CS251078B2 - Method of 5-(e)-(2-bromovinyl)-2-desoxyuridine derivatives production - Google Patents

Description

(54) · Method. production of 5- (E) - (2-bromovinyl) -2H-desoxyuridine derivatives;

Preparation of 5- (E) - (R) -bromvinyl) -2'-desoxyuridine derivatives of formula VI

in which

R represents a hydrogen atom, a benzoyl group substituted in the para position by a chlorine atom or an acetyl group, characterized in that 3 ‘, 5‘-di-O-acyl-5-ethyl-2-desoxyuridine is brominated, dehydrohalogenated and optionally acylated. The obtained compounds can be used in the pharmaceutical industry. A compound of the above general formula wherein R = H is the best known antiviral agent to date.

The present invention relates to a process for the preparation of 5- (E) - (2-bromovinyl) -2'-desoxyuridine derivatives of the general formula VI

0Г (vi)

OR in which

R represents a hydrogen atom, a benzoyl group substituted in the para position by a chlorine atom or an acetyl group.

These compounds are useful in the pharmaceutical industry.

The process for the preparation of 5- (E) - (2-bromovinyl) -2‘-desoxyuridine (Formula VI: R = H) is described in the literature. This compound is to date the best antiviral agent and non-toxic chemotherapeutic agent with the highest potency and best in vitro and in vivo selectivity against Herpes Simplex I and Varicella Zoster (E. DeClercq et al., Proc. Natl. Acad. Sci. USA 76, 2947) (1979); P., C. Mandgal et al., Graefes Arch. Ophthalmol. 216, 261 (1981); E. De Clercq et al., British Med. J. 281, 1178 (1980)].

One way is condensation: 5- (E) - (2-bromvinyl) uracil is condensed as a bis-O-trimethylsilyl derivative with 1-chloro-2-desoxy-3 ', 5'-di-O-p-toluyl-αD erythropentafuranose (AS Jones, RT Walker, PJ Barr and E. De Clercq, DOS 2 915 254).

The disadvantage of this method is the complicated synthesis of the starting 5-bromvinyluracil and low yield. The product of formula (VI) is not a single chemical individual; it consists of a mixture of α- and--isomers, only the β-anomer being of practical significance. 5-Bromvinyluracil was made from 5-acetyluracil via 5-vinyluracil. The yield of the compound of formula (VI) in which the R-H, based on 5-acetyluracil, is less than 10%, and this product must be chromatographically separated into the α- and β-anomer (AS Jones, G. Verhelst und RT Walker, Tetrahedron Letters 45, 4415 (1976). Currently, 5- (E) - (2-bromvinyl) uracil is produced in higher yield from 5-formyluracil over 5- (E) - (2-carboxyvinyl) uracil). However, condensation by the above method also leads to anomerization (α / β = 1: 3), although the sugar derivative used in the condensation, protected by a protective group and activated contains chlorine at the 1-position (PJ Barr, AS Jones, G. Verhelst and RT Walker, J. Chem., Soc., Perkin I, 1665 (1981).

Bergstrom method (DE Bergstrom and K. Ogawa, J. Am. Chem. Soc., 100, 8106 (1978)) and a modified version thereof (AS Jones, G. Verhelst and RT Walker, Tetrahedron Letters, 45, 4415) 1979) is preferable to condensation. From 2'-desoxyuridine, C-5-mercury-2'-desoxyuridine is prepared, which is converted to 5- (E) - (carbetoxyvinyl) -2'-desoxyuridine by reaction with Li 2 PdCl 4 and ethyl acrylate, followed by hydrolysis to give a compound of formula VI (R = H). No mixture of anomers is formed, as β-2‘-desoxyuridine was used as the starting product. The disadvantage of this method is that Li2PdCl4 and 2‘-desoxyuridine are very expensive and the final product has to be purified by column chromatography, so that production on a commercial scale is very expensive and time consuming.

5- (E) - (2-Bromvrnyl) -2'-desoxyuridine (Formula VI: R = H) was also produced by bromination from 5-ethyl-2'-desoxyuridine (D. Barwolff and P. Langen, Nucleic acids, Res Spec Publ 1, 29 (1975). The β'-anomer of 5-ethyl-2'-desoxyuridine is converted to 3 ', 5'-di-O-acetyl-5-ethyl-2'-desoxyuridine, after which the product is brominated with elemental bromine and then dehydrohalogenated with a tertiary base . Acetylation finally gives the final product of formula VI (R = H). The disadvantage of this process is that the (.alpha.-anner 5-ethyl-2 ' -desoxyuridine) must only be obtained by separation of the mixture of the .alpha.- and .alpha.-isomers resulting from the production of 5-ethyl-2 ' -desoxyuridine. This method can also result in anomerisation during bromination, resulting in a 1: 1 mixture of .alpha.-.alpha.-bromo product (VI) from pure .alpha.-compound (VI).

It is an object of the present invention to provide a novel process for preparing compounds of formula (VI) starting from another starting product.

The present invention provides a process for the preparation of 5- (E) - (2-bromovinyl) -2 2-desoxyuridine derivatives of formula VI

R represents a hydrogen atom, a benzoyl group substituted in the para position by a chlorine atom or an acetyl group, characterized in that 3 ‘, 5‘-di-O-acyl-5-ethyl-2‘-desoxyuridine of formula VI

(IV) wherein

R is as defined above, reacted with elemental bromine, wherein said bromination is carried out in an anhydrous halogenated hydrocarbon solvent, preferably dichloromethane, dichloroethane, chloroform or carbon tetrachloride, or mixtures thereof, under the influence of light and under a nitrogen or argon atmosphere at reflux temperature, and the dibromo derivative of formula V obtained

substances. To this end, the compounds are converted into solutions, emulsions, suspensions, powders and pastes by known methods.

Pharmaceutical applications of the compounds are practically without side effects.

Novel compounds are those compounds of formula VI wherein R is methylcarbonyl or p-chlorobenzoyl.

The starting compounds of formula IV protected by a di-O-acyl group are well brominated and the synthesis proceeds in a shorter time; moreover, de-acylation and re-acylation of the ethyl compound is unnecessary. A great advantage of the process according to the invention is that the α-, β-anomeric mixture can be used for bromination. Therefore, a substantially higher yield is achieved in this way. In fact, under the conditions of dehydrobromation, a substantial proportion of the β-form of the compound of the formula VI is separated together with the triethylamine hydrobromide and only a very small proportion of the β-anomer remains in solution in addition to the α-anomer. Starting from compound IV (pure), the yield of compound VI is 22.5%; starting from an α-β-mixture, a yield of 35.7% (based on sugar compound III) is obtained.

In the following, the invention will be explained in more detail by specific examples.

Example 1

1.1. Preparation of the starting p-chlorobenzoyl-5-ethylf2‘-desoxyuridine (// - anomer and α-β-anomer)

and)

2,4-bis-O-trimethylsilyl-5-ethylpyrimidine in which

R is as hereinbefore defined, optionally after isolation, dehydrohalogenated with an excess of tertiary base, said dehydrohalogenation being carried out in an anhydrous hydrocarbon solvent, preferably dichloromethane, dichloroethane, chloroform or carbon tetrachloride, or isopropylethylamine at room temperature, and then optionally obtained product de-acylated by treatment with sodium ethyl acetate or ammonia saturated methanol at 0 to 25 ° C.

Preferably, a mixture of the α- and β-anomer of 3 ‘, 5‘-di-O-p-chlorobenzoyl-5-ethyl-2‘-desoxyuridine is used as the diacyl derivative of the general formula IV.

The compounds of formula (VI) obtained can be used in the pharmaceutical industry in the form of pharmaceutical preparations. The compounds of formula VI (R = H or R = metabolically cleavable acyl group) are used either in pure form or together with other active substances and / or binders, solvents, diluents, flavoring agents and / or> other auxiliary Si)

CH _of CH ₃

()

100 g (0.71 mol) of 5-ethyluracil of formula I

dried under vacuum reacted with 200 at 150 ° C with ml (1.25 mol) 1,1,1,251078

3,3,3-hexamethyldisilazane for 24 hours under reflux and absolute conditions. Excess 1,1,13,3,3-hexamethylsilazane was distilled off from the resulting clear solution at normal pressure and the residue was rectified under vacuum.

Boiling point = 134 ° C / 1733 Pa; yield: 197.4 g (97%).

(b)

2'-deoxy-3 ', 5' / di-Op-cmloib: ienoyyl-and _L ^6, -D-R · bofuranosylchlorid (III) g 2 ^{t-desoxy-D-ribose} is dissolved in 190 ml of anhydrous methanol, 10 ml of anhydrous methanol containing 1% hydrogen chloride were added to the obtained solution, and after 20 minutes 5 g of freshly prepared AgCO3 was added. The mixture is then filtered through filter paper and the filtrate is concentrated on a rotary evaporator at 40 ° C. The evaporation is then repeated with 5 ml of absolute pyridine. The residue (syrup) is then dissolved in 85 ml of absolute pyridine and 22.5 ml of p-chlorobenzoyl chloride are added under ice-cooling in such a way that the temperature remains between 20 and 40 ° C. The flask was sealed with a calcium chloride tube and allowed to stand at room temperature for 16 hours. After addition of 50 ml of water, the solution obtained is extracted twice in a separatory funnel with 75 ml of dichloromethane, and the extract is then washed twice with 10 ml of a 10% aqueous potassium bicarbonate solution and dried over sodium sulfate. After evaporation of the solvent, the residue was dissolved in 75 ml of anhydrous ether and the solution was cooled to 0 ° C. After addition of 100 ml of anhydrous acetic acid saturated with hydrochloric acid, dry hydrogen chloride is introduced into the solution as long as the white product precipitates. The product obtained is quickly filtered off, washed with ice-cold ether and dried in an evacuated desiccator over phosphorus pentoxide and solid potassium hydroxide. The product is further processed without recrystallization.

Melting point: 118 ° C; yield: 24 g (75%).

The product obtained contained a 1: 1 mixture of the α- and ‘-anomer as determined by thin layer chromatography (Silica gel HF 254, Mercek AG, type 60) using a 7: 3 chloroform-ether system.

C)

3; 5‘-DiiCOp-chlorobenzoyl-5-ethyl-2‘-desoxyuridine (IV)

88.5 g (0.31 mole) of 2,4-l-l-l-l-l-l-ethyl-silyl-5-ethyl-pyrimidine (II) are dissolved in 3900 ml of absolute acetonitrile and then treated as follows: 300 g of molecular sieve (Merek, 4.10 [ ^mu] m), 104.6 g (0.243 mol) of Z2-deso-4-di-Op-chlorobenzoyl-4-di-4-di-4-diene were added rapidly to the obtained solution. ranosyl chloride (III) and 41.8 dry mercuric bromide. The solution is stirred and is initially clear for a few minutes before crystalline cleavage begins. The mixture was stirred slowly for 5 hours and then allowed to stand overnight at room temperature. On standing, pure (t-anomer of 3 ', 5'-di-Op-chlorobenzoyl-4,10-trimethylsilyl-5-desoxyuridine) precipitated.

C)

Isolation of pure / compound (IV)

The precipitate was filtered off (the filtrate contained a mixture of α- and an-isomer) and washed three times with 150 ml of chloroform; the molecular sieve remains on the filter as a residue. The combined chloroform solutions are shaken into 50 ml of a 30% potassium iodide solution in a separatory funnel. The chloroform phase is dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was boiled with 4 L of 96% ethanol for 2 hours. After cooling at room temperature, the white i-product IV precipitated and was then recrystallized from ethanol.

Melting point: 196-197 ° C; yield: 42.5 g (32.6% based on III).

(d)

Isolation of α, ₁ / thiomeric mixtures IV

After condensation, the reaction mixture was allowed to stand in acetonitrile solution for 12 hours at room temperature, then filtered and the precipitate dissolved in 150 ml of chloroform. The residual molecular sieve was washed three times with 150 ml of chloroform (IV dissolved). The acetonitrile filtrate (anomeric solution and / or) was evaporated and 1 liter of chloroform was added to the residue. A precipitate was formed which was filtered off and the combined chloroform solution was shaken in a separatory funnel into 150 ml of a 30% potassium iodide solution; the chloroform phase is separated, dried over magnesium sulphate and filtered. The solvent was then distilled off and the residue was heated to reflux with 6 liters of 96% ethanol for 30 minutes. Upon cooling to room temperature, (1--140) (m.p.

Yield: 96 g (73.8% overall yield);

ratio of isomers // a = 3: 1.

1.2. Production of 5- [E) - (2-bromovinyl) -2‘-desoxyuridine (Formula VI, R = H) from anomeric mixture IV

26.6 g (0.05 mol) of 3 ', ^5'-di-t 0-p-chlorobenzene-5-ethyl-2'-desoxyuridmu (a (' -anomerní blend ratio β / α = 3: 1) Dissolve in 350 ml of warm anhydrous dichloroethane under the influence of light under a stream of dry nitrogen.

6.8 ml (0.125 mol) of bromine in 60 ml of anhydrous dichloroethane are then added dropwise to the solution, depending on the reaction rate (about 20-25 minutes). After addition of bromine, the irradiation is terminated and the reaction mixture is refluxed under a strong stream of nitrogen for a further 15 minutes. Then the solvent was distilled off on a rotary evaporator and the residue was re-stirred with 20 ml of anhydrous dichloroethane and re-evaporated. The residue (hard foam) was then dissolved in 140 ml of anhydrous dichloroethane and 10.4 ml (0.075 mol) of triethylamine was added dropwise (about 15 minutes).

The (-compound VI (R = p-chlorobenzoyl) and triethylammonium hydrobromide precipitate from solution and are washed with dichloroethane and then 80% ethanol after filtration. The residue is pure (-product VI (R = p-chlorobenzoyl)).

Yield: 14.8 g (0.024 mol = 48%).

Depylation is performed as follows:

g (0.0345 mol) of product VI (R = p-chlorobenzoyl) is acylated by treatment with 130 ml (0.5 mol) of NaOCH 3 solution with stirring at room temperature for 3 hours. The pH of the solution is then adjusted to 5-6 with Dowex 50 H +. The ion exchanger was filtered off and washed with methanol. The combined methanol fractions were evaporated and the residue was recrystallized from water.

Melting point: 175-176 ° C. yield: 10.6 g of product VI (R = H) (92.6 percent).

Example 2

Preparation of 5- (E) - (2-bromvinyl) -2l-desoxyuridine (Formula VI, R = H) from pure

26.7 g (0.05 mol) of pure anomer of 3 ', 5'-di-O 1 - 4 H - (4-benzoyl-5-ethyl-2'-desoxyuridine ((-product IV)) is dissolved 6.8 ml (20 g; 0.125 mol) of bromine in 60 ml of anhydrous dichloroethane are added dropwise to the solution, depending on the reaction rate (over a period of 20-25 minutes) in 350 ml of warm anhydrous dichloroethane. the bromine addition was terminated and the reaction mixture was refluxed for 15 minutes with a strong nitrogen product.The solvent with HBr residue was then distilled off on a rotary evaporator and the evaporation was then repeated with 20 ml of anhydrous dichloroethane. then dissolved in 140 ml of anhydrous dichloroethane and 10.4 ml (7.59 g; 0.075 mol) of triethylamine are added dropwise over about 15 minutes, and the compound β-VI (R = p-chlorobenzoyl) and triethylammonium hydrobromide are precipitated The mixture is filtered and the precipitate is washed with dichloroethane and then with 80% ethanol anol, in which the hydrobromide is dissolved, residue (VI) (21 g · 0.0345 mol; 69%) is acylated with 130 ml (0.5 mol) of NaOCH ... at room temperature for 3 hours. The pH of the solution is then adjusted to 5-6 by adding Dowex 50 HP · ion exchanger. The ion exchanger was filtered off and washed twice with methanol. The combined methanol fractions were evaporated on a rotary evaporator and the residue was recrystallized from water.

Mp: 175-1 ° C ⁷ 6;

yield: 10.6 g [VI, R = H] (63.7% calculated on starting product IV and 92 3% calculated on VI (R - p-chlorobenzoyl)).

Starting from compound IV (R = p-chlorobenzoyl) (pure (Sforrna)), a yield of compound VI of 22.5% is obtained; on the other hand, a yield of 35 · 7% (calculated on sugar compound III) is obtained from α, β-mixture. .

Example 3

1.07 g (2 mmol) of 5-ethyl- (3 ', 5 ⁱ -di- p chlorbenzryl) -2' - (- desoxyuridmu was dissolved in 25 ml of absolute chloroform and the solution thus obtained at 500 W radiation emitter added 0.11 ml of bromine in 5 ml of chloroform The resulting hydrogen bromide is blown out of the solution with a stream of nitrogen, after addition of bromine, 0.6 ml of triethylamine is added and the mixture is heated for a further 10 minutes. triethylammonium bromide by aqueous extraction, after which the residue is recrystallized from ethanol.

Yield: 0.8 g (66%) of 5- (2-bromovinyl) ^-3-C, 5'-DIPP-chlorobenzoyl) -2 '- (- Pesoxyuridinu mp 235 ° C.

The protecting groups are aspirated by methanolysis.

Melting point: 170 ° C;

yield: 0.4 g = 60% of theory.

Example 4

340 mg of (3 ^< 5 > -diacetyl-5-ethyl-2'-desrxyuridine (1 nmol) is dissolved in 100 ml of carbon tetrachloride and added under light and reflux to 350 mg of bromine over a period of 1 to 2 hours. 2 hours, light source is 250W bulb, then the solvent is distilled off under vacuum and the residue is dissolved in 10 ml of diisoipropylethyl 251078 min and the mixture is heated to reflux for 15 minutes, whereupon 5- (E) - (2) is isolated. -bromvinyl) - (3 ', 5'-diacetyl) -2'-β-desoxyuridine (melting point = 164 ° C, needles crystallized from alcohol) or the acetyl group is cleaved immediately in a reaction solution of 50 ml saturated methanol After removal of the solvent, the residue is purified by chromatography.

Yield: 206 mg (62%) of 5- (2-bromovinyl) -2'-desoxyuridine;

mp: 162-163 ° C.

Example 5

To a solution of 3.4 g (10 nmoles) of 3 ', 5'-diacetyl-5-ethyl] -2'-desoxyuridine in 600 ml of tetrachlorometethap is introduced under a stream of dry nitrogen under reflux, under stirring and under the influence of light. 4 hours 1.1 ml bromine. 10 ml of triethylamine are then added to the reaction mixture and the mixture is heated for a further 15 minutes. The mixture was then evaporated on a rotary evaporator, de-acetylated with 100 ml of ammonia saturated methanol and eluted on silica gel (Merck) using chloroform / methanol (9: 1).

Yield: 1.3 g; melting point: 169 TL

Claims (2)

Subject A process for the preparation of 5- (E) - (2-bromovinyl) -2'-desoxyuridine derivatives of the general formula VI in which: R represents a hydrogen atom, a benzoyl group substituted <in the para position by a chlorine atom or an acetyl group, wherein ^x is 3, 5'-di-O-acyl-5-ethyl-2'-desoxyuridin formula IV INVENTION with elemental bromine, wherein said bromination is carried out in an anhydrous halogenated hydrocarbon solvent, preferably dichloromethane, dichloroethane, chloroform or carbon tetrachloride, or mixtures thereof, under the influence of light and under a nitrogen or argon atmosphere at reflux temperature, and obtained a bromo derivative of the general formula V 1f CH-CHn HN ' V. / if li ¹ ' > J Sí r ' RO ~~ n i 1 STEED in which R is as hereinbefore defined, optionally after isolation, dehydrohalogenated with an excess of tertiary base, said dehydrohalogenation being carried out in an anhydrous halogenated hydrocarbon solvent, preferably dichloromethane, dichloroethane, chloroform, carbon tetrachloride or isopropylethylamine, at room temperature and optionally optionally de-acylated of sodium ethylate or methanol saturated with ammonia at 0 to 25 degrees Celsius. 2. Process according to claim 1, characterized in that it is a diacyl derivative of the general formula IV uses a mixture of the α, α, β-anomer of 3‘, 5‘-di-O-β-chlorobenzoyl-5-ethyl-2‘-desoxyuridine. in which R is as defined above,