NL8104785A - PROCESS FOR PREPARING IMIDAZO 4.5-B-PYRIDINES AND PYRIMIDINES. - Google Patents

Description

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Process for the preparation of imidazo / 4.5-b-7 pyridines and pyrimidines.

British patent specification 1,445,824 and European patent publications 0.022.495 and 0.024.290 already disclose, inter alia, a process for preparing imidazo / 4.5-b / pyridines and pyrimidines of the general formula 1, in which Rj is a alkyl, alkoxy, alkyl mercapto or alkyl sulfinyl group with 1-4 carbon atoms or a halogen atom, an alkyl sulfinyl group with 1-4 carbon atoms or an alkoxy group with 2 or 3 carbon atoms, which are terminated by an alkyl sulfinyl group with 1-4 carbon atoms an aralkylsulfinyl-10 group with 7-9 carbon atoms, optionally mono-, di- or trisubstituted phenyl-sulfinyl group, which is optionally substituted by alkyl groups with 1-3 carbon atoms, alkoxy groups with 1-3 carbon atoms and / or halogen atoms; 3 carbon atoms, alkoxy groups of 1-3 carbon atoms and / or halo-15 atoms mono- or di-substituted nitrophenylsulfinyl group is substituted, and X represents the CH group or a nitrogen atom, the IH-tautomers d and its physiologically acceptable salts thereof with inorganic or organic acids, characterized in that a corresponding mercapto compound is 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 require cumbersome purification to prepare a pharmaceutical grade product.

Furthermore, from the handbooks of Organic Chemistry (C. Ferri, Reactions of Organic Synthesis, Verlag: G. Thieme (1978); Kharasch and Meyers: The Chemistry of Organic Sulfur Compounds, Vol. 1, 157-159 (1961)), 30 Pergamon Press NY; S. Oae: Organic Chemistry of Sulfer 385-387 (1977), Plenum Press NY, and London) known that bromine is an unsuitable oxidizing agent in the oxidation of a mercapto compound to the corresponding sulfur oxide. causes undesired side reactions, for example, a cleavage of the carbon-sulfur bond, the formation of carbon-bromine bonds and / or the bromination of the aromatic group.

Surprisingly, it has now been found that the compounds of the general formula 1 are obtained in higher purity and in excellent yields also by oxidation of a compound of the general formula 2, wherein X and R i have the meanings indicated above and R 1 is an alkyl mercapto group with 1 -4 carbon atoms or an alkoxy group with 2 or 3 carbon atoms, which is terminated by an alkyl mercapto group with 1-4 carbon atoms, an alkyl mercapto group with 7-9 carbon atoms, optionally by alkyl groups with 1-3 carbon atoms, alkoxy groups with 1- 3 carbon atoms and / or halogen atoms, mono-, di- or trisubstituted phenyl mercapto group, or optionally substituted by alkyl groups with 1-3 carbon atoms, alkoxy groups with 1-3 carbon atoms and / or halogen atoms substituted or di-substituted nitrophenyl mercapto group, with bromine or its addition compounds.

The oxidation is preferably in a solvent, for example, in an aqueous solvent, such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, hydrochloric acid or sulfuric acid, or in an anhydrous solvent, for example glacial acetic acid, methylene chloride, chloroform, dioxane, tetrahydrofuran, formic acid ethyl ester, acetic acid ethyl ester, dimethyl formamide, dimethyl sulfoxide or hexamethyl phosphoric acid triamide, carried out at temperatures between -10 and 80 ° C, but preferably at temperatures between 15 and 30 ° C, within a pH range of 0-10. However, the conversion within a pH range of 3-8 becomes particularly advantageous, expediently also in the presence of a buffer, for example in the presence of a carboxylate anion, for example alkali metal acetate, such as sodium acetate, in the presence of a phosphate, such as di sodium 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., 8104785 y-3 - for example, sodium hypobromite.

The compounds of the general formula (I) obtained according to the process of the invention can then, if desired, be converted into their acid addition salts with inorganic or organic, physiologically acceptable acids.

As acids, for example, hydrochloric, hydrobromic, sulfuric, lactic, citric, tartaric, maleic or fumaric acids have been found suitable.

The starting materials used in the process are largely known from the literature or can be prepared analogously to the process described in British Patent Specification 1,445,824, namely by cyclization of a corresponding 5.6-diaminopyrimidine and 2.3-diaminopyridine, respectively.

The invention is further illustrated but not limited by the following examples.

Reference example I

2- (2-methoxy-4-methylsulfinylphenyl) -1H-imidazo / 4.5-b-pyridine> 6,6 g 2- (2-methoxy-4-methyl mercapto-phenyl) -1H-midazo / 4.5 pyridine is dissolved in 100 ml of chloroform and added dropwise at -15 to -20 ° C for 5 hours to a solution of 2.96 g of 3-chloroperoxybenzoic acid in 600 ml of chloroform. It is then shaken with a dilute soda solution, the chloroform phase dried and concentrated. The residue is purified on a silica gel column (eluent: 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% to 30% of theory); melting point of the base 154-155 ° C.

Reference example II

2- (2-methoxy-4-methylsulfinylphenyl) -1H-imidazo / 4.5-b-pyridine hydrochloride

A solution of 135.6 g (0.5 mol) of 2- (2-metho-35-yl-4-methyl-mercaptophenyl) -1H-imidazo / 4.5-b-pyridine in 600 ml of 80 Vs acetic acid is provided with 57 g of 30% rs hydrogen peroxide 8104785 -4-.

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and then the reaction mixture is allowed to stand at the laboratory temperature for 2 days. After adding an additional 5 g of 30% hydrogen peroxide, the reaction mixture is left to stand at the laboratory temperature for 3 days. The oxidation is stopped, the reaction mixture is poured onto 3 liters of ice water, adjusted to pH 9 with concentrated ammonia and extracted three times with chloroform. The combined extracts are dried and concentrated in vacuo. The crude product, according to a thin layer chromatographic comparison study, contains about 3% starting material, 4% sulfone and 2% further unknown impurities.

Purification over 4000 g of silica gel (eluent: chloroform + 3% acetone) gives 72.2 g (50.3% of theory) of the desired product, mp 198-199 ° C, after recrystallization from acetone. The product contains, according to the thin layer chromatogram (finished silica gel plates 60 F 254 from E. Merck, Darmstadt; System: chloroform / ethanol (85/15)) 0.1% sulfide, 0.5% sulfone and 0.85 % unknown compounds as impurities.

Example I

2- (2-methoxy-4-methylsulfonylphenyl) -1H-imidazo / 4.5-b-pyridine. ............ '

To a suspension of 229.8 g of 2- (2-metho-xy-4-methylmercaotiphenyl) -1H-imidazo / 4.5-b / pyridine x 0.5 CH 2 OH and 72.1 g sodium acetate in 1.5 liters Glacial acetic acid is added 41.1 ml of bromine, dissolved in 150 ml of glacial acetic acid, dropwise at a temperature between 20 and 25 ° C, with vigorous stirring. The reaction mixture is then poured onto about 1 kg of ice and adjusted to pH 9 with concentrated ammonia at about 25 ° G. The aqueous phase is extracted three times with a total of 3 liters of chloroform. After the drying of the organic phase with magnesium sulfate and the treatment with activated carbon, the solvent is removed to a residue of 200 g and the initial crystallization is prevented by adding 40 ml of methanol and heating at about 40-45 ° G. The product precipitated with 1.2 liters of acetone is filtered off with suction, dissolved in a mixture of 8 1 0 4 7 85 - 5 - each from 300 ml of methanol and methylene chloride at 40 ° C and after concentration in vacuo to a solvent residue of about 150 g reprecipitated with 1 liter of acetone.

The product is filtered off and washed with a mixture of 200 ml of acetone and 300 ml of n-hexane. Yield 175.1 g, mp 201-202 ° C.

After the concentration of the mother liquor and the addition of acetone, 36.3 g with a melting point of 200-201 ° C are obtained. The total yield is 211.4 g (92 Z 10 of theory).

According to the thin layer chromatogram (finished silica gel plates 60 F 254 from E. Merck, Darmstadt; System: chloroform / ethanol (85/15)), the product thus obtained contains 0.05% sulfone and 0.25 Z unknown impurities.

Example II

2- (2-methoxy-4-methylsulfinylphenyl) -IH-imidazo / 4.5-b / pyridine_

To a solution of 5.4 g (0.02 mol) of 2- (2-methoxy-4-methyl-mercapto-phenyl) -1H-imidazo / 4,5-b / pyridine 20 in 30 ml of 50% acetic acid is added A solution is added dropwise for 20 minutes under stirring at room temperature, which is prepared in the following manner: To 6 g of sodium hydroxide in 50 ml of water are added dropwise with stirring and cooling with ice water to 4.8 g = 1.5 ml (0.03 mol ) bromine added. After the completion of the reaction, it is acidified with further cooling with 45 ml of glacial acetic acid.

The resulting reaction mixture is stirred for an additional 5 minutes, diluted with 100 ml of water, adjusted to pH 8 with concentrated ammonia and shaken three times with 30 vinegar ester. It is then extracted three 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 starts to crystallize immediately. The white product is filtered off with suction, washed with acetone and then with n-hexane and dried. Yield 4.8 g (83.6% of theory); mp. * 200-202 ° C.

8104785 * - 6 -

Example III

8- (2-methoxy-4-methylsulfonylphenyl) purine

To a suspension of 250.2 g of 8- (2-methoxy-4-methyl-mercaptophenyl) -purine hydrochloride in 1.4 liters of 50% acetic acid are added 142.0 g of anhydrous sodium acetate and then added for 20 stirred at room temperature for minutes. Then, with vigorous stirring, a solution of 127.9 g of bromine in 120 ml of glacial acetic acid is added dropwise within 1 hour. The temperature thereby increases from 22 ° C to 27 ° C. After the bromine addition has ended, stirring is continued for 10 minutes, then the pH value is adjusted to 7.5 with a saturated potassium carbonate solution and stirred at room temperature. After about 1 hour, a precipitate begins to crystallize. It is left to stand overnight, filtered off with suction, rinsed with cold water and dried in vacuo at 50 ° C. For purification, the substance is dissolved twice in about 1 liter of water at 50 ° C each time, treated with activated charcoal and slowly crystallized at 10 ° C. It is then dried in vacuo over phosphorus pentoxide at 70 ° C. Yield 167 g of 20 (72% of theory); mp. 236-238 ° C.

Analogous to Examples 1- III above, the following compounds were prepared: 2- (2-methoxy-4-ethylsulfinylphenyl) -1H-imidazo / 4.5-b / pyridine hydrochloride

25 mp. 122-123 ° C

2- (2-methoxy-5-methylsulfinylphenyl) -1H-imidazo / 4.5-b-pyridine melting point = 211-23 ° C

2- (2-ethoxy-5-methylsulfinylphenyl) -1H-imidazo / 4.5-b 7-pyridine melting point = 199-200 ° C

2- (2-ethoxy-4-ethylsulfonylphenyl) -1H-imidazo / 4.5-b-pyridine melting point = 167-168 ° C 35

2- (2-methoxy-4-propylsulfinyiphenyl) -1H-imidazo / 4.5-b-pyridine melting point = 182-183 ° G

8104785 * - 7 - 2- (2-ethoxy-4-propylsulfinylpheny1) -1H-imidazo / 4.5-b / pyridine melting point = 182.5-183.5 ° C (decomposition)

2- (2-ethoxy-4-butylsulfinylphenyl) -1H-imidazo / 4.5-b / pyridine 5 melting point = 187-188 ° C

2- (2-fluoro-5-methylsulfinylphenyl) -1H-imidazo / 4.5-b / pyridine melting point = 191-192 ° C

10 2- / 2- (2- (2-ethylsulfinylethoxy) -4-methoxyphenyl-1H-imidazo

/ 4.5-b / pyridine melting point = 188-189 ° G

2- / 2- (2-methylsulfinylethoxy) -4-methoxyphenyl-H-imidazo-15 / 4.5-b / pyridine

melting point = 231-232 ° C

2- / 2- (3-methylsulfinylpropoxy) -4-methoxyphenyl-1H-imidazo / 4.5-b / pyridine 20 melting point = 133-134 ° C

2- / 2- (3-ethylsulfinylpropoxy) -4-methoxy-enyl-1H-imidazo / 4.5-b-pyridine melting point = 127-128 ° G 25

2- / 2- (2-methylsulfinylethoxy) -4-methylsulfinylphenyl-1H-imidazo / 4.5-b / pyridine melting point = 193-194 ° C

2- / 2- (2-methylsulfinylethoxy) -4-methylphenyl-7H-imidazo-

/ 4.5-b / pyridine melting point = 191-192 ° C

2- / 2- (2-methylsulfinylethoxy) -4-chlorophenyl-1H-imidazo / 4.5-b7 "35 pyridine

melting point = 221-222 ° C

8104785 - 8 -

2- / 2-methoxy-4- (2-methylsulfinylethoxy) -phenyi-7H-imidazo / 4.5-b-pyridine melting point = 205-206 ° C

2 - / _ 2-methoxy-4- (2-ethylsulfinylethoxy) - β-enyl-7H-imxdazo-

/ 4.5-b_7pyrxdxne melting point = 215-217 ° C

2- / 2-methoxy-4- (3-methylsulphinylpropoxy) -phenyl-7H-xmidazo-10 / 4.5-b / pyrxdxne

melting point = 179-180 ° C

2- / 2-methoxy-4- (3-ethylsulfxnylpropoxy) -phenyl_7 "1H-xmxdazo- / 4.5-b_7pytidine 15 melting point = 166—167 ° C

2- / 2- (2-methylsulfinylethoxy) -5-methyl-mercaptophenyl_7-1H-xmxdazo / 4.5-b_7pytidxne melting point ® 191-192 ° C

20 8- (2-ethoxy-4-methylsulfinylphenyl) puridine hydrochloride melting point = 220-221 ° C (decomposition)

8- / 4-methoxy-2- (2-methylsulfxnylethoxy) -phenyl-purine 25 melting point = 228-229 ° C

2- / 2- (2-phenylsulf xnylethoxy) -4-methoxyphenyl-1H-imidazo - / 4.5-b-7pytidine melting point = 185-186 ° C 30

2- / 2- (2-benzylsulfinylethoxy) -4-methoxyphenyl_7-1H-xmxdazo / 4.5-b_7pyrxdxne melting point = 194-195 ° C

2- / 2- (2- (4-chlorophenylsulfinyl) ethoxy) -4-methoxyphenyl_7-1H-

imidazo / 4.5-b_7pyrxdine melting point = 172-173 ° G

8104785 - 9 -

2 - / - 2- (2- (4-methylphenylsulfinyl) -ethoxy) -4-methoxyphenyl-1H-imidazo / 4.5-b / pyridine melting point = 110-122 ° G

5 2- / 2- (2- (4-methoxyphenylsulfinyl) ethoxy) -4-methoxyphenyl -1 / - 1H-

imidazo / 4.5-b_7pyridine melting point = 200-201 ° C

2- / 2- (2- (2-methoxyphenylsulfinyl) ethoxy) -4-methoxy-pheny1 / -1H-10 imidazo / 4.5-b / pyridine melting point = 131-133 ° C

2- / 2- (2- (3,4-dimethoxyphenylsulfinyl) ethoxy) -4-methoxyphenyl / 1H-imidazo / 4.5-b / pyridine 15 melting point = 157-159 ° C

2- / 2- (2- (2-methyl-4,5-dimethoxyphenylsulfinyl) ethoxy) -4-methoxyphenyl-7_1H-imidazo / 4.5-b-pyridine melting point = 172-173 ° C

20

2- / 2- (2- (4-nitrophenylsulfinyl) -ethoxy) -4-methoxyphenyl-1H-imidazo / 4.5-b / pyridine melting point = 203-204 ° C

2- / 2- (2- (2,4-d-methoxyphenylsulfinyl) ethoxy) -4-methoxyphenyl-7H-imidazo / 4,5-pyridine mp = 179-180 ° C.

30 8104785

Claims (7)

A process for the preparation of imidazo / 4.5-b / pyridines and pyrimidines of the general formula 1, wherein R 1 is an alkyl, alkoxy, alkyl mercapto or alkyl sulfinyl-5 group, each having 1-4 carbon atoms or a halogen atom, R2 an alkyl sulfinyl group with 1-4 carbon atoms or an alkoxy group with 2 or 3 carbon atoms, which is terminated by an alkyl sulfinyl group with 1-4 carbon atoms, an aralkyl sulfinyl group with 7-9 carbon atoms, optionally by alkyl groups 10 with 1-3 carbon atoms, alkoxy groups with 1-3 carbon atoms and / or halogen atoms mono-, di- or tri-substituted phenylsulfinyl group or optionally mono or disubstituted by alkyl groups with 1-3 carbon atoms, alkoxy groups with 1-3 carbon atoms and / or halogen atoms nitrophenylsulfinyl group is substituted, and X and X represent the CH group or a nitrogen atom, as well as its 1 H tautomers and their physiologically acceptable salts with inorganic or organic acids, characterized in that a compound of the general formula II, wherein X and Rj have the meanings indicated above and Rx is an alkyl mercapto group having 1 to 4 carbon atoms or an alkoxy group having 2 or 3 'carbon atoms, which is terminated by an alkyl mercapto group having 1 to 4 carbon atoms an alkyl mercapto group with 7-9 carbon atoms, optionally mono-, di- or trisubstituted phenyl mercapto group, optionally by alkyl groups with 1-3 carbon atoms, alkoxy groups with 1-3 carbon atoms and / or halogen atoms, or alkoxy groups with 1-3 carbon atoms is substituted with 1-3 carbon atoms and / or halogen atoms mono- or disubstituted nitrophenyl mercapto group, is oxidized in a solvent with bromine or its addition compounds and, if desired, a compound of the general formula 1 or an 1H-tautomer thereof so obtained into a physiologically acceptable salt with an inorganic or organic acid. 2. Process according to claim 1, characterized in that an aqueous or anhydrous solvent is used as the solvent. .................... 3. Process according to claims 1 and 2, 8104785-11 - characterized in that the conversion is carried out at temperatures between -10 and 80 ° C, but preferably at temperatures between -15 and 30 ° C. 4. Process according to claims 1-3, 5, characterized in that the conversion is carried out in a pH range of 0-10, preferably however in a pH range of 3-8. 5. Process according to claims 1-4, characterized in that the reaction is carried out in the presence of a buffer, for example in the presence of a carboxylate, carbonate, hydrogen phosphate or dihydrogen phosphate anion. 6. Process according to claims 1-5, characterized in that the oxidation is carried out with bromine or sodium hypobromite. 15 7, Methods as described in the description and / or examples. 8104785 V. V χ · ίί ^ \ _ / - VR ’R» H 1 ^ n "^ N \ = y-R3 H 2 8104785 Dr. Karl Thomae Gesellschaft mit beschrankter Haftung, Biberach other Riss, B. Germany