RU2697804C1 - METHOD OF PRODUCING 1-(ω-HYDROXYALKYL)URACILS - Google Patents

Abstract

FIELD: chemistry.SUBSTANCE: invention relates to an improved method of producing 1-(-hydroxyalkyl)uracils, which can be used in pharmaceutical industry as intermediate products in synthesis of medicinal compounds. Method consists in that uracil is subjected to silylation with excess of hexamethyldisilazane in presence of trimethylchlorosilane, obtained 2,4-bis-[(trimethylsilyl)oxy]pyrimidine is alkylated with subsequent cooling and treatment with 5 wt% with aqueous solution of sodium pyrosulphite and tetrahydro silvane. Then organic phase is separated by removal of solvent, evaporation to dryness at low pressure and alkaline hydrolysis of obtained product with boiling 5M solution of potassium hydroxide in 95 wt% ethanol with further removal of solvent, dissolution of residue in water and saturation of mixture with carbon dioxide. Extraction of the end product is carried out with tetrahydrosilvano with removal of water and evaporation of the solvent.EFFECT: method increases output of end products to 57–72 % and simplifies the method by avoiding column chromatography.1 cl, 5 ex

Description

The invention relates to the field of synthesis of 1- (ω-hydroxyalkyl) uracils, which can be used in the pharmaceutical industry as intermediates in the synthesis of drug compounds.

A known method of producing 1- (2-hydroxyethyl) uracil by alkylation of uracil with ethylene carbonate in the presence of a catalytic amount of sodium salt of uracil. The reaction proceeds in anhydrous DMF for 1.5 hours [Nucleic acid components and their analogues. Xvii. Reaction of uracil and of its aza analogues with ethylene carbonate / Prystas M., Gut J. // Collection of Czechoslov. Chem. Commun. - 1962. - Vol. 27. - P. 1054-1056; N-Vinyl derivatives of substituted pyrimidines and purines / Pitha J., Ts'O P.O.P. // J. Org. Chem. - 1968. - Vol. 33. - P. 1341-1344; Synthesis of Dihydroisoxazole Nucleoside and Nucleotide Analogs Gi H.-J., Xiang Y., Schinazi R.F., Zhao K. // J. Org. Chem. - 1997. - Vol. 62. - P. 88-92]. The pure desired product is isolated by column chromatography.

The disadvantage of this method is the formation of a hardly separated mixture of alkylation products and a low yield of the target product (~ 47% of the technical product).

A known method for producing 1- (2-hydroxyethyl) uracil by alkylation of uracil with ethylene carbonate in dry dimethylformamide, in the presence of catalytic amounts of sodium hydroxide [Two simple protocols for the preparation of diallylaminoethyl-substituted nucleic bases: a comparison / Shatila R.S., Bouhadir K.H. // Tetrahedron Lett. - 2006. - Vol. 47. - P. 1767-1770].

The disadvantage of this method is the low yield (up to 33%) of the target product and the need to use column chromatography in its isolation.

A known method for producing 1- (4-hydroxybutyl) uracil by alkylation of an anhydrous uracil salt with an excess of 1,4-dibromobutane in anhydrous dimethylformamide [Synthesis and properties of pyrimidinylalkylphosphonic acids - Communication 9. Synthesis of some Ω- (oxodihydro-N-pyrimidinyl) alkyl phosphates and Ω- (oxodihydro-N-pyrimedinyl) phosphonates / Reznik VS, Shvetsov Yu.S., Bakulin VS, Salikhov I.Sh. // Bulletin of the Academy of Sciences of the USSR. - 1975 .-- Vol. 24. - N 6. - P. 1290-1293]. The oil product is isolated by chromatographic separation of the resulting mixture.

The disadvantage of this method is the low yield (7%).

A known method of producing 1- (2-hydroxyethyl) uracil, in which uracil under the influence of sodium hydride in dimethylformamide is converted into sodium salt, and the latter at a temperature of 80-150 ° C for 14.5 hours interacts with BrCH ₂ CH ₂ OAc. After crystallization, the obtained 1- (2-acetoxyethyl) uracil is subjected to acid hydrolysis and the target 1- (2-hydroxyethyl) uracil is obtained with a total yield of about 29% [An improved synthesis of 1- (2-hydroxyethyl) uracil / Garnaik B. // Organic Preparations and Procedures International: The New Journal for Organic Synthesis. - 1995. - Vol. 27. - P. 657-659].

The disadvantage of this method is its multi-stage and low yield of the target product.

A known method for producing 1- (4-hydroxybutyl) uracil and 1- (5-hydroxypentyl) uracil by alkylating the in situ salt of uracil with 4-chlorobutylbenzoate or 5-chloropentylbenzoate in anhydrous DMF, followed by removal of the benzoyl group with aqueous ethanolic ammonia solution by evaporation of the technical product with ethanol and subsequent recrystallization from the same solvent. The total yield of the product was 28-53%) [Search for a simplersyntheyic model system for intramolecular 1,3-dipolar cycloaddition to the 5,6-double bond of a pyrimidine nucleoside / Sasaki T., Minamoto K., Suzuki T., Yamashita S. // Tetrahedron. - 1980. - Vol. 36. - P. 865-870].

The disadvantage of this method is the need for separation of the obtained mixtures by column chromatography and low yield.

The closest is a method for producing 1- (ω-hydroxyalkyl) uracils with 4-7-day alkylation of the resulting silylation of uracil with an excess of hexamethyldisilazane in the presence of trimethylchlorosilane 2,4-bis - [(trimethylsilyl) oxy] pyrimidine 1,2-dibromoethane in the presence of a catalytic amount of iodine, followed by isolation by column chromatography and alkaline hydrolysis of the reaction product [Synthesis of uracil nucleotide analogs with a modified, acyclic ribose moiety as P2Y ₂ receptor antagonists / Sauer R., El-Tayeb A., Kaulich M., Muller CE / / Bioorganic & Medicinal Chemistry. - 2009. - Vol. 17. - P. 5071-5079]. The total reaction yield is 9-32%.

The disadvantage of this method is its duration, low yield of the target product and the need for its purification by column chromatography.

The objective of the invention is to develop a method of selective alkylation of uracil, which allows to obtain and isolate 1- (ω-hydroxyalkyl) uracils without the use of solvent, column chromatography and in a short time.

The technical result is to simplify the method and increase the yield of the reaction product.

The technical result is achieved in a method for producing 1- (ω-hydroxyalkyl) uracils, which consists in silylation of uracil with excess hexamethyldisilazane in the presence of trimethylchlorosilane, alkylation of the obtained 2,4-bis - [(trimethylsilyl) oxy] pyrimidine with heating, followed by alkaline hydrolysis of the reaction product the selection of the target product, while 2,4-bis - [(trimethylsilyl) oxy] pyrimidine is alkylated with an equimolar amount of ω- (benzoyloxy) alkyl halide by heating the reaction mass to 160-165 ° C for 2.5 hours, followed by by cooling and treatment with 5 wt. % aqueous solution of sodium pyrosulfite and tetrahydrosilvane, and the resulting two-layer solution is filtered, the organic phase is separated, washed with saturated sodium chloride solution, azeotropic distillation removes water from it, and after filtration through a layer of silica gel evaporated to dryness under reduced pressure, alkaline hydrolysis of the resulting product is carried out boiling 5M potassium hydroxide solution in 95 wt. % ethanol for 30 minutes, based on 4 ml of an aqueous-alcoholic alkaline solution per 1 mmol of the reaction product, and to isolate the target product under reduced pressure, remove the solvent, dissolve the residue in water and saturate the mixture with carbon dioxide, after which the target product is removed with tetrahydrosilvane, remove water and evaporate the solvent.

with n = 2-5, 7

The method is as follows. The starting uracil is silylated with an excess of hexamethyldisilazane in the presence of trimethylchlorosilane, resulting in the formation of 2,4-bis - [(trimethylsilyl) oxy] pyrimidine, in which the third position is sterically more shielded. Next, 2,4-bis- [(trimethylsilyl) oxy] pyrimidine is reacted with the corresponding alkylating agent, ω- (benzoyloxy) alkyl halide. As a result of the reaction, an alkylation product is formed in the first position, 1- [ω- (benzoyloxy) alkyl] uracil, which is isolated by treating the reaction mass with 5 wt. % aqueous solution of sodium pyrosulfite and tetrahydrosilvane, followed by azeotropic distillation of the remaining water by evaporation to dryness. The resulting alkylation product, 1- [ω- (benzoyloxy) ethyl] uracil, is hydrolyzed with a water-alcohol solution of potassium alkali, the solvent is removed, and the residue is dissolved in water and the mixture is saturated with carbon dioxide. As a result, the target 1- (ω-hydroxyethyl) uracil is formed, which is isolated by extraction with tetrahydrosilvane.

Example 1

2 g (17.9 mmol) of uracil, 50 ml (38.7 g, 239.8 mmol) of hexamethyldisilazane and 0.5 ml of trimethylchlorosilane are boiled with moisture protection until a clear solution is formed. Excess solvent is removed in vacuo, protected against moisture in the air. To the remaining (17.9 mmol) 2,4-bis - [(trimethylsilyl) oxy] pyrimidine in one step, an equimolar amount of an alkylating agent, 2-bromoethyl benzoate (β- (benzoyloxy) ethyl bromide), is added. The resulting mixture is heated to 160-165 ° C in an oil bath under reflux Allen and protection from moisture for 2.5 hours. Next, the reaction mass is slowly cooled to room temperature (25 ° C) and treated with 5 mass. % aqueous solution of sodium pyrosulfite and tetrahydrosilvane. The resulting mixture was stirred vigorously. After the formation of two transparent layers, the mixture is filtered on a Buchner funnel, the organic phase is separated and washed with a saturated solution of sodium chloride. Then, azeotropic distillation removes residual water. The hot bottom solution is filtered through a thin layer of silica gel for TLC. The filtrate was evaporated to dryness under reduced pressure.

The precipitated product of the alkylation reaction, 1- [β- (benzoyloxy) ethyl] uracil, is subjected to alkaline hydrolysis: the product of alkylation is poured with a boiling 5M potassium hydroxide solution in 95 wt. % ethanol, based on 4 ml of solution per 1 mmol of reaction product. The resulting mixture was boiled under stirring for 30 minutes, the solvent was removed under reduced pressure, and the residue was dissolved in water and the mixture was saturated with carbon dioxide.

The isolated target product is extracted with tetrahydrosilvane, the combined organic extracts are washed with a saturated solution of sodium chloride, water is distilled off with an azeotrope. The hot bottom solution is filtered through a thin layer of silica gel for TLC, the filtrate is evaporated to dryness under reduced pressure.

To remove traces of hydrated water, the residue is evaporated with toluene.

After recrystallization, the desired 1- (2-hydroxyethyl) uracil is obtained in a yield of 72%.

Example 2

It is carried out analogously to example 1 using 3-bromopropylbenzoate (3- (benzoyloxy) propyl bromide) as the alkylating agent. The yield of the desired 1- (3-hydroxypropyl) uracil is 61%.

Example 3

It is carried out analogously to example 1 using 4-iodobutylbenzoate (4- (benzoyloxy) butyl bromide) as the alkylating agent. The yield of the desired 1- (4-hydroxybutyl) uracil is 67%.

Example 4

It is carried out analogously to example 1 using 5-bromopentylbenzoate (5- (benzoyloxy) pentyl bromide) as an alkylating agent. The yield of the desired 1- (5-hydroxypentyl) uracil is 54%.

Example 5

It is carried out analogously to example 1 using 7-bromoheptyl benzoate (7- (benzoyloxy) heptyl bromide) as an alkylating agent. The yield of target 1- (7-hydroxyheptyl) uracil is 57%.

Thus, a method for producing 1- (ω-hydroxyalkyl) uracils, which consists in silylation of uracil with an excess of hexamethyldisilazane in the presence of trimethylchlorosilane, alkylation of the obtained 2,4-bis - [(trimethylsilyl) oxy] pyrimidine with an equimolar amount of ω- (benzoyloxy) alkyl halide mass for 2.5 hours, followed by cooling and processing of 5 mass. % aqueous solution of sodium pyrosulfite and tetrahydrosilvane, separation of the organic phase, its evaporation, subsequent alkaline hydrolysis and isolation of the target product in accordance with the described procedures, is simple to implement and provides an increase in the yield of the reaction product.

Claims (1)

The method of producing 1- (ω-hydroxyalkyl) uracils, which consists in silylation of uracil with an excess of hexamethyldisilazane in the presence of trimethylchlorosilane, alkylation of the obtained 2,4-bis - [(trimethylsilyl) oxy] pyrimidine with heating, followed by alkaline hydrolysis of the reaction product and isolation of the target product, characterized in that 2,4-bis - [(trimethyl silyl) oxy] pyrimidine is alkylated with an equimolar amount of ω- (benzoyloxy) alkyl halide by heating the reaction mass to 160-165 ° C for 2.5 hours, followed by cooling and processing th 5 wt. % aqueous solution of sodium pyrosulfite and tetrahydrosilvane, and the resulting two-layer solution is filtered, the organic phase is separated, washed with saturated sodium chloride solution, azeotropic distillation removes water from it, and after filtration through a layer of silica gel evaporated to dryness under reduced pressure, alkaline hydrolysis of the resulting product is carried out boiling 5M potassium hydroxide solution in 95 wt. % ethanol for 30 minutes at the rate of 4 ml of an aqueous-alcoholic alkaline solution per 1 mmol of the reaction product, and to isolate the target product under reduced pressure, remove the solvent, dissolve the residue in water and saturate the mixture with carbon dioxide, then extract the target product with tetrahydrosilvane, remove water and the solvent is evaporated.