WO2006121106A1 - Method for producing indole derivative having piperidine ring - Google Patents

Method for producing indole derivative having piperidine ring Download PDF

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Publication number
WO2006121106A1
WO2006121106A1 PCT/JP2006/309461 JP2006309461W WO2006121106A1 WO 2006121106 A1 WO2006121106 A1 WO 2006121106A1 JP 2006309461 W JP2006309461 W JP 2006309461W WO 2006121106 A1 WO2006121106 A1 WO 2006121106A1
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Prior art keywords
chemical
compound
following formula
reaction
represented
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PCT/JP2006/309461
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French (fr)
Japanese (ja)
Inventor
Naoyuki Shimomura
Atsushi Kamada
Mamoru Miyazawa
Koichi Ito
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Eisai R & D Management Co., Ltd.
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Priority claimed from US11/126,209 external-priority patent/US20050256103A1/en
Application filed by Eisai R & D Management Co., Ltd. filed Critical Eisai R & D Management Co., Ltd.
Priority to EP06746270A priority Critical patent/EP1880995B1/en
Priority to JP2007528313A priority patent/JP4932717B2/en
Priority to AU2006244916A priority patent/AU2006244916B2/en
Priority to CN2006800155608A priority patent/CN101171249B/en
Priority to CA2607907A priority patent/CA2607907C/en
Priority to US11/914,115 priority patent/US8110688B2/en
Publication of WO2006121106A1 publication Critical patent/WO2006121106A1/en
Priority to IL187282A priority patent/IL187282A0/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems

Definitions

  • the present invention relates to 1 ⁇ 1 [2- (7-methoxy-2, 2 dimethi] useful as a preventive or therapeutic agent for lower urinary tract symptoms, particularly urinary storage symptoms, having 5HT-1A antagonism and binding action.
  • 5HT-1A receptor As one of the seronin receptors, and a compound having 5HT-1A antagonism or binding action is a prophylactic or therapeutic agent for depression, anxiety, cognitive impairment, dysuria, etc. As expected. As such compounds, various compounds having a piperidine ring have already been reported (see Patent Document 1, Patent Document 2, and Patent Document 3).
  • Patent Document 1 Pamphlet of International Publication No. WO99Z06384
  • Patent Document 2 JP 2002-114684 A
  • Patent Document 3 International Publication No. W098Z43956 Pamphlet
  • R 1 and R 2 are adjacent substituents, and these substituents and the two carbon atoms to which each is bonded together are selected from the following substituent group B1, Substituted with 1 to 4 substituents,
  • R 3 represents a hydrogen atom or a methyl group
  • R 6 represents a substituent selected from the following substituent group A1.
  • Substituent group Al (l) hydrogen atom, (2) halogen atom, (3) cyano group, (4) hydroxyl group, (5) nitrile group, (6) carboxyl group, (7) C3-8 cycloalkyl group (8) C2-6 alkyl group, (9) C2-6 alkyl group, (10) C1-6 alkylthio group, (11) C1-6 alkoxy group, (12) C1— 6 alkylsulfol groups, (13) 16 alkyl groups (the 16 alkyl groups are selected from the group consisting of a halogen atom, a hydroxyl group, and a C 1-6 alkoxy group) Substituted with a substituent!), (14) C1 6 alkoxy group (the C 1-6 alkoxy group may be substituted with 1 to 3 halogen atoms), (15) amino group ( The amino group may be substituted with a substituent selected from the group consisting of a C16 alkyl group, a formyl group, a C16
  • Substituent group Bl (l) hydrogen atom, (2) halogen atom, (3) cyano group, (4) hydroxyl group, (5) nitrile group, (6) oxo group, (7) carboxyl group, (8) C3-8 cycloalkyl group, (9) C2-6 alkyl group, (10) C2-6 alkyl group, (11) C1 6 alkylthio group, (12) C1-6 alkoxycarbonyl group, ( 13) C1-6 alkylsulfonyl group, (14) C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group and a C1 6 alkoxy group), (15) Cl— 6 alkoxy group (the C1-6 alkoxy group may be substituted with 1 to 3 halogen atoms), (16) amino group (the amino group is a C1-6 alkyl group, formyl group, C1 6 Consists of alkanoyl group and C16 alkylsulf
  • Tetrahydrobiral group formed by C 13 alkyl group with oxygen atom together with carbon atom is disclosed.
  • This compound exhibits 5HT-1A antagonism and binding action, and is useful as a preventive or therapeutic agent for lower urinary tract symptoms, particularly urine accumulation symptoms.
  • an object of the present invention is to provide a method for producing compound (i) and an intermediate compound thereof.
  • X represents a protecting group for a hydroxyl group.
  • X 1 represents a hydrogen atom or a hydroxyl-protecting group.
  • Step (1) is a step of obtaining a compound represented by the following formula (i) by subjecting a compound represented by the following formula (a) and a compound represented by the following formula (b) to a coupling reaction. is there.
  • the coupling reaction in step (1) is preferably used for reductive amination reaction of a carbo-Louis compound and an amine compound, preferably under reductive amination reaction conditions. It can be performed under the same conditions as above.
  • the reduction reaction in this step is not particularly limited, but examples include reductive amination reaction with a reducing agent such as borane and borohydride complex, and catalytic reduction reaction in a hydrogen atmosphere using a metal catalyst. It is done.
  • Examples of reductive amination reactions using borohydride complexes include WS E merson, Organic Reactions, 4.174 "948), CF Lane, Synthesis, 135 (1975), JC Ctowell and SJ Pedegimas. Synthesis, 127 (1974) and AF Abdel—Magid, KG Carson, BD Harris, CA Marryanoff and RD Shah, Journal of Organic Chemistry, 61, 3849 (1996), etc.
  • Examples of borohydride complex compounds include sodium hydrogen borohydride, sodium cyanide borohydride, sodium triacetoxyborohydride, etc.
  • the solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but specifically, for example, methanol, ethanol, tetrahydrofuran, N, N dimethylformaldehyde. Amides, methylene chloride, 1, 2-Jikuroroetan and the like.
  • Compound (b) is used in an amount of 0.8 to 2.5 equivalents, preferably 1 to 1.5 equivalents, relative to compound (a).
  • the borohydride complex compound is used in an amount of 1 to 3 equivalents, preferably 1.5 equivalents, relative to compound (a).
  • the reaction time is not particularly limited, but is usually 0.5 to 48 hours, preferably 0.5 to 12 hours.
  • the reaction temperature is not particularly limited, but is usually a reflux temperature of 78 ° C. solvent, and preferably from ice cooling to room temperature.
  • the solvent used in the catalytic reduction reaction under a hydrogen atmosphere is not particularly limited as long as the solvent does not inhibit the reaction.
  • methanol, ethanol, tetrahydrofuran, 1, 4 dioxane and the like are used. Can be mentioned.
  • the metal catalyst used in the reaction include palladium, platinum oxide, Raney nickel and the like.
  • the reaction time is not particularly limited, but is usually 1 to 48 hours, preferably 1 to 24 hours.
  • the reaction conditions are not particularly limited, but the reaction can be carried out from room temperature to the reflux temperature of the solvent and normal pressure from 15 MPa, preferably from room temperature to 60 ° C. and from normal pressure to 0.5 MPa.
  • Compound (a) is obtained through the following steps (A-1), step (A-6) and step (A).
  • Step (A-1) is a step of obtaining a compound represented by the formula (a-1) by reacting 1 (1 ethoxyethoxy) 3-methoxybenzene with bromoacetate.
  • this step can be performed in the presence of a strong base such as n-butyllithium.
  • the reaction solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Specifically, for example, tetrahydrofuran, heptane, hexane, toluene, 1,2-dimethoxyethane, jetyl ether. 1, 2-dichloroethane and the like.
  • the reaction temperature is usually from ⁇ 78 ° C. to the reflux temperature of the solvent, preferably from ⁇ 78 to 0 ° C.
  • the reaction time is not particularly limited, but is usually 1 to 48 hours, preferably 1 to 24 hours.
  • step (A-2) the compound represented by the formula (a-1) is reduced by reducing the compound represented by the formula (a-1).
  • the compound represented by 2) is obtained.
  • the ester reduction reaction in the step (A-2) is carried out according to the conditions or conditions generally used as the reduction reaction described in, for example, the 4th edition, Experimental Chemistry Course 26 (pages 159-266). It can be carried out.
  • the reducing agent used in the reaction include lithium lithium aluminum, lithium borohydride, diisobutylaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, and the like.
  • the reaction solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • an ether solvent such as tetrahydrofuran, jetyl ether, dimethoxyethane, cyclopentyl methyl ether, etc.
  • aromatic hydrocarbon solvents such as toluene and xylene, or methylene chloride.
  • the reaction temperature is not particularly limited. Usually, the reaction temperature is from 78 ° C to the reflux temperature of the solvent, and preferably the 78 ° C force is also room temperature.
  • the reducing agent is used in an amount of 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to compound (a-1).
  • Step (A-3) is a step of obtaining a compound represented by the formula (a-3) by introducing a protecting group into the hydroxyl group of the compound represented by the formula (a-2). .
  • the hydroxyl protecting group represented by X is, for example, a known hydroxyl protecting group such as acetyl group or benzoyl group, preferably a benzoyl group.
  • benzoyl chloride is present in the presence of a base such as triethylamine, for example, an aromatic hydrocarbon solvent such as toluene or xylene, an ester solvent such as ethyl acetate, dimethoxyethane, or cyclopentyl.
  • the target product can be obtained by reacting in an ether-based solvent such as methyl ether.
  • the salty benzoyl can be used in an amount of 1 equivalent to a large excess relative to the compound (a-2).
  • N, N, ⁇ ', ⁇ Coexistence of '-tetramethylethylenediamine, diisopropylethylamine, N, N-dimethylaniline, etc. may give favorable results such as improved yield and reduced reaction time.
  • the reaction temperature is from 0 to 100 ° C, preferably the 0 ° C force is also room temperature.
  • the reaction time is not particularly limited, but is usually 0.5 to 48 hours, preferably 0.5 to 4 hours.
  • Step (A-4) is a step of obtaining a compound represented by the formula (a-4) by reacting a compound represented by the formula (a-3) with an acid.
  • the acid used in this step is not particularly limited as long as it is a commonly used acid, but hydrochloric acid is preferable.
  • the acid is used in an amount of 1 equivalent to a large excess relative to compound (a-3).
  • the reaction solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Specifically, for example, toluene, dimethoxyethane, tetrahydrofuran, water, or a mixed solvent thereof may be used. Can be mentioned.
  • the reaction temperature is 0 to 100 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is usually 0.5 to 48 hours, preferably 1 to 4 hours.
  • Step (A-5) is a step of obtaining a compound represented by the formula (a-5) by reacting the compound represented by the formula (a-4) with methylcrotonic acid.
  • reaction if necessary, a dehydrating agent such as quinolinic acid niline may be added.
  • the reaction solvent does not inhibit the reaction and the starting material is used. Is not particularly limited as long as it dissolves to some extent, but specific examples include methanesulfonic acid and the like.
  • the reaction temperature is from room temperature to 100 ° C., preferably 40 force is also 60 ° C.
  • the reaction time is not particularly limited, but is usually 0.5 to 48 hours, preferably 1 to 4 hours. is there.
  • Step (A-6) is a step of obtaining the compound represented by the formula (a-6) by deprotecting the hydroxyl-protecting group of the compound represented by the formula (a-5).
  • Conditions generally used as a method for deprotecting a protective group of an alcoholic hydroxyl group can be carried out under conditions similar to those described in TW Greene, PGM Wuts, “Protective Groups in Organic Synthesis, Second Edition”, John Wiley & Sons, Inc.
  • an alcoholic hydroxyl group protected with a benzoyl group can be obtained by reacting it with an aqueous solution of sodium hydroxide or sodium hydroxide in an organic solvent such as tetrahydrofuran, methanol or ethanol or a mixed solvent thereof. You can. Sodium hydroxide is used in an amount of 1 equivalent to a large excess based on compound (a-5).
  • the reaction temperature is from 0 to 100 ° C, preferably from room temperature to 50 ° C.
  • the reaction time is not particularly limited, but is usually 0.5 to 48 hours, preferably 1 to 5 hours.
  • Step (A) is a step of obtaining a compound represented by the formula (a) by acidifying the compound represented by the formula (a-6).
  • Alcohol compound strength aldehyde compound can be obtained by methods known to those skilled in the art.
  • Known acid-oxidation methods include, for example, Swan's acid oxidation (Swern oxidation), Cory-Kim oxidation (Corey-Kim oxidation), Moffat oxidation (Moffatt oxidation), PCC oxidation, PDC oxidation, Dess-Martin oxidation (Dess— Martin oxidation), SO—Pyridine oxidation, TEMPO oxidation
  • the reaction solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • the oxidizing agent a large excess of catalytic amount is used relative to compound (a-6).
  • the reaction temperature is not particularly limited, but usually ⁇ 78 ° C. force is the reflux temperature of the solvent, and preferably 5 ° C. force is also room temperature.
  • the reaction time is not particularly limited, but is usually 1 to 10 hours. Yes, preferably 1 to 5 hours.
  • reaction solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
  • reaction temperature is not particularly limited, it is usually from ⁇ 20 ° C. to room temperature, preferably from 5 ° C. to room temperature.
  • the reaction time is not particularly limited, but is usually 1 to 10 hours, preferably 1 to 5 hours.
  • reaction solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, chloroform, ethyl acetate, water, or a mixed solvent thereof, etc. Is mentioned.
  • oxidizing agent for example, dimethyl sulfoxide activator, for example, salt oxalyl, trifluoroacetic anhydride, acetic anhydride, cyclohexylimide, pentyl dianiline or the like is used with respect to compound (a-6). Double molar power is also used in large excess.
  • the reaction temperature is not particularly limited, but is usually 70 ° C to room temperature.
  • the reaction time is not particularly limited, but is usually 3 to 10 hours, preferably 3 to 5 hours.
  • Aldehyde compounds can be prepared by the method described in DP Kjell et al., “A Nobel, Non aqueous Method for Regeneration of Aldehydes from Bisuliite Add ucts” J.
  • a sodium bisulfite adduct can be obtained by reacting an aldehyde compound with, for example, an aqueous solution of sodium hydrogen sulfite in an organic solvent such as ethanol, ethyl acetate or methanol or a mixed solvent thereof.
  • the sodium bisulfite used is used in an amount of 1 equivalent to a large excess relative to the aldehyde compound.
  • the reaction temperature is not particularly limited, but is usually 10 to 40 ° C, preferably a chamber. It is warm.
  • the reaction time is not particularly limited, but is usually 1 to 48 hours, preferably 12 to 24 hours.
  • the sodium hydrogen sulfite adduct obtained in this way is mixed with potassium carbonate, sodium carbonate, sodium hydroxide, hydroxide in an organic solvent such as ethanol, ethyl acetate, methanol or a mixed solvent thereof.
  • Aldehyde compounds can be obtained by treatment with a base (aqueous solution) such as potassium salt.
  • the base used is 1 equivalent to a large excess with respect to the sodium bisulfite adduct.
  • the reaction temperature is not particularly limited, but is usually 10 to 40 ° C., preferably room temperature.
  • reaction time is not particularly limited, but is usually 1 to 48 hours, preferably 12 to 24 hours.
  • Compound (a) can be used to produce compound (i) that is purified or not purified.
  • the compound (b) used in the step (1) is, for example, the following step (B-1) to
  • Step (B-1) is a step of obtaining a compound represented by the above formula (b-1) by subjecting 3-tro 4-methylbenzoic acid and methylamine to a condensation reaction.
  • the condensing agent includes CDI (N, N'-carbodiimidazole), Bop (1H— 1, 2, 3 benzotriazole-1-yloxy (tri (dimethylamino)) phosphonium hexafluorophosphate), WSC ( Examples include 1-ethyl 3- (3 dimethylaminopropyl) carbodiimide 'hydrochloride), DCC (N, N dicyclohexylcarbodiimide), and jetyl phosphoryl cyanide. If necessary, 1 equivalent to a large excess of an organic base, such as triethylamine, may be added to 3-tro 4-methylbenzoic acid.
  • CDI N, N'-carbodiimidazole
  • Bop 1, 2, 3 benzotriazole-1-yloxy (tri (dimethylamino)) phosphonium hexafluorophosphate
  • WSC Examples include 1-ethyl 3- (3 dimethylaminopropyl) carbodiimide '
  • the reaction solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but specifically, for example, tetrahydrofuran, 1,4 dioxane, ethyl acetate, methyl acetate, dichloromethane, chloroform. Form, N, N dimethylformamide, toluene, xylene and the like.
  • the reaction temperature varies depending on the raw materials and solvent used, and is not particularly limited. However, the ice temperature is preferably the reflux temperature of the solvent.
  • the reaction time is not particularly limited, but is usually 0.5 to 48 hours, preferably 0.5 to 24 hours.
  • the obtained compound (b-1) can be used in the next step without purification or purification by a conventional method.
  • Step (B-2) is a step of obtaining compound (b-2) by reacting the compound represented by formula (b-1) with dimethylformaldehyde dimethylacetal.
  • This step is a synthesis method known to those skilled in the art, for example, the conditions described in Coe, JW; Vetelino, MG; Bradlee, MJ; Tetrahedron Lett., 37 (34), 6045-6048 (1996), etc.
  • the reaction can be performed under similar conditions.
  • the reaction solvent is not particularly limited as long as it does not inhibit this reaction and dissolves the starting material to some extent. For example, methanol, ethanol, tetrahydrofuran, ⁇ , ⁇ -dimethylformamide, methylene chloride, 1,2-dichloroethane, etc.
  • the reaction temperature is usually from room temperature to the reflux temperature of the solvent, preferably from room temperature to 100 ° C.
  • the reaction time is not particularly limited, but is usually 1 to 72 hours, preferably 1 to 48 hours.
  • the obtained compound (b-2) can be used in the next step without purification or purification by a conventional method.
  • Step (B-3) is a step of obtaining the compound represented by the above formula (b-3) by subjecting the compound represented by the above formula (b-2) to acetalization.
  • the acetal cake used in this step is described in, for example, Coe, JW Vetelino, MG; Bradlee, MJ; Tetrahedron Lett., 37 (34), 6045-6048 (1996). It can be performed under the same conditions as the conditions.
  • the reaction temperature is usually from room temperature to the reflux temperature of the solvent, preferably from room temperature to 100 ° C.
  • the reaction time is not particularly limited, but is usually 1 to 72 hours, preferably 1 to 48 hours.
  • the obtained compound (b-3) can be used in the next step without purification or purification by a conventional method.
  • step (B-4) the compound represented by the formula (b-3) is reduced to reduce the formula (b-3).
  • the reduction reaction in this step can be performed by a known method, for example, reduction by catalytic hydrogenation using a noble metal catalyst such as Raney nickel, noradium, ruthenium, rhodium or platinum.
  • a noble metal catalyst such as Raney nickel, noradium, ruthenium, rhodium or platinum.
  • Preferable examples in this case include a method using palladium, sodium hydroxide or the like.
  • Another example is a reduction reaction with iron under neutral conditions using salty ammonium.
  • the solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • methanol, ethanol, tetrahydrofuran, N, N, dimethylformamide, methylene chloride, 1,2-dichloroethane, etc. Can be used.
  • the reaction conditions are not particularly limited, and are from room temperature to the reflux temperature of the solvent, from normal pressure to 15 MPa, preferably from room temperature to 60 ° C., and from normal pressure to 0.5 MPa.
  • the reaction time is not particularly limited, but is usually 1 to 48 hours, preferably 1 to 24 hours.
  • the obtained compound (b-4) can be used in the next step without purification or purification by a conventional method.
  • step (5-5) the compound represented by the formula (b-4) and the compound represented by the formula (b-4 ⁇ ) are subjected to a reductive amination reaction, followed by a ring-closing reaction. And a step of obtaining a compound represented by the formula (b-5).
  • Examples of the protecting group for the secondary amine represented by Y include those known in the art, such as a benzyloxycarbonyl group and a tert-butyloxycarbonyl group.
  • the reductive amination reaction can be carried out under the same conditions as those usually used. For example, a reductive amination reaction with a reducing agent such as borane or a borohydride complex compound, or under a hydrogen atmosphere using a metal catalyst. And the like, and the like.
  • Examples of reductive amination reactions using borohydride complex compounds include WS Emerson, Organic Reactions, 4, 174 (1948), CF Lane, Syntheisis, 127 (1974), AF Abdel— Magid, KG Carson , BD Harris, CA Maryanoff and RD Shah, Journal of Organic Chemistry, 61, 3849 (1996).
  • the borohydride complex compound for example, sodium borohydride, cyanobium sodium borohydride, sodium triacetoxyborohydride and the like can be used.
  • the solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide, chloride Methylene, 1,2-dichloroethane, etc. can be used.
  • the strong acid is not particularly limited, but is preferably an example.
  • mineral acids such as hydrochloric acid
  • organic acids such as acetic acid
  • Lewis acid such as sodium chloride zinc, boron trifluoride jetyl ether complex, titanium (IV) tetraisopropoxide and the like.
  • the acid can also be used as a solvent.
  • Compound (b-4-4 is 0.8 to 2.5 equivalents, preferably 1 to 1.5 equivalents, relative to compound (b-4).
  • the borohydride complex compound is compound (b — Use 1 to 3 equivalents, preferably 1 to 1.5 equivalents to 4), although the reaction temperature varies depending on the raw materials and solvents used, and is not particularly limited.
  • the reaction time is not particularly limited, but is usually from 0.5 to 48 hours, preferably from 0.5 to 12 hours.
  • the solvent used in the catalytic reduction reaction under a hydrogen atmosphere is not particularly limited as long as it does not inhibit the reaction.
  • examples thereof include methanol, ethanol, tetrahydrofuran, and 1,4 dioxane.
  • the metal catalyst include palladium, platinum oxide, Raney nickel and the like.
  • the reaction conditions are not particularly limited, and the reaction temperature is from room temperature to the reflux temperature of the solvent, from atmospheric pressure to 15 MPa, preferably from room temperature to 60 ° C., and from atmospheric pressure to 0.5 MPa.
  • the reaction time is not particularly limited, but is usually 1 to 48 hours, preferably 1 to 24 hours.
  • the reaction solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • water, water and, for example, methanol, ethanol, tetrahydrofuran, 1,4 dioxane, benzene It can be carried out in an organic solvent such as toluene using a suitable acid in excess of 1 equivalent.
  • the acid include acetic acid, hydrogen chloride, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, trifluoroacetic acid, p toluenesulfonic acid, p toluenesulfo
  • Examples include acid 'pyridyl-um salt, camphorsulfonic acid and the like.
  • the reaction time is not particularly limited, but is usually 1 to 24 hours, preferably 1 to 24 hours.
  • the obtained compound (b5) can be used in the next step without purification or purification by a conventional method.
  • Step (B-6) is a step of obtaining the compound represented by the formula (b) by deprotecting the protecting group of the secondary amine of the compound represented by the formula (b-5). It is.
  • the compound (b) can also be obtained by the following step (B'-l), the step ( ⁇ '6) and the step ( ⁇ -6).
  • Step (B ⁇ -1) is a step of obtaining compound (-1) by reacting 3-tro- 4 methylbenzoic acid with dimethylformaldehyde dimethylacetal. This step can be performed under the same conditions as in step (B-2).
  • Step ( ⁇ ′2) is a step of obtaining compound (2) by subjecting compound (1) to acetalization. This step can be performed under the same conditions as in the above step ( ⁇ -3).
  • Step ( ⁇ ′3) is a step of obtaining compound (3) by reducing compound (2). This step can be performed under the same conditions as in the above step (IV-4).
  • Step ( ⁇ '4) is a step of obtaining compound (-4) by reacting compound (3) with compound (b-4-4) .This step is the same as step (B-5) above. This can be done according to the following conditions.
  • Step ( ⁇ ′5) is a step of obtaining compound (5) by hydrolyzing compound (4).
  • the reaction solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and examples thereof include methanol, ethanol, 2 propanol, tetrahydrofuran, 1,4 dioxane, water and the like.
  • the base is not particularly limited, but for example, sodium hydroxide, potassium hydroxide, lithium hydroxide and the like are preferable.
  • the amount of the base to be used is 1 equivalent to a large excess, preferably 1 to 20 equivalents, relative to compound (-4).
  • the reaction time is not particularly limited. Usually, the reaction time is 1 to 24 hours, preferably 1 to 6 hours.
  • the reaction temperature varies depending on the raw materials and solvent used, and is not particularly limited, but is usually from 78 ° C. to the reflux temperature of the solvent, preferably ice temperature room temperature.
  • the obtained compound (-5) can be used in the next step without purification or purification by a conventional method.
  • Step ( ⁇ '-6) is a step of obtaining compound (b5) by subjecting compound (-5) and methylamine to a condensation reaction. This step can be performed under the same conditions as in step (B-1).
  • compound (i) can also be obtained by the following steps (C-1) to (C-4). [Chemical 65]
  • Step (C 1) is a compound represented by the above formula (-4) [wherein Y represents a protecting group for secondary amine.
  • the compound represented by the formula (c 1) or a salt thereof is obtained by deprotecting the protecting group of the secondary amine.
  • the salt may be any known pharmacologically acceptable salt, but is preferably a hydrochloride.
  • This step can be carried out under the same conditions as in the above step (B-6).
  • step (C-2) the compound represented by the formula (c-2) is coupled with the compound represented by the formula (c-1) by coupling the compound represented by the formula (a). It is a process to obtain.
  • This step can be performed under the same conditions as in step (1).
  • step (C-3) the compound represented by the formula (c 2) is hydrolyzed, In this step, a compound represented by the formula (c 3) is obtained.
  • This step can be performed under the same conditions as in the above step ( ⁇ ′-5).
  • Step (C-4) is a step of obtaining the compound represented by the formula (i) by condensing the compound represented by the formula (c-3) and methylamine.
  • This step can be performed under the same conditions as in step (B-1).
  • room temperature means a range of 20 to 30 ° C., preferably 25 ° C.
  • 56.2 g (10% (containing 50% water)) of palladium-carbon was added, and 2055 mL of methanol was further added.
  • Cold water was circulated through the reaction can jacket, the reaction was started, the hydrogen pressure was controlled at 0.1 to 0.3 MPa (internal temperature 14 to 23 ° C), and the reaction solution was stirred for 2.5 hours.
  • the reaction solution was extracted from the reaction can and washed with 320 mL of methanol.
  • the catalyst was removed by filtration with a hypurose one parcel, and the catalyst was washed with 1080 mL of methanol. When the filtrate was concentrated (bath temperature 40 ° C), the crystallized title compound was precipitated. To this crystal, add 265 mL of 1,2 dimethochetan (hereinafter referred to as “DME”), dissolve it by heating to 40 ° C., reconcentrate to give a brown oil containing the title compound. Obtained.
  • DME 1,2 dimethochetan
  • reaction solution was transferred to a 20 L separator, and 5938 mL of toluene and 2969 mL of water were collected. After stirring, the aqueous layer was discarded. The organic layer was washed successively with 0.5N aqueous sodium hydroxide solution 4453 mL and 2969 mL, 5% brine 2969 mL twice and water 2969 mL sequentially.
  • the organic layer was concentrated (bath temperature 40 ° C) to give 1025. lg of a brown oil containing the title compound.
  • 1017 mL of methanol was dissolved in 1017. lg of this compound, and the seed compound of the title compound was dissolved at room temperature. 800 mg was added.
  • the crystals were collected by filtration and washed with 500 mL of methanol.
  • the crystals were dried under reduced pressure at 40 ° C. for about 2.5 hours to obtain 62.22 g of the title compound as slightly yellow crystals.
  • the ice water bath was switched to a water bath (24.5 ° C to 22.3 ° C), and the reaction solution was continuously stirred for 4 hours and 10 minutes at an internal temperature in the range of 20 ° C to 22 ° C.
  • the reaction solution was equally divided into two (3.62 L ⁇ 2), and each was post-treated in the same manner. 3.62 L of the reaction solution was cooled in an ice water bath, 2314 mL of tap water was added in 17 minutes, and then 1543 mL of ethyl acetate was added. When the internal temperature fell below 10 ° C, 420 mL of 2N hydrochloric acid was added to the reaction solution, and the pH of the aqueous layer was adjusted to 7. This solution was transferred to a 20 L separator, 2314 mL of tap water and 1543 mL of ethyl acetate were added, and the aqueous layer was discarded.
  • reaction solution was cooled in an ice-water bath, and when the internal temperature reached 10 ° C or less, 407 mL of 40% methylamine aqueous solution was added dropwise over 12 minutes, and the reaction solution was stirred at the same temperature for about 1.5 hours. .
  • 540 mL of 2N hydrochloric acid was added to the organic layer, the pH of the aqueous layer was adjusted to 3, and the phases were separated.
  • the organic layer was washed sequentially with 2975 g of 10% saline, 2975 g of 5% saline, and 1488 mL of tap water.
  • reaction solution is diluted with ethyl acetate, poured into 5% aqueous NaHCO solution, and extracted with ethyl acetate.
  • reaction solution was cooled in a cold water bath, 1.7 ml of water was added dropwise to the reaction solution, and then the reaction solution was heated and stirred at 100 ° C. for 5 hours.
  • Toluene was added to the reaction solution and extracted.
  • 1- (1-benzyloxycarbo-biperidine-4-yl) -N-methyl- 1H-indole-6 carboxamide was precipitated, and ethyl acetate was added to the aqueous layer.
  • Xylcarbol-biperidine-4-yl) -N-methyl-1H-indole-6 carboxamide was dissolved and then neutralized with 5N sodium hydroxide solution and extracted with ethyl acetate.
  • the reaction solution contains 75.2 g of 8% aqueous sodium hydrogen carbonate solution [57.2 g of sodium hydrogen carbonate is added to 658 mL of tap water. Prepared by dissolution] was added dropwise over 10 minutes.
  • the reaction solution was transferred to a 20 L separatory funnel, 1040 mL of tap water was added, 4550 mL of toluene was added for extraction, and the organic layer was washed twice with 1300 mL and 650 mL of tap water. The obtained organic layer was concentrated under reduced pressure at a bath temperature of 40 ° C. to obtain a pale yellow oil containing the title compound.
  • the coolant temperature setting was changed to -20 ° C, the internal temperature exceeded -20 ° C, the reaction solution was stirred for 1 hour, and the progress of the reaction was confirmed by HPLC.
  • 1435 mL of 28% aqueous ammonia was added to the reaction solution in about 30 minutes, and the coolant temperature was changed to 25 ° C.
  • 7174 mL of toluene was extracted from the cake, and the organic layer was washed sequentially with 28% ammonia water 1440 mL and tap water 1435 mLX3.
  • 127 mL (0.73 mol) of N, N diisopropylethylamine was added, followed by concentration under reduced pressure to obtain a pale orange oil containing the title compound.
  • the ice water bath was changed to a water bath, and the reaction solution was stirred for 2.5 hours.
  • the water bath was changed to an ice water bath, and the reaction solution was prepared by adding 4570 mL of water to 430 g of 8% (wZw) aqueous sodium hydroxide solution [93.0% sodium hydroxide. ] About 1.5L was dropped over 47 minutes.
  • the reaction solution was transferred to a 20 L separatory funnel, and the remaining amount of the prepared sodium hydroxide / sodium hydroxide solution was completely removed, and the aqueous layer was discarded.
  • the organic layer was washed three times with tap water (1417 mLX2, 709 mLX 1) and then concentrated under reduced pressure at 40 ° C., and the title compound contained in the concentrated residue was quantified.
  • Example 3 The organic layer obtained in Example 3 was transferred to a 15 L four-necked round bottom flask, 2126 mL of tetrahydrofuran was added, and the mixture was cooled in an ice water bath and stirred. To the reaction solution, 1417 mL of 5N hydrochloric acid was added dropwise over 23 minutes, and the reaction solution was stirred at the same temperature for about 1 hour, then the cold water in the bath was drained and stirring was continued for 2.5 hours. The reaction solution was transferred to a 20 L separatory funnel and the aqueous layer was discarded. The organic layer was adjusted by adding 1956 mL of water to 170 g of sodium hydrogen carbonate [170 g of sodium bicarbonate. ] And tap water (709 mLX2) twice. The obtained organic layer was concentrated under reduced pressure at a bath temperature of 40 ° C. to obtain 1463. Og of slurry.
  • the resulting slurry was washed into a 10 L four-necked round bottom flask with 709 mL of tetrahydrofuran. While stirring, 5670 mL of a toluene-heptane mixture (1: 8) was added dropwise to the reaction solution over about 2.5 hours, and the reaction solution was further stirred at room temperature for about 14 hours. The precipitated crystals were collected by filtration and washed with 708 mL of a toluene-heptane mixture (1: 8). It was dried at a bath temperature of 40 ° C under reduced pressure for about 4.5 hours to obtain the title compound as white crystals.
  • Example 5 844.9 g of the oil obtained in Example 5 was dissolved in 2.5 L of tetrahydrofuran and transferred to a 20 L four-necked round bottom flask.
  • 2.5L of methanol is cooled with water (water temperature: 22 ° C), and with stirring, 8% (wZw) aqueous solution of sodium hydroxide and sodium hydroxide [8% of sodium hydroxide (93.0%), 1678mL of water Was prepared. ] was added dropwise over 18 minutes.
  • the water bath was removed, and the reaction solution was stirred at room temperature for about 3.5 hours. 10 L of tap water was added dropwise to the reaction solution over about 1 hour.
  • the reaction vessel was ice-cooled, and the reaction solution was stirred at an internal temperature of 10 ° C or lower for about 1 hour.
  • the precipitated crystals were collected by filtration and washed sequentially with 2 L of tap water and a mixture of methanol and tap water (1: 4, 400 mL / 1600 mL).
  • the crystals obtained are dried under reduced pressure at 40 ° C until a constant weight is reached. Drying afforded 374.7 g of the crude title compound as a pale yellowish white solid.
  • the precipitated crystals were collected by filtration, and the crystals were washed with a mixed solution of ethanol Zethyl acetate (1Z1) (12 mL) to obtain 8.14 g of a sodium bisulfite adduct of the title compound.
  • reaction solution was stirred for 1 hour from the time when dissolution of the raw materials was confirmed at room temperature.
  • reaction solution was cooled to 10 ° C. or less in an ice-water bath, and sodium triacetoxyborohydride (356.3 g, 1.3 molar equivalent) was added in four portions to the reaction solution.
  • sodium triacetoxyborohydride 356.3 g, 1.3 molar equivalent
  • the reaction vessel was cooled in an ice-water bath, and 4500 mL of ethyl acetate was added to the reaction solution at about 10 ° C. Next, 5200 mL of 1N sodium hydroxide aqueous solution was added to the reaction solution over 36 minutes. The reaction solution was transferred to a 20 L separator, washed with 2156 mL of ethyl acetate, and the organic layer was separated. The organic layer was washed successively with 7% aqueous sodium hydrogen carbonate solution 1000 g, 5% brine (3328 g, 1000 g: 2 times) and tap water 3328 mL.
  • the organic layer was concentrated under reduced pressure, 1664 mL of ethanol was added and concentrated, and 1902.6 g of the resulting solution was quantified.
  • the content of the title compound was 581.lg, the yield was 91.8%, and the HPLC purity was 92.5%.
  • reaction solution was cooled in an ice-water bath, 87 mL of toluene and 29 mL of water were added, and the aqueous layer was discarded.
  • the organic layer was washed successively with 49 mL, 69 mL, and 30 mL of 1N sodium hydroxide aqueous solution, and then washed with 29 mL, 14 mL, and further 14 mL of water.
  • the solvent was distilled off to obtain 4.80 g of a crude product of the title compound.
  • the reaction mixture was cooled in an ice-water bath, and 12.2 mL of 1N hydrochloric acid and 0.5 mL of 1N-sodium hydroxide were added and adjusted to pH 7. As a result, crystals were precipitated. Further, 10 mL of water was added to the slurry, and the crystals were collected by filtration. The crystals were washed with 21 mL of a mixture of 2 propanol and water (5: 1). The crystals were dried under reduced pressure to obtain 2.45 g of the title compound.
  • reaction solution was cooled again in an ice-water bath, and 68 mL of toluene and 29 mL of water were collected. After clear filtration, 30 mL of toluene was collected, and the aqueous layer was discarded. The organic layer was washed with 29 mL of 1N sodium hydroxide aqueous solution, 29 mL X 2 of 5% saline and 29 mL of water. The solvent was distilled off to obtain 5.62 g of a crude product of the title compound.
  • Example 6 The compound of Example 6 can also be produced by the following reference examples.
  • the aqueous layer was separated and discarded, and the organic layer was washed three times with 1 mL of 1N aqueous potassium hydroxide and then with 20 mL of water, and then the solvent was distilled off to obtain 4.69 g of the target compound.
  • the crude product of the title compound (5.58 g) was dissolved in 14.5 mL of ethanol and 8.9 mL of water with stirring in a water bath at 50 ° C., and natural cooling was started at room temperature.
  • the temperature of the solution reached 35 ° C, seed crystals were added, and after confirming the start of precipitation, the solution was cooled in a water bath and an ice water bath.
  • the mixture was stirred for about 1 hour on an ice-water bath, and when the temperature of the crystallization liquid was 2.2 ° C, the crystals were collected by filtration and washed with 8 mL of 50% aqueous ethanol.
  • the crystals were dried under reduced pressure (30 ° C, 90 minutes) to obtain 3.89 g of the title compound.
  • Lithium diisopropylamide 5.0 mL (2MZ tetrahydrofuran'ethylbenzene, 1 Ommol) was stirred and cooled on a dry ice-ethanol refrigerant, and 2- (N, N-jetylcarbamoyloxy) 6-methoxytoluene 0.95 g (4.Ommol) Of tetrahydrofuran in OmL was added dropwise over 16 minutes. One minute later, heating was started at room temperature, and after stirring for 47 minutes, the mixture was allowed to stand overnight. 10 mL of toluene and 10 mL of water were stirred for 4 minutes, then moved to a separatory funnel and allowed to stand.
  • the aqueous layer was separated and combined with the aqueous layer extracted twice from the organic layer with a 2N aqueous solution of potassium hydroxide (5 OmL each).
  • the aqueous layer was washed with 1 OmL of toluene, and then 10 mL of toluene was added. Under stirring, 20 mL of 2N hydrochloric acid aqueous solution was moved into the caulking separatory funnel and allowed to stand.
  • the organic layer was separated and combined with the organic layer extracted from the aqueous layer with 5 mL of toluene. This organic layer was washed twice with 5 mL of water and concentrated under reduced pressure to obtain 0.81 g of the title compound.
  • 'H-NMR 400MHz, CDC1) ⁇ (ppm): 1. 29 (m, 6H), 3. 49 (m, 4H), 3. 8
  • the mixture was heated and stirred for 53 minutes in a 50 ° C water bath and allowed to stand overnight at room temperature. Then, 300 mL of isopropyl acetate and 200 mL of water were added, stirred for 5 minutes, moved into a separatory funnel, and left to stand. The aqueous layer was discarded, and the organic layer was washed twice with 100 mL of water, and then the solvent was distilled off. The residue was also crystallized with ethyl acetate-hexane, and the resulting crystals were dried under reduced pressure at 30 ° C. to obtain 3.12 g of the title compound.
  • the aqueous layer is separated and discarded, and the organic layer is washed twice with 40 mL of 1N potassium hydroxide aqueous solution and then with 20 mL of water, and then 2 mL of DME and 5 mL of water are added to the concentrate obtained by distilling off the solvent.
  • the precipitated crystals were collected by filtration (Crystal 3). The crystals 1 to 3 were combined, washed with 10 mL of water, and dried under reduced pressure at 40 ° C. for 1 hour to obtain 2.44 g of the title compound.

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Abstract

It is possible to commercially advantageously produce 1-{1-[2-(7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl] piperidin-4-yl}-N-methyl-1H-indole-6-carboxamide by coupling (7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)acetaldehyde, which is obtained by oxidizing 8-(2-hydroxyethyl)-7-methoxy- 2,2-dimethylchroman-4-one, with N-methyl-1-(piperidin-4-yl)- 1H-indole-6-carboxamide.

Description

明 細 書  Specification
ピぺリジン環を有するインドール誘導体の製造方法  Method for producing indole derivative having piperidine ring
技術分野  Technical field
[0001] 本発明は、 5HT- 1A拮抗作用及び結合作用を有する、下部尿路症状、特に蓄尿 症状の予防剤または治療剤として有用な 1 { 1 [2— (7—メトキシ—2, 2 ジメチ ルー 4—ォキソクロマン— 8—ィル）ェチル]ピぺリジン— 4—ィル }— N—メチル 1H インドール 6—カルボキサミドの製造方法に関する。  [0001] The present invention relates to 1 {1 [2- (7-methoxy-2, 2 dimethi] useful as a preventive or therapeutic agent for lower urinary tract symptoms, particularly urinary storage symptoms, having 5HT-1A antagonism and binding action. Luo 4-oxoxomann-8-yl) ethyl] piperidine-4-yl}-N-methyl 1H indole 6-carboxamide.
背景技術  Background art
[0002] セロニン受容体の一つとして、 5HT— 1A受容体があり、 5HT- 1A拮抗作用や結 合作用を有する化合物は、うつ病、不安症、認知障害、排尿障害などの予防もしくは 治療剤として期待されている。このような化合物として、ピぺリジン環を有する各種ィ匕 合物が既に報告されている (特許文献 1、特許文献 2、特許文献 3参照)。  [0002] There is a 5HT-1A receptor as one of the seronin receptors, and a compound having 5HT-1A antagonism or binding action is a prophylactic or therapeutic agent for depression, anxiety, cognitive impairment, dysuria, etc. As expected. As such compounds, various compounds having a piperidine ring have already been reported (see Patent Document 1, Patent Document 2, and Patent Document 3).
[0003] 特許文献 1：国際公開第 WO99Z06384号パンフレット  [0003] Patent Document 1: Pamphlet of International Publication No. WO99Z06384
特許文献 2：特開 2002— 114684号公報  Patent Document 2: JP 2002-114684 A
特許文献 3：国際公開第 W098Z43956号パンフレット  Patent Document 3: International Publication No. W098Z43956 Pamphlet
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0004] 本発明者らは、 5HT- 1A拮抗作用および結合作用を有する、新たなピぺリジン環 含有インドール誘導体として、下記一般式 (I) [0004] The present inventors have described the following general formula (I) as a new piperidine ring-containing indole derivative having 5HT-1A antagonistic action and binding action.
[化 1]  [Chemical 1]
R3 R 3
HN  HN
>=0 [式中、 R1および R2は、隣接する置換基であって、これら置換基とその各々が結合す る 2つの炭素原子とが一緒になつて、下記置換基群 B1から選択される、 1ないし 4個 の置換基で置換されてもょ 、、 > = 0 [Wherein R 1 and R 2 are adjacent substituents, and these substituents and the two carbon atoms to which each is bonded together are selected from the following substituent group B1, Substituted with 1 to 4 substituents,
(1) 5ないし 7員環式非芳香族炭化水素環基、  (1) a 5- to 7-membered cyclic non-aromatic hydrocarbon ring group,
(2) 5な ヽし 7員環式非芳香族複素環基、  (2) 5-tan 7-membered non-aromatic heterocyclic group,
(3) 6員環式芳香族炭化水素環基または  (3) 6-membered cyclic aromatic hydrocarbon ring group or
(4) 5もしくは 6員環式芳香族複素環基を形成し、  (4) forming a 5- or 6-membered aromatic heterocyclic group,
R3は、水素原子またはメチル基を示し、 R 3 represents a hydrogen atom or a methyl group,
R6は、下記置換基群 A1から選択される置換基を示す。 R 6 represents a substituent selected from the following substituent group A1.
置換基群 Al : (l)水素原子、（2)ハロゲン原子、（3)シァノ基、（4)水酸基、（5)ニト 口基、 （6)カルボキシル基、 （7) C3— 8シクロアルキル基、 （8) C2— 6ァルケ-ル基、 (9) C2— 6アルキ-ル基、（10) C1— 6アルキルチオ基、（11) C1— 6アルコキシ力 ルポ-ル基、 （ 12) C1— 6アルキルスルホ-ル基、 （13)じ1 6ァルキル基（該じ1 6アルキル基は、ハロゲン原子、水酸基および C 1—6アルコキシ基からなる群力 選 択される 1な 、し 3個の置換基で置換されてもよ!、）、（14) C1 6アルコキシ基 (該 C 1—6アルコキシ基は、 1ないし 3個のハロゲン原子で置換されてもよい）、（15)ァミノ 基 (該ァミノ基は、 C1 6アルキル基、ホルミル基、 C1 6アルカノィル基および C1 6アルキルスルホニル基カゝらなる群カゝら選択される置換基で置換されてもょ ヽ）およ び（16)力ルバモイル基 (該カルバモイル基は 1または 2個の C1 6アルキル基で置 換されてもよい)。  Substituent group Al: (l) hydrogen atom, (2) halogen atom, (3) cyano group, (4) hydroxyl group, (5) nitrile group, (6) carboxyl group, (7) C3-8 cycloalkyl group (8) C2-6 alkyl group, (9) C2-6 alkyl group, (10) C1-6 alkylthio group, (11) C1-6 alkoxy group, (12) C1— 6 alkylsulfol groups, (13) 16 alkyl groups (the 16 alkyl groups are selected from the group consisting of a halogen atom, a hydroxyl group, and a C 1-6 alkoxy group) Substituted with a substituent!), (14) C1 6 alkoxy group (the C 1-6 alkoxy group may be substituted with 1 to 3 halogen atoms), (15) amino group ( The amino group may be substituted with a substituent selected from the group consisting of a C16 alkyl group, a formyl group, a C16 alkanol group, and a C16 alkylsulfonyl group) and (16) A strong rubamoyl group (the carbamoyl group may be substituted by 1 or 2 C16 alkyl groups);
置換基群 Bl : (l)水素原子、（2)ハロゲン原子、（3)シァノ基、（4)水酸基、（5)ニト 口基、（6)ォキソ基、（7)カルボキシル基、（8) C3— 8シクロアルキル基、（9) C2— 6 ァルケ-ル基、 （ 10) C2— 6アルキ-ル基、 （ 11) C1 6アルキルチオ基、 （12) C1 —6アルコキシカルボ-ル基、 （ 13) C1— 6アルキルスルホ-ル基、 （14) C1— 6アル キル基 (該 C1 6アルキル基は、ハロゲン原子、水酸基および C1 6アルコキシ基 で置換されてもよい）、（15) Cl— 6アルコキシ基 (該 C1— 6アルコキシ基は、 1ないし 3個のハロゲン原子で置換されてもよい）、（16)アミノ基 (該ァミノ基は、 C1— 6アルキ ル基、ホルミル基、 C1 6アルカノィル基および C1 6アルキルスルホ-ル基からな る群カゝら選択される置換基で置換されてもょ ヽ）、（ 17)力ルバモイル基 (該カルバモ ィル基は、 1または 2個の C1 6アルキル基で置換されてもよい）、（18) Cl— 6アル コキシィミノ基、（19)同一炭素原子に結合する 2個の C1 3アルキル基が一緒にな つて形成する C5— 6シクロアルキル基および（20)同一炭素原子に結合する 2個の C 1 3アルキル基が酸素原子と共に当該炭素原子と一緒になつて形成するテトラヒド ロビラ-ル基。 ]で表される化合物を見出し、既に特許出願している（国際出願第 PC TZJP2005Z008632号および米国特許出願第 11Z126209号）。このィ匕合物は 、 5HT— 1A拮抗作用および結合作用を示し、下部尿路症状、特に蓄尿症状の予防 剤または治療剤として有用である。 Substituent group Bl: (l) hydrogen atom, (2) halogen atom, (3) cyano group, (4) hydroxyl group, (5) nitrile group, (6) oxo group, (7) carboxyl group, (8) C3-8 cycloalkyl group, (9) C2-6 alkyl group, (10) C2-6 alkyl group, (11) C1 6 alkylthio group, (12) C1-6 alkoxycarbonyl group, ( 13) C1-6 alkylsulfonyl group, (14) C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group and a C1 6 alkoxy group), (15) Cl— 6 alkoxy group (the C1-6 alkoxy group may be substituted with 1 to 3 halogen atoms), (16) amino group (the amino group is a C1-6 alkyl group, formyl group, C1 6 Consists of alkanoyl group and C16 alkylsulfol group (17) strong rubamoyl group (the carbamoyl group may be substituted with 1 or 2 C16 alkyl groups), (18) Cl-6alkoxymino group, (19) C5-6 cycloalkyl group formed by two C13 alkyl groups bonded to the same carbon atom, and (20) Bonded to the same carbon atom. Tetrahydrobiral group formed by C 13 alkyl group with oxygen atom together with carbon atom. And a patent application has already been filed (International Application No. PC TZJP2005Z008632 and US Patent Application No. 11Z126209). This compound exhibits 5HT-1A antagonism and binding action, and is useful as a preventive or therapeutic agent for lower urinary tract symptoms, particularly urine accumulation symptoms.
[0005] 特に、前記一般式 (I)に含まれる、下記式 (i) [0005] In particular, the following formula (i) included in the general formula (I):
[化 2]  [Chemical 2]
Figure imgf000004_0001
で示される化合物 1— { 1— [2— (7 メトキシ—2, 2—ジメチル 4 ォキソクロマン 8 ィル）ェチル]ピぺリジンー4ーィル }—N—メチルー 1H—インドールー 6—力 ルボキサミドが優れた作用を有するものとして期待される。
Figure imgf000004_0001
Compound 1— {1— [2— (7 Methoxy-2, 2-dimethyl-4-oxochroman 8 yl) ethyl] piperidine-4-yl} —N-methyl-1H-indole-6-force Is expected to have
そこで、本発明は、化合物 (i)の製造方法およびその中間体ィ匕合物を提供すること を目的とする。  Accordingly, an object of the present invention is to provide a method for producing compound (i) and an intermediate compound thereof.
課題を解決するための手段  Means for solving the problem
[0006] 本発明者らは、精力的に研究を重ねた結果、化合物 (i)の製造方法を見出し、本 発明を完成した。 [0006] As a result of extensive research, the present inventors have found a production method of the compound (i) and completed the present invention.
すなわち、本発明は、  That is, the present invention
(1)下記式 (a— 6) [化 3] (1) The following formula (a-6) [Chemical 3]
Figure imgf000005_0001
で表される 8— (2 ヒドロキシェチル） 7—メトキシ一 2, 2 ジメチルクロマン一 4— オンを酸ィ匕することにより得られる下記式 (a)
Figure imgf000005_0001
The following formula (a) obtained by acidifying 8- (2 hydroxyethyl) 7-methoxy-1,2,2 dimethylchroman-4-one represented by the following formula (a)
[化 4] [Chemical 4]
Figure imgf000005_0002
ォキソクロマン一 8—ィル）ァセトアル
Figure imgf000005_0002
Oxochroman 1 8-il)
Figure imgf000006_0001
で表される N—メチルー 1一（ピペリジンー4一ィル）一 1H—インド
Figure imgf000006_0001
N-methyl-1 (piperidine-4 1) 1 1H-India
キサミドとをカップリングすることを含む、 Coupling with oxamide,
下記式 (i) The following formula (i)
[化 6] [Chemical 6]
Figure imgf000006_0002
で表される 1— { 1— [2— (7—メトキシ一 2, 2—ジメチル一 4—ォキソクロマン一 8—ィ ル）ェチル]ピぺリジンー4ーィル }—N—メチルー 1H—インドールー 6—カルボキサ ミドの製造方法、
Figure imgf000006_0002
1— {1— [2— (7-methoxy-1,2,2-dimethyl-1,4-oxochroman-1,8-yl) ethyl] piperidine-4-yl} —N-methyl-1H-indole-6-carboxa A process for producing imide,
(2)下記式 (a— 6)  (2) Following formula (a-6)
[化 7]
Figure imgf000007_0001
で表される 8— (2—ヒドロキシェチル) 7—メトキシ 2, 2 ジメチルクロマン 4- オンは、下記式（a— 5) [Chemical 7]
Figure imgf000007_0001
8- (2-hydroxyethyl) 7-methoxy 2,2 dimethylchroman 4-one represented by the following formula (a-5)
[化 8] [Chemical 8]
Figure imgf000007_0002
で表される化合物 [式中、 Xは水酸基の保護基を示す。 ]の保護基を除去することに より得られる、上記（1)記載の製造方法、
Figure imgf000007_0002
[Wherein, X represents a protecting group for a hydroxyl group. The production method according to (1) above, which is obtained by removing the protecting group of
(3)下記式 (a— 6)  (3) Following formula (a-6)
[化 9] (a-6)
Figure imgf000008_0001
で表される 8— (2 ヒドロキシェチル） 7—メトキシ一 2, 2 ジメチルクロマン一 4- オンは、下記式（a— 4) [Chemical 9] (a-6)
Figure imgf000008_0001
8— (2 Hydroxyethyl) 7-methoxy-1,2,2 dimethylchroman-4-one represented by the following formula (a-4)
[化 10] [Chemical 10]
Figure imgf000008_0002
で表される化合物 [式中、 Xは水酸基の保護基を示す。 ]とメチルクロトン酸とを反応さ せて、下記式（a— 5)
Figure imgf000008_0002
[Wherein, X represents a protecting group for a hydroxyl group. ] And methylcrotonic acid are reacted to give the following formula (a-5)
[化 11] [Chemical 11]
Figure imgf000009_0001
で表される化合物 [式中、 Xは前記定義と同義である。 ]を得、次いで、該化合物（a - 5)の保護基を除去することにより得られる、上記（1)または (2)記載の製造方法、
Figure imgf000009_0001
[Wherein, X is as defined above.] And then removing the protecting group of the compound (a-5), the production method according to (1) or (2) above,
(4)下記式 (a— 6) (4) Following formula (a-6)
[化 12] [Chemical 12]
Figure imgf000009_0002
で表される 8— (2 ヒドロキシェチル） 7—メトキシ一 2, 2 ジメチルクロマン一 4— オンは、下記式（a— 3)
Figure imgf000009_0002
8- (2 Hydroxyethyl) 7-methoxy-1,2,2-dimethylchroman-4-one represented by the following formula (a-3)
[化 13]
Figure imgf000010_0001
で表される化合物 [式中、 xは水酸基の保護基を示す。 ]と酸とを反応させて、下記式[Chemical 13]
Figure imgf000010_0001
[Wherein x represents a hydroxyl-protecting group. ] And an acid, and the following formula
(a - 4) (a-4)
[化 14] [Chemical 14]
Figure imgf000010_0002
で表される化合物 [式中、 Xは前記定義と同義である。 ]を得、該化合物 (a ルクロトン酸とを反応させて、下記式 (a— 5)
Figure imgf000010_0002
[Wherein, X is as defined above.] The compound (a is reacted with lucrotonic acid to give the following formula (a-5)
[化 15] [Chemical 15]
Figure imgf000010_0003
で表される化合物 [式中、 Xは前記定義と同義である。 ]を得、次いで、該化合物 (a— 5)の保護基を除去することにより得られる、上記（1)から（3)の 、ずれかに記載の製 造方法、
Figure imgf000010_0003
[Wherein, X is as defined above.] And then removing the protecting group of the compound (a-5), the production method according to any one of (1) to (3) above,
(5)下記式 (a— 6)  (5) Following formula (a-6)
[化 16] [Chemical 16]
Figure imgf000011_0001
で表される 2— [2— (1—エトキシエトキシ） 6—メトキシフエニル]エタノールの水酸 基を保護して、下記式 (a— 3)
Figure imgf000011_0001
Protect the hydroxyl group of 2- [2— (1-ethoxyethoxy) 6-methoxyphenyl] ethanol represented by the following formula (a-3)
[化 18]
Figure imgf000012_0001
で表される化合物 [式中、 Xは水酸基の保護基を示す。 ]を得、該化合物 (a とを反応させて、下記式 (a— 4) [Chemical 18]
Figure imgf000012_0001
[Wherein, X represents a protecting group for a hydroxyl group. And reacting the compound (a with the following formula (a-4)
[化 19] [Chemical 19]
Figure imgf000012_0002
で表される化合物 [式中、 Xは前記定義と同義である。 ]を得、該化合物 (a ルクロトン酸とを反応させて、下記式 (a— 5)
Figure imgf000012_0002
[Wherein, X is as defined above.] The compound (a is reacted with lucrotonic acid to give the following formula (a-5)
[化 20] [Chemical 20]
Figure imgf000012_0003
で表される化合物 [式中、 Xは前記定義と同義である。 ]を得、次いで、該化合物（a— 5)の保護基を除去することにより得られる、上記（1)から (4)の 、ずれかに記載の製 造方法、
Figure imgf000012_0003
[Wherein, X is as defined above.] And then removing the protecting group of the compound (a-5), the production method according to any one of (1) to (4) above,
(6)下記式 (a— 6)  (6) The following formula (a-6)
[化 21] [Chemical 21]
Figure imgf000013_0001
で表される 8— (2 ヒドロキシェチル） 7—メトキシ一 2, 2 ジメチルクロマン一 4— オンは、下記式（a— 1)
Figure imgf000013_0001
8- (2 Hydroxyethyl) 7-methoxy-1,2,2 dimethylchroman-4-one represented by the following formula (a-1)
[化 22] [Chemical 22]
Figure imgf000013_0002
Figure imgf000013_0002
で表される [2—（1 エトキシエトキシ） 6—メトキシフエ-ル]酢酸ェチルを還元し て、下記式 (a— 2) [2- (1 ethoxyethoxy) 6-methoxyphenyl] ethyl acetate represented by the following formula (a-2)
[化 23]
Figure imgf000014_0001
で表される 2— [2— (1—エトキシエトキシ） 6—メトキシフエ-ル]エタノールを得、該 化合物の水酸基を保護して、下記式 (a— 3) [Chemical 23]
Figure imgf000014_0001
2- [2— (1-ethoxyethoxy) 6-methoxyphenol] ethanol represented by the following formula (a-3) is obtained by protecting the hydroxyl group of the compound:
[化 24][Chemical 24]
Figure imgf000014_0002
で表される化合物 [式中、 Xは水酸基の保護基を示す。 ]を得、該化合物 (a とを反応させて、下記式 (a— 4)
Figure imgf000014_0002
[Wherein, X represents a protecting group for a hydroxyl group. And reacting the compound (a with the following formula (a-4)
[化 25][Chemical 25]
Figure imgf000014_0003
で表される化合物 [式中、 Xは前記定義と同義である。 ]を得、該化合物 (a— 4)とメチ ルクロトン酸とを反応させて、下記式 (a— 5)
Figure imgf000014_0003
[Wherein, X is as defined above.] And the compound (a-4) and methyl By reacting with lucrotonic acid, the following formula (a-5)
[化 26] [Chemical 26]
Figure imgf000015_0001
で表される化合物 [式中、 Xは前記定義と同義である。 ]を得、次いで、該化合物（a - 5)の保護基を除去することにより得られる、上記（1)から（5)の 、ずれかに記載の製 造方法、
Figure imgf000015_0001
[Wherein, X is as defined above.] And then removing the protecting group of the compound (a-5), the production method according to any one of (1) to (5) above,
(7)下記式 (a— 6)  (7) Following formula (a-6)
[化 27] [Chemical 27]
Figure imgf000015_0002
で表される 8— (2 ヒドロキシェチル） 7—メトキシ一 2, 2 ジメチルクロマン一 4- オンは、下記式
Figure imgf000015_0002
8— (2 Hydroxyethyl) 7-methoxy-1,2,2-dimethylchroman-1-one represented by the formula
[化 28]
Figure imgf000016_0001
[Chemical 28]
Figure imgf000016_0001
メトキシベンゼンとブロモ酢酸ェチルとを
Figure imgf000016_0002
Methoxybenzene and bromoethyl acetate
Figure imgf000016_0002
で表される [2—（1 エトキシエトキシ） 6—メトキシフエ-ル]酢酸ェチルを得、該 化合物（a— 1)を還元して、下記式 (a— 2) [2- (1 ethoxyethoxy) 6-methoxyphenyl] ethyl acetate is obtained, and the compound (a-1) is reduced to give the following formula (a-2)
[化 30][Chemical 30]
Figure imgf000016_0003
Figure imgf000016_0003
で表される 2— [2— (1—エトキシエトキシ） 6—メトキシフエ-ル]エタノールを得、該 化合物 (a— 2)の水酸基を保護して、下記式 (a— 3) 2- [2- (1-Ethoxyethoxy) 6-methoxyphenol] ethanol represented by The hydroxyl group of the compound (a-2) is protected and the following formula (a-3)
[化 31] [Chemical 31]
Figure imgf000017_0001
で表される化合物 [式中、 Xは水酸基の保護基を示す。 ]を得、該化合物 (a とを反応させて、下記式 (a— 4)
Figure imgf000017_0001
[Wherein, X represents a protecting group for a hydroxyl group. And reacting the compound (a with the following formula (a-4)
[化 32] [Chemical 32]
Figure imgf000017_0002
で表される化合物 [式中、 Xは前記定義と同義である。 ]を得、該化合物 (a ルクロトン酸とを反応させて、下記式 (a— 5)
Figure imgf000017_0002
[Wherein, X is as defined above.] The compound (a is reacted with lucrotonic acid to give the following formula (a-5)
[化 33]
Figure imgf000018_0001
で表される化合物 [式中、 Xは前記定義と同義である。 ]を得、次いで、該化合物（a - 5)の保護基を除去することにより得られる、上記（1)から (6)の 、ずれかに記載の製 造方法。 [Chemical 33]
Figure imgf000018_0001
[Wherein, X is as defined above.] And then removing the protecting group of the compound (a-5), the production method according to any one of (1) to (6) above.
(8) Xがベンゾィル基である、上記（2)から（7)の 、ずれかに記載の製造方法、 (8) The production method according to any one of (2) to (7) above, wherein X is a benzoyl group,
(9)下記式 (II) (9) The following formula (II)
[化 34] [Chemical 34]
Figure imgf000018_0002
で表される化合物 [式中、 X1は水素原子または水酸基の保護基を示す。 ]、
Figure imgf000018_0002
[Wherein, X 1 represents a hydrogen atom or a hydroxyl-protecting group. ],
(10)水酸基の保護基がベンゾィル基である、上記（9)記載の化合物、  (10) The compound according to (9) above, wherein the hydroxyl-protecting group is a benzoyl group,
(11)安息香酸 2—（7—メトキシ—2, 2 ジメチルー 4 ォキソクロマンー8—ィル )ェチルまたは 8—（2 ヒドロキシェチル） 7—メトキシー 2, 2 ジメチルクロマン 4 オン、  (11) Benzoic acid 2- (7-methoxy-2,2 dimethyl-4-oxochroman-8-yl) ethyl or 8- (2 hydroxyethyl) 7-methoxy-2,2 dimethylchroman 4one,
(12)下記式 (c 3)  (12) The following formula (c 3)
[化 35] (c-3)[Chemical 35] (c-3)
Figure imgf000019_0001
で表される化合物とメチルァミンとを反応させることを含む、下記式 (i)
Figure imgf000019_0001
Wherein the compound represented by formula (i) is reacted with methylamine:
[化 36] [Chemical 36]
Figure imgf000019_0002
で表される1ー { 1ー [2—（7—メトキシー2, 2—ジメチルー 4一ォキソクロマンー8—ィ ル）ェチル]ピぺリジン— 4一ィル }— N—メチル一 1 H—インドール— 6—カルボキサ ミドの製造方法、
Figure imgf000019_0002
1- {1- [2- (7-Methoxy-2,2-dimethyl-4 oxochroman-8-yl) ethyl] piperidine-4 yl} — N-methyl-1 1 H-indole— 6-carboxamide production method,
( 13)下記式 (c一 3)  (13) The following formula (c 1 3)
[化 37] [Chemical 37]
Figure imgf000019_0003
で表される化合物は、下記式 (c一 2) [化 38]
Figure imgf000019_0003
The compound represented by the following formula (c 1 2) [Chemical 38]
Figure imgf000020_0001
で表される化合物を加水分解することにより得られる、上記（12)記載の製造方法、 (14)下記式 (c 3)
Figure imgf000020_0001
(14) The production method according to the above (12), which is obtained by hydrolyzing a compound represented by the following formula (c 3)
[化 39] [Chemical 39]
Figure imgf000020_0002
Figure imgf000020_0002
で表される化合物と、下記式 (c 1) And a compound represented by the following formula (c 1)
[化 41] [Chemical 41]
Figure imgf000021_0001
で表される化合物またはその塩とを反応させて、下記式 (c 2)
Figure imgf000021_0001
And a compound represented by the following formula (c 2)
[化 42] [Chemical 42]
Figure imgf000021_0002
で表される化合物を得、次いで、該化合物を加水分解することにより得られる、上記（ 12)記載の製造方法、
Figure imgf000021_0002
The production method according to (12) above, obtained by hydrolyzing the compound,
( 15)下記式 (c 3)  (15) The following formula (c 3)
[化 43] [Chemical 43]
Figure imgf000021_0003
で表される化合物は、下記式 (a)
Figure imgf000021_0003
The compound represented by the following formula (a)
[化 44] [Chemical 44]
Figure imgf000022_0001
で表される化合物 [式中、 Yは 2級ァミンの保護基を示す。 ]の保護基を除去して得ら れる下記式 (c 1)
Figure imgf000022_0001
[Wherein Y represents a protecting group for secondary amine. The following formula (c 1) obtained by removing the protecting group
[化 46] [Chem 46]
c-1 )c-1)
Figure imgf000022_0002
で表される化合物またはその塩とを反応させて、下記式 (c 2)
Figure imgf000022_0002
And a compound represented by the following formula (c 2)
[化 47]  [Chemical 47]
Figure imgf000023_0001
で表される化合物を得、次いで、該化合物（c 2)を加水分解することにより得られる 、上記（12)記載の製造方法、および
Figure imgf000023_0001
And then obtaining the compound (c 2) by hydrolysis, and the production method according to (12) above, and
(16) Yがべンジルォキシカルボニルである、上記（15)記載の製造方法  (16) The production method according to the above (15), wherein Y is benzyloxycarbonyl.
に関する。  About.
発明の効果  The invention's effect
[0007] 本発明により、 1— { 1— [2— (7—メトキシ一 2, 2 ジメチルー 4—ォキソクロマン一 8 ィル）ェチル]ピぺリジンー4ーィル }—N—メチルー 1H—インドールー 6 カル ボキサミドを工業的に有利に製造することができる。また、本発明により、力かる製造 に有利に使用される製造中間体が提供される。  [0007] According to the present invention, 1— {1— [2— (7-methoxy-1,2,2 dimethyl-4-oxochroman-1-ethyl) piperidine-4-yl} -N-methyl-1H-indole-6-carboxamide Can be produced industrially advantageously. In addition, the present invention provides a production intermediate that can be advantageously used in intensive production.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0008] 本発明に係る、下記式 (i)で表される化合物の製造方法を以下に示す。  [0008] A method for producing a compound represented by the following formula (i) according to the present invention is shown below.
ェ細  N
工程（1)は下記式 (a)で表される化合物と下記式 (b)で表される化合物をカップリン グ反応に付することにより下記式 (i)で表される化合物を得る工程である。  Step (1) is a step of obtaining a compound represented by the following formula (i) by subjecting a compound represented by the following formula (a) and a compound represented by the following formula (b) to a coupling reaction. is there.
[化 48]  [Chemical 48]
Figure imgf000023_0002
[0009] 工程（1)におけるカップリング反応は、好ましくは還元的ァミノ化反応条件下、すな わちカルボ-ルイ匕合物とアミンィ匕合物との還元的ァミノ化反応に通常用いられて 、る 条件と同様の条件で行うことができる。本工程の還元反応は特に限定されないが、例 えばボラン、水素化ホウ素錯体ィ匕合物等の還元剤による還元的ァミノ化反応、金属 触媒を用いた水素雰囲気下での接触還元反応等が挙げられる。
Figure imgf000023_0002
[0009] The coupling reaction in step (1) is preferably used for reductive amination reaction of a carbo-Louis compound and an amine compound, preferably under reductive amination reaction conditions. It can be performed under the same conditions as above. The reduction reaction in this step is not particularly limited, but examples include reductive amination reaction with a reducing agent such as borane and borohydride complex, and catalytic reduction reaction in a hydrogen atmosphere using a metal catalyst. It is done.
水素化ホウ素錯体ィ匕合物を用いた還元的ァミノ化反応の例として、例えば W. S. E merson, Organic Reactions, 4. 174 "948)、 C. F. Lane, Synthesis, 135 ( 1975) , J. C. Ctowell and S. J. Pedegimas, Synthesis, 127 (1974)および A. F. Abdel— Magid, K. G. Carson, B. D. Harris, C. A. Marryanoff a nd R. D. Shah, Journal of Organic Chemistry, 61, 3849 (1996)等の 文献記載の方法を挙げることができる。水素化ホウ素錯体ィ匕合物として、例えば水素 ィ匕ホウ素ナトリウム、シアンィ匕水素ホウ素ナトリウム、トリァセトキシ水素化ホウ素ナトリ ゥム等を用いることができる。還元剤として水素化ホウ素錯体ィ匕合物を用いる場合、 溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定され ないが、具体的に例えば、メタノール、エタノール、テトラヒドロフラン、 N, N ジメチ ルホルムアミド、塩化メチレン、 1, 2—ジクロロェタン等が挙げられる。  Examples of reductive amination reactions using borohydride complexes include WS E merson, Organic Reactions, 4.174 "948), CF Lane, Synthesis, 135 (1975), JC Ctowell and SJ Pedegimas. Synthesis, 127 (1974) and AF Abdel—Magid, KG Carson, BD Harris, CA Marryanoff and RD Shah, Journal of Organic Chemistry, 61, 3849 (1996), etc. Examples of borohydride complex compounds include sodium hydrogen borohydride, sodium cyanide borohydride, sodium triacetoxyborohydride, etc. When using a borohydride complex compound as a reducing agent The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but specifically, for example, methanol, ethanol, tetrahydrofuran, N, N dimethylformaldehyde. Amides, methylene chloride, 1, 2-Jikuroroetan and the like.
化合物 (b)は、化合物（a)に対して、 0. 8から 2. 5当量、好ましくは 1から 1. 5当量 である。水素化ホウ素錯体ィ匕合物は化合物 (a)に対して、 1から 3当量、好ましくは、 1 力も 1. 5当量使用する。反応時間は、特に限定されないが、通常、 0. 5から 48時間 であり、好ましくは 0. 5から 12時間である。反応温度は特に限定されないが、通常、 78°C力 溶媒の還流温度であり、好ましくは氷冷から室温である。  Compound (b) is used in an amount of 0.8 to 2.5 equivalents, preferably 1 to 1.5 equivalents, relative to compound (a). The borohydride complex compound is used in an amount of 1 to 3 equivalents, preferably 1.5 equivalents, relative to compound (a). The reaction time is not particularly limited, but is usually 0.5 to 48 hours, preferably 0.5 to 12 hours. The reaction temperature is not particularly limited, but is usually a reflux temperature of 78 ° C. solvent, and preferably from ice cooling to room temperature.
[0010] 水素雰囲気下での接触還元反応を用いる際に使用される溶媒は、溶媒は反応を 阻害しないものであれば特に限定されないが、例えばメタノール、エタノール、テトラ ヒドロフラン、 1, 4 ジォキサン等が挙げられる。反応に用いる金属触媒としては、例 えばパラジウム、酸化白金、ラネーニッケル等を挙げることができる。反応時間は、特 に限定されないが、通常 1から 48時間であり、好ましくは 1から 24時間である。反応条 件は、特に限定されないが、室温から溶媒の還流温度、常圧力も 15MPa、好ましく は室温から 60°C、常圧から 0. 5MPaで行うことができる。 [0011] 化合物（a)は以下の工程 (A— 1)な 、し工程 (A-6)および工程 (A)を経て得られ る。 [0010] The solvent used in the catalytic reduction reaction under a hydrogen atmosphere is not particularly limited as long as the solvent does not inhibit the reaction. For example, methanol, ethanol, tetrahydrofuran, 1, 4 dioxane and the like are used. Can be mentioned. Examples of the metal catalyst used in the reaction include palladium, platinum oxide, Raney nickel and the like. The reaction time is not particularly limited, but is usually 1 to 48 hours, preferably 1 to 24 hours. The reaction conditions are not particularly limited, but the reaction can be carried out from room temperature to the reflux temperature of the solvent and normal pressure from 15 MPa, preferably from room temperature to 60 ° C. and from normal pressure to 0.5 MPa. [0011] Compound (a) is obtained through the following steps (A-1), step (A-6) and step (A).
工程 (A— 1)  Process (A— 1)
[化 49]  [Chemical 49]
Figure imgf000025_0001
Figure imgf000025_0001
[0012] 工程 (A—1)は 1 （1 エトキシエトキシ） 3—メトキシベンゼンとブロモ酢酸ェチ ルとを反応させることにより式 (a— 1)で表される化合物を得る工程である。 Step (A-1) is a step of obtaining a compound represented by the formula (a-1) by reacting 1 (1 ethoxyethoxy) 3-methoxybenzene with bromoacetate.
本工程は、必要ならば n—ブチルリチウム等の強塩基の存在下で行うことができる。 反応溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定 されないが、具体的に例えば、テトラヒドロフラン、ヘプタン、へキサン、トルエン、 1, 2 ージメトキシェタン、ジェチルエーテル、 1, 2—ジクロロェタン等が挙げられる。反応 温度は、通常、—78°Cから溶媒の還流温度であり、好ましくは— 78から 0°Cである。 反応時間は、特に限定されないが、通常 1から 48時間であり、好ましくは 1から 24時 間である。  If necessary, this step can be performed in the presence of a strong base such as n-butyllithium. The reaction solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Specifically, for example, tetrahydrofuran, heptane, hexane, toluene, 1,2-dimethoxyethane, jetyl ether. 1, 2-dichloroethane and the like. The reaction temperature is usually from −78 ° C. to the reflux temperature of the solvent, preferably from −78 to 0 ° C. The reaction time is not particularly limited, but is usually 1 to 48 hours, preferably 1 to 24 hours.
[0013] 工程 (A-2)  [0013] Process (A-2)
[化 50]  [Chemical 50]
Figure imgf000025_0002
Figure imgf000025_0002
(a-1)  (a-1)
[0014] 工程 (A— 2)は、前記式 (a— 1)で表される化合物を還元することにより、前記式 (a [0014] In the step (A-2), the compound represented by the formula (a-1) is reduced by reducing the compound represented by the formula (a-1).
2)で表される化合物を得る工程である。 工程 (A— 2)におけるエステルの還元反応は、例えば第 4版実験化学講座 26 (15 9〜266ページ)等に記載された還元反応として一般に用いられている条件または条 件に準じて反応を行うことができる。反応に用いられる還元剤としては、例えば水素 ィ匕リチウムアルミニウム、水素化ホウ素リチウム、水素化ジイソブチルアルミニウム、水 素化ビス（2—メトキシエトキシ)アルミニウムナトリウム等が挙げられる。反応溶媒は、 反応を阻害せず、出発物質をある程度溶解するものであれば特に限定されないが、 具体的に例えば、好ましくはテトラヒドロフラン、ジェチルエーテル、ジメトキシェタン、 シクロペンチルメチルエーテル等のエーテル系溶媒、トルエン、キシレン等の芳香族 炭化水素系溶媒または塩化メチレン等が挙げられる。反応温度は特に限定されない 力 通常、 78°Cから溶媒の還流温度であり、好ましくは 78°C力も室温である。還 元剤は化合物（a— 1)に対して、 1から 3当量、好ましくは 1から 1. 5当量使用する。 In this step, the compound represented by 2) is obtained. The ester reduction reaction in the step (A-2) is carried out according to the conditions or conditions generally used as the reduction reaction described in, for example, the 4th edition, Experimental Chemistry Course 26 (pages 159-266). It can be carried out. Examples of the reducing agent used in the reaction include lithium lithium aluminum, lithium borohydride, diisobutylaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, and the like. The reaction solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Specifically, for example, preferably an ether solvent such as tetrahydrofuran, jetyl ether, dimethoxyethane, cyclopentyl methyl ether, etc. And aromatic hydrocarbon solvents such as toluene and xylene, or methylene chloride. The reaction temperature is not particularly limited. Usually, the reaction temperature is from 78 ° C to the reflux temperature of the solvent, and preferably the 78 ° C force is also room temperature. The reducing agent is used in an amount of 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to compound (a-1).
[0015] 工程 (A- 3) [0015] Process (A-3)
[化 51] H3
Figure imgf000026_0001
[Chemical 51] H3
Figure imgf000026_0001
(a-2) (a-3)  (a-2) (a-3)
[式中、 Xは水酸基の保護基を示す。 ] [Wherein X represents a hydroxyl-protecting group. ]
[0016] 工程 (A— 3)は、前記式 (a— 2)で表される化合物の水酸基に保護基を導入して、 前記式 (a— 3)で表される化合物を得る工程である。 [0016] Step (A-3) is a step of obtaining a compound represented by the formula (a-3) by introducing a protecting group into the hydroxyl group of the compound represented by the formula (a-2). .
Xで表される水酸基の保護基としては、例えば、ァセチル基またはベンゾィル基等 公知の水酸基の保護基が挙げられる力 好ましくは、ベンゾィル基である。本工程は 、例えばベンゾィル基で保護する場合、塩化ベンゾィルを、トリェチルァミン等の塩基 存在下、例えばトルエン、キシレン等の芳香族炭化水素系溶媒、酢酸ェチル等のェ ステル系溶媒、ジメトキシェタン、シクロペンチルメチルエーテル等のエーテル系溶 媒中反応させること〖こより目的物を得ることができる。塩ィ匕ベンゾィルは、化合物（a— 2)に対して 1当量から大過剰を用いることができる。本反応に、例えば N, N, Ν', Ν '—テトラメチルエチレンジァミン、ジイソプロピルェチルァミン、 N, N—ジメチルァニ リン等を共存させると収率の向上や反応時間の短縮等の好ましい結果を得ることがあ る。反応温度は、 0から 100°Cであり、好ましくは 0°C力も室温である。反応時間は、特 に限定されないが、通常 0. 5から 48時間であり、好ましくは 0. 5から 4時間である。 The hydroxyl protecting group represented by X is, for example, a known hydroxyl protecting group such as acetyl group or benzoyl group, preferably a benzoyl group. In this step, for example, when protecting with a benzoyl group, benzoyl chloride is present in the presence of a base such as triethylamine, for example, an aromatic hydrocarbon solvent such as toluene or xylene, an ester solvent such as ethyl acetate, dimethoxyethane, or cyclopentyl. The target product can be obtained by reacting in an ether-based solvent such as methyl ether. The salty benzoyl can be used in an amount of 1 equivalent to a large excess relative to the compound (a-2). For example, N, N, Ν ', Ν Coexistence of '-tetramethylethylenediamine, diisopropylethylamine, N, N-dimethylaniline, etc. may give favorable results such as improved yield and reduced reaction time. The reaction temperature is from 0 to 100 ° C, preferably the 0 ° C force is also room temperature. The reaction time is not particularly limited, but is usually 0.5 to 48 hours, preferably 0.5 to 4 hours.
[0017] 工程 (A—4) [0017] Process (A-4)
[化 52]  [Chemical 52]
Figure imgf000027_0001
Figure imgf000027_0001
[式中、 Xは前記定義と同義である。 ] [Wherein X is as defined above. ]
[0018] 工程 (A— 4)は、前記式 (a— 3)で表される化合物と酸とを反応させて、前記式 (a— 4)で表される化合物を得る工程である。  Step (A-4) is a step of obtaining a compound represented by the formula (a-4) by reacting a compound represented by the formula (a-3) with an acid.
本工程で用いられる酸としては、通常用いられる酸であれば何でもよいが、好ましく は、塩酸である。酸の量は、化合物（a— 3)に対し 1当量から大過剰用いる。反応溶 媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定されな いが、具体的に例えば、トルエン、ジメトキシェタン、テトラヒドロフラン、水またはそれ らの混合溶媒等が挙げられる。反応温度は 0から 100°Cであり、好ましくは 0°Cから室 温である。反応時間は、通常 0. 5から 48時間であり、好ましくは 1から 4時間である。  The acid used in this step is not particularly limited as long as it is a commonly used acid, but hydrochloric acid is preferable. The acid is used in an amount of 1 equivalent to a large excess relative to compound (a-3). The reaction solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Specifically, for example, toluene, dimethoxyethane, tetrahydrofuran, water, or a mixed solvent thereof may be used. Can be mentioned. The reaction temperature is 0 to 100 ° C., preferably 0 ° C. to room temperature. The reaction time is usually 0.5 to 48 hours, preferably 1 to 4 hours.
[0019] 工程 (A— 5)  [0019] Process (A-5)
[化 53]  [Chemical 53]
Figure imgf000027_0002
Figure imgf000027_0002
(a-5) [式中、 Xは前記定義と同義である。 ] (a-5) [Wherein X is as defined above. ]
[0020] 工程 (A- 5)は、前記式 (a— 4)で表される化合物とメチルクロトン酸とを反応させて 前記式 (a— 5)で表される化合物を得る工程である。  Step (A-5) is a step of obtaining a compound represented by the formula (a-5) by reacting the compound represented by the formula (a-4) with methylcrotonic acid.
本工程は、例えば、 T. Timarら、" Synthesis of 2, 2 - Dimethyl4 - Chroma nones", J. Heterocyclic Chem. , 37, 1389 (2000)； J. C. Jaszberenyiら、 "O n the Synthesis of Substituted 2, 2― Dimethyl— 4— Chromanones a nd Related Compounds, 'Tetrahedron Letters, 33 (20) , 2791— 2794, 1992 ;J. C. Jaszberenyiら、 Heterocycles, 38 (9) , 2099, 1994等に記載され た条件と同等の条件で反応を行うことができる。他にも、化合物 (a— 4)とメチルクロト ン酸をメシル酸存在下で反応させることにより、化合物（a— 5)を得ることができる。メ チルクロトン酸は化合物（a— 4)に対し 1当量から大過剰用いる。本反応は、必要なら ば五酸ィ匕ニリン等の脱水剤を添加してもよい。反応溶媒は、反応を阻害せず、出発 物質をある程度溶解するものであれば特に限定されないが、具体的に例えば、メタン スルホン酸等を挙げることができる。反応温度は室温から 100°Cであり、好ましくは 40 力も 60°Cである。反応時間は、特に限定されないが、通常、 0. 5から 48時間であり、 好ましくは 1から 4時間である。 This process is described in, for example, T. Timar et al., “Synthesis of 2, 2-Dimethyl4-Chroma nones”, J. Heterocyclic Chem., 37, 1389 (2000); JC Jaszberenyi et al., “On the Synthesis of Substituted 2, 2-Dimethyl— 4— Chromanones and the Related Compounds, 'Tetrahedron Letters, 33 (20), 2791— 2794, 1992; JC Jaszberenyi et al., Heterocycles, 38 (9), 2099, 1994, etc. In addition, the compound (a-5) can be obtained by reacting the compound (a-4) with methylcrotonic acid in the presence of mesylic acid. Use 1 equivalent to a large excess of compound ( a -4) .In this reaction, if necessary, a dehydrating agent such as quinolinic acid niline may be added.The reaction solvent does not inhibit the reaction and the starting material is used. Is not particularly limited as long as it dissolves to some extent, but specific examples include methanesulfonic acid and the like. The reaction temperature is from room temperature to 100 ° C., preferably 40 force is also 60 ° C. The reaction time is not particularly limited, but is usually 0.5 to 48 hours, preferably 1 to 4 hours. is there.
[0021] 工程 (A- 6)  [0021] Process (A-6)
[化 54]  [Chemical 54]
Figure imgf000028_0001
Figure imgf000028_0001
(a-6)  (a-6)
(a-5)  (a-5)
[式中、 Xは前記定義と同義である。 ] [Wherein X is as defined above. ]
工程 (A— 6)は、前記式 (a— 5)で表される化合物の水酸基の保護基を脱保護する ことにより、前記式 (a— 6)で表される化合物を得る工程である。  Step (A-6) is a step of obtaining the compound represented by the formula (a-6) by deprotecting the hydroxyl-protecting group of the compound represented by the formula (a-5).
アルコール性水酸基の保護基の脱保護の方法として一般に用いられる条件、たと えば T. W. Greene, P. G. M. Wuts, "Protective Groups in Organic Sy nthesis, Second Edition", John Wiley & Sons, Inc.の文献記載の条件と同 様の条件で反応を行うことができる。例えば、ベンゾィル基等で保護されたアルコー ル性水酸基は、例えばテトラヒドロフラン、メタノール、エタノール等の有機溶媒または これらの混合溶媒中、水酸ィ匕ナトリウム水等とを反応させることにより目的物を得るこ とができる。水酸ィ匕ナトリウムは、化合物（a— 5)に対して 1当量から大過剰を用いる。 反応温度は 0から 100°Cであり、好ましくは室温から 50°Cである。反応時間は、特に 限定されないが、通常、 0. 5から 48時間であり、好ましくは 1から 5時間である。 Conditions generally used as a method for deprotecting a protective group of an alcoholic hydroxyl group, For example, the reaction can be carried out under conditions similar to those described in TW Greene, PGM Wuts, “Protective Groups in Organic Synthesis, Second Edition”, John Wiley & Sons, Inc. For example, an alcoholic hydroxyl group protected with a benzoyl group can be obtained by reacting it with an aqueous solution of sodium hydroxide or sodium hydroxide in an organic solvent such as tetrahydrofuran, methanol or ethanol or a mixed solvent thereof. You can. Sodium hydroxide is used in an amount of 1 equivalent to a large excess based on compound (a-5). The reaction temperature is from 0 to 100 ° C, preferably from room temperature to 50 ° C. The reaction time is not particularly limited, but is usually 0.5 to 48 hours, preferably 1 to 5 hours.
[0023] 工程 (A) [0023] Process (A)
[化 55]  [Chemical 55]
Figure imgf000029_0001
Figure imgf000029_0001
(a-6) (a)  (a-6) (a)
[0024] 工程 (A)は、前記式 (a— 6)で表される化合物を酸ィ匕することにより、前記式 (a)で 表される化合物を得る工程である。 [0024] Step (A) is a step of obtaining a compound represented by the formula (a) by acidifying the compound represented by the formula (a-6).
当業者に公知の方法により、アルコールィ匕合物力 アルデヒドィ匕合物を得ることが できる。公知の酸ィ匕方法としては、例えばスワン酸ィ匕（Swern酸化）、コーリ一一キム 酸化（Corey— Kim酸化）、モファット酸化（Moffatt酸化）、 PCC酸化、 PDC酸化、 デス マーチン酸化（Dess— Martin酸化）、 SO— Pyridine酸化、 TEMPO酸化  Alcohol compound strength aldehyde compound can be obtained by methods known to those skilled in the art. Known acid-oxidation methods include, for example, Swan's acid oxidation (Swern oxidation), Cory-Kim oxidation (Corey-Kim oxidation), Moffat oxidation (Moffatt oxidation), PCC oxidation, PDC oxidation, Dess-Martin oxidation (Dess— Martin oxidation), SO—Pyridine oxidation, TEMPO oxidation
3  Three
などを挙げることができる。反応溶媒は、反応を阻害せず、出発物質をある程度溶解 するものであれば特に限定されないが、例えば、ジメチルスルホキシド、テトラヒドロフ ラン、トルエン、塩化メチレン、クロ口ホルム、酢酸ェチル、水またはそれらの混合溶媒 等が挙げられる。酸化剤は、化合物 (a— 6)に対して、触媒量力 大過剰を用いる。 反応温度は特に限定されないが、通常— 78°C力も溶媒の還流温度であり、好ましく は 5°C力も室温である。反応時間は、特に限定されないが、通常、 1から 10時間で あり、好ましくは 1から 5時間である。例えば TEMPO酸ィ匕の場合は、第 4版実験化学 講座 23 有機合成 V 酸ィ匕反応、丸善株式会社 (369— 403ページ)記載の方法に 準じて行うことができる。反応溶媒は、反応を阻害せず、出発物質をある程度溶解す るものであれば特に限定されないが、例えば、ジメチルスルホキシド、テトラヒドロフラ ン、トルエン、塩化メチレン、クロ口ホルム、酢酸ェチル、水またはそれらの混合溶媒 等が挙げられる。 2, 2, 6, 6—テトラメチルピペリジンォキシド—臭化ナトリウム存在 下、酸化剤、例えば炭酸水素ナトリウム水溶液中の次亜塩素酸ナトリウム等を、化合 物（a— 6)に対して当量以上用いる。反応温度は特に限定されないが、通常— 20°C から室温であり、好ましくは 5°Cから室温である。反応時間は、特に限定されないが 、通常、 1から 10時間であり、好ましくは 1から 5時間である。 And so on. The reaction solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, chloroform, formyl acetate, water, or theirs. Examples thereof include mixed solvents. As the oxidizing agent, a large excess of catalytic amount is used relative to compound (a-6). The reaction temperature is not particularly limited, but usually −78 ° C. force is the reflux temperature of the solvent, and preferably 5 ° C. force is also room temperature. The reaction time is not particularly limited, but is usually 1 to 10 hours. Yes, preferably 1 to 5 hours. For example, in the case of TEMPO acid, it can be carried out according to the method described in the 4th edition Experimental Chemistry Course 23 Organic Synthesis V Acid Reaction, Maruzen Co., Ltd. (pages 369-403). The reaction solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, chloroform, ethyl acetate, water, or theirs. Examples thereof include mixed solvents. 2, 2, 6, 6-Tetramethylpiperidine oxide-in the presence of sodium bromide, an oxidizing agent such as sodium hypochlorite in an aqueous solution of sodium hydrogen carbonate is equivalent to or greater than the compound (a-6). Use. Although the reaction temperature is not particularly limited, it is usually from −20 ° C. to room temperature, preferably from 5 ° C. to room temperature. The reaction time is not particularly limited, but is usually 1 to 10 hours, preferably 1 to 5 hours.
例えばスワン酸ィ匕の場合は、第 4版実験化学講座 23 有機合成 V 酸化反応、丸 善株式会社 (298— 346ページ)記載の方法に準じて行うことができる。反応溶媒は 、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定されないが 、例えば、ジメチルスルホキシド、テトラヒドロフラン、トルエン、塩化メチレン、クロロホ ルム、酢酸ェチル、水またはそれらの混合溶媒等が挙げられる。酸化剤としては、ジ メチルスルホキシドの活性化剤として、例えば塩ィ匕ォキサリル、無水トリフルォロ酢酸 、無水酢酸、シクロへキシルイミドまたは五酸ィ匕ニリンなどを、化合物（a— 6)に対して 、 2倍モル量力も大過剰用いる。反応温度は特に限定されないが、通常 70°Cから 室温である。反応時間は、特に限定されないが、通常、 3から 10時間であり、好ましく は 3から 5時間である。なお、アルデヒド化合物は、 D. P. Kjellら、 "A Nobel, Non aqueous Method for Regeneration of Aldehydes from Bisuliite Add ucts" J. Organic. Chemistry. 64, 5722— 5724 (1999)記載の方法【こ従!ヽ、 亜硫酸水素ナトリウム付加物に変換することにより簡便に精製することができ、また容 易にアルデヒドを再生することができる。アルデヒド化合物を、例えばエタノール、酢 酸ェチル、メタノールなどの有機溶媒またはそれらの混合溶媒中、例えば亜硫酸水 素ナトリウム水溶液とを反応させることにより亜硫酸水素ナトリウム付加物を得ることが できる。使用する亜硫酸水素ナトリウムはアルデヒド化合物に対して 1当量から大過 剰用いる。反応温度は特に限定されないが、通常 10から 40°Cであり、好ましくは室 温である。 For example, in the case of swannate, it can be carried out according to the method described in the 4th edition, Experimental Chemistry Course 23 Organic Synthesis V Oxidation Reaction, Maruzen Co., Ltd. (pages 298-346). The reaction solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, chloroform, ethyl acetate, water, or a mixed solvent thereof, etc. Is mentioned. As the oxidizing agent, for example, dimethyl sulfoxide activator, for example, salt oxalyl, trifluoroacetic anhydride, acetic anhydride, cyclohexylimide, pentyl dianiline or the like is used with respect to compound (a-6). Double molar power is also used in large excess. The reaction temperature is not particularly limited, but is usually 70 ° C to room temperature. The reaction time is not particularly limited, but is usually 3 to 10 hours, preferably 3 to 5 hours. Aldehyde compounds can be prepared by the method described in DP Kjell et al., “A Nobel, Non aqueous Method for Regeneration of Aldehydes from Bisuliite Add ucts” J. Organic. Chemistry. 64, 5722-5724 (1999). By converting to a sodium hydride adduct, it can be easily purified, and the aldehyde can be easily regenerated. A sodium bisulfite adduct can be obtained by reacting an aldehyde compound with, for example, an aqueous solution of sodium hydrogen sulfite in an organic solvent such as ethanol, ethyl acetate or methanol or a mixed solvent thereof. The sodium bisulfite used is used in an amount of 1 equivalent to a large excess relative to the aldehyde compound. The reaction temperature is not particularly limited, but is usually 10 to 40 ° C, preferably a chamber. It is warm.
反応時間は、特に限定されないが、通常、 1から 48時間であり、好ましくは 12から 24 時間である。  The reaction time is not particularly limited, but is usually 1 to 48 hours, preferably 12 to 24 hours.
[0026] このようにして得られた亜硫酸水素ナトリウム付加物を、例えばエタノール、酢酸ェ チル、メタノール等の有機溶媒またはそれらの混合溶媒中、炭酸カリウム、炭酸ナトリ ゥム、水酸化ナトリウム、水酸ィ匕カリウム等の塩基 (水溶液)で処理することによりアル デヒド化合物を得ることができる。使用する塩基は、亜硫酸水素ナトリウム付加物に対 し 1当量から大過剰用いる。反応温度は特に限定されないが、通常 10から 40°Cであ り、好ましくは室温である。  [0026] The sodium hydrogen sulfite adduct obtained in this way is mixed with potassium carbonate, sodium carbonate, sodium hydroxide, hydroxide in an organic solvent such as ethanol, ethyl acetate, methanol or a mixed solvent thereof. Aldehyde compounds can be obtained by treatment with a base (aqueous solution) such as potassium salt. The base used is 1 equivalent to a large excess with respect to the sodium bisulfite adduct. The reaction temperature is not particularly limited, but is usually 10 to 40 ° C., preferably room temperature.
反応時間は、特に限定されないが、通常、 1から 48時間であり、好ましくは 12から 24 時間である。なお、化合物 (a)は、精製または精製することなぐ化合物 (i)を製造す るために使用することができる。  The reaction time is not particularly limited, but is usually 1 to 48 hours, preferably 12 to 24 hours. Compound (a) can be used to produce compound (i) that is purified or not purified.
[0027] 一方、工程（1)において使用される化合物 (b)は例えば下記の工程 (B—1)ないし On the other hand, the compound (b) used in the step (1) is, for example, the following step (B-1) to
(B- 6)により得られる。  Obtained by (B-6).
工程（B— 1)  Process (B-1)
[化 56]  [Chemical 56]
Figure imgf000031_0001
Figure imgf000031_0001
(b-1)  (b-1)
[0028] 工程 (B—1)は、 3 -トロー 4 メチル安息香酸とメチルアミンを縮合反応させるこ とにより、前記式 (b— 1)で表される化合物を得る工程である。 [0028] Step (B-1) is a step of obtaining a compound represented by the above formula (b-1) by subjecting 3-tro 4-methylbenzoic acid and methylamine to a condensation reaction.
本反応は、以下の文献に記載された通常用いられている条件と同様の条件で行う ことができる。公知の方法として、例えば、 Rosowsky, A. ； Forsch, R. A. ； Moran, R. G. ； Freisheim, J. H. ； J. Med. Chem. , 34 (1) , 227- 234 (1991) , Brzostwska, M. ； Brossi, A. ； Flippen— Anders on, J. L. ； Heterocycles, 32 (10) , 1969— 1972 (1991) , Romero, D . L, ； Morge, R. A. ； Biles, C. ； Berrios— Pena, N. ； May, P. D. ； Palme r, J. R. ； Johnson, P. D. ； Smith, H. W. ； Busso, M. ； Tan, C. — K. ； Vo rman, R. L. ； Reusser, F. ； ALthaus, I. W. ； Downey, K. M ; So, A. G. ； Resnick, L ; Tarpley, W. G. , Aristoff, P. A. ； J. Med. Chem. , 37 (7) , 99 9 1014 (1994)等が挙げられる。 This reaction can be carried out under the same conditions as those usually used described in the following documents. Known methods include, for example, Rosowsky, A .; Forsch, RA; Moran, RG; Freisheim, JH; J. Med. Chem., 34 (1), 227-234 (1991), Brzostwska, M .; Brossi, A. ； Flippen— Anders on, JL ； Heterocycles, 32 (10), 1969— 1972 (1991), Romero, D Morge, RA; Biles, C .; Berrios— Pena, N .; May, PD; Palmer, JR; Johnson, PD; Smith, HW; Busso, M .; Tan, C. — K .; Volman, RL; Reusser, F .; ALthaus, IW; Downey, K. M; So, AG; Resnick, L; Tarpley, WG, Aristoff, PA; J. Med. Chem., 37 (7), 99 9 1014 (1994).
[0029] 縮合剤は、 CDI (N, N'—カルボ-ルジイミダゾール）、 Bop (1H— 1, 2, 3 ベン ゾトリァゾールー 1ーィルォキシ（トリ（ジメチルァミノ） )ホスホ-ゥム へキサフルォロホ スフェート）、 WSC (1 ェチル 3— (3 ジメチルァミノプロピル）カルボジイミド '塩 酸塩）、 DCC (N, N ジシクロへキシルカルボジイミド）、ジェチルホスホリルシア-ド 等が挙げられる。また必要に応じて、 3 -トロー 4 メチル安息香酸に対して 1当量 から大過剰の有機塩基、例えばトリェチルアミン等を加えてもよい。反応溶媒は、反 応を阻害せず、出発物質をある程度溶解するものであれば特に限定されないが、具 体的に例えば、テトラヒドロフラン、 1, 4 ジォキサン、酢酸ェチル、酢酸メチル、ジク ロロメタン、クロ口ホルム、 N, N ジメチルホルムアミド、トルエン、キシレン等が挙げら れる。反応温度は、使用する原料、溶媒等により異なり特に限定されないが、好ましく は氷温力も溶媒の還流温度である。反応時間は、特に限定されないが、通常、 0. 5 から 48時間であり、好ましくは 0. 5から 24時間である。得られた (b— 1)の化合物は 常法により精製または精製することなく次工程に使用することができる。  [0029] The condensing agent includes CDI (N, N'-carbodiimidazole), Bop (1H— 1, 2, 3 benzotriazole-1-yloxy (tri (dimethylamino)) phosphonium hexafluorophosphate), WSC ( Examples include 1-ethyl 3- (3 dimethylaminopropyl) carbodiimide 'hydrochloride), DCC (N, N dicyclohexylcarbodiimide), and jetyl phosphoryl cyanide. If necessary, 1 equivalent to a large excess of an organic base, such as triethylamine, may be added to 3-tro 4-methylbenzoic acid. The reaction solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but specifically, for example, tetrahydrofuran, 1,4 dioxane, ethyl acetate, methyl acetate, dichloromethane, chloroform. Form, N, N dimethylformamide, toluene, xylene and the like. The reaction temperature varies depending on the raw materials and solvent used, and is not particularly limited. However, the ice temperature is preferably the reflux temperature of the solvent. The reaction time is not particularly limited, but is usually 0.5 to 48 hours, preferably 0.5 to 24 hours. The obtained compound (b-1) can be used in the next step without purification or purification by a conventional method.
[0030] 工程（B— 2)  [0030] Process (B-2)
[化 57]  [Chemical 57]
Figure imgf000032_0001
工程 (B— 2)は、前記式 (b— 1)で表される化合物とジメチルホルムアルデヒドジメ チルァセタールとを反応させることにより、化合物 (b— 2)を得る工程である。 本工程は、当業者に公知の合成法である、例えば Coe, J. W. ； Vetelino, M. G. ； Bradlee, M. J. ； Tetrahedron Lett. , 37 (34) , 6045— 6048 (1996)等に記 載された条件と同様の条件で反応を行うことができる。反応溶媒は、本反応を阻害せ ず出発物質をある程度溶解するものであれば特に限定されないが、例えばメタノー ル、エタノール、テトラヒドロフラン、 Ν, Ν—ジメチルホルムアミド、塩化メチレン、 1, 2 ージクロ口エタン等を用いることができる。反応温度は、通常室温から溶媒の還流温 度であり、好ましくは室温から 100°Cである。反応時間は、特に限定されないが、通 常、 1から 72時間であり、好ましくは 1から 48時間である。得られた (b— 2)の化合物 は常法により精製または精製することなく次工程に使用することができる。
Figure imgf000032_0001
Step (B-2) is a step of obtaining compound (b-2) by reacting the compound represented by formula (b-1) with dimethylformaldehyde dimethylacetal. This step is a synthesis method known to those skilled in the art, for example, the conditions described in Coe, JW; Vetelino, MG; Bradlee, MJ; Tetrahedron Lett., 37 (34), 6045-6048 (1996), etc. The reaction can be performed under similar conditions. The reaction solvent is not particularly limited as long as it does not inhibit this reaction and dissolves the starting material to some extent. For example, methanol, ethanol, tetrahydrofuran, Ν, Ν-dimethylformamide, methylene chloride, 1,2-dichloroethane, etc. Can be used. The reaction temperature is usually from room temperature to the reflux temperature of the solvent, preferably from room temperature to 100 ° C. The reaction time is not particularly limited, but is usually 1 to 72 hours, preferably 1 to 48 hours. The obtained compound (b-2) can be used in the next step without purification or purification by a conventional method.
[0032] 工程（B— 3) [0032] Process (B-3)
[化 58]  [Chemical 58]
Figure imgf000033_0001
Figure imgf000033_0001
[0033] 工程 (B— 3)は前記式 (b— 2)で表される化合物をァセタールイ匕することにより、前 記式 (b— 3)で表される化合物を得る工程である。 Step (B-3) is a step of obtaining the compound represented by the above formula (b-3) by subjecting the compound represented by the above formula (b-2) to acetalization.
本工程のァセタールイ匕は、当業者に公知の方法が挙げられる力 例えば、 Coe, J. W. Vetelino, M. G. ； Bradlee, M. J. ； Tetrahedron Lett. , 37 (34) , 6045 - 6048 (1996)などに記載された条件と同様の条件で行うことができる。反応温度 は、通常室温から溶媒の還流温度であり、好ましくは室温から 100°Cである。反応時 間は、特に限定されないが、通常、 1から 72時間であり、好ましくは 1から 48時間であ る。得られた (b— 3)の化合物は常法により精製または精製することなく次工程に使 用することができる。  The acetal cake used in this step is described in, for example, Coe, JW Vetelino, MG; Bradlee, MJ; Tetrahedron Lett., 37 (34), 6045-6048 (1996). It can be performed under the same conditions as the conditions. The reaction temperature is usually from room temperature to the reflux temperature of the solvent, preferably from room temperature to 100 ° C. The reaction time is not particularly limited, but is usually 1 to 72 hours, preferably 1 to 48 hours. The obtained compound (b-3) can be used in the next step without purification or purification by a conventional method.
[0034] 工程（B— 4)  [0034] Process (B-4)
[化 59] [Chemical 59]
Figure imgf000034_0001
Figure imgf000034_0001
[0035] 工程 (B— 4)は、前記式 (b— 3)で表される化合物を還元することにより、前記式 (b [0035] In the step (B-4), the compound represented by the formula (b-3) is reduced to reduce the formula (b-3).
4)で表される化合物を得る工程である。  In this step, the compound represented by 4) is obtained.
本工程における還元反応は、公知の方法が挙げられる力 例えばラネーニッケル、 ノ ラジウム、ルテニウム、ロジウムまたは白金等の貴金属触媒を使用する接触水素化 による還元が挙げられる。この場合に好ましいのは、例えばパラジウムまたは水酸ィ匕 ノ ラジウム等を使用する方法が挙げられる。あるいは塩ィ匕アンモ-ゥムを用いる中性 条件下での鉄による還元反応等が挙げられる。溶媒は反応を阻害せず出発物質を ある程度溶解するものであれば特に限定されないが、例えばメタノール、エタノール、 テトラヒドロフラン、 N, N, ージメチルホルムアミド、塩化メチレン、 1, 2—ジクロ口エタ ン等を用いることができる。反応条件は、特に限定されないが、室温から溶媒の還流 温度、常圧から 15MPa、好ましくは室温から 60°C、常圧から 0. 5MPaである。反応 時間は、特に限定されないが、通常、 1から 48時間であり、好ましくは 1から 24時間で ある。得られた (b— 4)の化合物は常法により精製または精製することなく次工程に使 用することができる。  The reduction reaction in this step can be performed by a known method, for example, reduction by catalytic hydrogenation using a noble metal catalyst such as Raney nickel, noradium, ruthenium, rhodium or platinum. Preferable examples in this case include a method using palladium, sodium hydroxide or the like. Another example is a reduction reaction with iron under neutral conditions using salty ammonium. The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, methanol, ethanol, tetrahydrofuran, N, N, dimethylformamide, methylene chloride, 1,2-dichloroethane, etc. Can be used. The reaction conditions are not particularly limited, and are from room temperature to the reflux temperature of the solvent, from normal pressure to 15 MPa, preferably from room temperature to 60 ° C., and from normal pressure to 0.5 MPa. The reaction time is not particularly limited, but is usually 1 to 48 hours, preferably 1 to 24 hours. The obtained compound (b-4) can be used in the next step without purification or purification by a conventional method.
[0036] 工程（B— 5)  [0036] Process (B-5)
[化 60]
Figure imgf000035_0001
[Chemical 60]
Figure imgf000035_0001
(b- ) (b-5)  (b-) (b-5)
[式中、 Yは 2級ァミンの保護基を示す。 ] [Wherein Y represents a protecting group for secondary amine. ]
工程 (Β— 5)は、前記式 (b— 4)で表される化合物と前記式 (b— 4Ίで表される化 合物を還元的ァミノ化反応させた後、閉環反応を行うことにより、前記式 (b— 5)で表 される化合物を得る工程である。  In the step (5-5), the compound represented by the formula (b-4) and the compound represented by the formula (b-4Ί) are subjected to a reductive amination reaction, followed by a ring-closing reaction. And a step of obtaining a compound represented by the formula (b-5).
Yで表される 2級ァミンの保護基としては、公知のものが挙げられる力 例えば、ベ ンジルォキシカルボ-ル基、 tert—ブチルォキシカルボ-ル基等が挙げられる。還 元的ァミノ化反応は通常用いられる条件と同様の条件で行うことができるが、例えば 、ボラン、水素化ホウ素錯体化合物等の還元剤による還元的ァミノ化反応、金属触媒 を用いた水素雰囲気下での接触還元反応等が挙げられる。水素化ホウ素錯体化合 物を用いた還元的ァミノ化反応の例として、例えば W. S. Emerson, Organic Rea ctions, 4、 174 (1948)、 C. F. Lane, Syntheisis, 127 (1974)、 A. F. Abdel— Magid, K. G. Carson, B. D. Harris, C. A. Maryanoff and R. D. Shah, Jo urnal of Organic Chemistry, 61, 3849 (1996)等の文献記載の方法を挙げ ることがでさる。  Examples of the protecting group for the secondary amine represented by Y include those known in the art, such as a benzyloxycarbonyl group and a tert-butyloxycarbonyl group. The reductive amination reaction can be carried out under the same conditions as those usually used. For example, a reductive amination reaction with a reducing agent such as borane or a borohydride complex compound, or under a hydrogen atmosphere using a metal catalyst. And the like, and the like. Examples of reductive amination reactions using borohydride complex compounds include WS Emerson, Organic Reactions, 4, 174 (1948), CF Lane, Syntheisis, 127 (1974), AF Abdel— Magid, KG Carson , BD Harris, CA Maryanoff and RD Shah, Journal of Organic Chemistry, 61, 3849 (1996).
水素化ホウ素錯体ィ匕合物として、例えば水素化ホウ素ナトリウム、シアンィ匕水素化 ホウ素ナトリウム、トリァセトキシ水素化ホウ素ナトリウム等を用いることができる。還元 剤として水素化ホウ素錯体化合物を用いる場合、溶媒は反応を阻害せず出発物質 をある程度溶解するものであれば特に限定されないが、例えばメタノール、エタノー ル、テトラヒドロフラン、 N, N—ジメチルホルムアミド、塩化メチレン、 1, 2—ジクロロェ タン等を用いることができる。本反応は、酸の共存下に行うことで収率向上等のより好 ましい結果を得ることができる。力かる酸としては特に限定されないが、好適には、例 えば、塩酸等の鉱酸、酢酸等の有機酸、例えば塩ィ匕亜鉛、三フッ化ホウ素ジェチル エーテル錯体、チタニウム (IV)テトライソプロボキシド等のルイス酸等が挙げられる。 また、酸は溶媒としても用いることができる。 As the borohydride complex compound, for example, sodium borohydride, cyanobium sodium borohydride, sodium triacetoxyborohydride and the like can be used. When a borohydride complex compound is used as a reducing agent, the solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide, chloride Methylene, 1,2-dichloroethane, etc. can be used. By carrying out this reaction in the presence of an acid, more favorable results such as improved yield can be obtained. The strong acid is not particularly limited, but is preferably an example. For example, mineral acids such as hydrochloric acid, organic acids such as acetic acid, for example, Lewis acid such as sodium chloride zinc, boron trifluoride jetyl ether complex, titanium (IV) tetraisopropoxide and the like. The acid can also be used as a solvent.
[0038] 化合物（b— 4Ίは化合物（b— 4)に対し 0. 8から 2. 5当量、好ましくは 1から 1. 5当 量である。水素化ホウ素錯体ィ匕合物は化合物 (b— 4)に対し、 1から 3当量、好ましく は 1から 1. 5当量使用する。反応温度は、使用する原料、溶媒等により異なり特に限 定されないが、通常、 78°C力 溶媒の還流温度であり、好ましくは氷温から室温で ある。反応時間は、特に限定されないが、通常、 0. 5から 48時間であり、好ましくは 0 . 5から 12時間である。  [0038] Compound (b-4-4 is 0.8 to 2.5 equivalents, preferably 1 to 1.5 equivalents, relative to compound (b-4). The borohydride complex compound is compound (b — Use 1 to 3 equivalents, preferably 1 to 1.5 equivalents to 4), although the reaction temperature varies depending on the raw materials and solvents used, and is not particularly limited. The reaction time is not particularly limited, but is usually from 0.5 to 48 hours, preferably from 0.5 to 12 hours.
水素雰囲気下での接触還元反応を用いる際に使用される溶媒は、反応を阻害しな いものであれば、特に限定はされないが、例えばメタノール、エタノール、テトラヒドロ フラン、 1, 4 ジォキサン等が挙げられる。金属触媒としては、例えばパラジウム、酸 化白金、ラネーニッケル等を挙げることができる。反応条件は、特に限定されないが、 室温から溶媒の還流温度、常圧から 15MPa、好ましくは室温力も 60°C、常圧から 0 . 5MPaである。反応時間は、特に限定されないが、通常、 1から 48時間であり、好ま しくは 1から 24時間である。  The solvent used in the catalytic reduction reaction under a hydrogen atmosphere is not particularly limited as long as it does not inhibit the reaction. Examples thereof include methanol, ethanol, tetrahydrofuran, and 1,4 dioxane. . Examples of the metal catalyst include palladium, platinum oxide, Raney nickel and the like. The reaction conditions are not particularly limited, and the reaction temperature is from room temperature to the reflux temperature of the solvent, from atmospheric pressure to 15 MPa, preferably from room temperature to 60 ° C., and from atmospheric pressure to 0.5 MPa. The reaction time is not particularly limited, but is usually 1 to 48 hours, preferably 1 to 24 hours.
[0039] 閉環反応は、例えば、 Coe, J. W. ； Vetelino, M. G. ； Bradlee, M. J. ； Tetrah edron Lett. , 37 (34) , 6045— 6048 (1996)、 Arai, E. ； Tokuyama, H. ； Lin sell, M. S. ； Fukuyama, T. ； Tetrahedron Lett. , 39 (1) , 71— 74 (1998)、 Tishler, A. N, Lanza, T. J. ； Tetrahedron Lett. , 27 (15) , 1653 (1986)、 S akamoto Takao, Kondo Yoshinori, Yamanaka Hiroshi, Chem. Pharm . Bull. , Vol. 34, 2362 (1986)などに記載の条件と同様の条件で反応を行うこと ができる。  [0039] For example, Coe, JW; Vetelino, MG; Bradlee, MJ; Tetrah edron Lett., 37 (34), 6045-6048 (1996), Arai, E .; Tokuyama, H .; Lin sell Fukuyama, T .; Tetrahedron Lett., 39 (1), 71-74 (1998), Tishler, A. N, Lanza, TJ; Tetrahedron Lett., 27 (15), 1653 (1986), S akamoto The reaction can be carried out under the same conditions as described in Takao, Kondo Yoshinori, Yamanaka Hiroshi, Chem. Pharm. Bull., Vol. 34, 2362 (1986).
反応溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限 定されないが、具体的に例えば、水、水と例えばメタノール、エタノール、テトラヒドロ フラン、 1, 4 ジォキサン、ベンゼン、トルエン等の有機溶媒中で、適当な酸を 1当量 力 大過剰用いて行うことができる。酸としては、例えば酢酸、塩化水素、塩酸、臭化 水素酸、硫酸、硝酸、トリフルォロ酢酸、 p トルエンスルホン酸、 p トルエンスルホ ン酸 'ピリジ -ゥム塩、カンファースルホン酸等が挙げられる。反応時間は、特に限定 されないが、通常、 1から 24時間であり、好ましくは 1から 24時間である。得られた (b 5)の化合物は常法により精製または精製することなく次工程に使用することができ る。 The reaction solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Specifically, for example, water, water and, for example, methanol, ethanol, tetrahydrofuran, 1,4 dioxane, benzene, It can be carried out in an organic solvent such as toluene using a suitable acid in excess of 1 equivalent. Examples of the acid include acetic acid, hydrogen chloride, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, trifluoroacetic acid, p toluenesulfonic acid, p toluenesulfo Examples include acid 'pyridyl-um salt, camphorsulfonic acid and the like. The reaction time is not particularly limited, but is usually 1 to 24 hours, preferably 1 to 24 hours. The obtained compound (b5) can be used in the next step without purification or purification by a conventional method.
[0040] 工程（B - 6)  [0040] Process (B-6)
[化 61]  [Chemical 61]
Figure imgf000037_0001
Figure imgf000037_0001
[式中、 Yは前記定義と同義である。 ] [Wherein Y is as defined above. ]
[0041] 工程 (B— 6)は、前記式 (b— 5)で表される化合物の 2級ァミンの保護基を脱保護 することにより、前記式 (b)で表される化合物を得る工程である。 [0041] Step (B-6) is a step of obtaining the compound represented by the formula (b) by deprotecting the protecting group of the secondary amine of the compound represented by the formula (b-5). It is.
ァミノ化合物の保護基の脱理に一般に用いられる条件、例えば、 T. W. Green a nd P. G. M. Wuts, 'Protective Groups m Organic Chemistry, ¾ec ond Edition", John Wiley&Sons (1991) , 309—405等の文献記載の条件 と同様の条件で反応を行うことができる。例えば Yがべンジルォキシカルボニル基で 保護されている際は、例えばアルコール、テトラヒドロフラン等の溶媒中でパラジウム —炭素を触媒として水素添加することで脱保護し、化合物 (b)を得ることができる。 得られた (b)の化合物は常法により精製または精製することなく次工程に使用する ことができる。  Conditions generally used for deprotection of protecting groups of amino compounds, for example, conditions described in literature such as TW Green and PGM Wuts, 'Protective Groups m Organic Chemistry, ¾ec ond Edition ", John Wiley & Sons (1991), 309-405 For example, when Y is protected by a benzyloxycarbonyl group, it can be removed by hydrogenation using palladium-carbon as a catalyst in a solvent such as alcohol or tetrahydrofuran. The compound (b) can be used in the next step without purification or purification by a conventional method.
[0042] 化合物 (b)は前記の製造方法の他、下記工程 (B' - l)な 、し工程 (Β' 6)及び 前記工程 (Β— 6)〖こよっても得ることができる。  [0042] In addition to the above production method, the compound (b) can also be obtained by the following step (B'-l), the step (Β'6) and the step (Β-6).
[化 62]
Figure imgf000038_0001
[Chemical 62]
Figure imgf000038_0001
[化 63] [Chemical 63]
Figure imgf000038_0002
Figure imgf000038_0002
[化 64] [Chemical 64]
Figure imgf000038_0003
Figure imgf000038_0003
(b'.4) (b'-5) (b-5) (b)  (b'.4) (b'-5) (b-5) (b)
[0043] 工程（B— - 1) [0043] Process (B—-1)
工程（B^— 1)は、 3 -トロー 4 メチル安息香酸とジメチルホルムアルデヒドジメ チルァセタールとを反応させることにより、化合物 ( ー 1)を得る工程である。本工程 は、前記工程 (B— 2)と同様の条件により行うことができる。  Step (B ^ -1) is a step of obtaining compound (-1) by reacting 3-tro- 4 methylbenzoic acid with dimethylformaldehyde dimethylacetal. This step can be performed under the same conditions as in step (B-2).
[0044] 工程 2) [0044] Step 2)
工程 (Β' 2)は、化合物 ( 1)をァセタールイ匕することにより、化合物 ( 2) を得る工程である。本工程は、前記工程 (Β— 3)と同様の条件により行うことができる  Step (Β′2) is a step of obtaining compound (2) by subjecting compound (1) to acetalization. This step can be performed under the same conditions as in the above step (Β-3).
[0045] 工程 3) [0045] Step 3)
工程 (Β' 3)は、化合物 ( 2)を還元することにより化合物 ( 3)を得る工程 である。本工程は、前記工程 (Β— 4)と同様の条件により行うことができる。  Step (Β′3) is a step of obtaining compound (3) by reducing compound (2). This step can be performed under the same conditions as in the above step (IV-4).
[0046] 工程し — 4) 工程 (Β' 4)は、化合物 ( 3)と化合物 (b— 4Ίとを反応させることにより、化合 物 ( —4)を得る工程である。本工程は、前記工程 (B— 5)と同様の条件により行う ことができる。 [0046] Process — 4) Step (Β'4) is a step of obtaining compound (-4) by reacting compound (3) with compound (b-4-4) .This step is the same as step (B-5) above. This can be done according to the following conditions.
[0047] 工程 5) [0047] Step 5)
工程 (Β' 5)は、化合物 ( 4)を加水分解させることにより、化合物 ( 5)を 得る工程である。  Step (Β′5) is a step of obtaining compound (5) by hydrolyzing compound (4).
本工程は、例えば Mattasa. V. G. ； Brown, F. J. ； Bernstein, P. R. ； Shapir o, H. S. ； Maduskuie, T. P. J. ； Cronk, L. A. ； Vacek, E. P. ； Yee, Y. K. ； Snyder, D. W. ； Krell, R. D. ； Lerman, C. L. ； Maloney, J. J. ； J. Med. Che m. , 33 (9) , 2621— 2629 (1990)に記載の反応条件と同様の条件で反応を行うこ とができる。具体的には例えば、化合物 ( ー 4)の溶液に例えば水酸ィ匕ナトリウム等 の塩基 (水溶液)を加え、数時間から 1日攪拌後、例えばクェン酸溶液等の酸で処理 することにより、化合物 ( ー 5)を得ることができる。反応溶媒は、反応を阻害せず、 出発物質をある程度溶解するものであれば特に限定されな 、が、例えばメタノール、 エタノール、 2 プロパノール、テトラヒドロフラン、 1, 4 ジォキサン、水等を挙げるこ とができる。塩基としては、特に限定されないが、例えば水酸ィ匕ナトリウム、水酸化カリ ゥム、水酸化リチウム等が好ましい。塩基の使用量は、化合物 ( — 4)に対し 1当量 から大過剰であり、好ましくは 1から 20当量である。反応時間は、特に限定されない 力 通常、 1から 24時間であり、好ましくは 1から 6時間である。反応温度は、使用する 原料、溶媒等により異なり特に限定されないが、通常、 78°Cから溶媒の還流温度 であり、好ましくは氷温力 室温である。  Brown, FJ; Bernstein, PR; Shapiro, HS; Maduskuie, TPJ; Cronk, LA; Vacek, EP; Yee, YK; Snyder, DW; Krell, RD; Lerman, CL; The reaction can be carried out under the same conditions as described in Maloney, JJ; J. Med. Chem., 33 (9), 2621–2629 (1990). Specifically, for example, by adding a base (aqueous solution) such as sodium hydroxide to a solution of the compound (-4), stirring for several hours to 1 day, and then treating with an acid such as a citrate solution, Compound (-5) can be obtained. The reaction solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and examples thereof include methanol, ethanol, 2 propanol, tetrahydrofuran, 1,4 dioxane, water and the like. . The base is not particularly limited, but for example, sodium hydroxide, potassium hydroxide, lithium hydroxide and the like are preferable. The amount of the base to be used is 1 equivalent to a large excess, preferably 1 to 20 equivalents, relative to compound (-4). The reaction time is not particularly limited. Usually, the reaction time is 1 to 24 hours, preferably 1 to 6 hours. The reaction temperature varies depending on the raw materials and solvent used, and is not particularly limited, but is usually from 78 ° C. to the reflux temperature of the solvent, preferably ice temperature room temperature.
得られた ( ー 5)の化合物は常法により精製または精製することなく次工程に使用 することができる。  The obtained compound (-5) can be used in the next step without purification or purification by a conventional method.
[0048] 工程 - 6) [0048] Process-6)
工程 (Β'— 6)は、化合物 ( — 5)とメチルアミンを縮合反応させることにより、化合 物 (b 5)を得る工程である。本工程は、前記工程 (B—1)と同様の条件により行うこ とがでさる。  Step (Β'-6) is a step of obtaining compound (b5) by subjecting compound (-5) and methylamine to a condensation reaction. This step can be performed under the same conditions as in step (B-1).
[0049] 一方、化合物 (i)は下記の工程 (C—1)ないし (C— 4)によっても得ることができる。 [化 65] On the other hand, compound (i) can also be obtained by the following steps (C-1) to (C-4). [Chemical 65]
Figure imgf000040_0001
Figure imgf000040_0001
[化 66] [Chemical 66]
Figure imgf000040_0002
Figure imgf000040_0002
[0050] 工程（C 1) [0050] Step (C 1)
工程 (C 1)は、前記式 ( ー 4)で表される化合物 [式中、 Yは 2級ァミンの保護基 を示す。 ]の 2級ァミンの保護基を脱保護することにより、前記式 (c 1)で表される化 合物またはその塩を得る工程である。塩は、公知の薬理学的に許容できる塩であれ ば、何でもよいが、好ましくは塩酸塩である。  Step (C 1) is a compound represented by the above formula (-4) [wherein Y represents a protecting group for secondary amine. In this step, the compound represented by the formula (c 1) or a salt thereof is obtained by deprotecting the protecting group of the secondary amine. The salt may be any known pharmacologically acceptable salt, but is preferably a hydrochloride.
本工程は、前記工程 (B— 6)と同様の条件により行うことができる。  This step can be carried out under the same conditions as in the above step (B-6).
[0051] 工程（C— 2) [0051] Process (C-2)
工程 (C- 2)は、前記式 (c - 1)で表される化合物と前記式 (a)で表される化合物を カツプリングすることにより、前記式 (c - 2)で表される化合物を得る工程である。 本工程は、前記工程（1)と同様の条件により行うことができる。  In the step (C-2), the compound represented by the formula (c-2) is coupled with the compound represented by the formula (c-1) by coupling the compound represented by the formula (a). It is a process to obtain. This step can be performed under the same conditions as in step (1).
[0052] 工程（C— 3) [0052] Process (C-3)
工程 (C— 3)は、前記式 (c 2)で表される化合物を加水分解することにより、前記 式 (c 3)で表される化合物を得る工程である。 In the step (C-3), the compound represented by the formula (c 2) is hydrolyzed, In this step, a compound represented by the formula (c 3) is obtained.
本工程は、前記工程 (Β'— 5)と同様の条件により行うことができる。  This step can be performed under the same conditions as in the above step (Β′-5).
[0053] 工程（C 4) [0053] Step (C 4)
工程 (C— 4)は、前記式 (c— 3)で表される化合物とメチルアミンを縮合させることに より、前記式 (i)で表される化合物を得る工程である。  Step (C-4) is a step of obtaining the compound represented by the formula (i) by condensing the compound represented by the formula (c-3) and methylamine.
本工程は、前記工程 (B—1)と同様の条件により行うことができる。  This step can be performed under the same conditions as in step (B-1).
[0054] 以下、本発明を実施例により具体的に説明するが、本発明はこれらの実施例に制 限されるものではない。本明細書において、「室温」とは、 20から 30°Cの範囲で、好 ましくは 25°Cを意味する。 [0054] Hereinafter, the present invention will be specifically described by way of examples. However, the present invention is not limited to these examples. In the present specification, “room temperature” means a range of 20 to 30 ° C., preferably 25 ° C.
[0055] 製造例 1 [0055] Production Example 1
4一（ 2 ジメチルアミノ)ビュル 3 二トロ安息呑酸メチルの合成  Synthesis of 4- (2-dimethylamino) bulu-3-methylbenzoylbenzoate
[化 67]  [Chemical 67]
Figure imgf000041_0001
窒素雰囲気下の 10L四頸フラスコに 4ーメチルー 3 -トロ安息香酸 570. 0g (3. 1 5mol)、ジメチルホルムアミド（以下「DMF」と称す） 3420mLを加え、攪拌した。次い で、反応液に N, N ジメチルホルムアミドジメチルァセタール 1334mL (1197g、 9 . 44mol)を 3回に分けて加えた。反応液を室温で約 1時間攪拌した後に、反応容器 を油浴 (83°C)で加熱した。約 15時間後、 HPLCにて反応の進行を確認した後、カロ 熱を止め、氷水浴にて内温 28°Cまで冷却した。
Figure imgf000041_0001
To a 10 L four-necked flask under a nitrogen atmosphere, 56.0 g (3.15 mol) of 4-methyl-3-trobenzoic acid and 3420 mL of dimethylformamide (hereinafter referred to as “DMF”) were added and stirred. Next, 1334 mL (1197 g, 9.44 mol) of N, N dimethylformamide dimethylacetal was added to the reaction solution in three portions. After the reaction solution was stirred at room temperature for about 1 hour, the reaction vessel was heated in an oil bath (83 ° C.). About 15 hours later, after confirming the progress of the reaction by HPLC, the calorific heat was stopped and the internal temperature was cooled to 28 ° C. in an ice water bath.
15L四頸フラスコに水 9120mLを投入し、フラスコとを氷水浴上で冷却攪拌して、 冷水を準備した。ここへ前記の反応液を 6分間で注いだ。残った反応液を DMF100 mLで洗い出した後、氷水浴を外し、室温で 76分攪拌した。析出した固体を濾取し、 残った固体は水 1. 5Lで洗い出し、さらに、水 1. 5Lで固体を洗浄した。得られた粗 結晶を 20L ステンレス製容器へ投入し、メタノール 6840mLをカ卩え、反応液をメカ 二カルスターラーで室温下 65分間攪拌した。結晶を濾取し、メタノール 1140mLで 洗浄した。得られた結晶は 40°Cで減圧乾燥し、赤色固体として標記化合物 668.7g を得た。 9120 mL of water was put into a 15 L four-necked flask, and the flask was cooled and stirred on an ice water bath to prepare cold water. The above reaction solution was poured into this for 6 minutes. The remaining reaction solution was washed with 100 mL of DMF, then the ice-water bath was removed, and the mixture was stirred at room temperature for 76 minutes. The precipitated solid was collected by filtration, the remaining solid was washed out with 1.5 L of water, and the solid was further washed with 1.5 L of water. The obtained crude crystals were put into a 20 L stainless steel container, 6840 mL of methanol was added, and the reaction solution was stirred with a mechanical stirrer at room temperature for 65 minutes. The crystals were collected by filtration and methanol 1140mL Washed. The obtained crystals were dried under reduced pressure at 40 ° C. to obtain 668.7 g of the title compound as a red solid.
収率 84.9%  Yield 84.9%
'H-NMR (400MHz, CDC1 ) δ (ppm) :2.99 (s, 6H), 3.90 (s, 3H), 5.92 (  'H-NMR (400MHz, CDC1) δ (ppm): 2.99 (s, 6H), 3.90 (s, 3H), 5.92 (
3  Three
d, J=13.3Hz,lH), 7.16(d, J=13.3Hz, 1H), 7.47(d, J = 8.6Hz, 1H), 7.90(dd, J = 8.6, 1.8Hz, 1H), 8.49(d, J=l.8Hz, 1H) .  d, J = 13.3Hz, lH), 7.16 (d, J = 13.3Hz, 1H), 7.47 (d, J = 8.6Hz, 1H), 7.90 (dd, J = 8.6, 1.8Hz, 1H), 8.49 ( d, J = l.8Hz, 1H).
[0056] 製造例 2 [0056] Production Example 2
4 (2.2 ジメトキシェチル） 3 二トロ安息香酸メチルの合成  4 (2.2 Dimethoxyethyl) 3 Synthesis of methyl ditrobenzoate
[化 68]  [Chemical 68]
Figure imgf000042_0001
窒素雰囲気下の 10L四頸フラスコに、 4一（2 ジメチルァミノ）ビュル 3 -トロ 安息香酸メチル 522g(2.09mol)を投入し、メタノール 3500mLを加えた。この溶液 に硫酸 Zメタノール混液 (濃硫酸： 266g、メタノール： 676mL)を室温下 13分かけて 加えた。反応容器を 55°Cの油浴で加熱し、内温 40°Cを超えてから反応液を約 4時 間加熱攪拌した後、反応容器を氷水浴にて冷却した。反応液にトリェチルァミン 193 .5mLを投入した後、この溶液を減圧濃縮し、濃縮残渣にトルエン 6000mLおよび 水 2620mLを加えた。反応液をハイフロスーパーセル（Hyflo Super— Cel)を敷!ヽ たブフナーロートで濾過し、トルエン 525mLでブフナーローを洗って、不溶物を除去 した。この濾液を 20L分液装置に移し、水層を分液廃棄した。有機層は水 1305mL で洗浄した後、減圧濃縮 (浴温 40°C)し、標記化合物を含有する褐色油状物 625.7 gを得た。
Figure imgf000042_0001
To a 10 L four-necked flask under a nitrogen atmosphere was charged 522 g (2.09 mol) of methyl 4- (2-dimethylamino) bul 3-trobenzoate, and 3500 mL of methanol was added. To this solution was added sulfuric acid Z methanol mixture (concentrated sulfuric acid: 266 g, methanol: 676 mL) at room temperature over 13 minutes. The reaction vessel was heated in a 55 ° C oil bath, and after the internal temperature exceeded 40 ° C, the reaction solution was heated and stirred for about 4 hours, and then the reaction vessel was cooled in an ice-water bath. After adding 193.5 mL of triethylamine to the reaction solution, this solution was concentrated under reduced pressure, and 6000 mL of toluene and 2620 mL of water were added to the concentrated residue. The reaction solution was filtered with a Buchner funnel covered with Hyflo Super-Cel, and the Buchner funnel was washed with 525 mL of toluene to remove insoluble matters. The filtrate was transferred to a 20 L separator and the aqueous layer was discarded. The organic layer was washed with 1305 mL of water and then concentrated under reduced pressure (bath temperature 40 ° C.) to obtain 625.7 g of a brown oil containing the title compound.
— NMR(CDCl) δ (ppm) :3.28(d, J = 5.3Hz, 2H), 3.45 (s, 6H), 3.96  — NMR (CDCl) δ (ppm): 3.28 (d, J = 5.3Hz, 2H), 3.45 (s, 6H), 3.96
3  Three
(s, 3H), 4.57(t, J = 5.3Hz, 1H), 7.51(d, J = 8.1Hz, 1H), 8.16 (dd, J = 8. 1, 1.8Hz, 1H), 8.53(d, J=l.8Hz, 1H) .  (s, 3H), 4.57 (t, J = 5.3Hz, 1H), 7.51 (d, J = 8.1Hz, 1H), 8.16 (dd, J = 8.1, 1.8Hz, 1H), 8.53 (d, J = l.8Hz, 1H).
[0057] 製造例 3 3 アミノー 4 (2. 2 ジメトキシェチル）安息香酸メチルの合成 [0057] Production Example 3 Synthesis of methyl 3 amino-4 (2.2 dimethoxyethyl) benzoate
[化 69]  [Chem 69]
Figure imgf000043_0001
Figure imgf000043_0001
7Lオートクレーブに、 4 (2, 2 ジメトキシェチル） 3 -トロ安息香酸メチル（ 前工程の収率を 100%と仮定した場合の含量 = 562g、 2. 09mol)を、メタノール 30 OOmLで洗いこんだ。この溶液にパラジウム—炭素 56. 2g (10% (50%含水））をカロ えて、更にメタノール 2055mLを追加した。反応缶ジャケットに冷水を循環し、反応を 開始し水素圧を 0. 1〜0. 3MPaで制御し（内温 14〜23°C)、反応液を 2. 5時間攪 拌した。反応液を反応缶から抜き出し、メタノール 320mLで洗い出した。ハイフロス 一パーセルで触媒を濾去し、触媒をメタノール 1080mLで洗浄した。濾液を濃縮し たところ (浴温 40°C)、結晶化した標記化合物が析出した。この結晶に 1, 2 ジメトキ シェタン（以下、「DME」と称す。） 265mLをカ卩え、 40°Cに加温して溶解した後、再 度濃縮し、標記化合物を含有する褐色油状物を得た。 In a 7 L autoclave, methyl 4 (2, 2 dimethoxyethyl) 3 -trobenzoate (content = 562 g, 2.09 mol assuming a 100% yield from the previous step) was washed with 30 OOmL of methanol. . To this solution, 56.2 g (10% (containing 50% water)) of palladium-carbon was added, and 2055 mL of methanol was further added. Cold water was circulated through the reaction can jacket, the reaction was started, the hydrogen pressure was controlled at 0.1 to 0.3 MPa (internal temperature 14 to 23 ° C), and the reaction solution was stirred for 2.5 hours. The reaction solution was extracted from the reaction can and washed with 320 mL of methanol. The catalyst was removed by filtration with a hypurose one parcel, and the catalyst was washed with 1080 mL of methanol. When the filtrate was concentrated (bath temperature 40 ° C), the crystallized title compound was precipitated. To this crystal, add 265 mL of 1,2 dimethochetan (hereinafter referred to as “DME”), dissolve it by heating to 40 ° C., reconcentrate to give a brown oil containing the title compound. Obtained.
収量 572. 4gYield 572.4 g
— NMR (CDCl ) δ (ppm) : 2. 91 (d, J = 5. 3Hz, 2H) , 3. 38 (s, 6H) , 3. 88  — NMR (CDCl) δ (ppm): 2. 91 (d, J = 5.3 Hz, 2H), 3. 38 (s, 6H), 3. 88
3  Three
(s, 3H) , 4. 17 (br, 2H) , 4. 50 (t, J = 5. 3Hz, 1H) , 7. l l (d, J = 7. 6Hz, 1H ) , 7. 3— 7. 45 (m, 2H) .  (s, 3H), 4. 17 (br, 2H), 4. 50 (t, J = 5.3 Hz, 1H), 7. ll (d, J = 7.6 Hz, 1H), 7. 3— 7 .45 (m, 2H)
製造例 4 Production Example 4
1一（1一べンジルォキシカルボ-ルビペリジンー4 ィル） 1H—インドールー 6— カルボン酸メチルの合成  1 1 (1 benzyloxycarbo-biperidine-4-yl) 1H-indole 6- Synthesis of methyl carboxylate
[化 70] [Chemical 70]
Figure imgf000044_0001
窒素雰囲気下の 15L四頸丸底フラスコに、 3 ァミノ— 4— (2, 2 ジメトキシェチ ル）安息香酸メチル 475g (l. 99mol)を投入し、酢酸 3000mLで洗いこんだ。この 溶液に攪拌下、 4—ォキソ 1—ピぺリジンカルボン酸べンジル 695g (2. 98mol)を 投入し、酢酸 800mLで洗いこんだ。反応液を室温で 1時間攪拌した後に、氷水浴上 で冷却攪拌した。反応液にトリァセトキシ水素化ホウ素ナトリウム 631. lg (2. 98mol )を、内温 15°C以下を保ちながら 8分割して投入後、氷水浴を水浴に変更し、反応液 を約 3時間攪拌した。再度氷水浴で冷却し、反応液に水 3800mLを投入した。予め 100°Cに加温しておいた油浴で、反応液を加温し、内温が 80°Cに到達した時点から 6時間後に加熱を止めた。
Figure imgf000044_0001
Into a 15 L four-necked round bottom flask under nitrogen atmosphere was charged 475 g (l. 99 mol) of methyl 3-amino-4- (2,2 dimethoxyethyl) benzoate and washed with 3000 mL of acetic acid. To this solution, 695 g (2.98 mol) of 4-oxo-1-piperidinecarboxylate benzil was added with stirring and washed with 800 mL of acetic acid. The reaction solution was stirred at room temperature for 1 hour and then cooled and stirred on an ice-water bath. Add 631. lg (2.98 mol) of sodium triacetoxyborohydride to the reaction solution in 8 portions while keeping the internal temperature at 15 ° C or lower, then change the ice water bath to a water bath and stir the reaction solution for about 3 hours. . The mixture was cooled again in an ice water bath, and 3800 mL of water was added to the reaction solution. The reaction solution was heated in an oil bath preheated to 100 ° C, and the heating was stopped 6 hours after the internal temperature reached 80 ° C.
反応液を 20L分液装置へ移し、トルエン 5938mLおよび水 2969mLをカ卩え、攪拌 後、水層を廃棄した。有機層を 0. 5N水酸ィ匕ナトリウム水溶液 4453mL及び 2969m L、 5%食塩水 2969mLで 2回並びに水 2969mLで順次洗浄した。  The reaction solution was transferred to a 20 L separator, and 5938 mL of toluene and 2969 mL of water were collected. After stirring, the aqueous layer was discarded. The organic layer was washed successively with 0.5N aqueous sodium hydroxide solution 4453 mL and 2969 mL, 5% brine 2969 mL twice and water 2969 mL sequentially.
有機層を濃縮し (浴温 40°C)、標記化合物を含有する褐色油状物 1025. lgを得た この油状物 1017. lgにメタノール 1017mLをカ卩ぇ溶解し、室温下標記化合物の種 結晶 800mgを投入した。約 17時間攪拌した後、結晶を濾取し、メタノール 500mLで 洗いこんだ。結晶を約 2. 5時間 40°Cで減圧乾燥し、微黄色結晶として標記化合物 6 22. 2g得た。  The organic layer was concentrated (bath temperature 40 ° C) to give 1025. lg of a brown oil containing the title compound. 1017 mL of methanol was dissolved in 1017. lg of this compound, and the seed compound of the title compound was dissolved at room temperature. 800 mg was added. After stirring for about 17 hours, the crystals were collected by filtration and washed with 500 mL of methanol. The crystals were dried under reduced pressure at 40 ° C. for about 2.5 hours to obtain 62.22 g of the title compound as slightly yellow crystals.
収率 79. 3%Yield 79.3%
— NMR (CDCl ) δ (ppm) : 1. 80— 2. 05 (m, 2H) , 2. 05— 2. 23 (m, 2H) ,  — NMR (CDCl) δ (ppm): 1. 80— 2. 05 (m, 2H), 2. 05— 2. 23 (m, 2H),
3  Three
2. 92- 3. 15 (m, 2H) , 3. 96 (s, 3H) , 4. 30—4. 60 (m, 3H) , 5. 18 (s, 2H) , 6. 58 (dd, J = 0. 4, 2. 8Hz, 1H) , 7. 30— 7. 45 (m, 6H) , 7. 64 (dd, J = 0. 4 , 8. 4Hz, 1H) , 7. 80 (dd, J= l. 6, 8. 4Hz, 1H) , 8. 14 (s, 1H) . 2.92- 3.15 (m, 2H), 3.96 (s, 3H), 4.30—4.60 (m, 3H), 5.18 (s, 2H), 6.58 (dd, J = 0. 4, 2. 8Hz, 1H), 7.30—7.45 (m, 6H), 7.64 (dd, J = 0.4 , 8.4Hz, 1H), 7.80 (dd, J = l. 6, 8. 4Hz, 1H), 8.14 (s, 1H).
製造例 5 Production Example 5
1一（1一べンジルォキシカルボニルピペリジンー4 ィル） 1H—インドールー 6— カルボン酸の合成  Synthesis of 1H (Indoleoxycarbonylpiperidine-4-yl) 1H-indole 6-carboxylic acid
[化 71] [Chemical 71]
Figure imgf000045_0001
Figure imgf000045_0001
20L四頸丸底フラスコに 1一 （ 1一ベンジルォキシカルボ-ルビペリジン一 4一ィル） — 1H—インドール— 6—カルボン酸メチル 617. Og (l. 57mol)、 DME2036mL、 ジメチルスルホキシド 4072mLを順次投入し、氷水浴で冷却攪拌した。内温が 10°C になったところで、 8%水酸化ナトリウム水溶液 864. 7g (l. 10モル当量；水酸化ナト リウム 74. 4gを水道水 790mLに溶解したもの）を前記溶液に 7分かけて滴下した。 滴下終了後は、氷水浴を水浴（24. 5°C〜22. 3°C)に切り替え、反応液を内温 20°C 〜22°Cの範囲で 4時間 10分撹拌を続けた。 1 in a 20L 4-necked round bottom flask (1 benzyloxycarbo-rubiperidine 1-4-1) — 1H-indole-6-carboxylate 617. Og (l. 57 mol), DME 2036 mL, dimethyl sulfoxide 4072 mL in sequence The solution was added and cooled and stirred in an ice-water bath. When the internal temperature reached 10 ° C, 84.7% aqueous 8% sodium hydroxide solution (l. 10 molar equivalent; 74.4 g sodium hydroxide dissolved in 790 mL of tap water) was added to the above solution over 7 minutes. And dripped. After completion of the dropwise addition, the ice water bath was switched to a water bath (24.5 ° C to 22.3 ° C), and the reaction solution was continuously stirred for 4 hours and 10 minutes at an internal temperature in the range of 20 ° C to 22 ° C.
反応液を均等に二分割し（3. 62L X 2)、それぞれを同様に後処理した。反応液 3 . 62Lを氷水浴で冷却し、水道水 2314mLを 17分で加え、次いで酢酸ェチル 1543 mLを加えた。内温が 10°C以下になったところで、反応液に 2N塩酸 420mLをカロえ、 水層の pHを 7とした。この溶液を 20L分液装置に移し、水道水 2314mLおよび酢酸 ェチル 1543mLを加え、水層を廃棄した。  The reaction solution was equally divided into two (3.62 L × 2), and each was post-treated in the same manner. 3.62 L of the reaction solution was cooled in an ice water bath, 2314 mL of tap water was added in 17 minutes, and then 1543 mL of ethyl acetate was added. When the internal temperature fell below 10 ° C, 420 mL of 2N hydrochloric acid was added to the reaction solution, and the pH of the aqueous layer was adjusted to 7. This solution was transferred to a 20 L separator, 2314 mL of tap water and 1543 mL of ethyl acetate were added, and the aqueous layer was discarded.
二分割して処理した有機層を合わせ、 5%食塩水 3085gおよび水道水 3085mLで 順次洗浄した。有機層を減圧濃縮し始めると結晶が析出してきたので、濃縮を中止し 、テトラヒドロフラン 200mLをカ卩えて溶液とし、この溶液を HPLCで定量すること〖こより 収量を算出した。有機層を減圧濃縮し、トルエン 2468mL (2回の共沸のトータル使 用量)を用いて減圧下で 2回共沸操作を実施し、黄白色固体と液体の混合物 1333. 6gを得た。 標記化合物含有量 566. lg、収率 95. 2%The organic layers treated in two parts were combined and washed sequentially with 3085 g of 5% saline and 3085 mL of tap water. Crystals began to precipitate when the organic layer was concentrated under reduced pressure, so concentration was stopped, 200 mL of tetrahydrofuran was added to form a solution, and this solution was quantified by HPLC, and the yield was calculated. The organic layer was concentrated under reduced pressure, and azeotropic operation was performed twice under reduced pressure using 2468 mL of toluene (total azeotropic use of 2 times) to obtain 1333.3 g of a mixture of yellowish white solid and liquid. Title compound content 566.lg, yield 95.2%
— NMR (CDCC1 ) δ (ppm) : 1. 80— 2. 04 (m, 2H) , 2. 06— 2. 21 (m, 2H)  — NMR (CDCC1) δ (ppm): 1. 80— 2. 04 (m, 2H), 2. 06— 2. 21 (m, 2H)
3  Three
, 2. 94- 3. 16 (m, 2H) , 4. 30—4. 58 (m, 3H) , 5. 19 (s, 2H) , 6. 60 (dd, J =0. 8, 3. 6 Hz, 1H) , 7. 30— 7. 44 (m, 6H) , 7. 68 (dd, J = 0. 8, 8. 4Hz, 1 H) , 7. 88 (dd, J= l. 6, 8. 4Hz, 1H) , 8. 22 (s, 1H) .  , 2. 94- 3.16 (m, 2H), 4. 30--4.58 (m, 3H), 5. 19 (s, 2H), 6. 60 (dd, J = 0. 8, 3. 6 Hz, 1H), 7.30—7.44 (m, 6H), 7.68 (dd, J = 0. 8, 8. 4Hz, 1 H), 7.88 (dd, J = l. 6 , 8.4Hz, 1H), 8.22 (s, 1H).
製造例 6 Production Example 6
1一（1一べンジルォキシカルボニルピペリジン 4 ィル） N メチルー 1H—イン ドール 6—カルボキサミドの合成  Synthesis of 1- (1 benzyloxycarbonylpiperidine 4-yl) N-methyl-1H-indole 6-carboxamide
[化 72] [Chemical 72]
Figure imgf000046_0001
Figure imgf000046_0001
15L四頸丸底フラスコに窒素気流下、 1一（1一べンジルォキシカルボ-ルビベリジ ン— 4—ィル）—1H—インドール— 6—カルボン酸 1333. 6g (含有量 566. lg、 1. 5 Ommol)、テトラヒドロフラン 5950mLを投入し、室温で撹拌した。この溶液に N, N' カルボニルジイミダゾール (以下、「CDI」と称す。） 339. 5gを投入し、約 1時間後 に CDI17. 4gを追加投入した。約 1時間後に反応液を氷水浴で冷却し、内温 10°C 以下になった時点で 40%メチルァミン水溶液 407mLを 12分で滴下し、同温度で反 応液を約 1. 5時間撹拌した。 In a 15 L four-necked round-bottomed flask under nitrogen flow, 1 (1 benzoxycarbo-rubiberidine—4-yl) —1H—indole— 6-carboxylic acid 1333. 6 g (content 566. lg, 1 5 Ommol) and 5950 mL of tetrahydrofuran were added and stirred at room temperature. To this solution, 339.5 g of N, N ′ carbonyldiimidazole (hereinafter referred to as “CDI”) was added, and 17.4 g of CDI was added after about 1 hour. About 1 hour later, the reaction solution was cooled in an ice-water bath, and when the internal temperature reached 10 ° C or less, 407 mL of 40% methylamine aqueous solution was added dropwise over 12 minutes, and the reaction solution was stirred at the same temperature for about 1.5 hours. .
反応液を均等に 2分割し (有機層 = 3740mL X 2、水層 = 92mL X 2)、それぞれ を同様に後処理した。一方の反応液 (有機層 = 3740mL、水層 = 92mL)を 20L分 液装置に移し、酢酸ェチル 5950mL、水道水 2975mLを順次カロえ、分液した。有機 層に 2N塩酸 540mLをカ卩え、水層の pHを 3に調整し、分液した。有機層は 10%食 塩水 2975g、 5%食塩水 2975g、水道水 1488mLで順次洗浄した。  The reaction solution was equally divided into two (organic layer = 3740 mL × 2, aqueous layer = 92 mL × 2), and each was post-treated in the same manner. One reaction solution (organic layer = 3740 mL, aqueous layer = 92 mL) was transferred to a 20 L separator, and 5950 mL of ethyl acetate and 2975 mL of tap water were sequentially decanted and separated. 540 mL of 2N hydrochloric acid was added to the organic layer, the pH of the aqueous layer was adjusted to 3, and the phases were separated. The organic layer was washed sequentially with 2975 g of 10% saline, 2975 g of 5% saline, and 1488 mL of tap water.
二分割して処理した有機層を合わせ、有機層 14921. 6g中の標記化合物量を定 量した。 Combine the organic layers that were processed in two parts, and determine the amount of the title compound in 1492.6 g of the organic layer. Weighed.
HPLC定量時の含有量 561. 2g、収率 95. 9% Content at the time of HPLC quantification 561.2 g, yield 95.9%
— NMR (CDC1 ) δ (ppm) : 1. 93 (brs, 2H) , 2. 04— 2. 18 (m, 2H) , 3. 02 (  — NMR (CDC1) δ (ppm): 1. 93 (brs, 2H), 2. 04— 2. 18 (m, 2H), 3.02 (
3  Three
brs, 2H) , 4. 26—4. 60 (m, 3H) , 5. 18 (s, 2H) , 6. 58 (dd, J = 0. 8, 3. 2 H z, 1H) , 7. 28- 7. 44 (m, 7H) , 7. 65 (dd, J = 0. 4, 8. 4Hz, 1H) , 8. 10 (s, 1 H) . brs, 2H), 4.26--4.60 (m, 3H), 5.18 (s, 2H), 6.58 (dd, J = 0. 8, 3.2 Hz, 1H), 7. 28- 7. 44 (m, 7H), 7. 65 (dd, J = 0.4, 8. 4Hz, 1H), 8. 10 (s, 1 H).
この有機層の内、 12774. Ogにトルエン 1270mLを加え、減圧濃縮 (浴温 40°C)し 、濃縮物に再度トルエン 1270mLを加えて濃縮し、黄褐色油状物 986. 5gを得た。 これを以下の製造例 7で用いた。  Of this organic layer, 1270 mL of toluene was added to 12774. Og, and the mixture was concentrated under reduced pressure (bath temperature 40 ° C.). To the concentrate, 1270 mL of toluene was added again and concentrated to obtain 98.5 g of a tan oil. This was used in Production Example 7 below.
製造例 7 Production Example 7
N メチルー 1—(ピペリジンー4 ィル）—1H—インドールー 6 カルボキサミドの [化 73]  N Methyl-1- (piperidine-4-yl)-1H-indole-6 Carboxamide [Chemicals 73]
Figure imgf000047_0001
Figure imgf000047_0001
1— (1—ベンジルォキシカルボ-ルビペリジン— 4—ィル） N—メチル 1H—ィ ンドール— 6—カルボキサミドのトルエン溶液 985. 5g (含有量 489. 3g、 1. 25 mm ol)にテトラヒドロフラン 2447mLをカ卩えて溶解し、 7Lオートクレーブに入れた。次に、 反応容器にメタノール 2447mLおよび 10%パラジウム—炭素 49g (50%含水）を順 次投入した。反応容器内を窒素で 2回置換し、次いで水素で 2回置換した。水素圧を 0. IMPaから 0. 2MPaに制御しながら、反応液を約 2時間撹拌した。加圧を解除し 、窒素置換してオートクレープを開け、反応液を缶底力 排出した。オートクレープ内 をメタノール Zテトラヒドロフラン（lZi)の混液で洗い出し、反応液と洗液を合わせて 触媒を濾別し、濾宰をメタノール Zテトラヒドロフラン（lZi)で洗いこんだ。濾液を減 圧濃縮し、褐色溶液を 830. 5g得た。 1- (1-Benzyloxycarborubiperidine-4-yl) N-methyl 1H-indole-6-carboxamide in toluene (985.5 g, content 4889.3 g, 1.25 mm ol) in tetrahydrofuran 2447 mL Was dissolved in a 7 L autoclave. Next, 2447 mL of methanol and 49 g of 10% palladium-carbon (containing 50% water) were sequentially charged into the reaction vessel. The inside of the reaction vessel was replaced twice with nitrogen, and then replaced twice with hydrogen. The reaction solution was stirred for about 2 hours while controlling the hydrogen pressure from 0. IMPa to 0.2 MPa. The pressure was released, the atmosphere was replaced with nitrogen, the autoclave was opened, and the reaction solution was discharged from the bottom of the can. The autoclave was washed out with a mixed solution of methanol Z tetrahydrofuran (lZi), the reaction solution and the washing solution were combined, the catalyst was filtered off, and the filter cake was washed with methanol Z tetrahydrofuran (lZi). Reduce filtrate Concentration under pressure gave 85.5 g of a brown solution.
含有量 345. 6g、収率 98. 0% (1—（1一べンジルォキシカルボ-ルビペリジンー4 ィル） 1H—インドールー 6—力ルボン酸メチルからの通算収率）  Content 345.6 g, 98.0% yield (1— (1 benzyloxycarbo-biperidine-4-yl) 1H-indole-6-total yield from 6-methyl methyl boronate)
褐色溶液 799. 7g (含有量 332. 8g)に DME1468mLをカ卩え、濃縮し（水浴 40°C )、再度 DME1468mLをカ卩え、濃縮し、淡黄色固体と褐色溶液の混合物 677. Ogを 得た。 Add 1468 mL of DME to 79.7 g (content 33. 8 g) of the brown solution, concentrate (water bath 40 ° C), and again add 1468 mL of DME, concentrate, and concentrate the mixture of pale yellow solid and brown solution 677. Og Obtained.
— NMR (CDCl ) δ (ppm) : 1. 88— 2. 02 (m, 2H) , 2. 06— 2. 16 (m, 2H) ,  — NMR (CDCl) δ (ppm): 1. 88— 2. 02 (m, 2H), 2. 06— 2. 16 (m, 2H),
3  Three
2. 80— 2. 92 (m, 2H) , 3. 22— 3. 32 (m, 2H) , 4. 46 (tt, J=4. 0, 12. 0Hz, 1H) , 6. 58 (dd, J = 0. 8, 3. 2Hz, 1H) , 7. 36— 7. 44 (m, 2H) , 7. 65 (d, J = 8. 4Hz, 1H) , 8. 11 (s, 1H) .  2. 80— 2. 92 (m, 2H), 3. 22— 3. 32 (m, 2H), 4. 46 (tt, J = 4.0, 12.0Hz, 1H), 6. 58 (dd , J = 0. 8, 3. 2Hz, 1H), 7.36—7.44 (m, 2H), 7.65 (d, J = 8.4Hz, 1H), 8.11 (s, 1H) .
製造例 8 Production Example 8
N -せル 4 メチル 3ニトロべンズアミドの合成  Synthesis of N-sel 4 methyl 3 nitrobenzamide
[化 74] [Chemical 74]
Figure imgf000048_0001
Figure imgf000048_0001
3 二トロ一 4—メチル安息香酸 1. 83g (10mmol)をテトラヒドロフラン 18. 3mLに 溶解し、窒素雰囲気下、室温で、この溶液に CDI2. 43g (15mmol)を投入した。反 応液を室温で 1. 5時間攪拌した後、氷水浴で冷却し、反応液に 40%メチルァミン水 溶液 2. 33g (30mmol)を滴下した。反応液を氷水浴冷却で 15分間、室温で 2. 5時 間撹拌した。 3 1.83 g (10 mmol) of 2-methylbenzoic acid was dissolved in 18.3 mL of tetrahydrofuran, and 2.43 g (15 mmol) of CDI was added to this solution at room temperature under a nitrogen atmosphere. The reaction solution was stirred at room temperature for 1.5 hours, then cooled in an ice-water bath, and 2.33 g (30 mmol) of 40% aqueous methylamine solution was added dropwise to the reaction solution. The reaction solution was stirred in an ice-water bath for 15 minutes and at room temperature for 2.5 hours.
反応液を酢酸ェチルで希釈した後、 5%NaHCO水溶液に注ぎ、酢酸ェチルで抽 The reaction solution is diluted with ethyl acetate, poured into 5% aqueous NaHCO solution, and extracted with ethyl acetate.
3  Three
出した。有機層を 0. 1N塩酸、 5%炭酸水素ナトリウム水溶液、 5%塩ィ匕ナトリウム水 溶液及び水で順次洗浄した後、無水硫酸マグネシウムで乾燥し、濾別後、減圧濃縮 し、標記化合物 1. 75gを白色結晶として得た。 I put it out. The organic layer was washed successively with 0.1N hydrochloric acid, 5% aqueous sodium hydrogen carbonate solution, 5% aqueous sodium chloride solution and water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound 1. 75 g was obtained as white crystals.
収率： 90. 1% H— NMR(400MHz、 CDC1 ) δ (ppm) :2.66 (s, 3H), 3.05(d, J=4.8Hz,Yield: 90. 1% H-NMR (400MHz, CDC1) δ (ppm): 2.66 (s, 3H), 3.05 (d, J = 4.8Hz,
3 Three
3H), 6.20(brs, 1H), 7.44(d, J = 8.4Hz, 1H), 7.95(dd, J = 2.0, 8.4Hz , 1H), 8.34(d, J = 2.0Hz, 1H)  3H), 6.20 (brs, 1H), 7.44 (d, J = 8.4Hz, 1H), 7.95 (dd, J = 2.0, 8.4Hz, 1H), 8.34 (d, J = 2.0Hz, 1H)
ESI— MS: m/z 217(M + Na) + ESI— MS: m / z 217 (M + Na) +
製造例 9 Production Example 9
4一（2 ジメチルアミノビニル） N メチルー 3 二トロべンズアミドの合成  Synthesis of 4- (2 dimethylaminovinyl) N methyl-3 ditrobensamide
[化 75] [Chemical 75]
Figure imgf000049_0001
Figure imgf000049_0001
N—メチル 4—メチル 3 -トロべンズアミド 1.65g(8.49mmol)を DMF9.9 mLに溶解し、窒素雰囲気下、室温で、この溶液に N, N—ジメチルホルムアミドジメ チルァセタール 6.49g(50.90mmol)を滴下し、反応液を 80°Cで 46時間加熱攪拌 した。 Dissolve 1.65 g (8.49 mmol) of N-methyl 4-methyl 3-trobenamide in 9.9 mL of DMF and add 6.49 g (50.90 mmol) of N, N-dimethylformamide dimethylacetal to this solution at room temperature under nitrogen atmosphere Was added dropwise, and the reaction solution was heated and stirred at 80 ° C. for 46 hours.
反応液を減圧濃縮した後、残渣をフラッシュカラムクロマトグラフィーにより精製 (Me rck, Silica Gel 60, 230— 400 mesh;酢酸ェチル—ヘプタン， 1:1→2:1) した。 目的物を含有するフラクションを集め、減圧濃縮した後、残渣をフラッシュカラム クロマトグラフィーにより精製（Fuji silysia, NH— Silica Gel;酢酸ェチルーヘプ タン = 1： 1)した。 目的物を含有するフラクションを集め、減圧濃縮し、暗赤色結晶と して標記化合物 800.2mgを得た。  After the reaction solution was concentrated under reduced pressure, the residue was purified by flash column chromatography (Merck, Silica Gel 60, 230—400 mesh; ethyl acetate-heptane, 1: 1 → 2: 1). Fractions containing the desired product were collected and concentrated under reduced pressure, and the residue was purified by flash column chromatography (Fuji silysia, NH—Silica Gel; ethyl acetate heptane acetate = 1: 1). Fractions containing the desired product were collected and concentrated under reduced pressure to give 800.2 mg of the title compound as dark red crystals.
収率： 37.8% Yield: 37.8%
'H-NMR (400MHz, CDC1 ) δ (ppm) :2.97(s, 6H), 3.01(d, J=4.8Hz,  'H-NMR (400MHz, CDC1) δ (ppm): 2.97 (s, 6H), 3.01 (d, J = 4.8Hz,
3  Three
3H), 5.94(d, J=13.2Hz, 1H), 6.18(brs, 1H), 7. 12(d, J=13.2Hz, 1H ), 7.49(d, J = 8.4Hz, 1H), 7.78(dd, J = 2.0, 8.4Hz, 1H), 8.22 (d, J =2.0Hz, 1H)  3H), 5.94 (d, J = 13.2Hz, 1H), 6.18 (brs, 1H), 7.12 (d, J = 13.2Hz, 1H), 7.49 (d, J = 8.4Hz, 1H), 7.78 ( dd, J = 2.0, 8.4Hz, 1H), 8.22 (d, J = 2.0Hz, 1H)
ESI— MS: m/z 272(M + Na) + [0064] 製造例 10 ESI— MS: m / z 272 (M + Na) + [0064] Production Example 10
4 (2.2 ジメトキシェチル）—N メチルー 3 二トロべンズアミドの合成  Synthesis of 4 (2.2 dimethoxyethyl) -N methyl-3 ditrobensamide
[化 76]  [Chemical 76]
Figure imgf000050_0001
製造例 9で得られた 4一（2 ジメチルアミノビ-ル） N—メチルー 3 -トロベンズ アミド 100. Omg(0.40mmol)をメタノール 0.5mLに溶解し、室温でこの溶液に硫 酸 53.8mgZメタノール 0.5mLをカ卩え、 55°Cにて 5時間加熱攪拌した。
Figure imgf000050_0001
4- (2-dimethylaminovinyl) N-methyl-3-trobenzamide 100. Omg (0.40 mmol) obtained in Production Example 9 was dissolved in 0.5 mL of methanol, and this solution was dissolved in sulfuric acid 53.8 mgZ methanol 0.5 mL was added, and the mixture was heated and stirred at 55 ° C for 5 hours.
反応液を氷水浴で冷却してトリェチルァミン 243mg (2.40mmol)をカ卩えた後、減 圧濃縮した。残渣に水とトルエンを加え、トルエンで抽出した。有機層を無水硫酸ナト リウムで乾燥、し濾別後、減圧濃縮して標記化合物 93.5mgを燈赤色油状物として 得た。  The reaction mixture was cooled in an ice-water bath to obtain 243 mg (2.40 mmol) of triethylamine and concentrated under reduced pressure. Water and toluene were added to the residue and extracted with toluene. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 93.5 mg of the title compound as a pale red oil.
収率： 86.9% Yield: 86.9%
— NMR(400MHz、 CDC1 ) δ (ppm) :3.04(d, J=4.8Hz, 3H), 3.27 (d, J  — NMR (400MHz, CDC1) δ (ppm): 3.04 (d, J = 4.8Hz, 3H), 3.27 (d, J
3  Three
=5.2Hz, 2H), 3.35 (s, 6H), 4.56(t, J = 5.2Hz, 1H), 6.26(brs, 1H), 7 .50(d, J = 8.0Hz, 1H), 7.93(dd, J = 2.0, 8.0Hz, 1H), 8.26(d, J = 2.0 Hz, 1H)  = 5.2Hz, 2H), 3.35 (s, 6H), 4.56 (t, J = 5.2Hz, 1H), 6.26 (brs, 1H), 7.50 (d, J = 8.0Hz, 1H), 7.93 (dd , J = 2.0, 8.0Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H)
ESI— MS: m/z 291(M + Na) + ESI— MS: m / z 291 (M + Na) +
[0065] 製造例 11 [0065] Production Example 11
3 アミノー 4 (2.2 ジメトキシェチル） N メチルベンズアミドの合成  Synthesis of 3 amino-4 (2.2 dimethoxyethyl) N methylbenzamide
[化 77]  [Chemical 77]
H CHNH CHN
Figure imgf000050_0002
製造例 10で得られた、 4— (2, 2—ジメトキシェチル）—N—メチル—3— -トロベン ズアミド 93.5mg(0.35mmol)のメタノール 2mL溶液に 10%パラジウム 炭素 10 mgを加え、常温常圧で水素添加した。
Figure imgf000050_0002
To 10 mL of 10% palladium on carbon was added to 2 mL of methanol solution of 9-3.5 mg (0.35 mmol) of 4- (2,2-dimethoxyethyl) -N-methyl-3--trobenzamide obtained in Production Example 10. Hydrogenated at normal pressure.
反応終了後、ハイフロスーパーセルを用いて触媒を濾別、濾液を減圧濃縮して淡褐 色油状物として標記化合物 83.4mgを得た。 After completion of the reaction, the catalyst was filtered off using Hyflo Supercel, and the filtrate was concentrated under reduced pressure to obtain 83.4 mg of the title compound as a pale brown oil.
収率： 100%Yield: 100%
— NMR(400MHz、 CDC1 ) δ (ppm) :2.88(d, J = 5.2Hz, 2H), 2.98 (d, J  — NMR (400MHz, CDC1) δ (ppm): 2.88 (d, J = 5.2Hz, 2H), 2.98 (d, J
3  Three
=4.8Hz, 3H), 3.37 (s, 6H), 4. 18(brs, 2H), 4.49(t, J = 5.2Hz, 1H), 6 .09(brs, 1H), 7.00(dd, J=l.6, 8.0Hz, 1H), 7.08(d, J=8.0Hz, 1H), 7. 14(d, J=l.6Hz, 1H)  = 4.8Hz, 3H), 3.37 (s, 6H), 4.18 (brs, 2H), 4.49 (t, J = 5.2Hz, 1H), 6.09 (brs, 1H), 7.00 (dd, J = l.6, 8.0Hz, 1H), 7.08 (d, J = 8.0Hz, 1H), 7.14 (d, J = l.6Hz, 1H)
ESI— MS: m/z 261(M + Na) + ESI— MS: m / z 261 (M + Na) +
製造例 12 Production Example 12
1一（1一べンジルォキシカルボ-ルビペリジン 4 ィル） N メチルー 1H—イン ドール 6—カルボキサミドの合成  Synthesis of N-methyl (1H-indole) 6-carboxamide
[化 78] [Chemical 78]
Figure imgf000051_0001
製造例 11で得られた、 3 アミノー 4— (2, 2 ジメトキシェチル）— N—メチルベン ズアミド 83.4mg(0.35mmol)を酢酸 1.7mLに溶解し、室温で、この溶液に 4—ォ キソ— 1—ピぺリジンカルボン酸べンジル 123mg(0.52mmol)をカ卩え、窒素雰囲気 下、反応液を室温で攪拌した。 1時間後、反応液を冷水浴で冷却し、反応液に STA B (トリァセトキシ水素化ホウ素ナトリウム） 117mg(0.52mmol)を投入し、反応液を 室温で 1時間 20分攪拌した。次いで、反応液を冷水浴で冷却し、反応液に水 1.7m Lを滴下した後、 100°Cで反応液を 5時間加熱攪拌した。 反応液にトルエンをカ卩え、抽出した。ここで、 1— (1—ベンジルォキシカルボ-ルビ ペリジンー4 ィル）—N—メチルー 1H—インドールー 6 カルボキサミドが析出した ため、水層に酢酸ェチルをカ卩えて 1一（1一べンジルォキシカルボ-ルビペリジンー4 ィル）—N—メチルー 1H—インドールー 6 カルボキサミドを溶解させ、次いで、 5 N水酸ィ匕ナトリウム溶液で中和した後、酢酸ェチルで抽出した。有機層を無水硫酸マ グネシゥムで乾燥し、濾別後、減圧濃縮し、残渣をフラッシュカラムクロマトグラフィー により精製（Merck, Silica Gel 60, 230— 400 mesh;酢酸ェチル：ヘプタン = 2 : 1)して、無色油状物として 1一（1一べンジルォキシカルボ-ルビペリジンー4 ィル）—N—メチル—1H—インドール— 6—カルボキサミド 114. 9mgを得た。
Figure imgf000051_0001
83.4 mg (0.35 mmol) of 3 amino-4- (2,2 dimethoxyethyl) -N-methylbenzamide obtained in Preparation Example 11 was dissolved in 1.7 mL of acetic acid, and 4-oxo- 123 mg (0.52 mmol) of 1-piperidinecarboxylic acid benzyl was added, and the reaction solution was stirred at room temperature under a nitrogen atmosphere. After 1 hour, the reaction solution was cooled in a cold water bath, 117 mg (0.52 mmol) of STA B (sodium triacetoxyborohydride) was added to the reaction solution, and the reaction solution was stirred at room temperature for 1 hour and 20 minutes. Next, the reaction solution was cooled in a cold water bath, 1.7 ml of water was added dropwise to the reaction solution, and then the reaction solution was heated and stirred at 100 ° C. for 5 hours. Toluene was added to the reaction solution and extracted. Here, 1- (1-benzyloxycarbo-biperidine-4-yl) -N-methyl- 1H-indole-6 carboxamide was precipitated, and ethyl acetate was added to the aqueous layer. Xylcarbol-biperidine-4-yl) -N-methyl-1H-indole-6 carboxamide was dissolved and then neutralized with 5N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Merck, Silica Gel 60, 230—400 mesh; ethyl acetate: heptane = 2: 1). As a colorless oil, 119.9 mg of 1- (1benzyloxycarbo-rubiperidine-4-yl) -N-methyl-1H-indole-6-carboxamide was obtained.
得られた油状物をトルエン 0. 12mLに溶解し、室温攪拌下、この溶液にシクロペン チルメチルエーテル 0. 96mL)を滴下した。この溶液を 50°Cにて加熱攪拌し、 1— ( 1 ベンジルォキシカルボニルピペリジン— 4—ィル） N—メチルー 1H—インドー ルー 6 カルボキサミドの種結晶をカ卩えた。次いで、反応液に 50°C加熱攪拌下、へ プタン 0. 24mLを滴下し、 50°Cで 10分間反応液を加熱攪拌した。これを 10°CZl5 分のペースで室温まで徐冷した後、 10°Cにて 1時間攪拌した。析出した結晶を濾取 して白色結晶として 1— (1—ベンジルォキシカルボ-ルビペリジン一 4—ィル） N— メチルー 1H—インドールー 6 カルボキサミド 99. 3mgを得た。  The obtained oil was dissolved in 0.12 mL of toluene, and cyclopentyl methyl ether (0.96 mL) was added dropwise to this solution while stirring at room temperature. This solution was heated and stirred at 50 ° C. to obtain seed crystals of 1- (1 benzyloxycarbonylpiperidine-4-yl) N-methyl-1H-indoloux 6 carboxamide. Next, 0.24 mL of heptane was added dropwise to the reaction mixture with stirring at 50 ° C, and the reaction mixture was heated and stirred at 50 ° C for 10 minutes. This was gradually cooled to room temperature at a pace of 10 ° C Zl5, and then stirred at 10 ° C for 1 hour. The precipitated crystals were collected by filtration to obtain 99.3 mg of 1- (1-benzyloxycarbo-biperidine-4-yl) N-methyl-1H-indole-6 carboxamide as white crystals.
収率： 72. 7%Yield: 72.7%
— NMR (400MHz、 CDC1 ) δ (ppm) : 1. 83— 2. 02 (br, 2H) , 2. 04— 2. 1  — NMR (400MHz, CDC1) δ (ppm): 1. 83— 2. 02 (br, 2H), 2. 04— 2. 1
3  Three
6 (br, 2H) , 2. 94— 3. 10 (br, 2H) , 3. 06 (d, J=4. 8Hz, 3H) , 4. 30—4. 58 (m, 3H) , 5. 17 (s, 2H) , 6. 24 (brs, 1H) , 6. 56 (d, J = 3. 2Hz, 1H) , 7. 28 ( d, J = 3. 2Hz, 1H) , 7. 31— 7. 41 (m, 6H) , 7. 62 (d, J = 8. 4Hz, 1H) , 8. 05 (s, 1H)  6 (br, 2H), 2.94— 3.10 (br, 2H), 3.06 (d, J = 4.8Hz, 3H), 4.30—4.58 (m, 3H), 5. 17 (s, 2H), 6. 24 (brs, 1H), 6. 56 (d, J = 3.2 Hz, 1H), 7. 28 (d, J = 3.2 Hz, 1H), 7. 31— 7.41 (m, 6H), 7.62 (d, J = 8.4Hz, 1H), 8.05 (s, 1H)
ESI— MS : m/z 414 (M + Na) +  ESI— MS: m / z 414 (M + Na) +
製造例 13 Production Example 13
1一（1 エトキシエトキシ） 3 メトキシベンゼンの合成  1 (1 ethoxyethoxy) 3 Synthesis of methoxybenzene
[化 79]
Figure imgf000053_0001
窒素雰囲気下の 15L四頸丸底フラスコにテトラヒドロフラン 2600mLおよび 3—メト キシフエノール 650. 4g (5. 24mol)をカ卩えた。次いで、このテトラヒドロフラン溶液に ピリジ -ゥム p トルエンスルホナート 65. 8g (0. 26mol)を加え、攪拌を開始した。 この混合物を 8°Cに設定した恒温槽で冷却し、反応液にェチルビニルエーテル 760 . lg (10. 54mol)を約 1. 5時間かけて滴下した。同温度で 2. 7時間反応液を攪拌 した後に、恒温槽の温度を 15°Cに設定した。内温が 14°Cを越えた時点から、更に約 2時間攪拌した。恒温槽の温度を 8°Cに設定し、内温がおおよそ 10°Cになった時点 で、反応液に 8%炭酸水素ナトリウム水溶液 715. 2g [炭酸水素ナトリウム 57. 2gを水 道水 658mLに溶解して調製したもの]を 10分間で滴下した。反応液を 20L分液ロー トに移し、水道水 1040mLを追加し、トルエン 4550mLを加えて抽出し、有機層を水 道水 1300mLおよび 650mLで 2回洗浄した。得られた有機層を浴温 40°Cで減圧濃 縮し、標記化合物を含有する淡黄色油状物を得た。 [Chemical 79]
Figure imgf000053_0001
Tetrahydrofuran (2600 mL) and 3-methoxyphenol (650.4 g, 5.24 mol) were placed in a 15 L four-necked round bottom flask under a nitrogen atmosphere. Next, 65.8 g (0.26 mol) of pyridinium p-toluenesulfonate was added to the tetrahydrofuran solution, and stirring was started. This mixture was cooled in a thermostatic bath set at 8 ° C., and 760.lg (10.54 mol) of ethyl vinyl ether was added dropwise to the reaction solution over about 1.5 hours. After stirring the reaction solution for 2.7 hours at the same temperature, the temperature of the thermostatic bath was set to 15 ° C. From the time when the internal temperature exceeded 14 ° C, the mixture was further stirred for about 2 hours. When the temperature of the thermostatic chamber is set to 8 ° C and the internal temperature reaches approximately 10 ° C, the reaction solution contains 75.2 g of 8% aqueous sodium hydrogen carbonate solution [57.2 g of sodium hydrogen carbonate is added to 658 mL of tap water. Prepared by dissolution] was added dropwise over 10 minutes. The reaction solution was transferred to a 20 L separatory funnel, 1040 mL of tap water was added, 4550 mL of toluene was added for extraction, and the organic layer was washed twice with 1300 mL and 650 mL of tap water. The obtained organic layer was concentrated under reduced pressure at a bath temperature of 40 ° C. to obtain a pale yellow oil containing the title compound.
収量 1213. 5g、含量 1019. 3g、収率 99. 1% Yield 1213.5 g, content 1019.3 g, yield 99.1%
'H-NMR (400MHz, CDC1 ) δ (ppm) : 1. 21 (t, J = 6. 8Hz, 3H) , 1. 50 (d, J  'H-NMR (400MHz, CDC1) δ (ppm): 1.21 (t, J = 6.8Hz, 3H), 1.50 (d, J
3  Three
= 5. 2Hz, 3H) , 3. 50- 3. 60 (m, 2H) , 3. 79 (s, 3H) , 5. 38 (q, J = 5. 2Hz, 1H) , 6. 50-6. 66 (m, 3H) , 7. 13— 7. 20 (m, 1H) .  = 5. 2Hz, 3H), 3. 50- 3.60 (m, 2H), 3. 79 (s, 3H), 5. 38 (q, J = 5.2 Hz, 1H), 6. 50-6 66 (m, 3H), 7. 13— 7. 20 (m, 1H).
実施例 1 Example 1
「2—（1 エトキシエトキシ） 6 メトキシフエ二ル Ί酢酸ェチルの合成  Synthesis of 2- (1 ethoxyethoxy) 6 methoxyphenyl ェ ethyl acetate
[化 80]
Figure imgf000053_0002
H3CO 窒素雰囲気下で 20L反応装置に、 1— (1—エトキシエトキシ）—3—メトキシベンゼ ン 854. Og、含量 717.4g(3.66mol)を投人し、テトラヒドロフラン 7174mLで洗!ヽ 込み攪拌した。反応装置のジャケットに 4°Cに設定した冷却液を循環し、反応液に n ブチルリチウム 1156g(4.41mol) [2.71M、 n—へキサン溶液]を 41分で滴下し 、さらに同温度で反応液を約 1.5時間攪拌した。冷却液温を— 20°Cに設定し、内温 が— 10°C以下になったことを確認後、反応液にヨウ化銅 (1)417.8g(2.19mol)を 3回に分けて加え、反応液を同温度で約 14時間攪拌した。冷却液設定温を— 90°C に変更し、反応液にブロモ酢酸ェチル 702. lg(4.20mol)を 26分かけて滴下し、 テトラヒドロフラン 10mLで洗いこんだ。滴下終了後 44分間攪拌し、冷却液温設定を — 35°Cに変更し、更に約 1.8時間攪拌した。冷却液温設定を— 20°Cに変更し、内 温が― 20°Cを超えて力 反応液を 1時間攪拌し、 HPLCにて反応の進行を確認した 。同温度で反応液に 28%アンモニア水 1435mLを約 30分間でカ卩え、冷却液温を 2 5°Cに変更した。トルエン 7174mLをカ卩ぇ抽出し、有機層を 28%アンモニア水 1440 mL、水道水 1435mLX3で順次洗浄した。得られた有機層に、 N, N ジイソプロピ ルェチルァミン 127mL(0.73mol)を加えた後、減圧濃縮し、標記化合物を含有す る淡オレンジ色油状物を得た。 [Chemical 80]
Figure imgf000053_0002
H 3 CO Under a nitrogen atmosphere, 1- (1-ethoxyethoxy) -3-methoxybenzene 854. Og, content 717.4 g (3.66 mol) was thrown into a 20 L reactor, washed with 7174 mL of tetrahydrofuran, and stirred. Cooling liquid set at 4 ° C was circulated through the jacket of the reactor, and 1156 g (4.41 mol) [2.71M, n-hexane solution] of n-butyllithium was added dropwise to the reaction liquid in 41 minutes, followed by reaction at the same temperature. The solution was stirred for about 1.5 hours. Set the coolant temperature to -20 ° C and confirm that the internal temperature was -10 ° C or less, and then add 417.8 g (2.19 mol) of copper iodide (1) to the reaction solution in three portions. The reaction solution was stirred at the same temperature for about 14 hours. The coolant set temperature was changed to -90 ° C, and 702. lg (4.20 mol) of bromoethyl acetate was added dropwise to the reaction solution over 26 minutes, followed by washing with 10 mL of tetrahydrofuran. After completion of dropping, the mixture was stirred for 44 minutes, the coolant temperature setting was changed to -35 ° C, and further stirred for about 1.8 hours. The coolant temperature setting was changed to -20 ° C, the internal temperature exceeded -20 ° C, the reaction solution was stirred for 1 hour, and the progress of the reaction was confirmed by HPLC. At the same temperature, 1435 mL of 28% aqueous ammonia was added to the reaction solution in about 30 minutes, and the coolant temperature was changed to 25 ° C. 7174 mL of toluene was extracted from the cake, and the organic layer was washed sequentially with 28% ammonia water 1440 mL and tap water 1435 mLX3. To the obtained organic layer, 127 mL (0.73 mol) of N, N diisopropylethylamine was added, followed by concentration under reduced pressure to obtain a pale orange oil containing the title compound.
収量 1122.3g、含量 990.7g、収率 96.0% Yield 1122.3g, Content 990.7g, Yield 96.0%
'H-NMR (400MHz, CDC1 ) δ (ppm) :1.19(t, J = 7.2Hz, 3H), 1.24 (d, J  'H-NMR (400MHz, CDC1) δ (ppm): 1.19 (t, J = 7.2Hz, 3H), 1.24 (d, J
3  Three
=7.2Hz, 3H), 1.47(d, J = 5.2Hz, 3H), 3.46— 3.56 (m, 1H), 3.66— 3 .82 (m, 3H), 3.80 (s, 3H), 4.14(q, J = 7.2Hz, 2H), 5.39(q, J = 5.2Hz , 1H), 6.57(d, J = 8.4Hz, 1H), 6.70(d, J = 8.8Hz, 1H), 7.17(dd, J = 8 .8, 8.4Hz, 1H).  = 7.2Hz, 3H), 1.47 (d, J = 5.2Hz, 3H), 3.46— 3.56 (m, 1H), 3.66— 3.82 (m, 3H), 3.80 (s, 3H), 4.14 (q, J = 7.2Hz, 2H), 5.39 (q, J = 5.2Hz, 1H), 6.57 (d, J = 8.4Hz, 1H), 6.70 (d, J = 8.8Hz, 1H), 7.17 (dd, J = (8.8, 8.4Hz, 1H).
実施例 2 Example 2
2—「 1 エトキシエトキシ 1 6 メトキシフエニル Ίエタノールの合成  2- “1 Ethoxyethoxy 1 6 Methoxyphenyl ΊSynthesis of ethanol
[化 81] [Chemical 81]
Figure imgf000055_0001
窒素雰囲気下、 15L四頸丸底フラスコに、 [2— (1—エトキシェトキシ）— 6—メトキ シフエ-ル]酢酸ェチル 248.8g (含量 213. Og、0.754mol)および同ィ匕合物 561 .6g (含量 495.7g、 1.756mol)、トルエン（8504mL)、 DME(2126mL)を順次 加え、攪拌を開始し、反応容器を氷冷した。この溶液に、水素化ビス（2—メトキシエト キシ）アルミニウムナトリウム 1403.7g (65%トルエン溶液、 1.8モル当量）を 50分力、 けて滴下した。滴下終了後直ちに、氷水浴を水浴に変更し反応液を 2.5時間攪拌し た。水浴を氷水浴に変更し、反応液に 8% (wZw)水酸ィ匕ナトリウム水溶液 [93.0% 水酸化ナトリウム 430gに水 4570mLを加えて調製した。 ]約 1.5Lを 47分かけて滴 下した。反応液を 20L分液ロートに移し、調製した水酸ィ匕ナトリウム水溶液の残りを全 量カロえ、水層を廃棄した。有機層を水道水（1417mLX2、 709mLX 1)で 3回洗浄 した後、 40°Cで減圧濃縮し、濃縮残渣に含まれる標記化合物を定量した。
Figure imgf000055_0001
In a nitrogen atmosphere, in a 15 L four-necked round bottom flask, 248.8 g of [2- (1-ethoxyethoxy) -6-methoxyphenyl] ethyl acetate (content 213. Og, 0.754 mol) and the same compound 561 .6 g (Contents 495.7 g, 1.756 mol), toluene (8504 mL), and DME (2126 mL) were sequentially added, stirring was started, and the reaction vessel was ice-cooled. To this solution, 1403.7 g of sodium bis (2-methoxyethoxy) aluminum hydride (65% toluene solution, 1.8 molar equivalent) was added dropwise over 50 minutes. Immediately after completion of the dropwise addition, the ice water bath was changed to a water bath, and the reaction solution was stirred for 2.5 hours. The water bath was changed to an ice water bath, and the reaction solution was prepared by adding 4570 mL of water to 430 g of 8% (wZw) aqueous sodium hydroxide solution [93.0% sodium hydroxide. ] About 1.5L was dropped over 47 minutes. The reaction solution was transferred to a 20 L separatory funnel, and the remaining amount of the prepared sodium hydroxide / sodium hydroxide solution was completely removed, and the aqueous layer was discarded. The organic layer was washed three times with tap water (1417 mLX2, 709 mLX 1) and then concentrated under reduced pressure at 40 ° C., and the title compound contained in the concentrated residue was quantified.
濃縮残渣重量 1042.0g、含量 563.3g Concentrated residue weight 1042.0g, content 563.3g
'H-NMR (400MHz, CDC1 ) δ (ppm) :1.20(t, J = 7.2Hz, 3H), 1.50 (d  'H-NMR (400MHz, CDC1) δ (ppm): 1.20 (t, J = 7.2Hz, 3H), 1.50 (d
3  Three
, J = 5.6Hz, 3H), 3.00 (t, J = 6.8Hz, 2H), 3.48— 3.58 (m, 1H), 3.68— 3.90 (m, 3H), 3.82(s, 3H), 5.42(q, J=5.6Hz, 1H), 6.58(d, J = 8. OH z, 1H), 6.70(d, J = 8.4Hz, 1H), 7.13(dd, J = 8.4, 8. OHz, 1H) .  , J = 5.6Hz, 3H), 3.00 (t, J = 6.8Hz, 2H), 3.48—3.58 (m, 1H), 3.68— 3.90 (m, 3H), 3.82 (s, 3H), 5.42 (q, J = 5.6Hz, 1H), 6.58 (d, J = 8.OH z, 1H), 6.70 (d, J = 8.4Hz, 1H), 7.13 (dd, J = 8.4, 8.OHz, 1H).
実施例 3 Example 3
安息香酸 2—「2—（1 エトキシエトキシ） 6 メトキシフエニル Ίェチルの合成 [化 82] Benzoic acid 2- “2- (1 ethoxyethoxy) 6 methoxyphenyl ketyl synthesis
Figure imgf000056_0001
実施例 2で得られた有機層残渣 1042. Ogを窒素雰囲気下の 15L四頸丸底フラス コに移し、卜ルェン 8102mL、 DME2025mL,卜リエチルァミン 304.8g, N, N, N, N—テトラメチルエチレンジァミン 29.2gを順次カロえた。氷冷下に攪拌しながら、この 溶液に塩化ベンゾィル 388. lg(2.76 lmol)を 40分かけて滴下した。同温度で反 応液を 10分間攪拌した後に、氷浴を水浴に切り替え、さらに 2.8時間攪拌した。反 応液を 20L分液ロートに移し、水道水 3544mLおよび 709mLで洗浄した。得られた 有機層 10.84L中の標記化合物を定量した。
Figure imgf000056_0001
Organic layer residue 1042. Og obtained in Example 2 was transferred to a 15 L four-necked round bottom flask under a nitrogen atmosphere, 102Luen 8102 mL, DME 2025 mL, 卜 ethylamine 304.8 g, N, N, N, N-tetramethylethylene We ordered 29.2g of jamin sequentially. While stirring under ice cooling, 388.lg (2.76 lmol) of benzoyl chloride was added dropwise to this solution over 40 minutes. After the reaction solution was stirred for 10 minutes at the same temperature, the ice bath was switched to a water bath and stirred for another 2.8 hours. The reaction solution was transferred to a 20 L separatory funnel and washed with 3544 mL and 709 mL of tap water. The title compound in 10.84 L of the obtained organic layer was quantified.
含量 745. Og Content 745. Og
'H-NMR (400MHz, CDC1 ) δ (ppm) :1.18(t, J = 7.2Hz, 3H), 1.48 (d, J  'H-NMR (400MHz, CDC1) δ (ppm): 1.18 (t, J = 7.2Hz, 3H), 1.48 (d, J
3  Three
=5.2Hz, 3H), 3.17(t, J = 7.2Hz, 2H), 3.45— 3.56 (m, 1H), 3.66— 3 .80 (m, 1H), 3.76 (s, 3H), 4.45(t, J = 7.2Hz, 2H), 5.41(q, J = 5.2Hz , 1H), 6.55(d, J = 8.4Hz, 1H), 6.71(d, J = 8.0Hz, 1H), 7.13(dd, J = 8 .4, 8.0Hz, 1H), 7.36-7.44 (m, 2H), 7.50— 7.56 (m, 1H), 7.98— 8. 06 (m, 2H)  = 5.2Hz, 3H), 3.17 (t, J = 7.2Hz, 2H), 3.45— 3.56 (m, 1H), 3.66— 3.80 (m, 1H), 3.76 (s, 3H), 4.45 (t, J = 7.2Hz, 2H), 5.41 (q, J = 5.2Hz, 1H), 6.55 (d, J = 8.4Hz, 1H), 6.71 (d, J = 8.0Hz, 1H), 7.13 (dd, J = 8.4, 8.0Hz, 1H), 7.36-7.44 (m, 2H), 7.50—7.56 (m, 1H), 7.98—8.06 (m, 2H)
実施例 4 Example 4
安息呑酸 2—（2—ヒドロキシー6—メトキシフエニル)ェチルの合成 Synthesis of 2- (2-hydroxy-6-methoxyphenyl) ethyl benzoate
[化 83]  [Chemical 83]
Figure imgf000056_0002
実施例 3で得られた有機層を 15L四頸丸底フラスコに移し、テトラヒドロフラン 2126 mLをカ卩え、氷水浴で冷却し攪拌した。反応液に 5N塩酸 1417mLを 23分間で滴下 し、反応液を同温度で約 1時間攪拌した後、浴槽の冷水を抜き、 2.5時間攪拌を続 けた。反応液を 20L分液ロートへ移し、水層を廃棄した。有機層を 8%炭酸水素ナトリ ゥム水溶液 [炭酸水素ナトリウム 170gに水 1956mLをカ卩えて調整した。 ]および水道 水（709mLX2)で 2回洗浄した。得られた有機層を浴温 40°Cで減圧濃縮し、スラリ 一 1463. Ogを得た。
Figure imgf000056_0002
The organic layer obtained in Example 3 was transferred to a 15 L four-necked round bottom flask, 2126 mL of tetrahydrofuran was added, and the mixture was cooled in an ice water bath and stirred. To the reaction solution, 1417 mL of 5N hydrochloric acid was added dropwise over 23 minutes, and the reaction solution was stirred at the same temperature for about 1 hour, then the cold water in the bath was drained and stirring was continued for 2.5 hours. The reaction solution was transferred to a 20 L separatory funnel and the aqueous layer was discarded. The organic layer was adjusted by adding 1956 mL of water to 170 g of sodium hydrogen carbonate [170 g of sodium bicarbonate. ] And tap water (709 mLX2) twice. The obtained organic layer was concentrated under reduced pressure at a bath temperature of 40 ° C. to obtain 1463. Og of slurry.
得られたスラリーを 10L四頸丸底フラスコへテトラヒドロフラン 709mLで洗い込んだ 。攪拌しながら、反応液にトルエン—ヘプタン混合液（1:8) 5670mLを約 2.5時間 かけて滴下し、さらに室温で反応液を約 14時間攪拌した。析出した結晶を濾取し、ト ルェン—ヘプタン混合液（1： 8) 708mLで結晶を洗浄した。減圧下浴温 40°Cで約 4 .5時間乾燥し、標記化合物を白色結晶として得た。  The resulting slurry was washed into a 10 L four-necked round bottom flask with 709 mL of tetrahydrofuran. While stirring, 5670 mL of a toluene-heptane mixture (1: 8) was added dropwise to the reaction solution over about 2.5 hours, and the reaction solution was further stirred at room temperature for about 14 hours. The precipitated crystals were collected by filtration and washed with 708 mL of a toluene-heptane mixture (1: 8). It was dried at a bath temperature of 40 ° C under reduced pressure for about 4.5 hours to obtain the title compound as white crystals.
収量 535.9g、収率 78.4% Yield 535.9g, Yield 78.4%
'H-NMR (400MHz, CDC1 ) δ (ppm) :3.15(t, J = 7.2Hz, 2H), 3.79 (s, 3  'H-NMR (400MHz, CDC1) δ (ppm): 3.15 (t, J = 7.2Hz, 2H), 3.79 (s, 3
3  Three
H), 4.45(t, J = 7.2Hz, 2H), 5.86 (s, 1H), 6.48(d, J = 8.4Hz, 1H), 6. 53(d, J = 8.4Hz, 1H), 7.09(dd, J = 8.4, 8.4Hz, 1H), 7.44(dd, J = 7.6 , 7.6Hz, 2H), 7.56(dd, J = 7.6, 7.6Hz, 1H), 8.04(d, J = 7.6Hz, 1H) . 実施例 5  H), 4.45 (t, J = 7.2Hz, 2H), 5.86 (s, 1H), 6.48 (d, J = 8.4Hz, 1H), 6.53 (d, J = 8.4Hz, 1H), 7.09 ( dd, J = 8.4, 8.4Hz, 1H), 7.44 (dd, J = 7.6, 7.6Hz, 2H), 7.56 (dd, J = 7.6, 7.6Hz, 1H), 8.04 (d, J = 7.6Hz, 1H Example 5
安息呑酸 2—（7 メトキシー 2.2 ジメチルー 4 ォキソクロマン 8 ィル）ェチ ルの合成 Synthesis of benzoic acid 2- (7 methoxy-2.2 dimethyl-4-oxochroman 8 yl) ethyl
[化 84]  [Chemical 84]
Figure imgf000057_0001
10L四頸丸底フラスコに、 3 メチルクロトン酸 202.2g(2.020mol)およびメタン スルホン酸 2Lを加え、窒素気流下、 50°C水浴上で攪拌した。この溶液に実施例 4で 得られた安息香酸 2—（2 ヒドロキシー6—メトキシフエ-ル）ェチル 500.0g(l.8 36mol)を投入した。反応混合物を同温度で 1.8時間攪拌し、氷冷した。トルエン 2. 5Lを反応液に注入し、次いで、水道水 5Lを約 1時間かけて滴下した。内容物を 20L 分液装置に移し、分液し水層を廃棄した。有機層を水道水（5LX3)にて 3回洗浄し 、 40°C浴で減圧濃縮し、標題ィ匕合物 846. lgを得た。
Figure imgf000057_0001
To a 10 L four-necked round bottom flask, 202.2 g (2.020 mol) of 3 methylcrotonic acid and 2 L of methanesulfonic acid were added and stirred on a 50 ° C. water bath under a nitrogen stream. To this solution, 500.0 g (l.8 36 mol) of benzoic acid 2- (2hydroxy-6-methoxyphenyl) ethyl obtained in Example 4 was added. The reaction mixture was stirred at the same temperature for 1.8 hours and cooled on ice. Toluene (2.5 L) was poured into the reaction solution, and then 5 L of tap water was added dropwise over about 1 hour. The contents were transferred to a 20L separator and separated to discard the aqueous layer. The organic layer was washed 3 times with tap water (5LX3) and concentrated under reduced pressure in a 40 ° C bath to obtain 846.lg of the title compound.
'H-NMR (400MHz, CDC1 ) δ (ppm) :1.39 (s, 6H), 2.62 (s, 2H), 3. 13 (  'H-NMR (400MHz, CDC1) δ (ppm): 1.39 (s, 6H), 2.62 (s, 2H), 3.13 (
3  Three
t, J = 6.8Hz, 2H), 3.82(s, 3H), 4.45(t, J = 6.8Hz, 2H), 6.57(d, J = 8. 8Hz, 1H), 7.38-7.45 (m, 2H), 7.51— 7.57 (m, 1H), 7.82(d, J = 8.8 Hz, 1H), 7.98-8.04 (m, 2H) . t, J = 6.8Hz, 2H), 3.82 (s, 3H), 4.45 (t, J = 6.8Hz, 2H), 6.57 (d, J = 8.8Hz, 1H), 7.38-7.45 (m, 2H) , 7.51-7.57 (m, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.98-8.04 (m, 2H).
実施例 6 Example 6
8—（2 ヒドロキシェチル）ー7 メトキシ 2.2 ジメチルクロマンー4 オンの合成 [化 85]  Synthesis of 8- (2 hydroxyethyl) -7 methoxy 2.2 dimethylchroman-4-one [Chemical 85]
Figure imgf000058_0001
Figure imgf000058_0001
前記実施例 5で得られた油状物 844.9gをテトラヒドロフラン 2.5Lに溶力して、 20 L四頸丸底フラスコへ移した。このテトラヒドロフラン溶液にメタノール 2.5Lを力卩ぇ水 冷し (水温 22°C)、攪拌下 8% (wZw)水酸ィ匕ナトリウム水溶液 [水酸ィ匕ナトリウム（93 .0%)158gに水 1678mLをカ卩えて調製した。 ]を 18分かけて滴下した。滴下終了後 、水浴をはずし、反応液を室温で約 3.5時間攪拌した。反応液に水道水 10Lを約 1 時間かけて滴下した。反応容器を氷冷し、内温 10°C以下で反応液を約 1時間攪拌し た。析出した結晶を濾取し、水道水 2Lおよびメタノール一水道水混合物（1:4、 400 mL/1600mL)にて順次洗浄した。得られた結晶は恒量になるまで 40°Cで減圧乾 燥し、標記化合物の粗体 374. 7gを淡黄白色固体として得た。 844.9 g of the oil obtained in Example 5 was dissolved in 2.5 L of tetrahydrofuran and transferred to a 20 L four-necked round bottom flask. To this tetrahydrofuran solution, 2.5L of methanol is cooled with water (water temperature: 22 ° C), and with stirring, 8% (wZw) aqueous solution of sodium hydroxide and sodium hydroxide [8% of sodium hydroxide (93.0%), 1678mL of water Was prepared. ] Was added dropwise over 18 minutes. After completion of the dropwise addition, the water bath was removed, and the reaction solution was stirred at room temperature for about 3.5 hours. 10 L of tap water was added dropwise to the reaction solution over about 1 hour. The reaction vessel was ice-cooled, and the reaction solution was stirred at an internal temperature of 10 ° C or lower for about 1 hour. The precipitated crystals were collected by filtration and washed sequentially with 2 L of tap water and a mixture of methanol and tap water (1: 4, 400 mL / 1600 mL). The crystals obtained are dried under reduced pressure at 40 ° C until a constant weight is reached. Drying afforded 374.7 g of the crude title compound as a pale yellowish white solid.
収量 374. 7g、含量 305. 8g、収率 66. 6%  Yield 374.7 g, Content 305.8 g, Yield 66.6%
15L四頸丸底フラスコに、標記化合物の粗体 374. 7g (含量 305. 8g)および酢酸 ェチル 2Lを投入し、 80°Cに加熱した水浴で加熱攪拌を開始した。この懸濁液にさら に酢酸ェチル 4. 116Lを追加し、浴温設定を 75°Cに変更した。結晶の溶解を確認し た後、水浴の温度を徐々に下げ、内温 45. 3°Cで種結晶を投入した。種結晶投入か ら 6分後に結晶の析出を確認した。さらに水浴の温度を下げ、内温 30°C以下で、懸 濁液にヘプタン 6. 116Lを約 1時間でカ卩え、同温度で約 13時間攪拌した。懸濁液を 氷冷し、約 4時間攪拌後、結晶をブフナーロートで濾取し、酢酸ェチルーヘプタン混 合液（1： 2) 918mLで結晶を洗浄した。得られた結晶を 40°C水浴上で約 3時間減圧 乾燥、室温で約 14時間減圧乾燥を行い、標記化合物を灰白色固体として得た。 収量 294. 5g、含量 275. 4g、収率 90. 1%  Into a 15 L four-necked round bottom flask, 377.7 g (content 305.8 g) of the crude product of the title compound and 2 L of ethyl acetate were added, and heating and stirring were started in a water bath heated to 80 ° C. To this suspension, 4.116 L of ethyl acetate was further added, and the bath temperature setting was changed to 75 ° C. After confirming the dissolution of the crystals, the temperature of the water bath was gradually lowered, and seed crystals were introduced at an internal temperature of 45.3 ° C. Crystal deposition was confirmed 6 minutes after seeding. Further, the temperature of the water bath was lowered, and the internal temperature was 30 ° C or lower, and 6.116 L of heptane was added to the suspension in about 1 hour, followed by stirring at the same temperature for about 13 hours. The suspension was ice-cooled and stirred for about 4 hours. The crystals were collected by filtration with a Buchner funnel, and the crystals were washed with 918 mL of an ethyl acetate-heptane mixture (1: 2). The obtained crystals were dried under reduced pressure in a 40 ° C water bath for about 3 hours and then dried under reduced pressure at room temperature for about 14 hours to obtain the title compound as an off-white solid. Yield 294.5 g, content 275.4 g, yield 90.1%
'H-NMR (400MHz, CDC1 ) δ (ppm) : 1. 45 (s, 6H) , 2. 68 (s, 2H) , 2. 96 (  'H-NMR (400MHz, CDC1) δ (ppm): 1. 45 (s, 6H), 2. 68 (s, 2H), 2. 96 (
3  Three
t, J = 6. 8Hz, 2H) , 3. 73- 3. 80 (m, 2H) 3. 89 (s, 3H) , 6. 59 (d, J = 8. 8Hz , 1H) , 7. 81 (d, J = 8. 8Hz, 1H) .  t, J = 6.8Hz, 2H), 3.73- 3.80 (m, 2H) 3.89 (s, 3H), 6.59 (d, J = 8.8Hz, 1H), 7.81 (d, J = 8.8Hz, 1H).
[0074] 実施例 7 [0074] Example 7
8—（2 ヒドロキシェチル）ー7 メトキシ 2. 2 ジメチルクロマンー4 オンの合成 lOOmL四頸丸底フラスコに、標記化合物の粗体 3. 71g (含量 3. Og)およびメチル イソプチルケトン 45mLを投入し、 82°Cに加熱した油浴で加熱攪拌し、溶液とした。こ の溶液を徐冷し、内温 59°Cで種結晶を投入した。 30分ごとに油浴の温度設定を 5°C ずつ下げて徐冷し、内温 26. 7°Cでヘプタン 30mLを約 1時間かけて滴下した。 18 分経過後、懸濁液を冷水で冷却し、 1時間 50分後に結晶を濾取した。得られた結晶 は、メチルイソブチルケトン ヘプタン混合液（3 : 2) 3mLで洗浄し、 40°C水浴上で 約 1時間減圧乾燥し、標記化合物を白色固体として得た。  Synthesis of 8- (2 hydroxyethyl) -7 methoxy 2.2 dimethylchroman-4-one Into an lOOmL four-necked round bottom flask was charged 3.71 g (content 3. Og) of the crude product of the title compound and 45 mL of methyl isobutyl ketone. The solution was stirred in an oil bath heated to 82 ° C. to obtain a solution. The solution was slowly cooled and seed crystals were charged at an internal temperature of 59 ° C. Every 30 minutes, the temperature of the oil bath was lowered by 5 ° C and gradually cooled, and 30 mL of heptane was added dropwise over about 1 hour at an internal temperature of 26.7 ° C. After 18 minutes, the suspension was cooled with cold water, and the crystals were collected by filtration after 1 hour and 50 minutes. The obtained crystals were washed with 3 mL of methyl isobutyl ketone heptane mixture (3: 2) and dried under reduced pressure on a 40 ° C. water bath for about 1 hour to obtain the title compound as a white solid.
収量 2. 72g、含量 2. 64g、収率 87. 8%  Yield 2.72g, Content 2.64g, Yield 87.8%
[0075] 実施例 8 [0075] Example 8
丄 7 メヒキシ 2. _2 ジメチル 4 ォキソクロマン一 8 ィル _)ァセヒアルデヒドの合 丄 7 methoxy 2. _2 dimethyl 4-oxochroman -8) _) aldehyde
Figure imgf000060_0001
Figure imgf000060_0001
15L四頸丸底フラスコに 8— (2 ヒドロキシェチル） 7—メトキシ一 2, 2 ジメチル クロマン— 4—オン 248. 3g (含量 232. 7g、 0. 930mol)および同ィ匕合物 294. 0g ( 含量 274. 9g、 1. 098mol)、酢酸ェチル 7614mLを投入し攪拌した。この懸濁液を —4°C設定の冷浴にて冷却を開始し、臭化ナトリウム 161. 9g (l. 574mol)、水道水 508mL、 2, 2, 6, 6—テトラメチルピペリジンォキシド 3. 17g (20. 28mmol)を順次 投入した。内温力O°Cになってから、フラスコ内に次亜塩素酸ナトリウム溶液 5. 536m olと 7% (wZw)炭酸水素ナトリウム水溶液 2538gの混合液を約 2時間かけて滴下し た。滴下終了後、冷却バスの温度を 0°Cに変更し 45分間攪拌を続けた。反応液を 20 L分液ロートへ移し、水層を廃棄した。有機層を 10%塩ィ匕ナトリウム水溶液 2030g、 水道水 2030mLで順次洗浄した。得られた有機層を減圧濃縮 (40°C)し、スラリー 74 3. 7gを得た。得られたスラリーに、 DME500mLを加え、溶液とし、再び減圧濃縮（ 40°C)し、析出した結晶に再度 DME500mLを加えて溶解した。この溶液を 5L四頸 丸底フラスコへ移し、 40°Cの水浴でカ卩温した。さらに DME515mLをカ卩ぇ 183rpm で攪拌し、水道水約 500mLを投入し、 4分後に氷水浴で冷却を始めた。種結晶を加 え、約 1時間攪拌後、さらに水道水約 515mLを約 30分で加えた。更に 1. 3時間攪 拌後、ヘプタン 1523mLを約 1時間で投入し、同温度で約 1時間以上攪拌した。析 出した結晶を濾取し、 DMEZ水道水 Zヘプタンの混液 [約 600mL, DMEZ水道 水 Zヘプタン = 1Z1Z1. 5の割合で混ぜたものを使用]にて洗浄し、減圧乾燥 (浴 温 40°C)をほぼ恒量になるまで続け、標記化合物を黄白色固体として得た。 In a 15 L four-necked round bottom flask, 8- (2 hydroxyethyl) 7-methoxy-1,2,2 dimethylchroman-4-one 248.3 g (content 23. 7 g, 0.930 mol) and the same compound 294.0 g (Content 274.9 g, 1.098 mol) and 7614 mL of ethyl acetate were added and stirred. The suspension was cooled in a cold bath set at −4 ° C. 169.9 g (l. 574 mol) of sodium bromide, 508 mL of tap water, 2, 2, 6, 6-tetramethylpiperidine oxide 3 17g (20. 28mmol) was added sequentially. After the internal temperature reached O ° C, a mixed solution of 5.536 mol of sodium hypochlorite solution and 2538 g of 7% (wZw) sodium hydrogen carbonate aqueous solution was dropped into the flask over about 2 hours. After completion of dropping, the temperature of the cooling bath was changed to 0 ° C and stirring was continued for 45 minutes. The reaction solution was transferred to a 20 L separatory funnel and the aqueous layer was discarded. The organic layer was washed successively with 2030 g of 10% aqueous sodium chloride and 2030 mL of tap water. The obtained organic layer was concentrated under reduced pressure (40 ° C.) to obtain 74 3.7 g of a slurry. To the resulting slurry, 500 mL of DME was added to form a solution, which was again concentrated under reduced pressure (40 ° C.), and 500 mL of DME was added again to the precipitated crystals to dissolve them. This solution was transferred to a 5 L four-necked round bottom flask and heated in a 40 ° C water bath. DME515mL was stirred at 183rpm, and about 500mL of tap water was added. After 4 minutes, cooling in an ice water bath was started. After adding seed crystals and stirring for about 1 hour, about 515 mL of tap water was further added in about 30 minutes. After further stirring for 1.3 hours, 1523 mL of heptane was added in about 1 hour, and the mixture was stirred at the same temperature for about 1 hour or more. The precipitated crystals are collected by filtration, washed with a mixed solution of DMEZ tap water Z heptane (about 600 mL, mixed with DMEZ tap water Z heptane = 1Z1Z1.5), and dried under reduced pressure (bath temperature 40 ° C) was continued until almost constant weight to give the title compound as a pale yellow solid.
収量 478. 0g、含量 413. 9g、収率 82. 2% Yield 478.0 g, content 413.9 g, yield 82.2%
'H-NMR (600MHz, DMSO-d ) δ (ppm) : 1. 34 (s, 6H) , 2. 70 (s, 2H) , 3  'H-NMR (600MHz, DMSO-d) δ (ppm): 1.34 (s, 6H), 2.70 (s, 2H), 3
6  6
. 63 (s, 2H) , 3. 83 (s, 3H) , 6. 80 (d, J = 9. 0Hz, 1H) , 7. 72 (d, J = 9. 0Hz, 1H), 9.58 (s, 1H). 63 (s, 2H), 3. 83 (s, 3H), 6. 80 (d, J = 9.0 Hz, 1H), 7. 72 (d, J = 9.0 Hz, 1H), 9.58 (s, 1H).
実施例 9 Example 9
(7 メトキシ 2.2 ジメチルー 4 ォキソクロマンー8 ィル）ァセトアルデヒドの合 成  Synthesis of 7-methoxy 2.2 dimethyl-4-oxochroman-8yl) acetaldehyde
[化 87] [Chemical 87]
Figure imgf000061_0001
Figure imgf000061_0001
200mL四頸丸底フラスコに（7—メトキシ一 2, 2 ジメチルー 4—ォキソクロマン一 8—ィル）ァセトアルデヒド 6.54g (含量 6. Og)、エタノール 54mLおよび酢酸ェチル 6mLを加え反応液を室温で攪拌した。ここに、亜硫酸水素ナトリウム水溶液（2.51g を水 6mLに溶解したもの） 20分間で滴下した。次いで酢酸ェチル 60mLを 1.5時間 で滴下し、室温のまま反応液を終夜攪拌した。析出した結晶を濾取し、結晶はェタノ ール Z酢酸ェチル（1Z1)混液（12mL)で洗浄し、標記化合物の亜硫酸水素ナトリ ゥム付加体 8.14gを得た。 To a 200 mL four-necked round bottom flask (7-methoxy-1,2,2-dimethyl-4-oxochroman-1-8-yl) acetaldehyde 6.54 g (content 6. Og), ethanol 54 mL and ethyl acetate 6 mL were added, and the reaction mixture was allowed to cool at room temperature. Stir. A sodium bisulfite aqueous solution (2.51 g dissolved in 6 mL of water) was added dropwise thereto over 20 minutes. Next, 60 mL of ethyl acetate was added dropwise over 1.5 hours, and the reaction solution was stirred overnight at room temperature. The precipitated crystals were collected by filtration, and the crystals were washed with a mixed solution of ethanol Zethyl acetate (1Z1) (12 mL) to obtain 8.14 g of a sodium bisulfite adduct of the title compound.
標記化合物の亜硫酸水素ナトリウム付加体Sodium bisulfite adduct of the title compound
— NMR(600MHz, DMSO d ) δ (ppm) :1.35 (s, 3H), 1.36 (s, 3H), 2.  — NMR (600MHz, DMSO d) δ (ppm): 1.35 (s, 3H), 1.36 (s, 3H), 2.
6  6
66 (s, 2H), 2.88(dd, J=13.0, 3.0Hz, 1H), 3.00 (dd, J=13.0, 11.0Hz , 1H), 3.81 (s, 3H), 4.18(ddd, J=ll.0, 6.0, 3.0Hz, 1H), 4.35(d, J = 6.0Hz, 1H), 6.69(d, J = 9.0Hz, 1H), 7.60(d, J = 9.0Hz, 1H)  66 (s, 2H), 2.88 (dd, J = 13.0, 3.0Hz, 1H), 3.00 (dd, J = 13.0, 11.0Hz, 1H), 3.81 (s, 3H), 4.18 (ddd, J = ll. 0, 6.0, 3.0Hz, 1H), 4.35 (d, J = 6.0Hz, 1H), 6.69 (d, J = 9.0Hz, 1H), 7.60 (d, J = 9.0Hz, 1H)
300mL四頸丸底フラスコに標記化合物の亜硫酸水素ナトリウム付加体 6. Ogおよび 酢酸ェチル 120mLを加え攪拌した。この懸濁液に 10%炭酸カリウム水溶液 30gを 加え、 2時間以上室温で反応液を攪拌した。有機層を分取し、有機層を 10%食塩水 、水道水（2回）で順次洗浄した。有機層にトルエン 12mLを加えて減圧濃縮後、減 圧乾燥し、淡黄色固体として標記化合物 3.49gを得た。 To a 300 mL four-necked round bottom flask were added 6.Og of sodium bisulfite adduct of the title compound and 120 mL of ethyl acetate, and the mixture was stirred. To this suspension, 30 g of 10% aqueous potassium carbonate solution was added, and the reaction solution was stirred at room temperature for 2 hours or more. The organic layer was separated, and the organic layer was washed successively with 10% saline and tap water (twice). To the organic layer was added 12 mL of toluene, and the mixture was concentrated under reduced pressure and dried under reduced pressure to obtain 3.49 g of the title compound as a pale yellow solid.
実施例 10 Example 10
1— il—丄2— (Z—メ キシ一 2 2 ジメチル 4 ォキソクロマン 8 ィル) _ェチル Ίピぺリジン 4ーィル } Ν メチル 1H—インドール 6 カルボキサミドの合成1—il— 丄 2— (Z—methyl 2 2 dimethyl 4 oxochroman 8 yl) _ethyl Ί Piperidine 4-yl} メ チ ル Synthesis of methyl 1H-indole 6 carboxamide
[化 88] [Chemical 88]
Figure imgf000062_0001
Figure imgf000062_0001
15L四頸丸底フラスコに窒素気流下、製造例 7で合成した Ν—メチルー 1—(ピペリ ジン— 4—ィル）—1H—インドール— 6—カルボキサミド 677. Og (含有量 332. 8g、 1. 293mmol)およびテトラヒドロフラン 2000mLを加えた。さらに、この懸濁液に実 施例 8で得られた（7—メトキシ 2, 2 ジメチルー 4 ォキソクロマンー8 ィル）ァ セトァノレデヒド 426. 4g (含有量 369. 2g、 1. 15当量）、テトラヒドロフラン 1328mLお よび酢酸 148mL (2. 0モル当量)を順次投入し、室温で原料の溶解を確認した時点 から反応液を 1時間撹拌した。次いで、氷水浴で反応液を 10°C以下に冷却し、反応 液にトリァセトキシ水素化ホウ素ナトリウム（356. 3g、 1. 3モル当量)を 4分割して投 入した。全量投入終了から約 10分後に、氷水浴から水浴（21. 9°C)に切り替えて温 度制御し撹拌した。約 1時間後、反応液をサンプリングして HPLC分析し反応の終了 を確認した。反応容器を氷水浴で冷却し、約 10°Cで反応液に酢酸ェチル 4500mL を加えた。次に、反応液に 1N水酸ィ匕ナトリウム水溶液 5200mLを 36分間で投入した 反応液を 20L分液装置に移し、酢酸ェチル 2156mLで洗いこみ、有機層を分取し た。有機層を 7%炭酸水素ナトリウム水溶液 1000g、 5%食塩水（3328g、 1000g: 2 回）、水道水 3328mLで順次洗浄した。  Ν-Methyl-1- (piperidine-4-yl)-1H-indole-6-carboxamide 677. Og (content 332. 8g, 1) synthesized in Production Example 7 in a 15L four-necked round bottom flask 293 mmol) and 2000 mL of tetrahydrofuran were added. In addition, to this suspension (42-methoxy 2,2 dimethyl-4-oxochroman 8 yl) cetanoldehydride 426.4 g (content 369.2 g, 1.15 eq) obtained in Example 8 was added to 1328 mL of tetrahydrofuran. And 148 mL (2.0 molar equivalents) of acetic acid were sequentially added, and the reaction solution was stirred for 1 hour from the time when dissolution of the raw materials was confirmed at room temperature. Next, the reaction solution was cooled to 10 ° C. or less in an ice-water bath, and sodium triacetoxyborohydride (356.3 g, 1.3 molar equivalent) was added in four portions to the reaction solution. About 10 minutes after the end of charging, the ice water bath was switched to the water bath (21.9 ° C) and the temperature was controlled and stirred. About 1 hour later, the reaction mixture was sampled and analyzed by HPLC to confirm the completion of the reaction. The reaction vessel was cooled in an ice-water bath, and 4500 mL of ethyl acetate was added to the reaction solution at about 10 ° C. Next, 5200 mL of 1N sodium hydroxide aqueous solution was added to the reaction solution over 36 minutes. The reaction solution was transferred to a 20 L separator, washed with 2156 mL of ethyl acetate, and the organic layer was separated. The organic layer was washed successively with 7% aqueous sodium hydrogen carbonate solution 1000 g, 5% brine (3328 g, 1000 g: 2 times) and tap water 3328 mL.
有機層を減圧濃縮し、エタノール 1664mLを加えて、濃縮し、得られた溶液 1902. 6 gの定量を行った。標記化合物の含有量は 581. lg、収率 91. 8%、HPLC純度 92 . 5%であった。 The organic layer was concentrated under reduced pressure, 1664 mL of ethanol was added and concentrated, and 1902.6 g of the resulting solution was quantified. The content of the title compound was 581.lg, the yield was 91.8%, and the HPLC purity was 92.5%.
濃縮物にエタノール 1664mLを加えて溶解し、活性炭 57. Ogを投入後約 1時間攪 拌した。活性炭はハイフロスーパーセルを用いて濾去し、エタノール 400mLで洗い こんだ。濾液を減圧濃縮し (浴温 40°C)、褐色油状物として標記化合物を 1461. 8g 得た。含有量 552. 5g、 HPLC純度 92. 5% 1664 mL of ethanol was added to the concentrate to dissolve it, and 57. Og of activated carbon was added and stirred for about 1 hour. Activated carbon is filtered off using Hyflo Supercell and washed with 400 mL of ethanol. It was. The filtrate was concentrated under reduced pressure (bath temperature 40 ° C) to obtain 1461.8 g of the title compound as a brown oil. Content 552.5 g, HPLC purity 92.5%
実施例 11 Example 11
1 ピぺリジン 4ーィルー 1H—インドール 6 カルボン酸メチル 塩酸塩の合成 [化 89]  1 Piperidine 4-Iru 1H-indole 6 Synthesis of methyl carboxylate hydrochloride
Figure imgf000063_0001
Figure imgf000063_0001
1— (1—ベンジルォキシカルボ-ルビペリジン— 4—ィル）—1H—インドール— 6 一力ルボン酸メチル 27. 5gをメタノール 68. 75mLおよびテトラヒドロフラン 68. 75m Lに溶解し、 10%パラジウム—炭素 (約 50%含水品） 1. lg存在下、 0. 3MPa水素 雰囲気下で約 7. 5時間攪拌した。触媒を濾去し、溶媒を留去し、混合物 16. 69gを 得た。このうち 6. 96gを使用し、 2 プロパノール 77mLに溶解し、氷冷下濃塩酸 2. 73mLを徐々に加えた。析出した結晶を濾取し、結晶は 2 プロパノールで洗浄した 。減圧乾燥後、標記化合物 5. 89gを得た。 1- (1-Benzyloxycarborubiperidine-4-yl) -1H-indole-6 Dissolve 27.5 g of methyl rubonate in 68.75 mL of methanol and 68.75 mL of tetrahydrofuran and add 10% palladium- Carbon (about 50% water-containing product) 1. Stirred in the presence of 1 lg in a 0.3 MPa hydrogen atmosphere for about 7.5 hours. The catalyst was removed by filtration and the solvent was distilled off to obtain 16.69 g of a mixture. Of this, 6.96 g was used, dissolved in 77 mL of 2 propanol, and 2.73 mL of concentrated hydrochloric acid was gradually added under ice cooling. The precipitated crystals were collected by filtration, and the crystals were washed with 2 propanol. After drying under reduced pressure, 5.89 g of the title compound was obtained.
'H-NMR (400MHz, DMSO— d ) δ (ppm) : 2. 00— 2. 30 (m, 4H) , 3. 05—  'H-NMR (400MHz, DMSO— d) δ (ppm): 2. 00— 2. 30 (m, 4H), 3. 05—
6  6
3. 25 (m, 2H) , 3. 30— 3. 50 (m, 2H) , 3. 85 (s, 3H) , 4. 80— 5. 00 (m, 1H) , 6. 61 (d, J = 3. 1Hz, 1H) , 7. 61 (d, J = 3. 1Hz, 1H) , 7. 60— 7. 70 (m, 2H ) , 8. 26 (s, 1H) .  3. 25 (m, 2H), 3. 30— 3. 50 (m, 2H), 3. 85 (s, 3H), 4. 80— 5. 00 (m, 1H), 6. 61 (d, J = 3.1 Hz, 1H), 7.61 (d, J = 3.1 Hz, 1H), 7.60—7.70 (m, 2H), 8.26 (s, 1H).
実施例 12 Example 12
l— i l—「2—(7 メトキシー 2. 2 ジメチルー 4 ォキソクロマンー8 ィル）ェチル Ίピぺリジン 4ーィル } 1H インドールー 6 力ルボン酸メチルの合成 l— i l— “2— (7 methoxy-2,2 dimethyl-4-oxochroman-8 yl) ethyl Ίpiperidine 4-yl} 1H indole-6 force synthesis of methyl rubonate
[化 90] [Chemical 90]
Figure imgf000064_0001
Figure imgf000064_0001
1—ピぺリジン— 4—ィル— 1H—インドール— 6—カルボン酸メチル 塩酸塩 2.92 gおよび（7—メトキシ—2, 2 ジメチルー 4 ォキソクロマンー8 ィル）ァセトアルデ ヒド 2.92gにテトラヒドロフラン 58.4mLおよび酢酸 14.6mLを加え 40°Cにカロ温し、 反応液を約 3時間攪拌した。反応液を氷水浴で冷却し、トリァセトキシ水素化ホウ素 ナトリウム 2.52gを 3回に分けて加えた。反応液を室温に戻し、 30分後に、反応の進 行を確認した。再度、反応液を氷水浴で冷却し、トルエン 87mLおよび水 29mLをカロ え、水層を廃棄した。有機層は、 1N水酸ィ匕ナトリウム水溶液 49mL、 69mL、 30mL で順次洗浄後、 5%食塩水 29mL、 14mL、さらに水 14mLで洗浄した。溶媒を留去 し、標題化合物の粗体 4.80gを得た。 1-piperidine-4-yl- 1H-indole-6-carboxylic acid methyl hydrochloride 2.92 g and (7-methoxy-2,2-dimethyl-4-oxochroman-8-yl) acetoaldehyde 2.92 g tetrahydrofuran 58.4 mL and acetic acid 14.6 mL was added and the mixture was warmed to 40 ° C and the reaction was stirred for about 3 hours. The reaction solution was cooled in an ice water bath, and 2.52 g of sodium triacetoxyborohydride was added in three portions. The reaction solution was returned to room temperature, and the progress of the reaction was confirmed after 30 minutes. Again, the reaction solution was cooled in an ice-water bath, 87 mL of toluene and 29 mL of water were added, and the aqueous layer was discarded. The organic layer was washed successively with 49 mL, 69 mL, and 30 mL of 1N sodium hydroxide aqueous solution, and then washed with 29 mL, 14 mL, and further 14 mL of water. The solvent was distilled off to obtain 4.80 g of a crude product of the title compound.
'H-NMR (400MHz, CDC1 ) δ (ppm) :1.47(s, 6H), 2.10— 2.20 (m, 4H  'H-NMR (400MHz, CDC1) δ (ppm): 1.47 (s, 6H), 2.10— 2.20 (m, 4H
3  Three
), 2.25-2.40 (m, 2H), 2.50— 2.60 (m, 2H), 2.69 (s, 2H), 2.85— 2.9 5(m, 2H), 3.20-3.35 (m, 2H), 3.90 (s, 3H), 3.96 (s, 3H), 4.30—4. 45 (m, 1H), 6.50— 6.60 (m, 1H), 6.59(d, J = 8.8Hz, 1H), 7.42(d, J = 3. 1Hz, 1H), 7.64(d, J = 8.4Hz, 1H), 7.79(dd, J = 8.40, 1.50Hz, 1H) , 7.80(d, J = 8.8Hz, 1H), 8.16(s, 1H) .  ), 2.25-2.40 (m, 2H), 2.50— 2.60 (m, 2H), 2.69 (s, 2H), 2.85— 2.9 5 (m, 2H), 3.20-3.35 (m, 2H), 3.90 (s, 3H), 3.96 (s, 3H), 4.30—4. 45 (m, 1H), 6.50— 6.60 (m, 1H), 6.59 (d, J = 8.8Hz, 1H), 7.42 (d, J = 3. 1Hz, 1H), 7.64 (d, J = 8.4Hz, 1H), 7.79 (dd, J = 8.40, 1.50Hz, 1H), 7.80 (d, J = 8.8Hz, 1H), 8.16 (s, 1H).
実施例 13 Example 13
1一 ー「2—（7 メトキシ 2.2 ジメチルー 4 ォキソクロマンー8 ィル）ェチル Ίピぺリジン 4ーィル } 1H—インドール 6 カルボン酸の合成  1 1 “2- (7-methoxy 2.2 dimethyl-4-oxochroman-8yl) ethyl チ ル piperidine 4-yl} 1H-indole 6 Synthesis of carboxylic acid
[化 91]
Figure imgf000065_0001
[Chemical 91]
Figure imgf000065_0001
1— {1— [2— (7—メトキシ一 2, 2 ジメチルー 4—ォキソクロマン一 8—ィル）ェチ ル]ピぺリジンー4ーィル } 1H—インドールー 6—力ルボン酸メチルの前記粗体 3. 5gをテトラヒドロフラン 28. OmLに溶解し、 1N水酸化ナトリウム水溶液 14mLをカロえ た。メタノール 14mLを加え、 40°Cに加熱し 30分攪拌した。テトラヒドロフラン 7mLお よびメタノール 3.5mLを追加し、 2時間攪拌し、さら〖こ、同温度で約 16時間攪拌した 。反応液を氷水浴で冷却し、 1N塩酸 12.2mLおよび 1N—水酸ィ匕ナトリウム 0.5m Lをカ卩えて pH7に調整したところ、結晶が析出した。さらにこのスラリーに水 10mLを 加え、結晶を濾取し、結晶は 2 プロパノールと水の混合液（5:1) 21mLで洗浄した 。結晶を減圧乾燥し、標記化合物 2.45gを得た。 1— {1— [2— (7-methoxy-1,2,2 dimethyl-4-oxochroman-1-8-yl) ethyl] piperidine-4-yl} 1H-indole 6-the crude product of methyl rubonate 3 5 g was dissolved in 28. OmL of tetrahydrofuran, and 14 mL of 1N aqueous sodium hydroxide solution was added. 14 mL of methanol was added, heated to 40 ° C. and stirred for 30 minutes. Tetrahydrofuran (7 mL) and methanol (3.5 mL) were added, and the mixture was stirred for 2 hours, further stirred at the same temperature for about 16 hours. The reaction mixture was cooled in an ice-water bath, and 12.2 mL of 1N hydrochloric acid and 0.5 mL of 1N-sodium hydroxide were added and adjusted to pH 7. As a result, crystals were precipitated. Further, 10 mL of water was added to the slurry, and the crystals were collected by filtration. The crystals were washed with 21 mL of a mixture of 2 propanol and water (5: 1). The crystals were dried under reduced pressure to obtain 2.45 g of the title compound.
'H-NMR (400MHz, DMSO-d ) δ (ppm) :1.39 (s, 6H), 1.90— 2.10 (m  'H-NMR (400MHz, DMSO-d) δ (ppm): 1.39 (s, 6H), 1.90— 2.10 (m
6  6
, 4H), 2.20-2.35 (m, 2H), 2.40— 2.50 (m, 2H), 2.70 (s, 2H), 2.70 -2.80 (m, 2H), 3.05— 3. 15(m, 2H), 3.85(s, 3H), 4.40—4.55 (m, 1 H), 6.53(dJ = 3.4Hz, 1H), 6.73(d, J = 8.8Hz, 1H), 7.57(d, J = 8.0Hz , 1H), 7.61(dd, J = 8.0, 1.2Hz, 1H), 7.63(d, J = 8.8Hz, 1H), 7.72 (d , J = 3.4Hz, 1H), 8. 15 (s, 1H) .  , 4H), 2.20-2.35 (m, 2H), 2.40— 2.50 (m, 2H), 2.70 (s, 2H), 2.70 -2.80 (m, 2H), 3.05— 3.15 (m, 2H), 3.85 (s, 3H), 4.40-4.55 (m, 1 H), 6.53 (dJ = 3.4Hz, 1H), 6.73 (d, J = 8.8Hz, 1H), 7.57 (d, J = 8.0Hz, 1H), 7.61 (dd, J = 8.0, 1.2Hz, 1H), 7.63 (d, J = 8.8Hz, 1H), 7.72 (d, J = 3.4Hz, 1H), 8.15 (s, 1H).
実施例 14 Example 14
l— il—「2—(7 メトキシー 2.2 ジメチルー 4 ォキソクロマンー8 ィル）ェチル Ίピぺリジン 4ーィル } 1H インドールー 6 力ルボン酸メチルの合成 l— il— “2— (7 Methoxy-2.2 dimethyl-4-oxochroman-8-yl) ethyl Ίpiperidine 4-yl} 1H indole--6 synthesis of forceful methyl rubonate
[化 92] [Chemical 92]
Figure imgf000066_0001
Figure imgf000066_0001
1 -ピぺリジン 4 ィル— 1H インドール 6 カルボン酸メチル 2. 80gおよび（ 7—メトキシ一 2, 2 ジメチルー 4—ォキソクロマン一 8—ィル）ァセトアルデヒド 3. 16 gに DME28mL、テトラヒドロフラン 14mLおよび酢酸 1. 24mLをカ卩えた。結晶が析 出したが、反応液をそのまま 1時間攪拌した。反応液を氷水浴で冷却し、反応液にト リアセトキシ水素化ホウ素ナトリウム 2. 75gを 3回に分けて加えた。反応液を室温に戻 し、テトラヒドロフラン 3mLを追加し、約 1. 5時間後に、反応の進行を確認した。再度 、反応液を氷水浴で冷却し、トルエン 68mLおよび水 29mLをカ卩え、清澄濾過後、ト ルェン 30mLをカ卩え、水層を廃棄した。有機層は、 1N水酸ィ匕ナトリウム水溶液 29mL 、 5%食塩水 29mL X 2及び水 29mLで洗浄した。溶媒を留去し、標題化合物の粗 体 5. 62gを得た。  1-piperidine 4-yl- 1H indole 6 methyl carboxylate 2.80 g and (7-methoxy-1,2,2-dimethyl-4-oxochroman-1-8-yl) acetaldehyde 3.16 g in DME 28 mL, tetrahydrofuran 14 mL and Acetic acid 1. 24 mL was added. Crystals were precipitated, but the reaction solution was stirred as it was for 1 hour. The reaction solution was cooled in an ice-water bath, and 2.75 g of sodium triacetoxyborohydride was added to the reaction solution in three portions. The reaction solution was returned to room temperature, 3 mL of tetrahydrofuran was added, and after about 1.5 hours, the progress of the reaction was confirmed. The reaction solution was cooled again in an ice-water bath, and 68 mL of toluene and 29 mL of water were collected. After clear filtration, 30 mL of toluene was collected, and the aqueous layer was discarded. The organic layer was washed with 29 mL of 1N sodium hydroxide aqueous solution, 29 mL X 2 of 5% saline and 29 mL of water. The solvent was distilled off to obtain 5.62 g of a crude product of the title compound.
実施例 15 Example 15
l— i l—「2—(7 メトキシー 2. 2 ジメチル 4 ォキソクロマン 8 ィル）ェチル 1ピぺリジン— 4—ィルュ - 1H—インドール 6—カルボン酸の合成 l— i l— “2 -— (7 Methoxy-2.2 dimethyl 4-oxochroman 8 yl) ethyl 1piperidine—4-yl- 1H-indole 6-carboxylic acid synthesis
[化 93]  [Chemical 93]
Figure imgf000066_0002
Figure imgf000066_0002
1— { 1— [2— (7—メトキシ一 2, 2 ジメチルー 4—ォキソクロマン一 8—ィル）ェチ ル]ピぺリジンー4ーィル } 1H—インドールー 6—力ルボン酸メチルの前記粗体 4. Ogをテトラヒドロフラン 40. OmLに溶解し、 1N水酸化ナトリウム水溶液 16mLをカロえ た。メタノール 20mLを加えて反応液の分層を解消し、反応液 40°Cで約 20. 5時間 攪拌した。反応液を氷水浴で冷却し、 1N塩酸 15mLをカ卩えて pH7に調整したところ 、結晶が析出した。さらにこのスラリーに水 10mLをカ卩え、結晶を濾取し、結晶は 2— プロパノール Z水（1Z5、 24mL)で洗浄した。結晶を減圧乾燥し、標記化合物 3. 3 4gを得た。 1— {1— [2— (7-methoxy-1,2,2 dimethyl-4-oxochroman-1-8-yl) ethyl] piperidine-4-yl} 1H-indole 6-forced crude rubonic acid 4 . Og was dissolved in 40. OmL of tetrahydrofuran, and 16 mL of 1N aqueous sodium hydroxide solution was added. 20 mL of methanol was added to remove the layer separation of the reaction solution, and the mixture was stirred at 40 ° C for about 20.5 hours. When the reaction solution was cooled in an ice-water bath and 15 mL of 1N hydrochloric acid was added and the pH was adjusted to 7, crystals were precipitated. Further, 10 mL of water was added to the slurry, the crystals were collected by filtration, and the crystals were washed with 2-propanol Z water (1Z5, 24 mL). The crystals were dried under reduced pressure to obtain 4 g of the title compound 3.3.
[0083] 実施例 16 [0083] Example 16
1一 ー「2—（7 メトキシ 2. 2 ジメチルー 4 ォキソクロマンー8 ィル）ェチル Ίピぺリジン 4ーィル }—N メチルー 1H インドールー 6 カルボキサミドの合成 [化 94]  1-1- “2- (7-methoxy-2,2-dimethyl-4-oxochroman-8-yl) ethyl-piperidine 4-yl} —N Methyl-1H indole-6 Synthesis of carboxamide [Chemical 94]
Figure imgf000067_0001
Figure imgf000067_0001
1— { 1— [2— (7—メトキシ一 2, 2 ジメチルー 4—ォキソクロマン一 8—ィル）ェチ ル]ピぺリジン— 4—ィル } 1Η—インドール— 6—カルボン酸 1. Ogをエタノール 25 mLに溶解し、 1, Γ—カルボ-ルジイミダゾール 851mgをカ卩えた後、反応液を 40°C で 2時間攪拌した。反応液を氷水浴で冷却し、反応液に 40%メチルァミン水溶液 1. 81mLをカ卩え、 50分攪拌した。反応液に酢酸ェチル 40mLおよび水 20mLを力卩ぇ有 機層を分取した。有機層に 10%食塩水 20mLをカ卩え、 1N塩酸水 8. 5mLをカ卩え、 p H7として水層を廃棄し、有機層は水 10mLで洗浄した。有機層を減圧濃縮後、 1— プロパノール 3mLをカ卩えて再濃縮して、標記化合物を得た。 1— {1— [2— (7-methoxy-1,2,2 dimethyl-4-oxochroman-1-8-yl) ethyl] piperidine-4-yl} 1Η-indole- 6-carboxylic acid 1. Og Was dissolved in 25 mL of ethanol, and 851 mg of 1, Γ-carbodiimidazole was added thereto, and then the reaction solution was stirred at 40 ° C. for 2 hours. The reaction solution was cooled in an ice-water bath, and 1.81 mL of 40% methylamine aqueous solution was added to the reaction solution and stirred for 50 minutes. The organic layer was separated into 40 mL of ethyl acetate and 20 mL of water. To the organic layer, 20 mL of 10% saline was added, 8.5 mL of 1N hydrochloric acid was added, the aqueous layer was discarded as pH 7 and the organic layer was washed with 10 mL of water. After concentrating the organic layer under reduced pressure, 3 mL of 1-propanol was added and reconcentrated to obtain the title compound.
[0084] 実施例 6の化合物は、以下の参考例によっても製造することができる。 [0084] The compound of Example 6 can also be produced by the following reference examples.
参考例 1  Reference example 1
2. 6 ジァセトキシトルエンの合成 [化 95] 2.6 Synthesis of diacetoxytoluene [Chemical 95]
Figure imgf000068_0001
氷水浴上で撹拌している 2, 6 ジヒドロキシトルエン 6. 2g (50mmol)および炭酸 カリウム 27. 6g (200mmol)のァセトニトリル 62mL懸濁液へ、無水酢酸 15. OmL (l 6. 3g、 160mmol)を 3分間で滴下した。 27分後に撹拌を止め室温下にて一夜放置 し反応液を濾過、濾液にトルエン 1 OOmLおよび水 50mLをカ卩えて分液ロート中で撹 拌'静置した。水層を廃棄し、有機層を水 25mLで二度洗浄したのちに溶媒を留去し 標記化合物 10. 3gを得た。
Figure imgf000068_0001
To a 62 mL suspension of 2,6 dihydroxytoluene 6.2 g (50 mmol) and potassium carbonate 27.6 g (200 mmol) stirred in an ice-water bath, add acetic anhydride 15. OmL (l 6.3 g, 160 mmol). It was dripped in 3 minutes. After 27 minutes, stirring was stopped and the reaction solution was left standing overnight at room temperature. The filtrate was filtered with 1 OO mL of toluene and 50 mL of water, and stirred in a separatory funnel. The aqueous layer was discarded, and the organic layer was washed twice with 25 mL of water, and then the solvent was distilled off to obtain 10.3 g of the title compound.
'H-NMR (400MHz, CDC1 ) δ (ppm) : 2. 00 (s, 3H) , 2. 33 (s, 6H) , 6. 95 (  'H-NMR (400MHz, CDC1) δ (ppm): 2.00 (s, 3H), 2. 33 (s, 6H), 6. 95 (
3  Three
d, J = 8. 1Hz, 2H) , 7. 24 (t, J = 8. 3Hz, 1H) d, J = 8.1 Hz, 2H), 7.24 (t, J = 8.3Hz, 1H)
参考例 2 Reference example 2
2 ァセトキシ 6 ヒドロキシトルエンの合成  Synthesis of 2-acetoxy 6-hydroxytoluene
[化 96] [Chemical 96]
Figure imgf000068_0002
Figure imgf000068_0002
2, 6 ジァセトキシトルエン 8. 22g (39. 5mmol)をエチレングリコールジメチルェ 一テル 82mLに溶解し、水素化ホウ素ナトリウム 14. 9g (395mmol)をカ卩え、 60°Cの 水浴上で 9時間 44分加熱撹拌した。室温下にて一夜放置した反応液を、氷水浴上 で撹拌しているトルエン 100mL、水 lOOmLの混合液に投入し 5分間撹拌後、分液 ロート中へ移動、静置した。分液した水層よりトルエン 50mLで抽出し、合わせた有機 層を水 50mLで二度洗浄したのちに溶媒を留去し標記化合物 5. Olgを得た。 Dissolve 2,6 diacetoxytoluene 8.22 g (39.5 mmol) in 82 mL of ethylene glycol dimethyl ether, add 14.9 g (395 mmol) of sodium borohydride, and place on a 60 ° C water bath. The mixture was stirred for 9 hours and 44 minutes. The reaction solution left overnight at room temperature was put into a mixture of 100 mL of toluene and lOOmL of water stirred on an ice-water bath, stirred for 5 minutes, then moved into a separatory funnel and allowed to stand. Extract 50 mL of toluene from the separated aqueous layer and combine the organic The layer was washed twice with 50 mL of water, and then the solvent was distilled off to obtain 5. Olg of the title compound.
'H-NMR (400MHz, CDC1 ) δ (ppm) :2.04 (s, 3H), 2.34 (s, 3H), 6.63 ( 'H-NMR (400MHz, CDC1) δ (ppm): 2.04 (s, 3H), 2.34 (s, 3H), 6.63 (
3  Three
d, J = 8.8Hz, 1H), 6.65(d, J = 8.3Hz, 1H), 7.05(t, J = 8.3Hz, 1H) . 参考例 3 d, J = 8.8Hz, 1H), 6.65 (d, J = 8.3Hz, 1H), 7.05 (t, J = 8.3Hz, 1H) Reference Example 3
2 ァセトキシ 6 メトキシトルエンの合成  Synthesis of 2-acetoxy-6-methoxytoluene
[化 97] [Chemical 97]
Figure imgf000069_0001
Figure imgf000069_0001
2 ァセトキシ一 6 ヒドロキシトルエン 5. Olg (30. Ommol)のァセトニトリル 50mL 溶液に炭酸カリウム 12.44g(90. Ommol)およびヨウィ匕メチノレ 12.77g(90. Ommo 1)を加え、 90°Cの油浴上で 96分間加熱撹拌した。室温下にて約 3時間放置した反 応液を、氷水浴上で撹拌しているトルエン 100mL、水 lOOmLの混合液に投入し 2 分間撹拌後、分液ロート中へ移動、静置した。水層を分液廃棄し、有機層を 1規定の 水酸ィ匕カリウム水溶液 20mL、ついで水 20mLで三度洗浄した後に溶媒を留去し標 記化合物 4.69gを得た。 2 Acetoxy-6 hydroxytoluene 5. To a solution of Olg (30.Ommol) in 50 mL of acetonitrile, add 12.44 g (90.Ommol) of potassium carbonate and 12.77 g (90. And stirred for 96 minutes. The reaction solution which was allowed to stand at room temperature for about 3 hours was poured into a mixed solution of 100 mL of toluene and 100 mL of water stirred on an ice-water bath, stirred for 2 minutes, then moved into a separating funnel and left to stand. The aqueous layer was separated and discarded, and the organic layer was washed three times with 1 mL of 1N aqueous potassium hydroxide and then with 20 mL of water, and then the solvent was distilled off to obtain 4.69 g of the target compound.
'H-NMR (400MHz, CDC1 ) δ (ppm) :2.03 (s, 3H), 2.32 (s, 3H), 3.84 (  'H-NMR (400MHz, CDC1) δ (ppm): 2.03 (s, 3H), 2.32 (s, 3H), 3.84 (
3  Three
s, 3H), 6.65(d, J = 8. OHz, 1H), 6.74(d, J = 8.1Hz, 1H), 7.16(t, J = 8. 3Hz, 1H). s, 3H), 6.65 (d, J = 8. OHz, 1H), 6.74 (d, J = 8.1Hz, 1H), 7.16 (t, J = 8.3Hz, 1H).
参考例 4 Reference example 4
2 ヒドロキシ 6 メトキシトルエンの合成  Synthesis of 2-hydroxy-6-methoxytoluene
[化 98] [Chemical 98]
Figure imgf000070_0001
Figure imgf000070_0001
2 ァセトキシ一 6—メトキシトルエン 4. 69g (26. Ommol)のエタノール 360mL溶 液に濃硫酸 18. OmLの水 90mL溶液をカ卩え、 120°Cの油浴上で 36分間加熱撹拌し た。室温下にて一夜放置した反応液を分液ロートへ移しトルエン 50mLおよび 20mL で抽出、合わせた有機層を水 30mL、 5%炭酸水素ナトリウム水溶液 30mL、ついで 水 30mLで二度洗浄したのちに溶媒を留去し標記化合物 3. 15gを得た。 2-acetoxy 6-methoxytoluene 4. 69 g (26. Ommol) of ethanol was added to a solution of ethanol (360 mL) with concentrated sulfuric acid (18 OmL) in 90 mL of water, and the mixture was heated and stirred on a 120 ° C oil bath for 36 minutes. The reaction solution left overnight at room temperature is transferred to a separatory funnel, extracted with 50 mL and 20 mL of toluene, and the combined organic layer is washed twice with 30 mL of water, 30 mL of 5% aqueous sodium bicarbonate, and then with 30 mL of water, and then the solvent is added. Distillation gave 3.15 g of the title compound.
'H-NMR (400MHz, CDC1 ) δ (ppm) : 2. 12 (s, 3H) , 3. 82 (s, 3H) , 4. 71 ( 'H-NMR (400MHz, CDC1) δ (ppm): 2.12 (s, 3H), 3.82 (s, 3H), 4.71 (
3  Three
s, 1H) , 6. 45 (d, J = 8. 3Hz, 1H) , 6. 48 (d, J = 8. 8Hz, 1H) , 7. 03 (t, J = 8. 3Hz, 1H) . s, 1H), 6.45 (d, J = 8.3Hz, 1H), 6.48 (d, J = 8.8Hz, 1H), 7.03 (t, J = 8.3Hz, 1H).
参考例 5 Reference Example 5
2- (N, N ジェチルカルバモイルォキシ） 6 メトキシトルエンの合成  Synthesis of 2- (N, N Jetylcarbamoyloxy) 6 methoxytoluene
[化 99] [Chemical 99]
Figure imgf000070_0002
Figure imgf000070_0002
2 ヒドロキシ一 6—メトキシトルエン 3. 15g (22. 8mmol)のァセトニトリル 16mL溶 液に炭酸カリウム 3. 50g (25. lmmol)、ジェチルカルバモイルクロリド 3. 4g (25. 1 mmol)を加え、 100°Cの油浴上で 59分間加熱撹拌した。ジェチルカルバモイルク口 リド 0. 6g (4. 4mmol)を追加しさらに 38分間加熱した反応液へ、氷水浴上で撹拌し ながらトルエン 30mLおよび水 30mLを投入し 20分間撹拌後、分液ロート中へ移動、 静置した。水層を分液廃棄し、有機層を 2規定水酸化カリウム水溶液 10mL、ついで 水 10mLで二度洗浄したのちに溶媒を留去し標記化合物の粗体 5. 58gを得た。固 化したので一部を種晶として得た。 2 Hydroxy mono 6-methoxytoluene 3.15 g (22.8 mmol) of acetonitrile, 3.5 mL of potassium carbonate and 3.4 g (25.1 mmol) of jetylcarbamoyl chloride were added to 100 ° The mixture was heated and stirred on a C oil bath for 59 minutes. Add 0.6 g (4.4 mmol) of Jetylcarbamoyl chloride and heat to the reaction mixture for another 38 minutes, add 30 mL of toluene and 30 mL of water while stirring on an ice-water bath, stir for 20 minutes, and then in a separatory funnel. Moved to stand still. The aqueous layer was discarded, and the organic layer was washed twice with 10 mL of 2N aqueous potassium hydroxide solution and then with 10 mL of water, and then the solvent was evaporated to obtain 5.58 g of the crude title compound. Solid As a result, a part was obtained as a seed crystal.
標記化合物の粗体 5. 58gをエタノール 14. 5mLおよび水 8. 9mL中 50°Cの水浴 上で加熱撹拌溶解し、室温下で自然冷却を開始した。溶液の温度が 35°Cとなったと きに種晶を投入し、析出開始を確認して水浴および氷水浴で冷却した。氷水浴上で 約 1時間撹拌し結晶化液温が 2. 2°Cのときに結晶を濾取し 50%含水エタノール 8m Lで洗浄した。結晶を減圧乾燥 (30°C、 90分)し、標記化合物 3. 89gを得た。  The crude product of the title compound (5.58 g) was dissolved in 14.5 mL of ethanol and 8.9 mL of water with stirring in a water bath at 50 ° C., and natural cooling was started at room temperature. When the temperature of the solution reached 35 ° C, seed crystals were added, and after confirming the start of precipitation, the solution was cooled in a water bath and an ice water bath. The mixture was stirred for about 1 hour on an ice-water bath, and when the temperature of the crystallization liquid was 2.2 ° C, the crystals were collected by filtration and washed with 8 mL of 50% aqueous ethanol. The crystals were dried under reduced pressure (30 ° C, 90 minutes) to obtain 3.89 g of the title compound.
'H-NMR (400MHz, CDC1 ) δ (ppm) : 1. 24 (m, 6H) , 2. 05 (s, 3H) , 3. 43 'H-NMR (400MHz, CDC1) δ (ppm): 1. 24 (m, 6H), 2. 05 (s, 3H), 3. 43
3  Three
(m, 4H) , 3. 85 (s, 3H) , 6. 71 (d, J = 8. 3Hz, 1H) , 6. 71 (d, J = 8. 1Hz, 1H ) , 7. 13 (t, J = 8. 3Hz, 1H) .  (m, 4H), 3. 85 (s, 3H), 6. 71 (d, J = 8. 3Hz, 1H), 6. 71 (d, J = 8.1 Hz, 1H), 7. 13 (t , J = 8.3Hz, 1H).
参考例 6 Reference Example 6
N. N—ジェチルー（2—ヒドロキシー6—メトキシフエニル）ァセトアミドの合成  Synthesis of N.N-Jetylu (2-hydroxy-6-methoxyphenyl) acetamide
[化 100] [Chemical 100]
Figure imgf000071_0001
リチウム ジイソプロピルアミド 5. 0mL(2MZテトラヒドロフラン'ェチルベンゼン、 1 Ommol)をドライアイス—エタノール冷媒上で撹拌冷却し、 2— (N, N—ジェチルカ ルバモイルォキシ）一 6—メトキシトルエン 0. 95g (4. Ommol)のテトラヒドロフラン 8. OmL溶液を 16分間で滴下した。 1分後に室温下で加温を開始し、 47分間撹拌後に 一夜静置した。トルエン 10mLと水 10mLをカ卩ぇ 4分間撹拌後、分液ロート中へ移動 、静置した。水層を分液採取し有機層より 2規定水酸ィ匕カリウム水溶液にて二回 (各 5 . OmL)抽出した水層とあわせた。この水層をトルエン 1 OmLで洗浄したのちにトルェ ン 10mLを投入し撹拌下に 2規定塩酸水溶液 20mLをカ卩ぇ分液ロート中へ移動、静 置した。有機層を分液採取し水層よりトルエン 5mLにて抽出した有機層とあわせた。 この有機層を水 5mLで二回洗浄、減圧濃縮することで標記化合物 0. 81gを得た。 'H-NMR (400MHz, CDC1 ) δ (ppm) : 1. 29 (m, 6H) , 3. 49 (m, 4H) , 3. 8
Figure imgf000071_0001
Lithium diisopropylamide 5.0 mL (2MZ tetrahydrofuran'ethylbenzene, 1 Ommol) was stirred and cooled on a dry ice-ethanol refrigerant, and 2- (N, N-jetylcarbamoyloxy) 6-methoxytoluene 0.95 g (4.Ommol) Of tetrahydrofuran in OmL was added dropwise over 16 minutes. One minute later, heating was started at room temperature, and after stirring for 47 minutes, the mixture was allowed to stand overnight. 10 mL of toluene and 10 mL of water were stirred for 4 minutes, then moved to a separatory funnel and allowed to stand. The aqueous layer was separated and combined with the aqueous layer extracted twice from the organic layer with a 2N aqueous solution of potassium hydroxide (5 OmL each). The aqueous layer was washed with 1 OmL of toluene, and then 10 mL of toluene was added. Under stirring, 20 mL of 2N hydrochloric acid aqueous solution was moved into the caulking separatory funnel and allowed to stand. The organic layer was separated and combined with the organic layer extracted from the aqueous layer with 5 mL of toluene. This organic layer was washed twice with 5 mL of water and concentrated under reduced pressure to obtain 0.81 g of the title compound. 'H-NMR (400MHz, CDC1) δ (ppm): 1. 29 (m, 6H), 3. 49 (m, 4H), 3. 8
3  Three
0 (s, 2H) , 3. 82 (s, 3H) , 6. 43 (d, J = 8. 3Hz, 1H) , 6. 64 (d, J = 8. 3Hz, 1H ), 7. ll(t, J = 8.3Hz, 1H). 0 (s, 2H), 3.82 (s, 3H), 6. 43 (d, J = 8. 3Hz, 1H), 6. 64 (d, J = 8.3Hz, 1H ), 7.ll (t, J = 8.3Hz, 1H).
[0090] 参考例 7 [0090] Reference Example 7
4 メトキシ 3H ベンゾフラン一 2 -オンの合成  Synthesis of 4-methoxy 3H benzofuran 1-one
[化 101]  [Chemical 101]
Figure imgf000072_0001
Figure imgf000072_0001
N, N—ジェチル—（2 ヒドロキシ— 6—メトキシフエ-ル）ァセトアミド 0.47g(2.0 mmol)のトルエン 5. OmL溶液にトリフルォロ酢酸 0.92mL(l.36g、 12mmol)を 加え、 125°Cの油浴上で 71分間加熱撹拌した。室温下で冷却後、撹拌しながら 0.5 規定の水酸ィ匕ナトリウム水溶液 24mLをカ卩え、分液ロート中へ移動、静置した。水層 を分液廃棄し、有機層を水 5mLで二度洗浄したのちに溶媒を留去し標記化合物 0. 27gを得た。 N, N-Jetyl- (2hydroxy-6-methoxyphenyl) acetamide 0.47 g (2.0 mmol) in toluene 5. Add 0.92 mL (l.36 g, 12 mmol) trifluoroacetic acid to an OmL solution, and add 125 ° C oil bath The mixture was heated and stirred for 71 minutes. After cooling at room temperature, 24 mL of 0.5N sodium hydroxide aqueous solution was added with stirring and moved into a separatory funnel and allowed to stand. The aqueous layer was discarded, and the organic layer was washed twice with 5 mL of water, and then the solvent was distilled off to obtain 0.27 g of the title compound.
'H-NMR (400MHz, CDC1 ) δ (ppm) :3.66 (s, 2H), 3.86 (s, 3H), 6.67 (  'H-NMR (400MHz, CDC1) δ (ppm): 3.66 (s, 2H), 3.86 (s, 3H), 6.67 (
3  Three
d, J = 8.3Hz, 1H), 6.75(d, J = 8. OHz, 1H), 7.26(t, J = 8.3Hz, 1H) .  d, J = 8.3Hz, 1H), 6.75 (d, J = 8. OHz, 1H), 7.26 (t, J = 8.3Hz, 1H).
[0091] 参考例 8 [0091] Reference Example 8
2—（2 ヒドロキシ 6 メトキシフエニル)エタノールの合成  Synthesis of 2- (2-hydroxy-6-methoxyphenyl) ethanol
[化 102]  [Chemical 102]
Figure imgf000072_0002
Figure imgf000072_0002
4—メトキシ一 3H ベンゾフラン一 2—オン 10.76g(65.5mmol)のエチレングリ コールジメチルエーテル 150mL溶液に水素化ホウ素ナトリウム 7.18g(189mmol) をカロえ撹拌し、氷水浴上で冷却しながら濃硫酸 5.25mL(9.66g, 94.5mmol)の エチレングリコールジメチルエーテル 2 lmL溶液を 30分間で滴下した。この混合液を 50°Cの水浴上で 49分間加熱撹拌した後に氷水浴上で撹拌しながらメタノール 32m L(25.3g、 790mmol)を 6分間で滴下した。この混合液を 50°Cの水浴上で 53分間 加熱撹拌し室温下に一夜放置後、酢酸イソプロピル 300mLおよび水 200mLを投入 し 5分間撹拌、分液ロート中へ移動、静置した。水層を分液廃棄し、有機層を水 100 mLで二度洗浄したのちに溶媒を留去した。残渣カも酢酸ェチル—へキサンで結晶 化し、得られた結晶を 30°Cで減圧乾燥して標記化合物 3. 12gを得た。 4-Methoxy-1-3H benzofuran-2-one 10.76 g (65.5 mmol) in ethylene glycol dimethyl ether 150 mL solution 7.18 g (189 mmol) sodium borohydride The solution was stirred and cooled, while cooling on an ice-water bath, a solution of concentrated sulfuric acid 5.25 mL (9.66 g, 94.5 mmol) in 2 mL of ethylene glycol dimethyl ether was added dropwise over 30 minutes. This mixture was heated and stirred on a 50 ° C. water bath for 49 minutes, and then methanol (32 mL, 25.3 g, 790 mmol) was added dropwise over 6 minutes while stirring on an ice-water bath. The mixture was heated and stirred for 53 minutes in a 50 ° C water bath and allowed to stand overnight at room temperature. Then, 300 mL of isopropyl acetate and 200 mL of water were added, stirred for 5 minutes, moved into a separatory funnel, and left to stand. The aqueous layer was discarded, and the organic layer was washed twice with 100 mL of water, and then the solvent was distilled off. The residue was also crystallized with ethyl acetate-hexane, and the resulting crystals were dried under reduced pressure at 30 ° C. to obtain 3.12 g of the title compound.
'H-NMR (400MHz, CDC1 ) δ (ppm) :2.98(t, J = 5.1Hz, 2H), 3.79 (s, 3 'H-NMR (400MHz, CDC1) δ (ppm): 2.98 (t, J = 5.1Hz, 2H), 3.79 (s, 3
3  Three
H), 3.93(t, J = 5. 1Hz, 2H), 6.48(d, J = 8.1Hz, 1H), 6.59(d, J = 8. OH z, 1H), 7.09(t, J = 8.0Hz, 1H) .  H), 3.93 (t, J = 5.1 Hz, 2H), 6.48 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 8. OH z, 1H), 7.09 (t, J = 8.0 Hz , 1H).
参考例 9 Reference Example 9
酢酸 2- (2-ヒドロキシ 6 メトキシフエニル)ェチルの合成 Synthesis of 2- (2-hydroxy-6-methoxyphenyl) ethyl acetate
[化 103]  [Chemical 103]
Figure imgf000073_0001
Figure imgf000073_0001
2— (2 ヒドロキシ一 6—メトキシフエ-ル)エタノール 0.27g(l.6mmol)の酢酸 5 . OmL溶液へ、氷水浴上で冷却しながら濃硫酸 1. OmL(l.8g、 18mmol)を滴下し た。この混合液を室温下で 5分間撹拌し、エタノール 6. OmL (4.7g、 102mmol)を 滴下した。この混合液にトルエン 20mLおよび水 20mLを投入し 5分間撹拌後、分液 ロート中へ移動、静置した。水層を分液廃棄し、有機層を水 10mLで二度洗浄したの ちに溶媒を留去して標記化合物 0.16gを得た。 Concentrated sulfuric acid 1. OmL (l.8 g, 18 mmol) was added dropwise to a solution of 0.27 g (l.6 mmol) of 2- (2-hydroxy-6-methoxyphenol) ethanol in 5.OmL of acetic acid while cooling on an ice-water bath. It was. The mixture was stirred at room temperature for 5 minutes and ethanol 6. OmL (4.7 g, 102 mmol) was added dropwise. To this mixed solution, 20 mL of toluene and 20 mL of water were added and stirred for 5 minutes. The aqueous layer was discarded, and the organic layer was washed twice with 10 mL of water, and then the solvent was distilled off to obtain 0.16 g of the title compound.
'H-NMR (400MHz, CDC1 ) δ (ppm) :2.09 (s, 3H), 3.02(t, J = 7.1Hz, 2  'H-NMR (400MHz, CDC1) δ (ppm): 2.09 (s, 3H), 3.02 (t, J = 7.1Hz, 2
3  Three
H), 3.81 (s, 3H), 4.21 (t, J=7.1Hz, 2H), 6.48(d, J = 8.3Hz, 1H), 6. 53(d, J = 7.8Hz, 1H), 7.10(t, J = 8.3Hz, 1H) . [0093] 参考例 10 H), 3.81 (s, 3H), 4.21 (t, J = 7.1Hz, 2H), 6.48 (d, J = 8.3Hz, 1H), 6.53 (d, J = 7.8Hz, 1H), 7.10 ( t, J = 8.3Hz, 1H). [0093] Reference Example 10
8- (2 ァセトキシェチル） 7 メトキシ一 2.2 ジメチルクロマン一 4—オンの合 成  8- (2 Acetoxychetyl) 7 Methoxy-1-2.2 Dimethylchroman 4-Synthesis
[化 104]  [Chemical 104]
Figure imgf000074_0001
酢酸 2— (2 ヒドロキシ一 6—メトキシフエ-ル)ェチル 5.79g(27.5mmol)、2— メチルクロトン酸 3.03g(30.3mmol)および五酸化二リン 3.26g(16.9mmol)のメ タンスルホン酸 29. OmL溶液を 70°Cで 75分間加熱撹拌した。室温下でトルエン 50 mLおよび水 50mLを投入し 5分間撹拌、分液ロート中へ移動、静置した。水層を分 液廃棄し、有機層を 5%炭酸水素ナトリウム水溶液 25mL水 25mLで順次洗浄したの ちに、溶媒を留去して標記化合物粗体 7.85gを得た。これをシリカゲルクロマトダラ フィにて精製し (展開液組成： 10%酢酸ェチル—へキサン (体積比）、 Rf値: 0.4)、 標記化合物 2.96gを得た。
Figure imgf000074_0001
2- (2-hydroxy-6-methoxyphenyl) ethyl acetate 5.79 g (27.5 mmol), 2-methylcrotonic acid 3.03 g (30.3 mmol) and diphosphorus pentoxide 3.26 g (16.9 mmol) methanesulfonic acid 29. The OmL solution was heated and stirred at 70 ° C for 75 minutes. Toluene 50 mL and water 50 mL were added at room temperature, stirred for 5 minutes, moved into a separatory funnel, and left to stand. The aqueous layer was separated and discarded, and the organic layer was washed sequentially with 5% aqueous sodium hydrogen carbonate solution 25 mL water 25 mL, and then the solvent was distilled off to obtain 7.85 g of the title compound crude product. This was purified by silica gel chromatography (developing solution composition: 10% ethyl acetate-hexane (volume ratio), Rf value: 0.4) to obtain 2.96 g of the title compound.
'H-NMR (400MHz, CDC1 ) δ (ppm) :1.46 (s, 6H), 2.04 (s, 3H), 2.67(  'H-NMR (400MHz, CDC1) δ (ppm): 1.46 (s, 6H), 2.04 (s, 3H), 2.67 (
3  Three
s, 2H), 2.99(t, J = 7.3Hz, 2H), 3.88 (s, 3H), 4.18(t, J = 7.3Hz, 2H), 6.58(d, J = 9. OHz, 1H), 7.82(d, J = 8.8Hz, 1H) .  s, 2H), 2.99 (t, J = 7.3Hz, 2H), 3.88 (s, 3H), 4.18 (t, J = 7.3Hz, 2H), 6.58 (d, J = 9. OHz, 1H), 7.82 (d, J = 8.8Hz, 1H).
[0094] 参考例 11  [0094] Reference Example 11
8—（2 ヒドロキシェチル）ー7 メトキシ 2.2 ジメチルクロマンー4 オンの合成 [化 105] 8— (2 Hydroxyethyl) -7 methoxy 2.2 Synthesis of dimethylchroman-4-one [Chemical Formula 105]
Figure imgf000075_0001
Figure imgf000075_0001
8— (2—ァセトキシェチル）一 7—メトキシ一 2, 2—ジメチルクロマン一 4—オン 2. 8 Og (9. 58mmol)のエタノール 18. OmL溶液に室温撹拌下、濃硫酸 1. 80mL (3. 3 lg, 32. 4mmol)の水 9. OmL溶液を投入し、 100°Cの油浴上で 43分間加熱撹拌し た。室温下で冷却後、トルエン 90mLおよび水 18mLを投入すると白色の結晶が析 出したためこれを濾取 (結晶 1)し、さらに濾液を氷冷して析出した結晶を濾取 (結晶 2 )した。ここで得た濾液を分液ロート中へ移動'静置した。水層を分液廃棄し、有機層 を 1規定の水酸ィ匕カリウム水溶液 40mL、さらに水 20mLで二度洗浄したのちに、溶 媒を留去して得た濃縮物に DME2mLおよび水 5mLを加えて析出させた結晶を濾 取した (結晶 3)。結晶 1〜3を合わせて水 10mLで洗浄し、 40°Cで 1時間減圧乾燥す ることで標記化合物 2. 44gを得た。 8- (2-acetoxetyl) -1-7-methoxy-1,2-dimethylchroman-1-4-2.8 Og (9.58 mmol) in ethanol 18. Concentrated sulfuric acid 1.80 mL (3. 3 lg, 32.4 mmol) of water 9. OmL solution was added, and the mixture was heated and stirred in a 100 ° C oil bath for 43 minutes. After cooling at room temperature and adding 90 mL of toluene and 18 mL of water, white crystals were precipitated, which were collected by filtration (Crystal 1), and the filtrate was ice-cooled and the precipitated crystals were collected by filtration (Crystal 2). The filtrate obtained here was moved into a separating funnel and allowed to stand. The aqueous layer is separated and discarded, and the organic layer is washed twice with 40 mL of 1N potassium hydroxide aqueous solution and then with 20 mL of water, and then 2 mL of DME and 5 mL of water are added to the concentrate obtained by distilling off the solvent. In addition, the precipitated crystals were collected by filtration (Crystal 3). The crystals 1 to 3 were combined, washed with 10 mL of water, and dried under reduced pressure at 40 ° C. for 1 hour to obtain 2.44 g of the title compound.
'H-NMR (400MHz, CDC1 ) δ (ppm) : 1. 45 (s, 6H) , 2. 68 (s, 2H) , 2. 96 (  'H-NMR (400MHz, CDC1) δ (ppm): 1. 45 (s, 6H), 2. 68 (s, 2H), 2. 96 (
3  Three
t, J = 6. 8Hz, 2H) , 3. 77 (t, J = 6. 8Hz, 2H) , 3. 89 (s, 3H) , 6. 59 (d, J = 9. OHz, 1H) , 7. 81 (d, J = 8. 8Hz, 1H). t, J = 6.8Hz, 2H), 3.77 (t, J = 6.8Hz, 2H), 3.89 (s, 3H), 6.59 (d, J = 9. OHz, 1H), 7.81 (d, J = 8.8Hz, 1H).
産業上の利用可能性 Industrial applicability
本発明により、 1— { 1— [2— (7—メトキシ一 2, 2—ジメチルー 4—ォキソクロマン一 8—ィル）ェチル]ピぺリジンー4ーィル }—N—メチルー 1H—インドールー 6—カル ボキサミドを工業的に製造することが可能となった。  According to the present invention, 1— {1— [2— (7-methoxy-1,2,2-dimethyl-4-oxochroman-8-yl) ethyl] piperidine-4-yl} -N-methyl-1H-indole-6-carboxamide Can be produced industrially.

Claims

請求の範囲  The scope of the claims
T 己式 (a— 6)
Figure imgf000076_0001
で表される 8— (2 ヒドロキシェチル） 7—メトキシ一 2, 2 ジメチルクロマン一 4— オンを酸ィ匕することにより得られる下記式 (a) T self formula (a— 6)
Figure imgf000076_0001
The following formula (a) obtained by acidifying 8- (2 hydroxyethyl) 7-methoxy-1,2,2 dimethylchroman-4-one represented by the following formula (a)
[化 2][Chemical 2]
Figure imgf000076_0002
で表される（7—メトキシ 2, 2 ジメチルー 4 ォキソクロマンー8 ィル）ァセトアル デヒドと下記式 (b)
Figure imgf000076_0002
(7-methoxy 2,2 dimethyl-4-oxochroman-8 yl) acetoaldehyde represented by the following formula (b)
[化 3] [Chemical 3]
Figure imgf000077_0001
で表される N—メチルー 1—(ピペリジンー4 ィル） 1H—インドールー 6 力ルポ キサミドとをカップリングすることを含む、
Figure imgf000077_0001
Coupling with N-methyl-1- (piperidine-4-yl) 1H-indole-6-power lupoxamide represented by
下記式 (i) The following formula (i)
[化 4] [Chemical 4]
Figure imgf000077_0002
Figure imgf000077_0002
で表される 1— { 1— [2— (7—メトキシ一 2, 2 ジメチルー 4—ォキソクロマン一 8—ィ ル）ェチル]ピぺリジン 4 ィル } N メチル 1 H インドール 6 カルボキサ ミドの製造方法。 1— {1— [2— (7-Methoxy-1,2,2 dimethyl-4-oxochroman-1-ethyl) piperidine 4-yl} N methyl 1 H indole 6 Carboxamide .
下己式 (a— 6)  Lower self expression (a— 6)
[化 5] [Chemical 5]
Figure imgf000078_0001
で表される 8— (2 ヒドロキシェチル） 7—メトキシ一 2, 2 ジメチルクロマン一 4— オンは、下記式（a— 5)
Figure imgf000078_0001
8- (2 hydroxyethyl) 7-methoxy-1,2,2 dimethylchroman 4-one represented by the following formula (a-5)
[化 6][Chemical 6]
Figure imgf000078_0002
Figure imgf000078_0002
で表される化合物 [式中、 Xは水酸基の保護基を示す。 ]の保護基を除去することに より得られる、請求項 1記載の製造方法。 [Wherein, X represents a protecting group for a hydroxyl group. The production method according to claim 1, which is obtained by removing the protecting group of
下己式 (a— 6)  Lower self expression (a— 6)
[化 7]
Figure imgf000079_0001
で表される 8— (2 ヒドロキシェチル） 7—メトキシ一 2, 2 ジメチルクロマン一 4- オンは、下記式（a— 4) [Chemical 7]
Figure imgf000079_0001
8— (2 Hydroxyethyl) 7-methoxy-1,2,2 dimethylchroman-4-one represented by the following formula (a-4)
[化 8] [Chemical 8]
Figure imgf000079_0002
で表される化合物 [式中、 Xは水酸基の保護基を示す。 ]とメチルクロトン酸とを反応さ せて、下記式（a— 5)
Figure imgf000079_0002
[Wherein, X represents a protecting group for a hydroxyl group. ] And methylcrotonic acid are reacted to give the following formula (a-5)
[化 9] [Chemical 9]
Figure imgf000080_0001
で表される化合物 [式中、 Xは前記定義と同義である。 ]を得、次いで、該化合物（a - 5)の保護基を除去することにより得られる、請求項 1または 2記載の製造方法。
Figure imgf000080_0001
[Wherein, X is as defined above.] And then removing the protecting group of the compound (a-5).
[4] 下己式 (a— 6)  [4] Lower self expression (a— 6)
[化 10]  [Chemical 10]
Figure imgf000080_0002
で表される 8— (2 ヒドロキシェチル） 7—メトキシ一 2, 2 ジメチルクロマン一 4— オンは、下記式（a— 3)
Figure imgf000080_0002
8- (2 Hydroxyethyl) 7-methoxy-1,2,2-dimethylchroman-4-one represented by the following formula (a-3)
[化 11] [Chemical 11]
Figure imgf000081_0001
で表される化合物 [式中、 Xは水酸基の保護基を示す。 ]と酸とを反応させて、下記式 (a - 4)
Figure imgf000081_0001
[Wherein, X represents a protecting group for a hydroxyl group. ] And an acid, the following formula (a-4)
[化 12] [Chemical 12]
Figure imgf000081_0002
で表される化合物 [式中、 Xは前記定義と同義である。 ]を得、該化合物 (a ルクロトン酸とを反応させて、下記式 (a— 5)
Figure imgf000081_0002
[Wherein, X is as defined above.] The compound (a is reacted with lucrotonic acid to give the following formula (a-5)
[化 13] [Chemical 13]
Figure imgf000081_0003
で表される化合物 [式中、 Xは前記定義と同義である。 ]を得、次いで、該化合物（a -
Figure imgf000081_0003
[Wherein, X is as defined above.] And then the compound (a −
5)の保護基を除去することにより得られる、請求項 1から 3のいずれか 1項記載の製 造方法。 4. The production method according to any one of claims 1 to 3, obtained by removing the protecting group of 5).
[5] 己式 (a oノ  [5] Self formula (a o no
[化 14]  [Chemical 14]
Figure imgf000082_0001
で表される 8— (2 ヒドロキシェチル） 7—メトキシ一 2, 2 ジメチルクロマン一 4- オンは、下記式（a— 2)
Figure imgf000082_0001
8— (2 Hydroxyethyl) 7-methoxy-1,2,2 dimethylchroman-1-one represented by the following formula (a-2)
[化 15]  [Chemical 15]
Figure imgf000082_0002
で表される 2— [2—（1 エトキシエトキシ） 6—メトキシフエ-ル]エタノールの水酸 基を保護して、下記式 (a— 3)
Figure imgf000082_0002
Protect the hydroxyl group of 2- [2- (1 ethoxyethoxy) 6-methoxyphenyl] ethanol represented by the following formula (a-3)
[化 16] [Chemical 16]
Figure imgf000083_0001
Figure imgf000083_0001
Figure imgf000083_0002
で表される化合物 [式中、 Xは前記定義と同義である。 ]を得、該化合物 (a ルクロトン酸とを反応させて、下記式 (a— 5)
Figure imgf000083_0002
[Wherein, X is as defined above.] The compound (a is reacted with lucrotonic acid to give the following formula (a-5)
[化 18] [Chemical 18]
Figure imgf000083_0003
で表される化合物 [式中、 Xは前記定義と同義である。 ]を得、次いで、該化合物 (a- 5)の保護基を除去することにより得られる、請求項 1から 4のいずれか 1項記載の製 造方法。
Figure imgf000083_0003
[Wherein, X is as defined above.] The production method according to any one of claims 1 to 4, which is obtained by removing the protecting group of the compound (a-5).
下己式 (a— 6)  Lower self expression (a— 6)
[化 19][Chemical 19]
Figure imgf000084_0001
Figure imgf000084_0001
で表される 8— (2—ヒドロキシェチル）一7—メトキシー 2, 2—ジメチルクロマン一 4一 オンは、下記式（a— 1) 8— (2-Hydroxyethyl) -1-7-methoxy-2,2-dimethylchroman-one represented by the following formula (a-1)
[化 20]
Figure imgf000084_0002
で表される [2—（1一エトキシエトキシ）一 6—メトキシフエ-ル]酢酸ェチルを還元し て、下記式 (a— 2) [化 21][Chemical 20]
Figure imgf000084_0002
[2- (1 ethoxyethoxy) 1 6-methoxyphenyl] ethyl acetate represented by the following formula (a-2) [Chemical 21]
Figure imgf000085_0001
Figure imgf000085_0001
で表される 2— [2— (1—エトキシエトキシ） 6—メトキシフエ-ル]エタノールを得、該 化合物の水酸基を保護して、下記式 (a— 3) 2- [2— (1-ethoxyethoxy) 6-methoxyphenol] ethanol represented by the following formula (a-3) is obtained by protecting the hydroxyl group of the compound:
[化 22][Chemical 22]
Figure imgf000085_0002
で表される化合物 [式中、 Xは水酸基の保護基を示す。 ]を得、該化合物 (a とを反応させて、下記式 (a— 4)
Figure imgf000085_0002
[Wherein, X represents a protecting group for a hydroxyl group. And reacting the compound (a with the following formula (a-4)
[化 23][Chemical 23]
Figure imgf000085_0003
で表される化合物 [式中、 Xは前記定義と同義である。 ]を得、該化合物 (a ルクロトン酸とを反応させて、下記式 (a— 5)
Figure imgf000085_0003
[Wherein, X is as defined above.] The compound (a is reacted with lucrotonic acid to give the following formula (a-5)
[化 24]  [Chemical 24]
Figure imgf000086_0001
で表される化合物 [式中、 Xは前記定義と同義である。 ]を得、次いで、該化合物（a - 5)の保護基を除去することにより得られる、請求項 1から 5のいずれか 1項記載の製 造方法。
Figure imgf000086_0001
[Wherein, X is as defined above.] And then removing the protecting group of the compound (a-5). 6. The production method according to claim 1, wherein the protecting group is removed.
[7] 下己式 (a— 6)  [7] Lower self expression (a-6)
[化 25]  [Chemical 25]
Figure imgf000086_0002
で表される 8— (2 ヒドロキシェチル） 7—メトキシ一 2, 2 ジメチルクロマン一 4— オンは、下記式
Figure imgf000086_0002
8- (2 Hydroxyethyl) 7-methoxy-1,2,2 dimethylchroman 4-one represented by the formula
[化 26]
Figure imgf000087_0001
[Chemical 26]
Figure imgf000087_0001
メトキシベンゼンとブロモ酢酸ェチルとを
Figure imgf000087_0002
Methoxybenzene and bromoethyl acetate
Figure imgf000087_0002
で表される [2—（1 エトキシエトキシ） 6—メトキシフエ-ル]酢酸ェチルを得、該 化合物（a— 1)を還元して、下記式 (a— 2) [2- (1 ethoxyethoxy) 6-methoxyphenyl] ethyl acetate is obtained, and the compound (a-1) is reduced to give the following formula (a-2)
[化 28][Chemical 28]
Figure imgf000087_0003
で表される 2— [2— (1—エトキシエトキシ） 6—メトキシフエ-ル]エタノールを得、該 化合物 (a— 2)の水酸基を保護して、下記式 (a— 3)
Figure imgf000087_0003
2- [2— (1-Ethoxyethoxy) 6-methoxyphenol] ethanol represented by the following formula (a-3) is obtained by protecting the hydroxyl group of the compound (a-2):
[化 29]
Figure imgf000088_0001
で表される化合物 [式中、 Xは水酸基の保護基を示す。 ]を得、該化合物 (a とを反応させて、下記式 (a— 4) [Chemical 29]
Figure imgf000088_0001
[Wherein, X represents a protecting group for a hydroxyl group. And reacting the compound (a with the following formula (a-4)
[化 30][Chemical 30]
Figure imgf000088_0002
Figure imgf000088_0002
で表される化合物 [式中、 Xは前記定義と同義である。 ]を得、該化合物 (a ルクロトン酸とを反応させて、下記式 (a— 5) [Wherein, X is as defined above.] The compound (a is reacted with lucrotonic acid to give the following formula (a-5)
[化 31]
Figure imgf000089_0001
で表される化合物 [式中、 Xは前記定義と同義である。 ]を得、次いで、該化合物（a— 5)の保護基を除去することにより得られる、請求項 1から 6のいずれか 1項記載の製 造方法。 [Chemical 31]
Figure imgf000089_0001
[Wherein, X is as defined above.] And then removing the protective group of the compound (a-5). 7. The production method according to claim 1, wherein the protecting group is removed.
[8] Xがベンゾィル基である、請求項 2から 7のいずれか 1項記載の製造方法。  [8] The production method according to any one of claims 2 to 7, wherein X is a benzoyl group.
[9] 下記式 (Π)  [9] The following formula (Π)
[化 32]  [Chemical 32]
Figure imgf000089_0002
Figure imgf000089_0002
で表される化合物 [式中、 X1は水素原子または水酸基の保護基を示す。 ]。 [Wherein, X 1 represents a hydrogen atom or a hydroxyl-protecting group. ].
[10] 水酸基の保護基がベンゾィル基である、請求項 9記載の化合物。 [10] The compound according to claim 9, wherein the hydroxyl-protecting group is a benzoyl group.
[11] 安息香酸 2—（7—メトキシ 2, 2 ジメチルー 4 ォキソクロマンー8 ィル）ェチ ルまたは 8— (2—ヒドロキシェチル） 7—メトキシ一 2, 2—ジメチルクロマン一 4—ォ ン。 [12] 下記式 (c一 3) [11] Benzoic acid 2- (7-methoxy-2,2-dimethyl-4-oxochroman-8-yl) ethyl or 8-(2-hydroxyethyl) 7-methoxy-1,2-2-dimethylchroman-4-one. [12] The following formula (c 1 3)
[化 33]  [Chemical 33]
Figure imgf000090_0001
で表される化合物とメチルァミンとを反応させることを含む、下記式 (i)
Figure imgf000090_0001
Wherein the compound represented by formula (i) is reacted with methylamine:
[化 34]  [Chemical 34]
Figure imgf000090_0002
ーメトキシー2， 2—ジメチノレー 4一ォキソクロマン一 8—ィ ィル }— N—メチル一 1H—インドール一 6—カルボキサ
Figure imgf000090_0002
-Methoxy-2,2-dimethinole 4-1-oxochroman 1-yl} — N-methyl 1 1H-indole 1 6-carboxa
[13] [13]
Figure imgf000090_0003
で表される化合物は、下記式 (c 2) [化 36]
Figure imgf000090_0003
The compound represented by the following formula (c 2) [Chemical Formula 36]
Figure imgf000091_0001
Figure imgf000091_0001
Figure imgf000091_0002
Figure imgf000091_0002
で表される化合物と、下記式 (c 1) [化 39] And a compound represented by the following formula (c 1) [Chemical 39]
Figure imgf000092_0001
で表される化合物またはその塩とを反応させて、下記式 (c 2)
Figure imgf000092_0001
And a compound represented by the following formula (c 2)
[化 40]  [Chemical 40]
Figure imgf000092_0002
で表される化合物を得、次いで、該化合物を加水分解することにより得られる、請求 項 12記載の製造方法。
Figure imgf000092_0002
13. The production method according to claim 12, wherein the compound is obtained by obtaining the compound represented by: and then hydrolyzing the compound.
[15] 下記式 (c 3)  [15] The following formula (c 3)
[化 41]  [Chemical 41]
Figure imgf000092_0003
で表される化合物は、下記式 (a)
Figure imgf000092_0003
The compound represented by the following formula (a)
Figure imgf000093_0001
で表される化合物 [式中、 Yは 2級ァミンの保護基を示す。 ]の保護基を除去して得ら れる下記式 (c 1)
Figure imgf000093_0001
[Wherein Y represents a protecting group for secondary amine. The following formula (c 1) obtained by removing the protecting group
[化 44] [Chemical 44]
Figure imgf000094_0001
Figure imgf000094_0001
Figure imgf000094_0002
で表される化合物を得、次いで、該化合物（c 2)を加水分解することにより得られる 、請求項 12記載の製造方法。
Figure imgf000094_0002
13. The production method according to claim 12, wherein the compound is obtained by obtaining the compound represented by: and then hydrolyzing the compound (c2).
Yがべンジルォキシカルボニルである、請求項 15記載の製造方法。  16. The production method according to claim 15, wherein Y is benzyloxycarbonyl.
PCT/JP2006/309461 2005-05-11 2006-05-11 Method for producing indole derivative having piperidine ring WO2006121106A1 (en)

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AU2006244916A AU2006244916B2 (en) 2005-05-11 2006-05-11 Method for producing indole derivative having piperidine ring
CN2006800155608A CN101171249B (en) 2005-05-11 2006-05-11 Method for producing indole derivative having piperidine ring
CA2607907A CA2607907C (en) 2005-05-11 2006-05-11 Method for producing indole derivative having piperidine ring
US11/914,115 US8110688B2 (en) 2005-05-11 2006-11-05 Method for producing indole derivative having piperidine ring
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US11/126,209 2005-05-11
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