JPS61112073A - Production of 1-(2-tetrahydrofuryl)-5-fluorouracil - Google Patents

Abstract

PURPOSE:To obtain the titled compound economically and easily, in high yield and purity, by reacting 5-fluorouracil with 2,3-dihydrofuran in pyridine in the presence of a carboxylic acid, and treating the obtained reaction liquid with an aqueous solution of a carboxylic acid salt. CONSTITUTION:The objective compound of formula III can be prepared by reacting 5-fluorouracil of formula I with 2,3-dihydrofuran of formula II in the presence of a carboxylic acid such as lower aliphatic carboxylic acid at 80-180 deg.C, adding an aqueous solution of a carboxylic acid salt such as an alkali metal or alkaline earth metal salt of a <=8C carboxylic acid to the reaction solution, and treating at a temperature between room temperature and 100 deg.C. The amount of the carboxylic acid is 0.1-2.5mol per 1mol of the compound of formula I, and the concentration of the aqueous solution of carobxylic acid salt is 0.01-10mol. EFFECT:The carboxylic acid salt acts also as a salting-out agent in the extraction of the reaction product to improve the extraction efficiency. USE:Antitumor agent, antiviral agent, etc.

Description

[Detailed Description of the Invention] [Object of the Invention] 1-(2-Nato2 Human Frill)-5 of Honhatsu Shibusagi Purity
-Related to a method for manufacturing fluorouracil industrially at low cost and simply.

[Industrial application field]

1-(2-tetrahydrofuryl)-5-fluorouracil is a compound known as an antitumor agent, an antiviral agent, and the like.

[Conventional technology]

Conventionally, various methods have been known for producing 1-(2-tetrahydrofuryl)-5-fluorouracil, but there are several problems in producing it industrially at low cost and simply. The chemical structure of 1-(2-tetrahydrofuryl)-5-fluorouracil basically consists of a 5-fluorouracil moiety and a tetrahydrofuryl moiety, and there are many problems in how to combine these two moieties industrially. A lot of research has been done.

In the conventional method, 5-fluorouracil mercury salt (British patent, 44116
8391), 2,4-bis(trialkylsilyl)-5-fluorouracil (T,!:, t), JP-A-1983
-135989) or 2,4-bis(trialkylstannyl)-5-fluorouracil (for example, see JP-A-53-137973), but both of these methods are made from 5-fluorouracil. This method is unfavorable from an industrial perspective because of the cost and increase in the number of steps, since it requires storing expensive reagents in two containers. In particular, the method using 5-fluorouracil mercury salt has problems of mercury toxicity to the human body and environmental pollution. The manufacturing method that is considered to be industrially advantageous is 5, which is easily available.
- Fluorouracil itself is used to react with the reaction substrate of the tetrahydrofuryl moiety.

As the reaction substrate of the tetrahydrofuryl moiety, for example, 2-chlorotetrahydrofuran (for example, British Patent No. 1168391, Japanese Patent Publication No. 105101/1986,
1-8282, Tokuko Sho 53-
[1) 518), 2-alkoxytetrahydro7rane (for example, JP-A-49-1) 7981, JP-A-52
-118479), 2-acyloxytetrahydrofucn (e.g., JP-A-5C-50383, JP-A-53-
7688), but the chemical stability of these compounds is low, and in particular 2-chlorotetrahydrofuran is an extremely unstable compound, so -
Since the reaction must be carried out at a low temperature of about 60 DEG C. to -10 DEG C., it is industrially disadvantageous, including its handling. In addition, 2-alkoxytetrahydrofuran and 2-azoloquinotetrahydrofuran are usually produced from 2-chlorotetrahydro7rane or 2,3-dihydrofuran, and 2-chlorotetrahydrofuran is produced from 2,3-dihydrofuran. Since the method involves a large number of reaction steps, it cannot be said to be an industrially advantageous method.

Furthermore, a method is known in which tetrahydro7rane is used in the presence of sulfuryl chloride as a reaction substrate for the tetrahydrofuryl moiety to be reacted with the 5-fluorouracil moiety (
(Refer to Japanese Unexamined Patent Publication No. 53-119881.
-tetrahydrofuryl)-5-fluorouracil, the highly toxic sulfuryl chloride is used, and highly corrosive hydrogen chloride is generated during the reaction, so it is difficult to adopt it industrially.

Therefore, in view of the above-mentioned problems, the raw materials considered to be advantageous in terms of manufacturing cost are 5-fluorouracil moiety and tetrahydrofuryl moiety, which are easily available and chemically stable, and 5-fluorouranol and 2,3 - Dihydrofuran makes Roto 6. Furthermore, since the reaction between 5-fluorouracil and 2,3-dihydrofuran is expected to be a complete two-molecular bonding reaction (reaction number 2 shown below), it has the advantage that it requires only a few purification steps after the reaction and the separation operation is simple. Roru. For these reasons, several methods using both as raw materials have been reported. For example, a method of heating in a polar solvent (Japanese Unexamined Patent Publication No. 53)
-119880 and Japanese Patent Publication No. 53-28435), method of heating under pressurized conditions (see Japanese Patent Publication No. 54-1) 472)
However, in both cases, the reaction requires high temperature and long time, the reaction efficiency is low, and the by-product 1.3-
There was a drawback that bis(2-tetrahydrofuryl)-5-fluorouracul was produced, complicating the purification process in post-treatment. In order to compensate for these drawbacks, Lewis acids such as +11 anhydrous aluminum chloride (see JP-A-53-2484.52-89678),
(2) Phosphorus pentachloride (see JP-A-54-27583), (3
) chlorophosphite (see JP-A-54-301'87), (4) tertiary amine hydrochloride (JP-A-54-27)
584), (5) Amphoteric compounds such as amino acids (see Japanese Patent Publication No. 54-9179), and fi (6) strongly acidic thio/exchange resins, strong basic anion exchange resins, etc. (Japanese Patent Publication No. 53-3)
5954) have been reported, but these methods inevitably add complexity to the post-treatment purification process because they add solid compounds that cannot be distilled off under normal conditions. . In particular, the above (11
Under the reaction conditions of (3), a large amount of hydrogen chloride is generated during the reaction or in the post-treatment process, resulting in the problem of corrosion. Also(
In the case of 4), since 7g of salt is used, the problem of corrosion cannot be avoided. Furthermore, even in these methods, the production of 1,3-bis(2-tetrahydrofuryl)-5-fluorouracil as a by-product cannot be avoided, so problems remain in terms of the purification process and yield. . To solve this problem, 1-(2-tetrahydrofuryl)-5-, which is produced by acidic or alkaline hydrolysis of the by-produced 1,3-bis(2-tetrahydrofuryl)-5-fluorouracul, yields the desired product. Changed to fluorouracula
method (Japanese Unexamined Patent Publication No. 53-119880,
6-10911) has been proposed, but if one of the objects
-(2-tetrahydrofuryl) -5-fluorouracil is similarly hydrolyzed with acid or alkali and converted to the raw material 5-fluorouracil, so 1,3-bis(2-tetrahydrofuryl) is converted into the raw material 5-fluorouracil without causing side reactions. frill)-5
- The range of reaction conditions for selectively hydrolyzing only fluorouracules is very narrow. For this reason, there are many problems when trying to implement it industrially. In addition, in conventional hydrolysis, z"l fV requires operations such as distillation of the ρ medium after the preliminary reaction, and therefore cannot be called an industrially simple production method.

[Problems solved by the invention]

The inventors of the present invention took into account the above-mentioned problems and conducted intensive research to find an industrially simple and inexpensive manufacturing method. In the reaction, by coexisting a carboxylic acid in a pyridine solvent, the reaction efficiency is increased compared to when it is not present (see comparative example), and furthermore, the reaction solvent obtained can be carried out without distilling off the solvent. The 1-
It was discovered that the by-product (2-tetrahydrofuryl)-5-fluorouracil can be produced without causing any decomposition of (2-tetrahydrofuryl)-5-fluorouracil, and the present invention was created.

[Summary of the Invention] The present invention involves reacting 5-fluorouracul with 2.3-) and dolofuran in the presence of carvone mash in pyridine, and then
The special modification is to add an aqueous solution of carvone #salt to the obtained reaction solution for treatment.According to the present invention, highly pure 1-(-1-tetrahydrofuryl)-5-fluorourachlor can be easily prepared. [A] can be produced at low cost, in high yield, and with high purity.

2.3-') Use of pyridine 1 is 1.10 times the molar amount of 5-fluorouracil, or preferably 1 to 4 times the molar amount from the viewpoint of reaction efficiency and economical efficiency. Of course, it is safe to do this in the presence of carvone m. Carbon 6! Examples include formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, caprylic acid,
Examples include chlorine, co-phosphoric acid, benzoic acid, etc., but from the viewpoint of economy and the inkstone point of division after reaction, carbon atoms with 4 carbon atoms are used.
or less lower aliphatic carboxylic acids are preferred. The amount of carboxylic acid to be used can be selected from 0.1 to 2.5 moles per 1 to 5-fluorouracul. The effect of addition is small when it is less than 0.1 times the mole and when it is more than 2.5 times the mole. The reaction between 5-fluorouracul and 2.3-9 hydrofuran proceeds at a humidity temperature of 80°C to 18Ll″C, but in order to increase the reaction efficiency and the purity of the product,
00'Q, 160°C is preferred.

The present invention requires that the reaction solution obtained by the above reaction be treated with an aqueous solution of a carboxylate salt. Carboxylate salts include sodium acetate, potassium acetate, lithium acetate, magnesium acetate, calcium acetate, sodium glopionate, sodium formate, potassium formate, /
sodium ellaate, succinic acid) IJ cum, acetic acid steel,
Examples include zinc acetate, sodium butyrate, sodium valerate, sodium caprylate, sodium caprate, sodium stearate, sodium benzoate, etc., but from the viewpoint of economy, alkali metal carboxylates having 8 or less carbon atoms *Or alkaline earth metal salts are preferred.

The concentration of the aqueous solution of carboxylate is 0.01 molar to 10
It can be selected within a range of molar concentration, but the selectivity of the reaction,
From the viewpoint of effectiveness and economy, a molar ratio of 0.05 to 5 is preferred. Treatment temperature with an aqueous solution of carboxylic acid salt d ranges from household appliances to 100°C, but from the viewpoint of reaction efficiency, 40°C to 90°C is preferable. In the treatment of the rubonate salt with water e+4 ti, there is no problem in using other solvents such as methanol, ethanol, etc., as long as the advantages of this reaction are not impaired. In addition,
The acid groups of the carboxylic acid and the carboxylate may be the same or different.

In addition, the effect of carboxylate is not only the selective conversion of 1,3-bis(2-tetrahydrofuryl)-5-fluorouracil to 1-(2-tetrahydrofuryl)-5-fluorouracil, but also the effect of Acids are extracted from the aqueous layer with organic solvents (for example, chloroform), and carboxylic acid salts can also act as a salting-out effect during this process, so they have the additional advantage of increasing the efficiency of the extraction operation. The present invention will be explained in more detail with reference to Examples and Comparative Examples.

Implementation 1711 10m3 5-fluorouracil 0.2 to 3
5g (1.92mmol), 2.5g of pyridine, 5g of acetic acid
81v (0.97 mmol) and 10.27 g (3.8 mmol) of 2,3-one hydrofuran were sealed in a tube under deaerated conditions, and heated at 1) 0'(IX''ml,' for 24 hours. Allowed to cool. After that, 2.5 ml of 1.0 m//aqueous sodium acetate solution was added to the reaction solution, and the mixture was heated to 4.5 ml at 70°C.
Stir for hours. After removing N from the reaction solution under reduced pressure, take water a.
Roform was added and the liquids were separated. The chloroform layer was dried over magnesium sulfate and the chloroform was distilled off to obtain 0.347 g of 1-(2-tetrahydrofuryl)-5-fluorouracul as crystals. The yield was 90 cm. When analyzed using a thin-layer Chromadog 7F, it was found to be a single spot.

In addition, some of the obtained crystals were recrystallized from ethanol. The melting point and elemental analysis values of the beef were as follows.

Melting point 164-168'C (literature value 165-1690 Yakugyo Jihosha) Elemental analysis calculated value C: 48.00. H:4.53. N:14,0
0%.

Actual pick-up 11th shift C: 47.72. H:4.56. N:1
3.84%.

Examples 2-8 Table 1 shows the results conducted under various conditions.

Post-treatment was performed under the same conditions as in Example 1 except for conditions not listed. In addition, Example 1 is also included in Figure 1.

Comparative Example 5-7 Luo a +7 Rasil 0.25g (1,92m
acetic acid 11 to a mixture of 0.27 g (3.8 mmol), pyri2/2.5m, and 2.3-enhydrofuran
59 (1.92 mmol) and the reaction solution without acetic acid were sealed in a reaction tube at 1°C or higher under deaerated conditions and heated at 110°C for 24 hours.9.The reaction. When the liquid was analyzed, the reaction rate of 5-fluororafcyl was 82% in the case where acetic acid was added, whereas it was 50% in the case where acetic acid was not added.

Claims (6)

[Claims] (1) After reacting 5-fluorouracil and 2,3-dihydrofuran in pyridine in the presence of a carboxylic acid,
A method for producing 1-(2-tetrahydrofuryl)-5-fluorouracil, which comprises adding an aqueous solution of a carboxylic acid salt to the resulting reaction solution. (2) In the presence of carboxylic acid, in pyridine, from 80°C to 18°C
Claims characterized in that after 5-fluorouracil and 2,3-dihydrofuran are reacted at 0°C, an aqueous solution of a carboxylic acid salt is added to the resulting reaction solution and treated at room temperature to 100°C. The method described in paragraph (1). (3) The method according to claim (1) or (2), wherein the carboxylic acid is a lower aliphatic carboxylic acid. (4) The method according to claim (1), (2) or (3), wherein the amount of carboxylic acid used is 0.1 to 2.5 times by mole relative to 5-fluorouracil. . (5) Claims No. (1), (2), (3), or (4), wherein the carboxylic acid salt is an alkali metal salt or alkaline earth metal salt of a carboxylic acid having 8 or less carbon atoms. Method described. (6) Claims (1), (2), and (3) wherein the concentration of the aqueous solution of the carboxylate is 0.01 to 10 molar.
), (4) or (5).