CH648313A5 - Process for the preparation of imidazo[4,5-b]pyridines and -pyrimidines - Google Patents

Description

648313

2nd

PATENT CLAIMS 1. Process for the preparation of imidazo [4,5-b] pyridines and pyrimidines of the general formula

, (I)

in the

Ri is an alkyl, alkoxy, alkylmercapto or alkylsulfinyl group each having 1 to 4 carbon atoms or a halogen atom,

R2 is an alkylsulfinyl group with 1 to 4 carbon atoms or an alkoxy group with 2 or 3 carbon atoms, which is terminated by an alkylsulfinyl group with 1 to 4 carbon atoms, an aralkylsulfinyl group with 7 to 9 carbon atoms, one optionally with alkyl groups with 1 to 3 carbon atoms, alkoxy groups with 1 to 3 carbon atoms and / or halogen atoms mono-, di- or tri-substituted phenylsulfinyl group or one optionally substituted by alkyl groups with 1 to 3 carbon atoms, alkoxy groups with 1 to 3 carbon atoms and / or halogen atoms mono- or disubstituted nitrophenylsulfinyl group, and

X represents the CH group or a nitrogen atom, and of their 1H tautomers and of their physiologically tolerable salts with inorganic or organic acids, characterized in that a compound of the general formula

, (ii)

in the

X and Ri are as defined in the introduction and R3 is an alkyl mercapto group with 1 to 4 carbon atoms or an alkoxy group with 2 or 3 carbon atoms which is terminated by an alkyl mercapto group with 1 to 4 carbon atoms, an aralkyl mercapto group with 7 to 9 carbon atoms, one optionally with alkyl groups with 1 to 4 carbon atoms 3 carbon atoms, alkoxy groups with 1 to 3 carbon atoms and / or halogen atoms, mono-, di- or trisubstituted phenyl mercapto group or an optionally substituted by alkyl groups with 1 to 3 carbon atoms, alkoxy groups with 1 to 3 carbon atoms and / or halogen atoms, mono- or disubstituted nitrophenyl mercapto group, means is oxidized in a solvent with bromine or a hypobromite, and if desired a compound of the general formula I or its 1 H-tautomer obtained in this way is converted into a physiologically tolerable salt with an inorganic or organic acid.

2. The method according to claim 1, characterized in that an aqueous or anhydrous solvent is used as the solvent.

3. The method according to claims 1 and 2, characterized in that the reaction at temperatures between

See - 10 and 80 ° C, but preferably at temperatures between 15 and 30 ° C.

4. The method according to claims 1 to 3, characterized in that the reaction in a pH range from 0 to 10, but preferably in a pH range of 3

io to 8, is carried out.

5. The method according to claims 1 to 4, characterized in that the reaction in the presence of a buffer, e.g. in the presence of a carboxylate, carbonate, hydrogen gene phosphate or dihydrogen phosphate anion,

15 leads.

6. The method according to claims 1 to 5, characterized in that the oxidation is carried out with bromine or sodium hypobromite.

20th

In British Patent 1,445,824 and European Laid-Open Publications 0 022 495 and 0 024 290, 25 et al. already a process for the preparation of imidazo [4,5-pyyridines and pyrimidines of the general formula

. (I)

in the

40 Ri is an alkyl, alkoxy, alkylmercapto or alkylsulfinyl group each having 1 to 4 carbon atoms or a halogen atom,

R2 is an alkylsulfinyl group having 1 to 4 carbon atoms or an alkoxy group having 2 or 3 carbon atoms, the 45 being terminated by an alkylsulfinyl group having 1 to 4 carbon atoms, an aralkylsulfinyl group having 7 to 9 carbon atoms, one optionally by alkyl groups having 1 to 3 carbon atoms, alkoxy groups having 1 up to 3 carbon atoms and / or halogen atoms mono-, di- or tri-50 substituted phenylsulfinyl group or an optionally substituted by alkyl groups with 1 to 3 carbon atoms, alkoxy groups with 1 to 3 carbon atoms and / or halogen atoms mono- or disubstituted nitrophenylsulfinyl group, and 55 X represent the CH group or a nitrogen atom, of their 1H tautomers and of their physiologically tolerable salts with inorganic or organic acids, which is characterized in that a corresponding mercapto compound is oxidized with hydrogen peroxide 60 or a peracid. The sulfinyl compound obtained in this way contains a small amount of unconverted mercapto compound and a small amount of the corresponding sulfonyl compound, these impurities make complex cleaning necessary for the production of a pharmaceutical-quality product.

Furthermore, from the handbooks of organic chemistry (C. Ferri, reactions of organic synthesis, publisher: G. Thieme (1978); Kharasch and Meyers: The Chemi-

3rd

648313

stry of Organic Sulfur Compounds, Vol. 1,157-159 (1961), Pergamon Press N.Y .; S. Oae: Organic Chemistry of Sulfur, 385-387 (1977), Plenum Press N.Y. and London)

that bromine is an unsuitable oxidizing agent in the oxidation of a mercapto compound to the corresponding sulfoxide, since this causes undesirable side reactions, e.g. Cleavage of the carbon-sulfur bond, formation of carbon-bromine bonds and / or bromination of the aromatics.

Surprisingly, it has now been found that the io compounds of the general formula I can also be obtained in greater purity and in excellent yields by oxidation of a compound of the general formula

, (ii)

20th

the CH-PS 605 939 produce process, namely by ring closure of a corresponding 5,6-di-amino-pyrimidine or 2,3-diamino-pyridine.

The following examples are intended to explain the invention in more detail:

Reference example I

2- (2-methoxy-4-methylsulfinylphenyl) -1 H -imidazo- [4,5-b] pyridine

6.6 g of 2- (2-methoxy-4-methylmercapto-phenyl) -1 H-imi-dazo [4,5-b] pyridine are dissolved in 100 ml of chloroform and at −15 ° to -20 ° C. for 5 A solution of 2.96 g of 3-chloro-peroxy-benzoic acid in 600 ml of chloroform was added dropwise. The mixture is then shaken out with a dilute soda solution, the chloroform phase is dried and concentrated. The residue is purified on a silica gel column (mobile phase: chloroform / methanol = 9: 1). The yellow hydrochloride is obtained by adding ethereal hydrochloric acid to a methanolic solution of the base. Yield: 2.3 g (33.6% of theory),

Base melting point: 154-155 ° C.

in the

X and Ri are defined at the beginning and R? means an alkyl mercapto group with 1 to 4 carbon atoms or an alkoxy group with 2 or 3 carbon atoms, which is terminated by an alkyl mercapto group with 1 to 4 carbon atoms, an aralkyl mercapto group with 7 to 9 carbon atoms, one optionally with alkyl groups with 1 to 3 carbon atoms, alkoxy groups with 1 to 3 carbon atoms and / or halogen atoms mono-, di- or tri-substituted phenylmercapto group or one optionally substituted by alkyl groups with 1 to 3 carbon atoms, alkoxy groups with 1 to 3 carbon atoms and / or halogen atoms mono- or disubstituted nitrophenyl mercapto group, with bromine or a hypobromite obtained in a solvent.

The oxidation is carried out in a solvent, e.g. in an aqueous solvent such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, hydrochloric acid or sulfuric acid, or in an anhydrous solvent, e.g. Glacial acetic acid, methylene chloride, chloroform, dioxane, tetrahydrofuran, formic acid ethyl ester, ethyl acetate, dimethylformamide, dimethyl sulfoxide or hexamethyl-phosphoric acid triamide, at temperatures between -10 and 80 ° C, but preferably at temperatures between 15 and 30 ° C, in a pH range performed from 0 to 10. However, the reaction in a pH range from 3 to 8, particularly expediently in the presence of a buffer, e.g. in the presence of a carboxylate anion, e.g. Alkali acetate such as sodium acetate, in the presence of a phosphate such as disodium hydrogen phosphate or sodium dihydrogen phosphate, or in the presence of a carbonate such as sodium hydrogen carbonate or disodium carbonate, with bromine or with a hypobromite, e.g. Sodium hypobromite.

The compounds of general formula I obtained according to the process of the present invention can then, if desired, be converted into their acid addition salts with inorganic or organic physiologically tolerated acids. Examples of suitable acids have been found to be hydrochloric acid, hydrobromic acid, sulfuric acid, lactic acid, citric acid, tartaric acid, maleic acid or fumaric acid.

The starting materials used in the process are largely known from the literature or can be analogously to that in

Reference example II

2- (2-methoxy-4-methylsulfinylphenyl) -1 H-imidazo-25 [4,5-b] pyridine hydrochloride

A solution of 135.6 g (0.5 mol) of 2- (2-methoxy-4-methylmercaptophenyl) -IH-imidazo [4,5-b] pyridine in 600 ml of 80% acetic acid is mixed with 57 g of 30% Hydrogen peroxide was added and the mixture was left to stand at laboratory temperature for 30 days. After adding a further 5 g of 30% hydrogen peroxide, the reaction mixture is left to stand at laboratory temperature for a further 3 days. The oxidation is stopped, the reaction mixture is poured onto 31 ice water, with conc. Ammonia adjusted to pH 9 and extracted 3 times with Chlo-35 roform. The combined extracts are dried and concentrated in vacuo. According to a comparison by thin layer chromatography, the crude product contains about 3% starting material, 4% sulfone and 2% other unknown impurities.

40 By purification over 4000 g of silica gel (eluent: chloroform + 3% acetone), 72.2 g (50.3% of theory) of the desired product of melting point 198-199 ° C. are obtained after reprecipitation from acetone. According to the thin layer chromatogram, the product contains [ready-made silica gel plates 60 F 45 254 from E. Merck, Darmstadt; System: chloroform / ethanol (85/15)] 0.1% sulfide, 0.5% sulfone and 0.85% unknown compounds as impurities.

example 1

so 2- (2-methoxy-4-methylsulfinylphenyl) -1 H-imidazo- [4,5-b] pyridine

To a suspension of 229.8 g of 2- (2-methoxy-4-methylmercaptophenyl) -IH-imidazo [4,5-b] pyridine x 0.5 g of CH3OH and 72.1 g of sodium acetate in 1.51 glacial acetic acid 55 41.1 ml of bromine, dissolved in 150 ml of glacial acetic acid, are added dropwise at a temperature between 20 and 25 ° C. The reaction mixture is then poured onto about 1 kg of ice and concentrated with. Ammonia adjusted to pH 9 at approx. 25 ° C. The aqueous phase is extracted 3 times with a total of 60 31 chloroform. After drying the organic phase with magnesium sulfate and treating with activated carbon, the solvent is removed to a residue of 200 g and the beginning of the installation is prevented by adding 40 ml of methanol and heating to about 40-45 ° C. The 65 product precipitated with 1.21 acetone is filtered off with suction, dissolved in a mixture of 300 ml methanol and methylene chloride at 40 ° C. and, after being concentrated in vacuo to a solvent residue of approx. 150 g, again poured out with 11 acetone

648313

falls. It is suctioned off and washed with a mixture of 200 ml of acetone and 300 ml of n-hexane.

Yield: 175.1 g of melting point 201-202 ° C.

After concentrating the mother liquor and adding acetone, a further 36.3 g of melting point 200-201 ° C. are obtained.

Total yield: 211.4 g (92% of theory).

The product obtained in this way contains, according to the thin-layer chromatogram [ready-made silica gel plates 60 F 254 from E. Merck, Darmstadt; System: chloroform / ethanol (85/15)] 0.05% sulfone and 0.25% unknown impurities.

Example 2

2- (2-methoxy-4-methylsulfinylphenyl) -1 H -imidazo- [4,5-b] pyridine

A solution of 5.4 g (0.02 mol) of 2- (2-methoxy-4-methylmercapto-phenyl) -1 H-imidazo [4,5-b] pyridine in 30 ml of 50% acetic acid is dissolved in 20 A solution was added dropwise at room temperature for minutes, with stirring, which is prepared as follows: 4.8 g of 1.5 ml (0.03 mol) of bromine are added dropwise to 6 g of sodium hydroxide in 50 ml of water with stirring and ice-water cooling. When the reaction has ended, the mixture is acidified with 45 ml of glacial acetic acid while cooling further.

The reaction mixture obtained is stirred for 5 minutes, diluted with 100 ml of water, with conc. Ammonia adjusted to pH 8 and shaken 3 times with ethyl acetate. The mixture is then extracted 3 times with chloroform, the extract is dried over magnesium sulfate, the solvent is removed in vacuo and the honey-like residue is dissolved in 100 ml of acetone. The sulfoxide begins to crystallize out immediately. The white product is filtered off, washed with acetone and then with n-hexane and dried.

Yield: 4.8 g (83.6% of theory),

Melting point: 200-202 ° C.

Example 3

8- (2-methoxy-4-methylsulfinyl-phenyl) -purine To a suspension of 250.2 g of 8- (2-methoxy-4-methylmercaptophenyl) -purine hydrochloride in 1.4150% acetic acid, 142.0 g added anhydrous sodium acetate and stirred for 20 minutes at room temperature. A solution of 127.9 g of bromine in 120 ml of glacial acetic acid is then added dropwise with vigorous stirring within one hour. The temperature rises from 22 ° C to 27 ° C. When the bromine addition is complete, the mixture is stirred for 10 minutes, then adjusted to a pH of 7.5 with saturated potassium carbonate solution and stirred at room temperature. After about an hour, a precipitate begins to crystallize out. Allow to stand overnight, suction, wash with cold water and dry in vacuo at 50 ° C. For cleaning, the substance is dissolved twice in approx. 11 water at 50 ° C, treated with activated carbon and slowly brought to church at 10 ° C. The mixture is then dried at 70 ° C. in vacuo over phosphorus pentoxide.

Yield: 167 g (72% of theory),

Melting point: 236-238 ° C.

The following compounds were prepared analogously to Examples 1 to 3 above:

2- (2-methoxy-4-ethylsulfinyl-phenyl) -1 H-imidazo-

[4,5-b] pyridine hydrochloride

Melting point: 122-123 ° C

2- (2-methoxy-5-methylsulfinylphenyl) -1 H-imidazo-

[4,5-b] pyridine

Melting point: 211-212 ° C

2- (2-ethoxy-5-methylsulfinylphenyl) -1 H-imidazo [4,5-b] pyridine

Melting point: 199-200 ° C

2- (2-ethoxy-4-ethylsulfonylphenyl) -1 H -imidazo-

[4,5-bJpyridine

Melting point: 167-168 ° C

2- (2-methoxy-4-propylsulfinyl-phenyl) -1 H-imidazo-

[4,5-b] pyridine

Melting point: 182-183 ° C

2- (2-ethoxy-4-propylsulfinylphenyl) -1 H -imidazö- [4,5-b] pyridine

Melting point: 182.5-183.5 ° C (dec.) 2- (2-Ethoxy-4-butylsulfinylphenyl) -1 H-imidazo- [4,5-b] pyridine Melting point: 187-188 ° C

2- (2-fluoro-5-methylsulfinyl-phenyl) -IH-imidazo [4,5-b] pyridine

Melting point: 191-192 ° C

2- [2- (2-Ethylsulfmyl-ethoxy) -4-methoxy-phenyl] -1 H-imi-dazo [4,5-b] pyridine Melting point: 188-189 ° C

2- [2- (2-methylsulfinyl-ethoxy) -4-methoxy-phenyl] 1 H-imi-

dazo [4,5-b] pyridine

Melting point: 231-232 ° C

2- [2- (3-methylsulfinyl-propoxy) -4-methoxy-phenyl] -1 H-imi-

dazo [4,5-b] pyridine

Melting point: 133-134 ° C

2- [2- (3-ethylsulfinyl-propoxy) -4-methoxy-phenyl] -1 H-imi-

dazo [4,5-b] pyridine

Melting point: 127-128 ° C

2- [2- (2-methylsulfinylethoxy) -4-methylsulfinylphenyl] -1H-

imidazo [4,5-b] pyridine

Melting point: 193-194 ° C

2- [2- (2-methylsulfinyl-ethoxy) -4-methyl-phenyl] -lH-imi-

dazo [4,5-b] pyridine

Melting point: 191-192 ° C

2- [2- (2-methylsulfinyl-ethoxy) -4-chlorophenyl] -1 H-imi-

dazo [4,5-b] pyridine

Melting point: 221-222 ° C

2- [2-methoxy-4- (2-methylsulfinylethoxy) phenyl] -1 H-imi-

dazo [4,5-b] pyridine

Melting point: 205-206 ° C

2- [2-methoxy-4- (2-ethylsulfinyl-ethoxy) phenyl] -1 H-imi-

dazo [4,5-b] pyridine

Melting point: 215-217 ° C

2- [2-methoxy-4- (3-methylsulfinyl-propoxy) phenyl] -1 H-imi-

dazo [4,5-b] pyridine

Melting point: 179-180 ° C

2- [2-methoxy-4- (3-ethylsulfinyl-propoxy) phenyl] -1 H-imi-

dazo [4,5-b] pyridine

Melting point: 166-167 ° C

2- [2- (2-Methylsulfinyl-ethoxy) -5-methylmercapto-phenyl] -1 H-imidazo [4,5-b] pyridine Melting point: 191-192 ° C

8- (2-Ethoxy-4-methylsulfinyl-phenyl) -purine hydrochloride melting point: 220-221 ° C (dec.) 8- [4-methoxy-2- (2-methylsulfinyl-ethoxy) -phenyl] -purine melting point : 228-229 ° C

2- [2- (2-phenylsulfinylethoxy) -4-methoxyphenyl] -1 H-imi-

dazo [4,5-b] pyridine

Melting point: 185-186 ° C

2- [2- (2-benzylsulfinyl-ethoxy) -4-methoxy-phenyl] -1 H-imi-

dazo [4,5-b] pyridine

Melting point: 194-195 ° C

2- [2- (2- {4-ChlorophenylIsulfmyl} ethoxy) -4-methoxyphenyl] -1 H-imidazo [4,5-b] pyridine Melting point: 172-173 ° C

2- [2- (2- {4-MethylphenyIsulfinyI} ethoxy) -4-methoxyphenyl] -1 H-imidazo [4,5-b] pyridine Melting point: 110-122 ° C

4th

5

10th

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20th

25th

30th

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65

2- [2- (2- {4-Methoxyphenylsulfinyl} ethoxy) -4-methoxyphenyl] -1 H-imidazo [4,5-b] pyridine Melting point: 200-201 ° C

2- [2- (2- {2-methoxyphenylsulfinyl} ethoxy) -4-methoxyphenyl] -1 H-imidazo [4,5-b] pyridine melting point: 131-133 ° C

2- [2- (2- {3,4-Dimethoxyphenylsulfinyl} ethoxy) -4-methoxyphenyl] -1 H-imidazo [4,5-b] pyridine Melting point: 157-159 ° C

5 648313

2- [2- (2- {2-Methyl-4,5-dimethoxyphenylsulfinyl} ethoxy) -4-methoxyphenyl] -1 H-imidazo [4,5-b] pyridine Melting point: 172-173 ° C

2- [2- (2- {4-Nitrophenylsulfinyl} ethoxy) -4-methoxyphenyl] -s 1 H-imidazo [4,5-b] pyridine Melting point: 203-204 ° C

2- [2- (2- {2,4-Dimethoxyphenylsulfinyl} ethoxy) -4-methoxyphenyl] -1 H-imidazo [4,5-b] pyridine Melting point: 179-180 ° C

B