FI74289C - Process for the preparation of 5- (E) - (2-bromovinyl) -2'-deoxyuridine and its derivatives. - Google Patents

Description

74289 Method for the preparation of 5- (E) - (2-bromovinyl) -2'-deoxyuridine and its derivatives

The invention relates to a process of general formula VI 5 jK = c ^ Br hnij ^ Xh 1 o 'RO + v-r

OR

For the preparation of 5- (E) - (2-bromovinyl) -21-deoxyuridine and its derivatives according to claim 15, wherein in the formula VI R represents hydrogen, an alkanoyl group having 1 to 8 carbon atoms, unsubstituted or p- in the position by an alkyl group having 1 to 4 carbon atoms or a benzoyl group substituted by a halogen atom.

The compounds of the invention are useful in the pharmaceutical industry.

Methods for the preparation of 5- (E) - (2-bromo-vinyl) -2'-deoxyuridine (VI, R = H) are known from the literature.

This compound is by far the best antiviral agent, a non-toxic chemotherapist with the highest activity and the best selectivity in vitro and in vivo against Herpes Simplex I virus and Varicella Zoster (E. DeClercq et al., 30 Proc. Natl. Acad Sci. USA 76, 2947 (1979), PC Mändgal et al., Graefes Arch. Ophthamol. 216, 261 (1981); E. DeClercq et al., British Med. J. 281, 1178 (1980).

One method is condensation; 5- (E) - (2-Bromovinyl) -uracil is condensed as a bis-O-trimethylsillyl derivative with 1-chloro-2-deoxy-3 ', 5'-di-Op-toluyl-αD-erythropenturanose (AS Jones, RT Walker, PJ Barr, and 2,74289 E. DeClercq, DE 2,915,254). The disadvantage of this method is the complex synthesis of the starting 5-bromovinyluracil as well as the low yield. Product VI is not homogeneous, but contains a mixture of α, β-anomers, of which only the g-form is of practical importance. 5-Bromo-vinyluracil was prepared from 5-acetyluracil via 5-vinyl-uracil. The yield of compound VI (R = H), calculated from 5-acetyluracil, is less than 10%, and this amount still requires chromatographic separation of the α- and β-anomers (AS Jones, G. Verhelst and RT Walker, Tetrahedron Letters 45, 4415 (1976)). )). Currently, 5- (E) - (2-bromovinyl) -uracil is prepared from 5-formyluracil via 5- (E) - (2-carboxyvinyl) -uracil in higher yield. However, condensation according to said method also results in anomerization (α / β = 1: 3) even though the protected and activated sugar derivative used in the condensation contains chlorine in the 1-α position (PJ Barr, AS Jones, G. Verhelst and RT Walker, J. Chem. Soc.

Perkin I. 1665 (1,981)).

20 "Bergström method" (D. E. Bergström and M. K.

Ogawa, JACS 100, 8106 (1978)) and its modified form (A. S. Jones, G. Verhelst and R. T. Walker, Tetrahedron Letters, £ 5, 4415 (1979)) are more preferred than condensation.

From 21-deoxyuridine, C-5-mercury-21-deoxy-25 uridine is prepared, which together with Li 2 PdCl 2 and ethyl acrylate leads to 5- (E) - (carbethoxyvinyl) -21-deoxyuridine, from which hydrolysis gives compound VI (R = H). No anomer mixture is formed when β-21-deoxyuridine is used as a starting product. The disadvantage of this method is that Li 2 PdCl. and 2'-deoxyuridine are very expensive and that the final product has to be purified by column chromatography, so factory-scale production would become very expensive and complex.

5- (E) - (2-bromovinyl) -2'-deoxyuridine (VI, R = 35 H) has also been prepared by bromination of 5-ethyl-2'-deoxyuridine (D. Bärwolff and P. Langen, Nucleic Acids, I, 3,74289

Res. Spec. Pub. λ_, 29 (1975)). Here, the 3-anomer of 5-ethyl-2'-deoxyuridine was converted to 5'-di-O-acetyl-5-ethyl-2'-deoxyuridine, followed by bromination using elemental bromine and dehalogenation with a tertiary 5 base. After removal of the acetyl group, the final product VI (R = H) was finally obtained. The disadvantage of this method is that the β-anomer of 5-ethyl-2'-deoxyuridine used as starting material must first be obtained by separating it from the 10 et, β-anomer mixture formed in the preparation of 5-ethyl-21-deoxyuridine. In addition, the bromination of this process can be followed by anomerization to form a mixture of pure 3-diacyl compound (ivj) with α- and 3-bromo products (VI) (1: 1).

It is an object of the invention to provide a new process for the preparation of compounds VI which uses a second starting material.

The invention is based on the finding that the compounds of general formula IV are CH 2 -CH 3

HN ^ jr ^ 2 3 IV

„T # OR ·, in which hydrogen represents the same as R in formula VI, constitute an economically advantageous starting product.

The process according to the invention for the preparation of 5- (E) - (2-bromovinyl) -21-deoxyuridine of the formula VI and its derivatives is characterized in that the 35'-di-O-acyl-5-ethyl-2 * - a mixture of the α, 3-anomers of deoxyuridine is reacted with the elemental bromine, followed by the resulting dibroni-. derivative, 74289 4 o li ch-ch2

HN ^ jY '! | 2 V

In which R is the same as above, optionally after separation, it is dehydrohalogenated followed by removal of the acyl group.

In a preferred embodiment of the process, a 1 M a, β-anomeric mixture of 3 ', 5'-di-O-acyl-5-ethyl-2'-deoxyuridine of the general formula IV, preferably a 3', 5'-p-chlorobenzoyl derivative thereof, is dissolved. to a halogenated hydrocarbon, preferably dichloromethane, chloroform, dichloroethane, tetrachloromethane or a mixture thereof, and reacted with 2 to 3 M bromine under the influence of light. The resulting dibromo compound of general formula V is then dehydrohalogenated either directly in the reaction solution or, after separation and re-dissolution in a halogenated hydrocarbon, preferably dichloroethane, with a tertiary base, for example triethylamine in excess, and finally optionally removing the acyl residue with a lower alk.

The obtained compounds of general formula VI can be used in pharmaceutical preparations. Compounds VI (R = 30 H or a metabolically cleavable acyl group) are used either in pure form or in admixture with other active ingredients and / or binders, solvents, diluents, flavorings and / or other additives.

The compounds are further applied to solutions, emulsions, suspensions, powders and pastes by methods known per se. There are virtually no side effects associated with the pharmaceutical use of the compounds.

Novel are compounds of formula VI in which R represents a methylcarbonyl or p-chlorobenzoyl group.

The di-O-acyl-protected starting compounds are easily brominated-5 and the whole synthesis becomes shorter, in addition, the acyl removal and re-acylation of the ethyl compound is unnecessary. Another great advantage of the process according to the invention is that the α, β-anomer mixture can be used for bromination. Therefore, the yield of this method is significantly higher than before. Under the conditions of dehydrobromination, most of the β-form of compound VI is separated together with triethylamine hydrobromide and only a very small amount of β-anomer remains in solution along with the α-anomer. The yield of compound VI starting from compound IV (pure β form) is 22.5%, while it is 35.7% (calculated as sugar compound III) starting from the α, β mixture.

The invention is described in more detail below by means of working examples without in any way limiting the scope of the patent.

20

Example 1 1.1 Preparation of starting material p-chlorobenzoyl-5-ethyl-2'-des-oxuridine (β-anomer and α, β-anomers) a) 2,4-bis-O-trimethylsilyl-5-ethylpyrimidine OS, (CH3 ) 3 h 30 N 2 CH 2 -CH 3

1 I

(CH3) 3si (r ^ r 100 g (0.71 moles) of 5-35 ethyluracil (I) 6 74289 dried in vacuo at 150 ° C

O

VCHU CH 2

L J

5 0 '"I

is reacted with 1,1,1,3,3,3-hexamethyldisilazane (HMDS) 200 ml (1.25 M) for 24 hours at reflux under absolute conditions. From the clear solution formed, the excess HMDS is distilled off under normal pressure and the residue is purified in vacuo.

Boiling point = 134 ° C / 1733 Pa Yield: 197.4 g (97%) 15 b) 2'-deoxy-3 ', 5'-di-Op-chlorobenzoyl-α, 8-D-ribofuranosyl chloride (III) 20 RO4- .0.

OR

10 g of 2'-deoxy-D-ribose are dissolved in 190 ml of dry methanol, followed by the addition of 10 ml of 1% dry methanol containing hydrogen chloride and, after 20 minutes, 5 g of freshly prepared AglCO3. The mixture is filtered through filter paper and the solution is evaporated to dryness at 40 ° C. The evaporated liquid is dissolved in 5 ml of absolute pyridine. The residue (thick solution) is dissolved in 58 ml of absolute pyridine and 22.5 ml of p-chlorobenzoyl chloride are added under ice-cooling, keeping the temperature between 20 ° C and 40 ° C. The flask is sealed with a CaCl2 tube and allowed to stand for 35 to 16 hours at room temperature. After the addition of 50 ml of water, the solution is extracted twice with 75 ml of dichloromethane in a separatory funnel, the extract is washed twice with 10 ml of 10% aqueous KHCO3 solution and dried over Na2SO4. After evaporation of the solvent, the residue is dissolved in 75 ml of dry ether and the solution is cooled to 0 ° C. 100 ml of dry glacial acetic acid saturated with hydrochloric acid are added, after which dry hydrogen chloride gas is introduced into the solution until the white product separates. The product is quickly filtered off, washed with ice-cold water and dried over P 2 O 4 and CO 2 in a vacuum desiccator. The product is worked up without recrystallization.

Melting point: 118 ° C Yield: 24 g (75%)

The product contains a 1: 1 mixture of α, β-anomers, which is checked by thin layer chromatography (silica gel HF 254 15 (Merck AG Typ 60); eluent: 7: 3 mixture of chloroform and ether).

c) 3 ', 5'-Di-O-p-chlorobenzoyl-5-ethyl-2'-deoxyuridine (IV) 88.5 g (0.31 M) of 2,4-bis-O-trimethylsilyl 5-Ethylpyrimidine (II) is dissolved in 3,900 ml of absolute acetonitrile and then reacted with 2'-deoxy-3 ', 51-di-Op-chlorobenzoyl-α, 8-D-ribofuranosyl chloride (III) (104.6 g, 0.243 M) and dry Hg 2 O 2 (41.8 g) after the addition of 25 rapid molecular sieves (300 g, Merck 4 A). The solution clarifies on stirring within a few minutes and a crystalline substance begins to precipitate. The mixture is stirred slowly for 5 hours, after which it is allowed to stand overnight at room temperature. The pure β-anomer of 31,5'-di-O-p-chloro-30-benzoyl-4-O-trimethylsilyl-5-ethyl-2'-deoxyuridine then separates.

c / I) Separation of pure β-compound (IV)

The precipitate is filtered off (the filtrate contains a mixture of α, β) and washed three times with 150 ml of chloroform; a molecular sieve remains as a residue in the filter. The combined chloroform-8 74289 solution is shaken in a separatory funnel with 50 ml of 30% KJ solution. The chloroform phase is dried over MgSO 4, filtered and evaporated to dryness in vacuo. The residue is boiled for 2 hours in 4 liters of 96% ethanol. After cooling 5, pure β-IV is separated at room temperature, which is recrystallized from ethanol.

Melting point: 196-7 ° C

Yield: 42.5 g (32.6%, based on III) of 10 c / II) a, β-anomer mixture IV

After condensation, the reaction mixture is allowed to stand in acetonitrile solution for 12 hours at room temperature, then filtered and the precipitate is dissolved in 150 ml of chloroform. The remaining molecular sieve is washed three times with 150 ml of chloroform (β-IV dissolves). The acetonitrile filtrate (α, β-anomer solution) is evaporated to dryness and 1 l of chloroform is added to the residue. A precipitate forms which is filtered and the combined chloroform solution is shaken in a separatory funnel with 150 ml of 30% KJ solution, the chloroform phase is separated off, dried over MgSO4 and filtered. The solvent is then distilled off and the residue is refluxed for a further 30 minutes in 6 l of 96% ethanol. Cool to room temperature whereupon the α, β-product IV separates.

Yield: 96 g (total yield 73.8%) 25 Isomer ratio: β / α = 3: 1.

1.2. 5- (E) - (2-bromovinyl) -2'-deoxyuridine (VI,

R = H) Preparation from anomeric mixture IV

26.6 g (0.05 M) of 3 ', 5'-di-Op-chlorobenzoyl-5-ethyl-30'-deoxyuridine (α, β-anomer mixture: β / α = 3: 1) are dissolved in 350 ml of: warm dry dichloroethane under the influence of light in a dry stream of nitrogen. 6.8 ml (0.125 M) of bromine in 60 ml of dry dichloroethane are then added dropwise according to the reaction rate (approx. 20 to 25 minutes). After the addition of bromine, the irradiation is stopped and the reaction mixture is refluxed for a further 15 minutes using a strong stream of 9,74289 nitrogen. The solvent is evaporated off and a new evaporation is carried out using 20 ml of anhydrous dichloroethane. The residue (hard foam) is then dissolved in 140 ml of anhydrous dichloroethane 5 and reacted dropwise with 10.4 ml (0.075 M) of triethylamine over a period of about 15 minutes.

Compound 8-VI (R = p-chlorobenzoyl) and triethylammonium hydrobromide separate from the solution and are washed after filtration with dichloroethane and then with 80% ethanol. The residue is pure $ -VI (R = p-chlorobenzoyl).

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

The acyl removal is performed as follows: 21 g (0.0345 M) of VI (R = p-chlorobenzoyl) are subjected to an acyl deprotection reaction by stirring for three hours at room temperature in 130 ml (0.5 M) of NaOCH2 solution. The pH of the solution is adjusted to 5 ... 6 using a Dowex 50 H + ion exchanger. The ion exchanger is filtered off and washed with methanol. The combined methanol fractions are evaporated and the residue is recrystallized from water.

Melting point: 175-6 ° C

Yield: 10.6 g VI (R = H) (92.6%).

Example 2 Preparation of 5- (E) - (2-bromovinyl) -2'-deoxyuridine (VI, R = H) from pure 8-substrate 26.7 g (0.05 M) of 31,5'-di-Op- the pure β-anomer of chlorobenzoyl-5-ethyl-21-deoxyuridine (β-IV) is dissolved in 350 ml of warm anhydrous dichloroethane. Under a stream of light and nitrogen-30, 6.8 ml (20 g, 0.125 M) of bromine in 60 ml of anhydrous dichloroethane are added dropwise to the mixture according to the reaction rate (over a period of 20-25 minutes). After the addition of bromine, the irradiation is stopped and the reaction mixture is refluxed for 15 minutes under a strong stream of nitrogen. The solvent containing HBr residue 35 is evaporated off. The residue is redissolved in 20 ml of anhydrous dichloroethane. The clear 74289 1 o yellow residue is dissolved in 140 any anhydrous dichloroethane and reacted with dropwise addition of triethylamine (over about 15 minutes). Triethylamine is 10.4 ml (7.59 g; 0.075 M). The compounds β-VI 5 (R = p-chlorobenzoyl) and triethylammonium hydrobromide separate from the solution, are filtered off and the precipitate is washed with dichloroethane and then with 80% ethanol in which the hydrobromide is soluble. Residue (VI) of 21.0 g = 0.0345 M; 69%) is depilated using 10,130 mL (0.5 M) NaOCH 2 at room temperature for 3 hours. The pH of the solution is adjusted to 5 ... 6 with a Dowex 50 H + ion exchanger. The ion exchanger is filtered off and washed twice with methanol. The combined methanol fractions are evaporated and the residue is recrystallized from water.

Melting point: 175-6 ° C

Yield: 10.6 g (VI, R = H) (63.7% based on starting product IV and 92.3% of compound VI (R = p-chlorobenzoyl)).

Calculated from compound IV (R = p-chlorobenzoyl) (pure form B), the yield of compound VI is 22.5%, while starting from the α, β mixture, 35.7% is obtained (calculated as sugar compound III).

Example 3 1.07 g (2 mM) of 5-ethyl- (31,5'-di-p-chlorobenzoyl) -21-β-deoxyuridine are dissolved in 25 ml of absolute chloroform and reacted in a 500 W photoreactor. with bromine (0.11 ml) dissolved in chloroform. Bromine was added dropwise. The HBr 30 formed is blown out 11a. After the addition of bromine, 0.6 ml of triethylamine is added and the mixture is heated for a further 10 minutes. The solvent is evaporated off, the triethylammonium bromide is optionally removed by aqueous extraction first, and the residue is recrystallized from ethanol.

Yield: 0.8 g = 66% of 5- (2-bromovinyl) -3 ', 5'-di-p-chlorobenzoyl) -2'-β-deoxyuridine, m.p. = 235 ° C.

11 74289

The protecting groups are removed by methanolysis. Melting point: 170 ° C

Yield: 0.4 g = 60% of the title compound.

Example 4 340 mg of β-3 ', 5'-diacetyl-5-ethyl-2'-deoxyuridine (1 mM) are dissolved in 100 ml of CCl 4 and reacted with bromine (350 mg) for 1-2 hours under reflux and under light irradiation (250 W light source). The solvent is then removed in vacuo and the residue is dissolved in 20 ml of diisopropylethylamine. The mixture is refluxed for 15 minutes, after which 5- (E) - (2-bromovinyl) - (35'-diacetyl) -2'-β-deoxyuridine is separated (m.p. = 164 ° C, needle-like crystals from alcohol) or the acetyl group is cleaved. 50 ml of methanol saturated with ammonia in the reaction mixture. After removal of the solvent, the residue is purified by chromatography.

Yield: 206 mg (= 62%) of 5- (2-bromovinyl) -2'-deoxyuridine.

Melting point: 162-163 ° C.

Example 5

To a solution of 3.4 g of 3 ', 5'-diacetyl-5-ethyl-2'-deoxyuridine (10 mM) in 600 ml of tetrachlorocarbon-25 is blown with 1.1 ml of bromine in dry nitrogen gas for 2-4 hours, while refluxing, stirring and subjecting the solution to light. 10 ml of triethylamine are then added and the solution is heated for a further 15 minutes. The solution is filtered, evaporated and subjected to acetylation-removal reaction with 100 ml of ammonia-saturated methanol, followed by elution with silica gel (Merck) and a 9: 1 mixture of chloroform and methanol.

Yield: 1.3 g Melting point: 169 ° C.

Claims (3)

74289 12 1. Method of general formula VI 5 jK <Br vi 10 RO + .0. For the preparation of 5- (E) - (2-bromovinyl) -2'-deoxyuridine and its derivatives according to OR 15, wherein R represents a hydrogen, an alkanoyl group having 1 to 8 carbon atoms or an unsubstituted or p-position at 1 to 4 C benzoyl group substituted by an alkyl group or a halogen atom containing a 20-membered atom, characterized in that 25 HN ^ YCH * ~ CH3 0J ^ J IV A mixture of the α, β-anomers of 3 ', 51-di-O-acyl-5-ethyl-2'-deoxyuridine according to OR-i, wherein hydrogen is the same as R in formula VI, is reacted with the elemental bromine, followed by obtained from general formula V 13 74289 o li CH-CH, I 2 v I Br Br A dibromo derivative according to the formula R1 ° t / 0 \ Vr ORi 10, in the formula having the same meaning as above, optionally after separation, is dehydro-halogenated and optionally then subjected to acyl removal. Process according to Claim 1, characterized in that a mixture of α, β-anomers of 3 ', 5'-di-O-p-chlorobenzoyl-5-ethyl-21-deoxyuridine is used as the diacyl derivative of the general formula IV. Process according to Claim 1 or 2, characterized in that the bromination is carried out under the influence of light in a halogenated hydrocarbon, preferably dichloromethane, dichloroethane, chloroform, tetrachloromethane or a mixture thereof, followed by the resulting dibromo compound, either directly in the reaction solution or separated and halogenated. after dissolution in a hydrocarbon, preferably CH 2 Cl 2, is dehydrohalogenated with an excess of a tertiary base, preferably triethylamine, followed by acyl removal. 74289 14