RU2212406C1 - Method for preparing 6-substituted uracil - Google Patents

Abstract

FIELD: organic chemistry of heterocyclic compounds, chemical technology, pharmacy. SUBSTANCE: invention relates to the improved method for preparing 6-substituted uracils of the general formula (I)

wherein R is CH₃, C₆H₅CH₂, 2,6-F₂C₆H₃CH₂ that can be used in pharmaceutical industry for preparing medicinal preparations. Method involves interaction of 6- substituted 2-thiouracil taken among the group including 6-methyl-2-thiouracil, 6-benzyl-2-thiouracil, 6-(2,6- difluorobenzyl)-2-thiouracil with 2-methyloxirane in the presence of sodium hydroxide an aqueous solution in the mole ratio 6-substituted 2-thiouracil : 2-methyloxirane : sodium hydroxide = 1 : (1.0-1.2) : 1, respectively, followed by acidification and isolation of the end product. Method allows carrying out the process under mild conditions using inexpensive parent compounds that excludes formation of acid flows and provides preparing end products with practically quantitative yield. EFFECT: improved preparing method. 5 ex

Description

где R = СН₃, С₆Н₅СН₂, 2,6-F₂C₆H₃CH₂, которые находят применение как полупродукты для синтеза лекарственных препаратов и как самостоятельные лекарственные препараты.The present invention relates to the field of synthesis of heterocyclic compounds, specifically to a method for producing 6-substituted derivatives of uracil of the formula

where R = CH ₃ , C ₆ H ₅ CH ₂ , 2,6-F ₂ C ₆ H ₃ CH ₂ , which are used as intermediates for the synthesis of drugs and as independent drugs.

 Known methods for producing uracils by direct condensation of urea and β-ketoesters.

 However, these methods do not give a satisfactory yield of the final products in the case of sterically shielded β-ketoesters and are used only for simple β-ketoesters (for example, acetoacetic (Synthesis of Organic Preparations, 1949, vol. 2, p. 335) and oxalic-acetic acid monoethyl ether ( Chkhikvadze K.A., Britikova N.E., Magidson O.Yu., Zhokh, 1964, volume 34, p. 161)).

 A known method of producing substituted uracils from 2-thiouracil derivatives by acid hydrolysis of the latter by boiling in a 10% aqueous solution of chloroacetic acid (Johnson T.V., Ambelang J.C., J. Am. Chem. Soc., 1938, v 60, p. 2941). This method does not provide a high yield (for 6- (1-naphthylmethyl) -5-ethyluracil - about 53% (Danel K., Nielsen C., Pedersen E.V., Acta Chem. Scand., 1997, v. 51, p. 426)) of the reaction product, and also does not apply to the synthesis of derivatives containing acidophobic groups (for example, a 2-tetrahydropyranyloxy group). This requires prolonged boiling of the reaction mixture and uses a large excess of aqueous chloroacetic acid, which makes this method industrially unsuitable due to the presence of a large volume of difficultly regenerated acid effluents.

 Known methods for producing uracils from derivatives of 2-methoxy-4 (3H) -pyrimidinone (Botta M., Cavalieri M., Ceci D., De Angelis F., Finizia G., Nicoletti R., Tetrahedron, 1984, v. 40, p. 3313) and 2-alkylthio-4 (3H) -pyrimidinones (Renault J., Laduree D., Robba M., Nucleosides Nucleotides, 1994, v. 13, p. 1135).

 These methods are of little use due to the increased complexity of the synthesis and the associated lower availability and higher cost of the starting materials compared to 2-thiouracils.

 The closest is a method for producing 6-substituted uracils based on 6-substituted 2-thiouracils using oxidative hydrolysis of the thionic group under the influence of a 35% aqueous solution of hydrogen peroxide in an aqueous alkali solution (Johnson T.V., Schroeder E.F., J. Am. Chem. Soc., 1931, v. 53, p. 1989).

 This method, despite its relative simplicity and profitability, has significant disadvantages. Firstly, it is not applicable to oxidolabile compounds, and secondly, it involves the use of a dangerous and unstable reagent - perhydrol. Thirdly, it allows to obtain target uracils with a yield of only 40-88% (Tanaka H., Takashima H., Ubasawa M., Sekiya K., Nitta I., Baba M., Shigeta S., Walker TD, De Clerq E ., Miyasaka, T., J. Med. Chem., 1992, v. 35, p. 337).

 The objective of the proposed technical solution is to develop a new technologically advanced method for producing 6-substituted uracils, which allows synthesis under mild conditions using cheap starting compounds, eliminating the presence of acidic effluents and allowing 6-substituted uracils to be obtained in almost quantitative yield.

 The technical result is to increase the yield of the claimed compounds, simplifying the process of obtaining and isolation of final products.

где R = СН₃, С₆Н₅СН₂, 2,6-F₂C₆H₃CH₂, с использованием 6-замещенных 2-тиоурацилов в присутствии водного раствора гидроксида натрия, отличающийся тем, что в качестве 6-замещенных 2-тиоурацилов используют 6-метил-2-тиоурацил, 6-бензил-2-тиоурацил или 6-(2,6-дифторбензил)-2-тиоурацил, которые подвергают взаимодействию с 2-метилоксираном при мольном соотношении 6-замещенный 2-тиоурацил : 2-метилоксиран : гидроксид натрия, равном 1:1.0-1.2:1 с последующим выделением целевого продукта.The proposed technical result is achieved in a method for producing 6-substituted uracils of the general formula

where R = CH ₃ , C ₆ H ₅ CH ₂ , 2,6-F ₂ C ₆ H ₃ CH ₂ , using 6-substituted 2-thiouracils in the presence of an aqueous solution of sodium hydroxide, characterized in that as 6-substituted 2-thiouracils use 6-methyl-2-thiouracil, 6-benzyl-2-thiouracil or 6- (2,6-difluorobenzyl) -2-thiouracil, which are reacted with 2-methyloxyran in a 6-substituted 2-thiouracil molar ratio : 2-methyloxyran: sodium hydroxide, equal to 1: 1.0-1.2: 1, followed by isolation of the target product.

Использование 2-метилоксирана для десульфуризации производных 2-тиоурацила является нетрадиционным. В то время как при реакции с оксиранами аналогично ведут себя роданиды, тиокарбамид и тиосульфаты, взаимодействие арилмеркаптидов и алкилмеркаптидов с оксиранами проходит без десульфуризации и сопровождается получением замещенных S-(2-гидроксиэтильных) производных. Применение гидроксида натрия в предлагаемом процессе необходимо для переведения исходного 6-замещенного 2-тиоурацила в водорастворимую натриевую соль. Кроме того, анион 2-тиоурацила является частицей, которая на первой стадии осуществляет нуклеофильную атаку на трехчленный оксирановый цикл. Применение небольшого избытка 2-метилоксирана обусловлено необходимостью достижения полной конверсии исходного производного 2-тиоурацила в производное урацила вследствие значительной летучести 2-метилоксирана.The essence of the proposed method is the exchange of the exocyclic sulfur atom of 2-thiouracil to oxygen 2-methyloxyran with the formation of the target uracil in almost quantitative yield

The use of 2-methyloxyran for desulfurization of 2-thiouracil derivatives is unconventional. While thiocarbamide and thiosulfates behave similarly in the reaction with oxiranes, the interaction of aryl mercaptides and alkyl mercaptides with oxiranes proceeds without desulfurization and is accompanied by the production of substituted S- (2-hydroxyethyl) derivatives. The use of sodium hydroxide in the proposed process is necessary to convert the starting 6-substituted 2-thiouracil to a water-soluble sodium salt. In addition, the 2-thiouracil anion is a particle that, in the first stage, carries out a nucleophilic attack on the three-membered oxirane cycle. The use of a small excess of 2-methyloxyran is due to the need to achieve complete conversion of the starting 2-thiouracil derivative to the uracil derivative due to the significant volatility of 2-methyloxyran.

 The advantage of this method is the ability to obtain virtually any uracil derivatives, many of which are used as intermediates for the synthesis of drugs, in one step with a quantitative yield, as well as preparative ease of synthesis and ease of isolation of pure reaction products.

 The proposed method is as follows.

6-substituted 2-thiouracil is added to the aqueous sodium hydroxide solution and stirred at a temperature of 40-50 ^{° C.} until dissolved. To the resulting solution, cooled to room temperature, 2-methyloxyran was added with stirring at a molar ratio of 6-substituted 2-thiouracil: 2-methyloxyran: sodium hydroxide 1: 1.0-1.2: 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 and filtered. The precipitate is washed with water and dried in air to constant weight.

 The invention is illustrated by the following examples.

 Example 1

Синтез 6-метилурацила.

Synthesis of 6-methyluracil.

The original 6-methyl-2-thiouracil (0.57 g, 4 mmol) is added to 16 ml of a 0.25 M aqueous solution of sodium hydroxide and stirred at a temperature of 40-50 ^o C until almost complete dissolution. To the resulting solution, cooled to room temperature, 2-methyloxyran (2.55 g, 4.4 mmol) is added with stirring, the ratio of the starting reagents: 6-methyl-2-thiouracil: 2-methyloxyran: 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 dried in air to constant weight. The yield of 6-methyluracil is quantitative.

T. pl. = 300 ^o With decomposition, which corresponds to published data (The Merck Index, 12th Ed., 1996, p. 6212).

 Example 2

Синтез 6-бензилурацила.

Synthesis of 6-benzyluracil.

 It is carried out analogously to synthesis 1, except for the use of 6-benzyl-2-thiouracil (0.87 g, 4 mmol) as 6-substituted 2-thiouracil. The ratio of the starting reagents 6-benzyl-2-thiouracil: 2-methyloxyran: sodium hydroxide = 1: 1.1: 1.

 The yield of 6-benzyluracil is quantitative.

T. pl. = 261-262 ^o C, which corresponds to literature data (Johnson T.V., Ambelang J.C., J. Am. Chem. Soc., 1938, v. 60, p. 2941).

 Example 3

Синтез 6-(2,6-дифторбензил)урацила.

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

 It is carried out analogously to synthesis 1, except for the use of 6- (2,6-difluorobenzyl) -2-thiouracil (1.02 g, 4 mmol) as 6-substituted 2-thiouracil. The ratio of the starting reagents 6- (2,6-difluorobenzyl) -2-thiouracil: 2-methyloxyran: sodium hydroxide = 1: 1.1: 1.

 The yield of 6- (2,6-difluorobenzyl) uracil is quantitative.

It decomposes above 300 ^o C.

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 -F ₂ C ₆ H ₃ CH ₂ , 27%), 68 (M + - 2.6 - F ₂ C ₆ H ₃ CH ₂ -HNCO, 100%).

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

 Example 4

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

 It is carried out analogously to synthesis 3, with the exception of the ratio of the starting reagents 6- (2,6-difluorobenzyl) -2-thiouracil: 2-methyloxyran: sodium hydroxide = 1: 1.2: 1.

 The yield of 6- (2,6-difluorobenzyl) -2-thiouracil is quantitative.

 Example 5

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

 It is carried out analogously to synthesis 3, except for the ratio of the starting reagents 6- (2,6-difluorobenzyl) -2-thiouracil: 2-methyloxyran: sodium hydroxide = 1: 1: 1.

 The yield of 6- (2,6-difluorobenzyl) uracil is 92%.

 As follows from the presented examples, our proposed method for producing 6-substituted derivatives of uracils is technologically advanced, it allows to obtain a wide range of these compounds with quantitative yield and high purity.

Claims (1)

The method of obtaining 6-substituted uracils of the General formula

where R = CH ₃ , C ₆ H ₅ CH ₂ , 2,6-F ₂ C ₆ H ₃ CH ₂
using 6-substituted 2-thiouracil in the presence of an aqueous solution of sodium hydroxide, characterized in that 6-methyl-2-thiouracil, 6-benzyl-2-thiouracil or 6- (2.6 -difluorobenzyl) -2-thiouracil, which is reacted with 2-methyloxyran at a molar ratio of 6-substituted 2-thiouracil: 2-methyloxyran: sodium hydroxide equal to 1: 1.0-1.2: 1, followed by acidification and isolation target product.