JP2010285365A - Method of synthesizing intermediate derivative of isoindoline - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a complete route of synthesizing an intermediate derivative of isoindoline and a final derivative of isoindoline, which route enables industrial, economical and large scale production of the final derivative of isoindoline. <P>SOLUTION: The method of producing an intermediate derivative of isoindoline represented by formula (10) includes, (1) allowing indandicarboxylic acid anhydride to react with a specific Wittig reagent, (2) allowing the reaction product to react with aniline to produce an isoindoline derivative, (3) catalytically hydrogenating the isoindoline derivative in the presence of an asymmetric catalyst, and (4) subjecting the ester segment of the reaction product to hydrolysis or hydrogenolysis. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

The present invention relates to a method for synthesizing an isoindoline intermediate derivative.

Many compounds having an isoindoline skeleton have been known as drugs acting on the central nervous system. Among these many compounds, isoindoline derivatives described in Patent Document 1, Patent Document 2 and Non-Patent Document 1 have been shown to be useful as compounds that exhibit anesthetic action.

Regarding the synthesis route of isoindoline derivatives, in Patent Document 1, Patent Document 2 and Non-Patent Document 1, as shown below, after reacting an amine with a dicarboxylic anhydride, an equimolar amount or more of sodium borohydride was used. The intermediate is important as a precursor of isoindoline derivatives by reducing the carbonyl group, introducing a carbon skeleton with Wittig reagent, and then hydrolyzing the ester.

Since the precursor of the isoindoline derivative thus obtained exists as a racemic mixture, in order to obtain an optically active isoindoline derivative, the precursor is further subjected to optical resolution. This process is required.

As described above, in Patent Document 1, Patent Document 2, and Non-Patent Document 1, although a synthetic route is established, the synthesis scale is at the laboratory level, and the final compound is sufficient industrially and economically. However, it cannot be said that a synthetic route capable of mass production has been established, and it has been desired to establish a total synthetic route including such a synthetic route.

Also in Patent Document 3, which discloses a condensed pyrrolinone derivative that is useful as an anxiolytic agent, the reaction from the compound represented by formula (V) to the compound represented by formula (II-1a) in the above synthetic route A route is disclosed. However, the reaction route is synthesized through four steps, and further steps are required to obtain an optically active form, which is still a synthetic route that cannot be mass-produced industrially and economically. It was a design.

JP 2004-189733 A JP 2006-76913 A JP 58-189163 A

Chem. Phar. Bull. , 55 (12), 1682-1688 (2007)

The present invention has been made in view of the above problems, and provides a total synthesis route for isoindoline intermediate derivatives and isoindoline final derivatives capable of industrially and economically mass-producing final isoindoline derivatives as final compounds. With the goal.

As a result of diligent studies to achieve the above object, the present inventors have reacted Wittig reagent with a dicarboxylic acid anhydride, followed by catalytic hydrogen reduction in the presence of an asymmetric catalyst, followed by hydrolysis or hydrogenolysis. Or by performing catalytic hydrogenation in the presence of an asymmetric catalyst after hydrolyzing or hydrocracking, the number of steps can be reduced by 1 (details will be described later, but optical resolution is performed). And an economical and efficient total synthesis route that can further simplify the reaction procedure by providing a process that allows the reaction to proceed continuously in two batches in one batch. The headline and the present invention were completed.

で表されるインダンジカルボン酸無水物と下記式（α）：

（式（α）中、Ｐｈはフェニル基を表し、Ｒは炭素数１〜６の直鎖状又は分岐鎖状のアルキル基を表し、該アルキル基は１以上のアリール基を有していてもよい）
で表されるＷｉｔｔｉｇ試薬とを反応させて、式（６）：

（式（６）中、Ｒは式（α）と同じ置換基を表す）
で表されるエステル誘導体を得る工程；
上記エステル誘導体とアニリンとを反応させて、式（７）：

（式（７）中、Ｒは式（α）と同じ置換基を表す）
で表される第１のイソインドリン誘導体を得る工程；並びに
上記第１のイソインドリン誘導体を不斉触媒の存在下、接触水素化し、式（８）：

で表される第２のイソインドリン誘導体を得、上記第２のイソインドリン誘導体を加水分解若しくは加水素分解して式（１０）：

で表されるイソインドリン中間誘導体を得る工程、又は、
上記第１のイソインドリン誘導体を加水分解若しくは加水素分解して式（９）：

で表される第３のイソインドリン誘導体を得、上記第３のイソインドリン誘導体を不斉触媒の存在下、接触水素化して、式（１０）：

で表されるイソインドリン中間誘導体を得る工程を含むことを特徴とする。 That is, in order to achieve the above object, the method for synthesizing an isoindoline intermediate derivative according to the invention described in claim 1 has the formula (5):

Indane dicarboxylic acid anhydride represented by the following formula (α):

(In the formula (α), Ph represents a phenyl group, R represents a linear or branched alkyl group having 1 to 6 carbon atoms, and the alkyl group may have one or more aryl groups. Good)
Is reacted with a Wittig reagent represented by formula (6):

(In formula (6), R represents the same substituent as in formula (α))
Obtaining an ester derivative represented by:
The ester derivative is reacted with aniline to obtain the formula (7):

(In formula (7), R represents the same substituent as in formula (α))
A first isoindoline derivative represented by formula (8); and catalytic hydrogenation of the first isoindoline derivative in the presence of an asymmetric catalyst to obtain a compound of formula (8):

A second isoindoline derivative represented by the formula (10) is obtained by hydrolyzing or hydrogenolyzing the second isoindoline derivative:

Obtaining an isoindoline intermediate derivative represented by:
The first isoindoline derivative is hydrolyzed or hydrogenolyzed to give the formula (9):

A third isoindoline derivative represented by formula (10) is obtained by catalytic hydrogenation of the third isoindoline derivative in the presence of an asymmetric catalyst:

The process of obtaining the isoindoline intermediate derivative represented by these is characterized.

In the method for synthesizing the isoindoline intermediate derivative of the present invention, the asymmetric catalyst includes a metal selected from the group consisting of nickel, palladium, platinum, rhodium, iridium, and ruthenium and an optically active phosphorus-containing ligand. It is desirable.

（式中、Ａｒは１以上の置換基を有していてもよいアリール基を表し、Ｐｈはフェニル基を表し、Ｒは炭素数１〜６の直鎖状若しくは分岐鎖状のアルキル基又は１以上の置換基を有していてもよいフェニル基を表す）
で表される配位子のいずれかであることが望ましい。 In the method for synthesizing the isoindoline intermediate derivative of the present invention, the phosphorus-containing ligand has the following formulas (Ia-S), (Ia-R), (Im-RS) and (Im-SR):

(In the formula, Ar represents an aryl group which may have one or more substituents, Ph represents a phenyl group, R represents a linear or branched alkyl group having 1 to 6 carbon atoms, or 1 Represents a phenyl group which may have the above substituents)
It is desirable that it is either of the ligands represented by these.

で表されるインダンとハロゲンとを反応させて、式（２）：

（式（２）中、Ｘ及びＹはそれぞれ独立して、Ｃｌ、Ｂｒ又はＩを表す）
で表されるジハロゲノインダンを得る工程；
第１の遷移金属触媒及び塩基の存在下、上記ジハロゲノインダンと一酸化炭素及び水とを反応させ、式（４）：

で表されるインダンジカルボン酸を得る工程；並びに
上記インダンジカルボン酸と無水酢酸とを反応させて、式（５）：

で表されるインダンジカルボン酸無水物を得る工程、又は、
金属触媒の存在下、式（１）：

で表されるインダンとハロゲンとを反応させて、式（２）：

（式（２）中、Ｘ及びＹはそれぞれ独立して、Ｃｌ、Ｂｒ又はＩを表す）
で表されるジハロゲノインダンを得る工程；
第２の遷移金属触媒及び塩基の存在下、上記ジハロゲノインダンと、一酸化炭素及びアルコールとを反応させ、式（３）：

で表されるインダンジカルボン酸アルキルエステルを得る工程
（式（３）中、Ｒ^１は、炭素数１〜６の直鎖状又は分岐鎖状のアルキル基を表し、該アルキル基は１以上のアリール基を有していてもよい）；
上記インダンジカルボン酸アルキルエステルを加水分解して、式（４）：

で表されるインダンジカルボン酸を得る工程；並びに
上記インダンジカルボン酸と無水酢酸とを反応させて、式（５）：

で表されるインダンジカルボン酸無水物を得る工程をさらに含むことが望ましい。 In the method for synthesizing the isoindoline intermediate derivative of the present invention, in the presence of a metal catalyst, the formula (1):

Is reacted with an indane represented by formula (2):

(In formula (2), X and Y each independently represents Cl, Br or I)
Obtaining a dihalogenoindan represented by:
In the presence of the first transition metal catalyst and the base, the dihalogenoindane is reacted with carbon monoxide and water to obtain a compound represented by the formula (4):

A step of obtaining an indane dicarboxylic acid represented by formula (5): and reacting the indane dicarboxylic acid with acetic anhydride to obtain a compound of formula (5):

A step of obtaining an indane dicarboxylic acid anhydride represented by:
In the presence of a metal catalyst, formula (1):

Is reacted with an indane represented by formula (2):

(In formula (2), X and Y each independently represents Cl, Br or I)
Obtaining a dihalogenoindan represented by:
In the presence of a second transition metal catalyst and a base, the dihalogenoindane is reacted with carbon monoxide and an alcohol to obtain a compound represented by the formula (3):

(In formula (3), R ¹ represents a linear or branched alkyl group having 1 to 6 carbon atoms, and the alkyl group is one or more aryl groups. May have a group);
The indane dicarboxylic acid alkyl ester is hydrolyzed to give the formula (4):

A step of obtaining an indane dicarboxylic acid represented by formula (5): and reacting the indane dicarboxylic acid with acetic anhydride to obtain a compound of formula (5):

It is desirable to further include a step of obtaining an indane dicarboxylic acid anhydride represented by the formula:

In the method for synthesizing the isoindoline intermediate derivative of the present invention, the metal catalyst is preferably iron, the first transition metal catalyst is preferably palladium acetate, and the second transition metal catalyst is acetic acid. Palladium is desirable.

で表されるイソインドリン最終誘導体を合成するイソインドリン最終誘導体の合成方法も含まれる。 In the present invention, the isoindoline intermediate derivative obtained by the method for synthesizing the isoindoline intermediate derivative is reacted with a chlorinating agent, and the resulting product is reacted with N-methylpiperazine to obtain the formula (11). :

A method for synthesizing a final isoindoline derivative is also included.

(First embodiment)
Hereinafter, a first embodiment which is an embodiment of a method for synthesizing an isoindoline intermediate derivative and an isoindoline final derivative of the present invention will be described. The following figure shows the total synthesis route from the indane represented by the formula (1) as the starting material to the final isoindoline derivative represented by the formula (11) as the final product.

In the first embodiment, the isoindoline intermediate derivative represented by the formula (10) passes from the first isoindoline derivative represented by the formula (7) to the second isoindoline derivative represented by the formula (8). Adopt a route to get. In addition, in order to obtain indane dicarboxylic acid anhydride from indane as a starting material, a route through an indane dicarboxylic acid alkyl ester represented by formula (3) (that is, dihalogenoindane represented by formula (2); In the presence of the first transition metal catalyst, base and water, not the indane dicarboxylic acid alkyl ester represented by (3); then the indane dicarboxylic acid represented by formula (4) The synthesis route (the dihalogenoindane represented by the formula (2); the pathway proceeding in the order of the indane dicarboxylic acid represented by the formula (4)) via the carbon monoxide insertion reaction is employed. Hereinafter, it demonstrates in order of a process.

で示されるインダンとハロゲンとを反応させて、式（２）：

（式（２）中、Ｘ及びＹはそれぞれ独立して、Ｃｌ、Ｂｒ又はＩを示す）
で示されるジハロゲノインダンを得る。この工程を第１工程とする。 First, in this embodiment, in the presence of a metal catalyst, the formula (1):

Is reacted with an indane represented by formula (2):

(In Formula (2), X and Y each independently represent Cl, Br, or I)
The dihalogenoindan represented by is obtained. This step is the first step.

Indane, which is a starting material, is easily available industrially. A commercially available product can be purchased and used after purification by a conventionally known purification method. This indane dihalogenation is described, for example, in M.M. J. et al. Camenzind et al. , J .; Heterocyclic Chem. , 1985, 22, 575. That is, the dihalogenoindane represented by the formula (2) is obtained by reacting indane introduced into chloroform with halogen in the presence of a metal catalyst under light-shielded ice cooling.

Although it does not specifically limit as a metal catalyst, For example, iron halides, such as iron, aluminum, iron chloride, and iron bromide, aluminum halides, such as aluminum chloride and aluminum bromide, etc. can be used conveniently. Among these, iron is particularly preferable.

The halogen represented by XY, for example, an interhalogen compound of X = Br and Y = _Br 2 is Br, is X = I and _{Y = I I 2, X =} Br and Y = I BrI etc. Is mentioned. Of these halogens, Br ₂ is preferable in view of availability and ease of elimination from the benzene ring in a later step.

Examples of the solvent used in the first step include the above-mentioned chloroform, chlorinated solvents such as dichloromethane and carbon tetrachloride, and acetic acid.

The halogenation reaction temperature (temperature in the reaction system) may be any temperature under ice cooling so as to suppress the rapid progress of the reaction, preferably 0 to 10 ° C., more preferably 0. ~ 5 ° C.

（式（２）中、Ｘ及びＹは上述と同義）
で示されるジハロゲノインダンと一酸化炭素及び水とを反応させることで、式（４）：

で示されるインダンジカルボン酸を得ることができる。この工程を第２工程とする。 Then, the formula (2) obtained in the first step in the presence of the first transition metal catalyst and the base:

(In formula (2), X and Y are as defined above)
By reacting the dihalogenoindane represented by the formula (1) with carbon monoxide and water:

Can be obtained. This step is referred to as the second step.

The first transition metal catalyst is a Group VIII metal (Group 8, Group 9, Group 10 element) of the periodic table, and specifically, nickel, palladium, platinum, rhodium, ruthenium and the like are preferable. Further, a catalyst obtained by converting these metals into a complex form is more preferable, and a palladium complex is particularly preferable.

Examples of the palladium complex include palladium acetate (Pd (CH ₃ CO ₂ ) ₂ ), palladium chloride (PdCl ₂ ), tetrakis (triphenylphosphine) palladium (Pd (PPh ₃ ) ₄ ; Can be suitably used. Of these listed transition metal catalysts, palladium acetate is particularly preferred in consideration of availability and industrial necessity for mass production.

Examples of the base include tertiary amines such as triethylamine, tripropylamine, tributylamine, triallylamine, N, N-dimethylaniline, N, N-diethylaniline, acetates such as sodium acetate and potassium acetate, or Examples thereof include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate. Of these, tertiary amines are preferable, and triethylamine is particularly preferable.

In order to activate and stabilize the catalyst, a phosphine ligand may be present in the reaction system. Examples of the phosphine ligand include triphenylphosphine, tri-o-tolylphosphine, tri-m-tolylphosphine, tri-p-tolylphosphine, tri-n-butylphosphine, and triethylphosphine.

In the second step, the presence of water is essential for the conversion of halogen on the benzene ring to carboxylic acid in the presence of carbon monoxide. Although this conversion proceeds in the presence of water, coexistence of a water-soluble organic solvent facilitates the access of water to the benzene ring, increasing the reaction rate, and reducing the time and yield required for the reaction. It is desirable because it improves. Examples of the water-soluble organic solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxymethane, 1,2-dimethoxyethane, diglyme, dioxane, 1,3-dioxolane; ketone solvents such as acetone; dimethyl sulfoxide, sulfolane. A sulfur-containing solvent such as acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N, N-dimethylpropionamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, 1,3 -Nitrogen-containing solvents such as dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyridinone; lactone solvents such as γ-butyrolactone; carbonate solvents such as dimethyl carbonate. Of these water-soluble organic solvents, tetrahydrofuran is particularly preferred.

で示されるインダンジカルボン酸無水物を得る工程を行う。この工程を第３工程とする。 Next, the indane dicarboxylic acid and acetic anhydride are reacted to form the formula (5):

The process of obtaining the indane dicarboxylic anhydride shown by these is performed. This step is referred to as a third step.

In the third step, when indane dicarboxylic acid is heated in the presence of acetic anhydride, an intramolecular dehydration reaction of the dicarboxylic acid moiety occurs, and indane dicarboxylic acid anhydride is obtained. The product may be collected as it is after completion of the dehydration reaction, but it is preferable to cool the product after the reaction and then filter the product. This is because by cooling with ice, the solubility of the indane dicarboxylic acid anhydride, which is the product, is lowered and the anhydride is likely to precipitate, thereby improving the yield.

で表されるインダンジカルボン酸無水物と下記式（α）：

（式（α）中、Ｐｈはフェニル基を表し、Ｒは炭素数１〜６の直鎖状又は分岐鎖状のアルキル基を表し、該アルキル基は１以上のアリール基を有していてもよい）
で表されるＷｉｔｔｉｇ試薬とを反応させて、式（６）：

（式（６）中、Ｒは式（α）と同じ置換基を表す）
で表されるエステル誘導体を得る。 Subsequently, a 4th process is performed following a 3rd process. In the fourth step, the formula (5):

Indane dicarboxylic acid anhydride represented by the following formula (α):

(In the formula (α), Ph represents a phenyl group, R represents a linear or branched alkyl group having 1 to 6 carbon atoms, and the alkyl group may have one or more aryl groups. Good)
Is reacted with a Wittig reagent represented by formula (6):

(In formula (6), R represents the same substituent as in formula (α))
An ester derivative represented by

As the substituent R of the Wittig reagent, a linear or branched alkyl group having 1 to 6 carbon atoms is used, and specific examples thereof include, for example, a methyl group, an ethyl group, a butyl group, an isobutyl group, t -A butyl group etc. are mentioned. The alkyl group may further have one or more aryl groups, and specific examples of the alkyl group having an aryl group include a benzyl group and a 1-phenylethyl group. Of the alkyl groups described above, a methyl group or a benzyl group is preferred in view of ease of deprotection of the ester in the subsequent hydrolysis step or hydrogenolysis step.

By introducing a carbon-carbon double bond into the carbonyl carbon in the fourth step, the target optically active isoindoline intermediate derivative can be efficiently produced through the asymmetric reduction reaction in the subsequent step. That is, conventionally, (i) a carbonyl group of indane dicarboxylic acid anhydride is reduced with a reducing agent such as sodium borohydride, and (ii) a carbon-carbon bond is introduced with a Wittig reagent having an ester protecting group, iii) It was necessary to synthesize a compound having the desired configuration by deprotecting the ester moiety to give a free acid, and then (iv) further subjecting it to optical resolution or the like (this route) However, the amidation reaction is excluded, that is, when the amidation reaction is taken into consideration, there are five steps instead of four steps). On the other hand, in the present invention, (i) a carbon-carbon bond is introduced by a Wittig reagent having an ester protecting group in the fourth step, (ii) this is subjected to an asymmetric reduction reaction described later, By deprotecting the ester moiety by decomposition or the like to form a free acid (in this route, the amidation reaction is excluded. That is, considering the amidation reaction, there are four steps instead of three steps). A desired isoindoline intermediate derivative can be synthesized, one process can be reduced as compared with the conventional process, and the efficiency of the synthesis process can be improved.

The benzyl ester derivative may be isolated and purified before the amide bond introduction step with aniline as the fifth step following the fourth step, and then the reaction in the fifth step may be performed. And it is desirable to move to the fifth step as it is without performing purification. The reason for this is that it is possible to save the trouble of extracting the product from the reactor or isolating the product, and to simplify the operation.

（式（７）中、Ｒは式（α）と同じ置換基を表す）
で表される第１のイソインドリン誘導体を得る第５工程を行う。 Next, the ester derivative, which is the product of the fourth step, is reacted with aniline to obtain the formula (7):

(In formula (7), R represents the same substituent as in formula (α))
The 5th process of obtaining the 1st isoindoline derivative represented by these is performed.

In the fifth step, a reaction for converting a cyclic ester bond portion into a cyclic amide bond with aniline is performed using an acid as a catalyst. As mentioned above, since the 5th process is performed continuously following the 4th process, the yield of the 1st isoindoline derivative which is a product of the 5th process can be improved.

（式（８）中、Ｒは式（α）と同じ置換基を表す）
で表される第２のイソインドリン誘導体を得る第６工程（ａ）を行う。 Next, the first isoindoline derivative is catalytically hydrogenated in the presence of an asymmetric catalyst to obtain the formula (8):

(In formula (8), R represents the same substituent as in formula (α))
The 6th process (a) which obtains the 2nd isoindoline derivative represented by these is performed.

In the sixth step (a), the olefin moiety is stereoselectively catalytically hydrogenated in the presence of an asymmetric catalyst, and the carbon that forms a ring out of the olefin moiety carbon is the asymmetric carbon. A second isoindoline derivative that is a precursor of an optically active isoindoline intermediate derivative is produced. Thus, by performing asymmetric reduction using a predetermined asymmetric catalyst, the target configuration can be obtained in excess as compared with a compound having a configuration opposite to the target configuration. When catalytic hydrogenation is carried out without using an asymmetric catalyst for the first isoindoline derivative, two products of R form with configuration R and S form with configuration S are equivalent. Generate one by one. However, only the R-form is actually aimed at, and only a maximum of 50% of the compound with the desired configuration can be produced simply by catalytic hydrogenation. And in order to improve the yield in the synthetic route which employs this catalytic hydrogenation, after obtaining the R-form by the optical resolution method in the next step, the mother liquor rich in the remaining S-form is recovered, It is necessary to repeat a complicated operation of racemization and further optical division. On the other hand, in the asymmetric reduction reaction of the present invention, since the target R form is produced in excess, it is possible to obtain an isoindoline intermediate derivative more efficiently, and the production efficiency is greatly improved. Become.

The asymmetric carbon is not particularly limited as long as the asymmetric reduction reaction of the olefin moiety by catalytic hydrogenation can proceed, and examples thereof include an asymmetric catalyst containing a metal atom and an optically active ligand. .

Examples of the metal include typical metal atoms such as magnesium (Mg), zinc (Zn), boron (B), aluminum (Al), and tin (Sn); copper (Cu), nickel (Ni), titanium (Ti ), Scandium (Sc), lanthanum (La), platinum (Pt), iridium (Ir), rhodium (Rh), cobalt (Co), iron (Fe), silver (Ag), gold (Au), ruthenium (Ru) ), Transition metal atoms such as palladium (Pd), preferably a transition metal selected from Group 8 atom of the periodic table, Group 9 atom of the periodic table, Group 10 atom of the periodic table and Group 11 atom of the periodic table Atoms are used. Among these metals, transition metal atoms are preferable, and specifically, nickel, palladium, platinum, rhodium, ruthenium and iridium are preferable.

Examples of the optically active ligand include monodentate or polydentate optically active phosphine ligands, optically active phosphine-phosphite ligands, optically active phosphite ligands, and optically active phosphoramidites. Examples thereof include a ligand containing a hetero atom such as a phosphorus-containing ligand such as a ligand and a monodentate or multidentate optically active amine-containing ligand. Among these ligands, an optically active phosphorus-containing ligand such as an optically active multidentate phosphine ligand is preferable because a high asymmetric yield is obtained.

（式中、Ａｒは１以上の置換基を有していてもよいアリール基、Ｍｅはメチル基、Ｐｈはフェニル基、Ｂｎはベンジル基、Ｅｔはエチル基、Ｒは炭素数１〜６の直鎖状又は分岐鎖状のアルキル基又はフェニル基をそれぞれ表す）
で表される配位子等が挙げられる。
なお、これらの配位子のうち、式（Ｉｃ）から式（Ｉｌ）、及び、式（Ｉｎ）から式（Ｉｒ）で表される配位子については、各式で表された上記具体的な立体配置とは反対の立体配置を有する配位子を用いることもできる。 Specific examples of the optically active phosphorus-containing ligand used in the present invention include, for example, the following formula:

(In the formula, Ar is an aryl group which may have one or more substituents, Me is a methyl group, Ph is a phenyl group, Bn is a benzyl group, Et is an ethyl group, and R is a straight chain having 1 to 6 carbon atoms. A chain or branched alkyl group or a phenyl group, respectively)
The ligand etc. which are represented by these are mentioned.
Among these ligands, the ligands represented by the formula (Ic) to the formula (Il) and the formula (In) to the formula (Ir) are represented by the above specific formulas. A ligand having a configuration opposite to that of the other configuration can also be used.

（式中、Ａｒ、Ｍｅ、Ｐｈ、Ｒは上記置換基と同義）
で表される配位子が好ましく、下記式：

（式中、Ａｒ、Ｐｈ、Ｒは上記置換基と同義である）
で表される配位子がより好ましい。上記配位子はいずれも単独で又は組み合わせて用いてもよい。 Of the ligands listed above, the following formula:

(In the formula, Ar, Me, Ph, and R are as defined above)
Is preferably a ligand represented by the following formula:

(In the formula, Ar, Ph and R are as defined above)
The ligand represented by is more preferable. Any of the above ligands may be used alone or in combination.

Specific examples of substituents that can be more suitably used as substituents in the above-listed ligands are shown in Table 1. In Table 1, specific examples of substituents in each formula are shown in the middle part of the table, and the abbreviations of the ligands having substituents shown in the middle part of the table (for ligands that can be represented only by the respective formulas, only the abbreviations are used. Hereinafter, the abbreviations shown in Table 1 may be used to represent specific ligands).

Of the ligands shown in Table 1, the following:
S-Xyl-PhanePhos,
S-MeOXyl-PhanePhos,
R-PhanPhos,
R-Tol-PhanPhos,
R-An-PhanePhos,
RP-Phos,
R-Tol-P-Phos,
S-Xyl-P-Phos,
R-PhBoPhoz and S-MeBoPhoz
The following ligands are preferred:
S-Xyl-PhanePhos,
S-MeOXyl-PhanePhos,
R-PhanPhos,
R-Tol-PhanPhos,
R-An-PhanePhos,
R-PhBoPhoz and S-MeBoPhoz
The ligand is more preferred.

The asymmetric catalyst of the present invention includes a metal selected from the group consisting of nickel (Ni), palladium (Pd), platinum (Pt), iridium (Ir), rhodium (Rh) and ruthenium (Ru), and the above list. An asymmetric catalyst containing the optically active phosphorus-containing ligand is preferred. Specific examples of the asymmetric catalyst of the present invention include, for example, the following:
[R-PhanePhos-Rh (COD)] BF ₄ ,
[R-Tol-PhanePhos-Rh (COD)] BF ₄ ,
[R-An-PhanePhos-Rh (COD)] BF 4,
[S-Xyl-PhanePhos-Rh (COD)] BF ₄ ,
[S-MeOXyl-PhanePhos-Rh (COD)] BF ₄ ,
[R-P-Phos-Rh (COD)] BF ₄ ,
[R-Tol-P-Phos-Rh (COD)] BF ₄ ,
[S-Xyl-P-Phos -Rh (COD)] BF 4,
[Spiro-P-Rh (COD)] BF ₄ ,
[DIOP-Rh (COD)] BF 4,
[BINAM-P-Rh (COD)] BF ₄ ,
[BINAP-Rh (COD)] BF ₄ ,
[Tol-BINAP-Rh (COD)] BF ₄ ,
[NorPhos-Rh (COD)] BF ₄ ,
[Ferrotane-Rh (COD)] BF ₄ ,
[MeDUPHOS-Rh (COD)] BF ₄ ,
[DIPAMP-Rh (COD)] BF ₄ ,
[ChiraPhos-Rh (COD)] BF ₄ ,
[BDPP-Rh (COD)] BF ₄ ,
[ProPhos-Rh (COD)] BF ₄ ,
S-Xyl-PhanePhos + [Rh (acac) (C 2 H 4) 2],
S-Xyl-PhanePhos + [Rh (acac) (CO) ₂ ],
S-Xyl-PhanePhos + [Rh (OAC) ₂ (CO) ₂ ],
S-MeOXyl-PhanePhos + [Rh (acac) (C 2 H 4) 2],
S-MeBoPhos + [Rh (acac) ₂ (CO) ₂ ],
S-MeBoPhoz + [Ir (COD) Cl] ₂ ,
[RP-Phos-Ir (COD)] Cl,
R-P-Phos + [Ir (COD) Cl] ₂ ,
S-Xyl-P-Phos + [Ir (COD) Cl] ₂ ,
[RP-Phos-RuCl (p-cymene)] Cl,
[S-Xyl-P-Phos-RuCl (p-cymene)] Cl, and [S-MeBoPhoz-RuCl (benzene)] Cl,
(Where COD = 1,5-cyclooctadiene, Xyl = xylyl group, acac = acetylacetone, p-cymene = p-cymene (1-isopropyl-4-methylbenzene))
And asymmetric catalysts.

As the asymmetric catalyst of the present invention, any known ligand can be used. For example, Wiley-VCH, Catalytic Asymmetric Synthesis 2nd ed. , 2000, edited by Iwao Ojima, catalysts prepared based on these catalysts, and the like can also be suitably used.

The asymmetric catalyst as described above may be introduced into the reaction system in advance, or may be prepared in the reaction system, prepared in advance prior to the start of the catalytic hydrogenation reaction. A person skilled in the art can appropriately prepare the asymmetric catalyst used in the sixth step (a) by a known procedure.

The reaction temperature in the sixth step (a) may be usually 30 ° C to 70 ° C, preferably 30 ° C to 60 ° C, and more preferably 40 ° C to 50 ° C. If the reaction temperature is less than 30 ° C., the reaction may not proceed sufficiently, or even if the reaction proceeds, it may take a long time to complete the reaction. On the other hand, when the reaction temperature exceeds 70 ° C., the asymmetric catalyst may be deactivated.

Examples of the solvent used in this step include chlorine solvents (dichloromethane, dichloroethane, chloroform, etc.), alcohol solvents (methanol, ethanol, etc.), ether solvents (tetrahydrofuran, dioxane, etc.) and the like.

In the asymmetric reduction reaction by catalytic hydrogenation in the sixth step (a), for the purpose of improving the reaction yield or the asymmetric yield in the reaction, I ₂ , KI, KBr, AcOH, t-Bu ₄ NCl Here, Ac represents an acetyl group, and t-Bu represents a t-butyl group, respectively, and additives such as KPF ₆ and AgBF ₄ may coexist.

In addition, for the isoindoline intermediate derivative obtained through the asymmetric reduction reaction, even if the optical purity of the product after the reaction is lowered, the optical purity can be obtained by subjecting the product to optical resolution, if desired. Can also be increased. As a procedure for optical resolution, for example, an optically active protecting group (for example, (S)-(−)-phenylethylamine) is introduced into the product, and then the difference in elution degree in silica gel chromatography or the like is used. It is possible to employ a procedure in which an ester form of the target isoindoline intermediate derivative is separated and converted to a free acid by subsequent acid treatment to obtain the target isoindoline intermediate derivative.
In addition to such optical division, the optical purity can be increased only by performing a normal cleaning operation.

で表されるイソインドリン中間誘導体を得る第６´工程（ａ）を行う。 Next, the second isoindoline derivative is hydrolyzed or hydrogenolyzed to give the formula (10):

6th process (a) which obtains the isoindoline intermediate derivative represented by these is performed.

Hydrolysis or hydrogenolysis of the ester moiety of the second isoindoline derivative is carried out by methods known in the literature, for example, Green's protective groups in organic synthesis. 4th ed. 2006, Wiley-Interscience, Peter G. et al. M.M. Wuts and Theodora W. A person skilled in the art can appropriately perform the method using the method described in Green.

で示されるイソインドリン最終誘導体を合成する第７工程を行う。 In the present embodiment, the isoindoline intermediate derivative obtained by the method for synthesizing the isoindoline intermediate derivative is further reacted with a chlorinating agent, and the resulting product is reacted with N-methylpiperazine to give a formula ( 11):

The seventh step of synthesizing the final isoindoline derivative shown in FIG.

In the seventh step, the reactivity with N-methylpiperazine is enhanced by converting the isoindoline intermediate derivative into an acid chloride using a chlorinating agent. The chlorinating agent is not particularly limited, and thionyl chloride, oxalyl chloride, phosphorus trichloride, and phosphorus pentachloride can be suitably used.

By reacting the obtained acid chloride with N-methylpiperazine, an amide bond is formed on the side of the N atom having a small steric hindrance, and the final end product, isoindoline final derivative, can be obtained.

The effects of the synthesis method of the isoindoline intermediate derivative and the synthesis method of the isoindoline final derivative of this embodiment will be listed below.
(1) In the synthesis method of the present embodiment, (i) a carbon-carbon bond is introduced by a Wittig reagent in the fourth step, (ii) this is subjected to an asymmetric reduction reaction in a subsequent step, and (iii) By deprotecting the ester moiety by hydrolysis or the like to form a free acid (Note that this route excludes the amidation reaction. That is, considering the amidation reaction, there are four steps instead of three steps). The desired isoindoline intermediate derivative is synthesized. In contrast, conventionally, (i) the carbonyl group of indane dicarboxylic acid anhydride is reduced with a reducing agent such as sodium borohydride, and (ii) a carbon-carbon bond is introduced with a Wittig reagent, and (iii) After deprotecting the ester moiety to give a free acid, (iv) it was necessary to synthesize a compound having the desired configuration by subjecting it to optical resolution, etc. (In other words, when considering the amidation reaction, there are five steps instead of four steps). As described above, in the synthesis method of the present embodiment, by adopting the asymmetric reduction reaction using the asymmetric catalyst, one step can be reduced as compared with the conventional steps, and the efficiency of the synthesis route is improved. be able to.

(2) The target configuration as compared with a compound having a configuration opposite to the target configuration by performing asymmetric reduction using a predetermined asymmetric catalyst in the sixth step (a) An excess of the compound having can be obtained. When catalytic hydrogenation is carried out without using an asymmetric catalyst for the first isoindoline derivative, two products of R form with configuration R and S form with configuration S are equivalent. In this case, in the asymmetric reduction reaction of the present embodiment, the target R is reduced. In this case, the yield of the target product is lowered, or a complicated procedure is required to increase the yield. Since the body is excessively produced, the isoindoline intermediate derivative can be obtained more efficiently, and the production efficiency is greatly improved.

(3) Also, since the reaction product in the fourth step is used as it is as a starting material in the fifth step without isolation and purification in the transition from the fourth step to the fifth step, The isolation process can be reduced, and the efficiency of the reaction procedure can be improved.

(Second embodiment)
In the method for synthesizing the isoindoline intermediate derivative of the present embodiment, of the total synthetic routes shown in the first embodiment, the first isoindoline derivative represented by the formula (7) is represented by the formula (9). A route for synthesizing an isoindoline intermediate derivative represented by the formula (10) through 3 isoindoline derivatives is employed. In the first embodiment, the ester is hydrolyzed after the asymmetric reduction reaction of the olefin part of the first isoindoline derivative represented by the formula (7), whereas in the present embodiment, the formula (7 7) After the hydrolysis of the ester of the first isoindoline derivative represented by 7), an asymmetric reduction reaction of the olefin moiety is carried out. In this embodiment, a synthetic route in contrast to the first embodiment is used. Adopted. Since other steps are the same as those in the first embodiment, only the steps different from those in the first embodiment will be described below.

で表されるインダンジカルボン酸無水物と下記式（α）：

（式（α）中、Ｐｈはフェニル基を表し、Ｒは炭素数１〜６の直鎖状又は分岐鎖状のアルキル基を表し、該アルキル基は１以上のアリール基を有していてもよい）
で表されるＷｉｔｔｉｇ試薬とを反応させて、式（６）：

（式（６）中、Ｒは式（α）と同じ置換基を表す）
で表されるエステル誘導体を得る工程；
上記エステル誘導体とアニリンとを反応させて、式（７）：

（式（７）中、Ｒは式（α）と同じ置換基を表す）
で表される第１のイソインドリン誘導体を得る工程；並びに
上記第１のイソインドリン誘導体を加水分解若しくは加水素分解して式（９）：

で表される第３のイソインドリン誘導体を得、上記第３のイソインドリン誘導体を不斉触媒の存在下、接触水素化して、式（１０）：

で表されるイソインドリン中間誘導体を得る工程を行う。 The method of synthesizing the isoindoline intermediate derivative of the present embodiment has the formula (5):

Indane dicarboxylic acid anhydride represented by the following formula (α):

(In the formula (α), Ph represents a phenyl group, R represents a linear or branched alkyl group having 1 to 6 carbon atoms, and the alkyl group may have one or more aryl groups. Good)
Is reacted with a Wittig reagent represented by formula (6):

(In formula (6), R represents the same substituent as in formula (α))
Obtaining an ester derivative represented by:
The ester derivative is reacted with aniline to obtain the formula (7):

(In formula (7), R represents the same substituent as in formula (α))
A step of obtaining a first isoindoline derivative represented by formula (9): and hydrolyzing or hydrogenolysis of the first isoindoline derivative.

A third isoindoline derivative represented by formula (10) is obtained by catalytic hydrogenation of the third isoindoline derivative in the presence of an asymmetric catalyst:

The process of obtaining the isoindoline intermediate derivative represented by these is performed.

In this embodiment, since the process of obtaining the first isoindoline derivative represented by the formula (7) from the indane dicarboxylic acid anhydride represented by the formula (5) is the same as the first embodiment, Description is omitted.

で表される第３のイソインドリン誘導体を得る第６工程（ｂ）を行う。 First, the first isoindoline derivative is hydrolyzed or hydrogenolyzed to obtain the formula (9):

The 6th process (b) which obtains the 3rd isoindoline derivative represented by these is performed.

The sixth step (b) of the present embodiment is a step corresponding to the sixth 'step (a) of the first embodiment, and the deprotection of the ester of the first isoindoline derivative is performed by hydrolysis or hydrogenolysis. Is going. As the reaction procedure of the sixth step (b), the reaction procedure in the 6 ′ step (a) of the first embodiment can be suitably used, and thus detailed description thereof is omitted.

で表されるイソインドリン中間誘導体を得る第６´工程（ｂ）を行う。 Subsequently, the third isoindoline derivative is catalytically hydrogenated in the presence of an asymmetric catalyst to obtain the formula (10):

6th process (b) which obtains the isoindoline intermediate derivative represented by these is performed.

The sixth step (b) of the present embodiment is a step corresponding to the sixth step (a) of the first embodiment, and an olefin of the third isoindoline derivative is obtained by catalytic hydrogenation using an asymmetric catalyst. Asymmetric reduction of part is performed. As the reaction procedure of the 6 ′ step (b), the reaction procedure in the sixth step (a) of the first embodiment can be suitably used, and thus detailed description thereof is omitted.

In the present embodiment, the same effects (1), (2) and (3) as in the first embodiment can be achieved.

(Third embodiment)
In the method of synthesizing the isoindoline intermediate derivative of this embodiment, in order to obtain indane dicarboxylic acid anhydride from indane as a starting material, carbon monoxide is inserted in the presence of a second transition metal catalyst, a base and an alcohol. A procedure that employs a route in which an ester body is generated and indandicarboxylic acid is obtained by subsequent hydrolysis will be described in the order of steps. This route is a route via an indane dicarboxylic acid alkyl ester represented by the formula (3) among all synthetic routes shown in the first embodiment (that is, a dihalogenoindane represented by the formula (2); Indane dicarboxylic acid alkyl ester represented by (3); then, a pathway that proceeds in the order of indane dicarboxylic acid represented by formula (4). Since other steps are the same as those in the first embodiment, only steps different from those in the first embodiment will be described.

で示されるインダンとハロゲンとを反応させて、式（２）：

（式（２）中、Ｘ及びＹはそれぞれ独立して、Ｃｌ、Ｂｒ又はＩを表す）
で示されるジハロゲノインダンを得る工程；
第２の遷移金属触媒存在下、上記ジハロゲノインダンと、一酸化炭素及びアルコールとを反応させ、式（３）：

で示されるインダンジカルボン酸アルキルエステルを得る工程
（式（３）中、Ｒ^１は、炭素数１〜６の直鎖状又は分岐鎖状のアルキル基を表し、該アルキル基は１以上のアリール基を有していてもよい）；
上記インダンジカルボン酸アルキルエステルを加水分解して、式（４）：

で示されるインダンジカルボン酸を得る工程；並びに
上記インダンジカルボン酸と無水酢酸とを反応させて、式（５）：

で示されるインダンジカルボン酸無水物を得る工程を行う。 In this embodiment, in the presence of a metal catalyst, the formula (1):

Is reacted with an indane represented by formula (2):

(In formula (2), X and Y each independently represents Cl, Br or I)
Obtaining a dihalogenoindan represented by:
In the presence of a second transition metal catalyst, the dihalogenoindane is reacted with carbon monoxide and an alcohol to obtain a compound represented by the formula (3):

(In the formula (3), R ¹ represents a linear or branched alkyl group having 1 to 6 carbon atoms, and the alkyl group is one or more aryl groups. May have)
The indane dicarboxylic acid alkyl ester is hydrolyzed to give the formula (4):

A step of obtaining an indane dicarboxylic acid represented by formula (5); and reacting the indane dicarboxylic acid with acetic anhydride to obtain a compound represented by formula (5):

The process of obtaining the indane dicarboxylic anhydride shown by these is performed.

で示されるインダンとハロゲンとを反応させて、式（２）：

（式（２）中、Ｘ及びＹはそれぞれ独立して、Ｃｌ、Ｂｒ又はＩを表す）
で示されるジハロゲノインダンを得る工程は第一実施形態の第１工程と同じ手順を採用することができるので、ここでの説明は省略する。 In this embodiment, in the presence of a metal catalyst, the formula (1):

Is reacted with an indane represented by formula (2):

(In formula (2), X and Y each independently represents Cl, Br or I)
The step of obtaining the dihalogenoindane shown by can adopt the same procedure as the first step of the first embodiment, and thus the description thereof is omitted here.

で示されるインダンジカルボン酸アルキルエステルを得る工程
（式（３）中、Ｒ^１は、炭素数１〜６の直鎖状又は分岐鎖状のアルキル基を表し、該アルキル基は１以上のアリール基を有していてもよい）を行う。この工程を第２´工程（ａ）とする。 Next, the dihalogenoindane is reacted with carbon monoxide and an alcohol in the presence of a second transition metal catalyst and a base to obtain the formula (3):

(In the formula (3), R ¹ represents a linear or branched alkyl group having 1 to 6 carbon atoms, and the alkyl group is one or more aryl groups. May be included). This step is referred to as a second 'step (a).

The second transition metal catalyst is a Group VIII metal (Group 8, Group 9, Group 10 element) of the periodic table, and specifically, nickel, palladium, platinum, rhodium, ruthenium and the like are preferable. Further, a catalyst obtained by converting these metals into a complex form is more preferable, and a palladium complex is particularly preferable.

Examples of the palladium complex include palladium acetate (Pd (CH ₃ CO ₂ ) ₂ ), palladium chloride (PdCl ₂ ), tetrakis (triphenylphosphine) palladium (Pd (PPh ₃ ) ₄ ; Can be suitably used. Of these listed transition metal catalysts, palladium acetate is particularly preferred in consideration of availability and industrial necessity for mass production.

Examples of the base include tertiary amines such as triethylamine, tripropylamine, tributylamine, triallylamine, N, N-dimethylaniline, N, N-diethylaniline, acetates such as sodium acetate and potassium acetate, or Examples thereof include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate. Of these, tertiary amines are preferable, and triethylamine is particularly preferable.

In order to activate and stabilize the catalyst, a phosphine ligand may be present in the reaction system. Examples of the phosphine ligand include triphenylphosphine, tri-o-tolylphosphine, tri-m-tolylphosphine, tri-p-tolylphosphine, tri-n-butylphosphine, and triethylphosphine.

It does not specifically limit as said alcohol, Methanol, ethanol, propanol, isopropanol, butanol, 2-butanol, isobutanol, pentanol, hexanol, benzyl alcohol, etc. are mentioned. Of these alcohols, methanol is preferred in view of reactivity and ease of subsequent removal.

Before performing the hydrolysis step as the 2 ′ step (b) following the 2 ′ step (a), the indandicarboxylic acid alkyl ester is isolated and purified before the 2 ′ step (b). Although the reaction may be carried out, it is desirable to proceed directly to the 2 ′ step (b) without performing isolation and purification. The reason for this is that it is possible to save the trouble of extracting the product from the reactor or isolating the product, and to simplify the operation.

で示されるインダンジカルボン酸を得る工程を行う。 In the subsequent 2 ′ step (b), the indanedicarboxylic acid alkyl ester is hydrolyzed to obtain the formula (4):

The process of obtaining the indane dicarboxylic acid shown by this is performed.

Either acid or alkali may be used for the hydrolysis. Examples of the acid include hydrochloric acid and sulfuric acid. Examples of the alkali include sodium hydroxide and potassium hydroxide. In view of reactivity and yield, it is preferable to perform hydrolysis with an alkali, and among the alkalis, sodium hydroxide is preferable.

で示されるインダンジカルボン酸無水物を得る工程については、第一実施形態の第３工程と同じであるので、説明を省略する。 The following indane dicarboxylic acid and acetic anhydride are reacted to give the formula (5):

Since the step of obtaining the indane dicarboxylic acid anhydride represented by is the same as the third step of the first embodiment, description thereof is omitted.

In the present embodiment, the same effects (1), (2) and (3) as in the first embodiment can be achieved.

Examples that more specifically disclose the first embodiment of the present invention will be described below, but the present embodiment is not limited to these examples.

The isoindoline intermediate derivative was synthesized according to the reaction path from the first step to the sixth 'step (a) shown in the first embodiment. In addition, about the 7th process, the reference example which synthesize | combined the isoindoline final derivative using the isoindoline intermediate derivative synthesize | combined by the publicly known method is shown.

Example 1
(First step)
According to the following reaction formula, dibromoindane was synthesized from indane.

A 10 L glass reactor was charged with 1.08 kg (9.1 mol) of indane, 3.2 L of chloroform, and 25.6 g (5 mol%) of iron, and 3.0 kg (2.05 eq) of bromine for 2 hours under ice-cooling. It was dripped over. After completion of the dropwise addition, the mixture was stirred overnight at room temperature. The mixture was ice-cooled again, and a 3N sodium hydroxide aqueous solution was added dropwise over 2 hours. After the whole amount was added dropwise, the reaction solution was filtered through Celite, and the organic phase separated from the filtrate was washed with an aqueous sodium thiosulfate solution and concentrated. Next, recrystallization purification (chloroform / methanol = 1/1 (volume ratio)) yielded 1.67 kg of 5,6-dibromoindane (yield 66%, GC purity 99%).

¹ H NMR (reference material: TMS, solvent: CDCl ₃ ) δ (ppm): 2.08 (2H, quintet), 2.85 (4H, t), 7.46 (2H, s)

(Second step)
Indanedicarboxylic acid was synthesized from dibromoindane according to the following reaction formula.

In a 10 L autoclave, tetrahydrofuran (THF) 2.9 L, 5,6-dibromoindane 800 g (2.9 mol, 1 eq), palladium acetate 16 g (2.5 mol%), triphenylphosphine 78 g (10 mol%), triethylamine 1.32 kg ( 4.5 eq) and 1.44 kg (28 eq) of water were added, and after nitrogen substitution and carbon monoxide (CO) substitution, the temperature was raised to an internal temperature of 120 ° C., and CO was introduced to adjust the internal pressure to 0.9 MPa. . After the change in internal pressure ceased, the internal temperature was naturally cooled to 50 ° C. After purging with nitrogen, the entire reaction solution was extracted. The reaction solution filtered through Celite was concentrated, and THF and triethylamine were distilled off. To the residue, 1.5 L of toluene and 0.8 L of water were added, and the aqueous layer separated into two layers was washed again with toluene. Concentrated hydrochloric acid (440 g) was added dropwise to the aqueous layer, the precipitate was filtered, washed with water, and dried to obtain 535 g of a crude product of 5,6-indandicarboxylic acid (yield 90%, GC purity> 99%). ).

¹ H NMR (reference material: TMS, solvent: CDCl ₃ ) δ (ppm): 2.05 (2H, quintet), 2.91 (4H, t), 7.49 (2H, s)

(Third step)
Indane dicarboxylic acid anhydride was synthesized from indane dicarboxylic acid according to the following reaction formula.

A 10 L glass three-necked flask was charged with 3.5 L of acetic anhydride and 1.56 kg (7.6 mol) of 5,6-indandicarboxylic acid, heated to an internal temperature of 110 ° C., and stirred for 4 hours. The temperature was lowered while stirring overnight, and the mixture was cooled with ice and further stirred for 4 hours at an internal temperature of 5 ° C or lower. The reaction solution was filtered, washed and dried to obtain 1.22 kg of crude 6,6-indanedicarboxylic anhydride (yield 86%).

¹ H NMR (reference material: TMS, solvent: CDCl ₃ ) δ (ppm): 2.24 (2H, quintet), 3.08 (4H, t), 7.79 (2H, s)

(4th process and 5th process)
According to the following reaction formula, indandicarboxylic acid anhydride and Wittig reagent are reacted to form an ester derivative, and then the resulting ester derivative and aniline are reacted successively to obtain the first isoindoline derivative. Synthesized.

（式中、Ｐｈはフェニル基、Ｂｎはベンジル基を表す。）

(In the formula, Ph represents a phenyl group, and Bn represents a benzyl group.)

(4th process)
In a 10 L glass reactor, 550 g (2.9 mol) of a crude product of 5,6-indandicarboxylic anhydride, Wittig reagent (Ph ₃ P = CHCO ₂ Bn; where Ph represents a phenyl group, Bn represents a benzyl group ) After adding 1.26 kg (1.1 eq) and 5.5 L of tetrahydrofuran and heating under reflux for 12 hours, the entire amount of the solvent was distilled off to obtain a residue. The obtained residue was used as a starting material for the subsequent fifth step without being isolated and purified in this step (note that the yield was not calculated at this point).

(5th process)
To the residue obtained in the fourth step, 4.7 L of acetic acid and 286 g (1 eq) of aniline were added and stirred at 110 ° C. for 3 hours. Next, after cooling the internal temperature to 60 ° C., 1.7 L of methanol was added, the temperature was naturally lowered to room temperature, and then stirred at 5 ° C. or lower for 1 hour. Subsequently, filtration, washing, and drying are performed to obtain (3-oxo-2-phenyl-3,5,6,7-tetrahydro-2H-2-aza-s-indacene-1-ylidene as the first isoindoline derivative. ) Acetic acid benzyl ester was obtained in a yield of 1.04 kg (the yield obtained through both the fourth step and the fifth step was 90%).

¹ H NMR (reference material: TMS, solvent: CDCl ₃ ) δ (ppm): 2.19 (2H, quintet), 3.03 (2H, t), 3.05 (2H, t), 5.19 ( 2H, s), 5.49 (1H, s), 7.2-7.6 (10H), 7.76 (1H, s), 8.94 (1H, s)

(Sixth step (a))
According to the following reaction formula, a second isoindoline derivative was synthesized by performing asymmetric reduction by catalytic hydrogenation of the first isoindoline derivative in the presence of an asymmetric catalyst.

（式中、Ｒはベンジル基を表す。）

(In the formula, R represents a benzyl group.)

In a 13 mL autoclave, (3-oxo-2-phenyl-3,5,6,7-tetrahydro-2H-2-aza-s-indacene-1-ylidene) acetic acid benzyl ester 0.1 g (0.25 mmol), As an asymmetric catalyst ([(S) MeOXyl-PhanePhos-Rh (COD)] BF ₄ ]) (0.01 eq), 3 mL of 1,2-dichloroethane was introduced, hydrogen was introduced, and a pressure condition of 2.5 MPa Under stirring at 50 ° C. for 20 hours. After heating and stirring, when the reaction solution was measured by high performance liquid chromatography (HPLC), R- (3-oxo-2-phenyl-3,5,6,7-tetrahydro-2H-2 was used as the second isoindoline derivative. -Aza-s-indasen-1-yl) acetic acid benzyl ester was confirmed to be produced with an optical purity of 61% ee (conversion 99% or more). The solvent of the reaction solution was distilled off, and the product was separated by silica gel column chromatography (chloroform / toluene = 1/1).

¹ H NMR (reference substance: TMS, solvent: CDCl ₃ ) δ (ppm): 2.11 (2H, quintet), 2.49 (1H, dd), 2.87 (2H, t), 2.94 ( 1H, dd), 2.95 (2H, t), 5.10 (2H, dd), 5.50 (1H, dd), 7.2-7.6 (11H, m), 7.70 (1H , S)

(Example 2)
A second isoindoline derivative was synthesized in the same procedure as in Example 1 except that the asymmetric reduction reaction in the sixth step (a) was performed according to the following procedure.

In a 13 mL autoclave, (3-oxo-2-phenyl-3,5,6,7-tetrahydro-2H-2-aza-s-indacene-1-ylidene) acetic acid benzyl ester 0.1 g (0.25 mmol), As an asymmetric catalyst ([(S) Xyl-PhanePhos-Rh (COD)] BF ₄ )) (0.01 eq), 3 mL of 1,2-dichloroethane was introduced, hydrogen was introduced, and a pressure condition of 2.5 MPa Under stirring at 50 ° C. for 20 hours. After heating and stirring, when the reaction solution was measured by high performance liquid chromatography (HPLC), R- (3-oxo-2-phenyl-3,5,6,7-tetrahydro-2H-2-aza-s-indacene- It was confirmed that 1-yl) acetic acid benzyl ester was produced with an optical purity of 50% ee (conversion rate of 99% or more). The solvent of the reaction solution was distilled off, and the product was separated by silica gel column chromatography (chloroform / toluene = 1/1).
(Examples 3 to 4)
A second isoindoline derivative was synthesized in the same procedure as in Example 1 except that the asymmetric reduction reaction in the sixth step (a) was performed using the asymmetric catalyst and reaction conditions shown in Table 2. .

(Example 5)
According to the following procedure, Ph ₃ P═CHCO ₂ Me (wherein Ph represents a phenyl group and Me represents a methyl group) is used as the Wittig reagent in the fourth step, and the product of the fifth step is converted into a methyl ester form. The second isoindoline derivative was synthesized in the same procedure as in Example 1 except that the asymmetric reduction reaction of the methyl ester compound was performed in the sixth step (a) under the reaction conditions shown in Table 2. did.

(4th process)
In a 300 mL glass reactor, 10 g (53.1 mmol) of a crude product of 5,6-indandicarboxylic anhydride, 53.1 g (159 mmol, 3 eq) of Wittig reagent (Ph ₃ P = CHCO ₂ Me) described above, and 100 mL of tetrahydrofuran were added. The mixture was heated to reflux for 12 hours, and then the entire solvent was distilled off to obtain a residue. The obtained residue was used as a starting material for the subsequent fifth step without being isolated and purified in this step (note that the yield was not calculated at this point).

(5th process)
To the residue obtained in the fourth step, 85 mL of acetic acid and 5 g (1 eq) of aniline were added and stirred at 110 ° C. for 3 hours. After cooling the internal temperature to 60 ° C., 30 mL of methanol was added, the temperature was naturally lowered to room temperature, and then stirred at 5 ° C. or lower for 1 hour. Filtration, washing and drying gave (3-oxo-2-phenyl-3,5,6,7-tetrahydro-2H-2-aza-s-indacene-1-ylidene) acetic acid methyl ester in a yield of 15 g. (The yield obtained through both the fourth step and the fifth step was 88%).

(3-Oxo-2-phenyl-3,5,6,7-tetrahydro-2H-2-aza-s-indacene-1-ylidene) acetic acid methyl ester
¹ H NMR (reference material: TMS, solvent: CDCl ₃ ) δ (ppm): 2.19 (2H, quintet), 3.03 (2H, t), 3.08 (2H, t), 3.75 ( 3H, s), 5.46 (1H, s), 7.29 (2H, m), 7.46 (1H, m), 7.54 (2H, m), 7.76 (1H, s), 8.96 (1H, s)

(Example 6)
A second isoindoline derivative was synthesized in the same procedure as in Example 5 except that the sixth step (a) was performed using the reaction conditions shown in Table 2.
The reaction conditions in the 6th process (a) of Examples 1-6 are put together in Table 2, and are shown.

Thus, by performing asymmetric reduction using a predetermined asymmetric catalyst, an excessive amount of a compound having the desired configuration is obtained as compared with a compound having a configuration opposite to the desired configuration. Can do.

(Example 7)
According to the reaction formula shown below, the second isoindoline derivative of step 6a (a) was hydrolyzed or hydrogenolyzed to synthesize an isoindoline intermediate derivative.

(In the sixth step (a), R = benzyl group)
In a 50 mL autoclave, 0.1 g (0.25 mmol) of R- (3-oxo-2-phenyl-3,5,6,7-tetrahydro-2H-2-aza-s-indasen-1-yl) acetic acid benzyl ester, Palladium on carbon (0.01 eq) and 30 mL of methanol were added, hydrogen was introduced, and the mixture was heated and stirred at 50 ° C. for 9 hours under 1 MPa pressure.
After heating and stirring, the reaction solution was measured by high performance liquid chromatography, and R- (3-oxo-2-phenyl-3,5,6,7-tetrahydro-2H-2-aza-s-indasen-1-yl) was measured. It was confirmed that acetic acid was produced (conversion rate of 99% or more).

(In the 6 'step (a), when R = methyl group)
In a 100-mL glass reaction vessel, 0.1 g (0. 0) of R- (3-oxo-2-phenyl-3,5,6,7-tetrahydro-2H-2-aza-s-indasen-1-yl) acetic acid 3 mmol), 12N hydrochloric acid (3 eq), and 40 mL of methanol were added, and the mixture was stirred at 40 ° C. for 24 hours. After stirring, the reaction solution neutralized by high performance liquid chromatography was measured, and R- (3-oxo-2-phenyl-3,5,6,7-tetrahydro-2H-2-aza-s-indacene-1 was measured. -Yl) It was confirmed that acetic acid was produced (conversion rate of 98% or more).

¹ H NMR (reference material: TMS, solvent: CDCl ₃ ) δ (ppm): 2.09 (2H, quintet), 2.87 (1H, dd), 2.95 (2H, t), 2.97 ( 2H, t), 5.60 (1H, dd), 7.24 (1H, t), 7.46 (2H, t), 7.50 (1H, s), 7.59 (1H, s), 7.60 (2H, d)

(Reference example)
According to the following reaction formula, the final isoindoline derivative was synthesized from the isoindoline intermediate derivative. The isoindoline intermediate derivative was synthesized by a method known in the literature.

In a 5 L glass reactor, 250 g (0.8 mol) of R- (3-oxo-2-phenyl-3,5,6,7-tetrahydro-2H-2-aza-s-indasen-1-yl) acetic acid, toluene 2.5 L and 0.4 g of DMF were added, 205 g (1.7 mol) of thionyl chloride was added, and the mixture was heated at 70 ° C. for 1 hour. Subsequently, the internal temperature was lowered to 50 ° C., and 1 L of toluene was distilled off under reduced pressure. Next, the temperature was lowered to room temperature, 2.3 L of ethyl acetate was added, 166 g (1.7 mol) of N-methylpiperazine was added dropwise at 4 ° C., and the mixture was stirred at room temperature for 2 hours.

To the reaction solution, 1.3 L of 2N hydrochloric acid and 3 L of water were added to separate into two phases, and the lower phase after separation was washed with 1.5 L of ethyl acetate. To this lower phase, a 4N-NaOH aqueous solution was dropped over 45 minutes. The resulting precipitate was filtered, washed with 1.5 L of water, and dried to obtain a crude isoindoline final derivative (302 g, 0.78 mol, yield 96%). By recrystallization purification (acetone / water = 9/1 (volume ratio)), 181 g of (−)-2- (2-phenyl) -3- [2- (4-methyl) was obtained as the final isoindoline derivative. -1-Piperazyl) -2-oxoethyl] -3,5,6,7-tetrahydrocyclopenta [f] isoindoline-1 (2H) -one was obtained (recrystallization recovery rate 60%).

¹ H NMR (reference material: TMS, solvent: CDCl ₃ ) δ (ppm): 2.17 (4H, m), 2.26 (3H, s), 2.40 (3H, m), 2.89 ( 1H, dd), 2.99 (4H, t), 3.23 (2H, m), 3.68 (2H, m), 5.81 (1H, dd), 7.21 (1H, m), 7.44 (3H, m), 7.66 (2H, m), 7.73 (1H, s)

Hereinafter, examples more specifically disclosing the third embodiment of the present invention will be shown, but the present embodiment is not limited to only these examples.

(Example)
The above-mentioned 2 ′ step (a) and 2 ′ step (b) were performed in place of the second step in the reaction route shown in the first embodiment. Specifically, indanedicarboxylic acid was synthesized from dibromoindane via indanedicarboxylic acid dialkyl ester. Since other steps are the same as those in the first embodiment, description thereof is omitted.

(2 'process (a) and 2' process (b))
Indane dicarboxylic acid dialkyl ester was synthesized from dibromoindane according to the following reaction formula, and then indane dicarboxylic acid was synthesized continuously by hydrolysis with alkali.

(Second step (a))
A 10 L autoclave was charged with 3.8 L of methanol, 750 g (2.7 mol) of 5,6-dibromoindane, 15 g (2.5 mol%) of palladium acetate, 35.7 g (5 mol%) of triphenylphosphine, and 830 g (3 eq) of triethylamine. The temperature was raised to an internal temperature of 120 ° C. in a carbon monoxide (CO) atmosphere. Further, CO was introduced to adjust the internal pressure to 0.9 MPa and reacted for 5 hours. After 5 hours, the reaction solution was naturally cooled to room temperature, purged with nitrogen, and the whole reaction solution was extracted. The extracted reaction solution was filtered through Celite, and concentrated by distilling off methanol and triethylamine in the reaction solution after filtration. The residue was dissolved by adding 3.8 kg of 2N-hydrochloric acid and 3 L of ethyl acetate, and the organic layer separated into two layers was concentrated to the extent that it was not dried to obtain a concentrate. The obtained concentrate was not isolated in this step, and was used as it was as a starting material in the 2 ′ step (b) (note that the yield was not calculated at this point).

(2 ′ step (b))
To the concentrate obtained in the 2 ′ step (a), 326 g (3 eq) of sodium hydroxide and 4.3 L of water were added and heated at 80 ° C. for 2 hours. After 2 hours, the temperature was lowered to room temperature, and 1 L of toluene was added to separate the two layers. Next, 870 g of concentrated hydrochloric acid was dropped into the aqueous layer at 10 ° C. or lower, and the resulting precipitate was filtered and dried to obtain 455 g of 5,6-indandicarboxylic acid (second step (a) and second step). The yield obtained through both steps (b) was 81%).

¹ H NMR (reference material: TMS, solvent: CDCl ₃ ) δ (ppm): 2.05 (2H, quintet), 2.91 (4H, t), 7.49 (2H, s)

As described above, industrially, the product of the 2 ′ step (a) may be transferred to the 2 ′ step (b) without isolating and purifying the indane dicarboxylic acid dialkyl ester. For reference, NMR data of 5,6-indanedicarboxylic acid dimethyl ester synthesized in this example is shown below.

¹ H NMR (reference material: TMS, solvent: CDCl ₃ ) δ (ppm): 2.13 (2H, quintet), 2.95 (4H, t), 3.88 (6H, s), 7.55 ( 2H, s)

Claims (7)

Formula (5):

Indane dicarboxylic acid anhydride represented by the following formula (α):

(In the formula (α), Ph represents a phenyl group, R represents a linear or branched alkyl group having 1 to 6 carbon atoms, and the alkyl group may have one or more aryl groups. Good)
Is reacted with a Wittig reagent represented by formula (6):

(In formula (6), R represents the same substituent as in formula (α))
Obtaining an ester derivative represented by:
The ester derivative and aniline are reacted to form the formula (7):

(In formula (7), R represents the same substituent as in formula (α))
A first isoindoline derivative represented by formula (8): and catalytic hydrogenation of the first isoindoline derivative in the presence of an asymmetric catalyst;

And the second isoindoline derivative is hydrolyzed or hydrogenolyzed to give the formula (10):

Obtaining an isoindoline intermediate derivative represented by:
The first isoindoline derivative is hydrolyzed or hydrogenolyzed to give the formula (9):

A third isoindoline derivative represented by formula (10) is obtained by catalytic hydrogenation of the third isoindoline derivative in the presence of an asymmetric catalyst:

A method for synthesizing an isoindoline intermediate derivative comprising the step of obtaining an isoindoline intermediate derivative represented by The synthesis of the isoindoline intermediate derivative according to claim 1, wherein the asymmetric catalyst includes a metal selected from the group consisting of nickel, palladium, platinum, rhodium, iridium, and ruthenium and an optically active phosphorus-containing ligand. Method. The optically active phosphorus-containing ligand has the following formulas (Ia-S), (Ia-R), (Im-RS) and (Im-SR):

(In the formula, Ar represents an aryl group which may have one or more substituents, Ph represents a phenyl group, R represents a linear or branched alkyl group having 1 to 6 carbon atoms, or 1 Represents a phenyl group which may have the above substituents)
The method for producing an isoindoline intermediate derivative according to claim 2, wherein In the presence of a metal catalyst, formula (1):

Is reacted with an indane represented by formula (2):

(In formula (2), X and Y each independently represents Cl, Br or I)
Obtaining a dihalogenoindan represented by:
In the presence of a first transition metal catalyst and a base, the dihalogenoindane is reacted with carbon monoxide and water to obtain a compound represented by the formula (4):

A step of obtaining an indane dicarboxylic acid represented by formula (5): and reacting the indane dicarboxylic acid with acetic anhydride to obtain a compound represented by formula (5):

A step of obtaining an indane dicarboxylic acid anhydride represented by:
In the presence of a metal catalyst, formula (1):

Is reacted with an indane represented by formula (2):

(In formula (2), X and Y each independently represents Cl, Br or I)
Obtaining a dihalogenoindan represented by:
In the presence of a second transition metal catalyst and a base, the dihalogenoindane is reacted with carbon monoxide and an alcohol to obtain a compound represented by the formula (3):

(In formula (3), R ¹ represents a linear or branched alkyl group having 1 to 6 carbon atoms, and the alkyl group is one or more aryl groups. May have a group);
The indane dicarboxylic acid alkyl ester is hydrolyzed to obtain the formula (4):

A step of obtaining an indane dicarboxylic acid represented by formula (5): and reacting the indane dicarboxylic acid with acetic anhydride to obtain a compound represented by formula (5):

The method for synthesizing an isoindoline intermediate derivative according to any one of claims 1 to 3, further comprising a step of obtaining an indanedicarboxylic acid anhydride represented by the formula: The method for synthesizing an isoindoline intermediate derivative according to claim 4, wherein the metal catalyst is iron, and the first transition metal catalyst is palladium acetate. The method for synthesizing an isoindoline intermediate derivative according to claim 4, wherein the second transition metal catalyst is palladium acetate. By reacting the isoindoline intermediate derivative obtained by the method for synthesizing the isoindoline intermediate derivative according to any one of claims 1 to 6 with a chlorinating agent, and reacting the resulting product with N-methylpiperazine. Formula (11):

A method for synthesizing a final isoindoline derivative represented by the following formula.