The way to obtain a 6-substituted orallow

 

(57) Abstract:

The invention relates to an improved process for the preparation of 6-substituted orallow General formula I, where R = CH3WITH6H5CH2, 2,6-F2WITH6H3CH2that can be used in the pharmaceutical industry to obtain drugs. The method consists in the interaction of 6-substituted 2-thiouracil, selected from the group comprising 6-methyl-2-thiouracil, 6-benzyl-2-thiouracil, 6-(2,6-diferensial)-2-thiouracil, 2-methyloxirane in the presence of an aqueous solution of sodium hydroxide at a molar ratio of 6-substituted 2-thiouracil : 2-methyloxiran : sodium hydroxide is 1:1,0-1,2: 1, followed by acidification and isolation of the target product. The method allows to carry out the process under mild conditions, using cheap raw materials, excluding the presence of acidic waste and obtaining the target product with practically quantitative yield.

The present invention relates to the field of synthesis of heterocyclic compounds, specifically to a method for producing 6-substituted uracil derivative of the formula

< / BR>
where R = CH3WITH6H5CH2, 2,6-F2C

Known methods for producing orallow direct condensation of urea and-ketoesters.

However, these methods do not give satisfactory yield of the final product in the case of sterically shielded-ketoesters and used only for the simplest-ketoesters (for example, acetoacetic (Synthesis of organic drugs, 1949, volume 2, S. 335) and oxaloacetic acid of monoethylene ether (Chkhikvadze K. A., Britikova N. E., Magidson O. Y., GOH, 1964, volume 34, S. 161)).

A method of obtaining substituted orallow of derivatives of 2-thiouracil by acidic hydrolysis of the latter by boiling in 10% aqueous solution of Chloroacetic acid (Johnson T. C., Ambelang J. C., J. Am. Chem. Soc., 1938, v. 60, R. 2941). This method does not provide high output (6-(1-naphthylmethyl)-5-ethyluracil - about 53% (Danel, K., Nielsen, S., Pedersen E. C., Acta Chem. Scand., 1997, v. 51, p. 426)) of the reaction product, and is not applicable to the synthesis of derivatives containing acidopore group (for example, 2-tetrahydropyranyloxy-group). This requires long boiling of the reaction mixture and use a large excess of water Chloroacetic acid, which makes this method industrial unsuitable due to the large amount of hard regenerated acidic waste.

These methods are hardly applicable due to the high complexity of the synthesis and the associated lower availability and higher cost of initial substances compared with 2 torzilli.

The closest is the way to obtain a 6-substituted orallow on the basis of 6-substituted 2-thiouracil using oxidative hydrolysis of tinuloy group under the action of a 35% aqueous solution of hydrogen peroxide in an aqueous solution of alkali (Johnson T. C., Schroeder E. F., J. Am. Chem. Soc., 1931, v. 53, R. 1989).

This method despite its relative simplicity and efficiency has significant drawbacks. First, it does not apply to oxidisable compounds, and secondly, it involves the use of dangerous and unstable reagent - perhydrol. Thirdly, allows to obtain the target orally with access only 40-88% (Tanaka H., Takashima H., Ubasawa M., Sekiya, K., Nitta I. , Baba, M. , Shigeta, S., Walker, T. D., De Clerq E., T. Miyasaka, J. Med. Chem., 1992, v. 35, p. 337).

The objective of the proposed technical solution is the development of a new technological method of producing 6-substituted orallow, allowing to carry out the synthesis under mild conditions with Ispanya orally with almost quantitative yield.

The technical result is to increase the output of the claimed compounds, the simplification of the process of acquisition and allocation of final products.

This technical result is achieved in a method of producing 6-substituted orallow General formula

< / BR>
where R = CH3WITH6H5CH2, 2,6-F2C6H3CH2using 6-substituted 2-thiouracil in the presence of an aqueous solution of sodium hydroxide, characterized in that as a 6-substituted 2-thiouracil use 6-methyl-2-thiouracil, 6-benzyl-2-thiouracil or 6-(2,6-diferensial)-2-thiouracil, which is subjected to interaction with 2-methyloxirane at a molar ratio of 6-substituted 2-thiouracil : 2-methyloxiran : sodium hydroxide is 1:1.0-1.2:1, followed by separation of the target product.

The essence of the proposed method is currency ekzoticheskogo the sulfur atom of 2-thiouracil on oxygen 2-methyloxirane with the formation of the target uracil with practically quantitative yield

< / BR>
Using 2-methyloxirane for desulphurization derivatives of 2-thiouracil is unconventional. While the reaction with oxirane similarly behave Rodney, thiocarbamide and thiosulfate, Wei obtaining substituted S-(2-hydroxyethylene) derivatives. The use of sodium hydroxide in the proposed process, it is necessary to convert the original 6-substituted 2-thiouracil in the water-soluble sodium salt. In addition, the anion of 2-thiouracil is a particle, which in the first stage carries out a nucleophilic attack on the three oxiranyl cycle. The use of a small excess of 2-methyloxirane due to the need to achieve complete conversion of the initial derivative of 2-thiouracil in the derivative of uracil due to the significant volatility 2 methyloxirane.

The advantage of this method is the possibility of obtaining almost any derivatives of uracil, many of which are used as intermediates for the synthesis of medicinal substances in a single phase with a quantitative yield, as well as preparative ease of synthesis and ease of separating pure reaction products.

The proposed method is as follows.

To aqueous sodium hydroxide solution was added 6-substituted 2-thiouracil and stirred at a temperature of 40-50oWith up to dissolution. To the resulting solution was cooled to room temperature, with stirring, was added 2-methyloxiran at a molar ratio of 6-substituted 2-teature. After this time the reaction mixture was adjusted with concentrated hydrochloric acid to pH 5, stirred and filtered. The precipitate is washed with water and air-dried to constant weight.

The invention is illustrated by the following examples.

Example 1.

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Synthesis of 6-methyluracil.

To 16 ml of 0.25 M aqueous sodium hydroxide solution added, the original 6-methyl-2-thiouracil (0,57 g, 4 mmole) and stirred at a temperature of 40-50oWith up to almost complete dissolution. To the resulting solution was cooled to room temperature, with stirring, was added 2-methyloxiran (2.55 g, 4.4 mmole), the ratio of the initial reagents: 6-methyl-2-thiouracil : 2-methyloxiran : sodium hydroxide = 1:1.1:1. The reaction mass is stirred for 24 hours at room temperature. After this time the reaction mixture was adjusted with concentrated hydrochloric acid to pH 5, stirred for another 10 minutes and filtered. The precipitate was washed with water (10 ml) and air-dried to constant weight. Output 6-methyluracil - quantitative.

So pl. = 300oWith decomposition, which corresponds to literature data (The Merck Index, 12-th Ed., 1996, p. 6212).

Example 2.

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Synthesis of 6-benzylurea.

Output 6-benzylurea - quantitative.

So pl. = 261-262oS, which corresponds to literature data (Johnson T. C., Ambelang J. C., J. Am. Chem. Soc., 1938, v. 60, R. 2941).

Example 3.

< / BR>
Synthesis of 6-(2,6-diferensial)uracil.

Is carried out analogously to synthesis 1, except for use as 6-substituted 2-thiouracil 6-(2,6-diferensial)-2-thiouracil (1,02 g, 4 mmole). The ratio of initial reagents 6-(2,6-diferensial)-2-thiouracil: 2-methyloxiran: sodium hydroxide = 1:1.1:1.

Yield 6-(2,6-diferensial)uracil - quantitative.

Decomposes above 300oC.

Mass spectrum m/e: 256 (M+ H + F, 7%), 238 (M+, 32%), 219 (M+ -F, 0,1%), 195 (M+-HNCO, 0,8%), 175 (M+ - F - HNCO, 14%), 152 (M+ -2 HNCO, 8%) 127 (2,6-F2WITH6H3CH2, 27%), 68 (M+ - 2,6 - F2C6H3CH2-HNCO, 100%).

IR spectrum (KBr): 1660 cm-1 (C=0).

Example 4.

Synthesis of 6-(2,6-diferensial)uracil.

Is similar to that for synthesis of 3, except for the ratio of initial reagents 6-(2,6-diferensial)-2-thiouracil : 2-methyloxiran : sodium hydroxide = 1:1.2:1.

Yield 6-(2,6-diferensial)-2-thiouracil is illogical synthesis of 3, except for the ratio of initial reagents 6-(2,6-diferensial)-2-thiouracil : 2-methyloxiran : NaOH = 1:1:1.

Yield 6-(2,6-diferensial)uracil - 92%.

It follows from the presented examples, we proposed a method of obtaining a 6-substituted derivatives of orallow is a technology that allows to obtain a wide range of these compounds with quantitative yield and high purity.

The way to obtain a 6-substituted orallow General formula

< / BR>
where R = CH3WITH6H5CH2, 2,6-F2WITH6H3CH2< / BR>
using the 6-substituted 2-thiouracil in the presence of an aqueous solution of sodium hydroxide, characterized in that as a 6-substituted 2-thiouracil use 6-methyl-2-thiouracil, 6-benzyl-2-thiouracil or 6-(2,6-diferensial)-2-thiouracil, which is subjected to interaction with 2-methyloxirane at a molar ratio of 6-substituted 2-thiouracil: 2-methyloxiran: sodium hydroxide is 1: 1,0-1,2: 1, followed by acidification and isolation of the target product.

 

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