JP2001114767A - Production of pyrimidine compound and production of its intermediate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an industrial process for the easy production of a pyrimidine compound in high efficiency at a low cost. SOLUTION: A pyrimidine compound of formula (V) (X and Y are each O or S; R1 is H or a 1-5C alkyl; R3 is a 1-5C alkyl) is produced by the hydrogenative decomposition of a compound of formula (IV) (R2 is a 2-6C acyl which may be substituted with a halogen) in the presence of an alkylamine of formula (VII) (R4 to R6 are each H or a 1-6C alkyl or arbitrary two groups of R4 to R6 form a ring together with the bonding N atom and the remaining group is H or a 1-5C alkyl).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel method for producing a pyrimidine compound useful as a drug, particularly an antiviral agent, and a novel method for producing an intermediate thereof.

[0002]

2. Description of the Related Art Pyrimidine compounds are important compounds as pharmaceuticals, especially as antiviral agents, and various methods have been proposed for producing them. For example,
As a method for producing 6-benzyl-1-ethoxymethyl-5-isopropyluracil from 5-isopropyluracil, a production method including the following four steps is exemplified. (See the scheme below)

[0003]

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The steps (i) to (iv) in the above scheme will be described below.

Step (i) : After protecting the phenolic hydroxyl group of the pyrimidine base by reacting it with a silylating agent, a dialkoxymethane (for example, By reacting the compound with (diethoxymethane), the target compound in which the 1-position of pyrimidine is alkoxymethylated can be obtained (JP-A-10-130245). In this method, when one equivalent of dialkoxymethane is used with respect to 5-isopropyluracil, the reaction is not completed and the reaction rate is reduced. When dialkoxymethane is used in an excess amount relative to 5-isopropyluracil, a bis (alkoxymethyl) compound in which the pyrimidine is alkoxymethylated at the 3-position is by-produced, resulting in a decrease in yield. Therefore, even when the reaction is carried out using an excess amount of dialkoxymethane, no bis (alkoxymethyl) compound is produced.
-Development of a method for producing alkoxymethyl-5-isopropyluracil has been desired.

Step (ii) : As a method for synthesizing 6- (α-hydroxybenzyl) -1-ethoxymethyl-5-isopropyluracil, the 6-position of 1-ethoxymethyl-5-isopropyluracil is lithiated with an organolithium reagent. And then a reaction with benzaldehyde (JP-A-7-97324).

[0007] However, in this lithiation reaction, the nitrogen at the 3-position of the pyrimidine ring is also lithiated, so that the organolithium reagent is excessively consumed. The organolithium reagents used are n-butyllithium, lithium diisopropylamide, etc., which are very expensive and therefore increase the cost in this reaction.

Step (iii) : A hydroxyl group can be acetylated by reacting it with acetic anhydride in a pyridine solution of 6- (α-hydroxybenzyl) -1-ethoxymethyl-5-isopropyluracil (Japanese Patent Laid-Open No. 7
-97324). However, in this method, in addition to the target compound, a diacetyl compound in which the 3-position of the pyrimidine ring is acetylated is produced as a by-product, resulting in a decrease in yield. The diacetyl by-product can be easily converted back to 6- (α-acetoxybenzyl) -1-ethoxymethyl-5-isopropyluracil by heating in pyridine water. It is disadvantageous in that the number of processes increases and the processing time increases,
Development of a method for obtaining a simple monoacetyl form has been desired.

Step (iv) : Acetoxyl group is converted to a hydrogen atom by reacting 6- (α-acetoxybenzyl) -1-ethoxymethyl-5-isopropyluracil with hydrogen in the presence of palladium carbon or palladium hydroxide carbon. It can be reduced (JP-A-3-279366). However, in this method, in addition to the target compound, a dihydro form in which the 5- and 6-positions of the pyrimidine ring are hydrogenated is by-produced, resulting in a decrease in the yield and a decrease in the purity of the product. Therefore, the generation of by-products was suppressed and 6
-Development of a method for obtaining an aralkyl-substituted pyrimidine compound with high purity has been desired.

On the other hand, by reducing in the presence of an acid such as hydrochloric acid or acetic acid and a metal such as zinc, the by-product of the dihydro compound in which the 5- and 6-positions of the pyrimidine ring are hydrogenated is suppressed, and acetoxyl is obtained. A method of reducing a group to a hydrogen atom (JP-A-8-3143) is mentioned. However, this method requires the use of a large amount of zinc, which is problematic for an industrial production method.

[0011]

SUMMARY OF THE INVENTION An object of the present invention is to solve the above-mentioned problems and to provide a simple, efficient and inexpensive method for producing a pyrimidine compound and an intermediate thereof. It is to provide an excellent manufacturing method.

[0012]

Means for Solving the Problems In order to achieve the above object, the present inventors have made various studies on each step, and as a result, have obtained a simpler, more efficient, and less expensive method than the conventional method. A method for producing a pyrimidine compound and its intermediate has been found, and the present invention has been completed.

The present invention relates to the following. (1) General formula (I)

[0014]

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(Wherein X and Y are each independently:
R ¹ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms; (Hereinafter abbreviated as compound (I)) with a silylating agent to give a compound of the general formula (Ia)

[0016]

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(Wherein X and Y are each independently
R ¹ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms; ) (Hereinafter abbreviated as monosilylated product (Ia)) and then represented by the general formula (VI)

[0018]

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Wherein R ³ represents an alkyl group having 1 to 5 carbon atoms (hereinafter abbreviated as dialkoxymethane (VI)). General formula (II)

[0020]

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(Wherein X and Y are each independently
R ¹ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and R ³ represents a C 1 to 5 carbon atom;
Represents an alkyl group. )) (Hereinafter abbreviated as compound (II)). (2) Compound (II) is converted to a compound of the general formula (II-b) by an alkali metal hydroxide.

[0022]

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(Wherein X and Y are each independently
R ¹ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and R ³ represents a C 1 to 5 carbon atom;
And M represents an alkali metal atom. )
An alkali metal salt [hereinafter referred to as an alkali metal salt (I
Abbreviated as Ib)], reacted with an organolithium reagent, and then reacted with benzaldehyde.

[0024]

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Wherein X and Y are each independently:
R ¹ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and R ³ represents a C 1 to 5 carbon atom;
Represents an alkyl group. ) (Hereinafter abbreviated as compound (III)). (3) Compound (III) in the presence of 4- (N, N-dimethylamino) pyridine or 4-pyrrolidinopyridine
With an acid anhydride represented by the formula (R ² ) ₂ O (wherein R ² represents an acyl group having 2 to 6 carbon atoms which may be substituted with a halogen atom). General formula (IV)

[0026]

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(Wherein X and Y are each independently
Represents an oxygen atom or a sulfur atom, R ¹ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, R ² represents an acyl group having 2 to 6 carbon atoms which may be substituted with a halogen atom, R ³ Represents an alkyl group having 1 to 5 carbon atoms. ) (Hereinafter abbreviated as compound (IV)). (4) Compound (IV) is represented by the general formula (VII)

[0028]

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(Wherein R ⁴ , R ⁵ and R ⁶ each independently represent a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, or a nitrogen atom to which any two of them are bonded together (A ring may be formed together with the atom, and the remaining one may represent a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.)
[Hereinafter referred to as alkylamine (V
Abbreviated as II)] in the presence of the general formula (V)

[0030]

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(Wherein X and Y are each independently
R ¹ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and R ³ represents a C 1 to 5 carbon atom;
Represents an alkyl group. The method for producing a pyrimidine compound [hereinafter abbreviated as compound (V)] represented by the formula: (5) A compound (II) is produced by the method of the above (1), a compound (III) is produced from the compound by the method of the above (2), and a compound (III) is produced from the compound by the method of the above (3) A method for producing compound (V), and then producing compound (V) from the compound according to method (4) above.

[0032]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
The symbols used in the present specification are described below.

X and Y each independently represent an oxygen atom or a sulfur atom, wherein X is preferably an oxygen atom, and Y is preferably an oxygen atom.

The alkyl group having 1 to 5 carbon atoms represented by R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ may be any of linear, branched or cyclic. Ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and cyclopentyl.

When R ¹ is an alkyl group having 1 to 5 carbon atoms, preferred examples include methyl, ethyl and isopropyl, more preferably isopropyl. R
¹ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms,
Preferably it is a C1-C5 alkyl group, More preferably, it is isopropyl.

Preferred examples of the alkyl group having 1 to 5 carbon atoms represented by R ³ include methyl, ethyl and propyl, more preferably ethyl.

R ⁴ , R ⁵ and R ⁶ each independently represent a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, or any two of which together form a ring together with the nitrogen atom to which they are bonded. One formed and the remaining one may represent a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. R ⁴ , R ⁵
When R ⁶ and R ⁶ are each independently an alkyl group having 1 to 5 carbon atoms, preferred examples include ethyl, propyl, isopropyl and n-butyl. R ⁴ , R
⁵ and R ⁶ are not hydrogen atoms at the same time.
When any two of R ⁴ , R ⁵ and R ⁶ together form a ring with the nitrogen atom to which they are attached, and the remaining one represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms (ie, alkyl When the amine (VII) is a cyclic amine), the ring includes piperazinyl, piperidinyl, and morpholino. When the remaining one is an alkyl group having 1 to 5 carbon atoms, methyl is preferable.

Examples of the halogen atom which is a substituent of the optionally substituted acyl group having 2 to 6 carbon atoms represented by R ² include a fluorine atom and a chlorine atom. The acyl group having 2 to 6 carbon atoms which may be substituted by a halogen atom represented by R ² may be linear or branched, and includes, for example, acetyl, propionyl, butyryl, isobutyryl, chloroacetyl, triacetyl Fluoroacetyl. Preferred examples of R ² include acetyl, chloroacetyl, and trifluoroacetyl, and more preferred is acetyl.

As the alkali metal atom represented by M,
Examples include sodium and potassium, preferably sodium.

In the compounds (I) to (V), X and Y are oxygen atoms, R ¹ is isopropyl, R ²
Is preferably acetyl and R ³ is ethyl.
That is, as the object of the production method of the present invention, compound (I) is 5-isopropyluracil and compound (I
I) is 1-ethoxymethyl-5-isopropyluracil, compound (III) is 6- (α-hydroxybenzyl) -1-ethoxymethyl-5-isopropyluracil, and compound (IV) is 6- (α- Preferred examples of acetoxybenzyl) -1-ethoxymethyl-5-isopropyluracil and compound (V) include 6-benzyl-1-ethoxymethyl-5-isopropyluracil.

The production method of the present invention will be described in detail below. Step 1 : A method for producing compound (II) by reacting compound (I) with a silylating agent to give monosilylated product (Ia) and then reacting with dialkoxymethane (VI) Is reacted with a silylating agent to give the following general formula (Ia)

[0042]

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(Wherein X and Y are each independently
R ¹ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms; ) Through a monosilylated compound represented by the following formula (II-a) to react with dialkoxymethane (VI).

[0044]

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(Wherein X and Y are each independently
R ¹ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and R ³ represents a C 1 to 5 carbon atom;
Represents an alkyl group. ), That is, the formation of a bis-substitute substituted at the 3-position can be suppressed, and the desired compound (II) can be obtained in good yield.

The starting compound (I) is a known compound, and is disclosed in JP-A-7-17953 and JP-A-11-1.
It can be produced by the method described in Japanese Patent Application Laid-Open No. 89587/89.

The silylation reaction will be described below.
Examples of the silylating agent in the present invention include hexamethyldisilazane, bis (trimethylsilyl) acetamide, and bis (trimethylsilyl) urea, and hexamethyldisilazane and bis (trimethylsilyl) acetamide can be suitably used.

When using hexamethyldisilazane as a silylating agent, for example, compound (I) is dissolved or suspended in a solvent, and hexamethyldisilazane is added in the presence of a catalytic amount of ammonium sulfate or chlorotrimethylsilane. By performing a heating reaction, a monosilylated product (Ia) in which the 2-position substituent is silylated is generated.

Ammonium sulfate is used in an amount of 0.01 to 1 equivalent, preferably 0.05 to 0.1 equivalent, relative to compound (I).
Add 2 equivalents. The amount of chlorotrimethylsilane used is
The compound is added in the range of 0.1 to 2 equivalents, preferably 0.2 to 1 equivalent, relative to compound (I). Although both ammonium sulfate and chlorotrimethylsilane may be used, the use of ammonium sulfate alone is preferred.

Hexamethyldisilazane is compound (I)
0.5 to 0.75 times mol, preferably 0.5
Use 25 to 0.6 times mol.

This silylation reaction requires heating and is carried out at a temperature from 50 ° C. to the boiling point of the solvent, preferably at 75 ° C. to 80 ° C. The reaction time is 10 minutes to 5 hours, preferably 30 minutes to 2 hours.

When bis (trimethylsilyl) acetamide is used instead of hexamethyldisilazane, compound (I) is dissolved or suspended in a solvent, and bis (trimethylsilyl) acetamide is added thereto.
° C, preferably at a temperature of 20 ° C to 40 ° C for 10 minutes to 5 minutes.
The compound (II) can be obtained by stirring for a time, preferably for 30 minutes to 2 hours.

Bis (trimethylsilyl) acetamide is used in an amount of 0.9 to 1.5 times, preferably 1.0 to 1.2 times, the moles of Compound (I).

Solvents usable for the silylation reaction include:
Acetonitrile; halogenated hydrocarbons such as dichloromethane and chloroform, and the like, are not particularly limited, as long as they facilitate stirring of the reaction system. Double weight is preferred.

The resulting monosilylated product (Ia) can be isolated by distilling off the solvent, or the monosilylated reaction mixture can be used as it is in the reaction with dialkoxymethane (VI). Good.

Next, the monosilylated compound (Ia) is reacted with dialkoxymethane (VI) (that is, alkoxymethylated) to obtain the desired compound (II). In the present invention, since the monosilylated product is reacted, the formation of a bis-substitute having a 3-position substitution can be suppressed. Hereinafter, the alkoxymethylation will be described.

In the reaction solvent, a monosilylated compound (I-I) is added in the presence of a catalytic amount of a metal iodide compound or a metal bromide compound.
Compound (II) can be obtained by reacting a) with dialkoxymethane (VI).

The dialkoxymethane (VI) is used in an amount of 1 to 5 moles, preferably 1.2 to 2 moles, per mole of the compound (I).

The dialkoxymethane includes, for example, dimethoxymethane, diethoxymethane and dipropoxymethane, preferably diethoxymethane. Dialkoxymethane is commercially available.

As the solvent used in the reaction with dialkoxymethane (VI), the solvents used in the above silylation reaction, dimethylformamide, dichloroethane, tetrahydrofuran and the like can be used. The weight is preferably 1 to 10 times the weight of (VI).

The reaction is carried out at room temperature to the boiling point of the solvent, preferably at the boiling point of the solvent, for 1 to 10 hours, preferably 2 to 6 hours.
It's time to go.

As the metal iodide compound, a salt of iodine with an alkali metal such as sodium, potassium or cesium can be used. Examples thereof include sodium iodide, potassium iodide and cesium iodide, and preferably potassium iodide. It is. The amount of the metal iodide compound to be used is in the range of 0.005 to 1 equivalent relative to compound (I), and is preferably 0.05 to 1 equivalent.
0.2 equivalent is preferred. As the metal bromide compound, a salt of bromine with an alkali metal such as sodium, potassium, or cesium can be used. Examples thereof include sodium bromide, potassium bromide, and cesium bromide, and potassium bromide is preferable. The amount of the metal bromide compound used is that of compound (I)
In the range of 0.05 to 1 equivalent, 0.1 to 1 equivalent is preferable. Although both a metal iodide compound and a metal bromide compound may be used, it is preferable to use a metal iodide compound, and more preferably to use potassium iodide.

The alkoxymethylation reaction may be carried out after isolating the monosilylated compound (Ia) by the above-mentioned method and then dissolving or suspending the same in the above-mentioned appropriate solvent. It is preferable to use it as it is.

The reaction with dialkoxymethane according to the present invention is usually carried out for 1 to 10 hours. However, even if the reaction time is prolonged or an excess amount of dialkoxymethane is used, the formation of bis-form is suppressed. Therefore, by completing the reaction, the target compound (II) substituted only at the 1-position can be obtained in good yield. For example, the compound (I) of 0.1.
When monosilylation is performed using 5 to 0.75 moles of hexamethyldisilazane, the bis (alkoxymethyl) form by-produced is further extended by 20 hours after disappearance of the starting compound (I). In this case, it can be suppressed to 5% or less.

When performing the above silylation and alkoxymethylation reactions, the compounds used in each reaction may be added simultaneously, but may be added in an appropriate order.
After completion of the reaction, the reaction mixture containing the compound (II) is subjected to a post-treatment by a conventional method, for example, extraction, crystallization using an appropriate solvent, recrystallization, column chromatography, or another method to obtain the compound (II). Can be purified.

Step 2 : The compound (II) is converted to an alkali metal salt (II-b) with an alkali metal hydroxide, then reacted with an organolithium reagent, and then reacted with benzaldehyde to give the compound (II). Method for Producing (III) First, an alkali metal hydroxide is added to a solution or suspension of the compound (II) in an organic solvent to form a salt with nitrogen at the 3-position, and the alkali metal salt at the 3-position (II-
b) can be obtained and the water formed is removed by a dehydration operation.

Examples of the organic solvent include toluene and xylene, preferably toluene. The amount of the solvent used is 1 to 20 times, preferably 5 to 10 times the weight of compound (II).

Examples of the alkali metal hydroxide that can be used include sodium hydroxide and potassium hydroxide. The amount of the alkali metal hydroxide to be used depends on the compound (I
In the range of 0.8 to 1.5 equivalents to I), 0.8 to 1.
Two equivalents are preferred. In addition, an aqueous solution of an alkali metal may be used. In this case, an aqueous solution having a concentration of 10 to 50 w / w%, preferably 30 to 40 w / w% is used.

Before reacting the alkali metal salt (II-b) with the organolithium reagent, it is necessary to remove water generated when the compound (II) is converted to an alkali metal salt. Examples of the dehydration operation include an operation of forming a metal salt in toluene and then distilling off toluene at normal pressure.
In the case of using xylene, water can be removed by distillation under normal pressure similarly to toluene.

An ether solvent is added to the solution or suspension from which water has been removed to prepare a solution of the alkali metal salt (II-b), which can be used in the next reaction.

After removing water, the alkali metal salt (II-b) is reacted with an organolithium reagent in an ether solvent or in a mixture of the solvent used in forming the alkali metal salt and the ether solvent, to give the following general formula: (II-c)

[0072]

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(Wherein X and Y are each independently
R ¹ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and R ³ represents a C 1 to 5 carbon atom;
And M represents an alkali metal atom. )
Is synthesized. By reacting the 6-lithio compound with benzaldehyde, compound (III) which is a benzyl derivative at the 6-position can be synthesized with high yield.

By previously forming a salt with the alkali metal at the 3-position nitrogen of compound (II),
The amount of the organolithium reagent used for the 6-position lithiation reaction can be reduced by one equivalent to the compound (II) from the amount conventionally required.

The amount of n-butyllithium used as the organolithium reagent is 1.0 to 1.0 with respect to the compound (II).
Within the range of 3.0 equivalents, 1.5 to 2.5 equivalents are preferred.
In addition, the amount of benzaldehyde used is the same as that of compound (II).
, In the range of 1.0 to 3.0 equivalents, and 1.5 to 2.
Five equivalents are preferred.

As the organolithium reagent, besides n-butyllithium, methyllithium and sec-butyllithium can be used in an amount of 1.0 to 3.0 equivalents to compound (II). Yes, preferably 1.5 to
2.5 equivalents are used. A solution obtained by dropping these hexane solutions in an ether solvent while maintaining the temperature at -90 to -20 ° C can be used for the reaction.

As the ether solvent, for example, tetrahydrofuran, diethyl ether, dioxane, preferably tetrahydrofuran can be used. The amount of the solvent used is not particularly limited as long as it facilitates stirring of the reaction system. The weight is preferably 5 to 50 times the weight of the compound (II).

The reaction temperature of the reaction between the alkali metal salt (II-b) and the organolithium reagent and the reaction between the 6-lithio compound and benzaldehyde is -90 to -20 ° C, preferably -80 to -50 ° C. . In order to keep the temperature of the reaction solution within the above range, it is preferable to add the compounds to be used and their solutions dropwise to the reaction mixture.

10 minutes after the addition of the organolithium reagent
After reacting for 10 hours, preferably 30 minutes to 4 hours,
Add benzaldehyde and react for 10 minutes to 10 hours, preferably 30 minutes to 4 hours.

The termination of the reaction is carried out with respect to compound (II).
The reaction is carried out by adding acetic acid, propionic acid or butyric acid in an amount of up to 5 equivalents, preferably 3 to 3.5 equivalents.

After completion of the reaction, the reaction mixture containing the compound (III) is subjected to a post-treatment by a conventional method, for example, extraction, crystallization using an appropriate solvent, recrystallization, column chromatography, or the like. (III) can be purified. Further, the reaction mixture after the completion of the reaction is preferably subjected to the reaction of the next step 3 without isolation, purification or the like.

Step 3 : Compound (III) is converted to 4- (N,
(N-dimethylamino) pyridine or a method for producing compound (IV) by reacting with acid anhydride in the presence of 4-pyrrolidinopyridine Compound (III) is dissolved or suspended in an appropriate solvent,
In the presence of 4- (N, N-dimethylamino) pyridine or 4-pyrrolidinopyridine, a compound represented by the formula (R ² ) ₂ O
² has 2 to 6 carbon atoms which may be substituted with a halogen atom.
Represents an acyl group. The compound (IV) can be obtained by acylation using the acid anhydride represented by the formula (1). According to this method, the reaction can be completed in a short period of time, usually 30 minutes to 7 hours. By performing the acylation under these conditions, the acylation at the 3-position of the pyrimidine ring, which is a problem, can be suppressed. Can be.

In this acylation reaction, acetonitrile,
Dimethylformamide, dichloromethane, ethyl acetate,
Tetrahydrofuran, dioxane, n-hexane, n-
A single solvent such as heptane or a mixed solvent thereof is suitably used. In addition, when the compound (III) is added to acetic acid or the like in the step 2 and then subjected to the reaction in the step 3 without isolating the compound (III), an amount of the above solvent that facilitates stirring of the reaction system may be added as necessary. It may be added to the reaction mixture.

The amount of the solvent used is not particularly limited as long as the stirring of the reaction system is facilitated.
It is preferably 3 to 40 times the weight of I).

4- (N, N-dimethylamino) pyridine or 4-pyrrolidinopyridine may be used in a catalytic amount.
Preferably from 0.001 to 0.
Use 01 equivalents. Although both 4- (N, N-dimethylamino) pyridine and 4-pyrrolidinopyridine may be used, it is preferable to use 4- (N, N-dimethylamino) pyridine. In addition, in the above step 2, when acetic acid and the like are added and the compound (III) is directly subjected to the reaction in step 3 without isolation, 4- (N, N-dimethylamino) pyridine or 4-pyrrolidinopyridine Is used in an amount of 0.001 to 0.1 equivalent, preferably 0.001 to 0.01 equivalent, relative to compound (II). 4- (N, N-dimethylamino) pyridine and 4-pyrrolidinopyridine are commercially available (Kouei Chemical).

The acid anhydride is 1 to 1 relative to the compound (III).
10 equivalents, preferably 1.5 to 3 equivalents are used. Acid anhydrides that can be suitably used in the acylation reaction according to the present invention include, for example, acetic anhydride, chloroacetic anhydride, and trifluoroacetic anhydride, and preferably acetic anhydride. After adding acetic acid or the like in the step 2, the compound (II)
When I) is directly subjected to the reaction of Step 3 without isolation,
1 to 10 equivalents, preferably 2 to 10 equivalents to compound (II)
Use 5 equivalents of acid anhydride.

A base (such as triethylamine) for neutralizing the acid generated by the acylation reaction may be added to the reaction mixture. Compound (II) formed in Step 2
In the case of acylation without isolation of I), since the base formed in the step is present in the reaction mixture, it is not necessary to add a base for neutralizing the carboxylic acid formed in the acylation. The reaction can proceed.

The reaction is carried out at 10 to 40 ° C., preferably at room temperature.

After completion of the reaction, the reaction mixture containing the compound (IV) is subjected to a post-treatment by a conventional method, for example, by extraction, crystallization using an appropriate solvent, recrystallization, column chromatography or the like. (IV) can be purified.

When 4- (N, N-dimethylamino) pyridine or 4-pyrrolidinopyridine is used as a catalyst, the acylation reaction with an acid anhydride can be carried out in various solvents. For this reason, the acylation can be carried out even in the solvent used in Step 2, for example, after the reaction is stopped by adding acetic acid, propionic acid or butyric acid to the reaction solution in the synthesis step of Compound (III) (Step 2). Acylation can be carried out by a one-pot reaction. Compound (II)
By acylating I) without isolation, the compound (I)
Since the compound has higher lipophilicity than that of II) and can be isolated after being led to the compound (IV) having increased solubility in an organic solvent such as ethyl acetate, purification such as separation extraction operation becomes easy. In particular, 6 as an example of compound (III)
-(Α-hydroxybenzyl) -1-ethoxymethyl-
5-Isopropyluracil has low solubility in organic solvents such as toluene and ethyl acetate, and requires the use of halogenated hydrocarbons such as dichloromethane for extraction. Therefore, according to the production method of the present invention, complicated treatment of the aqueous layer after the extraction operation becomes unnecessary, and an industrially superior production method can be provided.

Step 4 : Compound (IV) is subjected to hydrogenolysis in the presence of alkylamine (VII) to give compound (V)
Compound (V) can be prepared by, for example, dissolving or suspending compound (IV) in a solvent, adding alkylamine (VII), and reacting with hydrogen in the presence of palladium carbon or palladium hydroxide carbon. It can be produced by reducing an acyloxy group to a hydrogen atom.

In the hydrogenolysis reaction of the acyloxy group of the compound (IV), hydrogenolysis is carried out by adding an alkylamine (VII) to thereby obtain a hyperreductant in which the 5- and 6-positions of the pyrimidine ring are hydrogenated. And the reaction rate is increased. Therefore, by this production method, the generation of by-products can be suppressed, and the reaction can be completed in a short time of usually 15 minutes to 10 hours, preferably 30 minutes to 5 hours.

The alkylamine (VII) is a compound (I)
V) is added in an amount of 0.1 to 5 equivalents, preferably 1 to 3
Add equivalent. Examples of the alkylamine (VII) include, for example, diethylamine, triethylamine, tri-n-butylamine, diisopropylethylamine, piperazine,
Examples include piperidine, morpholine, and N-methylmorpholine, preferably diethylamine, triethylamine or tri-n-butylamine.

The amount of palladium carbon used is, for example, 0.1 to 20 parts by weight, preferably 1 to 5 parts by weight, per 100 parts by weight of compound (IV) when 5% palladium carbon is used. The amount of palladium hydroxide carbon used is, for example, when 20% palladium hydroxide carbon is used, 0.1 to 20 parts by weight per 100 parts by weight of compound (IV),
Preferably it is 1 to 5 parts by weight. Although both palladium carbon and palladium hydroxide carbon may be used, palladium carbon is preferred.

The reaction temperature is from 10 ° C. to the boiling point of the solvent, preferably from 40 to 60 ° C. Solvents that can be used in this hydrogenolysis reaction include, for example, water, methanol, ethanol, 1-propanol, 2-propano-
, Tetrahydrofuran, dioxane, preferably 2-
And propanol, and a mixed solvent thereof may be used. The compound (IV) may have a weight of 3 to 30 times,
Preferably, the weight is used 4 to 15 times.

As a hydrogen source, formic acid is used in place of hydrogen in an amount of 1 to 10
By adding an equivalent, preferably 1 to 2 equivalents, the acyloxy group can be reduced to a hydrogen atom. Since formic acid can be used instead of hydrogen, which requires careful handling, a more advantageous industrial production method can be provided.

After completion of the reaction, the reaction mixture containing the compound (V) is subjected to a post-treatment by a conventional method, for example, extraction, crystallization using an appropriate solvent, recrystallization, column chromatography, or the like. (V) can be purified.

By the above steps 1-4, compound (II), compound (III), compound (IV) and compound (V) can be produced, respectively. It can be led to compound (V). This makes it possible to easily, efficiently and inexpensively produce compound (V), which is a synthetic intermediate of a drug useful as an anti-HIV drug or the like.

[0099]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which do not limit the present invention. Example 1 46.3 g of 5-isopropyluracil was suspended in 230 ml of acetonitrile, and 38 ml of hexamethyldisilazane was suspended.
And 3 g of ammonium sulfate. This suspension was heated under reflux for 1 hour to synthesize a 2-position trimethylsilyl compound. 5 g of potassium iodide and 45 ml of diethoxymethane were added to the reaction mixture, and the mixture was heated under reflux for 4 hours. When a part of the reaction solution was analyzed by liquid chromatography at a detection wavelength of 220 nm, 5-isopropyluracil as a raw material was not detected, and 98.5% of 1-ethoxymethyl-5-isopropyl as an area percentage was detected. Uracil and 0.5% 1,3
-Bis (ethoxymethyl) -5-isopropyluracil. When a part of the reaction solution continued to be heated and refluxed for further 4 hours was similarly analyzed by liquid chromatography, 1,3-bis (ethoxymethyl) -5-isopropyluracil was 0.6% in area percentage. Yes, 1, 3
The formation reaction of the bis (ethoxymethyl) compound hardly proceeded. The reaction solution was concentrated under reduced pressure, 225 ml of a 2N aqueous sodium hydroxide solution and 225 ml of toluene were added, dissolved and separated, and the obtained aqueous layer was neutralized with hydrochloric acid to give 1-ethoxymethyl-5-isopropyluracil. By precipitating the crystals and filtering the crystals,
56 g of 1-ethoxymethyl-5-isopropyluracil crystals were obtained at a yield of 88%. Melting point 78.4 ° C

Comparative Example 1 46.3 g of 5-isopropyluracil was suspended in 230 ml of acetonitrile, and 66 ml of hexamethyldisilazane was suspended.
And 3 g of ammonium sulfate. This suspension was heated under reflux for 1 hour to synthesize a bis (trimethylsilyl) compound.
5 g of potassium iodide and 75 ml of diethoxymethane were added to the reaction mixture, and the mixture was refluxed for 4 hours. A part of the reaction solution was detected by liquid chromatography at a detection wavelength of 220 nm.
As a result, 95.6% of 1-ethoxymethyl-5-isopropyluracil and 2.5% of 1,5-% in terms of area percentage were not detected.
It contained 3-bis (ethoxymethyl) -5-isopropyluracil. A part of the reaction solution further heated and refluxed for 1 hour was analyzed by liquid chromatography in the same manner. As a result, 88.3% by area percentage of 1-ethoxymethyl-5-isopropyluracil and 10.2% by weight of 1 , 3-bis (ethoxymethyl) -5-isopropyluracil. From this, if the reaction time is extended,
It was confirmed that bis (ethoxymethyl) -5-isopropyluracil was produced and the yield of the desired 1-ethoxymethyl-5-isopropyluracil was reduced. After 5 hours of the reaction, the reaction solution was concentrated under reduced pressure, 225 ml of a 2N aqueous sodium hydroxide solution and 225 ml of toluene were added, dissolved and separated, and the resulting aqueous layer was neutralized with hydrochloric acid to give 1-ethoxy. Crystals of methyl-5-isopropyluracil were precipitated, and the crystals were collected by filtration.
48 g of crystals of -ethoxymethyl-5-isopropyluracil were obtained in a yield of 75%. Melting point 78.4 ° C

Example 2 1-ethoxymethyl-5-isopropyluracil 68.
6 g was dissolved in 520 ml of toluene, and 12.9 g of flaky sodium hydroxide was added.
Was distilled off at normal pressure. Add tetrahydrofuran 3 to this solution.
00 ml was added (preparation solution). Tetrahydrofuran 6
20 ml was cooled to -70 ° C and 405 ml of a 15% n-butyllithium-hexane solution (corresponding to 1.6 mol / l)
To the solution added while maintaining the temperature below -60 ° C.
The above prepared solution was added dropwise so as to keep the temperature at -70 ° C, and the mixture was stirred at -75 to -70 ° C for 3 hours. 68.6 g of benzaldehyde was added dropwise to the reaction solution while keeping the temperature at -75 to -70 ° C, and the mixture was further stirred at -75 to -65 ° C for 3 hours. After the temperature was raised to 20 ° C, 64 g of acetic acid was added. . 0.12 g of 4-N, N-dimethylaminopyridine and 98.9 g of acetic anhydride were added to the reaction solution, and the mixture was stirred at 27 ° C. for 5 hours. 136 ml of water was added to the reaction solution, and a mixture of 67.0 g of potassium carbonate and 136 ml of water was further added, followed by concentration under reduced pressure. 832 ml of ethyl acetate was added to the residue to carry out a liquid separation operation, and the obtained organic layer was concentrated under reduced pressure.
The residue was crystallized from 2-propanol to give 76.3 g of crystals of 6- (α-acetoxybenzyl) -1-ethoxymethyl-5-isopropyluracil. 66% yield from 1-ethoxymethyl-5-isopropyluracil
Met. 158 ° C

Comparative Example 2 40 ml of tetrahydrofuran was cooled to -60.degree.
% N-butyllithium-hexane solution (1.6 mol / l
49.5 ml was added while keeping the temperature below -55 ° C, and then a solution of 5.1 g of 1-ethoxymethyl-5-isopropyluracil dissolved in 20 ml of tetrahydrofuran was kept at -60 to -55 ° C. Add dropwise,
The mixture was stirred at 65 to -60 ° C for 2 hours. To this solution, 7.3 g of benzaldehyde was added dropwise so as to keep the temperature at -60 to -55 ° C, and after stirring at -65 to -60 ° C for 3 hours, 4.9 g of acetic acid was kept at -55 ° C or less. And added. A part of this reaction solution was analyzed and quantified by liquid chromatography, and as a result, 5.4 g of 6- (α-hydroxybenzyl) -1-ethoxymethyl-5-isopropyluracil was generated in the reaction solution. . 4-
0.01 g of N, N-dimethylaminopyridine and 3.5 ml of acetic anhydride were added, and the mixture was stirred at 30 ° C. for 3 hours. After the reaction solution was concentrated under reduced pressure, 60 ml of ethyl acetate and 20 ml of water were added to carry out a liquid separation operation. The obtained organic layer was concentrated under reduced pressure, and the residue was crystallized from 2-propanol.
5.5 g of crystals of 6- (α-acetoxybenzyl) -1-ethoxymethyl-5-isopropyluracil were obtained. 1
The yield from -ethoxymethyl-5-isopropyluracil was 64%. 158 ° C

Example 3-1 8.0 g of 6- (α-hydroxybenzyl) -1-ethoxymethyl-5-isopropyluracil was suspended in 40 ml of acetonitrile, 5.2 ml of triethylamine, 3.5 ml of acetic anhydride and 4-N , N-dimethylaminopyridine (20 mg) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, 20 ml of ethyl acetate and 20 ml of water were added.
The resulting organic layer was concentrated under reduced pressure, and the residue was crystallized from 2-propanol to give 6-mL.
(Α-acetoxybenzyl) -1-ethoxymethyl-5
8.6 g of crystals of isopropyluracil, 95% yield
I got it. 158 ° C

Example 3-2 8.0 g of 6- (α-hydroxybenzyl) -1-ethoxymethyl-5-isopropyluracil was added to ethyl acetate 40.
The suspension was added with 5.2 ml of triethylamine, 3.5 ml of acetic anhydride and 20 mg of 4-N, N-dimethylaminopyridine, and the mixture was stirred at room temperature for 2 hours. 20 ml of water was added to the reaction solution to carry out a liquid separation operation, the obtained organic layer was concentrated under reduced pressure, and the residue was crystallized from 2-propanol.
8.7 g of crystals of 6- (α-acetoxybenzyl) -1-ethoxymethyl-5-isopropyluracil were obtained at a yield of 9
Obtained at 6%.

Example 3-3 8.0 g of 6- (α-hydroxybenzyl) -1-ethoxymethyl-5-isopropyluracil was suspended in a mixed solvent of 60 ml of tetrahydrofuran and 60 ml of n-hexane, and 5.2 ml of triethylamine was obtained. , Acetic anhydride 3.5m
1 and 20 mg of 4-N, N-dimethylaminopyridine
Was added and stirred at room temperature for 3 hours. After the reaction solution was concentrated under reduced pressure, 20 ml of ethyl acetate and 20 ml of water were added to carry out a liquid separation operation. The obtained organic layer was concentrated under reduced pressure, and the residue was crystallized from 2-propanol to give 6- (α- 8.6 g of crystals of (acetoxybenzyl) -1-ethoxymethyl-5-isopropyluracil were obtained in a yield of 95%. 158 ° C

Comparative Example 3 7.9 g of 6- (α-hydroxybenzyl) -1-ethoxymethyl-5-isopropyluracil was added to 32 m of pyridine.
and 6.5 ml of acetic anhydride was added.
Stirred for hours. After adding 12 ml of water to the reaction solution, 4
By stirring at 0 ° C. for 2 hours, a by-product 3-acetyl form was hydrolyzed. After the reaction solution was concentrated under reduced pressure, the residue was crystallized from 2-propanol to obtain 8.5 g of 6- (α-acetoxybenzyl) -1-ethoxymethyl-5-isopropyluracil as crystals at a yield of 94%. Was. 158 ° C

Example 4-1 4.0 g of 6- (α-acetoxybenzyl) -1-ethoxymethyl-5-isopropyluracil was suspended in 48 ml of 2-propanol, and 1.8 ml of triethylamine was added. This suspension was subjected to catalytic hydrogenation under normal pressure at 50 ° C. in the presence of 0.4 g of a 5% palladium carbon 50% wet product.
Time went. A part of the reaction solution was analyzed by liquid chromatography at a detection wavelength of 220 nm, and found to contain 3.5% by-product by area. The filtrate obtained by removing the catalyst from the reaction solution by filtration was concentrated under reduced pressure, and the residue was crystallized from a mixed solvent of 2-propanol and water and collected by filtration to give 6-benzyl-1-ethoxymethyl-. 5
2.7 g of isopropyluracil crystals, 80% yield
I got it. Melting point 109-110 ° C

Example 4-2 1.0 g of 6- (α-acetoxybenzyl) -1-ethoxymethyl-5-isopropyluracil was suspended in 12 ml of 2-propanol, and 0.8 ml of tri-n-butylamine was suspended.
Was added. This suspension was subjected to catalytic hydrogenation at normal pressure in the presence of 0.1 g of a 5% palladium carbon 50% wet product at 50 g.
C. for 1 hour. When a part of the reaction solution was analyzed by liquid chromatography at a detection wavelength of 220 nm, it contained 3.4% by-product in area percentage. The filtrate obtained by removing the catalyst from the reaction solution by filtration was concentrated under reduced pressure, and the residue was crystallized from a mixed solvent of 2-propanol and water and collected by filtration to give 6-benzyl-1-ethoxymethyl-. 0.67 crystals of 5-isopropyluracil
g, 80% yield. Melting point 109-110 ° C

Example 4-3 144.2 g of 6- (α-acetoxybenzyl) -1-ethoxymethyl-5-isopropyluracil was suspended in 865 ml of 2-propanol. After adding 58.5 g of diethylamine and 5.7 g of a 5% palladium carbon 50% wet product to the suspension, 31.4 g of 88% formic acid was added, and the mixture was stirred at 50 ° C. for 4 hours. A part of this reaction solution was analyzed by liquid chromatography at a detection wavelength of 220 nm and found to contain 1.7% in area percentage by-products. The filtrate obtained by removing the catalyst from the reaction solution by filtration was concentrated under reduced pressure, and the residue was crystallized from a mixed solvent of 2-propanol and water and collected by filtration to give 6-benzyl-1-ethoxymethyl-. 10-isopropyluracil crystals
6.9 g was obtained in a yield of 88%. Melting point 109-110 ° C

Comparative Example 4 2.9 g of 6- (α-acetoxybenzyl) -1-ethoxymethyl-5-isopropyluracil was suspended in 35 ml of 2-propanol. This suspension was subjected to catalytic hydrogenation at 50 ° C. for 2 hours under normal pressure in the presence of 0.3 g of a 5% palladium carbon 50% wet product. When a part of the reaction solution was analyzed by liquid chromatography at a detection wavelength of 220 nm, it contained 6.5% by-product in area percentage. The filtrate obtained by removing the catalyst from the reaction solution by filtration was concentrated under reduced pressure, and the residue was crystallized from a mixed solvent of 2-propanol and water and collected by filtration to give 6-benzyl-1-ethoxymethyl-. Crystals of 5-isopropyluracil
72 g, 71% yield. Melting point 109-110 ° C

[0111]

Industrial Applicability The present invention solves the problems of the conventional method, suppresses the formation of by-products, and simplifies the reaction process, thereby improving the yield and purity. Thus, the production method of the pyrimidine compound can be provided which is more excellent as an industrial method.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Ryoma Hanyu 3-1-1, Utajima, Nishiyodogawa-ku, Osaka-shi Inside Sumika Fine Chem Co., Ltd. (72) Tomoaki Kishimoto 3-1-1, Utashima, Nishiyodogawa-ku, Osaka-shi No. 21 Sumika Fine Chem Co., Ltd.

Claims (5)

[Claims] 1. A compound of the general formula (I) (Wherein, X and Y each independently represent an oxygen atom or a sulfur atom, and R ¹ represents a hydrogen atom or a carbon atom having 1 to 5 carbon atoms.
Represents an alkyl group. ) Is reacted with a silylating agent to give a compound of the general formula (Ia) (Wherein, X and Y each independently represent an oxygen atom or a sulfur atom, and R ¹ represents a hydrogen atom or a carbon atom having 1 to 5 carbon atoms.
Represents an alkyl group. ), And then converted to a compound represented by the general formula (VI): (Wherein, R ³ represents an alkyl group having 1 to 5 carbon atoms). The compound is reacted with a dialkoxymethane represented by the following general formula (II): (Wherein, X and Y each independently represent an oxygen atom or a sulfur atom, and R ¹ represents a hydrogen atom or a carbon atom having 1 to 5 carbon atoms.
R ³ represents an alkyl group having 1 to 5 carbon atoms. )). 2. A compound of the general formula (II) (Wherein, X and Y each independently represent an oxygen atom or a sulfur atom, and R ¹ represents a hydrogen atom or a carbon atom having 1 to 5 carbon atoms.
R ³ represents an alkyl group having 1 to 5 carbon atoms. ) Is converted to a compound represented by the general formula (II-b): (Wherein, X and Y each independently represent an oxygen atom or a sulfur atom, and R ¹ represents a hydrogen atom or a carbon atom having 1 to 5 carbon atoms.
R ³ represents an alkyl group having 1 to 5 carbon atoms, and M represents an alkali metal atom. ), And then reacted with an organolithium reagent,
Then, the compound is reacted with benzaldehyde. (Wherein, X and Y each independently represent an oxygen atom or a sulfur atom, and R ¹ represents a hydrogen atom or a carbon atom having 1 to 5 carbon atoms.
R ³ represents an alkyl group having 1 to 5 carbon atoms. )). 3. A compound of the formula (I) in the presence of 4- (N, N-dimethylamino) pyridine or 4-pyrrolidinopyridine.
II) (Wherein, X and Y each independently represent an oxygen atom or a sulfur atom, and R ¹ represents a hydrogen atom or a carbon atom having 1 to 5 carbon atoms.
R ³ represents an alkyl group having 1 to 5 carbon atoms. The compound represented by the formula (R ² ) ₂ O (wherein R ² represents an acyl group having 2 to 6 carbon atoms which may be substituted with a halogen atom) General formula (IV) characterized by reacting (Wherein, X and Y each independently represent an oxygen atom or a sulfur atom, and R ¹ represents a hydrogen atom or a carbon atom having 1 to 5 carbon atoms.
R ² represents an acyl group having 2 to 6 carbon atoms which may be substituted with a halogen atom, and R ³ represents an alkyl group having 1 to 5 carbon atoms. )). 4. A compound of the general formula (IV) (Wherein, X and Y each independently represent an oxygen atom or a sulfur atom, and R ¹ represents a hydrogen atom or a carbon atom having 1 to 5 carbon atoms.
R ² represents an acyl group having 2 to 6 carbon atoms which may be substituted with a halogen atom, and R ³ represents an alkyl group having 1 to 5 carbon atoms. )
General formula (VII) (Wherein R ⁴ , R ⁵ and R ⁶ each independently represent a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, or a ring together with a nitrogen atom to which any two of them are bonded together. And the remaining one may represent a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.) Hydrogenolysis in the presence of an alkylamine represented by the general formula (V): Formula 12 (Wherein, X and Y each independently represent an oxygen atom or a sulfur atom, and R ¹ represents a hydrogen atom or a carbon atom having 1 to 5 carbon atoms.
R ³ represents an alkyl group having 1 to 5 carbon atoms. A method for producing a pyrimidine compound represented by the formula: 5. The method according to claim 1, wherein the compound represented by the general formula (I)
I) (Wherein, X and Y each independently represent an oxygen atom or a sulfur atom, and R ¹ represents a hydrogen atom or a carbon atom having 1 to 5 carbon atoms.
R ³ represents an alkyl group having 1 to 5 carbon atoms. A compound represented by the general formula (III): (Wherein, X and Y each independently represent an oxygen atom or a sulfur atom, and R ¹ represents a hydrogen atom or a carbon atom having 1 to 5 carbon atoms.
R ³ represents an alkyl group having 1 to 5 carbon atoms. A compound represented by the formula (IV) is prepared from the compound by the method according to claim 3. (Wherein, X and Y each independently represent an oxygen atom or a sulfur atom, and R ¹ represents a hydrogen atom or a carbon atom having 1 to 5 carbon atoms.
R ² represents an acyl group having 2 to 6 carbon atoms which may be substituted with a halogen atom, and R ³ represents an alkyl group having 1 to 5 carbon atoms. A compound represented by the general formula (V) is produced from the compound by the method according to claim 4. (Wherein, X and Y each independently represent an oxygen atom or a sulfur atom, and R ¹ represents a hydrogen atom or a carbon atom having 1 to 5 carbon atoms.
R ³ represents an alkyl group having 1 to 5 carbon atoms. A) producing a pyrimidine compound represented by the formula: