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WO2010119877A1 - Procédé pour la production d'un dérivé d'amidine - Google Patents

Procédé pour la production d'un dérivé d'amidine Download PDF

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Publication number
WO2010119877A1
WO2010119877A1 PCT/JP2010/056624 JP2010056624W WO2010119877A1 WO 2010119877 A1 WO2010119877 A1 WO 2010119877A1 JP 2010056624 W JP2010056624 W JP 2010056624W WO 2010119877 A1 WO2010119877 A1 WO 2010119877A1
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Prior art keywords
group
hydroxyethoxy
compound
salt
acid
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English (en)
Japanese (ja)
Inventor
康太朗 岡戸
宣博 山中
さとみ 大塚
真 室野井
範康 片岡
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Ajinomoto Co Inc
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Ajinomoto Co Inc
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
    • C07C259/18—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to carbon atoms of six-membered aromatic rings

Definitions

  • the present invention relates to a method for producing an amidine derivative having inhibitory activity on activated blood coagulation factor X (hereinafter sometimes abbreviated as FXa). Further, the present invention relates to a novel compound useful as a synthetic intermediate for a compound applied to the production method.
  • FXa activated blood coagulation factor X
  • the extracorporeal blood circulation is an artificial blood circulation that passes through a blood circuit built outside the living body.
  • blood extracorporeal circulation is a circulation circuit that retransmits blood into the living body from a living body through an artificial blood flow path outside the body, and further through a device that performs a certain treatment, for example, an artificial heart-lung machine, a blood purification device, etc. Is done by.
  • Extracorporeal blood treatment may be required during blood purification therapy such as hemodialysis, blood filtration, hemodialysis fluid excess, blood festival exchange, and cardiopulmonary bypass during open heart surgery.
  • a typical example of the blood purification apparatus is a dialyzer.
  • Blood extracorporeal circuit consisting of artificial blood flow path and various devices during extracorporeal blood circulation is a foreign substance, and blood coagulates when it comes in contact with it, so it is necessary to take measures to prevent blood coagulation in extracorporeal blood circulation circuit by some method is there.
  • anti-blood coagulants such as unfractionated heparin and low molecular weight heparin have been used for the purpose of preventing thrombus in this extracorporeal circuit.
  • unfractionated heparin has thrombin inhibitory activity in addition to FXa inhibitory activity, there is a known risk of bleeding tendency and it cannot be used for patients with high bleeding risk.
  • low molecular weight heparin is a drug that chemically treats heparin to more selectively inhibit FXa against thrombin and has no thrombin inhibitory activity, thus reducing the risk of bleeding tendency and bleeding tendency Used for patients with
  • low molecular weight heparin since low molecular weight heparin has a long elimination half-life, it is difficult to stop bleeding when bleeding symptoms are observed.
  • Some serine protease inhibitors also have anticoagulant activity, for example, naphthostat mesylate is used during some extracorporeal circulation such as hemodialysis.
  • Nahuamostat mesylate is also used for patients who already have bleeding lesions because of its short elimination half-life in vivo.
  • nahuamostat mesylate has a weak inhibitory activity against FXa and thrombin and has a weak anticoagulant effect.
  • all drugs still have problems, and more effective and safe drugs are required.
  • a patient with an extracorporeal circuit has a problem of blood coagulation only when the circuit is used, and the situation is often different from a patient who must always prevent blood coagulation.
  • a selective small molecule FXa inhibitor with a short blood half-life can be safely and conveniently used as an anticoagulant for preventing blood coagulation for the extracorporeal circulation circuit. In the past, it has never been expected to reduce the amount to a minimum.
  • amidine compounds described in Patent Documents 1 to 3 are known as amidine compounds exhibiting anticoagulant activity based on FXa selective inhibitory action.
  • A′-COO-B ′ having an ester bond in the molecule described in Patent Document 3 [A ′ and B ′ represent an organic group, at least one of which includes an amidino group or a guanidino group structure]
  • the amidine derivative has an excellent activated blood coagulation factor X inhibitory activity and a short blood half-life, and was useful as a blood coagulation inhibitor for blood extracorporeal circuits.
  • the amidine derivative is specifically a compound shown below.
  • Patent Document 3 discloses a synthesis method via an alkyl bond forming reaction (alkyl bond forming route). This method is, for example, as follows, and a final compound is synthesized from the main skeleton formation through a plurality of side chain modifications.
  • X is a halogen atom
  • R is an alkyl group which may have a substituent
  • the process leading from the formation of the main skeleton to the drug substance is generally carried out in a controlled manufacturing facility that complies with the standards (GMP) of the regulatory authorities in each country, and advanced quality control and process control are performed. It takes a lot of cost to make it necessary. Therefore, simplification of the manufacturing process after the formation of the main skeleton is extremely important because it not only facilitates manufacturing and quality control, but also shortens the production period and reduces manufacturing costs. Therefore, there is a demand for a production method that can form the main skeleton in a shorter process than the alkyl bond formation route and obtain the drug substance.
  • the present invention relates to a production method suitable for industrialization of an amidine derivative having an ester bond, which is a highly useful compound as a drug having an anticoagulant action.
  • the present invention relates to a method for producing an amidine derivative having a target ester bond in a simple and high yield.
  • the present inventors can easily convert the amidine derivative having the desired ester bond into a high yield. For the first time. As a result of further intensive studies based on these findings, the present inventors have completed the present invention.
  • Ring A is a C 6-14 aryl group, a heteroaryl group, a nitrogen-containing non-aromatic heterocyclic group or a C 3-10 cycloalkyl group
  • V represents a hydrogen atom, a halogen atom, a C 1-10 alkyl group which may have a substituent, a C 1-10 alkoxy group which may have a substituent, or a substituent.
  • a C 1-10 alkylamino group, an optionally substituted C 1-10 alkylthio group, a cyano group, a nitro group, or an optionally substituted carbamoyl group, W is a heteroaryl group, or the following formula (A), (B) or (C)
  • Q represents a C 1-6 alkyl group, an optionally substituted amino group or a nitrogen-containing heterocyclic group having a bond to the nitrogen atom
  • R represents a C 1-6 alkyl group
  • m represents an integer of 1 to 3
  • Ring C represents a nitrogen-containing heterocyclic group
  • Y represents any of a nitrogen atom, an oxygen atom, a sulfur atom or a methylene group
  • Z represents a hydrogen atom, an amidino group which may be substituted with C 1-6 alkyl, or a C 1-6 alkyl group which may have imino at the 1-position
  • X is a halogen atom
  • An acid halide represented by the formula hereinafter sometimes referred to as “compound (1)” or “acid halide (1)”) or a salt thereof;
  • Ring B is a C 6-14 aryl group, a heteroaryl group, a nitrogen-containing non-aromatic heterocyclic group or a C 3-10 cycloalkyl group
  • T represents a hydrogen atom, a halogen atom, a hydroxy group, a C 1-10 alkoxy group which may have a substituent, an acyloxy group which may have a substituent, or a carbamoyl which may have a substituent.
  • An oxy group, an optionally substituted thiocarbamoyloxy group, an amino group, a cyano group, a nitro group, an optionally substituted C 1-10 alkyl group, and an optionally substituted group A good C 1-10 alkylamino group, an optionally substituted C 1-10 alkylthio group, an optionally substituted acylamino group, a carboxyl group, an optionally substituted C 1-10 alkoxy-carbonyl group, an optionally substituted carbamoyl group, or an optionally substituted thiocarbamoyl group, U has a hydrogen atom, an optionally substituted C 1-10 alkyl group, a carboxyl group, an optionally substituted C 1-10 alkoxy-carbonyl group, or a substituent.
  • a carbamoyl group that may be L is a nitrogen atom, oxygen atom, sulfur atom or methylene group, and n is an integer of 1 to 3)
  • a compound represented by formula (4) (hereinafter, may be referred to as “compound (3)” or “amidine compound (3)”) or a salt thereof:
  • each symbol is the same as [1].
  • the compound (3) or a salt thereof is condensed with a condensing agent.
  • the compound (1) or a salt thereof obtained by reacting the compound (2) or a salt thereof with an acid halogenating agent is condensed with the compound (3) or a salt thereof without isolation.
  • R ′′ is an optionally substituted C 1-10 alkyl group, and other symbols are the same as those in [1]
  • a compound (4) or a salt thereof characterized by condensing an ester compound represented by the formula (hereinafter sometimes referred to as “compound (5)”) or a salt thereof with a compound (3) or a salt thereof.
  • Salt production method [7] Ring A and ring B are a C 6-14 aryl group, V and U are hydrogen atoms, W is the formula (A)
  • T is hydrogen atom, hydroxy group, C 1-10 alkoxy or optionally C 1-10 alkoxy group optionally substituted by cyano
  • T ' is a hydroxy group, a C 1-10 alkoxy group or C 1-10 alkoxy group optionally substituted by cyano
  • compound (3 ′) 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine or a salt thereof; 4-hydroxy-3- (2-hydroxyethoxy) benzamidine or a salt thereof; 3- (2-hydroxyethoxy) -4-methoxybenzamidine or a salt thereof; 4-ethoxy-3- (2-hydroxyethoxy) benzamidine or a salt thereof; and a compound selected from 3- (2-hydroxyethoxy) -4- (2-methylpropoxy) benzamidine or a salt thereof; [10] 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine, or a hydrochloride thereof; 4-hydroxy-3- (2-hydroxyethoxy) benzamidine acetate and hydrochloride; 3- (2-hydroxyethoxy) -4
  • T ′′ is a sodium atom, a hydrogen atom, or a C 1-10 alkyl group which may be substituted with C 1-10 alkoxy; G is a cyano group or substituted with hydroxy; A good amidino group
  • compound (3 ′′) is a salt thereof (hereinafter sometimes referred to as “compound (3 ′′)”);
  • T ′ ′′ is a C 1-10 alkyl group substituted with C 1-10 alkoxy
  • R ′ ′′ is a hydrogen atom or a C 1-10 alkyl group.
  • a salt thereof hereinafter sometimes referred to as “compound (3 ′ ′′)”
  • R ′ is an alkoxy group which may have a substituent or a halogen atom
  • Q ′′ is a bond to a C 1-10 alkoxy group, an amino group which may have a substituent or a nitrogen atom.
  • an amidine derivative having an ester bond which is a highly useful compound as a drug having an anticoagulant action, easily and in high yield through fewer steps than the alkyl bond formation route.
  • the present invention has the following formula
  • a new method for producing an amidine derivative (4) having an ester bond, which is a highly useful compound as a drug having an anticoagulant action (hereinafter referred to as “the production method of the present invention”). And was completed based on the discovery that compound (4) can be produced by reacting compound (1), compound (2) or compound (5) with compound (3). . By this production method, the compound (4) can be produced simply and with high yield.
  • novel compound of compound (3) As will be described later, a novel compound of compound (3), a synthetic intermediate useful for obtaining compound (3), and compound (1) for producing compound (4) of the present invention. These novel compounds and the novel compound (5) are also included in the present invention.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom unless otherwise specified.
  • C 1-6 alkyl group means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethyl unless otherwise specified. It means propyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
  • examples of the “C 2-10 alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3- Methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl, etc. Is mentioned. Of these, a C 2-6 alkenyl group is preferable.
  • examples of the “C 2-10 alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- Examples include pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like. Of these, a C 2-6 alkynyl group is preferable.
  • C 1-6 alkoxy group means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy and the like unless otherwise specified. To do.
  • the “C 6-14 aryl group” means a monocyclic or bicyclic aromatic hydrocarbon ring group having 6 to 14 carbon atoms, or a 5- to 8-membered cycloalkyl ring (for example, a phenyl group) , Cyclopentane ring, cyclohexane ring, cycloheptane ring, cyclooctane ring and the like).
  • the C 6-14 aryl group may have a substituent described later.
  • Specific examples of the “C 6-14 aryl group” include a phenyl group, a naphthyl group, an indanyl group, and a tetrahydronaphthalenyl group. Of these, a C 6-10 aryl group is preferable, a phenyl group and a naphthyl group are more preferable, and a phenyl group is particularly preferable.
  • the “heteroaryl group” is a 4- to 7-membered monocyclic ring containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring-constituting atom.
  • an aromatic heterocyclic group having a formula and 8- to 12-membered fused aromatic heterocyclic group examples include a ring corresponding to these 4- to 7-membered monocyclic aromatic heterocyclic groups and a 5- or 6-membered aromatic heterocyclic ring containing 1 or 2 nitrogen atoms.
  • the heteroaryl group usually has 1 to 10 carbon atoms, preferably 1 to 9 carbon atoms.
  • Specific examples of such heteroaryl groups include pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (eg, 2-pyridinyl).
  • non-aromatic heterocyclic group that is, aliphatic heterocyclic group
  • the “non-aromatic heterocyclic group” includes 1 hetero atom selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to a carbon atom as a ring-constituting atom.
  • a 4- to 7-membered monocyclic non-aromatic heterocyclic group and an 8- to 12-membered condensed non-aromatic heterocyclic group containing ⁇ 4 are shown.
  • Examples of the fused non-aromatic heterocyclic group include, for example, a ring corresponding to the 4- to 7-membered monocyclic non-aromatic heterocyclic group, and a 5- or 6-membered aromatic group containing 1 or 2 nitrogen atoms.
  • 1 or 2 rings selected from a heterocycle eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine
  • a 5-membered aromatic heterocycle containing one sulfur atom eg, thiophene
  • a benzene ring examples thereof include a group derived from a condensed ring and a group obtained by partial saturation of the group.
  • the non-aromatic heterocyclic group preferably has 1 to 9 carbon atoms. Any carbon atom that is a ring-constituting atom may be substituted with an oxo group.
  • non-aromatic heterocyclic ring from which the non-aromatic heterocyclic group is derived include, for example, pyrrolidine ring, pyrazolidine ring, imidazolidine ring, pyrroline ring, pyrazoline ring, imidazoline ring, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydro Quinoline ring, tetrahydroisoquinoline ring, thiazolidine ring, piperidine ring, piperazine ring, quinuclidine ring, tetrahydropyran ring, morpholine ring, thiomorpholine ring, dioxolane ring, homopiperidine ring, homopiperazine ring, indoline ring, isoindoline ring, chroman ring And an isochroman ring.
  • Such non-aromatic heterocyclic groups include pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl), piperidinyl (eg, piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), homopiperidinyl, morpholinyl (eg, Morpholino), thiomorpholinyl (eg, thiomorpholino), piperazinyl (eg, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl), homopiperazinyl, hexamethyleneiminyl (eg, hexamethyleneimine-1-yl), oxazolidinyl (eg, Oxazolidin-2-yl), thiazolidinyl (eg, thiazolidin-2-yl), dihydrothiopyranyl (eg, dihydrothiopyran-3-yl, dihydrothiopyran-4-yl), imi
  • a non-aromatic heterocyclic group having 2 to 8 carbon atoms is preferable, more preferably pyrrolidinyl, pyrrolinyl, tetrahydrofuryl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperidinyl, homopiperazinyl, particularly preferably pyrrolidinyl, Piperidinyl and homopiperidinyl.
  • nitrogen-containing non-aromatic heterocyclic group that is, nitrogen-containing aliphatic heterocyclic group
  • nitrogen-containing non-aromatic heterocyclic group refers to a non-aromatic heterocyclic group containing a nitrogen atom in the ring.
  • nitrogen-containing non-aromatic heterocyclic group generally include nitrogen-containing non-aromatic heterocyclic groups having 1 to 9 carbon atoms (preferably 2 to 9 carbon atoms, more preferably 2 to 8 carbon atoms).
  • the “C 3-10 cycloalkyl group” represents a saturated or unsaturated cyclic aliphatic hydrocarbon group having 3 to 10 carbon atoms, and partially has an unsaturated bond in the ring. May be included. Further, it may be monocyclic or polycyclic. Examples of the C 3-10 cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexenyl, cyclopentenyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.
  • C 1-10 alkyl group or “C 1-10 alkylthio group”, “C 1-10 alkylamino group”, “C 1-10 alkoxy group”, “C 1-10 alkoxy-”
  • the C 1-10 alkyl group moiety in the “carbonyl group” and the like is a linear or branched alkyl group having 1 to 10 carbon atoms, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl.
  • a C 1-6 alkyl group is preferable, a methyl group, an ethyl group, an isopropyl group, and an isobutyl group are more preferable, and an alkyl group having 1 to 3 carbon atoms (a methyl group, an ethyl group, and an isopropyl group) is most preferable.
  • examples of the “C 1-10 alkylthio group” include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group, a sec-butylthio group, a tert-butylthio group, and a pentylthio group.
  • Isopentylthio group Isopentylthio group, neopentylthio group, hexylthio group, heptylthio group, octylthio group, nonylthio group, decylthio group, 1,1-dimethyl-propylthio group and the like.
  • examples of the “C 1-10 alkylamino group” include a methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, sec-butylamino group, tert.
  • examples of the “C 1-10 alkylsulfonamide group” include a methylsulfonamide group, an ethylsulfonamide group, a propylsulfonamide group, an isopropylsulfonamide group, a butylsulfonamide group, an isobutylsulfonamide group, sec-butylsulfonamide group, tert-butylsulfonamide group, cyclopropylmethylsulfonamide group, pentylsulfonamide group, isopentylsulfonamide group, neopentylsulfonamide group, hexylsulfonamide group, heptylsulfonamide group, octylsulfone Amide group, nonylsulfonamide group, decylsulfonamide group, 1,1-dimethyl-propylsulfonamide group, cyclopropy
  • examples of the “C 1-10 alkoxy group” include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, and a pentyloxy group.
  • it is a C 1-6 alkoxy group.
  • examples of the “C 1-10 alkoxy-carbonyl group” include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, and a sec-butoxycarbonyl group.
  • acyl group in the “acyl group”, “acyloxy group”, “acylamino group” and the like in this specification includes a formyl group, a C 1-10 alkyl-carbonyl group (for example, an acetyl group, an ethylcarbonyl group, a propyl group).
  • Carbonyl group isopropylcarbonyl group, butylcarbonyl group, isobutylcarbonyl group, sec-butylcarbonyl group, tert-butylcarbonyl group, cyclopropylmethylcarbonyl group, pentylcarbonyl group, isopentylcarbonyl group, neopentylcarbonyl group, hexylcarbonyl group , Heptylcarbonyl group, octylcarbonyl group, nonylcarbonyl group, 1,1-dimethyl-propylcarbonyl group, cyclopropylcarbonyl group, cyclobutylcarbonyl group, cyclopentylcarbonyl group, cyclohexyl group, A silcarbonyl group, a cycloheptylcarbonyl group, a cyclooctylcarbonyl group, etc.), a C 6-10 aryl-carbonyl group (for example, a benzo
  • examples of the “acyloxy group” include a formyloxy group, an alkylcarbonyloxy group having 2 to 10 carbon atoms (for example, an acetyloxy group, an ethylcarbonyloxy group, a propylcarbonyloxy group, an isopropylcarbonyloxy group, Butylcarbonyloxy group, isobutylcarbonyloxy group, sec-butylcarbonyloxy group, tert-butylcarbonyloxy group, pentylcarbonyloxy group, isopentylcarbonyloxy group, neopentylcarbonyloxy group, hexylcarbonyloxy group, heptylcarbonyloxy group Octylcarbonyloxy group, nonylcarbonyloxy group, 1,1-dimethyl-propylcarbonyloxy group, etc.), C 6-10 aryl-carbonyloxy group (for example, benzoyloxy group) Etc.).
  • examples of the “acylamino group” include a formylamino group, a C 1-10 alkyl-carbonylamino group (for example, acetylamino group, ethylcarbonylamino group, propylcarbonylamino group, isopropylcarbonylamino group, butyl Carbonylamino group, isobutylcarbonylamino group, sec-butylcarbonylamino group, tert-butylcarbonylamino group, pentylcarbonylamino group, isopentylcarbonylamino group, neopentylcarbonylamino group, hexylcarbonylamino group, heptylcarbonylamino group, octyl carbonylamino group, nonyl carbonylamino group, 1,1-dimethyl - propyl carbonylamino group, etc.), C 6-10 aryl - carbonyl amino group (e
  • the “nitrogen-containing heterocyclic group” refers to the “nitrogen-containing non-aromatic heterocyclic group” defined above and the “heteroaryl group” defined above having a nitrogen atom in the ring.
  • a nitrogen-containing heterocyclic group having 2 to 8 carbon atoms is preferred, more preferably a pyrrolidinyl group, piperidinyl group, homopiperidinyl group, morpholinyl group, thiomorpholinyl group, piperazinyl group, pyrrolinyl group, imidazolyl group, pyridyl group, pyrrolyl group, More preferred are pyrrolidinyl group, piperidinyl group, morpholinyl group, thiomorpholinyl group, and piperazinyl group.
  • alkylamino group in this specification, or “carbamoyl or thiocarbamoyl substituted with an alkyl group (which may have a substituent, carbamoyl group, thiocarbamoyl group, carbamoyloxy group, thiocarbamoyloxy group)
  • the alkylamino moiety as a component such as “in which the substituent is an alkyl group” includes a monoalkylamino group and a dialkylamino group.
  • the alkyl group may be bonded to form a ring (for example, a nitrogen-containing heterocycle of the nitrogen-containing heterocyclic group).
  • the “amidino group” in the present specification refers to a group represented by H 2 N—C ( ⁇ NH) —.
  • each substituent “which may have a substituent” for example, (1) a halogen atom, (2) a hydroxy group, (3) an amino group, (4) a C 1-10 alkyl group, (5) C 2-10 alkenyl group, (6) a C 2-10 alkynyl group, (7) a C 1-10 alkoxy group, (8) a C 1-10 alkylamino group, (9) a cyano group, (10) a guanidino group, (11) a carboxyl group, (12) a carbamoyl group, (13) a C 6-14 aryl group, (14) a heteroaryl group, (15) a C 3-10 cycloalkyl group, (16) a nitrogen-containing non-aromatic heterocyclic group, (17) a C 1-10 alkylthio group, (18) an acyloxy group, (19) an acylamino group, (20) a C 1-10 alkylsulfona
  • compound (1), compound (2), compound (3), compound (4) and compound (5) of the present invention include various stereoisomers such as geometric isomers, tautomers and optical isomers. And mixtures thereof and isolated ones.
  • X in the compound (1) is a halogen atom, preferably a chlorine atom.
  • Examples of the group represented by ring A in compound (1), compound (2), compound (4) and compound (5) include a C 6-14 aryl group, a heteroaryl group, a nitrogen-containing non-aromatic heterocyclic group or A C 3-10 cycloalkyl group, preferably a C 6-14 aryl group, and particularly preferably a phenyl group.
  • the positions of the substituents V and W on the ring A and the carbonyl group are not particularly limited as long as they are substitutable positions on the ring A. However, when the ring A is a phenyl group, the substitution position of the carbonyl group is 1 In the case of W, W is preferably 4th.
  • V in the compound (1), the compound (2), the compound (4) and the compound (5) is a hydrogen atom, a halogen atom, a C 1-10 alkyl group which may have a substituent, or a substituent.
  • compound (2) As W in compound (1), compound (2), compound (4) and compound (5), heteroaryl group, or the following formula (A), (B) or (C)
  • Q represents a C 1-6 alkyl group, an optionally substituted amino group or a nitrogen-containing heterocyclic group having a bond to the nitrogen atom
  • R represents a C 1-6 alkyl group
  • m represents an integer of 1 to 3
  • Ring C represents a nitrogen-containing heterocyclic group
  • Y represents any of a nitrogen atom, an oxygen atom, a sulfur atom or a methylene group
  • Z represents a hydrogen atom, an amidino group which may be substituted with C 1-6 alkyl, or a C 1-6 alkyl group which may have imino at the 1-position
  • W is preferably a formula (A)
  • Q is a nitrogen-containing non-aromatic heterocyclic group having a bond at the nitrogen atom), and more preferably an imino (pyrrolidin-1-yl) methyl group.
  • the group represented by ring B is a C 6-14 aryl group, a heteroaryl group, a nitrogen-containing non-aromatic heterocyclic group or a C 3-10 cycloalkyl group, A C 6-14 aryl group is preferred, and a phenyl group is particularly preferred.
  • the position of the substituents T, L and amidino group on ring B is not particularly limited as long as it is a substitutable position on ring B, but ring B is a phenyl group, and the position of substitution of the amidino group is In the first position, T is preferably the 4th position, and L is preferably the 3rd position.
  • a hydrogen atom, a halogen atom, a hydroxy group, an optionally substituted C 1-10 alkoxy group, and an optionally substituted acyloxy group A carbamoyloxy group which may have a substituent, a thiocarbamoyloxy group which may have a substituent, an amino group, a cyano group, a nitro group, or a C 1-10 which may have a substituent
  • An alkyl group, an optionally substituted C 1-10 alkylamino group, an optionally substituted C 1-10 alkylthio group, an optionally substituted acylamino group, a carboxyl group , which may have a substituent C 1-10 alkoxy - carbonyl group, which may have a substituent carbamoyl group or an optionally substituted thiocarbamoyl group Preferably, a hydrogen atom, hydroxy group, methoxy group, ethoxy group, prop
  • U in the compounds (3) and (4) is a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a carboxyl group, or a C 1-10 alkoxy which may have a substituent.
  • -A carbonyl group or an optionally substituted carbamoyl group preferably a hydrogen atom or a C 1-10 alkyl group, more preferably a hydrogen atom.
  • L in the compounds (3) and (4) is a nitrogen atom (—NH—), an oxygen atom (—O—), a sulfur atom (—S—) or a methylene group (—CH 2 —), preferably Is a nitrogen atom, an oxygen atom, or a sulfur atom, more preferably an oxygen atom or a sulfur atom, and particularly preferably an oxygen atom.
  • N in the compound (3) and the compound (4) is an integer of 1 to 3, preferably 1 or 2, and more preferably 1.
  • Compound (1) The compound (1) in the production method of the present invention has the formula (1)
  • Ring A represents a C 6-14 aryl group, a heteroaryl group, a nitrogen-containing non-aromatic heterocyclic group or a C 3-10 cycloalkyl group
  • V represents a hydrogen atom, a halogen atom, a C 1-10 alkyl group which may have a substituent, a C 1-10 alkoxy group which may have a substituent, or a substituent.
  • W is a heteroaryl group, or the following formula (A), (B) or (C)
  • Q represents a C 1-6 alkyl group, an optionally substituted amino group or a nitrogen-containing heterocyclic group having a bond to the nitrogen atom
  • R represents a C 1-6 alkyl group
  • m represents an integer of 1 to 3
  • Ring C represents a nitrogen-containing heterocyclic group
  • Y represents any of a nitrogen atom, an oxygen atom, a sulfur atom or a methylene group
  • Z represents a hydrogen atom, an amidino group which may be substituted with C 1-6 alkyl, or a C 1-6 alkyl group which may have imino at the 1-position
  • X represents a halogen atom
  • the positions of the substituents V, W and the carbonyl group on the ring A are not particularly limited as long as they are substitutable positions on the ring A.
  • W is preferably the 4th place where is the 1st place.
  • ring A is preferably a C 6-14 aryl group
  • V is a hydrogen atom
  • W is represented by the formula (A)
  • Q is a nitrogen-containing non-aromatic heterocyclic group having a bond to the nitrogen atom
  • X is a halogen atom, more preferably ring
  • Particularly preferred is 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid chloride.
  • the 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid chloride exemplified as the compound (1) is a novel compound.
  • the said compound can be preferably used as a compound (1) applied to the manufacturing method of this invention.
  • the salt may be a chemically acceptable salt.
  • Organic salts such as ammonium salts, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, aluminum salts, zinc salts, triethylamine, ethanolamine, morpholine, piperidine, dicyclohexylamine
  • salts with amines and salts with basic amino acids such as arginine and lysine.
  • a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, etc.
  • TFA trifluoroacetic acid
  • the compound (1) and a necessary acid or base are mixed in an appropriate amount ratio in a solvent or a dispersant, or cation exchange or anion exchange is carried out from other salt forms. It can also be obtained by doing.
  • compound (1) when W of compound (1) is a basic group, compound (1) is a salt with a strong acid (for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, etc.) Can be preferably formed.
  • a strong acid for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, etc.
  • hydrochloric acid is preferable as the strong acid.
  • Compound (1) includes a solvate of compound (1).
  • Compound (1) can be obtained by reacting compound (2) described later with an acid halogenating agent, or can be produced by applying a method known per se.
  • the acid halogenating agent to be applied is any commercially available reagent that can be used for the acid halogenation reaction.
  • the acid halogenating agent can be used, and as such an acid halogenating agent, thionyl chloride, oxalyl chloride, phosphorus pentachloride, phosphoryl chloride, dichlorotriphenylphosphorane, thionyl bromide, dibromotriphenylphosphorane, Examples include cyanuric fluoride (DAST).
  • a preferred acid halogenating agent is thionyl chloride.
  • the acid halogenation reaction proceeds without adding a catalyst, but according to a conventional method, an amide-based reagent such as N, N-dimethylformamide (DMF) or N-methyl-2-pyrrolidone (NMP), or 1, An imide-based reagent such as 3-dimethyl-2-imidazolidinone (DMI) can be added from a catalytic amount to a solvent amount.
  • an organic solvent that is generally commercially available and can be used for an acid halogenation reaction or the like can also be used as necessary.
  • the organic solvent can also contain the above amide or imide reagent.
  • the amount of the acid halogenating agent used is 1 mol to 7 mol, preferably 1.7 mol to 3.5 mol, per 1 mol of compound (2).
  • the reaction time is usually 1 to 10 hours, preferably 2 to 3 hours.
  • the reaction temperature is usually ⁇ 40 ° C. to 200 ° C., preferably 70 ° C. to 90 ° C.
  • the amount of the acid halogenating agent to be used is 1 to 3 mol, preferably 1.0 to 1.2 mol, per 1 mol of compound (2).
  • the reaction time is 10 minutes to 10 hours, preferably 1 to 2 hours.
  • the reaction temperature is usually ⁇ 40 ° C. to 200 ° C., preferably 0 to 20 ° C.
  • the compound (1) can be applied to the production method of the present invention without isolation as described later.
  • the acid halogenated reaction product of the compound (2) is used. By adding a poor solvent to the solution containing it, it precipitates as a solid and can be isolated by a general solid-liquid separation method.
  • compound (1 ') or a salt thereof among compound (1) or a salt thereof is a novel compound.
  • Compound (1 ') can be in the form of a salt as with Compound (1), but the salt in that case may be a chemically acceptable salt.
  • the chemically acceptable salt include those described above for the compound (1), among which strong acids (for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid) Etc.) are preferred.
  • strong acids for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid) Etc.
  • a strong acid is preferably hydrochloric acid.
  • Compound (2) reacts with the acid halogenating agent described above at the carboxyl group portion to form Compound (1).
  • the position of the substituents V, W and the carbonyl group on ring A is not particularly limited as long as it is a substitutable position on ring A, but when ring A is a phenyl group, the position of substitution of the carbonyl group is the 1st position.
  • W is preferably fourth.
  • ring A is preferably a C 6-14 aryl group
  • V is a hydrogen atom
  • W is represented by the formula (A)
  • Q is a nitrogen-containing non-aromatic heterocyclic group having a bond to the nitrogen atom
  • ring A is a phenyl group
  • V is A compound which is a hydrogen atom
  • W represents an imino (pyrrolidin-1-yl) methyl group
  • Q is a pyrrolidin-1-yl group
  • the salt may be a chemically acceptable salt.
  • Organic salts such as ammonium salts, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, aluminum salts, zinc salts, triethylamine, ethanolamine, morpholine, piperidine, dicyclohexylamine
  • salts with amines and salts with basic amino acids such as arginine and lysine.
  • a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, etc.
  • TFA trifluoroacetic acid
  • the compound (2) and a necessary acid or base are mixed in an appropriate amount ratio in a solvent or a dispersant, or cation exchange or anion exchange is carried out from other salt forms. It can also be obtained by doing.
  • compound (2) when W of compound (2) represents a basic group, compound (2) is a salt with a strong acid (for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, etc.) Can be preferably formed.
  • a strong acid for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, etc.
  • hydrochloric acid is preferable as the strong acid.
  • Compound (2) includes solvates of compound (2), such as hydrates and alcohol adducts.
  • Compound (2) can be produced by a method known per se.
  • a compound in which ring A is a C 6-14 aryl group and W is a group represented by formula (A) can be produced, for example, by the following method.
  • the amidine derivative can be synthesized from 4-cyanobenzoic acid with reference to International Publication WO1998 / 31661, International Publication WO1999 / 47503 and International Publication WO2006 / 083003.
  • R ′′ is an optionally substituted C 1-10 alkyl group, and other symbols are the same as those described for compound (1) above) It is an ester compound represented by these.
  • the positions of the substituents V and W on the ring A and the alkoxycarbonyl group are not particularly limited as long as they are substitutable positions on the ring A. However, when the ring A is a phenyl group, the position of the alkoxycarbonyl group is changed. In the case of 1st place, W is preferably 4th place.
  • R ′′ is a C 1-10 alkyl group
  • ring A is a C 6-14 aryl group
  • V is a hydrogen atom
  • W is a compound of the formula (A)
  • R ′′ is a C 1-6 alkyl group.
  • Ring A is a phenyl group
  • V is a hydrogen atom
  • W is an imino (pyrrolidin-1-yl) methyl group (where Q is a pyrrolidin-1-yl group)
  • a particularly preferred compound is methyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate.
  • the salt may be a chemically acceptable salt.
  • Organic salts such as ammonium salts, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, aluminum salts, zinc salts, triethylamine, ethanolamine, morpholine, piperidine, dicyclohexylamine
  • salts with amines and salts with basic amino acids such as arginine and lysine.
  • a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, etc.
  • TFA trifluoroacetic acid
  • the compound (5) and a necessary acid or base are mixed in an appropriate amount ratio in a solvent or a dispersant, or cation exchange or anion exchange is carried out from other salt forms. It can also be obtained by doing.
  • compound (5) when W of compound (5) represents a basic group, compound (5) is a salt with a strong acid (for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, etc.) Can be preferably formed.
  • a strong acid for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, etc.
  • hydrochloric acid is preferable as the strong acid.
  • Compound (5) includes solvates of compound (5), such as hydrates and alcohol adducts.
  • 4- [Imino (pyrrolidin-1-yl) methyl] benzoic acid methyl chloride is easily prepared by, for example, methyl esterification of 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride and methanol. Can be manufactured.
  • methyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate hydrochloride can also be produced by the following method.
  • Methyl 4-cyanobenzoate is derived into methyl 4-ethoxyiminomethylbenzoate hydrochloride in the presence of hydrogen chloride in ethanol. Next, toluene is added to carry out dehydrochlorination concentration, and then pyrrolidine is added to lead to methyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate hydrochloride.
  • the synthetic raw material used in this reaction can be prepared from commercially available raw materials by a general organic synthesis method.
  • the manufacturing method of the said compound (5) is an illustration, and is not necessarily limited to the said method, A person skilled in the art can design a synthetic route suitably and can manufacture a compound (5).
  • Ring B represents a C 6-14 aryl group, a heteroaryl group, a nitrogen-containing non-aromatic heterocyclic group or a C 3-10 cycloalkyl group
  • T represents a hydrogen atom, a halogen atom, a hydroxy group, a C 1-10 alkoxy group which may have a substituent, an acyloxy group which may have a substituent, or a carbamoyl which may have a substituent.
  • U has a hydrogen atom, an optionally substituted C 1-10 alkyl group, a carboxyl group, an optionally substituted C 1-10 alkoxy-carbonyl group, or a substituent.
  • Compound (3) easily condenses with compound (1) at the hydroxy group moiety to form compound (4).
  • Compound (3) is condensed with compound (2) by using a condensing agent to form compound (4). Further, compound (3) is condensed with compound (5) by transesterification to form compound (4).
  • the position of the substituents T, L and amidino group on ring B is not particularly limited as long as it is a substitutable position on ring B.
  • the position of substitution of the amidino group is the 1st position.
  • T is preferably in the 4th position
  • L is preferably in the 3rd position.
  • the preferred compound (3), ring B is a C 6-14 aryl group, T is a hydroxy group, C 1-10 alkoxy group or C 1-10 alkoxy group optionally substituted by cyano, L Is an oxygen atom and n is 1.
  • the salt of compound (3) is preferably hydrochloride or acetate.
  • the compound (3) is 4-hydroxy-3- (2-hydroxyethoxy) benzamidine or a salt thereof (hydrochloride, acetate), 3- (2-hydroxyethoxy) -4-methoxybenzamidine or a salt thereof (Hydrochloride, acetate), 4-ethoxy-3- (2-hydroxyethoxy) benzamidine or a salt thereof (hydrochloride, acetate), 3- (2-hydroxyethoxy) -4- (2-methylpropoxy)- Benzamidine or a salt thereof (hydrochloride, acetate), 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine or a salt thereof (hydrochloride).
  • the salt may be a chemically acceptable salt.
  • Organic salts such as ammonium salts, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, aluminum salts, zinc salts, triethylamine, ethanolamine, morpholine, piperidine, dicyclohexylamine
  • salts with amines and salts with basic amino acids such as arginine and lysine.
  • a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, etc.
  • the compound (3) and a necessary acid or base are mixed in an appropriate amount ratio in a solvent or a dispersant, or cation exchange or anion exchange is performed from other salt forms. It can also be obtained by doing.
  • the compound (3) preferably forms a salt with a strong acid (for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid) or acetic acid among the above-mentioned salts.
  • a strong acid for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid
  • acetic acid among the above-mentioned salts.
  • hydrochloric acid is preferable as the strong acid.
  • Compound (3) includes solvates of compound (3), such as hydrates and alcohol adducts.
  • ring B represents a C 6-14 aryl group
  • T represents hydroxy group, C 1-10 alkoxy group or a cyano with an optionally substituted C 1-10 alkoxy group
  • L is An example of a method for producing a compound showing an oxygen atom, U showing a hydrogen atom, and n showing 1 or a salt thereof, such as 4-hydroxy-3- (2-hydroxyethoxy) benzamidine hydrochloride, will be described.
  • 4-Hydroxy-3- (2-hydroxyethoxy) benzamidine hydrochloride can be produced by the following method using isovanillin as a starting material.
  • hydrochloric acid chloride with methanol / hydrogen chloride led to 4-hydroxy-3- (2-hydroxyethoxy) benzamidine hydrochloride.
  • the synthetic raw material used in this reaction can be prepared from commercially available raw materials by a general organic synthesis method.
  • the compound (3) is exemplified by a method for producing 3- (2-hydroxyethoxy) -4-methoxybenzamidine hydrochloride.
  • 3- (2-Hydroxyethoxy) -4-methoxybenzamidine hydrochloride can be produced by the following method using isovanillin as a starting material.
  • formyl group was cyanated from commercially available isovanillin according to a conventional method, leading to 3-hydroxy-4-methoxybenzonitrile. It was then alkylated with 2-chloroethanol leading to 3- (2-hydroxyethoxy) -4-methoxybenzonitrile.
  • hydrochloric acid was salified with methanol / hydrogen chloride, leading to 3- (2-hydroxyethoxy) -4-methoxybenzamidine hydrochloride.
  • 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride among the compounds (3) will be exemplified.
  • 4-Cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride can be produced by the following method using isovanillin as a starting material.
  • 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride can also be produced by the following method using vanillin as a starting material.
  • Cyanation of the formyl group was performed from commercially available vanillin according to a conventional method, leading to 4-hydroxy-3-methoxybenzonitrile.
  • alkylation was performed using bromoacetaldehyde diethyl acetal and potassium carbonate in DMF to obtain 4- (2,2-diethoxyethoxy) -3-methoxybenzonitrile.
  • tetramethylone 59 (33) 2003 6363-6373 is demethylated and the resulting 4- (2,2-diethoxyethoxy) -3-hydroxybenzonitrile is isolated.
  • the reaction was carried out using ethylene carbonate and potassium carbonate, leading to 4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzonitrile.
  • 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride was introduced in the same manner as described above.
  • the manufacturing method of the said compound (3) is an illustration, It is not necessarily limited to the said method, A person skilled in the art can design a synthetic route suitably and can manufacture a compound (3).
  • T ' is a hydroxy group, a C 1-10 alkoxy group or C 1-10 alkoxy group optionally substituted by cyano
  • a salt thereof (hereinafter sometimes referred to as compound (3 ′)) is a novel compound.
  • Compound (3 ′) can be in the form of a salt in the same manner as compound (3).
  • the salt may be a chemically acceptable salt. Examples of the chemically acceptable salt include those described above for compound (3).
  • T ′′ is a sodium atom, a hydrogen atom, or a C 1-10 alkyl group which may be substituted with C 1-10 alkoxy; G is a cyano group or substituted with hydroxy; A good amidino group
  • a salt thereof is also a novel compound.
  • These compounds can be used as a synthetic intermediate for obtaining the compound (3 ′).
  • the compound represented by the formula (3 ′′) can be in the form of a salt similarly to the target compound (3), and the salt in that case may be a chemically acceptable salt. Examples of the chemically acceptable salt include those described above for compound (3). Of these, a salt with hydrochloric acid and a salt with acetic acid can be preferably formed.
  • T ′ ′′ is a C 1-10 alkyl group substituted with C 1-10 alkoxy, and R is a hydrogen atom or a C 1-10 alkyl group
  • a salt thereof is a novel compound and can be preferably used as a synthetic intermediate for obtaining the compound (3 ′).
  • the compound represented by the formula (3 ′ ′′) can be in the form of a salt in the same manner as the target compound (3), but the salt in that case may be a chemically acceptable salt. Examples of the chemically acceptable salt include those described above for compound (3).
  • Compound (4) is the target compound in the production method of the present invention, obtained by condensing compound (1), compound (2) or compound (5) and compound (3).
  • the compound (4) or a salt thereof is useful as a low molecular weight FXa inhibitor. Therefore, an agent containing the compound (4) or a salt thereof as an active ingredient is an anti- (blood) coagulant for an extracorporeal blood circuit ( (Refer to International Publication No. 2006/083003 pamphlet).
  • Compound (4) can also be produced by the method for forming an alkyl bond described in International Publication No. 2006/083003 pamphlet, but according to the production method of the present invention, compound (4) can be produced in a simpler and higher yield than the above method. ) Can be obtained. This will be described in detail below.
  • the manufacturing method of the present invention has the following formula:
  • compound (4) is obtained by reacting compound (1), compound (2) or compound (5) with compound (3) to form an ester bond.
  • the following four methods (I) A method in which compound (2) is led to compound (1) using an acid halogenating reagent and then condensed with compound (3) without isolating said compound (1); (II) A method in which compound (2) is led to compound (1) using an acid halogenating reagent, and this is isolated and then condensed with compound (3); (III) A method of condensing compound (2) and compound (3) using a condensing agent; and (IV) a method of condensing compound (5) and compound (3) using a transesterification reaction: It is divided into.
  • each method will be described in detail.
  • the compound (2) having a carboxyl group is dissolved or suspended in an organic solvent.
  • the organic solvent used in this case is not particularly limited as long as it is a commercially available organic solvent that is generally used for acid halogenation reaction, etc., but preferably N, N-dimethylformamide (DMF), N, N Amide solvents such as dimethylacetamide (DMAC) and N-methyl-2-pyrrolidone (NMP) and imide solvents such as 1,3-dimethyl-2-imidazolidinone (DMI), more preferably NMP is there.
  • DMAC dimethylacetamide
  • NMP N-methyl-2-pyrrolidone
  • imide solvents such as 1,3-dimethyl-2-imidazolidinone (DMI), more preferably NMP is there.
  • an acid halogenating agent used in this case is as described above.
  • the reaction temperature of the acid halogenation is preferably ⁇ 40 to 200 ° C., more preferably around 0 to 20 ° C.
  • the benzamidine derivative (3) having a hydroxy group is added to the reaction solution containing the acid halide (1) to lead to the target compound (4).
  • the reaction temperature at this time is desirably ⁇ 40 ° C. to 200 ° C., more preferably 0 ° C. to 20 ° C.
  • this reaction proceeds without particularly adding a base, but a base may be added if necessary. Examples of the base include, but are not limited to, pyridine and triethylamine.
  • the progress of the reaction is confirmed by HPLC, and the reaction is terminated with the formation of the condensate (compound (4)) or the consumption of raw materials.
  • the reaction time for this reaction is usually about 1 to 24 hours.
  • water or an alcohol solvent preferably an alcohol solvent
  • an alcohol solvent preferably an alcohol solvent
  • methanol, ethanol, isopropyl alcohol and the like can be preferably used, but the alcohol solvent is not limited thereto.
  • the obtained compound (4) can be isolated by, for example, a solid-liquid separation method in which a poor solvent is added.
  • HMPA hexamethylphosphonic acid triamide
  • the condensing agent used in the reaction include, but are not limited to, acetic anhydride, trifluoroacetic anhydride (TFAA), N, N-carboxydiimidazole (CDI), and dicyclohexylcarbodiimide (DCC). However, it is preferable to use dicyclohexylcarbodiimide.
  • the reaction temperature of the reaction is usually ⁇ 40 to 100 ° C., preferably 0 to 50 ° C.
  • this reaction proceeds without particularly adding a base, but a base may be added if necessary.
  • the base include N, N-dimethylaminopyridine (DMAP) and pyridine, but are not limited thereto.
  • DMAP N-dimethylaminopyridine
  • the progress of the reaction is confirmed by general HPLC, and is completed with the formation of condensate or the consumption of raw materials. After confirming the progress of the reaction, the resulting compound can be isolated as described in (I).
  • each symbol is as described above.
  • Compound (5) and compound (3) are dissolved or suspended in an organic solvent, and an acid is added to conduct a condensation reaction by transesterification.
  • organic solvent used in the reaction any commercially available organic solvent can be used as long as it does not affect the condensation reaction, but N-methyl-2-pyrrolidone (NMP) is preferable. is there.
  • NMP N-methyl-2-pyrrolidone
  • the acid used in the reaction include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid, but are not limited thereto.
  • hydrochloric acid is preferably used.
  • the reaction temperature of the reaction is usually 50 to 200 ° C., preferably 100 to 150 ° C.
  • the progress of the reaction is confirmed by general HPLC, and is completed with the formation of condensate or the consumption of raw materials. After confirming the progress of the reaction, the resulting compound can be isolated as described in (I).
  • the various analysis means and analyzers are as follows.
  • the system consisting of the following was mainly used for the HPLC analyzer.
  • Pump Shimadzu LC-10AT and LC-10ATvp
  • Autosampler Kyowa Precision KMT-100X (injection volume is 10 ⁇ l unless otherwise specified)
  • Column oven Shodex AO-30C and GL Science C0631, Sugai U-620
  • UV detector Shimadzu SPD-10A and SPD-10Avp
  • HPLC controller Shimadzu Corporation SCL-10A and SCL-10Avp.
  • HORIBA D-52 was used for the pH meter, and HORIBA 9678 was used for the electrode. A sample calibrated with a pH standard solution was used.
  • Example 1 Compound (2) was led to compound (1) using an acid halogenating reagent, and then condensed with compound (3) without isolation of compound (1) to give compound (4) How to get
  • reaction completion liquid was added dropwise to 1550.0 ml of acetone and stirred overnight, and then the suspension was filtered under reduced pressure, washed with 100 ml of acetone and dried under reduced pressure at room temperature overnight to obtain 11.3 g of the title compound. .
  • reaction mixture was cooled to 8 ° C., quenched by adding 5.6 L of methanol, added with 12.9 L of methyl acetate, and stirred at 8 ° C. overnight.
  • Example 2 Method (1): Compound (2) is led to Compound (1) using an acid halogenating reagent, isolated and then condensed with Compound (3) to obtain Compound (4): Synthesis of 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride from 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride
  • NMP N-methyl-2-pyrrolidone
  • This reaction-terminated liquid was slowly added dropwise to another container in which 750 ml of ethyl acetate and 50 ml of ethanol had been added in advance, washed with 5 ml of ethanol, and then stirred at 15 ° C. overnight. Thereafter, the reaction mixture was filtered under reduced pressure, washed with 100 ml of ethyl acetate, and then dried under reduced pressure at room temperature for 4 hours to obtain 41.4 g of the title compound (net amount 36.5 g).
  • Example 3 Method of condensing compound (2) and compound (3) using a condensing agent to obtain compound (4) 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride and 4 2- [5-Amidino-2- (cyanomethoxy) phenoxy] ethyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate from cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride Synthesis of dihydrochloride
  • Example 4 Method of obtaining compound (4) by condensing compound (5) and compound (3) using transesterification (1): 4- [imino (pyrrolidin-1-yl) methyl] Synthesis of methyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate hydrochloride from benzoic acid chloride hydrochloride
  • Example 5 Synthesis of 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride from 3-hydroxy-4-methoxybenzaldehyde (isovanillin) (1): Synthesis of 3-hydroxy-4-methoxybenzonitrile from isovanillin Composition
  • the reaction mixture was filtered under reduced pressure to remove Pd / C and washed with 30 ml of methanol. At room temperature, 23.3 ml of 2M HCl / methanol was added to the filtrate to adjust the pH to around 3, and then concentrated to 38.5 g. After 90 ml of toluene was added dropwise at room temperature, the mixture was stirred at 10 ° C. for 3 hours or more. The suspension was filtered under reduced pressure, washed with toluene, and dried under reduced pressure at 60 ° C. for 2 hours to obtain 10.3 g of the title compound.
  • Example 6 Synthesis of 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride from isovanillin (alternative method) (1): Synthesis of sodium 4-cyano-2- (2-hydroxyethoxy) phenoxide from 3-hydroxy-4-methoxybenzonitrile
  • the obtained organic layer mixture was washed / separated with 60 ml of water, 1.5 g of activated carbon was added, and the mixture was stirred for 1 hour or more.
  • the reaction mixture was filtered under reduced pressure, and washed with 15 ml of toluene. While adding 64.7 ml of toluene little by little to the obtained filtrate, the solution was concentrated under reduced pressure to 90.3 g at 50 ° C. and then cooled to 35 ° C. 300 ml of n-heptane was added dropwise over 1 hour, cooled to 10 ° C. and stirred overnight.
  • the reaction mixture was separated by filtration under reduced pressure, washed with 60 ml of n-heptane, and then dried under reduced pressure at 60 ° C.
  • reaction solution was filtered under reduced pressure to remove Pd / C, and washed with 22.5 ml of methanol. 137 ml of 2M hydrogen chloride methanol solution was added to the filtrate and stirred at 40 ° C. for 16.5 hours or more. After confirming the completion of the reaction by HPLC, the mixture was concentrated to 135 g, and 90 ml of acetone was added to form a suspension. At 25 ° C., 180 ml of toluene was added dropwise over 5 minutes, cooled to 10 ° C. over 1.5 hours, and further stirred for 2 hours or more. The reaction mixture was filtered under reduced pressure, washed with 90 ml of toluene, and then dried under reduced pressure at 60 ° C. overnight to obtain 40.7 g of the title compound.
  • Example 7 Synthesis of 4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzonitrile from 4-hydroxy-3-methoxybenzaldehyde (vanillin) (1): 4-hydroxy-from vanillin Synthesis of 3-methoxybenzonitrile
  • Example 8 Synthesis of 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride from 4-cyanobenzoic acid (1): Synthesis of 4-ethoxyiminomethylbenzoic acid hydrochloride from 4-cyanobenzoic acid
  • Example 11 (1): Synthesis of 4-hydroxy-3- (2-hydroxyethoxy) benzamidine acetate from 4-hydroxy-3- (2-hydroxyethoxy) benzonitrile
  • the filtrate was concentrated. After raising the temperature to 60 ° C., the mixture was cooled to 50 ° C., and 245.0 ml of ethyl acetate was added. The suspension was cooled to 10 ° C., filtered under reduced pressure, and washed with 35 ml of ethyl acetate. The filtrate was dried under reduced pressure at 60 ° C. overnight to obtain 17.2 g of the title compound.
  • Example 12 (1): Synthesis of 3- (2-hydroxyethoxy) -4-methoxybenzamidine acetate from 3- (2-hydroxyethoxy) -4-methoxybenzonitrile
  • Example 13 (1): Synthesis of 4-ethoxy-3- (2-hydroxyethoxy) benzonitrile from sodium 4-cyano-2- (2-hydroxyethoxy) phenoxide
  • Example 14 (1): Synthesis of 3- (2-hydroxyethoxy) -4- (2-methylpropoxy) benzonitrile from sodium 4-cyano-2- (2-hydroxyethoxy) phenoxide
  • an amidine derivative having an ester bond which is a highly useful compound as a drug having an anticoagulant action, can be easily obtained in a high yield.

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Abstract

La présente invention a pour objet un procédé pour la production d'un dérivé d'amidine ayant une liaison ester, qui est un composé hautement utile en tant que substance ayant une activité anticoagulante, à une échelle industrielle. La présente invention concerne de manière spécifique un procédé pour la production d'un composé d'amidine (4), qui comprend la mise en réaction d'un halogénure d'acide (1), soit d'un composé (2) soit d'un composé (5), et d'un composé d'amidine (3) avec un autre pour former une liaison ester, les composés (1) à (5) étant représentés par les formules (chaque symbole étant tel que défini dans la description).
PCT/JP2010/056624 2009-04-13 2010-04-13 Procédé pour la production d'un dérivé d'amidine Ceased WO2010119877A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017179065A1 (fr) * 2016-04-15 2017-10-19 Davuluri Ramamohan Rao Procédé amélioré pour la préparation d'aprémilast
CN117567318A (zh) * 2023-10-25 2024-02-20 南京农业大学 一种木质素基芳香醛合成羟基苯甲腈的方法

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JP2004210716A (ja) * 2002-12-27 2004-07-29 Dai Ichi Seiyaku Co Ltd ジアミド誘導体
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017179065A1 (fr) * 2016-04-15 2017-10-19 Davuluri Ramamohan Rao Procédé amélioré pour la préparation d'aprémilast
US10774041B2 (en) 2016-04-15 2020-09-15 Davuluri Ramamohan Rao Process for the preparation of apremilast
CN117567318A (zh) * 2023-10-25 2024-02-20 南京农业大学 一种木质素基芳香醛合成羟基苯甲腈的方法

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