JPH08269020A - Production of 5-substituted dihydrouracils - Google Patents

Abstract

PURPOSE: To efficiently separate only acetylurea formed as a by-product and produce the subject high-purity and high-quality compounds by reacting an α-substituted acrylic acid with urea in the presence of acetic anhydride and then treating the resultant reactional mixture with a mineral acid. CONSTITUTION: An α-substituted acrylic acid of formula I (R is F or a 1-10C perfluoroalkyl) (e.g. α-trifluoromethylacrylic acid) is initially reacted with urea in the presence of acetic anhydride to afford the objective compounds of formula II. The resultant reactional mixture is subsequently treated with a mineral acid (e.g. hydrochloric acid) to selectively hydrolyze acetylurea. Specifically, the compound of formula I and urea are heated in the acetic anhydride to carry out the reaction. An aqueous solution of the mineral acid at 5-30% concentration is then preferably added to the reactional solution containing the objective compounds at 10-30 wt.% concentration to carry out the hydrolytic reaction. Furthermore, the reactional solution treated with the mineral acid is preferably crystallized at <=10 deg.C and filtered to dry the resultant crystal.

Description

Detailed Description of the Invention

[0001]

The present invention relates to the general formula (2)

Embedded image (In the formula, R is a fluorine atom or a C _{1 to} C ₁₀ perfluoroalkyl group) and a method for producing a 5-substituted dihydrouracil derivative.

More specifically, the general formula (1)

[Chemical 4] (Wherein R is a fluorine atom or a perfluoroalkyl group having ₁ to ₁₀ carbon atoms) and α-substituted acrylic acid is reacted with urea in acetic anhydride to produce a 5-substituted dihydrouracil derivative. The present invention provides an improved method.

[0003]

PRIOR ART The above general formula (2) obtained by the present invention
The 5-substituted dihydrouracils represented by are derived to 5-substituted uracils by elimination reaction of hydrogen groups at the 5th and 6th positions,
The 5-substituted uracils are not only compounds having physiological activity themselves, but also important substances as intermediates that can be induced into pharmaceuticals such as anticancer agents and antiviral agents.

Conventionally, as a method for producing 5-substituted dihydrouracil, α-substituted acrylonitrile is added in methanol,
A method is known in which a compound obtained by reacting with hydrogen bromide to form a β-bromo-α-substituted propionamide and then further reacting with urea or acetylurea to cyclize a compound in hydrochloric acid [C. Heidelberger, D.M. G. Pa
rsonsand D.M. C. Remy, J .; Med. C
hem. , 7, 1 (1964)].

However, this manufacturing method has a long process, and the total yield is as low as 7 to 16%, which is not satisfactory as an industrial manufacturing method.

A method for producing 5-substituted dihydrouracil or a derivative thereof from α-substituted acrylic acid and a urea derivative is known [Japanese Patent Publication No. 61-48830].

However, even in this method, an expensive condensing agent such as dicyclohexylcarbodiimide (hereinafter abbreviated as DCC) is used in the condensation reaction with unsubstituted or monosubstituted urea, and the yield is also low. It is generally not expensive, and further, an operation for distilling off the DCC-derived by-product after the reaction is necessary, which means that it is an industrially insufficient method.

Furthermore, a method of condensing α-substituted acrylic acid and a urea derivative in acetic anhydride is also known [Japanese Patent Publication No. 61-48830]. In this method α-
By using the urea derivative and acetic anhydride in excess with respect to the substituted acrylic acid, the target product is obtained in a relatively high yield of 65 to 70%. However, in this method, as a result of our supplementary test, acetylurea produced by the reaction between urea and acetic anhydride is mixed in the target substance in an amount of about 30 to 50% by weight, and acetylurea cannot be easily separated by an operation such as recrystallization. It has been found that there is a drawback that the desired product of high purity cannot be easily produced in high yield.

By the way, the 5-substituted dihydrouracil is replaced with 5
In the reaction to induce -substituted uracil, it has been found that the reaction proceeds in good yield by the method of Fatma et al. In which dimethyl sulfoxide is used as a solvent and a dehydrogenating agent and sulfuric acid and iodine are used as a catalyst, and the dehydrogenation reaction is carried out [ W. Fa
tma, J .; Iqbal, W.W. Rahman, Chem
st. & Indst. 315, 5, 1979].

As a result of various studies conducted by us in this reaction, it was found that acetylurea mixed with 5-substituted dihydrouracil inhibits the reaction and reduces the yield of the desired product. Therefore, in a reaction for deriving 5-substituted dihydrouracil into 5-substituted uracil useful as an intermediate for pharmaceuticals, acetylurea mixed with 5-substituted dihydrouracil is removed to produce high-quality 5-substituted dihydrouracil. I needed a way to do it.

[0011]

The problem to be solved by the present invention is to efficiently separate an acetylated urea derivative from a reaction mixture for producing a 5-substituted dihydrouracil, and to obtain a good quality 5-substituted dihydrouracil. Is to provide a method of manufacturing.

[0012]

Means for Solving the Problems In the method for producing 5-substituted dihydrouracils by condensing α-substituted acrylic acid and urea in acetic anhydride, the present inventors have mentioned the by-product acetylurea. The method for efficiently separating the derivative from the reaction mixture and producing a high-quality 5-substituted dihydrouracil was earnestly studied.

As a result, for example, α-trifluoromethylacrylic acid and urea were condensed in acetic anhydride to form 5-trifluoromethyldihydrouracil, and the reaction mass was concentrated to distill off excess acetic anhydride. It was found that when the reaction mixture was treated with a mineral acid such as hydrochloric acid, the by-produced acetylurea was selectively hydrolyzed and converted into urea, which was easily dissolved in water. -The quality of trifluoromethyldihydrouracil is significantly improved,
It was found that high-quality 5-trifluoromethyldihydrouracil can be obtained without performing purification operations such as recrystallization.

In addition, a reaction solution obtained by condensing α-trifluoromethylacrylic acid and urea in acetic anhydride to form 5-trifluoromethyldihydrouracil is treated by adding a mineral acid such as hydrochloric acid. High-quality 5-trifluoromethyldihydrouracil can also be obtained by selectively hydrolyzing the acetylurea by-produced in step (1) and then concentrating the solvent.

That is, the present invention has the general formula (1)

Embedded image (In the formula, R is a fluorine atom or a C _{1 to} C ₁₀ perfluoroalkyl group) and α-substituted acrylic acid is reacted with urea in the presence of acetic anhydride to give a compound represented by the general formula (2):

[Chemical 6] (Wherein R is a fluorine atom or a C _{1 to} C ₁₀ perfluoroalkyl group) in the method for producing 5-substituted dihydrouracils, characterized in that the reaction mixture is treated with a mineral acid. Is a method for producing a 5-substituted dihydrouracils.

A feature of the present invention is that, surprisingly, the reaction solution obtained by condensing α-substituted acrylic acid and urea in acetic anhydride to form 5-substituted dihydrouracil is treated with an aqueous mineral acid solution. By hydrolyzing and separating only the by-product acetylurea without decomposing the target 5-substituted dihydrouracil, a high-purity 5-substituted dihydrouracil can be obtained, and special purification can be performed. It can be used in the next step without any problem.

The method of the present invention will be specifically described below. In the method of the present invention, the reaction between the α-substituted acrylic acid represented by the general formula (1) and urea is basically the same as the method described in JP-B-61-48830. Heat in and let the reaction take place. From the economical viewpoint, the amount of urea and acetic anhydride in this reaction is 1.1 to 1.5 equivalents of α-substituted acrylic acid for urea and 3-1 for acetic anhydride.
It is 0 equivalent, preferably 3 to 6 equivalents. After completion of the reaction, the solvent is distilled off as it is, and an aqueous solution of mineral acid is added to the reaction solution and dissolved by heating to hydrolyze acetylurea.

The mineral acids mentioned here are hydrochloric acid, nitric acid, phosphoric acid,
Sulfuric acid, and the concentration of the aqueous mineral acid solution added is 2-5
0%, preferably 5 to 30% is desirable. Mineral acid concentration is 2
If it is lower than 50%, the hydrolysis rate of acetylurea becomes very slow, making purification difficult. If the concentration of mineral acid exceeds 50%, 5-
Degradation of the substituted dihydrouracils becomes remarkable and the yield is reduced.

The concentration of the 5-substituted dihydrouracils when adding the aqueous mineral acid solution is preferably 10 to 30% by weight. 5
-If the concentration of the substituted dihydrouracils is lower than 10% by weight, the yield decreases due to dissolution in the mother liquor during crystallization.
If it exceeds 0% by weight, the crystal is not completely dissolved during the dissolution before crystallization, so that the insoluble content remains in the crystal after crystallization and the quality is deteriorated.

Further, the temperature during hydrolysis is 50 to 100.
° C, preferably 70-90 ° C. If the temperature is lower than 50 ° C, the hydrolysis rate of acetylurea is very slow, which makes purification difficult. If the temperature exceeds 100 ° C, the 5-substituted dihydrouracils are significantly decomposed and the yield is lowered.

The above-mentioned hydrolysis reaction solution was crystallized at 10 ° C. or lower, filtered and dried to give 5-substituted dihydrouracil at a yield of 6 with respect to the starting α-substituted acrylic acid.
Obtained at 5-70 mol%.

[0022]

The present invention will be described in more detail with reference to the following examples. Example 1 500 g of α-trifluoromethylacrylic acid (3.57
Mol), urea 320 g (5.33 mol) and acetic anhydride 18
20 g (17.83 mol) was reacted at 90 ° C. for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure to 1200 g. 1350 g of 3.6% hydrochloric acid was added here, it melt | dissolved at 80 degreeC, and it hold | maintained for 1 hour. Then, the reaction solution is cooled to 5 ° C.
After being crystallized for 2 hours, the crystals were filtered and washed with 600 g of water at 5 ° C. This was dried to obtain 418 g of 5-trifluoromethyldihydrouracil (yield 64.0%). Purity 99.5% m.p. p. 202-205 ° C (decomposition) (literature value 203-2
05 ° C (decomposition) IR (KBr): 3700 to 2800 cm ^-1 (ν
_NH ) 1750,1710 cm ^-1 (ν _{C = o} ) ¹ H NMR (d ₆ -acetone: TMS): δ 3.4-
4.2 (m, 3H) 7.0 (bs, 1H) 9.5 (bs, 1H) ¹⁹ F NMR (d ₆ -acetone: CFCl ₃ ): δ −6
6.6 (m)

Comparative Example 1 100 g (0.71) of α-trifluoromethylacrylic acid
Mol), urea 56 g (0.93 mol) and acetic anhydride 362
g (3.55 mol) was reacted at 90 ° C. for 1 hour. After completion of the reaction, the reaction solution was cooled, crystals were precipitated at 5 ° C for 1 hour, the crystals were collected by filtration, and washed with 100g of water at 5 ° C. This was dried to obtain 117 g of 5-trifluoromethyldihydrouracil (yield 49.8%). Purity 55.0%

Example 2 200 g (1.43) of α-trifluoromethylacrylic acid
Mol), urea 112 g (1.87 mol) and acetic anhydride 51
5 g (5.04 mol) was reacted at 90 ° C. for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to 500 g. 600 g of 10% sulfuric acid was added thereto, dissolved at 80 ° C., and kept for 1 hour. After that, the reaction solution was cooled and crystallized at 5 ° C. for 2 hours, the crystals were filtered, and washed with 120 g of water at 5 ° C. This was dried to obtain 175 g (yield 67.0%) of 5-trifluoromethyldihydrouracil. 99.6% purity

Example 3 200 g (1.43) of α-trifluoromethylacrylic acid
Mol), urea 125 g (2.08 mol) and acetic anhydride 51
5 g (5.04 mol) was reacted at 85 ° C. for 1.5 hours. After the reaction was completed, it was concentrated under reduced pressure to 500 g.
600 g of 10% hydrochloric acid was added thereto, dissolved at 80 ° C. and kept for 1 hour. After that, the reaction solution was cooled and crystallized at 5 ° C. for 2 hours, the crystals were filtered, and washed with 120 g of water at 5 ° C. This was dried to obtain 174 g (yield 66.5%) of 5-trifluoromethyldihydrouracil. Purity 99.5%

Reference Example 1 5-trifluoromethyldihydrouracil (purity 99.5%) 184 g (1.0 mol) produced by the method of Example 1, 98% sulfuric acid 5 g (0.05 mol), iodine 12.
8 g (0.05 mol), dimethyl sulfoxide 400 g
Was reacted at 130 ° C. for 10 hours. After the reaction, water 700
g, 250 g of a saturated sodium sulfite aqueous solution, and 180 g of a saturated sodium hydrogen carbonate aqueous solution were sequentially added. After heating and distilling for 1 hour, insoluble matter was removed by hot filtration, and the obtained solution was cooled and crystallized at 5 ° C. for 1 hour. The crystals were collected by filtration and dried to give 145 g of trifluorothymine (yield 77.3).
%)Obtained. Purity 96.0% m.p. p. 239~240 ℃ IR (KBr): 1740,1707cm -1 (ν C = O) 1 H NMR (d 6 - acetone: TMS): δ8.0 (b
s, 1H) 10.4 (bs, 1H) ¹⁹ F NMR (d ₆ -acetone: CFCl ₃ ): δ −6
3.0 (d, J = 1)

Reference Example 2 100 g (0.30 mol) of 5-trifluoromethyldihydrouracil (purity 55.0%) produced by the method of Comparative Example 2, 1.5 g (0.015 mol) of 98% sulfuric acid, iodine 3.8 g (0.015 mol), dimethyl sulfoxide 1
20 g was reacted at 130 ° C. for 10 hours. After the reaction, water 2
10 g of saturated sodium sulfite aqueous solution 75 g and saturated sodium carbonate aqueous solution 54 g were sequentially added. After heating and distilling for 1 hour, insoluble matter was removed by hot filtration, and the obtained solution was cooled and crystallized at 5 ° C. The crystals were collected by filtration and dried to obtain 43 g (yield 73.2%) of trifluorothymine. Purity 92.0% 5-Trifluoromethyldihydrouracil 4.2%

[0028]

INDUSTRIAL APPLICABILITY As described above, in the method for producing 5-substituted dihydrouracil, α-substituted acrylic acid and urea are condensed in acetic anhydride, the solvent is concentrated, and then acetylurea is added in a mineral acid aqueous solution. Is hydrolyzed and the liquid is cooled to precipitate the 5-substituted dihydrouracil, whereby a highly pure 5-substituted dihydrouracil can be produced by hydrolysis without lowering the yield. The resulting 5-substituted dihydrouracil is a highly pure product with a purity of 99% or more.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Ryuichi Mita 3-5 Kasumigaseki 3-chome, Chiyoda-ku, Tokyo Mitsui Toatsu Chemical Co., Ltd.

Claims (2)

[Claims] 1. A general formula (1): (Wherein, R is a fluorine atom or a C _{1 to} C ₁₀ perfluoroalkyl group) and α-substituted acrylic acid is reacted with urea in the presence of acetic anhydride to give a compound represented by the general formula (2): (Wherein R is a fluorine atom or a C _{1 to} C ₁₀ perfluoroalkyl group) in the method for producing 5-substituted dihydrouracils, characterized in that the reaction mixture is treated with a mineral acid. A method for producing 5-substituted dihydrouracils. 2. The method according to claim 1, wherein the mineral acid is selected from the group of hydrochloric acid, nitric acid, phosphoric acid or sulfuric acid.