JP2001302644A - Method for producing 5-perfluoroalkyldihydrouracil derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for stably producing a 5- perfluoromethyldihydrouracil derivative in high yield. SOLUTION: This method for producing the 5-perfluoroalkyldihydrouracil derivative represented by general formula (3) (wherein, R1 and R2 are each independently a hydrogen atom or a lower alkyl group) is characterized in that an α-perfluoroalkylacrylic acid represented by general formula (2) (wherein, Rf is a 1-10C perfluoroalkyl group) is reacted with a mixture of a carboxylic anhydride, a urea derivative, and aromatic hydrocarbons or aliphatic hydrocarbons which may be substituted.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a compound of the general formula (3) useful as a raw material for pharmaceuticals.

[0002]

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Wherein R1 and R2 each independently represent a hydrogen atom or a lower alkyl group, and Rf represents a perfluoroalkyl group having 1 to 10 carbon atoms.
The present invention relates to a method for producing a perfluoroalkyldihydrouracil derivative.

[0004]

2. Description of the Related Art A 5-perfluoroalkyldihydrouracil derivative is obtained by an elimination reaction of a hydrogen group at the 5- or 6-position.
It can be derived to a perfluoroalkyluracil derivative. These 5-perfluoroalkyluracil derivatives are not only compounds having physiological activity themselves, but also important compounds as pharmaceutical intermediates of 5-perfluorouridine derivatives known as anticancer drugs and antiviral drugs.

Conventionally, 5-perfluoroalkyldihydrouracil derivatives have been prepared by (1) using perfluoroalkylmethyl ketone as cyanohydrin, acetylation and thermal decomposition to obtain α-perfluoroalkylacrylonitrile as methanol. , A compound obtained by reacting with hydrogen bromide to form β-bromo-α-perfluoroalkylpropionamide and then reacting with urea or acetylurea in hydrochloric acid [C.
erger, DG Parsons and DCRemy, J. Med.Chem., 7, 1 (196
4)], (2) a method of reacting 2-halo-3,3,3-trifluoropropene, a urea derivative and carbon monoxide in the presence of a catalyst [Japanese Patent Laid-Open No. 58-174371], (3)
a method of reacting an α-perfluoroalkylacrylic acid with a urea derivative [Japanese Patent Publication No. 61-48830],
(4) a method of reacting α-perfluoroalkylacrylic acid with a urea derivative in the presence of acetic anhydride or carboxylic anhydride [JP-A-60-19977],

(5) A method of reacting 2-hydroxymethyl-3,3,3-trifluoropropionic acid with urea in the presence of acetic anhydride [JP-A-61-254538],
(6) A method of sequentially adding α-perfluoroalkylacrylic acid to a urea derivative in the presence of acetic anhydride and reacting while removing generated acetic acid out of the system [Japanese Patent Laid-Open No. 11-49]
No. 757]. However, in the method (1), the number of steps is long and the yield is as low as 7 to 16%.
It cannot be called an industrial manufacturing method. In the method (2), the yield of the 5-perfluoroalkyldihydrouracil derivative is not always high, and is not satisfactory as an industrial production method.

In the method (3), an expensive condensing agent such as dicyclohexylcarbodiimide is required for the condensation reaction between α-perfluoroalkylacrylic acid and a urea derivative.
In addition, after the reaction, an operation of separating a by-product derived from dicyclohexylcarbodiimide is required, which is industrially inadequate.

In the method (5), since the synthesis is carried out from available α-perfluoroalkylacrylic acid through two steps, the number of steps becomes long and the production method is insufficient in terms of economy and overall yield.

The method (4) describes that the desired 5-perfluoroalkyldihydrouracil derivative can be obtained in a relatively high yield of 65 to 70%. As shown in the above, there is a problem that acetyl urea, which is an impurity, remains in crystals without being decomposed in mass synthesis, thereby lowering the purity of the obtained crystals.

Further, it is described that in the method (6), the heat of reaction is controlled and the desired 5-perfluoroalkyldihydrouracil derivative can be obtained in a relatively high yield of 68.5 to 82.8%. I have. However, in this method, the yield of the target product must be reduced unless the acetic acid generated is removed outside the system. Therefore, an apparatus for removing acetic acid is required, and equipment costs are required. The publication also states that by reacting while removing acetic acid generated in the reaction system, the production of acetyl urea as a by-product can be suppressed. Since it takes time, most of the raw urea is converted into acetyl urea during that time, and it has been found that it is actually difficult to control the acetyl urea generated when the temperature is raised.

Further, JP-A-11-49757 (6) discloses a method in which an acetic anhydride solution of α-perfluoroalkylacrylic acid and an acetic anhydride solution of a urea derivative are sequentially added to a solvent of acetic anhydride. Has been described. However, in this method, although the production of acetylurea is suppressed, the solubility of the urea derivative in acetic anhydride is low,
Because of problems such as poor volumetric efficiency, it is difficult to say that this method is preferable as an industrial production method.

[0012]

Accordingly, an object of the present invention is to provide a method for producing a 5-perfluoromethyldihydrouracil derivative, which is intended to produce the desired product in a stable and high yield on an industrial scale. Is to provide a way to obtain

[0013]

Means for Solving the Problems The present inventors have conducted intensive studies in order to solve the above problems, and as a result, when α-perfluoroalkylacrylic acid is reacted with a carboxylic acid anhydride or a urea derivative, If aromatic hydrocarbons or aliphatic hydrocarbons that may be present are present in advance, the solubility of the urea derivative in carboxylic acid anhydride is reduced, and the reactivity between the urea derivative and carboxylic acid anhydride is reduced. However, they have found that the formation of a reaction product between a urea derivative as a by-product and a carboxylic anhydride can be suppressed. From the above, it was found that a side reaction of a urea derivative as a raw material was prevented, and it was found that the desired 5-perfluoromethyldihydrouracil derivative could be stably produced at a high yield on an industrial scale, and the present invention was completed. Was. That is, the present invention relates to [1] a carboxylic anhydride and a compound represented by the general formula (1)

[0014]

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(Wherein R 1 and R 2 each independently represent a hydrogen atom or a lower alkyl group), and an optionally substituted aromatic or aliphatic hydrocarbon. In a mixture with a compound represented by the general formula (2):

[0016]

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Wherein Rf represents a perfluoroalkyl group having 1 to 10 carbon atoms, wherein α-perfluoroalkylacrylic acid represented by the following formula is reacted:
General formula (3)

[0018]

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(Wherein R1, R2 and Rf have the same meanings as described above), and a method for producing a 5-perfluoroalkyldihydrouracil derivative represented by the formula:
[2] The process according to [1], wherein Rf is a trifluoromethyl group, and [3] the optionally substituted aromatic or aliphatic hydrocarbon is toluene [1].
Or the production method according to [2].

[0020]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
The aromatic hydrocarbons or aliphatic hydrocarbons which may be substituted in the present invention may be any as long as they reduce the solubility of urea derivatives in carboxylic acid anhydrides, for example, benzene, toluene, xylene, Mesitylene, ethylbenzene, anisole, cresol, chlorobenzene, dichlorobenzene, bromobenzene, benzonitrile, hexane, heptane, octane, nonane, decane,
Examples thereof include petroleum ether and digroin. Preferably, toluene is used.

In the formulas (2) and (3), Rf is
An α-perfluoroalkyl group having 1 to 10 carbon atoms,
For example, trifluoromethyl group, pentafluoromethyl group, heptafluoropropyl group, nonafluorobutyl group, heptafluoro-iso-propyl group, nonafluoro-iso-butyl group, nonafluoro-sec-butyl group, nonafluoro-tert-butyl group , Dodecafluoropentyl group and the like. Particularly, a trifluoromethyl group is preferable. The purity of the α-perfluoroalkylacrylic acid is not particularly limited, but it is preferable to use one having a purity of 95% or more.

The urea derivative in the present invention is a compound represented by the above general formula (1), wherein R1, R2
Represents a hydrogen atom and a lower alkyl group each independently.
Specific examples include urea, methyl urea, ethyl urea, dimethyl urea, diethyl urea and the like.

The 5-perfluoroalkyldihydrouracil derivative, which is the object of the present invention, is a compound represented by the general formula (3). Specifically, for example, 5-trifluoromethyldihydrouracil, -Methyl-5-trifluorodihydrouracil, 3-methyl-5-trifluorodihydrouracil, 1,3-dimethyl-5-trifluorodihydrouracil, 5-pentafluoroethyldihydrouracil, 5-heptafluoropropyldihydrouracil, 5-heptafluoro-iso
-Propyldihydrouracil and the like.

Examples of the carboxylic anhydride used in the present invention include acetic anhydride, formic anhydride, trifluoroacetic anhydride, propionic anhydride, benzoic anhydride, succinic anhydride, glutaric anhydride and the like. Preferably, acetic anhydride is used, and ordinary commercial products can be used. The amount of the carboxylic anhydride to be used is generally 1 to 10 equivalents, preferably 2 to 6 equivalents, relative to α-perfluoroalkylacrylic acid. When the amount is more than 10 equivalents, the reactor becomes large, which is not economically preferable.

The amount of the urea derivative used is usually 1 to 10 equivalents to the α-perfluoroalkylacrylic acid used,
Preferably it is 1.5 to 3 equivalents. The urea derivative is
In the carboxylic acid anhydride liquid after the temperature rise, it may be charged at once as a solution or a slurry liquid.
There is no particular limitation. The amount of the aromatic hydrocarbons or aliphatic hydrocarbons which may be added is not particularly limited as long as it does not affect the reaction, but is usually 0.1 to 5% by weight based on the carboxylic anhydride. Times, preferably 0.5-3
Weight times.

In the present invention, the α-perfluoroalkylacrylic acid can be added as it is, or can be added by dissolving it in a carboxylic anhydride or an optionally substituted aromatic or aliphatic hydrocarbon. . In the case of dissolution, the carboxylic acid anhydride or the optionally substituted aromatic hydrocarbon or aliphatic hydrocarbon is usually 0.3 to 10 times by weight, preferably 0 to 10 times by weight based on α-perfluoroalkylacrylic acid. 0.5 to 3 times by weight.

The temperature at which the α-perfluoroalkylacrylic acid or a solution thereof is added is usually from 60 ° C. to 110 ° C.
° C or lower, preferably 70 ° C or higher and 105 ° C or lower. The time for addition is usually 0.1 to 5 hours. Here, when mass-producing on an industrial scale, it usually takes 3 to 6 hours to raise the temperature before adding the α-perfluoroalkylacrylic acid or a solution thereof. Note that this time is not particularly limited because it varies depending on the heating capacity and the scale of the reactor. The reaction temperature after the addition of the α-perfluoroalkylacrylic acid is from 60 ° C to 110 ° C, preferably from 70 ° C to 105 ° C. A reaction time of usually 0.5 to 5 hours is sufficient.

The thus obtained 5-perfluoroalkyldihydrouracil derivative can be recovered from the reaction solution by a usual separation method. For example, the reaction solution is depressurized by a vacuum pump, and carboxylic anhydride, added aromatic hydrocarbons or aliphatic hydrocarbons which may be substituted, and carboxylic acid are distilled off to obtain a concentrated reaction mother liquor. Ethanol, dilute hydrochloric acid, or dilute sulfuric acid aqueous solution is added to the concentrated reaction mother liquor, heated, and then cooled, whereby a desired 5-perfluoroalkyldihydrouracil derivative is crystallized.

The amount of the ethanol, dilute hydrochloric acid or dilute sulfuric acid aqueous solution to be added is preferably adjusted so that the concentration of the 5-perfluoroalkyldihydrouracil derivative is usually 5% by weight or more and 40% by weight or less. The crystallization temperature is usually -10 ° C
The temperature is preferably from 50 ° C to 50 ° C, more preferably from -10 ° C to 30 ° C. The crystallized 5-perfluoroalkyldihydrouracil derivative is filtered and dried to obtain the desired 5-perfluoroalkyldihydrouracil derivative.
-A perfluoroalkyldihydrouracil derivative (primary crystal) can be obtained in high yield. Further, the mother liquor is concentrated, for example, under reduced pressure and recrystallized to obtain a 5-perfluoroalkyldihydrouracil derivative (secondary crystal).

[0030]

Hereinafter, the present invention will be described in detail with reference to Examples.
The present invention is not limited to these. Example 1 85.8 g (1.43 mol) of urea, 294 g of acetic anhydride
(2.88 mol), and a mixture of 143.9 g of toluene was heated to 90 ° C. while stirring. Here the reaction temperature is 85
A solution of 100 g (0.71 mol) of trifluoromethylacrylic acid in 240 g of toluene was added while the temperature was maintained at from 95 ° C to 95 ° C, and the reaction solution was stirred for 2 hours. The obtained reaction mass was analyzed by HPLC, and the target 5-trifluoromethyldihydrouracil was obtained with a reaction yield of 84.3%. After concentrating the reaction mass under reduced pressure, 611.4 g of a 2.5% aqueous sulfuric acid solution was used.
The mixture was heated and stirred at 80 ° C. for 5 hours, cooled to 2 ° C., and the formed crystals were filtered and dried to give 5% of 99% content.
97.5 g of trifluoromethyldihydrouracil (primary crystals) were obtained. The mother liquor was further concentrated under reduced pressure and crystallized to give 5-trifluoromethyldihydrouracil (2
Next crystal (11 g) was obtained. The total yield of 5-trifluoromethyldihydrouracil including the primary crystal and the secondary crystal was 83.1%. The amount of acetylurea produced is 33.5.
g (0.33 mol, 23 mol% / urea). m. p: 203-205 ° C ¹ H-NMR (d6-DMSO, TMS): 3.4-
4.0 (m, 3H).

Example 2 Urea 4.29 g (0.071 mol), acetic anhydride 14.7
g (0.14 mol) and 7.5 g of toluene were heated to 90 ° C. while stirring. At this time, it took 2 hours to raise the temperature to 90 ° C. While maintaining the reaction temperature at 85 ° C to 95 ° C, trifluoromethylacrylic acid 5
g (0.036 mol) of a solution of 12 g of toluene,
The reaction was stirred for 2 hours. The obtained reaction mass is analyzed by HPLC.
And the target 5-trifluoromethyldihydrouracil was obtained with a reaction yield of 82.1%. The production amount of acetyl urea was 1.81 g (0.018 mol, 25 mol% / urea).

Example 3 17.1 g (0.29 mol) of urea, 48 g of acetic anhydride
(0.47 mol) and a mixture of 7.5 g of toluene was heated to 90 ° C. while stirring. At this time, it took 2 hours to raise the temperature to 90 ° C. While maintaining the reaction temperature at 85 ° C to 95 ° C, trifluoromethylacrylic acid 20
g (0.14 mol) of acetic anhydride 28 g (0.27 mol)
Was added and the reaction was stirred for 2 hours. The obtained reaction mass was analyzed by HPLC, and the target 5-trifluoromethyldihydrouracil was obtained with a reaction yield of 80.5%.
The amount of acetylurea produced was 7.4 g (0.073 mol, 2
5 mol% / urea).

Comparative Example 1 17.2 g (0.29 mol) of urea, 58.8 g of acetic anhydride
(0.58 mol) was heated to 90 ° C. while stirring. At this time, it took 2 hours to raise the temperature to 90 ° C. At this time, the reaction temperature is raised from 85 ° C. to 90 until 90.
20 g of trifluoromethyl acrylic acid while keeping at 5 ° C
(0.14 mol) of a solution of 48 g of toluene was added, and the reaction solution was stirred for 2 hours. The obtained reaction mass was analyzed by HPLC, and the target 5-trifluoromethyldihydrouracil was obtained with a reaction yield of 57.9%. The production amount of acetyl urea was 15.8 g (0.15 mol, 53.3 mol% / urea).

Reference Example 1 14.1 g (0.23 mol) of urea, 48 g of acetic anhydride
(0.47 mol), toluene was added under the conditions shown in the table below, and the mixture was heated and stirred at 85 to 90 ° C., and the change over time in the production rate of acetylurea was measured by HPLC. Table 1 shows the results.

[0035]

[Table 1]

The results in Table 1 also show that the presence of toluene suppresses the production of acetylurea.

[0037]

As is clear from the above Examples, Comparative Examples and Reference Examples, the present invention provides urea derivatives, carboxylic anhydrides, aromatic hydrocarbons and aliphatic hydrocarbons which may be substituted. By adding α-perfluoroalkylacrylic acid to the mixture of the above and reacting the mixture, by-products generated from the urea derivative can be suppressed, and industrial production can be performed simply, with high yield, and stably.

Claims (3)

[Claims] 1. A carboxylic anhydride and a compound represented by the general formula (1): (Wherein, R1 and R2 each independently represent a hydrogen atom or a lower alkyl group.) And an aromatic hydrocarbon or an aliphatic hydrocarbon which may be substituted. In the mixture, the compound represented by the general formula (2) Wherein Rf represents a perfluoroalkyl group having 1 to 10 carbon atoms, wherein α-perfluoroalkylacrylic acid represented by the general formula (3) is reacted:
[Formula 3] [Formula 3] (In the formula, R1, R2 and Rf have the same meanings as described above.) A method for producing a 5-perfluoroalkyldihydrouracil derivative represented by the formula: 2. The method according to claim 1, wherein Rf is a trifluoromethyl group. 3. The production method according to claim 1, wherein the optionally substituted aromatic hydrocarbon or aliphatic hydrocarbon is toluene.