JPH025757B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing theobromine derivatives useful as pharmaceuticals. More specifically, the present invention relates to the general formula (In the formula, n means an integer of 1 to 5.) The present invention relates to a method for easily producing 1-[(ω-1)oxoalkyl]theobromine with good yield.

As is well known, 1-[(ω
-1) Oxoalkyl] theobromine exhibits remarkable peripheral vasodilation and red blood cell deformability enhancing effects;
Moreover, it has the excellent characteristics of low toxicity and good solubility. In fact, among these, 1-(5-oxohexyl)theobromine is
It is used as an agent to improve sequelae caused by cerebral thrombosis.

Conventionally, these compounds have been synthesized by reacting theobromine with α, β-unsaturated methyl ketone or (ω-1) oxoalkyl halide, or by reacting 1-(ω-haloalkyl) theobromine with acetoacetate. A method of ketone decomposition after reaction (Japanese Patent Publication No. 45-21308,
JP-A-50-47992), or theobromine and (ω
-1) Method for obtaining 1-[(ω-1)oxoalkyl]theobromine by reacting with an alkynyl halide and then hydrating the triple bond (JP-A-55-45669
No.) etc. are known. However, these methods have drawbacks such as low yields, the generation of by-products and the need for complicated separation and purification operations, or the need to use heavy metal catalysts. This is not necessarily a preferable method for manufacturing pharmaceuticals.

Therefore, an object of the present invention is to provide a method for producing 1-[(ω-1)oxoalkyl]theobromine represented by the above general formula easily, with good yield, and without producing by-products. It's about doing.

1-[(ω-1)oxoalkyl] according to the present invention
The method for producing theobromine is based on the general formula Theobromine or its salt represented by and the general formula (In the formula, n means an integer of 1 to 5.) By reacting with α-acetyl lactones represented by the following in an aprotic polar solvent, the general formula (In the formula, n means an integer of 1 to 5.) It is characterized by obtaining 1-[(ω-1)oxoalkyl]theobromine represented by:

The compound represented by the above general formula (hereinafter referred to as a compound) is produced by an ester condensation reaction between lactones and an acetate ester derivative or by an acetone acetic acid ω
- It is a compound that can be easily obtained in good yield by an intramolecular cyclization reaction of a haloalkyl ester.

Salts of theobromine used in reactions between compounds include lithium salts, sodium salts,
Alkali metal salts such as potassium salts or ammonium salts such as tetraethylammonium salts, benzyltrimethylammonium salts, triethylammonium salts, diazabicycloundecenium salts, etc. can be used. Furthermore, it is also possible to add a basic substance that can become the alkali metal salt or ammonium salt to the reaction system of theobromine and the compound. Such basic substances include alkali metals such as lithium, sodium, and potassium; sodium ethoxide, potassium t-
Alkali metal alcoholates such as butoxide; alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; sodium hydrogen carbonate,
Alkali metal bicarbonates such as potassium hydrogen carbonate; alkali metal carbonates such as sodium carbonate and potassium carbonate; tertiary amines such as triethylamine, tributylamine, diazabicycloundecene; tetraethylammonium hydroxide, trimethylbenzylammonium fluoride Quaternary ammonium salts such as these can be used.

Although the reaction is carried out in a solvent, the compound can be obtained in good yield by using an aprotic polar solvent as the solvent. As a solvent, N,
Amides such as N-dimethylformamide and N-methylpyrrolidone, dimethylsulfoxide, hexamethylphosphortriamide, and the like can be mentioned.

In addition, the amount of the basic substance used in the reaction with the compound can range from a catalytic amount to an excess amount with respect to the compound, but the reaction usually proceeds smoothly when the amount is less than an equivalent amount. Preferably it is 0.05 to 1.0 equivalent. On the other hand, it is sufficient that the amount of the compound used is at least equivalent to the compound, and usually 1.0 to 1.5 equivalents are used. Although the reaction requires a relatively high temperature (100°C or higher), it is desirable to carry out the reaction at a temperature between 150 and 200°C, taking into account the solubility of the compound, the boiling point of the solvent, the reaction rate, the yield, etc.

The reaction crude product obtained under the above conditions can be easily separated into compounds by liquid separation and recrystallization, and the target compound can be obtained in good yield.

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

Example 1 [Production of 1-(4-oxopentyl)theobromine] 4.06 g (0.02 mol) of theobromine sodium salt and 3.84 g of α-acetyl-γ-butyrolactone
(0.03 mol) to 20 ml of N-methylpyrrolidone,
Heat and stir at 170-180°C for 4 hours. N-methylpyrrolidone is distilled off under reduced pressure, and methylene chloride and a 5% aqueous sodium hydroxide solution are added to the residue to separate the layers to remove unreacted theobromine. After treating the organic layer with activated carbon, it was concentrated under reduced pressure, and the obtained crude crystals were recrystallized from i-propanol to give 1-(4
-Oxopentyl) theobromine white powder
3.43g (65%, melting point 110-111°C) was obtained.

Example 2 [Production of 1-(4-oxopentyl)theobromine] 3.80 g (0.02 mol) of theobromine and 3.84 g (0.03 mol) of α-acetyl-γ-butyrolactone were added to 20 ml of dimethyl sulfoxide, and 1.52 g of diazabicycloundecene was added. 160-180 by adding g (0.01 mol)
Heat and stir at ℃ for 4 hours. Dimethyl sulfoxide was distilled off under reduced pressure, and the residue was diluted with methylene chloride and 5
% aqueous sodium hydroxide solution to separate the layers and remove unreacted theobromine. After treating the organic layer with activated carbon, it was concentrated under reduced pressure, and the obtained crude crystals were recrystallized from i-propanol to obtain 3.17 g of white powder of 1-(4-oxopentyl)theobromine.
(60%, melting point 110-111°C).

Example 3 [Production of 1-(5-oxohexyl)theobromine] 3.80 g (0.02 mol) of theobromine and 4.26 g (0.03 mol) of α-acetyl-δ-valerolactone were added to 20 ml of hexamethylphosphorotriamide, and hydrogenated. Add 96 mg (0.002 mol) of sodium, 180 ~
Heat and stir at 190°C for 2 hours. Hexamethylphosphortriamide is distilled off under reduced pressure, and methylene chloride and a 5% aqueous sodium hydroxide solution are added to the residue to separate the layers to remove unreacted theobromine. After treating the organic layer with activated carbon, it was concentrated under reduced pressure, and the obtained crude crystals were recrystallized from i-propanol to obtain 4.45 g of white powder of 1-(5-oxohexyl)theobromine (80%, melting point 102-103°C) was obtained.

Claims (1)

[Claims] 1. General formula Theobromine or its salt represented by and the general formula (In the formula, n means an integer of 1 to 5.) A general formula characterized by reacting with an α-acetyllactone represented by (In the formula, n means an integer of 1 to 5.) A method for producing 1-[(ω-1)oxoalkyl]theobromine represented by: 2. The production method according to claim 1, wherein the theobromine salt is an alkali metal salt or an ammonium salt. 3. The production method according to claim 1, wherein the reaction is carried out in an aprotic polar solvent. 4. The manufacturing method according to claim 3, wherein the aprotic polar solvent is N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide or hexamethylphosphorotriamide.