WO2011002075A1 - Method for producing lactam compound and production intermediate thereof - Google Patents

Abstract

Disclosed is a method for commercially producing a lactam compound with high yield and high quality. Specifically disclosed is a method for producing a lactam compound via an intermediate that is represented by formula (9). (In the formula, R¹ represents a C_1-6 alkyl group, a C_2-6 alkenyl group, a C_2-6 alkynyl group or a C_3-6 cycloalkyl group.)

Description

Process for producing lactam compound and production intermediate thereof

The present invention relates to a novel method for producing a lactam compound and a production intermediate thereof. More specifically, the present invention can be carried out under mild and safe conditions, and a simple and efficient method for producing a lactam compound as a therapeutic agent for diabetes or a production intermediate thereof, and a production intermediate useful for such a production method. About the body.

Diabetes is a lifestyle-related disease that has increased remarkably in recent years, and the development of therapeutic agents for it has been actively conducted. For example, a compound represented by the following formula (1) has been reported to have an excellent sugar transport enhancing action and a hypoglycemic action (Patent Document 1).

 
[式中の記号は、前記特許文献１を参照のこと。]
　すなわち式（２）で表されるシクロヘキサン誘導体と芳香族アルデヒド（３）を反応させ環化体（４）を得た後アシル化などを行うことにより化合物（５）を得ている。しかしながら、これらは式（１）の化合物の工業的製造方法とするにはいくつかの課題があることが判明した。
　例えば、式（４）においてＡが２－メチルベンゾフランを表す化合物である化合物（６）から、化合物（１）を得るには、下記スキームに示すように式（７）で表されるＯ－保護グリコール酸を例えば１－［３－（ジメチルアミノ）プロピル］－３－エチルカルボジイミド塩酸塩のような縮合剤を用いて、化合物（６）と縮合して下記式（８）で表されるアシル化体を得た後に脱保護する方法がある。

 
（式中、ＲａはＣ_１－６アルキル基を表す。）
　しかし、この縮合反応では縮合剤および（７）を大過剰に使用しないと十分な速度で反応が進行せず、工業的規模で製造するにはより安価で効率的な方法が望まれる。 By the way, the method shown to the following scheme is known as a synthesis method of the compounds represented by the following general formula (5) including the formula (1) (for example, refer to Patent Document 1 and Patent Document 2).

[See Patent Document 1 for symbols in the formula. ]
That is, the cyclohexane derivative represented by the formula (2) and the aromatic aldehyde (3) are reacted to obtain a cyclized product (4), followed by acylation and the like to obtain the compound (5). However, it has been found that there are some problems in the industrial production method of the compound of formula (1).
For example, in order to obtain the compound (1) from the compound (6) in which A represents 2-methylbenzofuran in the formula (4), the O-protection represented by the formula (7) as shown in the following scheme Acylation represented by the following formula (8) by condensing glycolic acid with compound (6) using a condensing agent such as 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride There is a method of deprotection after obtaining the body.

(In the formula, Ra represents a C _1-6 alkyl group.)
However, in this condensation reaction, unless the condensing agent and (7) are used in a large excess, the reaction does not proceed at a sufficient rate, and a cheaper and more efficient method is desired for production on an industrial scale.

In addition, the compound represented by the formula (8) is a compound that is difficult to handle in physical properties and difficult to isolate and purify, and is not a suitable compound as an intermediate in an industrial production method.

On the other hand, it was found that there was a problem in the production of the compound (6). (1R, 8R, 10R) -8- (2-methylbenzofuran-7-yl) -2,5,9-tria represented by the formula (6) which is an intermediate for obtaining the compound of the formula (1) Zatricyclo [8.4.0.0 ^3,7 ] tetradec-3 (7) -en-6-one can be synthesized according to the method described in Patent Document 1. However, the stereoselectivity with the (1R, 8S, 10R) isomer represented by the following formula (11) is not good and the decomposition reaction further proceeds, so that it has a necessary stereochemical structure (1R, 8R, 10R). ) It was difficult to obtain the product (6) in good yield.

Moreover, it turned out that there exists a subject also in manufacture of the compound represented by Formula (12) used as the raw material of the said compound (6). 2-methylbenzofuran-7-carbaldehyde represented by the formula (12) can be synthesized according to the method described in Patent Document 1 or Patent Document 3. However, in addition to the low yield, it was necessary to carry out a method that is not suitable for an industrial process, such as a high temperature condition of 250 ° C., a low temperature reaction condition of −78 ° C., and silica gel column purification.

International Publication No. 2006/118341 Pamphlet International Publication No. 2002/044180 Pamphlet WO 97/32870 pamphlet

An industrial production method for producing a lactam compound represented by formula (1) with higher yield and quality than conventional methods has been desired.

の化合物またはその塩を
下記式（９）

（式中、Ｒ^１はＣ_１－６アルキル基、Ｃ_２－６アルケニル基またはＣ_２－６アルキニル基、またはＣ_３－６シクロアルキル基を示す。）で表される化合物またはその塩に変換する工程を含む、下記式（１）

の化合物またはその塩を製造する方法。
［２］　式（６）の化合物またはその塩を式（１３）
ＸＣＯＣＨ_２ＯＣＯＲ^１　（１３）
（式中、Ｒ^１はＣ_１－６アルキル基、Ｃ_２－６アルケニル基、Ｃ_２－６アルキニル基、またはＣ_３－６シクロアルキル基を示し、Ｘはハロゲン原子を示す。）の化合物
と反応させる工程を含む、前記［１］に記載の方法。
［３］　塩基存在下で反応させる前記［２］に記載の方法。
［４］　式（９）の化合物またはその塩を塩基で処理する工程を含む前記［１］～［３］のいずれかに記載の方法。
［５］　ワンポットで反応を行うことができる前記［１］～［４］のいずれかに記載の方法。
［６］　下記式（２）

の化合物またはその塩と下記式（１２）

の化合物またはその塩をアルカリ性条件下で縮合環化させ式（６）の化合物を得る工程を含む前記［１］～［５］のいずれかに記載の方法。
［６－２］　下記式（２）

の化合物またはその塩と下記式（１２）

の化合物またはその塩をアルカリ性条件下で縮合環化させる式（６）

の化合物またはその塩の製造方法。
［７］　式（１４）

の化合物またはその塩を式（１２）に変換する工程を含む、前記［６］に記載の方法。
［８］　下記（１５）

で表される化合物をパラジウム触媒および酸化剤の存在下で環化し、さらに亜硫酸水素ナトリウムと反応させることにより式（１４）の化合物またはその塩を得る工程を含む前記［７］に記載の方法。
［９］　式（１５）をパラジウム触媒で処理し、
式（１６）

の化合物またはその塩を得る工程を含む前記［８］に記載の方法。
［１０］　パラジウム触媒が、２価のパラジウム触媒である前記［８］または［９］に記載の方法。
［１１］　酸化剤がキノン類である前記［８］に記載の方法。
［１２］　カラム精製を要しない前記［１］～［１１］に記載の方法。
［１３］　式（９）

（式中、Ｒ^１はＣ_１－６アルキル基、Ｃ_２－６アルケニル基、Ｃ_２－６アルキニル基、またはＣ_３－６シクロアルキル基を示す。）
で表される化合物またはその塩。
［１４］　Ｒ^１がメチルである前記［１３］に記載の化合物またはその塩。
［１５］　式（１４）

で表される化合物またはその塩。
［１６］　ろ過分離によって、式（６）で表される化合物またはその塩を回収する方法を含む、前記［５］に記載の方法。
［１７］　式（６）で表される化合物をアセトキシアセチルクロライドと反応させて式（９）のＲ^１がメチル基を表す化合物とし、該式（９）で表される化合物を単離せずに、金属アルコキシドと反応させて式（１）で表される化合物に変換することを含む、前記［１］に記載の製造方法。
［１８］　（ｉ）下記式（１７）

で表される化合物を、下記式（１８）

で表される化合物に変換する工程；および
（ｉｉ）式（１８）で表される化合物を式（１５）

で表される化合物に変換する工程；および
（ｉｉｉ）式（１５）で表される化合物を式（１２）で表される化合物に変換する工程；
を含む前記［９］に記載の方法。
［１９］　工程（ｉ）において、式（１７）で表される化合物と、アリルブロミドを反応させることを含む、前記［１８］に記載の方法。
［２０］　アセトニトリルを含む溶媒を用いる、前記［１９］に記載の方法。
［２１］　塩基存在下で行う、前記［１９］に記載の方法。
［２２］　工程（ｉｉ）を、無溶媒加熱条件下で行う、前記［１８］に記載の方法。
［２３］　工程（ｉｉｉ）において、式（１５）で表される化合物をパラジウム触媒および酸化剤とで反応させることを含む、前記［１８］に記載の方法。
［２４］　工程（ｉｉｉ）において、エーテル類を含む溶媒を用いる、前記［１８］に記載の方法。
［２５］　工程（ｉｉｉ）において、式（１５）で表される化合物から、パラジウム触媒存在下で式（１６）

を得てから酸化剤を加える、前記［２３］に記載の方法。
［２６］　エーテル類が、テトラヒドロフランである、前記［２４］に記載の方法。
［２７］　酸化剤が、ベンゾキノンである、前記［８］または［２３］に記載の方法。
［２８］　式（１２）で表される化合物から式（１４）の化合物を経る工程を含む式（１２）で表される化合物を精製する方法。
［２９］　（ｉｖ）式（１２）で表される化合物を、式（１４）で表される化合物に変換する工程；および
（ｖ）式（１４）で表される化合物を式（１２）で表される化合物に変換する工程；
を含む、前記［８］～［２８］のいずれかに記載の方法。
［３０］　工程（ｉｖ）において、式（１２）で表される化合物と、亜硫酸水素ナトリウムを反応させることを含む、前記［２９］に記載の方法。
［３１］　工程（ｉｖ）により得られる式（１４）で表される化合物の濾過分離による精製工程を含む、前記［２９］に記載の方法。
［３２］　工程（ｖ）において、酸または塩基と式（１４）で表される化合物とを反応させることを含む、前記［２９］に記載の方法。 That is, this invention relates to the industrial manufacturing method which manufactures the lactam compound shown below, and the novel intermediate body used for it.
[1] The following formula (6)

Or a salt thereof of the following formula (9)

(Wherein R ¹ represents a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, or a C _3-6 cycloalkyl group) or a salt thereof Including the step of:

Or a salt thereof.
[2] A compound of formula (6) or a salt thereof is represented by formula (13)
XCOCH ₂ OCOR ¹ (13)
(Wherein R ¹ represents a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, or a C _3-6 cycloalkyl group, and X represents a halogen atom) The method according to [1] above, comprising a step of reacting.
[3] The method according to [2], wherein the reaction is carried out in the presence of a base.
[4] The method according to any one of [1] to [3] above, comprising a step of treating the compound of formula (9) or a salt thereof with a base.
[5] The method according to any one of [1] to [4], wherein the reaction can be carried out in one pot.
[6] The following formula (2)

Or a salt thereof and the following formula (12)

The method according to any one of [1] to [5], further comprising the step of obtaining a compound of the formula (6) by condensation cyclization of the compound or a salt thereof under alkaline conditions.
[6-2] The following formula (2)

Or a salt thereof and the following formula (12)

Wherein the compound or salt thereof is condensed and cyclized under alkaline conditions (6)

Or a salt thereof.
[7] Formula (14)

The method of said [6] including the process of converting the compound of these, or its salt into Formula (12).
[8] Following (15)

The method according to [7], further comprising the step of obtaining a compound of the formula (14) or a salt thereof by cyclizing the compound represented by formula (I) in the presence of a palladium catalyst and an oxidizing agent and further reacting with sodium bisulfite.
[9] treating formula (15) with a palladium catalyst;
Formula (16)

The method of said [8] including the process of obtaining the compound of these, or its salt.
[10] The method according to [8] or [9], wherein the palladium catalyst is a divalent palladium catalyst.
[11] The method according to [8] above, wherein the oxidizing agent is a quinone.
[12] The method described in [1] to [11] above, which does not require column purification.
[13] Formula (9)

(In the formula, R ¹ represents a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, or a C _3-6 cycloalkyl group.)
Or a salt thereof.
[14] The compound or salt thereof according to [13], wherein R ¹ is methyl.
[15] Formula (14)

Or a salt thereof.
[16] The method according to [5] above, comprising a method of recovering the compound represented by formula (6) or a salt thereof by filtration separation.
[17] A compound represented by formula (6) is reacted with acetoxyacetyl chloride to form a compound in which R ¹ in formula (9) represents a methyl group, and the compound represented by formula (9) is isolated without isolation. The manufacturing method as described in said [1] including reacting with a metal alkoxide and converting into the compound represented by Formula (1).
[18] (i) The following formula (17)

A compound represented by the following formula (18)

And (ii) converting the compound represented by formula (18) into formula (15)

And (iii) a step of converting a compound represented by formula (15) into a compound represented by formula (12);
The method according to [9] above, comprising:
[19] The method according to [18] above, comprising reacting the compound represented by formula (17) with allyl bromide in step (i).
[20] The method according to [19] above, wherein a solvent containing acetonitrile is used.
[21] The method according to [19], which is performed in the presence of a base.
[22] The method according to [18], wherein step (ii) is performed under solvent-free heating conditions.
[23] The method according to [18] above, comprising reacting the compound represented by the formula (15) with a palladium catalyst and an oxidizing agent in the step (iii).
[24] The method according to [18] above, wherein in step (iii), a solvent containing ethers is used.
[25] In the step (iii), from the compound represented by the formula (15), in the presence of a palladium catalyst, the formula (16)

The method according to [23] above, wherein the oxidizing agent is added after obtaining the above.
[26] The method described in [24] above, wherein the ether is tetrahydrofuran.
[27] The method according to [8] or [23] above, wherein the oxidizing agent is benzoquinone.
[28] A method for purifying the compound represented by the formula (12) comprising the step of passing the compound of the formula (14) from the compound represented by the formula (12).
[29] (iv) a step of converting the compound represented by the formula (12) into a compound represented by the formula (14); and (v) converting the compound represented by the formula (14) by the formula (12) Converting to the represented compound;
The method according to any one of [8] to [28], comprising:
[30] The method according to [29] above, comprising reacting the compound represented by formula (12) with sodium hydrogen sulfite in step (iv).
[31] The method according to [29] above, comprising a purification step by filtration separation of the compound represented by formula (14) obtained by step (iv).
[32] The method according to [29] above, comprising reacting the acid or base with the compound represented by formula (14) in the step (v).

The present invention provides a production method suitable for mass synthesis of lactam derivatives and a novel intermediate. By using the production method of the present invention, a cyclized product that is an intermediate can be obtained in a stereoselective manner, and a lactam derivative that is a target compound is produced in high yield and high purity by way of a diacylated product. be able to. Moreover, the manufacturing method suitable for the mass synthesis of the benzofuran derivative which is a raw material is provided.

The possible combinations of the above [1] to [32] are preferable, and an embodiment obtained by combining a plurality of preferable embodiments described in this specification is preferable.
Examples of the “halogen atom” in the present invention include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and a chlorine atom or a bromine atom is preferable.
The “C _1-6 alkyl group” is a monovalent group derived by removing one arbitrary hydrogen atom from a linear or branched aliphatic hydrocarbon having 1 to 6 carbon atoms. Specifically, methyl group, ethyl group, isopropyl group, butyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group, pentyl group, isopentyl group, 2,3-dimethylpropyl group, hexyl group Etc. A C _1-3 alkyl group is preferred.

The “C _2-6 alkenyl group” is a monovalent group having at least one double bond among linear or branched aliphatic hydrocarbon groups having 1 to 6 carbon atoms. Specific examples of the C _2-6 alkenyl group include a vinyl group, an allyl group, a 1-propenyl group, a 2-propenyl group, a 1-butenyl group, a 2-butenyl group (including cis and trans), and 3-butenyl. Group, pentenyl group, hexenyl group and the like. A C _2-4 alkenyl group is preferred, and a C _2-3 alkenyl group is more preferred.
The “C _2-6 alkynyl group” is a monovalent group having at least one triple bond among linear or branched aliphatic hydrocarbon groups having 1 to 6 carbon atoms. Specific examples include ethynyl group, 1-propynyl group, propargyl group, 3-butynyl group and the like. A C _2-4 alkynyl group is preferable, and a C _2-3 alkynyl group is more preferable.
“C _3-6 cycloalkyl group” means a cyclic aliphatic hydrocarbon group, and specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like. A C _4-6 cycloalkyl group is preferred.

The salt used in the present invention includes a salt with a chemically acceptable acid and a salt with a chemically acceptable base.
Salts with chemically acceptable acids used in the present invention include inorganic acids (for example, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, etc.), organic carboxylic acids (for example, carbonic acid, acetic acid, Citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, trifluoroacetic acid, tannic acid, butyric acid, decanoic acid, salicylic acid, lactic acid, oxalic acid, mandelic acid, malic acid, etc.), organic sulfonic acid (for example, And salts with methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid and the like.
Salts with chemically acceptable bases include alkali metal salts (eg, sodium salts, potassium salts, lithium salts), alkaline earth metal salts (eg, calcium salts, magnesium salts), metal salts (eg, aluminum) Salt, etc.).
The salt of compound (1) is preferably a medically acceptable salt.
Medically acceptable salts include acid addition salts such as inorganic acid salts, organic acid salts and sulfonate salts; base addition salts such as alkali metal salts, alkaline earth metal salts, metal salts and ammonium salts. . Examples of the inorganic acid salt include hydrochloride, hydrobromide, sulfate, phosphate, and the like. Examples of the organic acid salt include carbonate, acetate, benzoate, oxalate, maleate, fumarate, tartrate, citrate and the like. Examples of the sulfonate include methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like. Examples of the alkali metal salt include sodium salt, potassium salt, lithium salt and the like. Examples of alkaline earth metal salts include calcium salts and magnesium salts. Examples of the metal salt include an aluminum salt.
In the present invention, carrying out the reaction in one pot means carrying out the reaction in one step without isolating and purifying the reaction product at each stage.
The compound represented by the formula (1) or a salt thereof (hereinafter sometimes referred to as “compound (1)”) includes hydrates and solvates thereof.
The compound represented by the formula (1) is preferably not in the form of a salt.
Compounds represented by the formulas (2), (6), (9), (9a) and (11) or chemically acceptable salts thereof (hereinafter sometimes referred to as “compound (2)”, etc.) Includes hydrates and solvates thereof.

（式中、Ｒ^１の定義は前記の通りである。）
　ここで、化合物（６）、（９）はそれぞれ塩の形態をとらないものが好ましい。
　以下、好ましい実施形態について更に詳細に記載する。 1. Process for Producing Lactam Compound (1) The present invention is a process for producing a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof, comprising using the following steps (a) and (b): It is the manufacturing method of the lactam compound characterized.
Step (a) is a step of converting a compound represented by formula (6) or a salt thereof into a compound represented by formula (9) or a salt thereof. Step (b) is a step of converting the compound represented by formula (9) or a salt thereof into the compound represented by formula (1) or a salt thereof.
That is, as shown in the following formula, the step (a) is a step of acylating the cyclized product represented by the formula (6) to obtain a diacylated product represented by the formula (9), and the step (b) Then, this diacylated form is deacylated to obtain a lactam compound represented by the formula (1).

(Wherein, R ^{1 is} as defined above.)
Here, it is preferable that the compounds (6) and (9) do not take salt forms.
Hereinafter, preferred embodiments will be described in more detail.

(Process (a))
In step (a), an O-protected glycolic acid halide (XCOCH ₂ OCOR ¹ ; preferably represented by the formula (13) in the presence of a base, wherein X and R ¹ are as defined above. ) Is acylated using 2 equivalents or more of the cyclized product (6), the diacylated product represented by the formula (9) is obtained with good selectivity.
The compound represented by formula (9) is easy to handle in terms of physical properties and easy to be isolated and purified, and can be obtained in good yield and quality. For example, the present compound (9) can be isolated and purified by obtaining it as a solid by filtration separation.
R ¹ of the O-protected glycolic acid halide represented by the formula (13) represents a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, or a C _3-6 cycloalkyl group. A C _1-6 alkyl group is preferred, and a methyl group is most preferred. X represents a halogen atom, and examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and a chlorine atom is preferable.

The acid halide is used in an amount of 2 equivalents or more based on the cyclized product, but 2.30 to 2.80 equivalents are most preferable from the viewpoints of yield, suppression of by-products, and economy.
As the base, a substituted amine such as triethylamine, N-methylmorpholine, N, N-diisopropyl-N-ethylamine, or pyridine is used, and a substituted amine is preferable, and triethylamine is most preferable.
The base is preferably used in an amount of 1 equivalent or more based on the acid halide used. When the acid halide is used in an amount of 2.30 to 2.80 equivalents based on the cyclized product, the base is most preferably used in an amount of 2.50 equivalents to 3.00 equivalents based on the cyclized product.

Examples of the reaction solvent for acylation include ethers such as tetrahydrofuran, dioxane, cyclopentylmethyl ether, 1,2-dimethoxyethane, esters such as ethyl acetate and isopropyl acetate, hydrocarbons such as hexane and heptane, toluene, xylene and the like. Aromatic hydrocarbons, ketones such as acetone and 2-butanone, halogenated hydrocarbons such as dichloromethane, chloroform and chlorobenzene, nitriles such as acetonitrile and propionitrile, N, N-dimethylformamide, N-methylpyrrolidone and the like Amides and mixtures thereof are used.
Preference is given to esters, ketones, and mixed solvents of aromatic hydrocarbons and hydrocarbons.
The order in which the raw materials and reagents are added is not particularly limited, but it is preferable to add the acid halide of formula (13), the cyclized product of formula (6), and the base in this order from the viewpoint of yield and suppression of side reactions.

The reaction temperature is between 0 ° C. and the boiling point of the reaction mixture. The temperature is preferably 10 ° C. or more, and most preferably 15 ° C. to 25 ° C. when the ester is a solvent, and 55 ° C. to 65 ° C. is most preferable when the ester is a mixed solvent of ketones and aromatic hydrocarbons and hydrocarbons.
The dropping time of the base is preferably 1 hour or longer. The reaction time depends on the type of solvent and the temperature, but is generally 1 to 24 hours.
After completion of the reaction, water is added to inactivate excess acid chloride to stop the reaction.
When the reaction is carried out in a mixed solvent of aromatic hydrocarbon and hydrocarbon, the compound of the formula (9) is precipitated, and it can be separated by filtration to obtain the target crystal.
When the reaction is carried out with esters or ketones, the reaction product is extracted with a reaction solvent. The extraction solvent is replaced with a solvent containing alcohols, and the target product is used in step (b) without isolation and purification. This method is useful as an industrial process because it does not require any complicated operation such as isolation and purification of solid using a centrifuge. Ethyl acetate and 2-butanone are preferable as the reaction solvent from this viewpoint.

The compound represented by the formula (9) obtained as described above is novel and is useful as an intermediate for producing the final product represented by the formula (1). Accordingly, the present invention provides the compound of formula (9) as such an intermediate. In the formula (9), a compound in which R ¹ is methyl ((1R, 8R, 10R) -5,9-bis (2-acetoxyacetyl) -8- (2-methylbenzofuran-7-yl)- 2,5,9-triazatricyclo [8.4.0.0 ^3,7 ] tetradec-3 (7) -en-6-one) is preferred.

(Process (b))
Next, step (b) will be described.
When the diacylated product (9) obtained in step (a) is treated with a base, the acyl group at the end of the acyloxyacetyl group introduced at the 9-position is removed, and at the same time, the acyloxyacetyl introduced at the 5-position is removed. The entire group is also removed, and the lactam compound represented by the formula (1) is obtained. That is, compound (1) can be easily produced with good yield and quality by going through (6) to (9).
Solvents used in the base treatment include alcohols such as methanol, ethanol and 2-propanol, water, a mixture of alcohols and water, aromatic hydrocarbons such as toluene, hydrocarbons such as hexane and heptane, alcohols and aroma such as toluene. A mixture with a hydrocarbon such as an aromatic hydrocarbon or hexane or heptane is used. A mixture of alcohols and water is particularly preferred.

As a base, metal alkoxide such as sodium methoxide and sodium ethoxide, metal hydroxide such as sodium hydroxide, potassium hydroxide and lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc. Although metal carbonate etc. are mentioned, Metal hydroxide is preferable and potassium hydroxide is especially preferable. Metal alkoxide is also preferable, and sodium methoxide is particularly preferable. Sodium methoxide may be used in its methanol solution.
The amount of the base is not particularly limited. However, when a metal hydroxide is used as the base and a solvent containing alcohols is used as the reaction solvent, 1 to 10 equivalents relative to the diacylated product (9) are preferable. From the viewpoint of suppression and from an economical viewpoint, 3 to 5 equivalents are most preferable.

There is no particular limitation on the order of starting materials and reagents.
The reaction temperature is between 0 ° C. and the boiling point of the reaction mixture. 25 to 60 ° C is preferable, and 45 to 55 ° C is most preferable.
The reaction time depends on the type of solvent and the temperature, but is generally 1 to 24 hours.
After completion of the reaction, the reaction mixture is cooled from room temperature to 0 ° C., and the precipitate can be separated by filtration to obtain compound (1) as a solid.

　以下、好ましい実施形態について更に詳細に記載する。
　縮合環化反応は、式（２）で表されるシクロヘキサン誘導体またはその塩、式（１２）で表される化合物、メタノール等の溶媒を用いて行われ、環化体を式（６）で表される（１Ｒ，８Ｒ，１０Ｒ）体と式（１１）で表される（１Ｒ，８Ｓ，１０Ｒ）体の混合物として与えるか、または選択的に高収率の式（６）で表される（１Ｒ，８Ｒ，１０Ｒ）体として与える。
式（２）で表されるシクロヘキサン誘導体はフリー体であっても塩であってもよいが、取り扱いやすさからは、化学的に許容されうる酸類との塩が好ましく、特に塩酸塩が好ましい。
　本縮合環化反応は、化学的に許容されうる酸類との塩を用いて行う場合には、アルカリ性条件下で行うのが好ましい。アルカリ性条件下で行うと、式（６）で表される（１Ｒ，８Ｒ，１０Ｒ）体を選択的に高収率（例えば、８５％以上）で得ることができる。 2. Method for Producing Cyclized Product (6) A method for producing the cyclized product represented by formula (6) in the present invention will be described. In this production method, as shown in the following formula, an isomer mixture of (6) and (11) is produced by a condensation cyclization reaction, and only (6) is selectively obtained as a solid by crystallization. .

Hereinafter, preferred embodiments will be described in more detail.
The condensed cyclization reaction is performed using a cyclohexane derivative represented by the formula (2) or a salt thereof, a compound represented by the formula (12), a solvent such as methanol, and the cyclized product is represented by the formula (6). (1R, 8R, 10R) and (1R, 8S, 10R) isomer represented by the formula (11) are given as a mixture or selectively represented by the formula (6) in high yield ( 1R, 8R, 10R).
The cyclohexane derivative represented by the formula (2) may be a free form or a salt, but from the viewpoint of ease of handling, a salt with a chemically acceptable acid is preferable, and a hydrochloride is particularly preferable.
This condensed cyclization reaction is preferably carried out under alkaline conditions when it is carried out using a salt with a chemically acceptable acid. When carried out under alkaline conditions, the (1R, 8R, 10R) isomer represented by the formula (6) can be selectively obtained in a high yield (for example, 85% or more).

Here, the alkaline condition means a condition in which a slightly excessive amount of base is added to the reaction mixture when the compound (2) used is a salt with a chemically acceptable acid. A slightly excessive amount of the base is preferably 1.02 to 1.08 equivalent, particularly preferably 1.04 to 1.06 equivalent. Further, the pH value is preferably pH 10.0 to 13.5, particularly preferably pH 12.2 to 12.8. Usable bases include metal alkoxides such as sodium methoxide and sodium ethoxide, metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, hydrogen carbonate Although metal carbonates, such as potassium, etc. are mentioned, Metal hydroxide is preferable and especially potassium hydroxide is preferable. Metal alkoxide is also preferable, and sodium methoxide is particularly preferable. Sodium methoxide may be used in its methanol solution. Furthermore, triethylamine, pyridine, N-methylmorpholine, N, N-diisopropyl-N-ethylamine and the like can also be used.

Examples of the base to be neutralized when the compound represented by the formula (2) is a salt with acids include the above-mentioned bases. Metal hydroxide is preferable, and potassium hydroxide is particularly preferable. Metal alkoxide is also preferable, and sodium methoxide is particularly preferable.
The ratio of the compound represented by the formula (2) and the compound represented by the formula (12) is not particularly limited, but a molar ratio of 1: 0.8 to 1: 1.2 is preferable from an economic viewpoint, More preferably, the molar ratio is 1: 0.95 to 1: 1.05.
The reaction temperature is between 0 ° C. and the boiling point of the reaction mixture. Preferably 40 ° C. to the boiling point of the reaction mixture, more preferably 55 ° C. to 65 ° C. is used.
The reaction time depends on temperature and the like, but is generally 1 to 24 hours.

As the reaction solvent, alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, n-, and t-butanol are used, and a solvent containing methanol is preferable, and methanol is particularly preferable.

After the condensation cyclization reaction, a poor solvent such as water is added and then cooled to room temperature to 0 ° C., and then the precipitated crystals are separated by filtration to selectively obtain the compound represented by the formula (6) as a solid. Is possible.

3. Method for producing benzofuran (12) The present invention is a method for producing a compound represented by the formula (12), wherein the following steps (c), (d), (e), (f) and (f) a process for producing a benzofuran derivative, characterized in that g) is used.
Step (c) is a step of converting the compound represented by formula (17) into the compound represented by formula (18). Step (d) is a step of converting the compound represented by formula (18) into the compound represented by formula (15). Step (e) is a step of converting the compound represented by formula (15) into the compound represented by formula (12) via the compound represented by formula (16). Step (f) is a step of converting the compound represented by the formula (12) into the compound represented by the formula (14) and isolating and producing it as crystals. Step (g) is a step of converting the compound represented by formula (14) into the compound represented by formula (12).

以下、好ましい実施形態について更に詳細に記載する。 That is, as shown in the following formula, the step (c) is a step of alkylating the phenol represented by the formula (17) to obtain an O-allylic compound represented by the formula (18), and the step (d) In this step, the allylated product is transferred to obtain a C-allylated product represented by the formula (15). Step (e) is a step of isomerizing this C-allylic compound into an internal olefin in the presence of a palladium catalyst, followed by oxidative cyclization to obtain benzofuran (12). In the step (f), this benzofuran is converted into a sodium hydrogen sulfite adduct, followed by isolation and purification. Step (g) is a step of treating this adduct under acidic or alkaline conditions to obtain a benzofuran represented by the formula (12).

Hereinafter, preferred embodiments will be described in more detail.

(Process (c))
In step (c), allyl halide (XCH ₂ CHCH ₂ ; X is as described above) is allylated in the presence of a base to obtain an O-allylic compound represented by formula (18). can get.
X of allyl halide represents a halogen atom.
The allyl halide is used in an amount of 1 equivalent or more based on the salicylaldehyde (17), but 1.0 to 1.3 equivalents are most preferable from the viewpoint of yield and economy.
Examples of the base include metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, and metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate. Metal carbonates are preferred. In particular, potassium carbonate is preferred. Furthermore, triethylamine, pyridine, N-methylmorpholine, N, N-diisopropyl-N-ethylamine and the like can also be used.

Solvents for allylation include ethers such as tetrahydrofuran, dioxane, cyclopentylmethyl ether and 1,2-dimethoxyethane, esters such as ethyl acetate and isopropyl acetate, hydrocarbons such as hexane and heptane, and aromatics such as toluene and xylene. Aromatic hydrocarbons, ketones such as acetone and 2-butanone, halogenated hydrocarbons such as dichloromethane, chloroform and chlorobenzene, nitriles such as acetonitrile and propionitrile, amides such as N, N-dimethylformamide and N-methylpyrrolidone And mixtures thereof are used. Of these, nitriles are preferable, and acetonitrile is particularly preferable.

The order in which the raw materials and reagents are added is not particularly limited, but it is preferable to add salicylaldehyde (17) last from the viewpoints of operability, yield, and side reactions.
The reaction temperature is between 0 ° C. and the boiling point of the reaction mixture. 10 ° C or higher is preferable, and 50 ° C to 70 ° C is most preferable.
The charging time of salicylaldehyde (17) is preferably 1 hour or longer. The reaction time depends on the type of solvent and the temperature, but is generally 1 to 24 hours.
After completion of the reaction, the desired product can be obtained by filtering the precipitate and concentrating it.

(Process (d))
Next, step (d) will be described.
When the O-allylated product (18) obtained in the step (c) is subjected to a heat treatment, a rearrangement reaction takes place and a C-allylated product (15) is obtained.
The reaction temperature is 100 ° C or higher, preferably 160 ° C to 210 ° C.
As the solvent for the transfer reaction, a high boiling point solvent such as dimethyl sulfoxide, N, N-diethylaniline, tetralin or the like and solvent-free conditions are used, and solvent-free conditions are most preferable.
After completion of the reaction, the residue is purified by distillation under reduced pressure to obtain the C-allylic compound (15) as an oil.

(Process (e))
Next, step (e) will be described.
When the C-allylated product (15) obtained in the step (d) is treated with a palladium catalyst, isomerization proceeds and an internal olefin (16) is obtained. When this is treated with a palladium catalyst and an oxidizing agent without isolation, an oxidative cyclization reaction proceeds and benzofuran (12) is obtained. That is, by going from (15) to (16), it can be easily converted to benzofuran (12) with good yield and quality.

As a series of solvents for isomerization and oxidative cyclization reaction, ethers such as tetrahydrofuran, dioxane, cyclopentylmethyl ether and 1,2-dimethoxyethane, esters such as ethyl acetate and isopropyl acetate, hydrocarbons such as hexane and heptane Aromatic hydrocarbons such as toluene and xylene, ketones such as acetone and 2-butanone, halogenated hydrocarbons such as dichloromethane, chloroform and chlorobenzene, nitriles such as acetonitrile and propionitrile, N, N-dimethylformamide, Amides such as N-methylpyrrolidone and mixtures thereof are used. Of these, ethers are preferable, and tetrahydrofuran is particularly preferable.

As a series of palladium catalysts for isomerization and oxidative cyclization reaction, divalent palladium catalysts such as paradymium acetate, palladium bisacetonitrile complex, palladium chloride bisbenzonitrile complex, palladium chloride bistriphenylphosphine complex are used. Of these, palladium chloride bisacetonitrile complex is most preferred.
The palladium catalyst is used in an amount of 0.005 equivalents to 0.5 equivalents relative to the C-allylic compound, but 0.005 equivalents to 0.02 equivalents is preferable from an economical viewpoint.

The isomerization reaction temperature is between 0 ° C. and the boiling point of the reaction mixture. 10 ° C or higher is preferable, and 35 ° C to 45 ° C is most preferable. The reaction time depends on the type of solvent and the temperature, but is generally 10 to 60 hours.

Oxidizing agents used in the oxidative cyclization reaction include oxygen gas, quinones such as benzoquinone and chloranil, organic peroxides such as hydrogen peroxide, benzoyl peroxide and t-butyl hydroperoxide, manganese dioxide and chromic acid. Examples include metal oxidants, but quinones are preferred, and 1,4-benzoquinone is most preferred.
The oxidizing agent is used in an amount of 1 equivalent or more with respect to the C-allylic compound, and is preferably 1.0 equivalent to 1.3 equivalents from the viewpoint of yield, suppression of by-products, and economics.
In the oxidative cyclization reaction, an inorganic salt such as sodium acetate or lithium chloride is used as an additive, and lithium chloride is preferred.
The additive is used in an amount of 0.2 to 5 equivalents with respect to the C-allylic compound, and is preferably 1.2 to 1.6 equivalents from the viewpoint of yield and economy.

The temperature of the oxidative cyclization reaction is carried out between 0 ° C. and the boiling point of the reaction mixture. 10 degreeC or more is preferable and 60 degreeC or more is the most preferable. The reaction time depends on the type of solvent and the temperature, but is generally 10 to 40 hours.
After completion of the reaction, it is replaced with a hydrocarbon such as hexane or heptane, an aromatic hydrocarbon such as toluene or xylene and a mixed solvent thereof, and washed with water and an aqueous sodium hydroxide solution. The organic layer can be concentrated to obtain a crude product of the target benzofuran (12). The organic layer may be used as it is in the step (f) without being concentrated.

(Process (f))
Next, step (f) will be described.
By treating the crude product of benzofuran (12) obtained in step (e) with an aqueous sodium hydrogen sulfite solution, the addition reaction proceeds to obtain the compound represented by formula (14).
Solvents for the addition reaction include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, dioxane, cyclopentylmethyl ether and 1,2-dimethoxyethane, esters such as ethyl acetate and isopropyl acetate, and carbonization such as hexane and heptane. Hydrogen, aromatic hydrocarbons such as toluene and xylene, ketones such as acetone and 2-butanone, halogenated hydrocarbons such as dichloromethane, chloroform and chlorobenzene, nitriles such as acetonitrile and propionitrile, N, N-dimethylformamide Amides such as N-methylpyrrolidone, and mixtures thereof are used. Of these, a mixture of alcohols and hydrocarbons is preferable, and a mixture of ethanol and heptane is particularly preferable.

Sodium bisulfite is used in an amount of 1 equivalent or more based on benzofuran (12), and 1.0 equivalent to 1.3 equivalents is most preferable from the viewpoint of yield and economy.
The addition reaction temperature is between 0 ° C. and the boiling point of the reaction mixture. 10 ° C or higher is preferable, and 25 ° C to 35 ° C is most preferable. The reaction time depends on the type and temperature of the solvent, but is generally less than 5 hours.
After completion of the reaction, the precipitate can be separated by filtration to obtain the compound (14) as a solid. Since benzofuran (12) is an oily substance and difficult to purify, it can be converted into adduct (14) and isolated and purified as a solid.

(Process (g))
Next, step (g) will be described.
Benzofuran (12) is obtained by hydrolyzing the adduct (14) obtained by the step (f) under acidic or alkaline conditions.
Solvents for the hydrolysis reaction include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, dioxane and 1,2-dimethoxyethane, ketones such as acetone and 2-butanone, nitriles such as acetonitrile, N, N— Amides such as dimethylformamide and N-methylpyrrolidone, water and mixtures thereof are used. Of these, water is most preferred.

Acids include inorganic acids (for example, hydrochloric acid, sulfuric acid, phosphoric acid, etc.), organic acids (for example, acetic acid, camphorsulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, formic acid, benzoic acid, pivalic acid, malonic acid, citric acid, etc. Acid, oxalic acid, tartaric acid, etc.), sulfuric acid, hydrochloric acid and acetic acid are preferred, and hydrochloric acid is most preferred.
Bases include metal alkoxides such as sodium methoxide and sodium ethoxide, metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, etc. Although metal carbonate etc. are mentioned, Metal hydroxide is preferable and especially sodium hydroxide is preferable. Sodium methoxide may be used in its methanol solution.

The hydrolysis reaction temperature is between 0 ° C. and the boiling point of the reaction mixture. 10 ° C or higher is preferable, and 45 ° C to 55 ° C is most preferable. The reaction time depends on the type and temperature of the solvent, but is generally less than 1 hour.
After completion of the reaction, extraction is performed with an organic solvent. As the extraction solvent, esters such as ethyl acetate and isopropyl acetate, hydrocarbons such as hexane and heptane, aromatic hydrocarbons such as toluene and xylene, and cyclopentyl methyl ether are used. Of these, esters are preferred, and ethyl acetate is particularly preferred. A concentrated product of benzofuran (12), which is the target product, can be obtained by concentrating the extraction solvent.

EXAMPLES Hereinafter, although an Example demonstrates the detail of this invention, this invention is not limited to a following example.
(Analysis conditions)
Analysis in the following examples was performed according to a conventional method using the following measuring apparatus.
(1) ¹ H-NMR and ¹³ C-NMR
Device: Bruker AVANCE400
(2) ESI-MS
Device: Thermo Quest TSQ700 or Japan Waters ZQ2000
(3) HPLC
Column: manufactured by Shiseido CAPCELL PAK C18 MGII 4.6 mm ID X 150 mm, 5 μm
Column temperature: 40 ° C
Detection wavelength: UV254nm
Flow rate: 1.0 mL / min
Analysis condition 1
Mobile phase: Solution A 10 mM phosphoric acid (sodium) aqueous solution [Na ₂ HPO ₄ , NaH ₂ PO ₄ each 5 mM, pH 7], solution B Acetonitrile Gradient conditions: Solution A / Solution B Initial 75/25, 75 minutes after 75 minutes , 30/15/85
Analysis condition 2
Mobile phase: Solution A 10 mM phosphoric acid (sodium) aqueous solution [Na ₂ HPO ₄ , NaH ₂ PO ₄ each 5 mM, pH 7], solution B Acetonitrile Gradient conditions: solution A / solution B initial 80/20, 80 minutes after 80 minutes , 30/15/85
In each step of synthesis, the content value (%) of the obtained target product was obtained by comparing the area area of HPLC with that of a standard product.

　撹拌機を備えた３００Ｌグラスライニング反応槽に、アセトニトリル８９．８ｋｇと炭酸カリウム２２．８ｋｇ（１６５ｍｏｌ）、アリルブロミド２０．０ｋｇ（１６５ｍｏｌ）を加え、６０℃に昇温した。サリチルアルデヒド１６．８ｋｇ（１３８ｍｏｌ）を1時間半かけて滴下し、アセトニトリル２．６ｋｇで洗いこみを行った。３時間反応を行った後、２５℃に冷却し、固体を吸引ろ過で分離後、アセトニトリル２６．４ｋｇで洗浄した。濾過液を減圧濃縮して表題化合物２１．８ｋｇを得た（収率９８％）。 Example 1
Compound (1) ((1R, 8R, 10R) -9- (2-hydroxyacetyl) -8- (2-methylbenzofuran-7-yl) -2,5,9-triazatricyclo [8.4. 0.0 ^3,7 ] tetradeca-3 (7) -en-6-one)
(Process 1)
Synthesis of 2-allyloxybenzaldehyde (18)

To a 300 L glass-lined reaction vessel equipped with a stirrer, 89.8 kg of acetonitrile, 22.8 kg (165 mol) of potassium carbonate and 20.0 kg (165 mol) of allyl bromide were added, and the temperature was raised to 60 ° C. 16.8 kg (138 mol) of salicylaldehyde was added dropwise over 1 hour and a half, followed by washing with 2.6 kg of acetonitrile. After reacting for 3 hours, the mixture was cooled to 25 ° C., the solid was separated by suction filtration, and washed with 26.4 kg of acetonitrile. The filtrate was concentrated under reduced pressure to obtain 21.8 kg of the title compound (yield 98%).

工程１で得られる化合物をコルベンに加え、加熱する操作を３バッチ行った（１バッチ目：化合物８．７３ｋｇ、１０Ｌコルベン、１７０℃～２００℃、１２．５時間、２バッチ目：化合物８．７３ｋｇ、１０Ｌコルベン、１７０℃～１８０℃、２０．５時間、３バッチ目：化合物４．３７ｋｇ、５Ｌコルベン、１７０℃～１８０℃、１８．５時間）。反応液を合わせて減圧蒸留精製を行い、表題化合物１５．１ｋｇ得た（含量８９．０％、収率６２％）。 (Process 2)
Synthesis of 2-allylsalicylaldehyde (15)

The compound obtained in step 1 was added to Kolben and heated for 3 batches (first batch: compound 8.73 kg, 10 L Kolben, 170 ° C. to 200 ° C., 12.5 hours, second batch: compound 8. 73 kg, 10 L Kolben, 170 ° C. to 180 ° C., 20.5 hours, third batch: Compound 4.37 kg, 5 L Kolben, 170 ° C. to 180 ° C., 18.5 hours). The reaction solutions were combined and purified by distillation under reduced pressure to obtain 15.1 kg of the title compound (content 89.0%, yield 62%).

工程２で得た化合物 １３．０ｋｇ（含量８９．０％、７１．３ｍｏｌ）とテトラヒドロフラン１２８ｋｇ、ビス（アセトニトリル）ジクロロパラジウム１０９ｇを加えて昇温し、３５℃～４４℃で５時間撹拌した。パラジウム触媒１０９ｇを加えてテトラヒドロフラン１ｋｇで洗いこみ、３６℃～４５℃で２３時間撹拌した。パラジウム触媒１１ｇを加えてテトラヒドロフラン０．１ｋｇで洗いこみ、さらに３６℃～４５℃で４２時間撹拌した。２６℃に冷却後、塩化リチウム５．３ｋｇと１，４－ベンゾキノン１０．９ｋｇを加えて昇温し、６０℃～６６℃で１５時間撹拌した。反応液を全量５０Ｌまで濃縮し、水３７ｋｇを加えた後に全量５０Ｌになるまで濃縮した。ヘプタン７１ｋｇと９．２％水酸化ナトリウム水溶液１５０ｋｇを加えて５０℃で４０分間弱く撹拌した後に１５分静置し、メタノール４．８ｋｇを弱く撹拌しながら３０分かけて滴下した。水層を除去後、有機層に７．５％水酸化ナトリウム水溶液２６ｋｇを加え、５０℃で３０分間弱く撹拌した後に１５分静置した。水層を除去後、有機層に水２３ｋｇを加え、５０℃で３０分間弱く撹拌した後に１５分静置した。水層を除去後に冷却し、有機層を濾過し、ヘプタン１１ｋｇで洗いこみを行った。全量３５Ｌまで濃縮後、エタノール１１９ｋｇを加え、さらに４Ｍ亜硫酸水素ナトリウム水溶液２０ｋｇを２５℃～３１℃で３０分かけて滴下した。３０℃で３時間撹拌した後に析出物を減圧濾過し、エタノール３１ｋｇで洗いこみを行った。湿固体を６０℃で減圧乾燥し、表題化合物１４．５ｋｇを得た（含量９７．５％、収率７５％）。
¹H-NMR (400MHz, DMSO-d₆): δ7.48 (dd, 1H), 7.37 (dd, 1H), 7.11, (dd, 1H), 6.53 (d, 1H), 6.18 (d, 1H), 5.57 (d, 1H), 2.43 (s, 3H)
¹³C NMR(100MHz, DMSO-d₆): δ154.99, 152.62, 128.22, 123.38, 122.65, 122.07, 118.99, 103.01, 79.10, 14.09 (Process 3)
Synthesis of (2-methylbenzofuran-7-yl) -methanediol allyl salicylaldehyde hydrogen sulfite sodium salt (14)

13.0 kg (content: 89.0%, 71.3 mol) of the compound obtained in Step 2, 128 kg of tetrahydrofuran and 109 g of bis (acetonitrile) dichloropalladium were added, and the temperature was raised, followed by stirring at 35 ° C. to 44 ° C. for 5 hours. 109 g of palladium catalyst was added and the mixture was washed with 1 kg of tetrahydrofuran and stirred at 36 ° C. to 45 ° C. for 23 hours. 11 g of palladium catalyst was added and the mixture was washed with 0.1 kg of tetrahydrofuran and further stirred at 36 ° C. to 45 ° C. for 42 hours. After cooling to 26 ° C., 5.3 kg of lithium chloride and 10.9 kg of 1,4-benzoquinone were added, the temperature was raised, and the mixture was stirred at 60 ° C. to 66 ° C. for 15 hours. The reaction solution was concentrated to a total volume of 50 L, added with 37 kg of water, and then concentrated to a total volume of 50 L. 71 kg of heptane and 150 kg of 9.2% aqueous sodium hydroxide solution were added, and the mixture was gently stirred at 50 ° C. for 40 minutes, then allowed to stand for 15 minutes, and 4.8 kg of methanol was added dropwise over 30 minutes with weak stirring. After removing the aqueous layer, 26 kg of a 7.5% aqueous sodium hydroxide solution was added to the organic layer, and the mixture was gently stirred at 50 ° C. for 30 minutes and allowed to stand for 15 minutes. After removing the aqueous layer, 23 kg of water was added to the organic layer, and the mixture was gently stirred at 50 ° C. for 30 minutes and then allowed to stand for 15 minutes. After removing the aqueous layer, the mixture was cooled, the organic layer was filtered, and washed with 11 kg of heptane. After concentrating to a total volume of 35 L, 119 kg of ethanol was added, and 20 kg of 4M aqueous sodium bisulfite solution was further added dropwise at 25 ° C. to 31 ° C. over 30 minutes. After stirring at 30 ° C. for 3 hours, the precipitate was filtered under reduced pressure and washed with 31 kg of ethanol. The wet solid was dried under reduced pressure at 60 ° C. to obtain 14.5 kg of the title compound (content 97.5%, yield 75%).
¹ H-NMR (400MHz, DMSO-d ₆ ): δ7.48 (dd, 1H), 7.37 (dd, 1H), 7.11, (dd, 1H), 6.53 (d, 1H), 6.18 (d, 1H) , 5.57 (d, 1H), 2.43 (s, 3H)
¹³ C NMR (100 MHz, DMSO-d ₆ ): δ154.99, 152.62, 128.22, 123.38, 122.65, 122.07, 118.99, 103.01, 79.10, 14.09

工程３で得た化合物 １８４ｇ(含量９７．６％、０．６８１ｍｏｌ)を２Ｍ水酸化ナトリウム水溶液４０９ｍＬに溶解させ、５０℃で１０分間撹拌した後、３０℃に冷却した。酢酸エチル２１８ｍＬを加え、抽出分離を行った後、取得した有機層を水１０９ｍＬで洗浄し、硫酸マグネシウムで乾燥させた。濾過後、１５ＫＰａ、５０℃（バス温）の条件で濃縮を行った後、さらに、室温下、真空ポンプで１４時間乾燥させ、１０６ｇの表題化合物（油状）を得た（収率９７％）。 (Process 4)
Synthesis of 2-methylbenzofuran-7-carbaldehyde (12)

184 g (content 97.6%, 0.681 mol) of the compound obtained in step 3 was dissolved in 409 mL of 2M aqueous sodium hydroxide solution, stirred at 50 ° C. for 10 minutes, and then cooled to 30 ° C. After adding 218 mL of ethyl acetate and performing extraction separation, the obtained organic layer was washed with 109 mL of water and dried over magnesium sulfate. After filtration, the mixture was concentrated under the conditions of 15 KPa and 50 ° C. (bath temperature), and further dried at room temperature with a vacuum pump for 14 hours to obtain 106 g of the title compound (oil) (yield 97%).

メタノール８２０ｍＬに水酸化カリウム３０．８ｇ（含量９６．２％、５２９ｍｍｏｌ）を溶解し、４－[（１Ｒ、２Ｒ）－２－アミノシクロヘキシルアミノ]－３－ピロリン－２－オン塩酸塩１３３．６ｇ（含量８８．８％、５１２ｍｍｏｌ）を加えた。２５℃で撹拌、中和の後、２０％水酸化カリウム－メタノール溶液を滴下してｐＨを１２．３３に調整した。工程４で得られる化合物８２．０ｇ（５１２ｍｍｏｌ）のメタノール２８７ ｍＬ溶液を加えて６０℃に昇温し、２２時間撹拌した。４５℃に冷却後、水４９２ ｍＬを約１時間かけて滴下し、溶媒を４６２ｇ濃縮した。水２４６ ｍＬを１０分で加えて一晩撹拌保存の後に溶媒を１５４ｇ濃縮し、水１６４ ｍＬと３０％メタノール水溶液１００ｇを順次加えて１０℃に冷却した。一晩撹拌の後に分離し、湿結晶を６０℃で減圧乾燥して表題化合物１６０ｇを得た（含量９８．０％、収率 ９０．８％)。 (Process 5)
(1R, 8R, 10R) -8- (2-Methylbenzofuran-7-yl) -2,5,9-triazatricyclo [8.4.0.0 ^3,7 ] tetradeca-3 (7)- Synthesis of en-6-one (6)

In 820 mL of methanol, 30.8 g (content 96.2%, 529 mmol) of potassium hydroxide was dissolved, and 133.6 g of 4-[(1R, 2R) -2-aminocyclohexylamino] -3-pyrrolin-2-one hydrochloride was dissolved. (Content 88.8%, 512 mmol) was added. After stirring and neutralizing at 25 ° C., a 20% potassium hydroxide-methanol solution was added dropwise to adjust the pH to 12.33. A solution of 82.0 g (512 mmol) of the compound obtained in Step 4 in 287 mL of methanol was added, the temperature was raised to 60 ° C., and the mixture was stirred for 22 hours. After cooling to 45 ° C., 492 mL of water was added dropwise over about 1 hour, and 462 g of the solvent was concentrated. 246 mL of water was added in 10 minutes, and after stirring and storing overnight, 154 g of the solvent was concentrated, and 164 mL of water and 100 g of 30% aqueous methanol solution were sequentially added and cooled to 10 ° C. The mixture was separated after stirring overnight, and the wet crystals were dried at 60 ° C. under reduced pressure to obtain 160 g of the title compound (content 98.0%, yield 90.8%).

酢酸エチル９３６ｍＬとアセトキシアセチルクロリド１０５ｍＬ（９７９ｍｍｏｌ）を混合し、１５℃で（１Ｒ，８Ｒ，１０Ｒ）－８－（２－メチルベンゾフラン－７－イル）－２，５，９－トリアザトリシクロ［８．４．０．０^３，７］テトラデカ－３（７）－エン－６－オン（６）１２３ｇ（含量９８．０％、３５６ｍｍｏｌ）を２回に分けて投入した。２０℃にてトリエチルアミン１４７ｍＬ（１．０５ｍｏｌ）を２時間１０分かけて滴下し、２時間撹拌した。水３６０ｍＬ、５％重曹水３６０ｍＬ、水１２０ｍＬで順次洗浄し、酢酸エチル層を濃縮、メタノールに置換して４３８ｇとした。メタノール５２８ｍＬと水１９２ｍＬの混合溶液に水酸化カリウム８３．０ｇ（含量９６．２％、１．４２ｍｏｌ)を溶解し、５０℃にて置換濃縮液を１時間１０分かけて滴下した。５０℃で５時間撹拌後、１０℃に冷却し、析出した結晶をろ過した。６０℃で真空乾燥後、表題化合物１１５ｇを得た（含量１００％、収率８２．０％）。 (Step 6)
(1R, 8R, 10R) -9- (2-hydroxyacetyl) -8- (2-methylbenzofuran-7-yl) -2,5,9-triazatricyclo [8.4.0.0 ^{3, 7} ] Synthesis of tetradeca-3 (7) -en-6-one (1)

936 mL of ethyl acetate and 105 mL (979 mmol) of acetoxyacetyl chloride were mixed, and (1R, 8R, 10R) -8- (2-methylbenzofuran-7-yl) -2,5,9-triazatricyclo [ 8.4.0.0 ^3,7 ] tetradec-3 (7) -en-6-one (6) 123 g (content 98.0%, 356 mmol) was added in two portions. At 20 ° C., 147 mL (1.05 mol) of triethylamine was added dropwise over 2 hours and 10 minutes, and the mixture was stirred for 2 hours. This was washed sequentially with 360 mL of water, 360 mL of 5% sodium bicarbonate water, and 120 mL of water, and the ethyl acetate layer was concentrated and replaced with methanol to obtain 438 g. In a mixed solution of 528 mL of methanol and 192 mL of water, 83.0 g (content 96.2%, 1.42 mol) of potassium hydroxide was dissolved, and the substitution concentrate was added dropwise at 50 ° C. over 1 hour and 10 minutes. After stirring at 50 ° C. for 5 hours, the mixture was cooled to 10 ° C., and the precipitated crystals were filtered. After vacuum drying at 60 ° C., 115 g of the title compound was obtained (content 100%, yield 82.0%).

(Example 2)
Compound (1) ((1R, 8R, 10R) -9- (2-hydroxyacetyl) -8- (2-methylbenzofuran-7-yl) -2,5,9-triazatricyclo [8.4. 0.0 ^3,7 ] tetradeca-3 (7) -en-6-one), part 2
936 mL of 2-butanone and 114.6 g (836 mmol) of acetoxyacetyl chloride were mixed and (1R, 8R, 10R) -8- (2-methylbenzofuran-7-yl) -2,5,9-triaza was mixed at 25 ° C. Tricyclo [8.4.0.0 ^3,7 ] tetradec-3 (7) -en-6-one (6) 123 g (content 97.9%, 356 mmol) was added in two portions. The temperature was raised to 60 ° C., and 92.3 g (907 mmol) of triethylamine was added dropwise over 2 hours and 20 minutes, followed by stirring for 2 hours. After cooling to 25 ° C., the mixture was washed successively with 360 mL of water, 360 mL of 5% aqueous sodium bicarbonate, and 240 mL of water. The 2-butanone layer was concentrated, filtered by replacing with methanol, and the filtrate was adjusted to a concentration of 432 g. 83.0 g (content 96.2%, 1.42 mol) of potassium hydroxide was dissolved in a mixed solution of 528 mL of methanol and 192 mL of water, and a filtrate whose concentration was adjusted at 50 ° C. was added dropwise over 1 hour. After stirring at 50 ° C. for 2 hours, the mixture was cooled to 10 ° C., and the precipitated crystals were filtered. After vacuum drying at 60 ° C., 118 g of the title compound was obtained (content 100%, yield 84.0%).

(Example 3)
Compound (9a) ((1R, 8R, 10R) -5,9-bis (2-acetoxyacetyl) -8- (2-methylbenzofuran-7-yl) -2,5,9-triazatricyclo [8 4.0.0 ^3,7 ] tetradeca-3 (7) -en-6-one)
270 mL of toluene and 14.7 mL (137 mmol) of acetoxyacetyl chloride and (1R, 8R, 10R) -8- (2-methylbenzofuran-7-yl) -2,5,9-triazatricyclo [8.4.0 .0 ^3,7] tetradeca -3 (7) - en-6-one (6) 20.53G (content 97.4%, 59.3 mmol) were mixed, triethylamine 20.7mL was heated to 60 ° C. (148 mmol) was added dropwise over 1 hour and 10 minutes, followed by stirring for 2 hours. After adding 100 mL of water, the mixture was concentrated and cooled to 10 ° C. The precipitated crystals were filtered and dried in vacuo at 60 ° C. to obtain 25.9 g of the title compound (content 89.0%, yield 72.3%).
¹ H-NMR (400MHz, DMSO-d ₆ ): δ7.80 (s, 1H), 7.51 (d, 1H), 7.16 (dd, 1H), 7.06 (d, 1H), 6.62 (s, 1H), 5.93 (brs, 1H), 5.47 (d, 1H), 5.04 (d, 1H), 4.99 (d, 1H), 4.87 (d, 1H), 4.33 (d, 1H), 4.25 (d, 1H), 4.06 (m, 1H), 2.96 (m, 1H), 2.47 (d, 3H), 2.35 (m, 1H), 2.11 (s, 3H), 2.08 (s, 3H), 2.06 (m, 1H), 1.47 ( m, 1H), 1.38 (m, 1H), 1.05 (m, 2H), 0.61 (m, 2H)

Claims (15)

Following formula (6)

Or a salt thereof of the following formula (9)

(Wherein R ¹ represents a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, or a C _3-6 cycloalkyl group) or a salt thereof The following formula (1) including the process to do

Or a salt thereof. A compound of the formula (6) or a salt thereof is represented by the formula (13)
XCOCH ₂ OCOR ¹ (13)
Wherein R ¹ represents a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, or a C _3-6 cycloalkyl group, and X represents a halogen atom. The method according to claim 1, further comprising a step of reacting with a salt thereof. The method according to claim 2, wherein the reaction is carried out in the presence of a base. The method according to any one of claims 1 to 3, comprising a step of treating the compound of the formula (9) or a salt thereof with a base. The method according to any one of claims 1 to 4, wherein the reaction can be carried out in one pot. Following formula (2)

Or a salt thereof and the following formula (12)

The method of Claim 1 thru | or 5 including the process of obtaining the compound of Formula (6) by carrying out the condensation cyclization of the compound of this, or its salt on alkaline conditions. Formula (14)

The method of Claim 6 including the process of converting the compound of these, or its salt into Formula (12). (15) below

The compound or its salt represented by these is cyclized in presence of a palladium catalyst and an oxidizing agent, and is further made to react with sodium hydrogen sulfite, The process of obtaining the compound or its salt of Formula (14) of Claim 7 is included. Method. Treating formula (15) with a palladium catalyst;
Formula (16)

The method of Claim 8 including the process of obtaining the compound of this, or its salt. The method according to any one of claims 8 to 9, wherein the palladium catalyst is a divalent palladium catalyst. The method according to claim 9, wherein the oxidizing agent is a quinone. The method according to any one of claims 1 to 11, which does not require column purification. Formula (9)

(In the formula, R ¹ represents a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, or a C _3-6 cycloalkyl group.)
Or a salt thereof. The compound or a salt thereof according to claim 13, wherein R ¹ is methyl. Formula (14)

Or a salt thereof.