WO2020171073A1 - Procédé de production d'un dérivé de benzazépine et d'intermédiaire correspondant - Google Patents

Procédé de production d'un dérivé de benzazépine et d'intermédiaire correspondant Download PDF

Info

Publication number
WO2020171073A1
WO2020171073A1 PCT/JP2020/006305 JP2020006305W WO2020171073A1 WO 2020171073 A1 WO2020171073 A1 WO 2020171073A1 JP 2020006305 W JP2020006305 W JP 2020006305W WO 2020171073 A1 WO2020171073 A1 WO 2020171073A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
formula
compound
substituted
halogen atom
Prior art date
Application number
PCT/JP2020/006305
Other languages
English (en)
Japanese (ja)
Inventor
和包 長井
祐花 久野
齊藤　幸治
浩代 片岡
Original Assignee
株式会社 三和化学研究所
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 株式会社 三和化学研究所 filed Critical 株式会社 三和化学研究所
Publication of WO2020171073A1 publication Critical patent/WO2020171073A1/fr

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
    • B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
    • B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
    • B01J23/44—Palladium
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines

Definitions

  • the present invention relates to a novel method for producing an optically active benzazepine derivative and an intermediate thereof.
  • Patent Document 1 discloses that 4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide is a compound having a V2 receptor agonizing effect and is effective in preventing or treating nocturia. ing.
  • Patent Document 1 N-[(S)-1-hydroxypropan-2-yl]-4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-2,3
  • the method for producing 4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide is described in Patent Document 1.
  • the compound is characterized in that it has a methyl group at the carbon located at the ⁇ -position of the ester group at the 4-position of the benzoazepine ring.
  • (R)- An optical resolution method using Phenylglycinol is known. Further, intermediates of the above compounds are reported in Patent Document 2, Patent Document 3 and Non-Patent Document 1.
  • Patent Document 4 As a method for asymmetric methylation of the carbon located at the ⁇ -position of the ester group, a method of alkylating the ⁇ -carbon of ⁇ -ketoester stereoselectively is known (Patent Document 4).
  • the present inventors have conducted an optical resolution method using (R)-Phenylglycinol described in Patent Document 1 to obtain N-[(S)-1-hydroxypropan-2-yl]-4-methyl-1-[2
  • An optically active form of -methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide was prepared.
  • there is a problem of inefficiency because half of the compound having an undesired three-dimensional structure is produced.
  • an object of the present invention is to provide an optically active N-[(S)-1-hydroxypropan-2-yl]-4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazole- It is to provide a novel production method capable of efficiently producing 1-yl)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide.
  • the main configuration of the present invention is as follows.
  • R 1 is optionally substituted by a halogen atom C 1 ⁇ C 6 alkyl group, or C 1 ⁇ C 4 alkyl or C 1 ⁇ C 4 alkoxy optionally substituted with a group
  • C 7 Represents a C 12 aralkyl group.
  • R 2 is a hydrogen atom, a C 2 -C 6 alkenyl group, a C 1 -C 4 alkyl group or a C 7 -C 12 aralkyl group which may be substituted with a C 1 -C 4 alkoxy group, —COR 3 , — It represents SO 2 R 4 or —CO 2 R 5 .
  • R 3 is selected from the group consisting of a halogen atom, an aromatic heterocyclic group optionally substituted with a C 1 -C 4 alkyl group, and a C 1 -C 6 alkyl group optionally substituted with a halogen atom.
  • R 4 represents a C 1 -C 4 alkyl group or a phenyl group which may be substituted with a C 1 -C 4 alkoxy group, or a C 1 -C 6 alkyl group which may be substituted with a halogen atom.
  • R 5 is substituted with a C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a C 1 -C 4 alkyl group or a C 1 -C 4 alkoxy group which may be substituted with a halogen atom. Also represents a C 7 to C 12 aralkyl group.
  • each R 6 independently represents a C 1 -C 4 alkyl group optionally substituted by a halogen atom, or an aryl group optionally substituted by a halogen atom.
  • R 7's each independently represent a C 1 -C 4 alkylene group or a naphthalenediyl group.
  • R 8 represents a single bond hydrogen atom or together.
  • X ⁇ represents a halide anion.
  • Formula (V) [In formula, R ⁇ 2 > is synonymous with the above and * represents an asymmetric center. ] Or a method for producing a solvate of the optically active compound, which comprises recrystallizing the optically active compound with a solvent.
  • R 1 is optionally substituted by a halogen atom C 1 ⁇ C 6 alkyl group, or C 1 ⁇ C 4 alkyl or C 1 ⁇ C 4 alkoxy benzyl group which may be substituted with a group Represents.
  • R 2 is a hydrogen atom, an allyl group, a C 1 -C 4 alkyl group or a benzyl group which may be substituted with a C 1 -C 4 alkoxy group, —COR 3 , —SO 2 R 4 , or —CO 2 R Represents 5 .
  • R 3 is selected from the group consisting of a halogen atom, an aromatic heterocyclic group optionally substituted with a C 1 -C 4 alkyl group, and a C 1 -C 6 alkyl group optionally substituted with a halogen atom.
  • R 4 represents a phenyl group which may be substituted with a C 1 -C 4 alkyl group.
  • R 5 is optionally substituted by a halogen atom C 1 ⁇ C 4 alkyl group, an allyl group, or a C 1 ⁇ C 4 alkyl or C 1 ⁇ C 4 alkoxy benzyl group which may be substituted with a group Represent ]
  • a halogen atom C 1 ⁇ C 4 alkyl group, an allyl group, or a C 1 ⁇ C 4 alkyl or C 1 ⁇ C 4 alkoxy benzyl group which may be substituted with a group Represent ]
  • an organic solvent the compound represented by
  • Formula (II-1) Methylated with a methylating agent in the presence of an asymmetric quaternary ammonium salt represented by, and a base, Formula (III): [In the formula, R 1 and R 2 have the same meanings as described above, and * represents an asymmetric center. ]
  • R 1 is a methyl group or an ethyl group.
  • R 2 is —COR 3 or —SO 2 R 4 , and R 3 is a halogen atom, an aromatic heterocyclic group which may be substituted with a C 1 -C 4 alkyl group, and a halogen atom.
  • R 2 is —COR 3
  • R 3 is [In formula, R ⁇ 9 > means the aromatic heterocyclic group which may be substituted by the methyl group. ]
  • R 2 is —COR 3
  • R 3 is The production method according to [12], which is a substituted phenyl group represented by: and the steric acid at the 4-position of the benzazepine ring of the compound represented by formula (III) is R.
  • R 1 is optionally substituted by a halogen atom C 1 ⁇ C 6 alkyl group, or C 1 ⁇ C 4 alkyl or C 1 ⁇ C 4 alkoxy benzyl group which may be substituted with a group Represents.
  • R 1 is optionally substituted by a halogen atom C 1 ⁇ C 6 alkyl group, or C 1 ⁇ C 4 alkyl or C 1 ⁇ C 4 alkoxy benzyl group which may be substituted with a group Represents.
  • a pharmaceutically acceptable salt thereof
  • R 1 is optionally substituted by a halogen atom C 1 ⁇ C 6 alkyl group, or C 1 ⁇ C 4 alkyl or C 1 ⁇ C 4 alkoxy benzyl group which may be substituted with a group Represents.
  • R 1 is optionally substituted by a halogen atom C 1 ⁇ C 6 alkyl group, or C 1 ⁇ C 4 alkyl or C 1 ⁇ C 4 alkoxy benzyl group which may be substituted with a group Represents.
  • a pharmaceutically acceptable salt thereof [17] The compound or a pharmaceutically acceptable salt thereof according to [15] or [16], wherein R 1 is a methyl group or an ethyl group.
  • the optically active N-[(S)-1-hydroxypropan-2-yl]-4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazole-1- Il)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide preferably (S)-N-[(S)-1-hydroxypropan-2-yl]- 4-Methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide (Hereinafter, referred to as compound A.
  • compound (I), compound (II) or the like a compound represented by formula (I), formula (II) or the like is hereinafter referred to as compound (I), compound (II) or the like). It can.
  • compound (V) and compound (VI) which are synthetic intermediates of compound A
  • the chemical purity and the yield of the optically active substance are improved, and the number of production steps is shortened in the production of compound A. can do.
  • the asymmetric methylation reaction can be accelerated.
  • compound A can be produced via the steps shown below.
  • R 1 is optionally substituted by a halogen atom C 1 ⁇ C 6 alkyl group, or C 1 ⁇ C 4 alkyl or C 1 ⁇ C 4 alkoxy optionally substituted with a group C 7 Represents a C 12 aralkyl group.
  • R 2 is a hydrogen atom, a C 2 -C 6 alkenyl group, a C 1 -C 4 alkyl group or a C 7 -C 12 aralkyl group which may be substituted with a C 1 -C 4 alkoxy group, —COR 3 , — It represents SO 2 R 4 or —CO 2 R 5 .
  • R 3 represents a phenyl group which may be substituted with one or more substituents selected from the substituent group A, a C 1 -C 6 alkyl group which may be substituted with a halogen atom, or a hydrogen atom.
  • R 4 represents a C 1 -C 4 alkyl group or a phenyl group which may be substituted with a C 1 -C 4 alkoxy group, or a C 1 -C 6 alkyl group which may be substituted with a halogen atom.
  • R 5 is substituted with a C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a C 1 -C 4 alkyl group or a C 1 -C 4 alkoxy group which may be substituted with a halogen atom.
  • a C 7 to C 12 aralkyl group also represents a C 7 to C 12 aralkyl group. * Represents an asymmetric center.
  • the substituent group A is composed of a halogen atom, an aromatic heterocyclic group which may be substituted with a C 1 to C 4 alkyl group, and a C 1 to C 6 alkyl group which may be substituted with a halogen atom. It is a group. ]
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • aromatic heterocyclic group means a monocyclic to tricyclic aromatic ring group containing at least one hetero atom such as nitrogen, oxygen or sulfur, and examples thereof include pyridyl group, thienyl group and furyl group.
  • the “C 1 -C 6 alkyl group” means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Examples thereof include methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, and various branched chain isomers thereof.
  • the “C 1 -C 4 alkyl group” means a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, a butyl group, And various branched chain isomers thereof.
  • the “C 1 -C 4 alkoxy group” means a group in which an oxygen atom is bonded to the above “C 1 -C 4 alkyl group”, and examples thereof include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, and these groups. And various branched chain isomers thereof.
  • the “C 7 -C 12 aralkyl group” means a group in which an aryl group is bonded to an alkyl group and has 7 to 12 carbon atoms, and examples thereof include a benzyl group and a phenethyl group.
  • the “C 2 -C 6 alkenyl group” means a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and having at least one double bond, for example, vinyl group. , Allyl group, 1-propenyl group and the like.
  • One embodiment of the present invention is a compound represented by formula (VI).
  • Compound (VI) is a novel synthetic intermediate of compound A.
  • R 1 is optionally substituted by a halogen atom C 1 ⁇ C 6 alkyl group, or C 1 ⁇ C 4 alkyl or C 1 ⁇ C 4 alkoxy benzyl group which may be substituted with a group Represents. ]
  • Compound (VI) can be obtained by the following first step. That is, R 2 of compound (I) is —COR 3 and R 3 is
  • the compound (VI) can be obtained by In the compound (VI), the stereo structure at the 4-position of the benzazepine ring is controlled to the R configuration.
  • the absolute configuration at the 4-position of the benzazepine ring of compound (VI) is determined by synthesizing compound A from compound (VI), converting it to an alcohol solvate, and performing single crystal X-ray structural analysis. be able to.
  • R 1 is optionally substituted by a halogen atom C 1 ⁇ C 6 alkyl group, or C 1 ⁇ C 4 alkyl or C 1 ⁇ C 4 alkoxy optionally substituted with a group C 7 Represents a C 12 aralkyl group.
  • R 2 is a hydrogen atom, a C 2 -C 6 alkenyl group, a C 1 -C 4 alkyl group or a C 7 -C 12 aralkyl group which may be substituted with a C 1 -C 4 alkoxy group, —COR 3 , — It represents SO 2 R 4 or —CO 2 R 5 .
  • R 3 represents a phenyl group which may be substituted with one or more substituents selected from the substituent group A, a C 1 -C 6 alkyl group which may be substituted with a halogen atom, or a hydrogen atom.
  • R 4 represents a C 1 -C 4 alkyl group or a phenyl group which may be substituted with a C 1 -C 4 alkoxy group, or a C 1 -C 6 alkyl group which may be substituted with a halogen atom.
  • R 5 is substituted with a C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a C 1 -C 4 alkyl group or a C 1 -C 4 alkoxy group which may be substituted with a halogen atom. Also represents a C 7 to C 12 aralkyl group.
  • the substituent group A is composed of a halogen atom, an aromatic heterocyclic group which may be substituted with a C 1 to C 4 alkyl group, and a C 1 to C 6 alkyl group which may be substituted with a halogen atom. It is a group. ]
  • the first step is a step of asymmetrically methylating the compound (I).
  • Compound (I) can be produced according to a known method described in JP-A-2016-40338 or JP-A-2016-185993.
  • the R 1 is preferably a methyl group or an ethyl group, more preferably an ethyl group.
  • the R 2 is preferably —COR 3 or —SO 2 R 4 , and more preferably —COR 3 .
  • R 3 is preferably a phenyl group which may be substituted with one or more substituents selected from the substituent group A.
  • the substituent group A is preferably an aromatic heterocyclic group which may be substituted with a C 1 -C 4 alkyl group or a C 1 -C 6 alkyl group which may be substituted with a halogen atom, and C 1 An aromatic heterocyclic group which may be substituted with a to C 4 alkyl group is more preferable.
  • R 3 is a phenyl group shown below.
  • R 4 is preferably a phenyl group which may be substituted with a C 1 -C 4 alkyl group or a C 1 -C 4 alkoxy group.
  • R 5 is preferably a C 1 -C 6 alkyl group optionally substituted with a halogen atom or a C 7 -C 12 aralkyl group optionally substituted with a C 1 -C 4 alkoxy group.
  • the first step can be carried out, for example, by methylating the 4-position of the benzazepine ring of compound (I) with an methylating agent in the presence of a catalyst and a base in an organic solvent.
  • This methylation reaction is preferably carried out in the presence of an inorganic salt in order to accelerate the reaction.
  • the crude product can be isolated and purified by a method well known to those skilled in the art. This method is excellent in stereoselectivity, and the compound (III) thus obtained has excellent optical purity. Furthermore, since the compound (III) can be obtained in good yield by this method, it is suitable for industrial production.
  • the catalyst used in the first step is the compound (II) of an asymmetric quaternary ammonium salt.
  • R 6's each independently represent a C 1 -C 4 alkyl group optionally substituted with a halogen atom or an aryl group optionally substituted with a halogen atom.
  • R 7's each independently represent a C 1 -C 4 alkylene group or a naphthalenediyl group.
  • R 8 represents a hydrogen atom or together represents a single bond.
  • X ⁇ represents a halide anion.
  • R 6 is preferably a 3,5-bistrifluoromethylphenyl group or a 3,4,5-trifluorophenyl group, more preferably a 3,5-bistrifluoromethylphenyl group.
  • R 7 is preferably a normal butanediyl group or a naphthalenediyl group, more preferably a naphthalenediyl group. It is preferable that the R 8 s together form a single bond.
  • the compound (II) of the asymmetric quaternary ammonium salt include (R,R)-3,5-bistrifluoromethylphenyl-NAS bromide and (R,R)-3,4 as follows. ,5-Trifluorophenyl-NAS bromide, (11bR)-( ⁇ )-4,4-dibutyl-4,5-dihydro-2,6-bis(3,5-ditrifluoromethylphenyl-3H-dinaphtho[2 ,1-c:1′,2′-e]azepinium bromide, and (11bR)-( ⁇ )-4,4-dibutyl-4,5-dihydro-2,6-bis(3,4,5) -Trifluorophenyl-3H-dinaphtho[2,1-c:1',2'-e]azepinium bromide, preferably (R,R)-3,5-bistrifluoromethylphenyl-NAS bromide.
  • the compound (II) of the asymmetric quaternary ammonium salt can be used in an amount of 0.0001 to 1 equivalent based on 1 equivalent of the compound (I), but 0.001 to 0.1 equivalent. It is preferably used, and more preferably 0.005 to 0.02 equivalent. Setting the amount of the compound (II) of the asymmetric quaternary ammonium salt to be within this range contributes to completion of asymmetric methylation and suppression of formation of a by-product of a methylated product.
  • the organic solvent used in the first step is not particularly limited as long as it does not hinder the progress of the reaction, for example, toluene, xylene, mesitylene, cumene, heptane, ethyl acetate, methyl isobutyl ketone, methyl tertiary butyl ether, Tetrahydrofuran, methylene chloride, chlorobenzene, bromobenzene, nitrobenzene, anisole, 1-butyl-3-methylimidazolium tetrafluoroborate and the like can be mentioned. These solvents may be used alone, or two or more kinds may be mixed or used with water.
  • a highly soluble aromatic organic solvent is preferable, and toluene, xylene, chlorobenzene, or bromobenzene is more preferable. By using these solvents, generation of impurities can be suppressed and the asymmetric methylation reaction can be completed.
  • the amount of the solvent used is preferably 3 to 20 equivalents, and more preferably 5 to 10 equivalents, relative to 1 equivalent of compound (I).
  • the base used in the first step may be an organic base or an inorganic base.
  • the organic base include triethylamine, pyridine, N,N'-dimethylaminopyridine and the like.
  • the inorganic base include sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, barium hydroxide, rubidium hydroxide, potassium carbonate, cesium carbonate, rubidium carbonate and the like.
  • An inorganic base is preferred, and sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, barium hydroxide, rubidium hydroxide, potassium carbonate, cesium carbonate, or rubidium carbonate is preferred. More preferably potassium hydroxide, potassium carbonate, cesium carbonate, or cesium hydroxide.
  • the methylating agent used in the first step is not particularly limited as long as it is a commonly used methylating agent, and is preferably trimethyloxonium tetrafluoroborate, methyl trifluoromethanesulfonate, dimethylsulfate, methyl bromide, or iodide. Methyl, more preferably methyl bromide or methyl iodide.
  • the amount of the methylating agent used is preferably 1 to 20 equivalents, and more preferably 1 to 10 equivalents, relative to 1 equivalent of compound (I).
  • the inorganic salt used in the first step is preferably an alkali metal salt, for example, cesium fluoride, cesium chloride, cesium bromide, cesium iodide, lithium chloride, lithium bromide, potassium chloride, potassium bromide, potassium iodide. , Sodium chloride, sodium bromide, rubidium chloride, and rubidium bromide. More preferably, it is cesium fluoride, cesium chloride, potassium bromide, sodium bromide, rubidium chloride, or rubidium bromide.
  • the amount of the inorganic salt used is preferably 0.01 to 1 equivalent, and more preferably 0.05 to 0.5 equivalent, relative to 1 equivalent of compound (I).
  • the reaction temperature in the first step is not particularly limited, but is preferably ⁇ 20 to 20° C., more preferably 1 to 10° C. By adjusting the reaction temperature within this range, it contributes to the completion of asymmetric methylation and the suppression of the formation of by-products in the methylated form.
  • the compound (III) obtained in the first step can be isolated by a conventional method. For example, it can be purified by recrystallizing the obtained crude product or by column chromatography.
  • the solvent used for recrystallization is preferably methanol, ethanol, 2-propanol, ethyl acetate, toluene, or acetonitrile, and more preferably ethyl acetate or acetonitrile.
  • Compound (VII) is a novel synthetic intermediate of Compound A.
  • R 1 is optionally substituted by a halogen atom C 1 ⁇ C 6 alkyl group, or C 1 ⁇ C 4 alkyl or C 1 ⁇ C 4 alkoxy benzyl group which may be substituted with a group Represents.
  • Compound (VII) can be obtained by the following second step.
  • R 2 is the same as the compound (VI) described above.
  • the stereo structure at the 4-position of the benzazepine ring does not change.
  • [Second step] [In the formula, R 1 and R 2 have the same meanings as those in the first step, and * represents an asymmetric center. ]
  • the second step is a step of reducing compound (III) to compound (IV).
  • it can be obtained by reducing the carbonyl group at the 5-position of the benzazepine ring of compound (III) using an reducing agent in an organic solvent or a mixed solvent with water.
  • the reducing agent used in the second step is preferably a borane compound, which allows selective reduction of carbonyl groups.
  • the borane compound is preferably sodium borohydride, potassium borohydride, lithium borohydride, or a borane-ammonia complex, more preferably a borane-ammonia complex.
  • the borane-ammonia complex those prepared in advance by the method described in the literature (Inorganic Chemistry 2007, 46, 7810) can be used.
  • the amount of borane compound used is preferably 0.5 to 2 equivalents, and more preferably 1.0 to 1.5 equivalents, relative to 1 equivalent of compound (III).
  • the organic solvent used in the reaction is preferably toluene, tetrahydrofuran, ethyl acetate, or a mixed solution of these organic solvents and water, more preferably a mixed solution of toluene and water.
  • the reaction temperature in the second step is not particularly limited, but is preferably 20 to 100°C, more preferably 40 to 60°C. By adjusting the reaction temperature of the second step within this range, the reduction reaction proceeds smoothly and carbonyl group-selective reduction can be performed. Isolation and purification of the resulting compound (IV) can be carried out by a conventional method.
  • the compound A can be obtained as the compound (V) from the compound (IV) through the following third step to sixth step.
  • the steric structure at the 4-position of the benzazepine ring does not change.
  • the third step is a step of chlorinating the hydroxyl group at the 5-position of the benzazepine ring in an organic solvent.
  • the chlorination reaction can be carried out, for example, by dissolving the compound (IV) in an organic solvent and adding a chlorinating agent to cause the reaction.
  • a chlorinating agent an electrophilic chlorinating agent is preferable. It is also preferable to carry out chlorination in the presence of a base.
  • the chlorinating agent is preferably thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or N-chlorosuccinimide, more preferably thionyl chloride or phosphorus oxychloride.
  • the amount of the chlorinating agent used is preferably 0.5 to 3 equivalents, and more preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IV).
  • the organic solvent used in the reaction is preferably toluene, methylene chloride, or chloroform, more preferably toluene.
  • the reaction temperature is preferably 20 to 120°C, more preferably 60 to 100°C.
  • the compound (VIII) thus obtained can be isolated and purified by a conventional method.
  • the fourth step is a step of reductively dechlorinating the chloro group at the 5-position of the benzoazepine ring with hydrogen in an organic solvent in the presence of a metal catalyst.
  • the dechlorination can be carried out, for example, by dissolving the compound (VIII) in an organic solvent, adding a metal catalyst to the resulting solution, and further carrying out the reaction under a hydrogen gas atmosphere.
  • the metal catalyst is preferably a palladium catalyst, a platinum catalyst, or a nickel catalyst.
  • the palladium catalyst include palladium carbon and palladium hydroxide.
  • platinum catalysts include platinum carbon and platinum oxide hydrate.
  • the nickel catalyst include Raney nickel and nickel carbon.
  • the metal catalyst is more preferably a palladium catalyst.
  • the amount of the metal catalyst used is preferably 0.01 to 1 equivalent, and more preferably 0.05 to 0.2 equivalent, relative to 1 equivalent of compound (VIII).
  • the organic solvent used in the reaction is preferably methanol, ethanol, tetrahydrofuran, or ethyl acetate, more preferably methanol or ethanol.
  • the hydrogen pressure is preferably 1 to 5 atm, more preferably 1 to 3 atm.
  • the reaction temperature is not particularly limited, but is preferably 20 to 100°C, more preferably 20 to 60°C.
  • Isolation and purification of the resulting compound (IX) can be carried out by a conventional method.
  • the carbonyl group at the 5-position of the benzazepine ring can be regioselectively reduced.
  • the reaction can be performed according to a conventional method.
  • compound (IX) is treated with a base (eg, sodium hydroxide, potassium hydroxide, etc.) in a suitable solvent (eg, alcohol solvent such as methanol, ethanol, etc., water), usually at room temperature to an organic solvent.
  • a base eg, sodium hydroxide, potassium hydroxide, etc.
  • a suitable solvent eg, alcohol solvent such as methanol, ethanol, etc., water
  • the carboxylic acid compound of the compound (X) can be obtained by reacting at the boiling point of the solvent for 30 minutes to 1 day.
  • the obtained carboxylic acid compound is subjected to amidation with L-alaninol to obtain the compound (V).
  • a method using a condensing agent for example, the carboxylic acid compound and L-alaninol are condensed in a suitable organic solvent (chloroform, dimethylformamide, etc.) in the presence of a base (eg, diisopropylethylamine, triethylamine, etc.) (for example, 1 , 3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), etc.) alone or in combination with 1-hydroxybenztriazole (HOBt).
  • a base eg, diisopropylethylamine, triethylamine, etc.
  • a mixed acid anhydride for example, a carboxylic acid compound in an appropriate organic solvent (eg, dichloromethane, toluene, etc.) in the presence of a base (eg, pyridine, triethylamine, etc.), an acid chloride (eg, pivaloyl chloride, Tosyl chloride, etc.) or an acid derivative (eg, ethyl chloroformate, isobutyl chloroformate, etc.), and the resulting mixed acid anhydride is reacted with L-alaninol usually at 0° C. to room temperature to give compound (V). Can be obtained.
  • an appropriate organic solvent eg, dichloromethane, toluene, etc.
  • a base eg, pyridine, triethylamine, etc.
  • an acid chloride eg, pivaloyl chloride, Tosyl chloride, etc.
  • an acid derivative eg, ethyl chloroformat
  • an acid chloride is obtained by using a chlorinating agent (eg, thionyl chloride, oxalyl chloride, etc.) in a suitable organic solvent (eg, toluene, xylene, etc.)
  • a chlorinating agent eg, thionyl chloride, oxalyl chloride, etc.
  • a suitable organic solvent eg, toluene, xylene, etc.
  • Acid chloride in the presence of a base eg sodium carbonate, triethylamine etc.
  • a suitable organic solvent eg ethyl acetate, toluene etc.
  • L-alaninol usually at 0° C. to room temperature
  • Compound (V) can also exist as a solvate.
  • the solvate of compound (V) can be obtained by a conventional method for producing a solvate. Specifically, it can be obtained by mixing the compound (V) with a solvent while heating, if necessary, and then cooling the mixture while stirring or leaving it to crystallize. It is desirable that the cooling be carried out while adjusting the cooling rate as necessary in consideration of the influence on the crystal quality and grain size. For example, cooling at a cooling rate of 20 to 1° C./hour is preferable, and cooling at a cooling rate of 10 to 3° C./hour is more preferable.
  • the organic solvent used in these methods is preferably an alcohol solvent such as methanol, ethanol, propanol, isopropanol, normal propanol, and tertiary butanol.
  • the amount of the organic solvent used is preferably 3 to 20 times by weight, more preferably 5 to 10 times by weight, relative to the compound (V).
  • Compound A can be prepared as a pharmaceutical preparation by mixing with a pharmaceutically acceptable additive. These can be prepared by a known method (for example, the method described in the general rules for formulation of Japanese Pharmacopoeia 17th edition).
  • Compound A acts as a V2 receptor agonist, it is a pharmaceutical composition for the prevention or treatment of central diabetes insipidus, nocturnal enuresis, nocturia, overactive bladder, hemophilia, or von Willebrand disease. It is already known that can be used as.
  • Thermogravimetric measurement The TGA thermogram was performed using Perkin Elmer (Pyris1-TGA). The measurement conditions were 20 mL/min of nitrogen gas, isothermal for 1 minute at an initial temperature of 80° C., then increased to 170° C. at 5° C./minute, and isothermal for 1 minute at 170° C.
  • Example 12 1420 mL of acetonitrile was added to the crude wet crystals (72% ee), and the mixture was heated and dissolved at 60°C and then stirred at 5°C for 3 hours. The precipitated crystals were collected by filtration, washed with 230 mL of cooled acetonitrile, and then dried at 50° C. overnight to obtain 134 g of a white solid (99% ee).
  • the 1 H-NMR and LC-MS measurement results of the product obtained in Example 12 were the same as those shown in Example 1.
  • Example 13 4-Methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-5-oxo-2,3,4,5-tetrahydro-1H- Synthesis of benzo[b]azepine-4-carboxylic acid t-butyl ester (first step) [In the formula, * represents an asymmetric center. ]
  • Example 16 The asymmetric yield of Example 16 was found to be 1-t-butyl-4-ethyl-4-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepinedicarboxylate obtained. Convert ester to 4-methyl-5-oxo-1-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester And measured by HPLC. As a result, the asymmetric yield was 63% ee.
  • Examples 17 to 30 are 1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-5-oxo-2,3,4,5-tetrahydro-1H of Example 1.
  • -Benzo[b]azepine-4-carboxylic acid ethyl ester was changed to the substrate shown in Table 3, and the reaction was performed according to the reaction conditions shown in Table 3.
  • the isolated yield and the asymmetric yield (% ee) are shown in Tables 3 and 4, and the data of the synthesized compounds are shown in Table 5.
  • the organic layer was washed with 0.5 L of 10% saline solution, 0.5 L of 10% sodium hydrogen carbonate solution and 0.5 L of 5% saline solution in this order, and the organic layer was concentrated under reduced pressure to obtain 70 g of a pale yellow amorphous substance.
  • Example 36 Isopropanol solvate of compound A To 5.0 g of compound A obtained in Example 35, 65 mL of isopropanol was added, and the mixture was stirred at room temperature for 30 minutes. The precipitated suspension was heated and dissolved, and then allowed to cool to room temperature and stirred overnight at 5°C. The suspension was collected by filtration, washed with cold isopropanol, and dried at 40° C. overnight to obtain 4.9 g of a white solid. When the obtained compound was analyzed by a thermogravimetric apparatus, the content of isopropanol was 8.2% with respect to the compound A, and the molar ratio was 0.7 times that of the compound A.
  • Example 37 Ethanol solvate of compound A To 0.15 g of compound A obtained in Example 35, 2 mL of ethanol was added, and the mixture was stirred at room temperature for 30 minutes. The precipitated suspension was heated and dissolved, and then allowed to cool to room temperature and stirred overnight at 5°C. The suspension was collected by filtration, washed with cold ethanol, and dried at 40° C. overnight to obtain 0.07 g of a white solid.
  • the obtained compound was analyzed by a thermogravimetric apparatus, the content of ethanol was 5.7% with respect to the compound A, and the molar ratio was 0.6 times the amount with respect to the compound A.
  • Example 38 Normal propanol solvate of compound A To 5.0 g of the compound A obtained in Example 35, 31 mL of normal propanol was added, and the mixture was stirred at room temperature for 15 minutes. The precipitated suspension was heated and dissolved, and then allowed to cool to room temperature and stirred overnight at 5°C. The suspension was collected by filtration, washed with cold normal propanol, and dried at 40° C. overnight to obtain 4.1 g of a white solid. When the obtained compound was analyzed by a thermogravimetric apparatus, the content of normal propanol was 8.1% with respect to the compound A, and the molar ratio was 0.7 times the amount of the compound A.
  • the method of the present invention is a method for industrially and safely producing compound (VI) and compound (VII) which are useful as pharmaceutical intermediates, and a compound A useful as a pharmaceutical is industrially safe and inexpensive. It is useful as a manufacturing method.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Catalysts (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention concerne un procédé de production d'un ester éthylique d'acide (R)-4-méthyl-1-(2-méthyl-4-(3-méthyl-1H-pyrazol-1-yl)benzoyl)-5-oxo-2, 3, 4, 5-tétrahydro-1H-benzo[b]azépine-4-carboxylique par méthylation d'un ester éthylique d'acide 1-(2-méthyl-4-(3-méthyl-1H-pyrazol-1-yl)benzoyl)-5-oxo-2, 3, 4, 5-tétrahydro-1H-benzo[b]azépine-4- carboxylique au moyen d'un agent de méthylation dans un solvant organique en présence d'un sel d'ammonium quaternaire asymétrique spécifique et d'une base. L'invention concerne également du N-[(S)-1-hydroxypropan-2-yl]-4-méthyl-1-[2-méthyl-4-(3-méthyl-1H-pyrazol-1-yl)benzoyl]-2, 3, 4, 5-tétrahydro-1H-benzo[b]azépine-4-carboxamide optiquement actif et un intermédiaire de celui-ci pouvant être produits de manière efficace au moyen dudit procédé de production.
PCT/JP2020/006305 2019-02-19 2020-02-18 Procédé de production d'un dérivé de benzazépine et d'intermédiaire correspondant WO2020171073A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2019-026983 2019-02-19
JP2019026983A JP2022055368A (ja) 2019-02-19 2019-02-19 ベンゾアゼピン誘導体の製造方法及びその中間体

Publications (1)

Publication Number Publication Date
WO2020171073A1 true WO2020171073A1 (fr) 2020-08-27

Family

ID=72144346

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2020/006305 WO2020171073A1 (fr) 2019-02-19 2020-02-18 Procédé de production d'un dérivé de benzazépine et d'intermédiaire correspondant

Country Status (2)

Country Link
JP (1) JP2022055368A (fr)
WO (1) WO2020171073A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114950492A (zh) * 2022-05-31 2022-08-30 安徽大学 一种用于光电催化杀灭细菌的1,2-二氨基蒽醌-二硫化钼复合抗菌材料

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62164668A (ja) * 1985-12-12 1987-07-21 イ−・ア−ル・スクイブ・アンド・サンズ・インコ−ポレイテツド ベンズアゼピン誘導体
JPS6440462A (en) * 1987-07-27 1989-02-10 Squibb & Sons Inc Benzazepine derivative
JPS6471859A (en) * 1987-08-26 1989-03-16 Squibb & Sons Inc Benzazepine derivative
JP2003514022A (ja) * 1999-11-18 2003-04-15 アンテックスファーマ・インコーポレーテッド 置換された１−ベンズアゼピンとその誘導体
JP2003529572A (ja) * 2000-03-31 2003-10-07 ポリメーリ エウローパ ソシエタ ペル アチオニ 置換多環式シクロペンタジエン及びその製造方法
JP2004175758A (ja) * 2002-11-28 2004-06-24 Nagase & Co Ltd β−ケトエステルを用いてアルキル化物を立体選択的に製造するための方法
JP2004536079A (ja) * 2001-05-16 2004-12-02 アンテックスファーマ・インコーポレーテッド 置換１−ベンズアゼピンおよびその誘導体
WO2014104209A1 (fr) * 2012-12-26 2014-07-03 株式会社 三和化学研究所 Nouveau dérivé de benzazépine et utilisation pharmaceutique associée
JP2016040338A (ja) * 2015-12-18 2016-03-24 株式会社三和化学研究所 １−ベンゾイル−５−オキソ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ［ｂ］アゼピン−４−カルボン酸エステルの製造方法
JP2016185993A (ja) * 2016-08-02 2016-10-27 株式会社三和化学研究所 １−ベンゾイル−５−オキソ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ［ｂ］アゼピン−４−カルボン酸エステルの製造方法

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62164668A (ja) * 1985-12-12 1987-07-21 イ−・ア−ル・スクイブ・アンド・サンズ・インコ−ポレイテツド ベンズアゼピン誘導体
JPS6440462A (en) * 1987-07-27 1989-02-10 Squibb & Sons Inc Benzazepine derivative
JPS6471859A (en) * 1987-08-26 1989-03-16 Squibb & Sons Inc Benzazepine derivative
JP2003514022A (ja) * 1999-11-18 2003-04-15 アンテックスファーマ・インコーポレーテッド 置換された１−ベンズアゼピンとその誘導体
JP2003529572A (ja) * 2000-03-31 2003-10-07 ポリメーリ エウローパ ソシエタ ペル アチオニ 置換多環式シクロペンタジエン及びその製造方法
JP2004536079A (ja) * 2001-05-16 2004-12-02 アンテックスファーマ・インコーポレーテッド 置換１−ベンズアゼピンおよびその誘導体
JP2004175758A (ja) * 2002-11-28 2004-06-24 Nagase & Co Ltd β−ケトエステルを用いてアルキル化物を立体選択的に製造するための方法
WO2014104209A1 (fr) * 2012-12-26 2014-07-03 株式会社 三和化学研究所 Nouveau dérivé de benzazépine et utilisation pharmaceutique associée
JP2016040338A (ja) * 2015-12-18 2016-03-24 株式会社三和化学研究所 １−ベンゾイル−５−オキソ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ［ｂ］アゼピン−４−カルボン酸エステルの製造方法
JP2016185993A (ja) * 2016-08-02 2016-10-27 株式会社三和化学研究所 １−ベンゾイル−５−オキソ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ［ｂ］アゼピン−４−カルボン酸エステルの製造方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
VANDORMAEL BART ET AL.: "Asymmetric Synthesis and Conformational Analysis by NMR Spectroscopy and MD of Aba- and alpha-MeAba-Containing Dermorphin Analogues", CHEMMEDCHEM, vol. 6, no. 11, 2011, pages 2035 - 2047, XP008166307, DOI: 10.1002/cmdc.201100314 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114950492A (zh) * 2022-05-31 2022-08-30 安徽大学 一种用于光电催化杀灭细菌的1,2-二氨基蒽醌-二硫化钼复合抗菌材料
CN114950492B (zh) * 2022-05-31 2023-09-08 安徽大学 一种用于光电催化杀灭细菌的1,2-二氨基蒽醌-二硫化钼复合抗菌材料

Also Published As

Publication number Publication date
JP2022055368A (ja) 2022-04-08

Similar Documents

Publication Publication Date Title
JP5632279B2 (ja) 塩酸イバブラジンの調製方法及びポリモルフ
TW201210990A (en) Manufacturing method for compounds having HIV integrase inhibitory activities
JP2008534657A (ja) トランス−５−クロロ−２−メチル−２，３，３ａ，１２ｂ−テトラヒドロ−１Ｈ−ジベンズ［２，３：６，７］−オキセピノ［４，５−ｃ］ピロールの調製のための中間体化合物
JP2014514292A (ja) アミン中間体化合物を使用してドロネダロンを製造するための還元アミノ化方法
JP2010150259A (ja) イバブラジン及び薬学的に許容されうる酸とのその付加塩の合成のための新たな方法
JP2014514291A (ja) メシル化によるドロネダロンの製造方法
CA2773064C (fr) Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable
JP5815702B2 (ja) アセナピンの新規な製造方法
WO2020171073A1 (fr) Procédé de production d'un dérivé de benzazépine et d'intermédiaire correspondant
KR101166280B1 (ko) 시탈로프램 및 에난티오머의 제조 방법
KR100753353B1 (ko) 졸미트립탄 화합물의 제조방법
CA2503172A1 (fr) Benzoxazocines et utilisation de ceux-ci comme inhibiteurs de la recapture des mono-amines
KR20160027536A (ko) 실로도신 합성에 유용한 중간체의 제조방법
EA027080B1 (ru) Способ синтеза (2e)-3-(3,4-диметоксифенил)проп-2-еннитрила, применение в синтезе ивабрадина и его фармацевтически приемлемых кислотно-аддитивных солей
JP2009533370A (ja) ８−アリール−オクタノイル誘導体の製造方法
CN112679411B (zh) 一种手性5-(甲胺基)六氢环戊并[c]吡咯-2(1H)-Boc甲磺酸盐的制备方法
CN115784922B (zh) 一种(2s)-2-氨基-4-(环丙基/环丁基)丁酸的制备方法
JP4011819B2 (ja) インドール誘導体の製造法およびその中間体
JPS635087A (ja) （＋）−トランス−１ａ，２，３，４ａ，５，６−ヘキサヒドロ−９−ヒドロキシ−４−プロピル−４Ｈ−ナフト〔１，２−ｂ〕−１，４−オキサジンのキラル合成
JP2022114189A (ja) ６－ハロゲノイソインドリノン誘導体の製造方法
KR20160109041A (ko) 광학 활성을 갖는 인돌린 유도체 또는 이의 염의 신규 제조 방법
IE913936A1 (en) Chemical process
CA3214107A1 (fr) Nouveau procede de synthese de derives de 5-{5-chloro-2-[(3s)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoleine-2(1h)-carbonyl]phenyl}-1,2-dimethyl-1h-pyrrole-3-acide carboxylique et son application pour la production de composes pharmaceutiques
JP4968602B2 (ja) ベンズアミド誘導体の製造方法
KR100896087B1 (ko) 광학적으로 순수한 2-메틸피롤리딘 및 그 염의 제조방법

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20759466

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20759466

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP