JPS5840958B2 - Production method of 1↓-(5↓-oxohexyl)theobromine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing 1-(5-oxohexyl)theobromine, which is useful as a medicine.

1-(5-oxohexyl)theobumine is a compound represented by the formula, and it is widely marketed as a drug because it exhibits remarkable vasodilation and red blood cell deformability-enhancing effects, as well as having few side effects. ing.

Until now, the method for producing 1-(5-oxohexyl)theobromine has been to add 5-
React with oxohexyl halide or 1
A method is known in which -(3-halopropyl)theobromine and acetoacetate are reacted and then ketone decomposition is performed (% Publication No. 45-21308).

However, in the former method, the 5-
Oxohexyl halide is an unstable substance that discolors and decomposes during storage, and produces by-products in addition to the desired 1(5-oxohexyl)theobromine, requiring complicated purification and other operations. Therefore, it cannot be said that it is necessarily satisfactory for industrial implementation.

In addition, the latter method requires two additional steps, a saponification step and a decarboxylation step, after reacting 1-(3-halopropyl)theobromine with ethyl acetoacetate, which requires complicated operations. Therefore, it is not preferred as a method to be implemented industrially.

The present inventors have conducted various studies in order to overcome the drawbacks of these conventional methods and develop a process for producing 1-(5-oxohexyl)theobromine suitable for industrial implementation. As a result, the general formula ( X represents a halogen) 1-(3-halopropyl)thiobrone and acetone are heated to 8°C or higher in a closed container under alkaline conditions to react, thereby producing 1-(5-oxohexyl) represented by the formula ) We have discovered that theobromine can be produced easily and with good yield.

The present invention has been made based on this knowledge.

X in general formula (i) is, for example, a halogen such as CI or Br.

In the method of the present invention, 1-(3-halopropyl)theobromine is suspended in acetone, an alkali metal compound or an alkaline earth metal compound is added, the conditions are set to alkaline, and the mixture is heated to 80°C or higher in an autoclave. Stir and carry out the reaction.

The raw material 1(3-halopropyl)theobromine of general formula (I) used in the present invention is a known compound, and theobromine and 1,3-dihalopropane or 1='
(3-Phenoxyprobyl) It can be easily synthesized from theobromine and hydrohalic acid.

Examples of 1-(3-halopropyl)theobromine represented by general formula (I) include 1(3-bromopropyl)theobromine where X=Br, 1. -(3-chloropropyl)theobromine.

In addition, examples of the alkali metal compounds used in the present invention include alkali metal hydroxides and alkali metal carbonates, such as sodium hydroxide, potassium hydroxide,
Examples include sodium carbonate and potassium carbonate.

Examples of alkaline earth metal compounds include alkaline earth metal hydroxides and alkaline earth metal carbonates, examples of which include calcium hydroxide, barium hydroxide, calcium carbonate, and barium carbonate. I can do it.

In the method of the present invention, in order to obtain a good yield, it is desirable to use acetone in large excess with respect to the compound of general formula (I) as a raw material, and to conduct the reaction by heating to 80° C. or higher in a closed container.

Acetone is used as both a reaction reagent and a solvent.
Further, as a solvent, an aprotic polar solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide, acetonitrile, nitromethane, etc. can be added and reacted.

In the method of the present invention, the optimum amount of the alkali metal compound or alkaline earth metal compound to be used is determined by the general formula (I
) is preferably selected within the range of 1.0 to 5.0 equivalents.

If this amount is used in excess, it is undesirable because it will lead to decomposition of the target product.

The reaction temperature in the method of the present invention is from 80°C to 200°C.
The temperature can be selected within the range of C, but if it is too low, the reaction will take a long time to proceed, and if the temperature is too high, the reaction will be in a closed system, resulting in high pressure and increasing danger. Advantageously, the temperature is selected within the range from 170°C to 170°C.

The reaction mixture thus obtained was then purified by distilling off the solvent under reduced pressure, adding water to the residue and then adding methylene chloride or chloroform to extract the product. -oxohexyl) theobromine can be obtained.

Next, this material is recrystallized using isopropanol, for example.
If purified by column chromatography or the like, the target compound with high purity can be obtained.

According to the method of the present invention, highly purified 1(5-oxohexyl)theobromine can be obtained in high yield and without by-products by extremely simple operations.

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited by these.

Example 1 903 m9 of l-(3-bromopropyl)theobromine is placed in an autoclave, and 10 ml of acetone is added to suspend it.

After adding 120 μm of powdered hydroxide, the mixture was sealed and reacted with stirring at an external temperature of 150° C. for 4 hours.

After the reaction was completed, the solvent was distilled off, water was added to the residue, extracted with chloroform, and further washed with water.

After drying over anhydrous sodium sulfate, chloroform was distilled off to give a crude product of 71 ml? (Yield 85% based on theobromine) was obtained.

This was recrystallized from infropanol to obtain 660 ml (5-oxohexyl)theobromine (yield 79%).

The physical properties of this product were as follows.

Melting point: 104-105°C UV: pH 7 (H2O) 2.5ffl, (5-1,
.

□λm ax XIO, ) , KBr IR,,3118,1722,1700゜μma .32 6.73 20.20 Example 2 The same procedure as in Example 1 was carried out except that 770 mg of 1-(3-chloropropyl)theobromine was used instead of 903rnIl of 1-(3-bromopropyl)theobromine. , 625 ml of 1-(5-oxohexyl)theobromine was obtained.

Yield 75%. Melting point 104-105°C.

Example 3 In Example 1, except that 360 rIIg of sodium hydroxide was used instead of 120 μg of IJium hydroxide.
The same procedure was repeated to obtain 615 ml of 1-(5-oxohexyl)theobromine.

Yield 78%. Melting point 104-105°C.

Example 4 The same procedure as in Example 1 was repeated except that 337rII9 potassium hydroxide was used instead of 120μ of sodium hydroxide, to obtain 635μ of 1-(5-oxohexyl)theobromine.

Yield 76%. Melting point 104-105°C.

Example 5 The same procedure as in Example 1 was carried out except that 346 kg of potassium carbonate was used instead of 1201 n9 of sodium hydroxide, and 1-(5-oxohexyl)theobromine 6
011rI9 was obtained.

Yield 72%. Melting point 104-105°C.

Example 6 The procedure of Example 1 was repeated except that 74 μm of calcium hydroxide was used instead of 1201 n9 of sodium hydroxide, and 1-(5-oxohexyl)theobromine 6
101n9 was obtained.

Yield 73%. Melting point 104-105°C.

Claims (1)

[Claims] 1 1-(3-halopropyl)theobromine represented by the general formula (X represents halogen) and acetone were heated at 80°C to 2°C in a closed container under alkaline conditions.
A method for producing 1-(5-oxohexyl)theobromine represented by the formula, characterized by heating to 00°C and reacting. 2. The production method according to claim 1, wherein the 1-(3-halopropyl)theobromine used is 1-(3-bromopropyl)theobromine. 3. The production method according to claim 1, wherein the 1-(3-halopropyl)theobromine used is 1-(3-chloropropyl)theobromine. 4. The production method according to claim 1, wherein alkaline conditions are achieved by adding an alkali metal compound or an alkaline earth metal compound. 5. The manufacturing method according to claim 4, wherein alkaline conditions are achieved by adding an alkali metal compound. 6. The manufacturing method according to claim 5, wherein the alkali metal compound is an alkali metal hydroxide. 7. The method according to claim 6, wherein the alkali metal hydroxide is sodium hydroxide or potassium hydroxide. 8. The production method according to claim 5, wherein the alkali metal compound is an alkali metal carbonate. 9. The manufacturing method according to claim 4, wherein alkaline conditions are achieved by adding an alkaline earth metal compound. 10. The production method according to claim 9, wherein the alkaline earth metal compound is an alkaline earth metal hydroxide. 11 The amount of alkali metal compound used is based on general formula (I)
The manufacturing method according to claim 5, wherein the amount is 1.0 to 5.0 equivalents based on the compound. 12 The amount of alkaline earth metal compound used is determined by the general formula (
The manufacturing method according to claim 9, wherein the amount is 1.0 to 5.0 equivalents based on the compound I). 13. The process according to claim 1, wherein the temperature used is between 120°C and 170'C.