JP2008069089A - Method for producing 4-amino-2-mercapto-5-pyrimidine carbaldehyde - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an industrially preferable simple method for producing 4-amino-2-mercapto-5-pyrimidine carbaldehyde, by which the 4-amino-2-mercapto-5-pyrimidine carbaldehyde can be produced in a high yield. <P>SOLUTION: This method for producing the 4-amino-2-mercapto-5-pyrimidine carbaldehyde represented by general formula (2) is characterized by reacting a 4-amino-2-mercapto-5-pyrimidine carbaldehyde alkali metal salt represented by general formula (1) (M is an alkali metal atom) with an acid. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a process for producing 4-amino-2-mercapto-5-pyrimidinecarbaldehyde. 4-Amino-2-mercapto-5-pyrimidinecarbaldehyde is a useful compound as a raw material and synthetic intermediate for pharmaceuticals and agricultural chemicals, for example.

Conventionally, the alkali metal salt of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde used as a raw material in the reaction of the present invention is a compound that can be easily obtained from a reaction solution and handled. However, since the compound is a novel compound, a method for producing 4-amino-2-mercapto-5-pyrimidinecarbaldehyde using this as a starting material has not been known. A method for producing 4-amino-2-mercapto-5-pyrimidinecarbaldehyde from 3,3-diethoxy-2-formylpropionitrile potassium salt and thiourea is known (see, for example, Patent Document 1). . However, this method has a problem that the operability is extremely poor because the reaction solution becomes a thick slurry.
Special Table 2004-507540

  The object of the present invention is to solve the above-mentioned problems and to produce 4-amino-2-mercapto-5-pyrimidinecarbaldehyde in a high yield by a simple method, which is industrially suitable 4-amino- The object is to provide a process for the preparation of 2-mercapto-5-pyrimidinecarbaldehyde.

  The subject of the present invention is that the general formula (1)

(In the formula, M represents an alkali metal atom.)
Wherein an acid is reacted with an alkali metal salt of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde represented by the following formula (2):

It is solved by a process for producing 4-amino-2-mercapto-5-pyrimidinecarbaldehyde represented by the following formula.

  According to the present invention, an industrially suitable process for producing 4-amino-2-mercapto-5-pyrimidinecarbaldehyde, which can produce 4-amino-2-mercapto-5-pyrimidinecarbaldehyde in a high yield by a simple method. Can be provided.

  The compound (1) used in the present invention is represented by the general formula (1). In the general formula (1), M is an alkali metal atom, and specific examples thereof include a lithium atom, a sodium atom, a potassium atom, a rubidium atom, and a cesium atom, preferably a sodium atom and a potassium atom. It is.

  Compound (1) used in the reaction of the present invention is, for example, at least one selected from the group consisting of 3,3-dialkoxypropanenitrile and 3-alkoxy-2-propenenitrile in the presence of a base containing an alkali metal. It can be obtained by reacting thiourea with an alkali metal salt of 3,3-dialkoxy-2-hydroxymethylenepropane nitrile obtained by reacting a nitrile compound with a formate at -10 to 30 ° C. It is a compound (described in Reference Example 1 and Reference Example 2 later).

The reaction of the present invention is preferably carried out in a solvent in the presence of an acid.

  Examples of the acid used in the reaction of the present invention include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid; organic carboxylic acids such as formic acid, acetic acid, and propionic acid; and organic sulfonic acids such as methanesulfonic acid and trifluoromethanesulfonic acid. Of these, hydrochloric acid, sulfuric acid, acetic acid, propionic acid, and methanesulfonic acid are preferably used. In addition, you may use these acids individually or in mixture of 2 or more types.

  The amount of the acid to be used is preferably 0.6 to 10 mol, more preferably 0.8 to 5 mol, relative to compound (1).

  The solvent used in the reaction of the present invention is not particularly limited as long as it does not inhibit the reaction. For example, water; alcohols such as methanol, ethanol, isopropyl alcohol, t-butyl alcohol, methoxyethanol, ethoxyethanol, and butoxyethanol Nitriles such as acetonitrile, propionitrile and benzonitrile; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; urea such as N, N′-dimethylimidazolidinone Sulphoxides such as dimethyl sulphoxide; sulphones such as sulpholane, and the like, preferably water, alcohols, more preferably water, methanol, and ethanol. In addition, you may use these solvents individually or in mixture of 2 or more types.

  The amount of the solvent used is appropriately adjusted depending on the uniformity and stirring properties of the reaction solution, but is preferably 1 to 100 g, more preferably 5 to 50 g, relative to 1 g of compound (1).

  The reaction of the present invention is performed by, for example, a method of mixing the compound (1), an acid and a solvent and reacting them while stirring. The reaction temperature at that time is preferably 0 to 200 ° C., more preferably 0 to 100 ° C., and the reaction pressure is not particularly limited.

  Compound (2) is obtained by the reaction of the present invention, which is isolated and purified by a general method such as extraction, filtration, concentration, recrystallization, crystallization, column chromatography after completion of the reaction. The

  Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto.

Reference Example 1 (Compound (1) [M = sodium atom]; synthesis of sodium salt of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde)
To a glass flask having an internal volume of 200 ml equipped with a stirrer, thermometer, dropping funnel and reflux condenser, 11.51 g (100 mmol) of 3,3-dimethoxypropanenitrile, 10.80 g (200 mmol) of sodium methoxide and 20 ml of tetrahydrofuran were added. It was. Next, while maintaining the liquid temperature at 5 to 10 ° C., a solution obtained by dissolving 9.16 g (120 mmol) of 97% by mass of ethyl formate in 10 ml of tetrahydrofuran was slowly added and reacted at the same temperature for 4.5 hours while stirring. A solution containing sodium salt of 3-dimethoxy-2-hydroxymethylenepropanenitrile as a main component was obtained. Next, 7.99 g (105 mmol) of thiourea, 25 ml of 2-butoxyethanol and 30 ml of isopropyl alcohol were added to a solution mainly composed of sodium salt of 3,3-dimethoxy-2-hydroxymethylenepropanenitrile, and the mixture was stirred at 50 ° C. For 3 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, 11.2 ml of methanol and 37.5 ml of water were added to the concentrate, and the mixture was stirred at 20 to 25 ° C. for 1 hour. The obtained solid was filtered to obtain a sodium salt of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde as a crude product.

Reference Example 2 (Compound (1) [M = potassium atom]; synthesis of potassium salt of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde)
To a 200 mL glass flask equipped with a stirrer, thermometer, dropping funnel and reflux condenser, 11.51 g (100 mmol) of 3,3-dimethoxypropanenitrile, 14.77 g (200 mmol) of 95% by weight potassium methoxide and Tetrahydrofuran 50ml was added. Next, while maintaining the liquid temperature at 5 to 10 ° C., a solution obtained by dissolving 9.16 g (120 mmol) of 97% by mass of ethyl formate in 10 ml of tetrahydrofuran was slowly added and reacted at the same temperature for 4.5 hours while stirring. A solution containing a potassium salt of 3-dimethoxy-2-hydroxymethylenepropanenitrile as a main component was obtained. Next, 7.99 g (105 mmol) of thiourea, 25 ml of 2-butoxyethanol and 30 ml of isopropyl alcohol were added to a solution mainly composed of potassium salt of 3,3-dimethoxy-2-hydroxymethylenepropanenitrile, and the mixture was stirred at 50 ° C. For 3 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, 11.2 ml of methanol and 37.5 ml of water were added to the concentrate, and the mixture was stirred at 20 to 25 ° C. for 1 hour. The obtained solid was filtered to obtain a potassium salt of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde as a crude product.

Example 1 (Compound (2); Synthesis of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde)
A 60.4% by mass 4-amino-2-mercapto-5-pyrimidinecarbamate before drying under reduced pressure obtained in the same manner as in Reference Example 1 was placed in a glass flask having an internal volume of 200 ml equipped with a stirrer, a thermometer and a dropping funnel. 12.7 g (71.7 mmol) of sodium salt of aldehyde and 74.5 ml of purified water were added. Next, while maintaining the liquid temperature at 20 to 30 ° C., 4.3 g (71.7 mmol) of acetic acid was slowly added and reacted at the same temperature for 0.5 hours while stirring. Next, the precipitated crystals were filtered and then dried under reduced pressure to give 4-amino-2-mercapto-5-pyrimidinecarbaldehyde 10.9 with a purity of 96% by mass (quantitative value by high performance liquid chromatography) as a pale yellow powder. g was obtained (isolated yield based on sodium salt of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde; 94%).

¹ H-NMR (DMSO-d ₆ , δ (ppm)); 8.05 (1H, brs), 8.33 (1H, s), 8.55 (1H, brs), 9.56 (1H, s), 12.84 (1H, brs)

Example 2 (Compound (2); Synthesis of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde) A 200 mL glass flask equipped with a stirrer, a thermometer and a dropping funnel was used as in Reference Example 1. 12.7 g (71.7 mmol) of sodium salt of 60.4 mass% 4-amino-2-mercapto-5-pyrimidinecarbaldehyde obtained before drying under reduced pressure, 17 ml of purified water and 70 ml of methanol were added. Next, while maintaining the liquid temperature at 20 to 30 ° C., 4.3 g (71.7 mmol) of acetic acid was slowly added and reacted at 40 ° C. for 1 hour with stirring. The precipitated crystals were then filtered and washed with 38 ml warm water and 13 ml methanol. The obtained crystals were dried under reduced pressure to obtain 11.7 g of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde having a purity of 93.6% by mass (quantitative value by high performance liquid chromatography) as a pale yellow powder. (Isolated yield based on sodium salt of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde; 98%).

Example 3 (Compound (2); Synthesis of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde) A 200 mL glass flask equipped with a stirrer, a thermometer and a dropping funnel was used as in Reference Example 1. 27.6 g (69.7 mmol) of sodium salt of 44.7 mass% 4-amino-2-mercapto-5-pyrimidinecarbaldehyde obtained before drying under reduced pressure, 17.5 ml of purified water and 91 ml of ethanol were added. Next, 4.4 g (73.3 mmol) of acetic acid was slowly added while maintaining the liquid temperature at 20 to 30 ° C., and the mixture was reacted at 40 ° C. for 1 hour with stirring. Next, the precipitated crystals were filtered and washed with 37 ml of warm water and 12 ml of methanol. The obtained crystals were dried under reduced pressure to obtain 10.6 g of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde having a purity of 96.6% by mass (quantitative value by high performance liquid chromatography) as a pale yellow powder. (Isolated yield based on sodium salt of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde; 95%).

Example 4 (Compound (2); Synthesis of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde) A 200 mL glass flask equipped with a stirrer, a thermometer and a dropping funnel was used as in Reference Example 1. 27.6 g (69.7 mmol) of sodium salt of 44.7 mass% 4-amino-2-mercapto-5-pyrimidinecarbaldehyde obtained before drying under reduced pressure and 77 ml of purified water were added. Subsequently, 11.6 ml (69.7 mmol) of 6 mol / l hydrochloric acid was slowly added while maintaining the liquid temperature at 20 to 30 ° C., and the mixture was reacted at 40 ° C. for 1 hour with stirring. Next, the precipitated crystals were filtered and washed with 12 ml of warm water and 12 ml of methanol. The obtained crystals were dried under reduced pressure to obtain 11.4 g of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde having a purity of 94.7% by mass (quantitative value by high performance liquid chromatography) as a pale yellow powder. (Isolated yield based on sodium salt of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde; 99%).

Example 5 (Compound (2); Synthesis of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde) A glass flask having an internal volume of 200 ml equipped with a stirrer, a thermometer and a dropping funnel was used as in Reference Example 1. 27.6 g (69.7 mmol) of sodium salt of 44.7 mass% 4-amino-2-mercapto-5-pyrimidinecarbaldehyde obtained before drying under reduced pressure and 77 ml of purified water were added. Next, 6.84 g (69.7 mmol) of concentrated sulfuric acid was slowly added while maintaining the liquid temperature at 20-30 ° C., and the mixture was reacted at 40 ° C. for 1 hour with stirring. Next, the precipitated crystals were filtered and washed with 12 ml of warm water and 12 ml of methanol. The obtained crystals were dried under reduced pressure to obtain 11.1 g of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde having a purity of 96.7% by mass (quantitative value by high performance liquid chromatography) as a pale yellow powder ( Isolated yield based on sodium salt of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde; 99%).

Example 6 (Compound (2); Synthesis of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde) A 200 mL glass flask equipped with a stirrer, a thermometer and a dropping funnel was used as in Reference Example 1. 27.6 g (69.7 mmol) of sodium salt of 44.7 mass% 4-amino-2-mercapto-5-pyrimidinecarbaldehyde obtained before drying under reduced pressure, 17.5 ml of purified water and 91 ml of ethanol were added. Next, 7.0 g (72.8 mmol) of methanesulfonic acid was slowly added while maintaining the liquid temperature at 20 to 30 ° C., and the mixture was reacted at 40 ° C. for 1 hour with stirring. Next, the precipitated crystals were filtered and washed with 37 ml of warm water and 12 ml of methanol. The obtained crystals were dried under reduced pressure to obtain 10.7 g of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde having a purity of 95% by mass (quantitative value by high performance liquid chromatography) as a pale yellow powder. (Isolated yield based on sodium salt of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde; 94%).

Example 7 (Compound (2); Synthesis of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde)
Potassium of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde synthesized in the same manner as in Reference Example 2 instead of the sodium salt of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde in Example 1 Even when the reaction is carried out using a salt, 4-amino-2-mercapto-5-pyrimidinecarbaldehyde is obtained in high yield.

  The present invention relates to a process for producing 4-amino-2-mercapto-5-pyrimidinecarbaldehyde. 4-Amino-2-mercapto-5-pyrimidinecarbaldehyde is a useful compound as a raw material and synthetic intermediate for pharmaceuticals and agricultural chemicals, for example.

Claims (4)

General formula (1)

(In the formula, M represents an alkali metal atom.)
Wherein an alkali metal salt of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde represented by the formula (2) is reacted.

A process for producing 4-amino-2-mercapto-5-pyrimidinecarbaldehyde represented by the formula:   The process for producing 4-amino-2-mercapto-5-pyrimidinecarbaldehyde according to claim 1, wherein the reaction is carried out in the presence of a solvent.   The alkali metal salt of 4-amino-2-mercapto-5-pyrimidinecarbaldehyde according to claim 1 is obtained by reacting an alkali metal salt of 3,3-dialkoxy-2-hydroxymethylenepropanenitrile with thiourea. The process for producing 4-amino-2-mercapto-5-pyrimidinecarbaldehyde according to claim 1, which is obtained.   The alkali metal salt of 3,3-dialkoxy-2-hydroxymethylenepropanenitrile according to claim 3, wherein 3,3-dialkoxypropanenitrile and 3-alkoxy-2-propenenitrile are present in the presence of a base containing an alkali metal. The 4-amino-2-mercapto-5-pyrimidinecarbamate according to claim 1, which is obtained by reacting at least one nitrile compound selected from the group consisting of formate with -10-30 ° C. Rudehide manufacturing method.