CH615199A5 - Process for the preparation of N(6)-substituted adenosine nucleotides - Google Patents

Description

The invention relates to a process for the preparation of N6-substituted adenosines of the general formula I.

3rd

615 199

Binding via 2 hydroxyl groups of different i molecules creates a di- or polynucleotide bridged via the 3.5 position:

CH - 0-P-0 OH CH)

ÖH

The residues of ribose and deoxyribose are particularly suitable as sugar residues.

The majority of the compounds are already known, they have antiproliferative and cardiovascular activity.

A method which comes closest to the present method is described in DE-OS 21 51 013.

It is not necessary for the reaction according to the invention to isolate the starting compounds of the general formula II. The 6-trialkylsilyloxyadenosine nucleotides formed in situ can be reacted with ammonia or an amine in the reaction solution directly to give the corresponding adenosine nucleotides.

The type of implementation depends on the connection HNR, R; and the catalyst. The treatment of the silyl compound of the general formula II with primary or secondary amines is preferably carried out at 0 to 180 ° C. When .h salts of primary and secondary amines are used, the amine salt also serves as a catalyst.

Examples of primary amines are: methylamine, ethylamine, propylamine, butylamine, aniline, p-anisidine, benzylamine, homoveratrylamine, tryptamine, N, N-ô dimethylethylenediamine, dopamine hydrochloride, etc.

The following secondary amines are preferably used: dimethylamine, diethylamine, pyrrolidine, piperidine, morpholine, hexamethyleneimine, N-methylpiperazine, etc.

615 199

4th

Silylating agent and primary and secondary amine can be used simultaneously.

The reaction with ammonia is preferably carried out under elevated NH 3 pressure of about 30-50 atm. The reaction is usually complete after 20 to 80 hours at 0 to 180 ° C. In the case of silylation with hexamethyldisilazane, in which ammonia is released anyway, silylation and reaction with ammonia can be carried out in one step.

Excess amine HNR, R2 is particularly suitable as a solvent for the reaction, but indifferent solvents such as toluene, xylene, anisole, dioxane, glyme, pyridine or dimethylformamide or sulfolane are preferred for the less soluble silyl compounds.

Lewis acids, in particular metal oxides, metal salts, and salts of amines are particularly suitable as catalysts. The metal salts are optionally used in the reaction with excess amine HNR, R2.

The catalysts are generally used in the reaction in amounts of 0.001 mol to 5 mol based on the nucleotide, but preferably in amounts of 0.05 to 1 mol.

Acidic aluminum oxide, mercury-II chloride, mercury-II-acetate as well as zinc-II-chloride, tin-IV-chloride, titanium-IV-chloride and boron trifluoride etherate, which are used in combination with excess amine, proved to be the most effective. and salts of amines such as ammonium sulfate, tryptamine hydrochloride, dopamine hydrochloride, pyridinium chloride, etc.

It is surprising that the reaction with amines at temperatures up to 180 ° C does not break the phosphoric ester bond.

example 1

N6-benzyladenosine-5'-monophosphoric acid

A suspension of 117.65 g (0.3 mol) of inosine-5'-monophosphoric acid disodium salt in 188.7 ml (0.9 mol) of hexamethyldisilazane and 113.7 ml (0.9 mol) of trimethylchlorosilane was added for 12 hours 145 ° C bath temperature heated under reflux. The suspension was then mixed with 200 ml of 1,2-dichloroethane (abs.) And filtered with the exclusion of moisture. The residue obtained after evaporating the filtrate was added 27 hours at 145 after addition of 62.9 ml (0.3 mol) of hexamethyldisilazane as well as 163.7 ml (1.5 mol) of benzylamine and 3.96 g (0.03 mol) of ammonium sulfate ° C bath temperature stirred. The resulting hexamethyldisiloxane (bp 101 ° C) was distilled off over a Vigreux column (10 cm). The brown reaction mixture was mixed with 600 ml of methanol and stirred at room temperature for 16 hours. The precipitated benzylamine salt of N6-benzyladenosine-5'-monophosphoric acid was filtered off, washed with ethanol and dried. After crystallizing the concentrated filtrate from ethanol, filtering off and drying the substance, 146.8 g of benzylamine salt were obtained. By ion exchange chromatography in water over a DOWEX column (type 50 WX2, H + form;

2.5 X120 cm), concentration of the fractions and crystallization from ethanol / water, 93.5 g (71%) of colorless-crystalline N6-benzyladenosine-5'-monophosphoric acid with a melting point of 173-175 ° C. were obtained.

Example 2

Vß- [2- (5-methoxy-3-indolyl) ethyl] adenosine-5'-monophosphoric acid, trihydrate.

11.765 g (30 mmol) of lxiosm-5'-monophosphate di sodium salt were refluxed in 18.87 ml (90 mmol) of hexamethyldisilazane and 11.35 ml (90 mmol) of trimethylchlorosilane at 145 ° C. bath temperature, undissolved substance after cooling and addition of 100 ml of 1,2-dichloroethane (absolute) filtered off under argon.

The oily residue remaining after the concentration was mixed with 5.24 ml (25 mmol) of hexamethyldisilazane, 9.51 g (50 mmol) of 5-methoxy-tryptamine and 0.446 g (0.25 mmol) of p-toluenesulfonic acid (monohydrate) and 20 Hours at s 145-150 ° C bath temperature with simultaneous distillation (5 cm Vigreux column, bp> 98 °).

The reaction solution was boiled in 200 ml of CH3OH for 3 hours and then evaporated.

The residue was dissolved in 300 ml Na2CO, solution! » taken and extracted 3 times with 200 ml of methylene chloride. The Na2C03 phase was evaporated to dryness and extracted 5 times with 200 ml of CH3OH hot. The residue remaining after the methanol had been evaporated was dissolved in 100 ml of H20 (pH 9) and acidified with dilute hydrochloric acid (pH 2), i 5 light brown fluffy substance precipitated out.

The precipitate was filtered off and recrystallized from H20 = 8.2 g = 57.1% N6- [2- (5-methoxy-3-indolyl) ethyl] adenosine-5'-monophosphoric acid, trihydrate,

(Mp = 161-165 °).

2 (1st

Example 3

N6.N6- [N- (2-hydroxyethyl) -3-aza-pentamethylene] adeno-sin-5 'monophosphoric acid, monohydrate.

39.22 g (100 mmol) of inosine 5'-monophosphate di-sodium 3 salt were suspended in 62.72 ml (300 mmol) of hexamethyldisilazane and 37.89 ml (300 mmol) of trimethylchlorosilane and for 10 hours at 145 ° C. bath temperature cooked at reflux.

After cooling and adding 150 ml of 1,2-dichloroethane (absolute), the dark brown, cloudy solution was filtered under argon and concentrated in vacuo. The oily residue was treated with 40.9 ml (195 mmol) of hexamethyldisilazane, 25.8 ml (210 mmol) of N- (2-hydroxyethyl) piperazine and 1.902 g (10 mmol) of p-toluenesulfonic acid (monohydrate) and then for 14 hours at 145-150 ° C bath temperature with simultaneous distillation (5 cm Vigreux column, bp> 98 °). The reaction solution was boiled in 500 ml of CH3OH for 4 hours at 100 ° C. and concentrated.

The remaining residue was dissolved in 600 ml H20 and chromatographed over 300 ml Dowex 50 WX2 H + form. 40 Fractions 3-20 (600 ml H20 each) after concentration and crystallization from CH30H / H20 gave 34.2 g = 71.5% N6.N6- [N- (2-hydroxyethyl) -3-aza-pentamethylene] - adenosine-5'-monophosphoric acid, monohydrate (mp 203-206 °).

Example 4

N6-benzyl-2-aminoadenosine-5 'monophosphoric acid, monohydrate.

40.72 g (100 mmol) guanosine 5'-monophosphate disodium salt were suspended in 62.72 ml (300 ml) hexamethyldisilazane, 37.89 ml (300 mmol) trimethylchlorosilane and 80 ml pyridine (abs.) And 72 h at 145 ° C bath temperature cooked. The soluble substance was filtered off under argon, washed with pyridine and the filtrate evaporated in vacuo.

The residue was mixed with 20.91 ml (100 mmol) of hexamethyldisilazane, 54.56 ml (500 mmol) of benzylamine and 1.32 g (10 mmol) of ammonium sulfate and stirred for 18 h at 145 ° C bath temperature while distilling off hexamethyldisiloxane (Sdpt 98 ° C, 6 cm Vigreux column). After adding 500 ml of methanol and boiling for 1 h, the mixture was concentrated and the viscous brown residue was triturated 3 times with 600 ml of ether each time and the resulting crystalline substance was filtered off. After dissolving in methanol / water, the mixture was acidified to pH 2 with hydrochloric acid, concentrated after carbon treatment and recrystallized from water; Schmpt. 229-232 ° C; Yield:

65 39.8 g (88%), (84.6% as monohydrate).

POOR QUALITY

50

55

Claims (4)

615 199 2. The method according to claim 1, characterized in that the heterocyclic ring has the meaning of R, and R2 has 4-, 5-, 6- or 7-members. 2nd PATENT CLAIMS l. Process for the preparation of Nh-substituted adenosines of the general formula I (I), (I) wherein R! and R 1 each individually represents a hydrogen atom or an alkyl, aralkyl, aryl or heterocyclic group or R, a hydrogen atom and R: a hydroxy, amino or an optionally terminally substituted alkyl group or R, and R: together including the N Atoms represent a heterocyclic ring, R represents a hydrogen atom or an amino group, and Z represents a sugar residue with a phosphoric acid residue bonded via one or two hydroxyl groups of the same molecule or via two hydroxyl groups of different molecules, characterized in that a 6-trialkylsilyloxy purine derivative of the general formula wherein i? R! and R2 each individually represents a hydrogen atom or an alkyl, aralkyl, aryl or heterocyclic group or Rt represents a hydrogen atom and R2 represents a hydroxy, amino or an optionally terminally substituted alkyl group or R, and R2 together including the N- Represent a hetero-: n cyclic ring, preferably of 4-, 5-, 6- or 7-members, R3 is a hydrogen atom or an amino group, and Z represents a sugar residue with a phosphoric acid residue bonded via one or two hydroxyl groups of the same molecule or via two hydroxyl groups of different molecules. The process according to the invention is characterized in that a 6-trialkylsilyloxy-purine derivative of the general formula II Alkyl alkyl alkyl Alkyl alkyl alkyl (II) in which alkyl in each case means the same lower alkyl radical, R3 'is a hydrogen atom or an amino group protected intermediately with a tri-alkylsilyl radical and Z' has the meaning of the radical Z in which the free hydroxyl groups of the sugar and of the phosphoric acid ester are intermediately silylated, with ammonia or an amine of the formula HNR, R2 or a salt of the amine. 3. The method according to claim 1, characterized in that in the compounds of formula II, the alkyl radicals are methyl radicals. 4. The method according to claim 1, characterized in that one carries out the reaction in the presence of a Lewis acid as a catalyst. (II) in which alkyl in each case means the same lower alkyl radical, 45 R3 'is a hydrogen atom or an intermediate with a tri- J i is alkylsilyl radical protected amino group and Z 'has the meaning of the radical Z in which the free hydroxyl groups of the sugar and the phosphoric acid ester are intermediately silylated, reacted with ammonia or an amine of the formula HNR, R2 or 50 a salt of the amine. In the compounds of the formula II, alkyl preferably denotes the methyl radical. The process according to the invention can be carried out in the presence of Lewis acids as a catalyst. 55 The phosphoric acid is bound in the sugar residue Z and Z 'of the general formula I and II via one or two hydroxyl groups, the binding being carried out via two hydroxyl groups on one molecule or over two molecules. When binding via 2 hydroxy groups of the same M1 molecule, e.g. a cyclic monophosphate of the general formula