HU188027B - Process for producing 5-substituted uracil-derivatives - Google Patents

Abstract

The invention relates to a process for the preparation of 5- or 1,5-di-substituted uracyl derivatives of the formula Iworin, for example: R is an alkyl group having 1-10 carbon atoms, an optionally substituted carboxyl group u. R1, hydrogen, an alkenyl or alkynyl group having 2-10 carbon atoms and the like; a.Ziel the invention is to provide a simple and economical process for the production on an industrial scale. According to the invention, for example, a geminal dihalocarboxylic acid halide of the general formula II is reacted with a urea derivative of the general formula (III) and the resulting acylated urea derivative of the general formula (IV) cyclized in an alkanol having 1-4 carbon atoms with an alkali metal hydroxide under heating dehalogenated

Description

(57) EXTRAS

The present invention relates to a novel industrial process for the preparation of 5-substituted uracil derivatives of formula (I) wherein R is alkyl, phenyl or phenylalkyl. According to the invention, the process is carried out by:

a) reacting a dihalocarboxylic acid halide with urea and then cyclizing the resulting acylated urea derivative in a C 1 -C 4 alkanol by heating with an alkali metal hydroxide, or

b) reacting an acryloyl urea derivative in an inert organic solvent with an elemental halide of formula Xi and then cyclizing the resulting dihaloacyl urea derivative in a C 1-4 alkanol by heating with an alkali metal hydroxide, or

c) cyclization of a dihaloacyl urea derivative in a C 1 -C 4 alkanol by dehalogenation under heating with an alkali metal hydroxide. The compounds of the formula I have antiviral and anticancer activity.

The present invention relates to a novel industrial process for the preparation of 5-substituted uracil derivatives of formula I wherein

H

R is C 1 -C 10 alkyl, phenyl or phenyl (C 1 -C 4) alkyl.

Known (C. Heidelberger, "Cancer Medicine," J. F. Holland and Frei, eds., Lee and Febiger, Philadelphia, 1973, p. 768; E. De Clark, J. Descamps, P. J. Barr, A. Jones, P. Serafinowski, R.J. Walker, GF Huang, PF Torrence, CL Schmidt, P. Mertes, T. Kulikowski and D. Shugar, "Antimetabolites in Biochemistry, Biology and Medicine", J. Skoda and P. Lángén, eds, Pergamon Press, Oxford, 1978, p. 275; Proc. Natl. Acad. Sci., USA, 76, 2947 (1979); Biochem. Pharmacol., 25, 1233 (1976); FEBS Letters, 40, Supplement, S48 (1974)]. Certain 5-substituted uracil derivatives have anticancer and antiviral activity. Some 5-substituted orocic acid derivatives are also known to inhibit pyrimidine biosynthesis (Theoret. Bioi., 26, 19 (1970); Collect. Czech. Chem. Commun., 3, 1778 (1968)] Based on their biological activity, these compounds are active in anticancer, antiviral and antibacterial pharmaceutical compositions. can be used.

Several laboratory procedures are known for the preparation of compounds of the formula I. A J. A. C. S., 55, 1733-35. (1933) describes the preparation of thymine (R in the formula I) starting from a-cyanopropionic acid. This is heated with urea in the presence of acetic anhydride to give α-cyanopropionyl urea. The a-cyanopropionyl urea is hydrogenated in a warm aqueous medium in the presence of a platinum catalyst and, after removal of the catalyst, the reaction mixture is acidified to give thymine. The industrialization of the process is made very difficult by the hydrogenation step.

A. J. A. C. S 68, 912-13. (1946) discloses an improved process for the preparation of thymine. From diethyloxalate and ethyl propionate, Claisen condensation is used to make ethyl ethoxalyl propionate, which is reduced in the presence of platinum oxide under hydrogen atmosphere, the resulting diethyl 3-methyl malate is hydrolyzed and the free 3-methyl malic acid obtained is condensed with fuming carboxylic acid. The industrial realization of this process is severely hampered by both hydrogenation in the presence of platinum oxide and condensation of fuming sulfuric acid.

J. Chem. Soc., 157-161. (1958) further describes a process for the preparation of uracil and thymine analogs. The starting material is β-alkoxy acryloyl isocyanate and β-alkoxy α2 methyl acryloyl isocyanate. They are prepared from appropriately substituted acrylic acid chloride with silver cyanate. The resulting isocyanates are highly reactive and decomposable. According to the process described, they are reacted with primary amines to produce the corresponding N '- (β-alkoxyacryloyl) -N-substituted urea, which is then cyclized by heating in aqueous methylamine, ammonia or sodium hydroxide. The process is not industrially applicable because it makes silver cyanate very expensive and the degradability of the intermediate can cause significant production losses.

Urea and ethyl (β-formyl) propionate and ethyl (β-formyl) butyrate are produced in a fuming sulfuric acid medium with ethyl and uracil in 50% and 41% yield, respectively. Lags. Nauk. SSSR Ger. Khim., 1968 (4), 918-920. and Article 197,597. Soviet Patent Specification. The industrial application of the process is made very difficult by the fuming sulfuric acid medium.

6-Chloro-5-substituted-uracil is prepared from 5-substituted barbituric acid in the presence of water with phosphorus oxychloride or thionyl chloride and then reduced to thymine analogues by known methods. according to a disclosure document in the Federal Republic of Germany. The industrial application here is also questioned by the corrosive medium.

Thymine is prepared from α-methyl acryloyl urea using lithium palladium chloride as a catalyst in Chem. Ind. (London), 11, 485-86. (1976). The process would be expensive to use under industrial conditions due to the catalyst used.

No. 81,34,671. Japanese Patent Laid-open Publication No. 3,684,011 discloses a process for preparing thymine from ethyl (α-formyl) propionate. According to this, ethyl (aformyl) propionate is reacted with urea in methanolic hydrochloric acid at 50 ° C for 4 hours, and the resulting oil is heated in methanol with sodium methylate at 100 ° C for 4 hours. The process is complicated by the fact that the sodium methylate reaction is carried out in anhydrous medium.

A J. A. C. S., 74, 2432-34. (1952) make thiothymine from ethyl (P, P-diethoxy-α-methyl) propionate and thiourea in the presence of sodium ethoxide in anhydrous medium. The difficulty here again is the need for an anhydrous medium and the product even having to be desulfurized, for example by treatment with hydrogen peroxide.

It will be appreciated that none of the processes known to date permit the economical, simple industrial preparation of thymine or substituted uracil derivatives of formula (I).

It is an object of the present invention to provide a process which allows the industrial preparation of the compounds of formula I under simple reaction conditions.

Surprisingly, it has been found that the compounds of formula I can be readily prepared industrially if

a) a dihalocarboxylic acid halide of formula II - wherein R is as defined above,

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X ¹ X '

CH ₂ - C ^- C0 ^- X ode R

X ¹ and X ^{2 are} halogen - reacted with urea in an aprotic polar organic solvent and the resulting acylated

X ¹ X '

CH, -C-CO-NH-CO-NH ₂ (Uh I

The urea K, wherein R and X * are as defined above, is cyclized by dehalogenation in a C 1 -C 4 alkanol with heating with an alkali metal hydroxide, or

b) an acryloylurea derivative of the Formula IV wherein R is

CH ₂ = CR-CO-NH-CO-NH ₂ (IV) is reacted with an elemental halogen of formula Xj in the above inert organic solvent and then the acylated urea derivative of formula (III) - wherein R and X ¹ are above - is cyclized by dehalogenation in a C 1-4 alkanol by heating with an alkali metal hydroxide, or

c) cyclization of an acylated urea derivative of formula III wherein R and X ¹ are as defined above in a C 1 -C 4 alkanol by heating with an alkali metal hydroxide.

The dihalocarboxylic acid halides of formula (II) may be prepared from the acrylic acid derivatives having the R substituent. In the first step, they are reacted with an elemental halogen of formula X ₂ , for example as described in process b), to give the corresponding dihalocarboxylic acid and then converted into the corresponding acid halide by reaction with halogenating agents in a manner known per se.

The acryloylurea derivatives of formula (IV) may be prepared from the corresponding substituted acrylic acid ester and alkali metal derivatives of urea in a manner known per se. Of course, it is also possible to react a corresponding substituted acrylic acid halide with urea, for example as described in process a).

C 1 -C 10 alkyl is understood to mean straight-chain or branched chain groups having free valence at any point.

Examples include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl, and where appropriate the straight and branched chain isomers thereof, and their normal, secondary, and secondary isomers. - and tertiary representatives.

Preferred C 1 -C 10 alkyl groups are C 1 -C 4 alkyl groups. These include, for example, methyl, ethyl, n- and i-propyl, η, i, chair and tert-butyl.

The halogen atoms represented by X ¹ and X ² are preferably chlorine or bromine.

C 1 -C 4 alkanols may contain one of the C 1 -C 4 alkyl groups defined above. Preferred are methanol and ethanol.

Preferred alkali metal hydroxides are sodium hydroxide and potassium hydroxide.

A preferred representative of aprotic polar solvents is acetonitrile.

Further details of the present invention are illustrated by the following non-limiting examples.

Example 1 is # -Dibromo-α-methylpropionylurea

2.6 g (0.21 mol) of urea are suspended in 100 ml of acetonitrile and 26.4 g (0.1 mol) of α, β-dibromo-α-methylpropionyl chloride are added dropwise with stirring at room temperature. After addition, the reaction mixture was stirred for 1 hour at room temperature and for 1 hour at 50 ° C, and then heated under reflux for 2 hours. The solvent was distilled off, and the resulting crystalline mass was mixed with 50 ml of water, filtered, covered with water and then with ethanol and finally dried. 24.8 g (86.1%) of the title compound are obtained. 134-136'C.

Example 2 α, β-Dibromo-α-ethylpropionylurea

18.6 g (0.31 mol) of urea are suspended in 100 ml of acetonitrile and 27.85 g (0.1 mol) of α, β-dibromo-α-ethylpropionyl chloride are added dropwise with stirring at room temperature. After addition, the reaction mixture was stirred at room temperature for 2 hours and at 50 ° C for 2 hours and then heated under reflux for 5 hours. The solvent was distilled off and the resulting oily residue was taken up in 50 ml of water and extracted with ethyl acetate. The ethyl acetate solution was washed neutral with saturated sodium bicarbonate solution and then with distilled water, dried over anhydrous sodium sulfate, and evaporated. The residual dense oil crystallizes on cooling

26.3 g (87%) of the title compound are obtained. 98-103'C.

Example J 5-Melyl-uracil

A solution of 28.8 g (0.1 mol) of α, β-dibromo-α-methylpropionyl urea in 240 ml of ethanol was added / sprayed into 16.8 g (0.3 mol) of potassium hydrovide

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250 ml of ethanol at 40 ° C with stirring. The reaction mixture was stirred at this temperature for 1 hour and then heated under reflux for 2 hours. After cooling, the precipitated crystals are filtered off and dissolved in 40 ml of water. The resulting solution was acidified to pH 2 with concentrated hydrochloric acid and cooled with ice water. The precipitated crystals of the title compound are filtered off, washed with a little water and then with ethanol and dried. 8.26 g (65.55%) of the title compound are obtained. Mp: 318-322 ° C.

Example 4 5-Methyl-uracil

A solution of α, β-dibromo-α-methylpropionyl urea (14.4 g, 0.05 mol) in methanol (100 ml) was added dropwise with stirring at 45 ° C, potassium hydroxide (8.4 g, 0.15 mol) in methanol (100 ml). added. The reaction mixture is stirred at this temperature for 1 hour, then refluxed for 3 hours, cooled, the precipitated salts are filtered off and dissolved in 30 ml of water. The resulting solution was acidified to pH 2 with concentrated hydrochloric acid, cooled and the precipitated title compound was filtered off, washed with a little water, covered with ethanol and dried. 4.9 g (77%) of the title compound are obtained. 317-320 'C.

Example 5 5-Methyl-uracil

A solution of α, β-dibromo-α-methylpropionylurea (28.8 g, 0.1 mol) in ethanol (240 mL) was added dropwise to a stirred solution of 4.6 g of sodium metal in 200 mL of ethanol at 40 ° C. The reaction mixture was stirred at this temperature for 1 hour and then heated under reflux for 2 hours. After cooling, the precipitated salts are filtered off, dissolved in 30 ml of water and the pH of the solution is adjusted to 2 with concentrated hydrochloric acid. The solution is cooled, the crystals of the excellent title compound are filtered off, washed with a little water and ethanol, and dried. 10.52 g of the title compound are obtained (83.5%). 320-322 'C.

Example 6 5-Methyl-uracil

A solution of α, β-dichloro-α-methylpropionyl urea (19.9 g, 0.1 mole) in ethanol (200 ml) was added dropwise, with stirring at 40 ° C, to potassium hydroxide (16.8 g, 0.3 mole) in ethanol (250 ml). added. The reaction mixture was stirred at this temperature for 1 hour and then heated under reflux for 2 hours. After cooling, the precipitated salts are filtered off, dissolved in 30 ml of water, adjusted to pH 2 with concentrated hydrochloric acid, and after cooling, the precipitated title compound is filtered off, washed with a little water, ethanol and dried. 82 g (54.1%) of the title compound are obtained. 315-318 'C.

Example 7 5-Methyl-uracil

A solution of α, β-dichloro-α-methylpropionyl urea (19.9 g, 0.1 mol) in methanol (100 ml) was added dropwise with stirring at 45 ° C to a solution of sodium hydroxide (12.0 g, 0.3 mol) in methanol (150 ml). added. The reaction mixture was stirred at this temperature for 1 hour and then heated under reflux for 3 hours. After cooling, the precipitated salts are filtered off, washed with 30 ml of water and ethanol and dried. 7.09 g (56.2%) of the title compound are obtained. 316-320 'C. After concentration, the crystals of the title compound precipitated after repeated cooling, washed with a little water and ethanol, and dried. 316-320 'C.

Example 8 5-Ethyl-uracil

A solution of α, β-dibromo-α-ethylpropionyl urea (30.2 g, 0.1 mol) in ethanol (100 ml) was added dropwise with potassium hydroxide (16.8 g, 0.3 mol) in ethanol (100 ml) at 40 ° C. added. The reaction mixture was refluxed for 1 hour and then refluxed for 3 hours. After cooling, the precipitated salts are filtered off, dissolved in 80 ml of water, the pH of the solution is adjusted to 2 with concentrated hydrochloric acid, and after repeated cooling, the crystals of the title compound are filtered off, washed with a little water, ethanol and dried. 8.32 g (59.42%) of the title compound are obtained. Mp: 301-304 'C.

Example 9 5-Ethyl-uracil

A solution of α, β-dibromo-α-ethylpropionyl urea (15.1 g, 0.05 mol) in methanol (50 ml) was added dropwise at 45 ° C with stirring.

8.4 g (0.15 mol) of potassium hydroxide in 100 ml of methanol. The reaction mixture was stirred at this temperature for an additional hour and then refluxed for 2 hours. After cooling, the precipitated salts are filtered off, dissolved in 30 ml of water, and the solution is adjusted to pH 2 with concentrated hydrochloric acid. Upon repeated cooling, the title compound precipitates. It is filtered off, washed with a little water, ethanol and dried. 3.72 g (53.14%) of the title compound are obtained. 304-308 'C.

Example 10 5-Ethyl-uracil

A solution of α, β-dibromo-α-ethylpropionyl urea (30.2 g, 0.1 mol) in methanol (100 ml) was added dropwise at 45 ° C to a solution of sodium hydroxide (12 g, 0.3 mol) in methanol (150 ml). The reaction mixture was stirred at this temperature for 1 hour and then refluxed for 3 hours. Then cool, excellent

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The crystals were filtered off, dissolved in water (60 mL), and the solution was adjusted to pH 2 with concentrated hydrochloric acid and cooled again. The excellent crystals of the title compound are filtered off, washed with a little water, ethanol and dried. 10.96 g (78.2%) of the title compound are obtained. 306-310 ° C.

Example 11 α, β - Dibromo-α-isopropylpropionylurea

12.6 g (0.21 mol) of urea are suspended in 100 ml of acetonitrile and 29.25 g (0.1 mol) of α, β-dibromo-α-isopropylpropionyl chloride are added dropwise with stirring at room temperature. After addition, the mixture was stirred at room temperature for 1 hour, at 50 ° C for 1 hour and then at reflux for 2 hours. The solvent was distilled off and the crystalline residue was stirred with 50 ml of water, filtered, covered with water and then with ethanol and dried. This gave 25.8 g (81.6%) of the title compound. 141-144 ° C.

Example 12 α-Dibromo-α-methylpropionyl urea

38.4 g of α-methyl acryloyl urea are dissolved in 200 ml of carbon tetrachloride with stirring and heating. 48 g of anhydrous bromine are slowly added dropwise to the 70-72 ° C solution while stirring, always waiting for the color of the bromine to disappear. Towards the end of the reaction, crystallization begins. After the addition of bromine, the reaction mixture was stirred for an additional 30 minutes while adding 75 ml of carbon tetrachloride. After cooling the reaction mixture, the precipitated crystalline material is filtered off and dried. 83.2 g (96.5%) of the title compound are obtained. 134-136 ° C.

Example 13 α, β-Dibromo-α-ethyl-propionylurea

14.2 g of α-ethyl acryloyl urea are dissolved in 100 ml of carbon tetrachloride with stirring. To the hot solution was added dropwise 16 g of anhydrous bromine slowly with vigorous stirring. After completion of the reaction, 25 ml of carbon tetrachloride are added to the reaction mixture, cooled and the precipitated crystals are filtered off. 29.3 g (97%) of the title compound are obtained. 99-101 ° C.

1-13. The following compounds were also prepared according to the procedure described in Example 3a:

5- (n-propyl) uracil, m.p. 294-297 ° C; 5- (n-butyl) uracil, m.p. 290-292 ° C; 5- (n-hexyl) -uracil, m.p. 271-273 'C; 5- (i-propyl) uracil, m.p. 308-310 ° C; 5-benzyluracil, m.p. 293-296 ° C;

5-phenyluracil, m.p.

For the latter compound, the calculated and measured elemental composition is given as additional identification data: elemental analysis for C ₁₀ H ₈ N ₂ O ₂ :

Found: C, 63.83; H, 4.25; N, 14.89; Found: C, 63.28; H, 4.82; N, 14.73.

Patent claims

Claims (8)

A process for the preparation of 5-substituted jracyl derivatives of the formula I H wherein R is C 1 -C 10 alkyl, phenyl or phenyl (C 1 -C 4) alkyl; a) a dihalocarboxylic acid halide of formula II I '2 CH, -C-CO-X ² d i R wherein R is as defined above, X ¹ and X ^{2 are} halogen atoms - is reacted with urea in an aprotic polar organic solvent and the resulting acylated X ¹ X ¹ The urea derivative CH ₂ -C-CO-NH-CO ₂ NH ₂ R ', wherein R and X ¹ are as defined above, is dehalogenated in a C 1 -C 4 alkanol by heating with an alkali metal hydroxide, or b) an acryloylurea derivative represented by the general formula (IV) CH ₂ - CR - co - nh - conh _{2 (IV)} wherein R is as defined above, is reacted with an elemental halogen of formula X _{2 in} an inert organic solvent and the resulting acylated urea derivative of formula (III) wherein R and X * are as defined above is treated with an alkali metal cyclized by dehalogenation with hydroxide during heating, or c) cyclization of an acylated urea derivative of formula III wherein R and X ¹ are as defined above in a C 1 -C 4 alkanol by heating with an alkali metal hydroxide. Process (a) according to claim 1, characterized in that the aprotic polar solvent is acetonitrile. -53. Process (a), (b) or (c) according to claim 1, wherein the C 1 -C 4 alkanol is methanol. Process a), b) or c) according to claim 1, wherein the C 1 -C 4 alkanol is ethanol. 5. The process according to any one of claims 1 to 3, wherein the alkali metal hydroxide is sodium hydroxide. 6. The process according to any one of claims 1 to 3, wherein the alkali metal hydroxide is used. 7. Process according to any one of claims 1 to 3, characterized in that the cyclization during the dehalogenation is carried out at a temperature between 40 ° C and the boiling point of the reaction mixture. 8. A method according to any preceding claim characterized in that the dehalogenation during cyclization ⁵ X ¹ is acylated urea derivatives of formula Cl (III) - wherein R is used as defined in claim 1. 9. The method of any preceding claim wherein said acylated urea derivatives of formula cyclization during the dehalogenation X ¹ is Br (III) - wherein R is used as defined in claim 1.