JP2017039721A - Method for producing hydrobenz isoquinoline compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel method for producing a hydrobenz isoquinoline compound.SOLUTION: A method for producing a hydrobenz isoquinoline compound represented by formula (7) includes subjecting an amine compound represented by formula (4) to carbamate reaction and cyclization reaction (where X is a chlorine atom, a bromine atom and others, Ris a phenyl group and others, Ris an isopropyl group, an ethyl group and others).SELECTED DRAWING: None

Description

  The present invention relates to a process for producing a hydrobenzisoquinolinone compound and an intermediate.

  The hydrobenzisoquinolinone compound (compound (1)) represented by the formula (1) is useful as a therapeutic agent for digestive symptom associated with administration of an antineoplastic agent (see Non-Patent Document 1).

  As a production method of the compound (1), for example, there is a method in which diphosgene or triphosgene is allowed to act on the compound represented by the formula (2) (compound (2)) and then cyclized using boron trifluoride. It has been reported (see Patent Documents 1 and 2). However, the yield is moderate, and the boron trifluoride used requires special equipment because it reacts with water to generate hydrogen fluoride and corrodes many materials used as manufacturing equipment. There is a problem. Therefore, an industrially suitable new manufacturing method has been desired.

Chinese Patent Publication No. 101186607 Chinese Patent Publication No. 102329314

Journal of Medicinal Chemistry, 1993, 36, 2645-2657

  The present invention provides a novel process for producing compound (1). Furthermore, the present invention provides a novel production intermediate obtained by the method.

As a result of intensive studies in view of the above circumstances, the inventors of the present invention obtained a quaternary ammonium chloride of compound (2).
(1) Carbamate reaction proceeds well without using a highly toxic reagent such as diphosgene or triphosgene, for example, using a highly safe reagent such as chloroformate, and
(2) In the presence of phosphorus oxychloride, the cyclization reaction with diphosphorus pentoxide proceeds with high reaction selectivity, and a hydrobenzisoquinolinone compound can be obtained in a high yield, thereby completing the present invention.

（式中Ｘは、ハロゲン原子、Ｃ_１−６アルキルスルホニルオキシ基、Ｃ_１−６ハロアルキルスルホニルオキシ基又は置換基を有していてもよいＣ_６−１４アリールスルホニルオキシ基を表し、Ｒ^１は、水素原子、Ｃ_１−６アルキル基、Ｃ_３−６シクロアルキル基、置換基を有していてもよいＣ_６−１４アリール基又は置換基を有していてもよい５−１０員複素環基を表し、Ｒ^２は、Ｃ_１−６アルキル基を表す。）
〔２〕
化合物（６）が、以下の（ｂ）の工程で得られることを特徴とする、〔１〕に記載のヒドロベンズイソキノリノン化合物の製造方法：
（ｂ）
アミン化合物（４）にクロロギ酸エステル（５）を反応させて、カーバメート化合物（６）を得る工程。

（式中Ｘは、ハロゲン原子、Ｃ_１−６アルキルスルホニルオキシ基、Ｃ_１−６ハロアルキルスルホニルオキシ基又は置換基を有していてもよいＣ_６−１４アリールスルホニルオキシ基を表し、Ｒ^１は、水素原子、Ｃ_１−６アルキル基、Ｃ_３−６シクロアルキル基、置換基を有していてもよいＣ_６−１４アリール基又は置換基を有していてもよい５−１０員複素環基を表し、Ｒ^２は、Ｃ_１−６アルキル基を表す。）
〔３〕
化合物（４）が、以下の（ａ）の工程で得られることを特徴とする、〔２〕に記載のヒドロベンズイソキノリノン化合物の製造方法：
（ａ）
化合物（２）にアルキル化剤（３）を反応させて、アミン化合物（４）を得る工程。

（式中Ｘは、ハロゲン原子、Ｃ_１−６アルキルスルホニルオキシ基、Ｃ_１−６ハロアルキルスルホニルオキシ基又は置換基を有していてもよいＣ_６−１４アリールスルホニルオキシ基を表し、Ｒ^１は、水素原子、Ｃ_１−６アルキル基、Ｃ_３−６シクロアルキル基、置換基を有していてもよいＣ_６−１４アリール基又は置換基を有していてもよい５−１０員複素環基を表す。）
〔４〕
Ｘが塩素原子又は臭素原子であり、Ｒ^１が置換基を有していてもよいフェニル基である、〔１〕乃至〔３〕の何れかに記載のヒドロベンズイソキノリノン化合物の製造方法。
〔５〕
Ｘが塩素原子であり、Ｒ^１がフェニル基である、〔４〕に記載のヒドロベンズイソキノリノン化合物の製造方法。
〔６〕
Ｒ^２がＣ_１−３アルキル基である、〔１〕乃至〔５〕の何れかに記載のヒドロベンズイソキノリノン化合物の製造方法。
〔７〕
Ｒがイソプロピル基である、〔６〕に記載のヒドロベンズイソキノリノン化合物の製造方法。
〔８〕
式（４）

（式中Ｘは、ハロゲン原子、Ｃ_１−６アルキルスルホニルオキシ基、Ｃ_１−６ハロアルキルスルホニルオキシ基又は置換基を有していてもよいＣ_６−１４アリールスルホニルオキシ基を表し、Ｒ^１は、水素原子、Ｃ_１−６アルキル基、Ｃ_３−６シクロアルキル基、置換基を有していてもよいＣ_６−１４アリール基又は置換基を有していてもよい５−１０員複素環基を表す。）で表されるアミン化合物。
〔９〕
Ｘが塩素原子又は臭素原子であり、Ｒ^１が置換基を有していてもよいフェニル基である、〔８〕に記載のアミン化合物。
〔１０〕
Ｘが塩素原子であり、Ｒ^１がフェニル基である、〔９〕に記載のアミン化合物。
〔１１〕
式（６）

（式中Ｘは、ハロゲン原子、Ｃ_１−６アルキルスルホニルオキシ基、Ｃ_１−６ハロアルキルスルホニルオキシ基又は置換基を有していてもよいＣ_６−１４アリールスルホニルオキシ基を表し、Ｒ^１は、水素原子、Ｃ_１−６アルキル基、Ｃ_３−６シクロアルキル基、置換基を有していてもよいＣ_６−１４アリール基又は置換基を有していてもよい５−１０員複素環基を表し、Ｒ^２は、Ｃ_１−６アルキル基を表す。）で表されるカーバメート化合物。
〔１２〕
Ｘが塩素原子又は臭素原子であり、Ｒ^１が置換基を有していてもよいフェニル基である、〔１１〕に記載の化合物。
〔１３〕
Ｘが塩素原子であり、Ｒ^１がフェニル基である、〔１２〕に記載のカーバメート化合物。
〔１４〕
Ｒ^２がＣ_１−３アルキル基である、〔１１〕乃至〔１３〕の何れかに記載のカーバメート化合物。
〔１５〕
Ｒ^２がイソプロピル基である、〔１４〕に記載のカーバメート化合物。
〔１６〕
式（７）

（式中Ｘは、ハロゲン原子、Ｃ_１−６アルキルスルホニルオキシ基、Ｃ_１−６ハロアルキルスルホニルオキシ基又は置換基を有していてもよいＣ_６−１４アリールスルホニルオキシ基を表し、Ｒ^１は、水素原子、Ｃ_１−６アルキル基、Ｃ_３−６シクロアルキル基、置換基を有していてもよいＣ_６−１４アリール基又は置換基を有していてもよい５−１０員複素環基を表す。）で表されるヒドロベンズイソキノリノン化合物。
〔１７〕
Ｘが塩素原子又は臭素原子であり、Ｒ^１が置換基を有していてもよいフェニル基である、〔１６〕に記載のヒドロベンズイソキノリノン化合物。
〔１８〕
Ｘが塩素原子であり、Ｒ^１がフェニル基である、〔１７〕に記載のヒドロベンズイソキノリノン化合物。 That is, the present invention relates to the following [1] to [18].
[1]
A process for producing a hydrobenzisoquinolinone compound represented by the formula (7), wherein the carbamate compound (6) is reacted with diphosphorus pentoxide in the presence of phosphorus oxychloride.

(In the formula, X represents a halogen atom, a C _1-6 alkylsulfonyloxy group, a C _1-6 haloalkylsulfonyloxy group, or a C _6-14 arylsulfonyloxy group which may have a substituent, and R ¹ represents , A hydrogen atom, a C _1-6 alkyl group, a C _3-6 cycloalkyl group, an _optionally substituted C _6-14 aryl group, or an _optionally substituted 5-10 membered heterocyclic ring And R ² represents a C _1-6 alkyl group.)
[2]
The method for producing a hydrobenzisoquinolinone compound according to [1], wherein the compound (6) is obtained in the following step (b):
(B)
A step of reacting the amine compound (4) with the chloroformate (5) to obtain the carbamate compound (6).

(In the formula, X represents a halogen atom, a C _1-6 alkylsulfonyloxy group, a C _1-6 haloalkylsulfonyloxy group, or a C _6-14 arylsulfonyloxy group which may have a substituent, and R ¹ represents , A hydrogen atom, a C _1-6 alkyl group, a C _3-6 cycloalkyl group, an _optionally substituted C _6-14 aryl group, or an _optionally substituted 5-10 membered heterocyclic ring And R ² represents a C _1-6 alkyl group.)
[3]
The method for producing a hydrobenzisoquinolinone compound according to [2], wherein the compound (4) is obtained in the following step (a):
(A)
A step of reacting compound (2) with alkylating agent (3) to obtain amine compound (4).

(In the formula, X represents a halogen atom, a C _1-6 alkylsulfonyloxy group, a C _1-6 haloalkylsulfonyloxy group, or a C _6-14 arylsulfonyloxy group which may have a substituent, and R ¹ represents , A hydrogen atom, a C _1-6 alkyl group, a C _3-6 cycloalkyl group, an _optionally substituted C _6-14 aryl group, or an _optionally substituted 5-10 membered heterocyclic ring Represents a group.)
[4]
The method for producing a hydrobenzisoquinolinone compound according to any one of [1] to [3], wherein X is a chlorine atom or a bromine atom, and R ¹ is a phenyl group which may have a substituent.
[5]
The method for producing a hydrobenzisoquinolinone compound according to [4], wherein X is a chlorine atom and R ¹ is a phenyl group.
[6]
The method for producing a hydrobenzisoquinolinone compound according to any one of [1] to [5], wherein R ² is a C _1-3 alkyl group.
[7]
The method for producing a hydrobenzisoquinolinone compound according to [6], wherein R is an isopropyl group.
[8]
Formula (4)

(In the formula, X represents a halogen atom, a C _1-6 alkylsulfonyloxy group, a C _1-6 haloalkylsulfonyloxy group, or a C _6-14 arylsulfonyloxy group which may have a substituent, and R ¹ represents , A hydrogen atom, a C _1-6 alkyl group, a C _3-6 cycloalkyl group, an _optionally substituted C _6-14 aryl group, or an _optionally substituted 5-10 membered heterocyclic ring An amine compound represented by:
[9]
The amine compound according to [8], wherein X is a chlorine atom or a bromine atom, and R ¹ is a phenyl group which may have a substituent.
[10]
The amine compound according to [9], wherein X is a chlorine atom and R ¹ is a phenyl group.
[11]
Formula (6)

(In the formula, X represents a halogen atom, a C _1-6 alkylsulfonyloxy group, a C _1-6 haloalkylsulfonyloxy group, or a C _6-14 arylsulfonyloxy group which may have a substituent, and R ¹ represents , A hydrogen atom, a C _1-6 alkyl group, a C _3-6 cycloalkyl group, an _optionally substituted C _6-14 aryl group, or an _optionally substituted 5-10 membered heterocyclic ring A carbamate compound represented by: R ² represents a C _1-6 alkyl group.
[12]
The compound according to [11], wherein X is a chlorine atom or a bromine atom, and R ¹ is a phenyl group which may have a substituent.
[13]
The carbamate compound according to [12], wherein X is a chlorine atom and R ¹ is a phenyl group.
[14]
The carbamate compound according to any one of [11] to [13], wherein R ² is a C _1-3 alkyl group.
[15]
The carbamate compound according to [14], wherein R ² is an isopropyl group.
[16]
Formula (7)

(In the formula, X represents a halogen atom, a C _1-6 alkylsulfonyloxy group, a C _1-6 haloalkylsulfonyloxy group, or a C _6-14 arylsulfonyloxy group which may have a substituent, and R ¹ represents , A hydrogen atom, a C _1-6 alkyl group, a C _3-6 cycloalkyl group, an _optionally substituted C _6-14 aryl group, or an _optionally substituted 5-10 membered heterocyclic ring A hydrobenzisoquinolinone compound represented by:
[17]
The hydrobenzisoquinolinone compound according to [16], wherein X is a chlorine atom or a bromine atom, and R ¹ is a phenyl group which may have a substituent.
[18]
The hydrobenzisoquinolinone compound according to [17], wherein X is a chlorine atom and R ¹ is a phenyl group.

  INDUSTRIAL APPLICABILITY According to the present invention, a novel industrially suitable production method capable of obtaining a compound (1) useful as a pharmaceutical in high yield could be provided.

Hereinafter, the present invention will be described in more detail.
In the present invention, "n-" is normal, "i-" is iso, "s-" and "sec-" are secondary, "t-" and "tert-" are tertiary, and "o-" is ortho. , “M-” is meta, “p-” is para, “Ph” is phenyl, “Bu” is butyl, [Boc ”is tertiary butoxycarbonyl,“ Z ”is benzyloxycarbonyl,“ Ts ”is p- Toluenesulfonyl, “Bn” means benzyl.

  First, terms used for describing the chemical structure in the present specification will be described.

  “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The “C _1-6 alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples thereof include a methyl group, an ethyl group, an n-propyl group, and isopropyl. Group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group and n-hexyl group.

“C _1-3 alkyl group” means a methyl group, an ethyl group, an n-propyl group or an isopropyl group.

The “C _3-6 cycloalkyl group” means a cyclic alkyl group having 3 to 6 carbon atoms, and specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

The “C _1-6 alkoxy group” means an oxy group substituted by the aforementioned C _1-6 alkyl group. Specific examples thereof include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n- Examples thereof include a butoxy group, an isobutoxy group, and a t-butoxy group.

The “C _1-6 haloalkyl group” is 1 selected independently or differently from a substituent group consisting of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom at an arbitrary position of the aforementioned C _1-6 alkyl group. It means a substituent in which more than one halogen atom is substituted.

The “C _6-14 aryl group” means an aromatic hydrocarbon group having 6 to 14 carbon atoms, and specific examples thereof include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a 1-anthracenyl group, Examples include 2-anthracenyl group, 9-anthracenyl group, and biphenyl group.

  The 5- to 10-membered heterocyclic group has 5 to 10 atoms constituting the ring, and one atom selected from the group consisting of a nitrogen atom, an oxygen atom or a sulfur atom in the atoms constituting the ring Or a heterocyclic group of a monocyclic or condensed ring system containing the same or different 2 to 4 heteroatoms. The heterocyclic group may be saturated, partially unsaturated, or unsaturated, and specific examples thereof include pyrrolidinyl group, tetrahydrofuryl group, tetrahydrothienyl group, piperidyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group. , Pyrrole group, furyl group, thienyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, azepanyl group, oxepanyl group, thiepanyl group, azepinyl group, oxepinyl group, thiepinyl group, imidazolyl group, pyrazolyl group, oxazolyl group, thiazolyl group, imidazolinyl group Group, pyrazinyl group, morpholinyl group, thiazinyl group, indolyl group, isoindolyl group, benzimidazolyl group, purinyl group, quinolyl group, isoquinolyl group, quinoxalinyl group, cinnolinyl group, pteridinyl group, chromenyl group, isochromenyl group And the like.

The term “which may have a substituent” means that it is unsubstituted or substituted with any number of arbitrary substituents.
Examples of the “arbitrary substituent” are not particularly limited as long as the substituent does not adversely affect the reaction targeted by the present invention. Specific examples of the optional substituent include a halogen atom, a cyano group, a nitro group, a C _1-6 alkyl group, a C _3-6 cycloalkyl group, and a C _1-6 alkoxy group.

The “C _1-6 alkylsulfonyloxy group” means a sulfonyloxy group substituted by the aforementioned C _1-6 alkyl group, and specific examples thereof include a methanesulfonyloxy group.

The “C _1-6 haloalkylsulfonyloxy group” means a sulfonyloxy group substituted by the aforementioned C _1-6 haloalkyl group, and specific examples thereof include a trifluoromethanesulfonyloxy group.

The “C _6-14 arylsulfonyloxy group” means a sulfonyloxy group substituted by the above-mentioned C _6-14 aryl group which may have a substituent, and specific examples thereof include p-toluenesulfonyloxy. Group, p-nitrobenzenesulfonyloxy group.

  In the figure, “+” surrounded by a circle means a cation, and “−” surrounded by a circle means an anion.

In the present specification, the compound represented by the general formula (A) is abbreviated as the compound (A).
The production method of the compound (1) of the present invention is shown in the following scheme.

（式中Ｘは、ハロゲン原子、Ｃ_１−６アルキルスルホニルオキシ基、Ｃ_１−６ハロアルキルスルホニルオキシ基又は置換基を有していてもよいＣ_６−１４アリールスルホニルオキシ基を表し、Ｒ^１は、水素原子、Ｃ_１−６アルキル基、Ｃ_３−６シクロアルキル基、置換基を有していてもよいＣ_６−１４アリール基又は置換基を有していてもよい５−１０員複素環基を表し、Ｒ^２は、Ｃ_１−６アルキル基を表す。）

(In the formula, X represents a halogen atom, a C _1-6 alkylsulfonyloxy group, a C _1-6 haloalkylsulfonyloxy group, or a C _6-14 arylsulfonyloxy group which may have a substituent, and R ¹ represents , A hydrogen atom, a C _1-6 alkyl group, a C _3-6 cycloalkyl group, an _optionally substituted C _6-14 aryl group, or an _optionally substituted 5-10 membered heterocyclic ring And R ² represents a C _1-6 alkyl group.)

  The solvent used in the present invention is not limited as long as it does not inhibit the progress of the reaction, but preferred examples include aprotic polar organic solvents (for example, N, N-dimethylformamide, dimethyl sulfoxide, N, N-dimethyl). Acetamide, tetramethylurea, sulfolane, N-methylpyrrolidone, N, N-dimethylimidazolidinone, etc.), ether solvents (eg, diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, etc.), aliphatic carbonization Hydrogen solvents (eg pentane, n-hexane, c-hexane, octane, decane, decalin, petroleum ether, etc.), aromatic hydrocarbon solvents (benzene, chlorobenzene, o-dichlorobenzene, nitrobenzene, toluene, xylene, mesitylene, etc. Tetralin ), Halogenated hydrocarbon solvents (eg, chloroform, dichloromethane, dichloroethane, carbon tetrachloride, etc.), lower aliphatic acid ester solvents (eg, methyl acetate, ethyl acetate, butyl acetate, methyl propionate, etc.), alkoxyalkane solvents (For example, dimethoxyethane, diethoxyethane, etc.) and alcohol solvents (for example, methanol, ethanol, 1-propanol, 2-propanol, etc.) are mentioned. A particularly preferable solvent in each step will be described later.

  As the solvent to be used, one kind of solvent may be used alone, or two or more kinds of mixtures may be used.

The compound (2) used in the present invention can be synthesized by the method described in Fushiro Kako, 2010, Vol. 39, pages 14-16, using the hydronaphthalene quinuclidineamide compound (8) as a starting material. The hydronaphthalene quinuclidinamide compound (8) is available as a commercial product, or can be synthesized by a method well known to those skilled in the art.

  A seed crystal can be used for crystallization in each step. The seed crystal can be obtained by a method well known to those skilled in the art, such as rubbing the wall of a container containing the target solution with a spatula.

Step (a):
Compound (4) can be synthesized by reacting compound (2) with alkylating agent (3). The alkylating agent (3) is commercially available or can be synthesized by methods well known to those skilled in the art.

  0.5-3.0 molar equivalent is preferable with respect to 1 molar equivalent of compound (2), and, as for the usage-amount of an alkylating agent, 0.7-1.5 molar equivalent is more preferable, and 1.0-1. Two molar equivalents are more preferred.

  The type of alkylating agent that can be used in this reaction is not limited as long as it does not affect the reaction. Examples thereof include methyl bromide, methyl iodide, ethyl bromide, n-propyl chloride, n-butyl chloride, Benzyl chloride, benzyl bromide, p-chlorobenzyl chloride, p-bromobenzyl chloride, p-methoxybenzyl chloride, methyl p-toluenesulfonate, benzyl methanesulfonate, benzyl p-toluenesulfonate, benzyl trifluoromethanesulfonate, etc. And preferably benzyl chloride or benzyl bromide, more preferably benzyl chloride.

  The solvent used in this reaction is more preferably an aromatic hydrocarbon solvent, and more preferably toluene.

  The reaction temperature is preferably 30 to 100 ° C, more preferably 80 to 90 ° C.

Step (b):
Compound (6) can be synthesized by reacting compound (4) with a chloroformate. The chloroformate is available commercially or can be synthesized by methods well known to those skilled in the art.

  0.5-5.0 molar equivalent is preferable with respect to 1 molar equivalent of compound (4), and, as for the usage-amount of chloroformic acid ester, 0.7-3.0 molar equivalent is more preferable, and 1.0-2. More preferred is 0 molar equivalent.

  The type of chloroformate that can be used in this reaction is not limited as long as it does not affect the reaction. Examples thereof include methyl chloroformate, ethyl chloroformate, n-propyl chloroformate, isopropyl chloroformate, and n-chloroformate. Butyl etc. are mentioned, Preferably it is isopropyl chloroformate.

  This reaction is preferably performed in the presence of a base from the viewpoint of reaction efficiency. The amount of the base used is preferably 0.5 to 5.0 molar equivalents, more preferably 0.7 to 3.0 molar equivalents, and 1.0 to 2.0 molar relative to 1 molar equivalent of the compound (4). The equivalent is more preferable.

The type of base that can be used in this reaction is not limited as long as it does not affect the reaction. Examples thereof include hydroxides (for example, sodium hydroxide and potassium hydroxide), hydrogen carbonates (for example, sodium hydrogen carbonate, Potassium carbonate), carbonates (eg, sodium carbonate, potassium carbonate), amines (eg, tertiary amines such as triethylamine, aromatic amines such as pyridine), etc., preferably amines, more preferably Is tri (C _1-6 alkyl) amine, more preferably diisopropylethylamine.

  The solvent used in this reaction is more preferably a halogenated hydrocarbon solvent, and even more preferably chloroform.

  30-100 degreeC is preferable and, as for reaction temperature, 40-60 degreeC is more preferable.

Step (c):
Compound (7) can be produced by reacting compound (6) with diphosphorus pentoxide in the presence of phosphorus oxychloride.

  The amount of phosphorus oxychloride used is preferably 10 to 30 molar equivalents, more preferably 10 to 20 molar equivalents, and even more preferably 10 to 15 molar equivalents relative to 1 molar equivalent of compound (6).

  1.0-5.0 molar equivalent is preferable with respect to 1 molar equivalent of a compound (6), and, as for the usage-amount of diphosphorus pentoxide, 1.0-3.0 molar equivalent is more preferable, 1.5-2 More preferred is 5 molar equivalents.

  The solvent used in this reaction is more preferably a halogenated hydrocarbon solvent, and even more preferably chloroform.

  The reaction temperature is preferably 50 to 130 ° C, more preferably 90 to 110 ° C.

Step (d):
The hydrobenzisoquinolinone compound (1) can be synthesized by reacting the compound (7) with hydrogen gas in the presence of hydrochloric acid and palladium carbon.

  1-100 mass% is preferable with respect to the mass of a compound (7), as for the usage-amount of palladium carbon, 1-50 mass% is more preferable, and 10-20 mass% is further more preferable.

  The amount of hydrochloric acid used is preferably 0 to 5 molar equivalents, more preferably 0 to 2 molar equivalents, and even more preferably 0.5 to 1 molar equivalents relative to 1 molar equivalent of the compound (7).

  The hydrogen pressure at the time of carrying out the reaction can be carried out at an arbitrary pressure, but from the viewpoint of contribution to the reaction and adaptability to industrial production, it is preferably in the range of 0.1 to 4.0 MPa, more preferably 0. The range is from 1 to 1.0 MPa.

  The solvent used in this reaction is more preferably an alcohol solvent, and even more preferably methanol.

  10-60 degreeC is preferable and, as for reaction temperature, 20-40 degreeC is more preferable.

Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples.
¹ H-NMR, unless otherwise specified, uses JNM-ECP300; manufactured by JEOL or JNM-ECX300; manufactured by JEOL, with tetramethylsilane as an internal standard at 300 MHz. It was measured. The measurement result represents the chemical shift δ (unit: ppm) (division pattern, integral value) of the signal with tetramethylsilane as an internal standard.

^In the description of ¹ H-NMR data, “s” is a singlet, “d” is a doublet, “t” is a triplet, “q” is a quartet, “quint” is a quintet, “m” is a multiplet, and “br” is Broad, “J” means coupling constant, and “CDCl ₃ ” means deuterated chloroform.

富代化工、２０１０年、３９巻、１４−１６頁に記載の方法に準じて合成した化合物（２）（９．２７ｇ、３４．３ｍｍｏｌ）をトルエン（９５ｇ）に溶解させ、その溶液を８６℃に加温した後、塩化ベンジル（４．９０ｇ、３８．７ｍｍｏｌ）を加え、８６℃で２時間撹拌した。反応混合物を２５℃に冷却し、析出した固体をろ取し、トルエンで洗浄した後乾燥し、化合物（９）（１３．４ｇ、収率９８％）を白色結晶として得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ₃）
δｐｐｍ：１．６８−２．３５（ｍ，９Ｈ），２．７０−２．８６（ｍ，５Ｈ）３．１３−３．２４（ｍ，２Ｈ），３．５３−３．７５（ｍ，３Ｈ），３．９７（ｍ，１Ｈ），４．２１（ｍ，１Ｈ），４．８８（ｄ，Ｊ＝１２．６Ｈｚ，１Ｈ），５．００（ｄ，Ｊ＝１２．６Ｈｚ，１Ｈ），７．０４−７．１３（ｍ，４Ｈ），７．３８−７．４７（ｍ，３Ｈ），７．６１−７．６４（ｍ，２Ｈ） Synthesis Example 1: Synthesis of compound (9)

Compound (2) (9.27 g, 34.3 mmol) synthesized according to the method described in Fumiyo Kako, 2010, Vol. 39, pages 14-16, was dissolved in toluene (95 g), and the solution was dissolved at 86 ° C. After being heated to benzyl chloride (4.90 g, 38.7 mmol) was added and stirred at 86 ° C. for 2 hours. The reaction mixture was cooled to 25 ° C., and the precipitated solid was collected by filtration, washed with toluene, and dried to obtain compound (9) (13.4 g, yield 98%) as white crystals.
¹ H-NMR (CDCl ₃ )
δppm: 1.68-2.35 (m, 9H), 2.70-2.86 (m, 5H) 3.13-3.24 (m, 2H), 3.53-3.75 (m, 3H), 3.97 (m, 1H), 4.21 (m, 1H), 4.88 (d, J = 12.6 Hz, 1H), 5.00 (d, J = 12.6 Hz, 1H) 7.04-7.13 (m, 4H), 7.38-7.47 (m, 3H), 7.61-7.64 (m, 2H)

合成例１で得られた化合物（９）（２．１４ｇ、５．４０ｍｍｏｌ）のクロロホルム（２１．４ｇ）溶液に、ジイソプロピルエチルアミン（１．０５ｇ、８．０９ｍｍｏｌ）を加え、４７℃に加温した後、クロロギ酸イソプロピル（０．９９ｇ、８．０９ｍｍｏｌ）を加え、４５℃で３時間撹拌した。反応混合物を２５℃に冷却し、５質量％炭酸水素ナトリウム水溶液（１３．６ｇ）を加え分液した。得られた有機層に５質量％塩酸（１１．７ｇ）を加えて分液し、さらに５質量％塩化ナトリウム水溶液（６．３１ｇ）を加えて分液した。得られた有機層にセライト（２．１ｇ）を加えて撹拌した後、セライトをろ別した。得られたろ液を濃縮し、クロロホルムを加えて化合物（１０）（７．８５ｇ）をクロロホルム溶液として得た。得られた溶液を７６℃に加温し、オキシ塩化リン（１０．４ｇ）、五酸化二リン（１．５３ｇ、１０．８ｍｍｏｌ）を加え、さらに１０５℃に加温して３時間撹拌した後、反応混合物を室温に冷却した。５０質量％水酸化カリウム水溶液（３５．５ｇ）、イソプロパノール（２．６１ｇ）を混合した溶液に反応混合物を加え、さらにクロロホルム（１３．１ｇ）を加えて、析出した固体を濾別した。得られたろ液を分液し、水層にクロロホルム（１３．１ｇ）を加えて分液し、さらに１０質量％塩化ナトリウム水溶液（７．８３ｇ）を加えて分液した。得られた有機層（有機層Ａと呼ぶ）を濃縮した後、メタノールを加えて化合物（１１）（３８．２ｇ）をメタノール溶液として得た。
この溶液に、１０質量％パラジウム炭素（０．４６ｇ）、３５質量％塩酸（０．５６ｇ、５．４１ｍｍｏｌ）を加え、２４℃にて撹拌し、水素ガスで置換して２時間撹拌した後、窒素置換し、パラジウム炭素を濾別した。得られたろ液を濃縮し、２−ブタノン（２２．９ｇ）を加え、濃縮した。この操作を２回行い、得られた残渣に２−ブタノン（２２．９ｇ）を加えて４５℃に加温して３０分撹拌した。その後、反応溶液を２５℃に冷却して析出した固体を濾過し、２−ブタノンで洗浄した後乾燥し、化合物（１）（１．６９ｇ、収率９４％：３工程）を白色結晶として得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ₃）
δｐｐｍ：１．３１−１．４４（ｍ，１Ｈ），１．７０−２．４０（ｍ，８Ｈ），２．７５−３．１５（ｍ，３Ｈ）３．２５−３．４５（ｍ，４Ｈ），３．６９−３．８５（ｍ，４Ｈ），４．９５（ｍ，１Ｈ），７．２８（ｍ，２Ｈ），７．６７（ｍ，１Ｈ），１２.３（ｂｒ，1Ｈ）， Synthesis Example 2: Synthesis of compound (1)

Diisopropylethylamine (1.05 g, 8.09 mmol) was added to a solution of the compound (9) obtained in Synthesis Example 1 (2.14 g, 5.40 mmol) in chloroform (21.4 g) and heated to 47 ° C. Thereafter, isopropyl chloroformate (0.99 g, 8.09 mmol) was added, and the mixture was stirred at 45 ° C. for 3 hours. The reaction mixture was cooled to 25 ° C., and 5% by mass aqueous sodium hydrogen carbonate solution (13.6 g) was added for liquid separation. To the obtained organic layer, 5% by mass hydrochloric acid (11.7 g) was added for liquid separation, and further 5% by mass aqueous sodium chloride solution (6.31 g) was added for liquid separation. Celite (2.1 g) was added to the resulting organic layer and stirred, and then the celite was filtered off. The obtained filtrate was concentrated and chloroform was added to obtain compound (10) (7.85 g) as a chloroform solution. The obtained solution was heated to 76 ° C., phosphorus oxychloride (10.4 g) and diphosphorus pentoxide (1.53 g, 10.8 mmol) were added, and the mixture was further heated to 105 ° C. and stirred for 3 hours. The reaction mixture was cooled to room temperature. The reaction mixture was added to a solution obtained by mixing a 50 mass% aqueous potassium hydroxide solution (35.5 g) and isopropanol (2.61 g), chloroform (13.1 g) was further added, and the precipitated solid was separated by filtration. The obtained filtrate was separated, chloroform (13.1 g) was added to the aqueous layer for separation, and a 10% by mass aqueous sodium chloride solution (7.83 g) was further added for separation. After concentrating the obtained organic layer (referred to as organic layer A), methanol was added to obtain compound (11) (38.2 g) as a methanol solution.
To this solution, 10% by mass palladium carbon (0.46 g) and 35% by mass hydrochloric acid (0.56 g, 5.41 mmol) were added, stirred at 24 ° C., replaced with hydrogen gas, and stirred for 2 hours. The atmosphere was replaced with nitrogen, and palladium on carbon was filtered off. The obtained filtrate was concentrated, 2-butanone (22.9 g) was added, and the mixture was concentrated. This operation was performed twice, 2-butanone (22.9 g) was added to the resulting residue, the mixture was heated to 45 ° C. and stirred for 30 minutes. Thereafter, the reaction solution was cooled to 25 ° C. and the precipitated solid was filtered, washed with 2-butanone and dried to obtain compound (1) (1.69 g, yield 94%: 3 steps) as white crystals. It was.
¹ H-NMR (CDCl ₃ )
δppm: 1.31-1.44 (m, 1H), 1.70-2.40 (m, 8H), 2.75-3.15 (m, 3H) 3.25-3.45 (m, 4H), 3.69-3.85 (m, 4H), 4.95 (m, 1H), 7.28 (m, 2H), 7.67 (m, 1H), 12.3 (br, 1H) ),

合成例２に準じて、合成例１の方法で得られた化合物（９）（５．９９ｇ、１５．１ｍｍｏｌ）から化合物（１１）まで合成し、分液後の有機層Ａ（１６９ｇ）を得た（合成例２参照）。この有機層の一部（３６．９ｇ）に、室温下、活性炭（０．２１ｇ）を加えて２５分間撹拌し、さらに硫酸マグネシウムを加えて撹拌した。不溶物をろ過し、クロロホルムで洗浄した。得られたろ液を濃縮し、化合物（１１）の濃縮液（１．６８ｇ）を得た。この濃縮液の一部（０．２４１ｇ）に、クロロホルム（５．００ｇ）を加え、さらにリン酸（４８ｍｇ）を溶解した水（１．００ｇ）を加えて分液した。得られた水層にクロロホルム（１．００ｇ）を加えて抽出した。得られた有機層を混合し、５質量％塩酸（０．８０ｇ）を加えて分液した。得られた有機層に５質量％塩化ナトリウム水溶液（０．４０ｇ）を加えて分液した。得られた有機層を濃縮後、クロロホルム（０．６０ｇ）を加えた。この溶液にテトラヒドロフラン（０．２０ｇ）を加え、種晶（参考合成例１で合成した）を添加した。１８分間撹拌後、さらにテトラヒドロフラン（０．４０ｇ）を滴下した。室温で４２分間撹拌後、溶液にトルエン（１．２０ｇ）を滴下し、さらに２５分間撹拌して、０℃まで冷却した。０℃で３０分間撹拌した後、溶液にトルエン（０．８０ｇ）を滴下した。その後０℃で２５分間撹拌し、析出した固体をろ過し、トルエンで洗浄した。得られた固体を５０℃で減圧乾燥して、化合物（１１）（０．１７２ｇ、収率 ８６％）を淡黄色結晶として得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ₃）
δｐｐｍ：１．２８−１．４０（ｍ，１Ｈ），１．７３−２．４１（ｍ，８Ｈ）２．７３−２．９１（ｍ，２Ｈ），３．０６−３．１４（ｍ，１Ｈ），３．２４−３．３２（ｍ，１Ｈ），３．５６−３．７５（ｍ，３Ｈ），３．９７−４．０４（ｍ，１Ｈ），４．１８−４．２３（ｍ，１Ｈ），４．５８−４．６２（ｍ，１Ｈ），４．６７−４．７８（ｍ，１Ｈ），４．８３−４．９１（ｍ，１Ｈ），４．９６−５．０８（ｍ，２Ｈ），７．２５−７．２７（ｍ，２Ｈ），７．４２−７．４７（ｍ，３Ｈ），７．６１−７．６５（ｍ，２Ｈ），７．７８−７．８１（ｍ，１Ｈ） Synthesis Example 3: Synthesis of compound (11)

According to Synthesis Example 2, compound (9) (5.99 g, 15.1 mmol) obtained by the method of Synthesis Example 1 was synthesized from Compound (11) to obtain organic layer A (169 g) after liquid separation. (See Synthesis Example 2). Activated carbon (0.21 g) was added to a part of this organic layer (36.9 g) at room temperature and stirred for 25 minutes, and magnesium sulfate was further added and stirred. The insoluble material was filtered and washed with chloroform. The obtained filtrate was concentrated to obtain a concentrated liquid (1.68 g) of compound (11). Chloroform (5.00 g) was added to a part (0.241 g) of this concentrated solution, and water (1.00 g) in which phosphoric acid (48 mg) was dissolved was further added to separate the layers. Chloroform (1.00 g) was added to the obtained aqueous layer for extraction. The obtained organic layers were mixed, and 5% by mass hydrochloric acid (0.80 g) was added for liquid separation. A 5% by mass aqueous sodium chloride solution (0.40 g) was added to the obtained organic layer for liquid separation. After the obtained organic layer was concentrated, chloroform (0.60 g) was added. Tetrahydrofuran (0.20 g) was added to this solution, and seed crystals (synthesized in Reference Synthesis Example 1) were added. After stirring for 18 minutes, tetrahydrofuran (0.40 g) was further added dropwise. After stirring at room temperature for 42 minutes, toluene (1.20 g) was added dropwise to the solution, and the mixture was further stirred for 25 minutes and cooled to 0 ° C. After stirring at 0 ° C. for 30 minutes, toluene (0.80 g) was added dropwise to the solution. Thereafter, the mixture was stirred at 0 ° C. for 25 minutes, and the precipitated solid was filtered and washed with toluene. The obtained solid was dried under reduced pressure at 50 ° C. to obtain compound (11) (0.172 g, yield 86%) as pale yellow crystals.
¹ H-NMR (CDCl ₃ )
δ ppm: 1.28-1.40 (m, 1H), 1.73-2.41 (m, 8H) 2.73-2.91 (m, 2H), 3.06-3.14 (m, 1H), 3.24-3.32 (m, 1H), 3.56-3.75 (m, 3H), 3.97-4.04 (m, 1H), 4.18-4.23 ( m, 1H), 4.58-4.62 (m, 1H), 4.67-4.78 (m, 1H), 4.83-4.91 (m, 1H), 4.96-5. 08 (m, 2H), 7.25-7.27 (m, 2H), 7.42-7.47 (m, 3H), 7.61-7.65 (m, 2H), 7.78- 7.81 (m, 1H)

合成例１で得られた化合物（９）（１０．０ｇ 、２５．２ｍｍｏｌ） のジクロロメタン（１５０ｇ）溶液に、ジイソプロピルエチルアミン（６．５４ｇ、５０．４ｍｍｏｌ）を加えた。室温下、クロロギ酸イソプロピル（９．２９ｇ、７５．６ｍｍｏｌ）を加えた後、還流下、１時間２２分間撹拌した。反応混合物を室温まで冷却し、５質量％炭酸水素ナトリウム水溶液（３０．０ｇ）を加え、分液した。得られた有機層に５質量％塩酸（３０．０ｇ） を加え、分液した。得られた有機層に１０質量％塩化ナトリウム水溶液（３０．０ｇ）を加えて分液した。得られたろ液を濃縮し、粗生成物（１３．２ｇ）を得た。この粗生成物の一部（０．７３８ｇ）をアセトン（２．９２ｇ）に溶解して−７８℃に冷却し、結晶を析出させた。−７８℃で３０分間撹拌後、結晶をろ過し、アセントンで洗浄した。５０℃で減圧乾燥して、化合物（１０）（０．４４６ｇ、収率６０％）を白色結晶として得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ₃）
δｐｐｍ：１．２４ (ｄ，３Ｈ，Ｊ＝６．１３Ｈｚ)，１．２９ (ｄ，３Ｈ，Ｊ＝６．１３Ｈｚ)，１．７１−２．３１（ｍ，９Ｈ），２．７８（ｂｒ，２Ｈ）３．０３−３．１６（ｍ，２Ｈ），３．７１−４．２０（ｍ，８Ｈ），４．８３−４．９５（ｍ，３Ｈ），６．９７−７．１３（ｍ，４Ｈ），７．４２−７．４９（ｍ，３Ｈ），７．５８−７．６１（ｍ，２Ｈ） Synthesis Example 4: Synthesis of compound (10)

Diisopropylethylamine (6.54 g, 50.4 mmol) was added to a solution of the compound (9) obtained in Synthesis Example 1 (10.0 g, 25.2 mmol) in dichloromethane (150 g). After adding isopropyl chloroformate (9.29 g, 75.6 mmol) at room temperature, the mixture was stirred at reflux for 1 hour and 22 minutes. The reaction mixture was cooled to room temperature, 5% by mass aqueous sodium hydrogen carbonate solution (30.0 g) was added, and the mixture was separated. 5% by mass hydrochloric acid (30.0 g) was added to the obtained organic layer to separate the layers. A 10% by mass aqueous sodium chloride solution (30.0 g) was added to the obtained organic layer for liquid separation. The obtained filtrate was concentrated to obtain a crude product (13.2 g). A part of this crude product (0.738 g) was dissolved in acetone (2.92 g) and cooled to −78 ° C. to precipitate crystals. After stirring at −78 ° C. for 30 minutes, the crystals were filtered and washed with asenton. It dried under reduced pressure at 50 degreeC and obtained the compound (10) (0.446g, 60% of yield) as a white crystal | crystallization.
¹ H-NMR (CDCl ₃ )
δppm: 1.24 (d, 3H, J = 6.13 Hz), 1.29 (d, 3H, J = 6.13 Hz), 1.71-2.31 (m, 9H), 2.78 (br , 2H) 3.03-3.16 (m, 2H), 3.71-4.20 (m, 8H), 4.83-4.95 (m, 3H), 6.97-7.13 ( m, 4H), 7.42-7.49 (m, 3H), 7.58-7.61 (m, 2H)

合成例２で得られた化合物（１）（０．６５１５ｇ、１．９６ｍｍｏｌ）にトルエン（１０．００ｇ）及び５質量％炭酸水素ナトリウム水溶液（４．９２ｇ）を加えて撹拌し、分液した。得られた水層にトルエン（５．００ｇ）を加え、分液した。得られた水層に、５質量％炭酸水素ナトリウム水溶液（４．０ｇ）及びトルエン（５．００ｇ）を加え、分液した。１回目及び２回目の分液操作で得られた有機層を混合し、１０質量％塩化ナトリウム水溶液 （５．００ｇ）を加えて分液し、有機層を濃縮した。別途、３回目の分液で得られた有機層を濃縮した。これらの濃縮物を混合し、トルエン（５．００ｇ）及び水（２．００ｇ）を加えて分液し、有機層を濃縮した。濃縮物にトルエン（７．５０ｇ）を加え、その混合物を８０℃に加温した後、塩化ベンジル（０．４４１ｇ、３．４８ｍｍｏｌ）のトルエン（１．０ｇ）溶液を滴下し、さらにトルエン（７．５０ｇ）を加えた。混合物を８０℃で、４時間４５分撹拌した後、室温に冷却し、室温で５０分間撹拌した。析出した固体をろ過し、トルエンで洗浄した。さらに得られた固体にトルエン（６．２ｇ）を加えて、室温で２時間３１分撹拌した。固体をろ過し、５０℃で減圧乾燥して、化合物（１１）（０．５９９ｇ、収率 ７２％）を白色結晶として得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ₃）
δｐｐｍ：１．２８−１．３９（ｍ，１Ｈ），１．７４−２．４０（ｍ，８Ｈ）２．７２−２．９０（ｍ，２Ｈ），３．０４−３．１３（ｍ，１Ｈ），３．２３−３．３１（ｍ，１Ｈ），３．５４−３．７８（ｍ，３Ｈ），３．９６−４．０４（ｍ，１Ｈ），４．１８−４．２３（ｍ，１Ｈ），４．５４−４．６３（ｍ，１Ｈ），４．７０−４．７７（ｍ，１Ｈ），４．８５−４．９１（ｍ，１Ｈ），５．０２−５．１２（ｍ，２Ｈ），７．２３−７．２８（ｍ，２Ｈ），７．３９−７．４６（ｍ，３Ｈ），７．６２−７．６６（ｍ，２Ｈ），７．７５−７．８０（ｍ，１Ｈ） Reference Synthesis Example 1: Synthesis of compound (11)

Toluene (10.00 g) and 5% by mass aqueous sodium hydrogen carbonate solution (4.92 g) were added to Compound (1) (0.6515 g, 1.96 mmol) obtained in Synthesis Example 2 and the mixture was stirred and separated. Toluene (5.00 g) was added to the obtained aqueous layer and the layers were separated. To the obtained aqueous layer, a 5% by mass aqueous sodium hydrogen carbonate solution (4.0 g) and toluene (5.00 g) were added and separated. The organic layers obtained by the first and second liquid separation operations were mixed, and 10% by mass aqueous sodium chloride solution (5.00 g) was added for liquid separation, and the organic layer was concentrated. Separately, the organic layer obtained in the third separation was concentrated. These concentrates were mixed, toluene (5.00 g) and water (2.00 g) were added and liquid-separated, and the organic layer was concentrated. Toluene (7.50 g) was added to the concentrate, and the mixture was heated to 80 ° C. Then, a solution of benzyl chloride (0.441 g, 3.48 mmol) in toluene (1.0 g) was added dropwise, and toluene (7 .50 g) was added. The mixture was stirred at 80 ° C. for 4 hours 45 minutes, then cooled to room temperature and stirred at room temperature for 50 minutes. The precipitated solid was filtered and washed with toluene. Furthermore, toluene (6.2 g) was added to the obtained solid, and the mixture was stirred at room temperature for 2 hours and 31 minutes. The solid was filtered and dried under reduced pressure at 50 ° C. to obtain compound (11) (0.599 g, yield 72%) as white crystals.
¹ H-NMR (CDCl ₃ )
δ ppm: 1.28-1.39 (m, 1H), 1.74-2.40 (m, 8H) 2.72-2.90 (m, 2H), 3.04-3.13 (m, 1H), 3.23-3.31 (m, 1H), 3.54-3.78 (m, 3H), 3.96-4.04 (m, 1H), 4.18-4.23 ( m, 1H), 4.54-4.63 (m, 1H), 4.70-4.77 (m, 1H), 4.85-4.91 (m, 1H), 5.02-5. 12 (m, 2H), 7.23-7.28 (m, 2H), 7.39-7.46 (m, 3H), 7.62-7.66 (m, 2H), 7.75- 7.80 (m, 1H)

  The present invention is useful in that the compound (1) useful as a pharmaceutical can be produced in a high yield.

Claims (18)

A process for producing a hydrobenzisoquinolinone compound represented by the formula (7), wherein the carbamate compound (6) is reacted with diphosphorus pentoxide in the presence of phosphorus oxychloride.

(In the formula, X represents a halogen atom, a C _1-6 alkylsulfonyloxy group, a C _1-6 haloalkylsulfonyloxy group, or a C _6-14 arylsulfonyloxy group which may have a substituent, and R ¹ represents , A hydrogen atom, a C _1-6 alkyl group, a C _3-6 cycloalkyl group, an _optionally substituted C _6-14 aryl group, or an _optionally substituted 5-10 membered heterocyclic ring And R ² represents a C _1-6 alkyl group.) The method for producing a hydrobenzisoquinolinone compound according to claim 1, wherein the compound (6) is obtained by the following step (b):
(B)
A step of reacting the amine compound (4) with the chloroformate (5) to obtain the carbamate compound (6).

(In the formula, X represents a halogen atom, a C _1-6 alkylsulfonyloxy group, a C _1-6 haloalkylsulfonyloxy group, or a C _6-14 arylsulfonyloxy group which may have a substituent, and R ¹ represents , A hydrogen atom, a C _1-6 alkyl group, a C _3-6 cycloalkyl group, an _optionally substituted C _6-14 aryl group, or an _optionally substituted 5-10 membered heterocyclic ring And R ² represents a C _1-6 alkyl group.) The method for producing a hydrobenzisoquinolinone compound according to claim 2, wherein the compound (4) is obtained by the following step (a):
(A)
A step of reacting compound (2) with alkylating agent (3) to obtain amine compound (4).

(In the formula, X represents a halogen atom, a C _1-6 alkylsulfonyloxy group, a C _1-6 haloalkylsulfonyloxy group, or a C _6-14 arylsulfonyloxy group which may have a substituent, and R ¹ represents , A hydrogen atom, a C _1-6 alkyl group, a C _3-6 cycloalkyl group, an _optionally substituted C _6-14 aryl group, or an _optionally substituted 5-10 membered heterocyclic ring Represents a group.) The method for producing a hydrobenzisoquinolinone compound according to any one of claims 1 to 3, wherein X is a chlorine atom or a bromine atom, and R ¹ is a phenyl group which may have a substituent. The method for producing a hydrobenzisoquinolinone compound according to claim 4, wherein X is a chlorine atom and R ¹ is a phenyl group. The method for producing a hydrobenzisoquinolinone compound according to any one of claims 1 to 5, wherein R ² is a C _1-3 alkyl group.   The method for producing a hydrobenzisoquinolinone compound according to claim 6, wherein R is an isopropyl group. Formula (4)

(In the formula, X represents a halogen atom, a C _1-6 alkylsulfonyloxy group, a C _1-6 haloalkylsulfonyloxy group, or a C _6-14 arylsulfonyloxy group which may have a substituent, and R ¹ represents , A hydrogen atom, a C _1-6 alkyl group, a C _3-6 cycloalkyl group, an _optionally substituted C _6-14 aryl group, or an _optionally substituted 5-10 membered heterocyclic ring An amine compound represented by: The amine compound according to claim 8, wherein X is a chlorine atom or a bromine atom, and R ¹ is a phenyl group which may have a substituent. The amine compound according to claim 9, wherein X is a chlorine atom and R ¹ is a phenyl group. Formula (6)

(In the formula, X represents a halogen atom, a C _1-6 alkylsulfonyloxy group, a C _1-6 haloalkylsulfonyloxy group, or a C _6-14 arylsulfonyloxy group which may have a substituent, and R ¹ represents , A hydrogen atom, a C _1-6 alkyl group, a C _3-6 cycloalkyl group, an _optionally substituted C _6-14 aryl group, or an _optionally substituted 5-10 membered heterocyclic ring A carbamate compound represented by: R ² represents a C _1-6 alkyl group. The compound according to claim 11, wherein X is a chlorine atom or a bromine atom, and R ¹ is an optionally substituted phenyl group. The carbamate compound according to claim 12, wherein X is a chlorine atom and R ¹ is a phenyl group. The carbamate compound according to any one of claims 11 to 13, wherein R ² is a C _1-3 alkyl group. The carbamate compound according to claim 14, wherein R ² is an isopropyl group. Formula (7)

(In the formula, X represents a halogen atom, a C _1-6 alkylsulfonyloxy group, a C _1-6 haloalkylsulfonyloxy group, or a C _6-14 arylsulfonyloxy group which may have a substituent, and R ¹ represents , A hydrogen atom, a C _1-6 alkyl group, a C _3-6 cycloalkyl group, an _optionally substituted C _6-14 aryl group, or an _optionally substituted 5-10 membered heterocyclic ring A hydrobenzisoquinolinone compound represented by: The hydrobenzisoquinolinone compound according to claim 16, wherein X is a chlorine atom or a bromine atom, and R ¹ is a phenyl group which may have a substituent. The hydrobenzisoquinolinone compound according to claim 17, wherein X is a chlorine atom and R ¹ is a phenyl group.