NO814012L - PROCEDURE FOR PREPARING IMIDAZO (4,5-B) -PYRIDINES AND PYRIMIDINES - Google Patents

Description

In British patent 1 445 824 and the European publication documents 0.022.495 and 0.024.290, e.g. a method for the preparation of imidazo[4,5-b]pyridine- and

-pyrimidine derivatives of the general formula

where

means an alkyl, alkoxy, alkylmercapto or alkylsulfinyl group each having 1-4 carbon atoms or a halogen atom,

1*2 means an alkylsulfinyl group with 1-4 carbon atoms or an alkoxy group with 2 or 3 carbon atoms, which is substituted in the terminal position with an alkylsulfinyl group with 1-4 carbon atoms, an aralkylsulfinyl group with 7-9 carbon atoms, an optionally with alkyl groups with 1- 3 carbon atoms, alkoxy groups with 1-3 carbon atoms and/or halogen atoms mono-,

di- or tri-substituted phenylsulfinyl group or a mono- or di-substituted nitrophenylsulfinyl group optionally with alkyl groups with 1-3 carbon atoms, alkoxy groups with 1-3 carbon atoms and/or halogen atoms, and

X means a CH group or a nitrogen atom,

of their 1H-tautomers and of their physiologically compatible salts with inorganic or organic acids, which method is characterized by a corresponding mercapto compound being oxidized with hydrogen peroxide or a peracid. The sulfinyl compound thus obtained contains a small amount of unreacted mercapto compound and a small amount of the corresponding sulfonyl compound, and these impurities necessitate a careful purification to produce a product of pharmaceutical quality.

Furthermore, it is from handbooks in organic chemistry (C. Ferri, Reaktionen der Organischen Synthese, Verlag: G. Thieme (1978); Kharasch and Meyers: The Chemistry 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) known, that bromine when oxidizing a mercapto compound to the corresponding sulfoxide represents an unsuitable oxidizing agent as it causes unwanted side reactions, e.g. cleavage of the carbon-sulfur bond, formation of carbon-bridge bonds and/or bromination of aromatics.

It has now surprisingly been found that the compounds of the general formula I can be prepared with better purity and in excellent yields also by oxidation of a compound of the general formula

where

X and R^ are as indicated at the outset, and

R3 means an alkyl mercapto group with 1-4 carbon atoms or an alkoxy group with 2 or 3 carbon atoms, which is substituted in the end position with an alkyl mercapto group with 1-4 carbon atoms, an aralkyl mercapto group with 7-9 carbon atoms, one optionally with alkyl groups with 1-3 carbon atoms, alkoxy groups with 1-3 carbon atoms and/or halogen atoms mono-, di- or tri-substituted phenyl mercapto group or an optionally with alkyl groups with 1-3 carbon atoms, alkoxy groups with 1-3 carbon atoms and/or halogen atoms mono- or di-substituted nitrophenyl mercapto group,

with bromine or addition compounds thereof.

The oxidation is preferably 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, acetic acid ethyl ester, dimethylformamide, dimethyl sulfoxide or hexamethyl phosphoric acid triamide, at temperatures between -10 and 80°C, preferably at temperatures between 15 and 30°C, in a pH range from 0 to 10. The reaction is particularly advantageously carried out in a pH range from 3 to 8, suitably also 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 produced by the method according to the invention can then optionally be transferred to their acid addition salts with inorganic or organic physiologically compatible acids. Suitable acids have been found to be, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, lactic acid, citric acid, tartaric acid, maleic acid or fumaric acid.

The starting materials used in the method are, for the most part, known from the literature or can be prepared analogously to the method described in British patent 1 4 45 82 4, namely by cyclization of a corresponding 5,6-diamino-pyrimidine resp. 2,3-diamino-pyridine.

The following examples will further illustrate the invention: Comparative example I

2-(2-Methoxy-4-meth<y>lsulfin<y>l-phen<yi>)-1H-imidazo[4,5-b]pyridine

6.6 g of 2-(2-methoxy-4-methylmercapt6-phenyl)-1H-imidazo[4,5-b]-pyridine is dissolved in 100 ml of chloroform, and at -15 to -20°C is added dropwise over 5 hours a solution of 2.96 g of 3-chloro-peroxybenzoic acid in 600 ml of chloroform. It is then shaken out with a dilute soda solution, the chloroform phase is dried and evaporated. The residue is purified over a silica gel column (eluent: chloroform/methanol = 9:1). By adding ethereal hydrochloric acid to a methanolic solution of the base, the yellow hydrochloride is obtained.

Yield: 2.3 g (33.6% of the theoretical),

melting point of the base: 154-155°C.

Comparative example II

2-(2-Methoxy-4-methylsulfinyl-phenyl)-1H-imidazo[4,5-b]pyridine hydrochloride

A solution of 135.6 g (0.5 mol) 2-(2-methoxy-4-methyl-mercapto-phenyl)-1H-imidazo[4,5-b]pyridine in 600 ml of 80% acetic acid is added to 57 g 30% hydrogen peroxide and allowed to stand for 2 days at laboratory temperature. After adding a further 5 g of 30% hydrogen peroxide, the reaction mixture is allowed to stand at laboratory temperature for a further 3 days. The oxidation is interrupted, the reaction mixture is poured into 3 liters of ice water, adjusted to pH 9 with concentrated ammonia and extracted 3 times with chloroform. The combined extracts are dried and evaporated in vacuo. According to thin-layer chromatographic comparison, the raw product contains approx. 3% starting material, 4% sulfone and 2% other, unknown impurities.

Purification over 4000 g of silica gel (eluent: chloroform + 3% acetone) gives, after precipitation from acetone, 72.2 g (50.3% of the theoretical) of the desired product with a melting point of 198-199°C. According to the thin-layer chromatogram (silica gel ready plates 60 F 254 from the company E. Merck, Darmstadt; system: chloroform/ethanol (85/15)) the product contains 0.1% sulphide, 0.5% sulphone and 0.85% unknown compounds as pollutants. Example 1 2-(2-Methoxy-4-methylsulfinyl-phenyl)-1H-imidazo[4,5-b]pyridine To a suspension of 229.8 g of 2-(2-methoxy-4-methylmercapto-phenyl)-1H -imidazo[4,5-b]pyridine x 0.5 CH^OH and 72.1 g of sodium acetate in 1.5 1 glacial acetic acid are added dropwise with vigorous stirring to 41.1 ml of bromine, dissolved in 150 ml of glacial acetic acid, at a temperature between . 20 and 25°C. The reaction mixture is then poured into approx. 1 kg of ice and adjusted to pH 9 with concentrated ammonia at approx. 25°C. The aqueous phase is extracted 3 times with a total of 3 liters of chloroform. After drying the organic phase with magnesium sulfate and treatment with activated charcoal, the solvent is removed except for a residue of 200 g, and the incipient crystallization is prevented by adding 40 ml of methanol and heating to approx. 40-45°C. The product that is precipitated with 1.2 1 acetone is filtered off, dissolved in a mixture of 300 ml each of methanol and methylene chloride at 40°C, and after evaporation in vacuum to a solvent residue of approx. 150 g, a new precipitation is carried out with 1 liter of acetone. The product is suctioned off and then washed with a mixture of 200 ml acetone and 300 ml n-hexane.

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

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

Total yield: 211.4 g (92% of the theoretical).

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

Example 2

2-(2-Methoxy-4-methylsulfinyl-phenyl)-1H-imidazo[4,5-b]pyridine

To a solution of 5.4 g (0.02 mol) 2-(2-methoxy-4-methylmercapto-phenyl)-1H-imidazo[4,5-b]pyridine in 30 ml of 50% acetic acid is added dropwise in the course of 20 minutes while stirring at room temperature, a solution is prepared as follows: To 6 g of sodium hydroxide in 50 ml of water, 4.8 g of 1.5 ml (0.03 mol) of bromine are added dropwise while stirring and cooling with ice water. After completion of the reaction, acidify with 45 ml of glacial acetic acid below

further cooling.

The resulting reaction mixture is stirred for 5 minutes, diluted with 100 ml of water, adjusted to pH 8 with concentrated ammonia and decanted 3 times with ethyl acetate. It 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 immediately begins to crystallize. The white product is filtered off, washed with acetone and then with n-hexane and dried.

Yield: 4.8 g (83.6% of the theoretical),

melting point: 200-202°C.

Example 3

8-(2-Methoxy-4-methylsulfinyl-phenyl)-purine

142.0 g of anhydrous sodium acetate is added to a suspension of 250.2 g of 8-(2-methoxy-4-methylmercapto-phenyl)-purine hydrochloride in 1.4 1 of 50% acetic acid, and the mixture is 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 over the course of one hour. The temperature thereby rises from 22 to 27°C. After the addition of bromine is finished, stirring is continued for 10 minutes, then the reaction mixture is adjusted to a pH value of 7.5 with saturated potassium carbonate solution, and the mixture is stirred at room temperature. After approx. an hour, a precipitate begins to crystallize. The whole thing is left to stand overnight, suctioned off, washed with cold water and dried in a vacuum at 50°C. For cleaning, dissolve the product twice in approx. 1 liter of water each time at 50°C, treated with activated charcoal and brought slowly to crystallization at 10°C. It is then dried at 70°C in a vacuum over phosphorus pentoxide.

■Yield: 167 g (72% of the theoretical),

melting point: 236-238°C.

Analogous to the above examples 1-3, the following compounds were prepared: 2-(2-methoxy-4-ethylsulfinyl-phenyl)-1H-imidazo[4,5-b]pyridine hydrochloride

Melting point: 122-123°C

2-(2-Methoxy-5-methylsulfinyl-phenyl)-1H-imidazo[4,5-b]pyridine Melting point: 211-212°C

2-(2-ethoxy-5-methylsulfinyl-phenyl)-1H-imidazo[4,5-b]pyridine Melting point: 199-200°C

2-(2-ethoxy-4-ethylsulfinyl-phenyl)-1H-imidazo[4,5-b]pyridine Melting point: 167-168°C

2-(2-Methoxy-4-propylsulfinyl-phenyl)-1H-imidazo[4,5-b]pyridine Melting point: 182-183°C

2-(2-ethoxy-4-propylsulfinyl-phenyl)-1H-imidazo[4,5-b]pyridine Melting point: 182.5-183.5°C (decomp.)

2-(2-ethoxy-4-butylsulfinyl-phenyl)-1H-imidazo[4,5-b]pyridine Melting point: 187-188°C

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

2-[2-(2-ethylsulfinyl-ethoxy)-4-methoxy-phenyl]-1H-imidazo-[4,5-b]pyridine

Melting point: 188-189°C

2-[2-(2-methylsulfinyl-ethoxy)-4-methoxy-phenyl]-1H-imidazo-[4,5-b]pyridine

Melting point: 231-232°C

2-[2-(3-methylsulfinyl-propoxy)-4-methoxy-phenyl]-1H-imidazo-[4,5-b]pyridine

Melting point: 133-134°C

2-[2-(3-ethylsulfinyl-propoxy)-4-methoxy-phenyl]-1H-imidazo-[4,5"-b]pyridine

Melting point: 127-128°C 2-[2-(2-methylsulfinyl-ethoxy)-4-methylsulfinyl-phenyl]-1H-imidazo[4,5-b]pyridine

Melting point: 193-194°C

2-[2-(2-methylsulfinyl-ethoxy)-4-methyl-phenyl]-1H-imidazo-[4,5-b]pyridine

Melting point: 191-192°C

2-[2-(2-methylsulfinyl-ethoxy)-4-chloro-phenyl]-1H-imidazo-[4,5-b]pyridine

Melting point: 221-222°C

2-[2-Methoxy-4-(2-methylsulfinyl-ethoxy)-phenyl]-1H-imidazo-[4,5-b]pyridine

Melting point: 205-206°C

2-[2-Methoxy-4-(2-ethylsulfinyl-ethoxy)-phenyl]-1H-imidazo-[4,5-b]pyridine

Melting point: 215-217°C

2-[2-Methoxy-4-(3-methylsulfinyl-propoxy)-phenyl]-1H-imidazo-[4,5-b]pyridine

Melting point: 179-180°C

2-[2-Methoxy-4-(3-ethylsulfinyl-propoxy)-phenyl]-1H-imidazo-[4,5-b]pyridine

Melting point: 166-167°C

2-[2-(2-methylsulfinyl-ethoxy)-5-methylmercapto-phenyl]-1H-imidazo-[4,5-b]pyridine

Melting point: 191-192°C

8-(2-ethoxy-4-methylsulfinyl-phenyl)-purine hydrochloride Melting point: 220-221°C (decomp.)

8-[4-methoxy-2-(2-methylsulfinyl-ethoxy)-phenyl}-purine Melting point: 228-229°C

2-[2-(2-phenylsulfinyl-ethoxy)-4-methoxy-phenyl]-1H-imidazo-[4,5-b]pyridine

Melting point: 185-186°C

2-[2-(2-benzylsulfinyl-ethoxy)-4-methoxy-phenyl]-1H-imidazo-[4,5-b]pyridine

Melting point: 194-195°C 2-[ 2-(2-(4-chlorophenylsulfinyl)-ethoxy)-4-methoxy-phenyl]-1H-imidazo[4,5-b]pyridine

Melting point: 172-173°C

2-[2-(2-(4-methylphenylsulfinyl)-ethoxy)-4-methoxy-phenyl]-1H-imidazo[4,5-b]pyridine

Melting point: 110-122°C

2-[2-(2-(4-Methoxyphenylsulfinyl)-ethoxy)-4-methoxy-phenyl]-1H-imidazo[4,5-b]pyridine

Melting point: 200-201°C

2-[2-(2-(2-Methoxyphenylsulfinyl)-ethoxy)-4-methoxy-phenyl]-1H-imidazo[4,5-b]pyridine

Melting point: 131-133°C

2-[2-(2-(3,4-dimethoxyphenylsulfinyl)-ethoxy)-4-methoxy-phenyl]-1H-imidazo[4,5-b]pyridine

Melting point: 157-159°C

2-[2-(2-(2-methyl-4,5-dimethoxyphenylsulfinyl)-ethoxy)-4-methoxy-phenyl]-1H-imidazo[4,5-b]pyridine

Melting point: 172-173°C

2-[2-(2-(4-nitrophenylsulfinyl)-ethoxy)-4-methoxy-phenyl]-1H-imidazo[4,5-b]pyridine

Melting point: 203-204°C

2-[2-(2-(2,4-dimethoxyphenylsulfinyl)-ethoxy)-4-methoxy-phenyl]-1H-imidazo[4,5-b]pyridine

Melting point: 179-180°C

Claims (6)

1. Process for the preparation of imidazo[4,5-b]pyridine and pyrimidine derivatives with the general formula where R^ means an alkyl-, alkoxy-, alkylmercapto- or alkylsulfinyl- group with each 1-4 carbon atoms or a halogen atom, R 2 means an alkylsulfinyl group with 1-4 carbon atoms or a alkoxy group with 2 or 3 carbon atoms which is substituted in the terminal position with an alkylsulfinyl group with 1-4 carbon atoms, an aralkylsulfinyl group with 7-9 carbon atoms, an optionally with alkyl groups with 1-3 carbon atoms, alkoxy groups with 1-3 carbon atoms and/or halogen atoms mono- , di- or trisubstituted phenylsulfinyl group or one optionally with alkyl groups with 1-3 carbon atoms, alkoxy groups with 1-3 carbon atoms and/or halogen atoms mono- or di- substituted nitrophenylsulfinyl group, and X means a CH group or a nitrogen atom, and their 1H tautomers and physiologically compatible salts with inorganic or organic acids, characterized in that a compound with the general formula where X and R^ are as indicated at the outset, and R^ means an alkyl mercapto group with 1-4 carbon atoms or an alkoxy group with 2 or 3 carbon atoms which is substituted in the end position with an alkyl mercapto group with 1-4 carbon atoms, an aralkyl mercapto group with 7-9 carbon atoms, a optionally with alkyl groups with 1-3 carbon atoms, alkoxy groups with 1-3 carbon atoms and/or halogen atoms mono-, di- or tri-substituted phenyl mercapto group or one optionally with alkyl groups with 1-3 carbon atoms, alkoxy groups with 1-3 carbon atoms and/or halogen atoms mono- or di- substituted nitrophenyl mercapto group, is oxidized in a solvent with bromine or addition compounds thereof, and optionally a compound thus obtained with the general formula I or its 1H tautomers is transferred to a physiologically compatible salt with an inorganic or organic acid. 2. Method according to claim 1, characterized in that an aqueous or anhydrous solvent is used as solvent. 3. Method according to claims 1 and 2, characterized in that the reaction is carried out at temperatures between -10 and 80°C, preferably at temperatures between -15 and 30°C. 4. Method according to claims 1 to 3, characterized in that the reaction is carried out in a pH range from 0 to 10, preferably in a pH range from 3 to 8. 5. Method according to claims 1 to 4, characterized in that the turnover is carried out in the presence of a buffer, e.g. in the presence of a carboxylate, carbonate, hydrogen phosphate or dihydrogen phosphate anion. 6. Process according to claims 1 to 5, characterized in that the oxidation is carried out with bromine or sodium hypobromite.