compound represented by the general formula (10) is obtained by reacting this compound with a base, water and Z or an alcohol.
  • the compound After producing the compound represented by the formula, the compound is crystallized by adding an organic solvent without distilling off the inorganic acid and the alcohol, thereby obtaining the compound represented by the above general formula.
  • the present invention also provides a method for producing an aniline derivative shown below (in the following general formula, R 2 represents a lower alkoxy group.
  • R 4 and R 5 may be the same or different. Each represents a hydrogen atom, a lower alkyl group, or may be taken together to form a 3- to 8-membered ring, and Y 2 , ⁇ 3 , ⁇ 4 may be the same or different,
  • the present invention also provides a method for producing a thioperia derivative shown below (in the following general formula, R 2 represents a lower alkoxy group.
  • R 3 represents a lower alkyl group, a lower alkoxy group, or
  • R 4 and R 5 may be the same or different and each represent a hydrogen atom or a lower alkyl group, or together form a 3- to 8-membered ring ⁇ 2 , ⁇ 3 , ⁇ 4 may be the same or different, and each is a lower alkoxy group, a lower alkyl group, a lower alkyl group which may be substituted with a hydrogen atom, a halogen atom, an aromatic hydrocarbon group, an optionally substituted cyclic alkyl group having 3 to 6 carbon atoms or, represents a _ ⁇ 5 ⁇ 6, wherein, Upsilon 5, Upsilon 6, which may be the same or different, are each a hydrogen atom , Lower alkyl groups, Or may be taken together to form a 3-
  • the compound represented by the general formula (9) is obtained by reacting the compound with a base and water and ⁇ or an alcohol.
  • the present invention provides a method for producing an aniline derivative shown below (in the following general formula, represents a lower alkyl group.
  • R 2 represents a lower alkoxy group.
  • R 4 and R 5 may be the same or different, and each represents a hydrogen atom or a lower alkyl group, or may be taken together to form a 3- to 8-membered ring, Y or Y 2 , ⁇ 3 ,
  • Upsilon 4 may be the same or different, are each a hydrogen atom, a halogen atom, an aromatic hydrocarbon optionally substituted lower alkoxy group optionally substituted with a group, a lower alkyl group, optionally cyclic may have a substituent
  • the present invention provides a compound represented by the general formula (11), wherein the deprotection reaction of the protecting group for the amino group is carried out by using a deprotecting agent comprising an inorganic acid as the deprotecting agent. It is intended to provide a method for producing a compound represented by the formula (2) or an inorganic acid salt thereof.
  • anirin derivative represented by the following is a lower alkyl group.
  • 1 2 Oyobi 6 may be the same or different Each represents a lower alkoxy group, R 3 represents a lower alkyl group, a lower alkoxy group, or an aromatic hydrocarbon group, and R 4 and R 5 may be the same or different, and each represents a hydrogen atom Or a lower alkyl group or may be taken together to form a 3- to 8-membered ring ⁇ 2 , ⁇ 3 , ⁇ 4 may be the same or different, and each represents a hydrogen atom, a halogen, atoms, an aromatic hydrocarbon lower alkoxy group optionally substituted with a group, a lower alkyl group, a cyclic ring which may have a substituent alkyl group of 3-6 carbon atoms, or represents an ⁇ 5 ⁇ 6 , Where ⁇ 5 , ⁇ 6 May be the same or different, and may each be
  • the compound represented by the general formula (2) is obtained by performing a deprotection reaction of a protecting group for an amino group of the compound using a deprotecting agent comprising an inorganic acid.
  • a compound represented by the general formula (13) is obtained by reacting a compound represented by the general formula (12) with a compound represented by the general formula (8).
  • a process for producing a compound represented by the general formula (14) in a one-pot reaction by reacting the compound with a base, water, water or an alcohol.
  • anirin derivative represented by the following (the following general formula, 1 ⁇ is a lower alkyl group.
  • Feet 2 Oyobi 1 ⁇ 6 are the same or different Each represents a lower alkoxy group, R 3 represents a lower alkyl group, a lower alkoxy group, or an aromatic hydrocarbon group, and R 4 and R 5 may be the same or different, Each represents a hydrogen atom, a lower alkyl group, or may be taken together to form a 3- to 8-membered ring, ⁇ 2 , ⁇ 3 , ⁇ 4 may be the same or different, a hydrogen atom, a halogen atom, an aromatic hydrocarbon lower alkoxy group optionally substituted with a group, a lower alkyl group, a cyclic ring which may have a substituent alkyl group of 3-6 carbon atoms, or, one Nyuupushiron 5 indicates Upsilon 6, wherein, Upsilon 5 Upsilon
  • a method for producing a compound represented by H ⁇ 3 " 4 (2) which comprises converting a compound represented by the general formula (12) into a compound represented by the general formula (8):
  • the compound represented by the general formula (14) is obtained by reacting the compound with a base and water and / or alcohols.
  • the compound After producing the compound represented by the formula, the compound is crystallized by adding an organic solvent without distilling off the inorganic acid and the alcohol, thereby obtaining the compound represented by the above general formula.
  • the lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon chains, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl. Group, tert-butyl group, pentyl group, hexyl group and the like.
  • a methyl group, an ethyl group, and an isopropyl group are preferable, a methyl group and an ethyl group are more preferable, and an ethyl group is particularly preferable.
  • the lower alkyl group which may form a 3- to 8-membered ring together is a linear or branched alkyl group having 1 to 6 carbon atoms or 3 carbon atoms.
  • Examples of the linear or branched alkyl group having 1 to 6 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, sec Mono-butyl, tert-butyl, pentyl, hexyl, etc.
  • Examples of the cyclic alkyl group having 3 to 8 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Examples thereof include a cycloheptyl group and a cyclooctyl group, and a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group and a cyclopentyl group are preferred.
  • a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, and a cyclopentyl group are preferable, and a hydrogen atom, a methyl group, an ethyl group, A cyclopropyl group, a cyclobutyl group and a cyclopentyl group are preferred, and a hydrogen atom is particularly preferred.
  • a methyl group and an ethyl group are preferred.
  • examples of the cyclic C 3-6 alkyl group include a cyclopropyl group and a cyclobutyl group And a cyclopentyl group and a cyclohexyl group, and a cyclopropyl group, a cyclobutyl group and a cyclopentyl group are preferred.
  • the lower alkoxy group means an alkoxy group in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms, such as methoxy, ethoxy, ⁇ -propoxy, isopropoxy, and ⁇ . —Butoxy, sec —butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy And so on.
  • a methoxy group, an ethoxy group and a tert-butoxy group are preferred.
  • the aromatic hydrocarbon substituted lower ⁇ alkoxy group optionally substituted with a group in Upsilon 4, a methoxy group, an ethoxy group, eta - propoxy group, iso epoxy group, .eta. butoxy group, sec _ Butoxy group, isobutoxy group, tert-butoxy group, pentyloxy group, hexyloxy group, benzyloxy group and the like are preferable, and methoxy group, ethoxy group and benzyloxy group are particularly preferable.
  • aromatic hydrocarbon group examples include a phenyl group, a tolyl group, and a naphthyl group, and a phenyl group is preferable.
  • Halogen atom refers to fluorine, chlorine, bromine and iodine.
  • halogen atom for X chlorine and bromine are preferable.
  • the halogen atom in Y 2 , 3 and 4 is preferably a chlorine atom, a fluorine atom or a bromine atom, more preferably a chlorine atom or a fluorine atom.
  • the 3- to 8-membered ring which may be formed together includes, for example, an aziridine-1-yl group, an azeridin-1-yl group, a pyrrolidine-1-yl group, a piperidine — 1-yl group, preferably pyrrolidine-1-yl group and piperidine-1-yl group, more preferably pyrrolidine-1-yl group.
  • Upsilon 5 is a hydrogen atom, a methyl group, Echiru group, pyrrolidin - 1 Iru group, piperidine - 1-I le group are preferable, a hydrogen atom, a methyl group, Echiru group, Pi port lysine - 1 An r group is preferred.
  • ⁇ represents an integer of 0 or 1, and is preferably 0.
  • the group represented by — (CH 2 ) n CR 4 R 5 NH 2 is preferably a meta-position or a para-position with respect to the alkylisothioperia group, Further Is preferably in the meta position.
  • Examples of the alkali metal in I ⁇ include lithium, sodium, potassium, rubidium, and cesium, with sodium and potassium being preferred.
  • Examples of alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, pentanol, and hexanol.
  • Examples of the inorganic acid include hydrochloric acid, sulfuric acid, nitric acid and the like.
  • Examples of the organic acid include acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, tartaric acid, methanesulfonic acid, and trifluoroacetic acid.
  • DBU means 1,8-diazabicyclo [5.4.0] pendase 7-ene.
  • diluting agent examples include di-tert-butyl dicarbonate, tert-butylazidoformate, 2-tert-butoxycarbonyloxyimino-2--2-phenylacetonitrile, and S-tert-butoxy. Carbonyl-4,6-dimethyl-12-mercaptopyrimidine; [p_ (tert-butoxycarbonyloxy) phenyl] dimethylsulfonium methanesulfonate;
  • Performing the reaction in one pot means that when performing a plurality of reactions, the reactions are performed without isolating or purifying the reaction product of each reaction.
  • the in-pot reaction referred to here includes not only a case where a single reaction vessel is used, but also a case where a plurality of reaction vessels are used without isolation and purification, for example, when a reaction vessel is moved.
  • Esters include methyl acetate, ethyl acetate, butyl acetate and the like.
  • ethers include getyl ether, tetrahydrofuran, dioxane, and the like.
  • reaction route 1 An example of the production method of the present invention is shown below (reaction route 1). Reaction path 1 Phthalimidization
  • X,. 1 ⁇ is that a halogen atom, a lower alkyl group.
  • R 2 represents a lower alkoxy group.
  • 1 4 Oyobi 1 ⁇ 5 may be the same or different, Each may be a hydrogen atom, a lower alkyl group, or may be taken together to form a 3- to 8-membered ring, and ⁇ 2 , ⁇ 3 , ⁇ 4 may be the same or different, and Atom, halogen atom, lower alkoxy group, lower alkyl group, cyclic group which may have a substituent Represents an alkyl group having 3 to 6 carbon atoms.
  • n represents an integer of 0 or 1.
  • a compound represented by the general formula (4) is obtained by reacting a compound represented by the general formula (1) with a compound represented by the general formula (3).
  • the compound represented by the general formula (3) used in the phthalimidation reaction includes, for example, alkali metal salts of phthalimide such as sodium phthalimide and potassium phthalimide, and phthalimide DBU salt. Is preferred.
  • the solvent to be used is preferably a solvent that does not affect the reaction, for example, dimethylformamide, acetonitrile, and the like are preferable, and dimethylformamide is particularly preferable.
  • the reaction temperature is preferably about 0 to 80 T: more preferably about 30 ° C.
  • the reaction time is preferably from about 30 minutes to 3 hours, particularly preferably from 1 hour to 2 hours.
  • the obtained compound represented by the general formula (4) is subjected to a deprotection reaction to deprotect a phthalimide group.
  • the deprotecting agent include hydrazine, a methylamine methanol solution, a methylamine aqueous solution and the like, and preferably a methylamine methanol solution and a methylamine aqueous solution. Of these, a 40% methylamine methanol solution and a 40% methylamine aqueous solution are preferable, and a 40% methylamine methanol solution is particularly preferable.
  • the solvent used is preferably a solvent that does not affect the reaction, for example, methanol, acetonitrile, and the like are preferable, and methanol is particularly preferable.
  • the reaction temperature is preferably from 0 ° C. to the boiling point of the reaction mixture, and particularly preferably a temperature near the boiling point of the reaction mixture.
  • the reaction time is about 30 minutes to 5 hours, preferably about 1 hour to 2 hours.
  • the obtained compound represented by the general formula (5) is reacted with a carboxylate agent to convert an amino group into a propyl bamate, and the nitro group is reduced, whereby the compound represented by the general formula (7) is obtained. Get.
  • di-tert-butyl dicarbonate for example, di-tert-butyl dicarbonate, tert-butyl azidoformate, 2-tert-butoxycarponyloxy minnow 2 —Phenylacetonitrile, S—tert-butoxycarbonyl _ 4, 6-Dimethyl-2-mercaptopyrimidine, [p- (tert-butoxycarbonyloxy) phenyl] dimethylsulfonium methanesulfonate, etc., and di-tert-butyl dicarbonate is preferred.
  • the solvent used is preferably a solvent that does not affect the reaction, for example, ethyl acetate, toluene, tert-methyl methyl ether, and the like are preferable, and ethyl acetate is particularly preferable.
  • the reaction temperature is preferably from 110 to the boiling point of the reaction mixture, more preferably from 5 ° C to the boiling point of the reaction mixture.
  • the reaction time is about 30 minutes to 3 hours, preferably about 2 hours.
  • the reduction reaction of the nitro group in the second step can be performed by a usual catalytic hydrogenation reaction, but catalytic hydrogenation using a palladium-carbon catalyst is preferable.
  • the hydrogen source ammonium formate and the like can be used in addition to hydrogen.
  • the catalytic hydrogenation reaction may be performed under pressure.
  • the solvent used is preferably a solvent that does not affect the reaction, for example, alcohols are preferable, and methanol is particularly preferable.
  • the reaction temperature is preferably from 1 ° C. to the boiling point of the reaction mixture, particularly preferably about 40 to 60.
  • the reaction time is about 1 to 5 hours, preferably about 2 to 3 hours.
  • the obtained compound represented by the general formula (7) is reacted with the compound represented by the general formula (8) to form an acylthiodiarea.
  • the acyl group is removed by hydrolysis or solvolysis.
  • the acylthioureation, hydrolysis or solvolysis reaction is preferably performed in one pot.
  • the solvent used is preferably a solvent that does not affect the reaction, for example, acetone, toluene, ethyl acetate and the like are preferable, and acetone is particularly preferable.
  • the reaction temperature is preferably a temperature from 0 "C to the boiling point of the reaction mixture.
  • the reaction time is from about 30 minutes to about 3 hours, and preferably from about 30 minutes to about 1 hour.
  • the removal is carried out by a conventional method of hydrolysis or solvolysis of an acyl group, preferably by deprotection under basic conditions, for example, potassium carbonate, sodium hydroxide, or carbonate.
  • Inorganic bases such as sodium hydrogen and the like, metal alkoxides such as sodium methoxide and sodium methoxide, etc. are preferable, and potassium carbonate is preferable.
  • the reaction solvent used does not affect the reaction. Solvent is preferable, for example, water, alcohols and the like are preferable, and methanol is particularly preferable.
  • the reaction temperature includes a temperature from 0 to the boiling point of the reaction mixture, and a temperature near the boiling point of the reaction mixture is preferable.
  • the reaction time is about 30 minutes to about 1 hour, preferably about 30 minutes. If this acylthioureation, hydrolysis or carosol decomposition reaction is performed in one pot, after the completion of the first-stage acylthioureation reaction, only the second-stage reaction solvent and base need to be added, and the first-stage reaction solvent is distilled off. do not have to.
  • the compound represented by the general formula (8) used in the acylthioureation reaction a commercially available compound may be used, or the compound may be synthesized from an acid halide and a thiocyanic acid compound.
  • examples of the compound represented by the general formula (8) include benzoyl thiocyanate and ethoxycarbonyl isothiocyanate, and benzoyl thiocyanate is preferable.
  • the compound represented by the general formula (8) is synthesized from an acid halide and a thiocyanate compound, a known method, for example, described in JP-A-8-269006
  • the acid halide used include, for example, benzoyl chloride, acetyl chloride, and the like.
  • Benzoyl chloride is preferred.
  • the thioic acid compound used include: Examples thereof include metal salts of potassium thiocyanate such as potassium thiocyanate and sodium thiocyanate, and ammonium thiocyanate, with sodium thiocyanate being preferred.
  • An alkylating agent is allowed to act on the obtained compound represented by the general formula (10) to alkylate the thiourea group.
  • the alkylating agent include an alkyl halide, a dialkyl sulfate, and an alkyl sulfonate, and an alkyl halide is preferable.
  • the solvent to be used is preferably a solvent which does not affect the reaction, for example, acetone, ethyl acetate, acetonitrile, alcohols and the like are preferable, and ethyl acetate is particularly preferable.
  • the reaction temperature is preferably from room temperature to the boiling point of the reaction mixture, and particularly preferably a temperature near the boiling point of the reaction mixture.
  • the reaction time is preferably about 30 minutes to 3 hours, particularly preferably about 1 hour to 2 hours.
  • the deprotection reaction of the protecting group for the amino group of the compound represented by the general formula (11) is carried out by a usual deprotection method.
  • the deprotecting agent include inorganic acids and organic acids, with inorganic acids being preferred.
  • inorganic acids include hydrochloric acid, sulfuric acid, nitric acid And hydrochloric acid is preferred.
  • the solvent used in the deprotection reaction include alcohols, and ethanol is preferable, but alcohols need not be used. That is, the deprotecting agent used in this deprotection reaction is preferably an ethanolic hydrochloric acid solution, particularly preferably a 4N ethanolic hydrochloric acid solution.
  • the reaction temperature is from 0 to the boiling point of the reaction mixture, and preferably about 50.
  • the reaction time is about 30 minutes to 3 hours, preferably about 2 hours.
  • the obtained inorganic acid salt of the compound represented by the general formula (2) may optionally be subjected to a reaction solvent after the completion of the deprotection reaction of the protecting group for the amino group of the compound represented by the general formula (11). It can be produced by crystallization by adding an organic solvent or the like without leaving. Examples of the organic solvent include esters and ethers, and esters are preferable, and ethyl acetate is particularly preferable.
  • the crystallization temperature is preferably from about 0 to room temperature, particularly preferably about 25.
  • the crystallization time is preferably about 1 to 3 hours, particularly preferably about 1.5 to 2 hours.
  • the inorganic acid salt of the compound represented by the general formula (2) is produced by adding an inorganic acid and an organic solvent to the compound represented by the general formula (2), if necessary. be able to.
  • ⁇ 5 and ⁇ 6 are May be the same or different, and may each be a hydrogen atom, a lower alkyl group, or may be taken together to form a 3- to 8-membered ring.
  • Upsilon have Upsilon 2, Upsilon 3, among Upsilon 4, at least one of an ⁇ 5 ⁇ 6 compounds (here, Upsilon 5, Upsilon 6 represent.
  • a compound represented by the general formula (4), wherein at least one of ⁇ 2 , ⁇ 3 and ⁇ 4 is — ⁇ 5 ⁇ 6 (where ⁇ 5 and ⁇ 6 are ) can be produced by a known method, for example, a method described in JP-A-8-269006.
  • the compound represented by the general formula (2) is obtained by using the compound represented by the general formula (5) as a starting material, after the reaction of the reaction formula 1 with the compound represented by the general formula (5). It can be manufactured by going through the same steps as the above steps.
  • the compound represented by the general formula (5) can be obtained by a known method, for example, a method described in Japanese Patent Application Laid-Open No. 8-269006, in addition to the method disclosed in the present specification. Can also be manufactured.
  • the compound represented by the general formula (2) is obtained by using the compound represented by the general formula (7) as a starting material in the same manner as the subsequent steps of the acylthiourea-forming reaction of the general formula (7) in the above reaction path 1. It can be manufactured through a process.
  • the compound represented by (7) can be produced by a known method, for example, a method described in JP-A-8-269006, in addition to the method disclosed in the present specification.
  • the compound represented by the general formula (2) is obtained by using the compound represented by the general formula (12) as a starting material in the same manner as in the steps after the acylthiourea reaction of the general formula (7) in the above reaction path 1.
  • the compound represented by the general formula (12) can be produced by a known method, for example, a method described in JP-A-8-269006.
  • the compound represented by the general formula (12) can be obtained by starting from the compound represented by the general formula (1) as a starting material, for example, the method disclosed in the present specification, for example, Examples 50 and 51. It can also be manufactured by a manufacturing method.
  • the multiple of the capacity with respect to the weight value indicates a capacity obtained by multiplying the multiple of the capacity per 1 kg of weight by 1 L.
  • “dissolving 3-nitrobenzyl chloride in dimethylformamide (5 times the weight of 3-nitrobenzyl chloride)” means “3-nitrobenzyl chloride is 5 L of dimethyl per 1 kg of 3-nitrobenzyl chloride. Dissolves in formamide.
  • Example 2 Synthesis of tert-butyl N- (3-aminobenzyl) potassium rubbamate 40% methylamine was added to a mixture of the compound obtained in Example 1 and methanol (10 times the weight of the compound obtained in Example 1). A methanol solution (10 equivalents to the compound obtained in Example 1) is added, and the mixture is refluxed for 1 hour.
  • the reaction solution was concentrated under reduced pressure, and after purging with nitrogen, methanol (5 times the weight of the compound obtained in Example 1) and 10% palladium-carbon (50% water content, 2 mol 1%) is added to the obtained compound, and the mixture is heated at an internal temperature of 50. Subsequently, the atmosphere is replaced with hydrogen and stirred for 3 hours. The reaction solution is filtered, and the filtrate is concentrated under reduced pressure. Methanol (5 times the weight of the compound obtained in Example 1) and water (7 times the weight of the compound obtained in Example 1) are reduced to 25%. After stirring for 30 minutes, water (1 volume of the compound obtained in Example 1) was added, and the mixture was stirred for 30 minutes, cooled to 0, and stirred for 1 hour.
  • Example 3 To a mixture of the compound obtained in Example 3 and ethyl acetate (5 times the weight of the compound obtained in Example 3) was added methyl iodide (1.5% by weight of the compound obtained in Example 3) as a reactant. And reflux for 1.5 hours. The reaction solution is cooled to 25 ° C, methanol (1.5 times the weight of the compound obtained in Example 3) is added, and the mixture is heated and dissolved. The organic layer is washed twice with an aqueous saturated sodium bicarbonate solution (5 times the weight of the compound obtained in Example 3), and then washed with saturated saline (5 times the weight of the compound obtained in Example 3).
  • Example 5 Synthesis of N- (3-aminomethylphenyl) -1-S-methylisothiourea.dihydrochloride
  • Example 6 Synthesis of tert-butyl N- (3- (S-ethylisothioureido) benzyl) carbamate
  • Example 7 Synthesis of N- (3-aminomethylphenyl) -l-S-ethylisothiodrea, dihydrochloride
  • Example 50 Synthesis of di-tert-butyl N- (3-nitrobenzyl) iminodicarboxylate
  • Example 52 2 Synthesis of di-tert-butyl N- (3-thioperidobenzyl) iminodicarboxylate
  • Example 53 Synthesis of di-tert-butyl N- (3- (S-methylthioureidobenzyl) iminodicarboxylate
  • Example 54 Synthesis of N- (3- (aminomethylphenyl) -S-methylisothiourea dihydrochloride
  • Example 55 Synthesis of di-tert-butyl N- (3- (S-ethylthioureidobenzyl) iminodicarboxylate Using the compound obtained in Example 52 as a starting material, the title compound is obtained in the same manner as in Example 6.
  • Example 56 Synthesis of N- (3- (aminomethylphenyl) -S-ethylisothiourea dihydrochloride
  • Example 55 Using the compound obtained in Example 55 as a starting material, the title compound is obtained in the same manner as in Example 7.
  • Tables 1 to 5 further show production examples according to the present invention.
  • the table shows the chemical formulas of the starting materials and the final products and the preparation methods.
  • “1, 2, 3, 4, 5” means the same as the method described in Examples 1, 2, 3, 4, and 5 described above. Means to do.
  • Example 67 To a mixture of the compound (6.5 kg) obtained in Example 67 and methanol (51.4 kg) was added a 40% methylamine-methanol solution (17.0 kg), and the mixture was heated under reflux for 1 hour. After the reaction solution was concentrated under reduced pressure, ethyl acetate (47.0 kg) was added. Cool the suspension to 5 ° C, add di-tert-butyl dicarbonate (8.6 kg), stir at 5 for 30 minutes, stir at 25 ° C for 30 minutes, and heat for 1 hour Refluxed. The mixture was cooled to 51 :, a 40% methylamine-methanol solution (2.1 kg) was added, and the mixture was stirred for 30 minutes.
  • the reaction solution was concentrated under reduced pressure, and after purging with nitrogen, methanol (25.7 kg) and 10% palladium-carbon (0.9 kg) were added to the concentrate, and the mixture was heated to an internal temperature of 30. Subsequently, the atmosphere was replaced with hydrogen and stirred for 3 hours.
  • the reaction solution was filtered, the filtrate was concentrated under reduced pressure, methanol (25.7 kg) and water (45.5 kg) were added at 25, and the mixture was stirred for 30 minutes, and then water (6.5 kg) was further added. After stirring for 30 minutes, the mixture was cooled to 0 and stirred for 1 hour. The resulting suspension is filtered and the filtrate is filtered.
  • Example 68 After cooling a mixture of sodium thiocyanate (1.5 kg) and acetone (16.6 kg) to 5, adding benzoyl chloride (2.3 kg) and stirring for 30 minutes, it was obtained in Example 68. The compound (3.5 kg) was added. After stirring at 5 for 5 minutes, the mixture was heated under reflux for 30 minutes. After cooling the reaction solution to 30 ° C, methanol (13.9 kg) and potassium carbonate (2.5 kg) were added, and the mixture was heated under reflux for 30 minutes. The reaction solution was concentrated under reduced pressure, ethyl acetate and water (15.8 kg and 17.5 kg) were added, and the mixture was heated under reflux to dissolve the concentrate, cooled to 30 and the ethyl acetate layer was concentrated under reduced pressure. .
  • Example 69 Compound obtained in Example 69 (3.4 kg) and ethyl acetate (15.3 kg) The mixture was heated under reflux for 1.5 hours using iodo chill (2.7 k) as a reactant. The reaction solution was cooled to 25, methanol (4.0 kg) was added, and the mixture was dissolved by heating. The organic layer was washed twice with a saturated aqueous sodium hydrogen carbonate solution (17.0 kg), and then washed with a saturated saline solution (17.0 kg). The organic layer was concentrated under reduced pressure, ethanol (8.0 kg) was added to dissolve the concentrate, water (6.2 kg) and seed crystals (3.4 g) were added at 25 ° C, and the mixture was stirred for 1 hour. .
  • Example 70 To a compound (2.8 kg) obtained in Example 70 was added a 4N hydrochloric acid ethanol solution (10.
  • the purification in each reaction step required to obtain a purified product of the final product can be performed only by recrystallization without using column chromatography; ⁇ ) — Carbamate formation of the amino group of the compound represented by the general formula (5) and reduction reaction of the nitro group of the compound represented by the general formula (6) can be performed in one pot.
  • the number of steps can be reduced as compared to conventional production methods, such as the ability to convert the compound represented by acylthiourea and the removal of the acyl group by hydrolysis or solvolysis in one pot;
  • Crystallization can be achieved only by adding an organic solvent without removing the reaction solvent such as hydrochloric acid to obtain a purified product of the final product.

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Abstract

Cette invention concerne un procédé de préparations d'hydrochlorures de composés correspondant à la formule générale (2) où R1 représente alkyle inférieur. R4 et R5 représentent chacun hydrogène ou analogue, Y1, Y2, Y3 et Y4 représentent chacun hydrogène ou analogue, tandis que n est égal à 0 ou 1. Ce procédé se caractérise en ce que l'on transforme un composé correspondant à la formule générale (2), où X représente halogéno, en un phtalimide. On effectue ensuite le déblocage du groupe phtalimide. On effectue ensuite tant la transformation du groupe amino résultant en un groupe carbamate que la réduction du groupe nitro dans un même pot, on alkyle le groupe thio-urée résultant, n retire le groupe de protection amino à l'aide d'acide chlorhydrique et d'un alcool, puis on cristallise le composé résultant en ajoutant un solvant organique sans retirer l'acide chlorhydrique ni l'alcool. Ce procédé permet d'effectuer une réduction dans un certain nombre d'étapes par rapport aux procédés précédents, d'améliorer l'atmosphère de travail grâce à l'utilisation de réactifs et de solvants plus sûrs, d'améliorer la sécurité du travail, etc., ce qui permet de l'utiliser dans des processus industriels.
PCT/JP2000/004588 1999-07-09 2000-07-10 Procede de preparation de derives d'amiline Ceased WO2001004088A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU58514/00A AU5851400A (en) 1999-07-09 2000-07-10 Process for the preparation of aniline derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP11/195438 1999-07-09
JP19543899 1999-07-09

Publications (1)

Publication Number Publication Date
WO2001004088A1 true WO2001004088A1 (fr) 2001-01-18

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996009286A1 (fr) * 1994-09-20 1996-03-28 Astra Aktiebolag Derives d'isothiouree en tant qu'inhibiteurs de no synthase
WO1997006162A1 (fr) * 1995-08-07 1997-02-20 Zeneca Limited Synthese en un seul creuset de derives de 2-oxazolidinone
EP0798292A1 (fr) * 1994-12-12 1997-10-01 Chugai Seiyaku Kabushiki Kaisha Derives d'aniline a activite inhibant la monoxyde d'azote synthase
WO1998028257A1 (fr) * 1996-12-24 1998-07-02 Chugai Seiyaku Kabushiki Kaisha Derives d'amine aromatiques ayant une action inhibitrice a l'egard des nos

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996009286A1 (fr) * 1994-09-20 1996-03-28 Astra Aktiebolag Derives d'isothiouree en tant qu'inhibiteurs de no synthase
EP0798292A1 (fr) * 1994-12-12 1997-10-01 Chugai Seiyaku Kabushiki Kaisha Derives d'aniline a activite inhibant la monoxyde d'azote synthase
WO1997006162A1 (fr) * 1995-08-07 1997-02-20 Zeneca Limited Synthese en un seul creuset de derives de 2-oxazolidinone
WO1998028257A1 (fr) * 1996-12-24 1998-07-02 Chugai Seiyaku Kabushiki Kaisha Derives d'amine aromatiques ayant une action inhibitrice a l'egard des nos

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