JPH083143A - Production of 6-aralkyl substituted pyrimidine derivative - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as an antiviral agent, especially an antiretrovirus agent in high purity and yield by reducing a specific pyrimidine derivative in the presence of a metal or its salt and an acid. CONSTITUTION:This method for producing a 6-aralkyl substituted pyrimidine derivative of formula II {R<1> is H, a halogen, a 1-5C alkyl, a 3-8C cycloalkyl, etc.; R<2> is H, a 1-5C alkyl or a (substituted) 7-12C aralkyl; R<3> is H or a group of (CH2)n-R<6>R<7> [R<6> is O, S or methylene; R<7> is H or a 1-5C alkyl; (n) is 0 or 1]; R<4> is a (substituted)6-10C aryl; X and Y are independently each O or S} (e.g. 6-benzyl-1-ethoxymethyl-5-isopropyluracil) is to reduce a pyrimidine derivative of formula I (R<5> is H or a 1-6C acyl) in the presence of a metal (preferably Zn) or its salt and an acid. The formation of by-products according to a well- known method is suppressed by the method.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a 6-aralkyl-substituted pyrimidine derivative, and more particularly to a novel method for synthesizing a 6-aralkyl-substituted pyrimidine derivative useful as an antiviral agent, particularly as an antiretroviral agent.

[0002]

2. Description of the Related Art In recent years, human acquired immunodeficiency virus (HIV) infection, which is one of retroviruses, has become a major social problem. Some of the present inventors have previously found that 6-substituted acyclopyrimidine nucleoside compounds have antiretroviral activity such as anti-HIV action (WO89 / 09213).
JP-A-3-279366, JP-A-3-28467
No. 0). Among these 6-substituted acyclopyrimidine nucleoside compounds, 6-aralkyl-substituted acyclopyrimidine nucleosides have a good balance of antiviral activity and water solubility, and have favorable properties as pharmaceuticals and their synthetic method (Mol. Pharmacol. 44,895
-900 (1993)) is known. For example, 6-
Benzyl-1-ethoxymethyl-5-ethyluracil is synthesized by the following method.

[0003]

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(M in the above formula represents a metal.) That is, 1-ethoxymethyl-5-ethyluracil, n-alkyllithium, lithium diisopropylamide (LDA), lithium-2,2,6,6-tetra An organic alkali metal such as methyl piperidide (LTMP), potassium bistrimethylsilylamide, sodium bistrimethylsilylamide, etc. is allowed to act, and the obtained alkali metal salt of 1-ethoxyethyl-5-ethyluracil is reacted with benzaldehyde to obtain 1-ethoxymethyl-6
The hydroxyl group is reduced to a hydrogen atom by reacting-(α-hydroxybenzyl) -5-ethyluracil with hydrogen in the presence of palladium on carbon or palladium hydroxide.

However, in this method, in addition to the target compound, a dihydro body in which the 5- and 6-positions of the pyrimidine ring are hydrogenated is by-produced, which leads to a decrease in yield and a decrease in product purity. There was a problem. Therefore, development of a method for obtaining a highly pure 6-aralkyl-substituted pyrimidine derivative while suppressing generation of by-products has been desired.

[0006]

Means for Solving the Problems As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that by reducing a 6- (α-hydroxyaralkyl) -pyrimidine derivative under specific conditions. The inventors have found that a 6-aralkyl-substituted pyrimidine derivative of high purity can be obtained while suppressing the production of by-products, and completed the present invention.

That is, the gist of the present invention is the following general formula (I)

[0008]

[Chemical 4]

(In the above formula, R¹Is hydrogen atom, halogen
Atom, C₁~ C_FiveAlkyl group of C₃~ C ₈Cycloarch
Lu group, C₂~ C₆May have an acyl group or a substituent of
C₂~ C ₆Alkenyl group of C₂~ C₆An alkynyl group of C
₇~ C₁₂Arylcarbonyl group of C₈~ C₁₂Aryl
Carbonylalkyl group, C₆~ C_TenThe arylthio group of
It is C₇~ C₁₂Represents an aralkyl group of R²Is hydrogen
Child, C₁~ C_FiveMay have an alkyl group or a substituent of
C₇~ C₁₂Represents an aralkyl group of R³Is a hydrogen atom or
-(CH₂)_n-R⁶R⁷A group represented by (R⁶Is an oxygen atom,
Represents a sulfur atom or a methylene group, R⁷Is a hydrogen atom
Is C which may have a substituent₁~ C_FiveRepresents an alkyl group of
n represents an integer of 0 or 1. ), R^FourIs a substituent
May have C₆~ C_TenRepresents an aryl group of R^FiveIs water
Elementary atom or C₂~ C₆Represents an acyl group of X and Y are
Each independently represents an oxygen atom or a sulfur atom. )so
The represented pyrimidine derivative is a metal or its salt and an acid.
The following general formula (II) is characterized by being reduced in the presence of

[0010]

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(In the above formula, R ¹ , R ² , R ³ , R ⁴ , X and Y are as defined above) 6-
It exists in a method for producing an aralkyl-substituted pyrimidine derivative.
In the compounds represented by the above general formulas (I) and (II), R
¹ alkenyl group C ₂ -C ₆ represents a halogen atom, a cyano group, an aryl group of C ₆ -C _10, may have a alkoxycarbonyl group or a carbamoyl group of C ₂ -C ₆ as substituent groups, C alkynyl group ₂ -C ₆ may have as a substituent an aryl group of C ₆ -C _10, an arylcarbonyl group C ₇ -C _12, arylcarbonylalkyl group C ₈ ~C _12, C ₆ ~ Each of the C ₁₀ arylthio group and the C _{7 to} C ₁₂ aralkyl group may have a halogen atom, a C _{1 to} C ₅ alkyl group or a C _{1 to} C ₅ alkoxy group as a substituent.

The C ₇ -C ₁₂ aralkyl group of R ² may have a halogen atom, a C ₁ -C ₅ alkyl group or a C ₁ -C ₅ alkoxy group as a substituent. R ^3- (CH ₂ )
a group represented by _n -R ⁶ R ^7, alkyl C ₁ -C ₅ of R ⁷ is halogen atom, a hydroxyl group, 6-membered ring nitrogen-containing carbonyl group, formyloxy group, C ₂ -C ₆ Alkylcarbonyloxy group, C ₄ -C ₉ cycloalkylcarbonyloxy group, C ₈ -C ₁₃ aralkylcarbonyloxy group, C ₇ -C ₁₂ arylcarbonyloxy group, azido group or halogen atom, C ₆ -C ₁₀ aryl groups,
C ₁ -C ₅ alkyl group, C ₁ -C ₅ alkoxy group, C ₁
To C ₃ haloalkyl group and the like may have a C _{2 to} C ₆ alkoxycarbonyloxy group, C _{2 to} C ₆ N-alkylcarbamoyloxy group, C _{7 to} C ₁₂ N-.
Arylcarbamoyloxy group, C ₂ -C ₆ of N- alkylthiocarbamoyl group, N- arylthiocarbamoyl group of C ₇ ~C _12, C ₁ ~C alkoxy group _5, aralkyloxy group C ₇ -C ₁₂ , A C ₆ -C ₁₀ branched alkyl group, a C ₃ -C ₈ cycloalkyl group or C ₆
An aryl group having -C ₁₀ which may have a substituent.

The C ₆ -C ₁₀ aryl group of R ⁴ may have a halogen atom, a C ₁ -C ₅ alkyl group or a C ₁ -C ₅ alkoxy group as a substituent. Among the compounds represented by the above general formulas (I) and (II), R ¹ is methyl group, ethyl group, n-propyl group, i-propyl group, n-
C ₁ -C _5, such as butyl, t- butyl group, n- pentyl group
Represents an alkyl group, R ² represents a hydrogen atom, and R ³ represents -C.
A group represented by H ₂ —R ⁶ R ⁷ (R ⁶ represents an oxygen atom, R ⁷
Represents a methyl group or a hydroxylmethyl group. And a compound in which R ⁴ represents an aryl group such as a phenyl group or a xylyl group is preferable.

The 6-aralkyl-substituted pyrimidine derivative represented by the general formula (II) is obtained by converting the pyrimidine derivative represented by the general formula (I) into alcohols such as methanol and ethanol, acetonitrile, tetrahydrofuran (TH).
F), dimethylformamide, dioxane, pyrimidine, etc. in a suitable solvent, and obtained by reacting with a metal such as zinc, tin, stannic chloride, iron, aluminum, magnesium or a salt thereof and an acid such as hydrochloric acid, acetic acid, etc. . It is preferable to use zinc as the metal. The reaction temperature is not particularly limited, but the reaction is preferably performed at 10 to 100 ° C. The obtained 6-aralkyl-substituted pyrimidi derivative is purified by a conventional method for separating and purifying nucleosides, for example, recrystallization,
It can be separated and purified by appropriately selecting adsorption or ion exchange chromatography.

[0015]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to the following examples unless it exceeds the gist thereof. Example 1 Synthesis of 6-benzyl-1-ethoxymethyl-5-isopropyluracil 1-ethoxymethyl-6- (α-hydroxybenzyl)
3.18 g of -5-isopropyluracil was dissolved in 20 ml of acetonitrile, then 6 g of zinc powder and 20 m of concentrated hydrochloric acid.
1 was added, and the mixture was stirred at room temperature for 2 hours. 50 ml of water was added thereto, and the mixture was extracted 3 times with 20 ml of ethyl acetate. The organic layer was washed with deuterium oxide water, neutralized, and concentrated under reduced pressure. The residue was dissolved in 5 ml of ethanol and crystallized at 0 to 4 ° C to obtain the title compound (yield 89%, melting point 109 to 110 ° C). .

Example 2 Synthesis of 6-benzyl-1-ethoxymethyl-5-isopropyluracil In Example 1, 3.6 g of 6- (α-acetoxybenzyl) -1-ethoxymethyl-5-isopropyluracil was used as a raw material. Using the same reaction as in Example 1,
The title compound (yield 87%) was obtained. Example 3 Synthesis of 6-benzyl-1-ethoxymethyl-5-isopropyluracil 1-Ethoxymethyl-6- (α-hydroxybenzyl)
-5-isopropyl uracil 3.18 g acetic acid 20 ml
And zinc powder 6 g were added, followed by stirring at reflux temperature for 16 hours. 50 ml of water was added, and the mixture was extracted 3 times with 20 ml of ethyl acetate. The organic layer was washed with deuterium oxide water, neutralized, and concentrated under reduced pressure. The residue was dissolved in 5 ml of ethanol and the temperature was 0 to 4 ° C.
Was crystallized to give the title compound (yield 88%). Example 4 In the same manner as in Example 1, various 6-aralkyl-substituted pyrimidine derivatives were obtained with a yield of 87 to 90%. The compounds obtained are shown in Table 1.

[0017]

[Table 1]

Comparative Example 1 Reduction Method Using Palladium Hydroxide Carbon 1-Ethoxymethyl-6- (α-hydroxybenzyl)
3.18 g of -5-ethyluracil was added to 17 m of dioxane.
1, ethanol (9 ml) and acetic acid (3 ml), and the mixture was stirred in the presence of 0.43 g of palladium hydroxide carbon under a hydrogen atmosphere at 60 ° C. for 72 hours. When a part of the reaction solution was examined by liquid chromatography, it contained about 10% by-products. After stirring for 72 hours, palladium hydroxide carbon was filtered off and the filtrate was concentrated. The residue was crystallized from ethanol to obtain 1.37 g (yield 45%) of 6-benzyl-1-ethoxymethyl-5-ethyluracil, which was the target substance.

[0019]

EFFECTS OF THE INVENTION According to the method of the present invention, a 6-aralkyl-substituted pyrimidine derivative useful as an antiviral agent can be produced with high purity and high yield.

Claims (3)

[Claims] 1. The following general formula (I):(In the above formula, R¹Is hydrogen atom, halogen atom, C₁~ C
_FiveAlkyl group of C₃~ C ₈Cycloalkyl group, C₂~ C
₆C which may have an acyl group or a substituent₂~ C ₆A
Lucenyl group, C₂~ C₆An alkynyl group of C₇~ C₁₂A
Reel carbonyl group, C₈~ C₁₂Aryl carbonyl
Alkyl group, C₆~ C_TenArylthio group or C₇~
C₁₂Represents an aralkyl group of R²Is a hydrogen atom, C₁~ C_Five
C which may have an alkyl group or a substituent₇~ C₁₂of
Represents an aralkyl group, R³Is a hydrogen atom or-(CH₂)
_n-R⁶R⁷A group represented by (R⁶Is an oxygen atom, a sulfur atom or
Represents a methylene group, R⁷Has a hydrogen atom or a substituent
May be C₁~ C_FiveRepresents an alkyl group, and n is 0 or
Represents an integer of 1. ), R^FourMay have a substituent
I C₆~ C_TenRepresents an aryl group of R^FiveIs a hydrogen atom or
C₂~ C₆Represents an acyl group, and X and Y are independent
And represents an oxygen atom or a sulfur atom. ) Represented by
Reduction of a midine derivative in the presence of metal or its salt and acid
The following general formula (II) is characterized by(In the above formula, R¹, R², R³, R^Four, X and Y are already
As defined. ) 6-aralkyl device represented by
A method for producing a substituted pyrimidine derivative. 2. The method of claim 1 wherein the metal is zinc. 3. R¹Is C₁~ C_FiveRepresents an alkyl group of R,²Is
Represents a hydrogen atom, R ³Is -CH₂-R⁶R⁷Group represented by
(R⁶Represents an oxygen atom, R⁷Is a methyl group or hydroxy
Represents a silmethyl group. ) A contract characterized by being represented by
The method according to claim 1 or 2.