JP2010270092A - Acetyl compound, method for producing the acetyl compound, and method for producing naphthol compound using the acetyl compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for improving production conditions of naphthol compounds and chromene compounds by synthesizing the naphthol compounds and the chromene compounds which are obtained by passing many processes making a precursor of high storage stability as a raw material. <P>SOLUTION: An acetyl compound of high storage stability is shown by formula (1), wherein R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP>and R<SP>4</SP>denote a hydrogen atom, an alkyl group or the like respectively, and R<SP>5</SP>and R<SP>6</SP>denote an alkyl group, a halogeno-alkyl group, an alkoxy group or the like respectively. A method of synthesizing the chromene compound comprises as follows. The acetyl compound is deacetylated by an acid or a base to produce the naphthol compound, and the obtained naphthol compound is made to react with a propargyl alcohol compound to produce the chromene compound. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a novel acetyl compound and a method for producing the acetyl compound. The present invention also relates to a novel method for producing a naphthol compound using the acetyl compound and a novel method for producing a chromene compound using the naphthol compound.

  Some benzopyran compounds (they are sometimes called chromene compounds because they have a chromene skeleton) are colored by changing their chemical structure by irradiating light containing ultraviolet rays such as sunlight. It is known that when the irradiation is stopped, the original chemical structure is restored and the coloring disappears, and this is the main component of the photochromic lens currently on the market.

  Usually, this chromene compound can be produced by reacting a naphthol compound with a propargyl compound. A naphthol compound that is a raw material for a chromene compound having excellent photochromic properties can be produced, for example, by the following method (see Patent Document 1).

  Explaining the above reaction formula, first, a Grignard reagent represented by the above formula (A) is reacted with α-tetralone to synthesize a compound represented by the above formula (B), and the carboxylic acid protecting group of the compound is removed. Protection is performed to obtain a carboxylic acid compound represented by the formula (C). Next, the carboxylic acid compound is cyclized in polyphosphoric acid under heating conditions to produce the naphthol compound represented by the formula (D). As described in Patent Document 1, the naphthol compound obtained by this method can be used as a raw material for a chromene compound having excellent photochromic properties.

  However, as described above, the conventional method uses polyphosphoric acid that is difficult to handle in the production of a naphthol compound, and there is room for improvement in terms of operability.

  In the above method, a carboxylic acid compound derived from the Grignard reagent represented by the formula (A) is by-produced, and such a by-product is very similar to the carboxylic acid compound represented by the formula (C). Yes. Therefore, it is difficult to separate the carboxylic acid compound from the by-product. Usually, the naphthol compound represented by the formula (D) is obtained after reacting the mixture containing the by-product and the carboxylic acid compound. And the by-product had to be separated. At this time, the by-product can be separated by a liquid separation operation under weakly basic conditions. However, the above method is also used in that a part of the naphthol compound is separated together with the by-product and the yield of the naphthol compound is reduced. There was room for improvement.

  Further, according to the study by the present inventors, the produced naphthol compound is difficult to be preserved because it is prone to oxidative degradation, and if it is not immediately reacted with a next reaction, for example, a propargyl compound, production of a chromene compound It was found that the sex decreased.

  As described above, the conventional method has room for improvement as an industrial production method in terms of operability, stability of the substance, yield of naphthol compound, and the like.

US Patent Application Publication No. 2007/0246692

  As a naphthol compound raw material, if there is a compound that can be easily separated from by-products, has excellent storage stability, and can be easily converted into a naphthol compound, not only can the productivity of the naphthol compound be improved, but also the naphthol compound It is thought that the productivity of chromene compounds made from the raw material can also be improved. In particular, naphthol compounds and chromene compounds are obtained through a number of processes. Therefore, if the storage stability of the precursor (raw material) is high, it will be very advantageous for their industrial production.

  Accordingly, an object of the present invention is to provide a raw material compound of the naphthol compound as described above, and to provide a method for producing a naphthol compound with improved operability and yield. Furthermore, it is providing the manufacturing method with which the yield of chromene compound and the manufacturing conditions were improved by making the obtained naphthol compound and a propargyl compound react.

  The present inventors have intensively studied to solve the above problems. As a result, it has been found that an acetyl compound having a specific structure is a compound that can be easily separated from by-products, has excellent storage stability, and can be easily converted into a naphthol compound. It has been found that the productivity of naphthol compounds and chromene compounds can be improved by using them to produce naphthol compounds and chromene compounds, and the present invention has been completed.

  That is, the present invention provides the following formula (1)

(Wherein R ¹ , R ² , R ³ , and R ⁴ are each a hydrogen atom, an alkyl group, a halogen atom, an aralkyl group, or an aryl group, and R ¹ , R ² , R ³ , and R are each Two groups selected from ⁴ may form together an aliphatic hydrocarbon ring,
R ⁵ and R ⁶ are each an alkyl group, an alkoxy group, an aralkoxy group, an amino group, a heterocyclic group having a nitrogen atom as a hetero atom, and bonded by the nitrogen atom, a cyano group, a halogen atom, an aralkyl group, or An aryl group,
a, and b are each an integer of 0 to 3, a, and when b is 2 to 3 integer, each ^{R 5,} and ^{R 6} each may be the same group, together Different groups may be used. )
It is an acetyl compound shown by these.

  The acetyl compound is represented by the following formula (2)

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , a, and b have the same meanings as those in the formula (1).)
Can be produced by heating in the presence of acetic anhydride and acetate.

In the present invention, the acetyl compound is deacetylated with an acid or a base,
Following formula (3)

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , a, and b have the same meanings as those in the formula (1).)
A naphthol compound represented by the formula:

  Furthermore, the present invention provides a naphthol compound represented by the above formula (3) by the above method, and then obtained naphthol compound and the following formula (4):

(In the formula, R ⁷ and R ⁸ are each an alkyl group, an alkoxy group, an aralkoxy group, an amino group, a heterocyclic group having a nitrogen atom as a hetero atom, and bonded by the nitrogen atom, a cyano group, a halogen atom, An aralkyl group or an aryl group,
c and d are each an integer of 0 to 3, and when c and d are an integer of 2 to 3, each R ⁷ and R ⁸ may be the same group, Different groups may be used. By reacting with a propargyl compound represented by
Following formula (5)

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , a, and b have the same meanings as those in formula (1),
R ⁷ , R ⁸ , c, and d have the same meaning as in the formula (4). )
A method for producing a chromene compound represented by the formula:

  The acetyl compound of the present invention (acetyl compound represented by the above formula (1)) can be easily produced in the presence of acetic anhydride and acetate. Moreover, the obtained acetyl compound can remove a by-product by a liquid separation operation under a weak basic condition or by recrystallization, and as a result, a high-purity compound can be easily obtained. Furthermore, the acetyl compound is excellent in storage stability and can be easily converted into a naphthol compound by hydrolysis under acid or base conditions.

  Therefore, by using the acetyl compound of the present invention, the yield and production conditions of the naphthol compound and the chromene compound can be improved. In particular, the acetyl compound is useful as a precursor (raw material) for producing a naphthol compound obtained through a number of production steps and a chromene compound.

(Acetyl compound)
The present invention provides the following formula (1)

(Wherein R ¹ , R ² , R ³ , and R ⁴ are each a hydrogen atom, an alkyl group, a halogen atom, an aralkyl group, or an aryl group,
Two groups selected from R ¹ , R ² , R ³ , and R ⁴ may be combined to form an aliphatic hydrocarbon ring,
R ^5, and R ⁶ are each an alkyl group, alkoxy group, aralkoxy group, a heterocyclic group bonded through a nitrogen atom include an amino group, a nitrogen atom as a hetero atom, a cyano group, a halogen atom, an aralkyl group, or An aryl group,
a and b are each an integer of 0 to 3, and when a and b are an integer of 2 to 3, each R ⁵ and R ⁶ may be the same group, Different groups may be used. ) Is an acetyl compound.
First, the substituent of this acetyl compound is demonstrated.

(Groups R ¹ , R ² , R ³ , and R ⁴ )
In the groups R ¹ , R ² , R ³ , and R ⁴ , the alkyl group is not particularly limited, but generally an alkyl group having 1 to 6 carbon atoms is preferable. , Ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl, n-hexyl group, cyclopentyl group, cyclohexyl group and the like.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

  As the aralkyl group, an aralkyl group having 7 to 11 carbon atoms is preferable. Examples of suitable aralkyl groups include benzyl group, phenylethyl group, phenylpropyl group, phenylbutyl group and the like. Further, the aralkyl group may have a substituent, and as the aralkyl group having this substituent, one or more hydrogen atoms of the aralkyl group are an alkyl group, an alkoxy group, an aralkoxy group, an amino group. , Substituted with a halogen atom, an aralkyl group or an aryl group.

  As the aryl group, an aryl group having 6 to 10 carbon atoms is preferable. Examples of suitable aryl groups include phenyl and naphthyl groups. The aryl group may have a substituent, and as the aryl group having the substituent, one or more hydrogen atoms of the aryl group are an alkyl group, an alkoxy group, an aralkoxy group, an amino group. , Substituted with a halogen atom, an aralkyl group, or an aryl group.

Further, two groups selected from R ¹ , R ² , R ³ , and R ⁴ may be combined to form an aliphatic hydrocarbon ring. When a suitable ring is illustrated, it is preferable that it is a C4-C8 aliphatic hydrocarbon ring, and it is preferable that it is a C4-C8 cycloalkyl ring. The aliphatic hydrocarbon ring includes a carbon atom having a basic skeleton to which R ¹ , R ² , R ³ , and R ⁴ are bonded. Specific examples include a cyclobutyl ring, a cyclopentyl ring, a cyclohexyl ring, a cycloheptyl ring, and a cyclooctyl ring. Among them, it is desirable that R ¹ and R ³ or R ⁴ are combined, or R ² and R ³ or R ⁴ are combined to form an aliphatic hydrocarbon ring, and particularly preferably R ¹ and R ¹ are combined. , R ³ or R ⁴ together, or R ² and R ³ or R ⁴ together form a cycloalkyl ring having 4 to 8 carbon atoms.

Among them, in the groups R ¹ , R ² , R ³ , and R ⁴ , the carboxylic acid compound described in detail below becomes a compound similar to the by-product, and the acetyl compound exhibits a particularly effective effect for separating the by-product. Furthermore, in order for the finally obtained chromene compound to exhibit excellent effects, it is preferably a hydrogen atom, an alkyl group, an aralkyl group, or an aryl group. In order to exert the above effect, R ² and R ⁴ are hydrogen atoms, and R ¹ and R ³ are combined to form a cycloalkyl ring having 4 to 8 carbon atoms (provided that R ¹ and R 3 It is preferable to form a cycloalkyl ring containing a carbon atom of the basic skeleton to which ³ is bonded. Among these, the groups R ¹ , R ² , R ³ , and R ⁴ are particularly preferably a hydrogen atom, an alkyl group, or form the cycloalkyl ring.

(Groups R ⁵ and R ⁶ )
In the formula (1), each of the groups R ⁵ and R ⁶ includes an alkyl group, a halogenoalkyl group, an alkoxy group, a halogenoalkoxy group, an aralkoxy group, an amino group, and a nitrogen atom as a heteroatom. It is a heterocyclic group, a cyano group, a halogen atom, an aralkyl group, or an aryl group to be bonded.

Here, an alkyl group, an alkoxy group, an aralkoxy group, an amino group, a heterocyclic group having a nitrogen atom as a heteroatom and bonded by the nitrogen atom, a cyano group, a halogen atom, an aralkyl group, and an aryl group are the above-described groups R ^{1, R} 2, ^{R 3,} and the same groups as described in ^{R 4} are exemplified as preferable examples.

  Examples of the halogenoalkyl group include those in which one or two or more hydrogen atoms of the alkyl group are substituted with a fluorine atom, a chlorine atom, or a bromine atom. Among these, those substituted with fluorine atoms are preferred. Suitable examples of the halogenoalkyl group include a fluoromethyl group, a difluoromethyl group, and a trifluoromethyl group.

  Examples of the halogenoalkoxy group include those in which one or more hydrogen atoms of the alkoxy group are substituted with a fluorine atom, a chlorine atom, or a bromine atom. Among these, those substituted with fluorine atoms are preferred. Particularly preferred examples of the halogenoalkoxy group include a fluoromethoxy group, a difluoromethoxy group, and a trifluoromethoxy group.

Among them, the groups R ⁵ and R ⁶ are obtained in the following manner, in which the carboxylic acid compound described in detail below becomes a compound similar to the by-product, and the acetyl compound exerts a particularly effective effect on the separation of the by-product. In order for the chromene compound to exhibit excellent effects, it is preferably an alkyl group, a halogenoalkyl group, an alkoxy group, a halogenoalkoxy group, an aralkoxy group, a halogen atom, an aralkyl group, or an aryl group. Of these, the groups R ⁵ and R ⁶ are particularly preferably a hydrogen atom, an alkyl group, a halogenoalkyl group, or a halogen atom.

(Number of groups R ⁵ and R ⁶ a, b)
a and b represent the number of substituents of R ⁵ and R ⁶ , and a and b are integers of 0 to 3. When a and b are integers of 2 to 3, each R ⁵ and R ⁶ may be the same group or different from each other. Among these, a and b are preferably integers of 0 to 2 and are preferably integers of 0 to 1 in order to exhibit the effects of the present invention.

(Preferred acetyl compound)
Such acetyl compounds can be removed by-products by liquid separation operation under weakly basic conditions or by recrystallization, and as a result, high purity compounds can be easily obtained. Further, the acetyl compound is excellent in storage stability and can be easily converted into a naphthol compound by hydrolysis under acid or base conditions.

  Therefore, the use of the acetyl compound of the present invention can improve the yield and production conditions of naphthol compounds and chromene compounds with many production steps. Among these acetyl compounds, the following acetyl compounds are particularly exemplified as those that exhibit the above effects.

  Next, the manufacturing method of this acetyl compound is demonstrated.

(Method for producing acetyl compound)
The acetyl compound of the present invention has the following formula (2)

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , a, and b have the same meanings as those in the formula (1).)
Can be produced by reacting in the presence of acetic anhydride and acetate.
First, the carboxylic acid compound represented by the formula (2) will be described.

(Carboxylic acid compounds that are acetyl compound raw materials and by-products)
The carboxylic acid compound represented by the formula (2) is a known compound as described in Patent Document 1. Therefore, this carboxylic acid compound can be produced by a known method, for example, the Grignard method described in Patent Document 1. However, although the manufacturing method of this carboxylic acid compound is demonstrated below, when manufacturing this carboxylic acid compound, the by-product which has a similar structure arises.

(Production of carboxylic acid compound 1 Grignard method)
A method for producing the carboxylic acid compound represented by the formula (2) by the Grignard method will be described in more detail.

  A 2-bromophenylacetic acid derivative is converted into an ortho ester derivative represented by the following formula (6) by a known method, and then reacted with metallic magnesium to obtain a Grignard reagent (7) represented by the following formula (7). . The Grignard reagent (7) is reacted with a tetralone derivative at 50 to 70 ° C., and then an acid and a base are added to hydrolyze the orthoester (8) to obtain a carboxylic acid represented by the following formula (2). A compound is produced. At this time, phenylacetic acid (a compound of the following formula (9)) is generated as a by-product.

  A carboxylic acid compound can be produced by the reaction as described above. However, according to the study by the present inventors, in the above method, a by-product (phenylacetic acid) derived from a Grignard reagent as a by-product is produced in about 60 to 70% in the whole. This by-product is similar in structure to the carboxylic acid compound and has a large production amount, so that separation at this point is difficult.

  In order to further reduce such by-products, it is preferable to employ a method utilizing a metal halogen exchange reaction shown below. Next, this method will be described.

(Production Method 2 of Carboxylic Acid Compound Metal Halogen Exchange Reaction)
In order to further reduce the by-product and improve the yield of the acetyl compound, the carboxylic acid compound represented by the formula (2) is preferably produced by a method utilizing a metal halogen exchange reaction. Specifically, the carboxylic acid compound can be produced by the following method.

  First, the 2-bromophenylacetic acid derivative is converted into an orthoester compound represented by the following formula (6) by a known method. By reacting this with a tetralone derivative at 0 to 5 ° C. in the presence of a base (for example, n-butyllithium), and then adding an acid and a base to hydrolyze the orthoester (8), A carboxylic acid compound represented by the formula (2) can be produced. At this time, phenylacetic acid (a compound represented by the following formula (9)) is generated as a by-product.

  According to the above reaction, the production of by-products is small (however, by-products are produced in about 40 to 50%), and the carboxylic acid compound can be produced with good yield. This reaction will be described in detail.

(Metal halogen exchange reaction base)
The base used for the metal halogen exchange reaction is not particularly limited, and n-butyllithium, s-butyllithium, or t-butyllithium can be used. The amount of butyllithium used is not particularly limited, but is preferably 1 to 10 mol, more preferably 1 to 5 mol, particularly 1 to 3 mol, relative to 1 mol of the orthoester as a raw material. It is preferable that

  In addition, this reaction is preferably performed in an organic solvent. The reaction solvent is not particularly limited as long as it is inert to the reaction and dissolves the raw material. For example, ethers, specifically tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, or aromatic carbon In particular, solvents such as toluene and benzene can be used. The amount of the reaction solvent used is not particularly limited, but considering the kettle yield, it is preferably 3 to 200 parts by mass, more preferably 5 to 100 parts by mass with respect to 1 part by mass of the orthoester compound. Particularly preferred is 10 to 50 parts by mass.

  The reaction temperature is preferably −100 ° C. to room temperature, particularly preferably −80 to 10 ° C. The reaction time may be appropriately determined by confirming the yield of the target compound, but is usually preferably 0.1 to 10 hours, and more preferably 0.5 to 5 hours.

(Hydrolysis of ortho ester moiety)
After the reaction, in order to hydrolyze the orthoester, the reaction solution obtained by the metal halogen exchange reaction is mixed with an acid and a base. The acid and the base are preferably mixed after the acid is mixed. The acid to be used is not particularly limited, and an inorganic acid such as hydrochloric acid or sulfuric acid can be used. The amount of the acid used is about 5 to 50 times with respect to 1 mol of the ortho ester. is there. The base to be used is not particularly limited, and inorganic bases such as sodium hydroxide, potassium hydroxide and lithium hydroxide can be used. The amount of the base used is 1 mol of orthoester. About 5 to 50 times.

  As described above, the above-mentioned by-product (phenylacetic acid) is produced at the same time as the carboxylic acid compound regardless of the Grignard method or the metal halogen exchange reaction, and these (carboxylic acid compound and by-product) are separated. Is difficult because of the similar structure. Depending on the degree of purification, the Grignard method contains 60 to 70% by-product (phenylacetic acid), and the metal halogen exchange reaction method contains 40 to 50% by-product.

In the present invention, an acetyl compound is produced from the carboxylic acid compound represented by the formula (2), but the acetyl compound can be produced in a state where the carboxylic acid compound and the by-product are mixed.
Next, a method for producing an acetyl compound from this carboxylic acid compound will be described.

  (Method for producing acetyl compound from carboxylic acid compound)

  In the present invention, in order to produce the acetyl compound represented by the formula (1) from the carboxylic acid compound represented by the formula (2), the carboxylic acid compound can be reacted in the presence of acetate and acetic anhydride. That's fine. This reaction is preferably carried out with stirring. At this time, the by-product may be contained in the reaction system. In this reaction, since the by-product does not participate in the reaction, only the carboxylic acid compound represented by the formula (2) becomes the acetyl compound represented by the formula (1).

  In the present invention, the amount of acetic anhydride to be used is not particularly limited, but is preferably 1 to 100 mol, more preferably 1 to 70 mol, relative to 1 mol of the carboxylic acid compound represented by the formula (2). It is preferable that it is 2-50 mol especially.

  The acetate is not particularly limited, and examples thereof include an alkali metal salt of acetic acid, specifically sodium acetate, potassium acetate, lithium acetate, cesium acetate and the like. Among these, it is preferable to use sodium acetate or potassium acetate from the viewpoint of production cost. The amount of acetate used is not particularly limited, but is preferably 0.1 to 10 mol, more preferably 0.5 to 5 mol, with respect to 1 mol of the carboxylic acid compound, from the viewpoint of stirring efficiency. Particularly preferred is 0.8 to 1.5 mol.

  This reaction can be carried out without solvent or using a reaction solvent. When a reaction solvent is used, the reaction solvent is not particularly limited as long as it is inert to the reaction and dissolves the carboxylic acid compound represented by the formula (2). Specifically, toluene, xylene, benzene, or halogen solvents such as chloroform or dichloromethane can be used. The amount of reaction solvent used is not particularly limited, but considering the kettle yield, it is preferably 3 to 1000 parts by mass, and more preferably 5 to 300 parts by mass with respect to 1 part by mass of the carboxylic acid compound. Particularly preferred is 10 to 100 parts by mass.

  Further, this reaction is preferably performed by heating. What is necessary is just to heat so that the reaction temperature in that case may become room temperature or more, Specifically, it is preferable to set it as room temperature or more and 200 degrees C or less, and also it is preferable to set it as 50 degrees C or more and 150 degrees C or less. The reaction time may be appropriately determined according to the yield of the target compound, but is usually preferably 0.01 to 48 hours, and more preferably 0.1 to 24 hours.

  In addition, the reaction for synthesizing an acetyl compound from a carboxylic acid compound is a method in which all of the carboxylic acid compound, acetate salt, acetic anhydride, and reaction solvent are charged in a reaction vessel and then stirred and mixed. A known solid-liquid reaction, such as a method in which acetate is added to a solvent mixture and stirring and mixing, a method in which a carboxylic acid compound (which may be dissolved in a reaction solvent) is added to a mixed solution of acetate and acetic anhydride, etc. The method can be adopted without any particular limitation.

(Purification and storage stability of acetyl compounds)
The acetyl compound represented by the formula (1) can be produced by the reaction conditions as described above. After completion of the reaction, after distilling off excess acetic anhydride, the target product (acetyl compound) can be isolated by adding an organic solvent that is not compatible with water and a basic aqueous solution, followed by liquid separation. . At this time, the by-product contained as impurities can be easily removed by washing the separated organic layer (an organic solvent that is hardly compatible with water) with a weakly basic aqueous solution.

  The purification of this acetyl compound will be specifically described. After distilling off excess acetic anhydride, it is preferable to use a solvent that is hardly compatible with water, specifically toluene, benzene, ethyl acetate, dichloromethane, chloroform, etc. Add 10 to 100 times, more preferably 20 to 40 times. Subsequently, a basic inorganic salt aqueous solution, specifically 5 to 20% by mass of sodium bicarbonate water, or 5 to 20% by mass of potassium carbonate aqueous solution is preferably 5 to 50 times, more preferably, relative to the residual weight of the kettle. Add 10 to 20 times and perform a liquid separation operation. By performing such an operation, phenylacetic acid (a by-product represented by the formula (8)) can be reduced to 1% or less.

  In addition, column chromatography (developing solvents include aliphatic hydrocarbon solvents such as hexane and heptane, aromatic hydrocarbon solvents such as toluene and benzene, and halogen solvents such as chloroform and dichloromethane. Or a polar solvent such as ethyl acetate or methanol, or a mixed solvent thereof may be used.) Or by recrystallization with an alcohol solvent such as ethanol or isopropanol. The product acetyl compound can be obtained with a purity of 98% or more.

  Thus, it was difficult to separate the carboxylic acid compound represented by the formula (2) having a structure similar to that of the byproduct (phenylacetic acid) into the acetyl compound represented by the formula (1). By-products can be easily removed. Furthermore, although the obtained acetyl compound depends on the kind of the compound, it is a very stable compound, and even when stored at room temperature for 1 month or more, coloring and decomposition are not observed. According to the study by the present inventors, coloring and decomposition were not observed even when stored at room temperature for 3 months. On the other hand, as will be described in detail in the following examples, the naphthol compound represented by the formula (3) was colored when allowed to stand at room temperature for 6 days, depending on the type of the compound.

The structure of the acetyl compound purified by the above method is identified by measuring proton nuclear magnetic resonance spectrum ( ¹ H-NMR), mass spectrometry, and ¹³ C-nuclear magnetic resonance spectrum ( ¹³ C-NMR). can do.
Next, a method for producing a naphthol compound from this acetyl compound will be described.

(Method for producing naphthol compound)
The acetyl compound purified by the above method is deacetylated with an acid or a base, and the following formula (3)

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , a, and b have the same meanings as those in the formula (1).)
It can be set as the naphthol compound shown by these.
First, the reaction of deacetylation using an acid will be described.

(Deacetylation reaction using acid)
Although the kind of acid to be used is not particularly limited, hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid and the like can be used. Among these, hydrochloric acid is preferably used for economic reasons. The amount of acid used is not particularly limited, but is preferably 0.01 to 10 mol, more preferably 0.05 to 5 mol, per 1 mol of acetylnaphthol (acetyl compound). . In view of the nature of the reaction, the reaction is carried out with a catalytic amount of acid, so 0.08 to 1 mol is particularly preferred.

  In addition, when deacetylation is performed using an acid, it can be carried out in the absence of an organic solvent, but it is preferably carried out in an organic solvent in view of decomposition of the resulting naphthol compound. When an organic solvent is used, the solvent is not particularly limited as long as it is inert to the reaction and dissolves the raw material, and it is preferable to use an alcohol-based solvent, particularly methanol, ethanol, A solvent such as n-propanol can be used. The amount of the organic solvent used is not particularly limited, but is preferably 1 to 100 parts by mass, and more preferably 2 to 50 parts by mass with respect to 1 part by mass of the acetylnaphthol compound (acetyl compound).

  Moreover, when using an acid, it is preferable that reaction temperature shall be room temperature or more and 200 degrees C or less, and it is preferable to set it as 50 degrees C or more and 150 degrees C or less. The reaction time may be appropriately determined according to the yield of the target compound, but is usually preferably 0.1 to 72 hours, and more preferably 1 to 48 hours.

In addition, in order to reduce the coloring of the naphthol compound obtained, it is preferable to use the acid rather than the base described in detail below.
Next, the deacetylation reaction using a base will be described.

(Deacetylation reaction using a base)
The base to be used is not particularly limited, but sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, or the like can be used. Among these, it is preferable to use sodium hydroxide in consideration of economy. The amount of the base used is not particularly limited, but is preferably 0.1 to 50 mol, more preferably 1 to 30 mol, relative to 1 mol of the acetylnaphthol compound (acetyl compound). Especially, it is preferable to set it as 1-10 mol especially from the point of shortening of reaction time and suppression of a side reaction.

  In addition, when deacetylation is performed using a base, it can be carried out in the absence of an organic solvent, but it is preferably carried out in an organic solvent in view of decomposition of the resulting naphthol compound. When an organic solvent is used, the solvent is not particularly limited as long as it is inert to the reaction and dissolves the raw material, and it is preferable to use a solvent having high affinity for water. Specifically, solvents such as methanol, ethanol, n-propanol, and tetrahydrofuran can be used. The amount of the organic solvent used is not particularly limited, but is preferably 1 to 100 parts by mass, and more preferably 2 to 50 parts by mass with respect to 1 part by mass of the acetylnaphthol compound (acetyl compound).

  In the case of using a base, the reaction temperature is not particularly limited, but is preferably −30 ° C. or higher and 100 ° C. or lower, and more preferably −10 ° C. or higher and 50 ° C. or lower. The reaction time may be appropriately determined according to the yield of the target compound, but is preferably 0.01 to 48 hours, and more preferably 0.1 to 24 hours.

(Purification of naphthol compounds)
As described above, after completion of the deacetylation reaction using an acid or a base, the reaction system is neutralized, the solvent used is distilled off, and an organic solvent that is not easily compatible with water, for example, Toluene, ethyl acetate, dichloromethane, and water are added for liquid separation, and the target product (naphthol compound) is isolated. In the present invention, since a by-product can be removed at the time of the acetyl compound, it is not necessary to use a basic solution in the isolation of the naphthol compound. Therefore, a naphthol compound can be obtained with a high yield. Further, the obtained naphthol compound can be further purified by using a method such as column chromatography or recrystallization, if necessary.

Thus, if the acetyl compound of the present invention is used, a high-purity naphthol compound can be easily produced with good yield. This naphthol compound is low in storage stability because of its oxidative deterioration due to the properties of the compound. Therefore, the method for producing a naphthol compound via the highly stable acetyl compound of the present invention is an industrially very advantageous method.
Next, a method for synthesizing a chromene compound from the obtained naphthol compound will be described.

(Manufacture of chromene compounds)
In the present invention, after the naphthol compound is produced by the above method, the obtained naphthol compound and the following formula (4)

(Where
R ⁷ and R ⁸ are each an alkyl group, an alkoxy group, an aralkoxy group, an amino group, a heterocyclic group having a nitrogen atom as a hetero atom, and bonded by the nitrogen atom, a cyano group, a halogen atom, an aralkyl group, or An aryl group,
c and d are each an integer of 0 to 3, and when c and d are an integer of 2 to 3, each R ⁷ and R ⁸ may be the same group, Different groups may be used. By reacting a propargyl compound represented by the following formula (5):

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , a, and b have the same meanings as those in formula (1),
R ⁷ , R ⁸ , c, and d have the same meaning as in the formula (4). )
The chromene compound shown by these can be manufactured.
First, the propargyl compound will be described.

(Propargyl compound)
The naphthol compound can be reacted with the propargyl compound represented by the formula (4) to produce a chromene compound having excellent ftchromic properties. This propargyl compound can be synthesized by reacting a ketone derivative having a corresponding structure with a metal acetylene compound such as lithium acetylide.

(Group R ⁷ and Group R ⁸ )
In the formula (4), the groups R ⁷ and R ⁸ are an alkyl group, an alkoxy group, an aralkoxy group, an amino group, a heterocyclic group having a nitrogen atom as a hetero atom, and bonded by the nitrogen atom, a cyano group, a halogen, An atom, an aralkyl group, or an aryl group. Specific examples of these groups include the same groups as those described for the groups R ¹ , R ² , R ³ , and R ⁴ described above.

Among them, the above groups R ⁷ and R ⁸ are preferably a hydrogen atom, a methyl group, a propyl group, a methoxy group, a propoxy group, in order for the chromene compound obtained by reacting with the naphthol compound to exert an excellent effect. An isopropoxy group, a dimethylamino group, or a morpholino group is preferable. Among them, the groups R ⁷ and R ⁸ are particularly preferably a methyl group or a methoxy group.

(Number of groups R ⁷ and R ⁸ c, d)
c and d represent the number of substituents of R ⁷ and R ⁸ , each of which is an integer of 0 to 3, and when c and d are integers of 2 to 3, each R ⁷ and R ⁸ May be the same group or different groups.

(Reaction of naphthol compound with propargyl compound)
The naphthol compound and the propargyl compound may be mixed by a known method, for example, in the presence of an acid catalyst. At this time, in order to effectively contact the naphthol compound and the propargyl compound with the acid catalyst, it is preferable to use an organic solvent.

  Although it does not specifically limit as an acid catalyst used in this reaction, What is necessary is just an organic and inorganic acid, Specifically, p-toluenesulfonic acid, camphorsulfonic acid, silica gel, acidic alumina, etc. can be used, but reaction Silica gel is preferred from the viewpoint of yield.

  The organic solvent used in the reaction is not particularly limited as long as it is inert to the reaction and dissolves the raw material, and is an aromatic hydrocarbon solvent, specifically toluene, xylene, nitrile. Solvents such as acetonitrile, specifically acetonitrile, halogen solvents, specifically chloroform, ketone solvents, and specifically methyl isobutyl ketone can be used. The amount of reaction solvent used is not particularly limited, but considering the yield of the kettle, it is preferably 3 to 1000 parts by mass, more preferably 5 to 300 parts by mass with respect to 1 part by mass of the naphthol compound. In particular, the content is preferably 10 to 100 parts by mass.

  The amount of the naphthol compound and propargyl compound used is not particularly limited. However, in consideration of production cost, it is preferable to use 0.1 to 5 mol of propargyl compound with respect to 1 mol of naphthol compound, and further 0.8 to 2 mol. It is preferable to use it, and it is especially preferable to use 0.9-1.3 mol.

  The reaction of the naphthol compound and the propargyl compound is carried out by mixing all of the naphthol compound, the propargyl compound, the acid catalyst, and the organic solvent in a reaction vessel and then stirring and mixing, a mixed solution of the naphthol compound, the propargyl compound, and the organic solvent. In particular, known solid-liquid reaction methods such as a method of adding an acid catalyst and stirring and mixing, a method of adding a naphthol compound and a propargyl compound (which may be dissolved in an organic solvent) to a mixed solution of an acid catalyst and a reaction solvent, etc. Can be used without restriction.

  The reaction temperature is preferably room temperature or higher and 200 ° C. or lower, more preferably 70 ° C. or higher and 130 ° C. or lower. Although reaction time can be suitably determined according to the yield of the target compound, it is usually preferably 0.01 to 50 hours, more preferably 0.1 to 15 hours.

  After completion of the reaction, the desired product can be isolated by adding an appropriate organic solvent and water to separate the layers. Further, the chromene compound can be obtained with a purity of 99% or more by methods such as column chromatography and recrystallization.

  The chromene compound thus obtained has the following formula (5):

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , a, and b have the same meanings as those in formula (1),
R ⁷ , R ⁸ , c, and d have the same meaning as in the formula (4). )
It becomes a compound excellent in photochromic characteristics.

  According to the present invention, by using an acetyl compound that is a precursor of a naphthol compound, the production conditions of the chromene compound can also be improved. The acetyl compound can be stored for a long period of time and can be easily converted to a naphthol compound. Therefore, the acetyl compound is very suitable for industrial production of chromene compounds having a number of production steps.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples.

  Production Example 1 (Synthesis of carboxylic acid compound)

Ortho ester I (238.0 g, 795.6 mmol) was dissolved in anhydrous toluene (1190 ml) and stirred in an ice bath. Under a nitrogen atmosphere, a 1.6M n-butyllithium-hexane solution (373.8 ml, 875 mmol) was added dropwise at an internal temperature of 0 ° C., and the mixture was stirred for 30 minutes. An α-tetralone-toluene solution (210.0 g, weight ratio 1: 1) was added dropwise, the ice bath was removed, and the mixture was stirred for 2 hours. After completion of the reaction, a 5% by mass ammonium chloride aqueous solution (400 ml) was added and stirred for 1 hour, and the aqueous layer was extracted with toluene. The obtained toluene solution was concentrated under reduced pressure. (The selectivity of compounds II and III was measured by high performance liquid chromatography (HPLC) and found to be compound II: compound III = 81: 19.)
To the reaction residue containing the obtained compounds II and III, THF (680 ml) was added, 18% by mass hydrochloric acid (566 ml) was added, and the mixture was stirred at 60 ° C. for 2 hours. After completion of the reaction, the organic layer was washed 3 times with 15% by mass brine (500 ml). Subsequently, toluene (266 ml), water (268 ml) and potassium hydroxide (53.4 g, 954.6 mmol) were added and stirred at 50 ° C. for 2 hours. After completion of the reaction, water (270 ml) was added to the reaction solution cooled to 25 ° C. to separate the layers. After removing the organic layer, toluene (250 ml) was newly added to the aqueous layer to wash the aqueous layer. 36% by mass hydrochloric acid (136 ml) was added to the aqueous layer to adjust the pH of the aqueous layer to 1, and then toluene (250 ml) was added to extract carboxylic acid form IV (carboxylic acid compound) and compound III from the aqueous layer. After washing twice with water (240 ml), a toluene solution (480 ml) containing carboxylic acid form IV (carboxylic acid compound) and compound III was obtained (the selectivity of compounds IV and III was measured by HPLC. : Compound III = 81: 19).

  Example 1 (Synthesis of acetyl compound)

The toluene solution (238 ml) containing the carboxylic acid form IV and compound III (byproduct) obtained in Production Example 1 was concentrated under reduced pressure to a volume of 100 ml, and then this solution was added to acetic anhydride (545.2 ml, 5757.6 mmol). And sodium acetate (18.9 g, 230.7 mmol) at 100 ° C. and stirred at 110 ° C. for 2 hours. After completion of the reaction, water (244.0 kg, 13551.6 mmol) was added dropwise at an internal temperature of 45 ° C., and the mixture was stirred for 15 minutes. Thereafter, liquid separation was performed to remove the aqueous layer, and the organic layer (toluene layer) was further washed twice with water (80 ml) and a 5% by mass aqueous sodium hydrogencarbonate solution (80 ml) to remove compound III. Further, water (80 ml) was added, and the organic layer was washed again. After liquid separation and removal of the aqueous layer, the organic layer was concentrated under reduced pressure. Then, isopropyl alcohol (333.0 ml) was added to perform recrystallization, and acetylnaphthol compound (acetyl compound) V (yield 26.26). 6 g, yield of 3 steps (23.2%) was obtained as a white solid. The identification result of the obtained acetylnaphthol body V (acetyl compound) is shown below.
¹ H-NMR (CDCl ₃ ): 2.39 (s, 3H), 2.70-2.82 (m, 4H), 7.26-7.50 (m, 6H), 7.79-7. 83 (m, 1H), 7.88-7.91 (d, 1H), 8.49-8.54 (m, 1H), HPLC purity 98.2%,
Molecular mass 289 (M + 1) by liquid chromatograph mass spectrometer (LCMS).

  Example 2 (Synthesis of naphthol compound)

  Under a nitrogen atmosphere, the acetylnaphthol compound V (26.6 g, 92.3 mmol) obtained in Example 1 was dissolved in methanol (266.0 ml), and 36 mass% hydrochloric acid (1.9 g, 18.5 mmol) was dissolved. The mixture was further stirred at reflux temperature for 1 hour. After completion of the reaction, the reaction mixture was cooled to 25 ° C., and ethyl acetate (532.2 ml) and water (532.2 ml) were added for liquid separation. After the organic layer was washed with 5% by mass brine, the solvent was distilled off, and naphthol compound VI (naphthol compound) (20.7 g, 91% yield from acetylnaphthol compound V, 21% yield from orthoester compound I. 1%) was obtained. The HPLC purity was 96.0%.

  Example 3 (Production of chromene compound)

  Under a nitrogen atmosphere, the naphthol compound VI obtained in Example 2 (18.6 g, 75.5 mmol) and the propargyl alcohol compound VII (18.7 g, 75.5 mmol) were added to toluene (280 ml) and stirred. Silica gel (19.0 g) was added, and the mixture was stirred at 120 ° C. for 3 hours. Water (140 ml) was added to wash the organic layer 4 times in total, and the organic layer was distilled off under reduced pressure. The obtained reaction residue was purified by recrystallization (isopropyl alcohol: acetonitrile, 10: 2) to obtain chromene compound VIII (15.4 g, yield 44.0%). The HPLC purity was 99.4%.

  Comparative Example 1 (Production of naphthol compound)

  Toluene solution (238 ml, Compound IV: Compound III = 81: 19) containing carboxylic acid form IV and Compound III obtained in Production Example 1 was added to toluene (500 ml) and polyphosphoric acid (106.2 g, 596.7). mmol) was added and reacted at reflux temperature for 7 hours. After completion of the reaction, ice water (200 ml) was added and stirred for 30 minutes, followed by liquid separation, and the organic layer was washed with water (200 ml). The organic layer was washed twice with a 5% by mass aqueous sodium hydrogencarbonate solution (200 ml), and then washed again with water (200 ml). The organic layer was concentrated under reduced pressure to obtain naphthol compound VI (naphthol compound) (15.5 g, yield from orthoester compound I 15.8%). The HPLC purity was 92.2%.

Comparative Example 2 (Production of chromene compound)
A chromene compound VIII was obtained in the same manner as in Example 3 except that the naphthol compound VI obtained in Comparative Example 1 was used (11.1 g, yield 38.1%, HPLC purity 99.1%). .

Production Example 2 (Production of carboxylic acid compound)
In Production Example 1, the same operation as in Production Example 1 was performed, except that 4-methyltetralone having the same number of moles as α-tetralone was used. A toluene solution (480 ml) containing a carboxylic acid form X (carboxylic acid compound) of the following formula and compound III was obtained. Compound X in the following formula: Compound III = 81: 19.

  Example 4 (Production of acetyl compound)

The same operation as in Example 1 was carried out except that the toluene solution (238 ml) containing the carboxylic acid form X obtained in Production Example 2 and Compound III was used, and acetylnaphthol form XI (acetyl compound) (yield 27.27). 4 g, yield of 3 steps, 22.5%) was obtained as a white solid. The identification results of the obtained acetylnaphthol XI (acetyl compound) are shown below.
¹ H-NMR (CDCl ₃ ): 1.40 (s, 3H), 2.39 (s, 3H), 2.70-2.82 (m, 3H), 7.26-7.50 (m, 6H), 7.79-7.83 (m, 1H), 7.88-7.91 (d, 1H), 8.49-8.54 (m, 1H), HPLC purity 98.4%,
Molecular mass by LCMS 303 (M + 1).

  Example 5 (Production of naphthol compound)

  Under a nitrogen atmosphere, the acetylnaphthol XI (27.4 g, 90.6 mmol) obtained in Example 4 was dissolved in methanol (270.0 ml), and 36 mass% hydrochloric acid (1.9 g, 18.5 mmol) was added. The mixture was further stirred at reflux temperature for 1 hour. After completion of the reaction, the reaction mixture was cooled to 25 ° C., and ethyl acetate (535.0 ml) and water (535.0 ml) were added for liquid separation. After the organic layer was washed with 5% by mass brine, the solvent was distilled off, and naphthol XII (naphthol compound) (21.5 g, yield 88.0% from acetylnaphthol XI, yield from orthoester I 19.8%). The purity of HPLC was 95.3%.

  Example 6 (Production of chromene compound)

  Under a nitrogen atmosphere, the naphthol compound XII (10.0 g, 38.4 mmol) obtained in Example 5 and the propargyl alcohol compound XIII (10.3 g, 38.4 mmol) were added to toluene (150 ml) and stirred. Silica gel (10.0 g) was added and stirred at 110 ° C. for 2 hours. Water (120 ml) was added to wash the organic layer 4 times in total, and the organic layer was distilled off under reduced pressure. The obtained reaction residue was purified with a silica gel column (solvent chloroform) to obtain a chromene compound IX (9.4 g, yield 47.9%).

Production Example 3 (Production of carboxylic acid compound)
In Production Example 1, the same operation as in Production Example 1 was performed except that 6-methoxytetralone having the same number of moles as α-tetralone was used. A toluene solution (480 ml) containing a carboxylic acid form XV (carboxylic acid compound) of the following formula and compound III was obtained. Compound XV of the following formula: Compound III = 79: 21.

  Example 7 (Production of acetyl compound)

The same procedure as in Example 1 was carried out except that the toluene solution (238 ml) containing the carboxylic acid compound XV obtained in Production Example 3 and Compound III was used, and the acetylnaphthol compound XVI (acetyl compound) (yield 32. 1 g, 3 step yield 25.4%) was obtained as a white solid. The identification results of acetylnaphthol XVI (acetyl compound) are shown below.
¹ H-NMR (CDCl ₃ ): 2.40 (s, 3H), 2.70-2.82 (m, 4H), 3.83 (s, 3H), 6.64-6.69 (m, 2H), 7.27-7.40 (m, 4H), 7.69-7.90 (m, 2H), HPLC purity 98.1%,
Molecular weight by LCMS 319 (M + 1).

  Example 8 (Production of naphthol compound)

  Under a nitrogen atmosphere, acetylnaphthol XVI (13.8 g, 47.0 mmol) was dissolved in methanol (135.0 ml), 36% by mass hydrochloric acid (0.95 g, 9.3 mmol) was added, and the mixture was refluxed at 1 Stir for hours. After completion of the reaction, the reaction mixture was cooled to 25 ° C., and ethyl acetate (270.0 ml) and water (270.0 ml) were added for liquid separation. After the organic layer was washed with 5% by mass brine, the solvent was distilled off, and naphthol XVII (naphthol compound) (9.4 g, yield 72.3% from acetylnaphthol XVI, yield from orthoester I 20.4%). The HPLC purity was 95.3%.

  Example 9 (Production of chromene compound)

  Under a nitrogen atmosphere, naphthol XVI (3.0 g, 10.8 mmol) obtained in Example 8 and propargyl alcohol XVII (3.0 g, 10.8 mmol) were added to toluene (50 ml), and the mixture was stirred. Silica gel (3.0 g) was added and stirred at 110 ° C. for 2 hours. Water (40 ml) was added to wash the organic layer 4 times in total, and the organic layer was distilled off under reduced pressure. The obtained reaction residue was purified with a silica gel column (solvent chloroform) to obtain a chromene compound XIX (2.1 g, yield 36.0%). The HPLC purity was 99.4%.

Production Example 4 (Production of carboxylic acid compound)
In Production Example 1, the same operation as in Production Example 1 was performed, except that 6-trifluoromethyltetralone having the same number of moles as α-tetralone was used. A toluene solution (475 ml) containing a carboxylic acid form XX (carboxylic acid compound) of the following formula and compound III was obtained. Compound XX of the following formula: Compound III = 78: 22.

  Example 10 (Production of acetyl compound)

The same operation as in Example 1 was carried out except that the toluene solution (230 ml) containing the carboxylic acid form XX obtained in Production Example 4 and Compound III was used, and the acetylnaphthol form XXI (acetyl compound) (yield 31. 6 g, 3 step yield 22.3%) was obtained as a pale yellow solid. The identification result of acetyl naphthol form XXI (acetyl compound) is shown below.
¹ H-NMR (CDCl ₃ ): 2.40 (s, 3H), 2.70-2.83 (m, 4H), 7.27-7.40 (m, 6H), 7.70-7. 80 (m, 2H), HPLC purity 98.1%,
Molecular weight by LCMS 357 (M + 1).

  Example 11 (Production of naphthol compound)

  Under a nitrogen atmosphere, acetylnaphthol XXI (12.3 g, 34.5 mmol) was dissolved in methanol (130.0 ml), and 36% by mass hydrochloric acid (0.88 g, 8.7 mmol) was added. Stir for hours. After completion of the reaction, the reaction mixture was cooled to 25 ° C., and ethyl acetate (260.0 ml) and water (260.0 ml) were added for liquid separation. After the organic layer was washed with 5% brine, the solvent was distilled off, and naphthol XXII (naphthol compound) (9.4 g, yield 86.5% from acetylnaphthol XXI, yield 19 from orthoester I) .3%) was obtained. The HPLC purity was 95.6%.

  Example 12 (Production of chromene compound)

  Under a nitrogen atmosphere, naphthol form XXII (3.0 g, 9.55 mmol) and propargyl alcohol form XVIII (3.0 g, 10.8 mmol) obtained in Example 11 were added to toluene (50 ml), and the mixture was stirred. (3.0 g) was added and stirred at 110 ° C. for 2 hours. Water (40 ml) was added to wash the organic layer 4 times in total, and the organic layer was distilled off under reduced pressure. The obtained reaction residue was purified with a silica gel column (solvent chloroform) to obtain a chromene compound XXIV (2.4 g, yield 43.3%). The HPLC purity was 99.2%.

Production Example 5 (Production of carboxylic acid compound)
In Production Example 1, the same operation as in Production Example 1 was performed except that ortho ester XXV having the same number of moles as ortho ester I was used. A toluene solution (482 ml) containing a carboxylic acid form XXVI (carboxylic acid compound) of the following formula and a compound XXVII was obtained. Compound XXV of the following formula: Compound XXVI = 79: 21.

  Example 13 (Production of acetyl compound)

The same operation as in Example 1 was carried out except that the toluene solution (230 ml) containing the carboxylic acid form XXVI and the compound XXVII obtained in Production Example 5 was used, and the acetylnaphthol form XXVIII (acetyl compound) (yield 27. 9 g, yield of 3 steps (23.2%) was obtained as a pale yellow solid. The identification results of acetylnaphthol form XXVIII (acetyl compound) are shown below.
¹ H-NMR (CDCl ₃ ): 2.39 (s, 3H), 2.45 (s, 3H), 2.70-2.82 (m, 4H), 7.26-7.50 (m, 6H), 7.79-7.83 (m, 1H), 8.49-8.54 (m, 1H), HPLC purity 98.2%,
Molecular weight by LCMS 303 (M + 1).

  Example 14 (Production of naphthol compound)

  Under a nitrogen atmosphere, acetylnaphthol XXVIII (10.4 g, 34.5 mmol) was dissolved in methanol (130.0 ml), 36 mass% hydrochloric acid (0.88 g, 8.7 mmol) was added, and the mixture was stirred at reflux temperature for 1 hour. did. After completion of the reaction, the reaction mixture was cooled to 25 ° C., and ethyl acetate (260.0 ml) and water (260.0 ml) were added for liquid separation. After the organic layer was washed with 5% by mass brine, the solvent was distilled off, and naphthol form XXIX (naphthol compound) (9.4 g, yield from acetylnaphthol form XVIII 86.5%, yield from orthoester form XXV 19.3%) was obtained. The HPLC purity was 95.8%.

  Example 14 (Production of chromene compound)

  Under a nitrogen atmosphere, the naphthol form XXIX (3.0 g, 11.5 mmol) and propargyl alcohol form VII (3.3 g, 13.3 mmol) obtained in Example 13 were added to toluene (50 ml) and stirred. Silica gel (3.0 g) was added and stirred at 110 ° C. for 2 hours. After completion of the reaction, water (40 ml) was added to wash the organic layer 4 times in total, and the organic layer was concentrated under reduced pressure. The reaction residue was purified by a silica gel column (solvent chloroform) to obtain a chromene compound XXX (2.1 g, yield 43.8%). The HPLC purity was 99.4%.

Example 15 (Evaluation of storage stability)
The storage stability of the acetylnaphthol compound (acetyl compound) and naphthol compound (naphthol compound) obtained in the above examples was examined. The compounds stored for 1 week at room temperature and 3 months at room temperature were evaluated by TLC (thin layer chromatography), HPLC (high performance liquid chromatography) purity, and visual evaluation. The results are shown in Table 1. Evaluation of the TLC spot in Table 1 was “Yes” when a spot of a compound (decomposed product) other than the corresponding compound was confirmed when a compound stored for 1 week and 3 months was developed by TLC, and was not confirmed. The thing was described as “none”.

  One week after storage at room temperature, no decomposition was observed for each acetylnaphthol compound (acetyl compound). On the other hand, each naphthol body (naphthol compound) changed from a transparent oily substance to a reddish brown oily substance. Moreover, the spot of the decomposition product was confirmed under the spot of the naphthol body (naphthol compound) on TLC.

  Furthermore, each acetyl naphthol compound (acetyl compound) was stable even when stored at room temperature for 3 months, but the naphthol compound was changed to a brown oily substance.

Example 16
Using the acetyl naphthol compound V stored for 3 months in Example 15, the same operation as in Example 2 was performed to obtain naphthol compound VI (yield 92.0%, HPLC purity 96.2%). Both the reaction yield and HPLC purity were the same as in Example 2.

Example 17
Using the naphthol compound VI obtained in Example 16, the same operation as in Example 3 was performed to obtain a chromene compound VIII. (Yield 42.0%, HPLC purity 99.5%).
The same results as in Example 3 were obtained for both the reaction yield and HPLC purity.

Claims (4)

Following formula (1)

(Wherein R ¹ , R ² , R ³ , and R ⁴ are each a hydrogen atom, an alkyl group, a halogen atom, an aralkyl group, or an aryl group,
Two groups selected from R ¹ , R ² , R ³ , and R ⁴ may be combined to form an aliphatic hydrocarbon ring,
R ⁵ and R ⁶ are each an alkyl group, a halogenoalkyl group, an alkoxy group, an aralkoxy group, a halogenoalkoxy group, an aralkoxy group, an amino group, a nitrogen atom as a hetero atom, and a heterocyclic group bonded by the nitrogen atom. , A cyano group, a halogen atom, an aralkyl group, or an aryl group,
a and b are each an integer of 0 to 3, and when a and b are an integer of 2 to 3, each R ⁵ and R ⁶ may be the same group, Different groups may be used. )
An acetyl compound represented by Following formula (2)

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , a, and b have the same meanings as those in the formula (1).)
The method for producing an acetyl compound according to claim 1, wherein the carboxylic acid compound represented by the formula is reacted in the presence of acetic anhydride and acetate. The acetyl compound according to claim 1 is deacetylated with an acid or a base, the following formula (3)

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , a, and b have the same meanings as those in the formula (1).)
The manufacturing method of the naphthol compound shown by these. The naphthol compound represented by the formula (3) is produced by the method according to claim 3, and then the naphthol compound obtained and the following formula (4)

(In the formula, R ⁷ and R ⁸ are each an alkyl group, an alkoxy group, an aralkoxy group, an amino group, a heterocyclic group having a nitrogen atom as a hetero atom, and bonded by the nitrogen atom, a cyano group, a halogen atom, An aralkyl group or an aryl group,
c and d are each an integer of 0 to 3, and when c and d are an integer of 2 to 3, each R ⁷ and R ⁸ may be the same group, Different groups may be used. )
A reaction with a propargyl compound represented by the following formula (5):

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , a, and b have the same meanings as those in formula (1),
R ⁷ , R ⁸ , c, and d have the same meaning as in the formula (4). )
The manufacturing method of the chromene compound shown by these.