HU186458B - Process for preparing 5-alkyl-cytidines - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to a novel process for the preparation of 5-alkylcytidines. The essence of our process is to condense the bis-trimethylsilyl derivative of the 5-substituted-cytosine readily prepared with fully acylated sugar in the presence of SnBr. Without isolation of the protected nucleoside with good yield, the free 5-alkylcytidine or its salt is obtained by conventional means (NH1 / MeOH). The most important advantage of using the present invention is that the process involves a chromatographic purification process 186458-1-

Description

The present invention relates to a novel process for the preparation of the 5-position optionally substituted cytidine compounds of the formulas III and IV and their acid addition salts having the formula:

R 'represents a hydrogen atom, a halogen atom, a C 1 -C 8 straight or branched alkyl group or a five- or six-membered heterocyclic group linked through a nitrogen atom, and the R' CO groups are the same or different as known in nucleoside chemistry. , aliphatic or aromatic acyl protecting groups.

Practically available methods for the production of substituted antimetabolite compounds of cellular division and viral proliferation can be divided into two groups.

The most commonly used method is to convert the relatively easily accessible carbonyl group at the 4-position to the imino group in steps 1-3 via an intermediate active derivative (Liebigs Ann. Chem. 1975, 988). However, the preparation or further modification of the active intermediate requires vigorous reaction conditions that will cause significant degradation of the nucleoside in sensitive R 'substituents. The by-products can be separated from the target compound only by chromatography.

The other known solution, the condensation of cytosine with ribose, is not considered well developed. Condensation is carried out in the presence of various catalysts ΓAngew. Int. Ed., 14, 421 (1975); Tetrahedron Lett. 1977, 933; Tetrahedron Lett. 1978, 1339; Nucl. Ac. Slit. 8, 4755 (1980); Chemistry Lelt. (Tokyo, 1974, 449; J. Heterocyl. Chem. 6, 109 (1969); Chem. Abstr. 95, 62605w (1981)). The catalysts used are difficult to access, complex compounds which are expensive to produce, either in addition or not. The tin (IV) chloride (Chem. Abstr. 88, 23300d, 90, 87784b), which is widely used as a catalyst for the preparation of related compounds, does not catalyze the reaction of cytosine and ribose. According to some of the cited publications, glycosyl halides used as reagents are unstable, degradable compounds, and N ⁴ -acylcylosines, especially 5-alkyl-derivatives, are difficult to access.

The present invention seeks to overcome the disadvantages of the prior art.

In our experiments it was found that when tetraacyl ribosides are condensed with bis (trimethylsilyl) cytosine compounds in the presence of tin (XV) bromide or a mixture of tin (IV) chloride and tin (IV) bromide, the reaction proceeds even at room temperature. , and the corresponding protected nucleoside in high yield, pure formation. The protecting groups are conveniently cleaved using methanolic ammonia in the known manner to give the desired cytidine 5-optionally substituted.

The present invention therefore relates to a process for the preparation of compounds of formula (III) and (IV) wherein R 'and R "CO- are as defined above.

and condensation of the compounds of formulas (I) and (II), wherein R 'and R' CO- are as defined above, in the presence of a catalyst in anhydrous aprotic medium to remove their acyl protecting groups and from the reaction mixture. in the form of an acid addition salt

- by segregation. According to the present invention, the catalyst used in the reaction is a tin (IV) bromide or a tin (IV) chloride containing up to 50 mol% of tin (IV) chloride, at least one mol of the compound of formula (II). 0.5 mol of catalyst.

1-2 moles of catalyst are preferably used per mole of compound (II). Further advantages of increasing the amount of catalyst to more than 2 moles are no longer achieved.

The reaction is carried out in an anhydrous aprotic medium. The reaction medium is preferably anhydrous dichloroethane or acetonitrile.

In the compounds of the formula (Π), the glycosylated hydroxyl group of the sugar molecule is preferably protected by the acetyl group, and the other free hydroxyl groups may conveniently be protected by a benzoyl or halobenzoyl group.

The following examples illustrate the invention without limiting it.

Example 1

5.04 g (10 mmol) of 2,3,5-tri-O- (p-chlorobenzoyl) -1-O-acyl-η-D-ribofuranoside and 11 mmol of crude 5-piperidylbis (trimel-1-benzyl) ) cytosine (11 molar product of 5-piperidyl cytosine in hexamethyldisilazane at boiling point) in 60 ml of anhydrous dichloroethane at 20 ° C with stirring 8.76 g (20 mmol) of tin (IV) bromide We are added. After 20 hours, the reaction mixture was washed neutral with aqueous potassium bicarbonate solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from ether (10 mL). M.p. 153-158 DEG C., m.p. 153-158 DEG C. (74%), m.p.

¹⁵ C NMR lines: 23.6 (C3), 26.1 (C '2), 53.6 (C'1), 62.8 (C'5), 71.0 (C'2), 73 , 9 (C'3), 80.6 (C'4), 90.1 (C'1),

123.9 (C5), 133.0 (CG), 149.3 (C2), 160.0 (C4) ppm.

Example 2 2,3,5-tri-O- (p-chlorobenzoyl) -1-O-acetyl-6-D-ribofuranoside and crude 5-fluorobis (trimethylsilyl) cytosine (11 mol) A solution of 5-fluorocytosine in hexamelyldisilazane (boiling point) in 60 ml of anhydrous acetonitrile at 20 ° C was treated with 4.3 g (10 mmol) of tin (IV) bromide and 2.61 g (10 mmol) of tin ( IV) chloride is added. After 20 hours, the reaction mixture was concentrated under reduced pressure, the residue was washed with cold water and the crystalline material was dissolved in chloroform. The chloroform solution was washed neutral with aqueous potassium bicarbonate solution, dried over magnesium sulfate, filtered and the filtrate was evaporated. The residue was treated with 50 ml of saturated abs. methanolic ammonia solution. After 20 hours, the solvent was evaporated, and the silver syrup was crystallized with ether and 10 ml of 10% methanolic hydrochloric acid were added to the crystalline material and the mixture was evaporated. 179180'C is obtained, m.p. 5-fluorocytidine hydrochloride.

Example 3

The procedure described in Example 2 is the same as thousands, except that bisftriroethylsilylcylosine is used as starting material. Melting cytidine hydrochloride 209-210 'Con was obtained in 78% yield.

Analysis: Calculated for C 8 H 11 O 3 Na.HCl: C, 38.6; H, 5.0; N, 15.0;

found; C: 38.3%, H: 5.2%, N: 14.7%.

CD spectrum: λ nra / w / o p. 279 / + 3.0; 241/0; 216 / -3.8.

Example 4

The procedure of Example 2 was followed except that starting from 5-isopropylbis (trimethylsilyl) cytosine and using dichloroethane as the reaction medium. 5-isopropylcytidine melting at 200 'C is obtained in a yield of 72%.

Analysis calculated for C 11 H 10 O 3 Na: C, 50.5; H, 6.7; N, 14.7;

Found: C, 50.1; H, 7.0; N, 14.4.

CD spectrum: λ max: < o > 287 / + 2.65;

2.45 / 0; 218 / -2.5.

The hydrochloride of the product melts at 182-186 ° C.

Example 5

The procedure of Example 2 was followed except that starting from 5-hexyl-bis (trimethylsilyl) -cytosine, sulfuric acid was used as the acid for salt formation. 5-Hexylcytidine hemisulfate was obtained in 75% yield.

Analysis based on the formula C15H25O5N3.I / 2 HaSO «:

Calculated: C, 47.9; Found: C, 48.17.

CD spectrum: 244/0; 220 / -1.9.

II: 6.9%, N: 11.2%;

11: 7.2%, N: 10.8%.

ληιη / ΔΕ o.e .: 285 / + 2.0;

Claims (3)

Patent claims Ifi 1. A process for the preparation of compounds of formula III and IV and their acid addition salts R 'is hydrogen, halogen, C 1 -C 8 straight or branched alkyl 20, or five or six membered heterocyclic groups linked through the nilogen atom, and the RCO groups are the same or different; 25 aliphatic or aromatic acyl protecting groups commonly used in nucleoside chemistry are compounds of Formula I and Formula II wherein R 'and R' - condensation in the presence of a catalyst in an anhydrous aprotic medium, optionally cleavage of the acyl protecting groups and isolation from the reaction mixture, optionally in the form of an acid addition salt, characterized in that the reaction catalyst is tin (IV) -brinide or tin (IV) bromide containing mole% of stannous chloride - using a mixture of tin (IV) chloride, at least 0.5 mole of catalyst per mole of compound (n) (Priority: 22 August 1984). 2. Process according to claim 1, characterized in that 1-2 moles of catalyst are used per mole of the compound of formula II. 45 (Priority: August 22, 1984) 3. A process according to claim 1 for the preparation of compounds of formula III and IV and their acid addition salts wherein R 'is hydrogen or C 1 -C 8 straight or branched alkyl and R' CO A process according to claim 1, characterized in that 2 moles of catalyst per mole of the compound of formula II 55 mol of tin (IV) bromide or a mixture of 1 mol of tin (IV) chloride and 1 mol of tin (IV) bromide are used. (Priority; December 23, 1981)