JP2006265266A - Method for producing uracil derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new method for producing a 5-acylamino-6-aminouracil derivative useful as a synthetic intermediate of a xanthine derivative having diuretic activity, kidney-protecting activity, antidemential activity, activity for treating Parkinson's disease or the like. <P>SOLUTION: The method for producing the uracil derivative of synthesizing a 5-acylamino-6-aminouracil derivative represented by formula (IV) [wherein, R<SP>1</SP>and R<SP>2</SP>are the same or different and each hydrogen or a lower alkyl; and R<SP>3</SP>is a lower alkyl, a cycloalkyl, -(CH<SB>2</SB>)<SB>n</SB>-R<SP>4</SP>(wherein, R<SP>4</SP>is a substituted or nonsubstituted aryl or a substituted or nonsubstituted heterocyclic group; and n is an integer of 0-4) or the like] involves acylating a 5,6-diaminouracil derivative or an acid addition salt thereof obtained by reducing a 6-amino-5-nitrouracil derivative without isolating the derivative. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a method for producing a 5-acylamino-6-aminouracil derivative useful as a synthetic intermediate for a xanthine derivative having a diuretic action, a renal protective action, an anti-dementia action, a Parkinson's disease treatment action, and the like.

Formula (IV)

{Wherein R ¹ and R ² are the same or different and each represents hydrogen or lower alkyl, R ³ is lower alkyl, cycloalkyl, — (CH ₂ ) _n —R ⁴ (wherein R ⁴ is substituted or unsubstituted Aryl or a substituted or unsubstituted heterocyclic group, and n represents an integer of 0 to 4), or

Wherein Y ¹ and Y ² are the same or different and each represents hydrogen or lower alkyl, and Z represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group} Acylamino-6-aminouracil derivative [hereinafter, a compound represented by the formula (IV) is referred to as a compound (IV). The same applies to the compounds of other formula numbers. ] Is known as a synthetic intermediate of a xanthine derivative having a diuretic action and a renal protective action (Patent Document 1, Non-Patent Document 1, Non-Patent Document 2). Compound (IV) is also known as a synthetic intermediate of a xanthine derivative having an anti-dementia effect (Patent Document 2). Furthermore, compound (IV) is also known as a synthetic intermediate of a xanthine derivative useful as a therapeutic agent for Parkinson's disease (Patent Document 3).

For the synthesis of compound (IV), compound (II) obtained according to a known method (for example, Non-Patent Document 3) (wherein R ¹ and R ² are as defined above) or an acid addition salt thereof And a compound (III) (wherein R ³ is as defined above) or a reactive derivative thereof is known (for example, Patent Document 4). However, in the above method, it is necessary to isolate the starting material compound (II) or an acid addition salt thereof, but depending on the type, it is susceptible to hydrolysis and unstable and difficult to isolate. It is known that it is not suitable (Non-patent Document 4).
Japanese Patent Laid-Open No. 6-16668 JP-A-5-105631 Japanese Unexamined Patent Publication No. 6-16559 JP 59-42383 Journal of Medicinal Chemistry (J. Med. Chem.), 1991, Volume 34, p. 466 Journal of Medicinal Chemistry (J. Med. Chem.), 1992, Volume 35, p. 3066 Journal of the American Chemical Society (J. Am. Chem. Soc.), 1953, vol. 75, p. 114 Journal of the American Chemical Society (J. Am. Chem. Soc.), 1954, vol. 76, p. 2798

  An object of the present invention is to provide a novel method for producing a 5-acylamino-6-aminouracil derivative useful as a synthetic intermediate for a xanthine derivative having a diuretic action, a renal protective action, an anti-dementia action, a Parkinson's disease therapeutic action, and the like. There is.

The present invention is a compound of formula (I)

(Wherein R ¹ and R ² are the same or different and each represents hydrogen or lower alkyl), a 6-amino-5-nitrosouracil derivative represented by formula (II)

(Wherein R ¹ and R ² have the same meanings as described above), and without the diamino compound being isolated, the formula (III)

{Wherein R ³ is lower alkyl, cycloalkyl, — (CH ₂ ) _n —R ⁴ (wherein R ⁴ represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group, and n is 0 Represents an integer of ~ 4), or

Wherein Y ¹ and Y ² are the same or different and each represents hydrogen or lower alkyl, and Z represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group} Or a reaction thereof with a reactive derivative thereof, characterized in that it has the formula (IV)

(Wherein R ¹ , R ² and R ³ have the same meanings as described above), and a method for producing a 5-acylamino-6-aminouracil derivative.

  According to the present invention, a 5-acylamino-6-aminouracil derivative useful as a synthetic intermediate of a xanthine derivative having a diuretic action, a renal protective action, an anti-dementia action, a Parkinson's disease treatment action, etc. is converted into an unstable intermediate (5 , 6-diaminouracil derivative) can be produced in high yield without isolation.

That is, the present invention provides the following production process

(Wherein R ¹ , R ² and R ³ have the same meanings as described above), compound (II) obtained by reducing compound (I) (step 1 or 2) is isolated without isolation. This is directly reacted with carboxylic acid (III) or a reactive derivative thereof to be acylated (step 3) to obtain compound (IV) with good yield. In the definition of each group of the formulas (I) to (IV), lower alkyl is linear or branched, having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert -Represents butyl, pentyl, neopentyl, hexyl and the like, and cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like having 3 to 8 carbon atoms. Aryl represents, for example, phenyl, naphthyl, biphenyl, anthryl and the like having 6 to 14 carbon atoms, and the heterocyclic group represents furyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, indolyl, quinolyl and the like. Examples of the substituent for the aryl or heterocyclic group include the same or different, and having 1 to 3 substituents such as lower alkyl, hydroxy, lower alkoxy, halogen, nitro, amino and the like. In the substituent, the alkyl part of lower alkyl and lower alkoxy has the same meaning as the lower alkyl, and halogen represents each atom of fluorine, chlorine, bromine or iodine.

Examples of the acid addition salt of the compound (I), (II) or (IV) in the present invention include inorganic acid salts such as hydrochloride, sulfate and phosphate, and acetate, maleate, fumarate and tartaric acid. Examples thereof include organic acid salts such as salts and citrates.
The present invention is described in detail below.
The starting compound (I) can be obtained by a known method (for example, J. Am. Chem. Soc. (Journal of the American Chemical Society), 76, 2798 (1954), or JP-A-59-42383. ).

Compound (II) can be obtained by reducing compound (I). As the reduction reaction, various substances can be used as long as they can convert a nitroso group into an amino group, but preferably, reduction using sodium hyposulfite (Step 1) or catalytic reduction (Step 2) is used. Compound (II) can be used for the next reaction without purification.
Process 1
As the solvent, various organic solvents, water and the like can be used, but preferably alcohols such as methanol, ethanol and isopropanol, ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, water and the like. A single or a mixture is used in an amount of 1.0 to 100 times, preferably 10 to 20 times the weight of compound (I).

Sodium hyposulfite is used by adding 1.0 to 50 equivalents, preferably 1.0 to 3.0 equivalents, in small portions with respect to compound (I).
The reaction is carried out at −20 to 50 ° C., preferably 0 to 25 ° C., for 0.5 to 50 hours, usually 0.5 to 1.5 hours.
Since the compound (I) may be unstable under acidic conditions and the solubility of the compound (I) may be higher under basic conditions than under neutral conditions, this reaction is It is desirable to perform in the presence of a base. As the base for this purpose, various inorganic bases or organic bases can be used. Preferably, potassium carbonate, sodium hydroxide, potassium hydroxide, ammonia, triethylamine, etc. are 0.1 to 15 equivalents relative to Compound (I). 1-8 equivalents are preferably used.

Process 2
As the solvent, various organic solvents, water and the like can be used. Preferably, alcohols such as methanol, ethanol and isopropanol, ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, N, N -Dimethylformamide, water or the like is used alone or in mixture and used in a weight ratio of 1.0 to 100 times, preferably 10 to 20 times the amount of compound (I).

As the catalytic reduction catalyst, palladium / carbon, platinum dioxide / carbon, rhodium / carbon, etc. are 0.01 to 2.0 times, preferably 0.05 to 1.0 times in weight ratio to the compound (I). The amount is more preferably 0.1 to 0.2 times.
The reaction is carried out at −20 to 50 ° C., preferably 0 to 25 ° C., under a hydrogen atmosphere of 1.0 to 60 atm, preferably 1.0 to 5.0 atm, for 0.5 to 100 hours, usually 1. 0 to 3.0 hours.

Process 3
Compound (IV) can be obtained by reacting compound (II) with carboxylic acid (III) or a reactive derivative thereof. Examples of reactive derivatives include acid halides such as acid chloride or acid bromide, active esters formed using p-nitrophenyl ester or N-oxysuccinimide, commercially available acid anhydrides or 1-ethyl-3 Examples include acid anhydrides produced using carbodiimides such as-(3-dimethylaminopropyl) carbodiimide, diisopropylcarbodiimide, dicyclohexylcarbodiimide, and mixed acid anhydrides such as carbonic acid monoethyl ester and carbonic acid monoisobutyl ester.

When carboxylic acid (III) is used, the reaction is carried out without solvent at 100 to 200 ° C. for 1 to 10 hours.
When a reactive derivative of carboxylic acid (III) is used, various organic solvents, water, and the like can be used alone or as a mixture, but Schotten-Baumann conditions are preferably used. That is, a reactive derivative of carboxylic acid (III) dissolved in a solvent immiscible with water is added to an aqueous solution or suspension of compound (II) in the presence of a base and reacted in a two-layer system. Examples of the solvent immiscible with water include methylene chloride, chloroform, dichloroethane, diethyl ether, diisopropyl ether, and ethyl acetate. As the base, various inorganic bases or organic bases can be used. Preferably, potassium carbonate, sodium hydroxide, potassium hydroxide, ammonia, triethylamine, etc. are 0.1 to 15 equivalents, preferably 0.1 to 15 equivalents relative to compound (I). 1-8 equivalents are used. When compound (II) is obtained in the above step 1 etc. and used in this step without purification, it is not necessary to add a base when a preferable amount of base already exists in the reaction system. The reactive derivative of carboxylic acid (III) is used in an amount of 1.0 to 1.5 equivalents, preferably 1.0 to 1.1 equivalents, relative to compound (I) because the production of by-products increases when used in excess. The reaction is carried out at −20 to 50 ° C., preferably 0 to 25 ° C., for 0.5 to 50 hours, usually 0.5 to 1.0 hour.

  The reduction reaction for obtaining compound (II) from compound (I) and the acylation reaction for obtaining compound (IV) can also be carried out independently, but without isolating compound (II), compound (I) In addition, the number of steps can be reduced by continuously carrying out reduction and acylation, and the yield of compound (IV) can be further improved. In particular, when compound (II) is unstable and difficult to isolate, the yield of compound (IV) is significantly improved.

Using the compound (IV) thus obtained, for example, a method described in JP-A-6-16668 or a method analogous thereto, a xanthine derivative having a diuretic action and a renal protective action, or JP-A-5-105631 A xanthine derivative having an anti-dementia effect or a Parkinson's disease therapeutic effect can be synthesized by a method described in the publication or a method based thereon.
Examples of the present invention and reference examples are shown below.

(E) -N- (6-Amino-1,2,3,4-tetrahydro-2,4-dioxo-1,3-di-n-propyl-5-pyrimidyl) -3,4-dimethoxycinnamic acid Production of amide (compound 1)
Mixture of 15.68 g (65.3 mmol) of 6-amino-1,2,3,4-tetrahydro-5-nitroso-2,4-dioxo-1,3-di-n-propylpyrimidine and 235.2 mL of 2 N aqueous potassium carbonate solution Was stirred at room temperature for 30 minutes. While cooling in a water bath, 34.09 g (196.0 mmol) of sodium hyposulfite was added little by little to this mixture, and the mixture was stirred at room temperature for 5 hours. To the aqueous solution of 5,6-diamino-1,2,3,4-tetrahydro-2,4-dioxo-1,3-di-n-propylpyrimidine thus obtained, 78.4 mL of dichloromethane was added, and the mixture was ice-cooled. Below, 956.0 mL (196.0 mmol) of a dichloromethane solution of 0.205 mol / L (E) -3,4-dimethoxycinnamic acid chloride obtained in Reference Example 1 was added dropwise and stirred for 1 hour. 50 mL of ethanol was added to the reaction mixture, and the mixture was separated, and the organic layer was concentrated under reduced pressure. Ethanol (80 mL) and water (240 mL) were added to the residue, and the mixture was heated to 70 ° C. and stirred for 1 hour to obtain a homogeneous solution. The mixture was gradually cooled to room temperature over 5 hours, and the precipitated crystals were collected by filtration to obtain 18.87 g (45.3 mmol, 69.4%) of Compound 1.
Melting point: 199.5-200.3 ° C
MS (m / e): 416 (M ⁺ )
_{NMR (CDCl 3) δ (ppm} ): 7.60 (1H, d, J = 15.5Hz), 7.48 (1H, brs), 7.11 (1H, dd, J = 8.3,1.9Hz), 7.05 (1H, d, J = 1.5Hz), 6.88 (1H, d, J = 8.3Hz), 6.51 (1H, d, J = 15.5Hz), 5.76 (2H, brs), 3.96 (4H, m), 3.93 (3H, s), 3.92 (3H, s), 1.72 (2H, m), 1.66 (2H, m), 1.03 (3H, t, J = 7.5Hz), 0.94 (3H, t, J = 7.5Hz)

(E) -N- (6-Amino-1,3-diethyl-1,2,3,4-tetrahydro-2,4-dioxo-5-pyrimidyl) -3,4-dimethoxycinnamic amide (Compound 2 )Manufacturing of
Add 6.50 g (30.7 mmol) of 6-amino-1,3-diethyl-1,2,3,4-tetrahydro-5-nitroso-2,4-dioxopyrimidine to 65.0 mL of 2N aqueous potassium carbonate, For 30 minutes. While cooling in a water bath, 16.0 g (92.1 mmol) of sodium hyposulfite was added little by little to the mixture, and the mixture was stirred at room temperature for 2 hours. To the aqueous solution of 5,6-diamino-1,3-diethyl-1,2,3,4-tetrahydro-2,4-dioxopyrimidine thus obtained, 21.7 mL of dichloromethane was added, and the mixture was further cooled with ice. 150 mL (30.7 mmol) of a 0.205 mol / L (E) -3,4-dimethoxycinnamic acid chloride dichloromethane solution obtained in Reference Example 1 was added dropwise and stirred for 30 minutes. Ethanol (33 mL) and water (33 mL) were added to the reaction mixture, the phases were separated, and the organic layer was concentrated. 33 mL of ethanol and 99 mL of water were added to the residue, heated to 70 ° C. and stirred for 30 minutes to obtain a uniform solution. The mixture was gradually cooled to room temperature over 1 hour, and further allowed to stand at room temperature for 2 hours. The precipitated crystals were collected by filtration to obtain 10.3 g (26.5 mmol, 86.4%) of Compound 2.
Melting point: 115.6-116.5 ° C
MS (m / e): 388 (M ⁺ )
_{NMR (CDCl 3) δ (ppm} ): 8.06 (1H, s), 7.50 (1H, d, J = 15.5Hz), 7.00 (1H, dd, J = 8.3,1.5Hz), 6.95 (1H, d, J = 1.5Hz), 6.78 (1H, d, J = 8.3Hz), 6.60 (1H, d, J = 15.5Hz), 5.84 (2H, brs), 3.92 (4H, m), 3.88 (3H, s), 3.86 (3H, s), 1.26 (3H, t, J = 7.0Hz), 1.16 (3H, t, J = 7.0Hz)
Reference example 1
Preparation of (E) -3,4-dimethoxycinnamic acid chloride in dichloromethane
To a mixture of (E) -3,4-dimethoxycinnamic acid 80.0 g (0.384 mol), dichloromethane 0.80 L and N, N-dimethylformamide 0.96 mL, thionyl chloride 33.6 mL (0.461 mol) was added dropwise at 25 ° C. Stir for 2 hours. The reaction mixture was concentrated under reduced pressure, dichloromethane was added to the residue to dissolve the precipitated crystals, and a dichloromethane solution (concentration 0.205 mol / L) of (E) -3,4-dimethoxycinnamic acid chloride was prepared.
Reference example 2
(E) Preparation of 8- (3,4-dimethoxystyryl) -7-methyl-1,3-di-n-propylxanthine (Compound a) Compound 1, obtained in Example 1, 125 g (0.300 mol) Ethanol (0.75 L) and 4N aqueous sodium hydroxide solution (0.95 L) were added, and the mixture was stirred at 80 ° C. for 4 hours and then cooled to 25 ° C. To the reaction solution adjusted to pH 7 by adding concentrated hydrochloric acid, 2.07 L of chloroform was added, stirred for 10 minutes, allowed to stand for 10 minutes, and then separated. The organic layer was concentrated under reduced pressure to 0.15 L, and 1.87 L of N, N-dimethylformamide, 62.2 g (0.45 mol) of potassium carbonate and 22.4 mL (0.36 mol) of methyl iodide were added to the residue, and the mixture was stirred at 40 ° C. for 4 hours. did. The reaction mixture was cooled to 25 ° C., 1.87 L of water was added over 30 minutes with stirring, and the mixture was further stirred for 2 hours. The precipitated pale yellow needle crystals were collected by filtration and washed with 0.25 L of water to obtain 107.8 g (0.261 mol, 87.1%) of compound a.
Melting point: 168.5-169.5 ° C
MS (m / e): 412 (M ⁺ )
IR (KBr) ν _max (cm ^-1 ): 3000-2800,1691,1657,1518,1267,959,789
_{NMR (CDCl 3) δ (ppm} ): 7.73 (1H, d, J = 15.7Hz), 7.19 (1H, dd, J = 8.3,1.9Hz), 7.09 (1H, d, J = 1.9Hz), 6.90 ( 1H, d, J = 8.3Hz), 6.77 (1H, d, J = 15.7Hz), 4.10 (2H, m), 4.06 (3H, s), 3.98 (2H, m), 3.96 (3H, s), 3.94 (3H, s), 1.85 (2H, m), 1.68 (2H, m), 1.01 (3H, t, J = 7.4Hz), 0.97 (3H, t, J = 7.4Hz)
Reference Example 3
(E) Preparation of 1,3-diethyl-8- (3,4-dimethoxystyryl) -7-methylxanthine (Compound b) Compound 2, obtained in Example 2, 300 g (0.773 mol) with 1.20 L of ethanol and 1.50 L of 4N aqueous sodium hydroxide solution was added, and the mixture was stirred at 80 ° C. for 3 hours, and then cooled to 25 ° C. Chloroform 2.28L was added to the reaction solution adjusted to pH 7 by adding concentrated hydrochloric acid, stirred for 10 minutes, allowed to stand for 10 minutes and then separated. The organic layer was concentrated under reduced pressure to 0.74 L, and N, N-dimethylformamide 3.96 L, potassium carbonate 161 g (1.165 mol) and methyl iodide 57.6 mL (0.925 mol) were added to the residue, and the mixture was stirred at 40 ° C. for 4 hours. . The reaction mixture was cooled to 25 ° C., 3.96 L of water was added over 30 minutes with stirring, and the mixture was further stirred for 2 hours. The precipitated pale yellow needles were collected by filtration and washed with 0.24 L of water to obtain 231.8 g (0.603 mol, 78.0%) of compound b.
Melting point: 191.5-192.5 ° C
MS (m / e): 384 (M ⁺ )
IR (KBr) ν _max (cm ^-1 ): 3000-2800,1695,1655,1516,1269,1024,964
NMR (CDCl ₃ ) δ (ppm): 7.73 (1H, d, J = 15.7Hz), 7.18 (1H, dd, J = 8.3, 1.9Hz), 7.09 (1H, d, J = 1.9Hz), 6.89 ( 1H, d, J = 8.3Hz), 6.76 (1H, d, J = 15.7Hz), 4.21 (2H, q, J = 7.0Hz), 4.09 (2H, q, J = 7.0Hz), 4.06 (3H, s), 3.96 (3H, s), 3.93 (3H, s), 1.39 (3H, t, J = 7.0Hz), 1.26 (3H, t, J = 7.0Hz)

Claims (1)

Formula (I)

(Wherein R ¹ and R ² are the same or different and each represents hydrogen or lower alkyl), a 6-amino-5-nitrosouracil derivative represented by formula (II)

(Wherein R ¹ and R ² have the same meanings as described above), and without the diamino compound being isolated, the formula (III)

{Wherein R ³ is lower alkyl, cycloalkyl, — (CH ₂ ) _n —R ⁴ (wherein R ⁴ represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group, and n is 0 Represents an integer of ~ 4), or

Wherein Y ¹ and Y ² are the same or different and each represents hydrogen or lower alkyl, and Z represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group} Or a reaction thereof with a reactive derivative thereof, characterized in that it has the formula (IV)

(Wherein R ¹ , R ² and R ³ have the same meanings as described above), a method for producing a 5-acylamino-6-aminouracil derivative.