CS223849B2 - Method of making the imidazo /4,5-b/pyridine and a pyridine - Google Patents

Description

In the British atentním ^p s ^p isu с. ^1,445,824 and in European laid-open specifications No. 0,022,495 and 0,024,290, among others. Already described a method of ^{y. and} imidazo ^[4, 5- ^{b] pyridine} IR ^{and U} and din ^ -j ňmidinů general formula R '

AND 1 ^H (1)

in which

R a ^and a ^{plurality of projections, salicylic,} altoxýlovou alkyl · mercapto- or "alkylsulfinyl group having 1 to 4 carbon atoms or halogen,

RZ ^p pose a alk ^ suhinydovou SKU ^pi comprising 1 to 4 carbon atom ^s alkyl or ^alk ox ^y s ^k UPRN with 2 or 3 carbon atoms substituted in the end ^P oloze al ^{alkyl sulfone} in ^y alkoxycarbonyl having 1-4 'carbon atoms, ^p aralkylsulfinyl sku and another with ^{7 of} 9 carbon atom of ^{Y, f} enylsul ^fi n ^y ^ ^kt nominal group era of ^p and ^{DE or} mono-, di- n ^e b ^of trisubstituted by ^a and the ^{plurality of projections} of ^the at nominal another ^p 1 ^to 3 of ^Y ^ u Uhl. and ^o ox ^y with u ^{p to} another with 1-3 ^y uhlíkrn atom and / or halogen, or ^Y ňitrofenylsulfin LoVo group optionally mono- or disubstituted by alkyl having 1-3 carbon atoms, alkoxy of 1 ^and 3, ^the atom ^Y carbon and ^/ or halogen, and

X is CH or N; their ta-tautomers and their physiologically tolerable salts with inorganic or organic acids, characterized in that the corresponding mercapto compound is oxidized with hydrogen peroxide or a peracid.

The sulfinyl derivative thus obtained contains a small amount of unreacted mercapto compound and a small amount of the corresponding sulfonyl compound. Due to the presence of these impurities, expensive cleaning is required to prepare pharmaceutical grade products.

In addition, it is from organic chemistry textbooks [see 'C. Ferri, Reaktionen der 'Organischen Synthese, Georg Thieme Verlag (1978); Kharash and Meyers, The Chemistry of Organic Sulfur Compounds, Vol. 1, 157-159 (1961), Pergamon Press NY; S. Oae, Organic Chemists of SuKu 385-387 (1977), Plenum Press, NY and London] known that bromine is not a suitable oxidizing agent when oxidizing the mercapto compounds to the corresponding sulfoxides ^, since it ^{is the} most ^The reaction is, for example ^{, a} carbon-sulfur graft graft, a carbon-bromine 'bonding' and / or a bromoacetate aromatic.

Surprisingly, it has now been found that the compounds of formula (I) above can be obtained in a higher purity and in an excellent yield also by oxidation of the compound o-. of formula II N in ^H III)

in which

X and R 1 are as defined above and

R3 is C1 -C4 alkylmercapto or C2 -C3 -alkoxy substituted at the end position with C1 -C4 alkylmercapto, C7 -C9 aralkylmercapto, phenylmercapto optionally mono-; di- or trisubstituted by C 1 -C 3 alkyl, C 1 -C 3 alkoxy and / or halogen, or nitrophenylmercapto optionally mono- or disubstituted by C 1 -C 3 alkyl, C 1 -C 3 alkoxy 1 to 3 carbon atoms and / or halogen, bromine or addition compounds thereof.

This oxidation is preferably carried out in a solvent, for example an aqueous solvent, such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, hydrochloric acid or sulfuric acid. or in an anhydrous solvent such as acetic acid, methylene chloride _; du ,. chloroform, dioxane, tetrahydrofuran, ethyl formate, ethyl acetate, dimethylformamide, diethylsulfoxide, or hexamethylphosphoric triamide, at a temperature between -10 ° C and 80 ° C, preferably between 15 ° C and 30 ° C, at a pH in It is particularly advantageous to carry out the reaction at a pH of 3 to 8, preferably also in the presence of a buffer, for example in the presence of a carboxylate anion, for example an alkali metal acetate, such as sodium acetate, in the presence of a phosphate such as monohydrogen phosphate. sodium or sodium dihydrogen phosphate, or in the presence of a carbonate such as sodium bicarbonate or sodium carbonate, by treatment with bromine or hypobromite, for example sodium hypobromite.

The compounds of the formula I obtained by the process according to the invention can, if desired, be converted into acid addition salts with inorganic or organic physiologically compatible acids. Suitable acids include, for example, hydrochloric acid, sulfuric acid, lactic acid, citric acid, tartaric acid, maleic acid or fumaric acid.

The starting materials used in the process according to the invention are for the most part known in the literature or can be obtained according to the process described in British Patent 1445 824, in particular by cyclization of the corresponding 5,6-diaminooyrimidine or 2,3-diaminopyridine .

The invention is illustrated by the following non-limiting examples.

Reference Example

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

6.6 g of 2- (2-methyl-4-methylmercoprophenyl) -1H-imidazo [4,5-b] pyridine are dissolved in 100 ml of chloroform and treated at -15 to -20 ° C for 5 hours. A solution of 2.96 g of 3-chloroperoxybenzoic acid in 600 ml of chloroform is added dropwise, the reaction mixture is shaken with a dilute sodium carbonate solution, the chloroform phase is dried and evaporated, and the residue is purified by silica gel column chromatography using chloroform / methanol ( Addition of ethereal hydrogen chloride to a methanolic base solution gives a yellow colored hydrochloride.

Yield: 2.3 g (33.6%). Base - melts at 154-155 ° C.

Reference Example II

2- (2-Methoxy-4-methylsulfinylphenyl) -ΙΗ-imidazo [4,5-b] pyridine hydrochloride

To a solution of 135.6 g (0.5 mol) of 2- (2-methoxy-4-methylmercaptophenyl) -4-imidazo [4,5-b] pyridine in 600 ml of 80% acetic acid is added 57 g 30% hydrogen peroxide was allowed to stand at room temperature for 2 days, then an additional 5 g of 30% hydrogen peroxide was added and the reaction mixture was allowed to stand at room temperature for a further 3 days. Poured into 3 liters of ice water, made alkaline to pH 9 with concentrated ammonia and extracted three times with chloroform, dried and evaporated in vacuo to give a crude product of about 3% starting material, 4% by comparison with thin layer chromatography. sulfone and 2% other unknown impurities.

Purification by chromatography on 4000 g of silica gel eluting with chloroform with 3% acetone gave 72.2 g (50.3% of theory) of the desired product after precipitation from acetone, m.p. 198-199 ° C. According to thin-layer chromatography (silica gel 60- - F 254 from E. Merek, Darmstadt) in a solvent system - chloroform-ethanol (85: 15), the product contains 0.1% sulfide, 0.5% sulfone and 0.85% of unknown compounds as impurities.

Example 1

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

To a suspension of 229.8 g of 2- (2-methoxy-4-methylmercaptophenyl) -1H-imidazo [4,5-b] pyridine with 0.5 mol of methanol and 72.1 g of sodium acetate in 1.5 liter of acetic acid under vigorous ^h MIC even ^when the TE ^pl about ^{the 20} to ²⁵ ° C at ^the e and ^p mites ^41.1 m ^{to 1 150} m of bromine in ¹ te ^d b ^{s y} Selin ^alkyl acetate. REAL was ^{characterized} hje to about 1 ^{g ki} lo RAM saying ^{eh d 1} e ^d ua its ^{pH to} oncenfoovaným amon'ia ^to em u ^p rav ^{even with} the ^ nd the tote about 25 ° C at pH 9. The aqueous phase was · extracted three times with a total of 3 liters of chloroform, the organic phase is dried over magnesium sulphate and you ^clarified with aldivmm ufom NACE ^F solvent is evaporated to a residue weighing 200 grams, and an incipient crystallization of avoiding ^added n ^s m ⁴⁰ m ^l mefoanolu and ^AHR Evo ' 40 ° C to 45 ° C. The precipitated product is suctioned off by adding 1.2 liters of acetone, dissolved in a mixture of 300 ml of methanol and 300 ml of methylene chloride heated to 40 DEG C., the solvent is evaporated to a residue of about 150 g and the product is precipitated again with 1 liter of acetone. After aspiration, the product is washed with a mixture of 200 ml of acetone and 300 ml of n-hexane.

The yield of product melting at 201-202 C. ^{H stupmc,} mm 17 ^{5 1 g.}

Evaporation of the mother liquors and addition of acetone gave an additional 36.3 g of product, m.p. 200 DEG-201 DEG.

Total yield 211.4 g, which corresponds to ⁹² % of theory.

The product thus obtained contains by thin layer chromatography on silica gel (finished plates silica gel 60 F 254 from E. Merck, Darmstadt) in a solvent system cMoroform - etoanol ⁽⁸ 5: 15] ^{0.05 p} rocent ^sulfone and ^0.25% gentle ^and mYC nemstot ^h.

Example 2

2- (2-Methoxy-4-methylsulfinyphenyl) -1H-imidazo [4,5-b] pyridine was extracted three times with chloroform. The extracts are ^{characterized} over ^{dissemination} su ^{y t} ečna ю ^{of Ym,} rozpoujštédto was evaporated in vacuo and the residue of honey-like consistency · are dissolved in 100 ml of acetone. The sulfoxide formed immediately starts to crystallize from the solution. The white product was filtered off, washed first with acetone and then n-hexane, and ^y su ^š Í. Gains ^{and 4.8 g} (836% of theory) ^{of p} ro ^d u ^to the ^pl of the ²⁰⁰ th nd the tote and ^{from 202} ° C.

Example 3

8- (2-Meth oxy-4 - ^ e ^ tt ^ h ^ ЬшШпуЬ phen ^yl) purine ^{To a} sus ^p Enzi ^{250.2 g of 8} - ^{(2-Me th} ox ^y - ⁴ -mei ^] ^-yl mercaptophenyl ^ ^ urm- drocMoridu in Шru ^1.4 to 50% ^{y y} Selin acid was added ^{EXAMPLE 14} 2 ^. ^g anhydrous sodium acetate and the mixture was stirred for 20 minutes at room temperature then was added dropwise with vigorous stirring over 1 hour solution of 127.9 g of bromine in 120 ml of glacial acetic acid, the temperature rising from 22 DEG C. to 27 DEG C. After completion of the bromine addition, the reaction mixture was stirred for 10 minutes, then basified to pH with saturated potassium carbonate solution. 7.5 and stirred at room temperature. after about 1 hour, · · begins to separate a crystalline precipitate. the mixture was allowed to stand overnight, the precipitate is suctioned off, washed with cold water and dried in a ^{width y} in vacuo teptotě pn · ⁵⁰ ° C. Produ ^kT Square ^or twice so that the extended-ISH in ^ZDY in 1 liter of water at 50 ° C, the solution is clarified with charcoal and at 10 ° C was slowly brought to crystallisation. Finally, the product is then dried at 70 ° C in vacuo over shčn ^{alkyl CART} em phosphorus.

Yield: 167 ^g (72% of theory);

The following compounds were prepared in an analogous manner to the preceding Examples 1 to 3:

2- (Χ) -6167 llsHin τ- ^{4-phenoxy-yl)} -lH-imidazo [4,5-b] pyridine hydrochloride, m.p. 122-123 ° C, ² - ⁽² -me ^t hoxy- ^- ) -me ^t h ^{l -yl} 1SL fin ^y butylphenyl ^yl) -lH-imidazo [4,5-b] pyridine, m.p. 211-212 ° C,

A solution of 5.4 g (0.02 mol) of 2- (2-methoxy-4-meth ylmerkaptofenyl] -lH-imidazo [4,5-b] ^pyridine in ³⁰ ridfou m is ^{1 to 50% alkyl} acetate Selm ^y stirring The solution prepared as follows is added dropwise at room temperature over 20 minutes: 4.8 g (about 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 cooling with ice water. reacting the mixture for about Neus ^Standing cWazern ^alkyl Seh about 45 m ^{1 s} Ted ^alkyl acetate petroleum jelly.

The resulting reaction mixture for 5 minutes míctó, pa ^as from ^before the ^I 100 m ¹ of water ^{1 to} oncentrovaným · ammonia was basified to pH 8 at ^{Ri to} Rat ^{characterized} in ^three e ^p e EFO acetate, NACE ^F

2- (2-ox ^y еН1 -5-ΐϋ Ίν ^ ^f ^ зиПШу-en ^yl) HH-imidazo ^(4, 5-b] ^pyridine, m.p. 199-200 ° C,

2- (2-ethoxy-4-ethylsulfinylphenyl) -1H-imidazo [4,5-b] pyridine, m.p. 167-168 ° C;

2- (2-methoxy-4-pyopy1sulfiny1feny) -1H-imidazo [4,5-b] pyridine, m.p. 182-183 ° C, ² - ⁽² eth oxy-4 ^-) popyteu Шп yl ^{phenyl -)} HH-imiclazo ^[4, 5-b] pyridine tajrn for detuning s ^{P 182.5} 18 ³ to ⁵ ° C,

WITH

2- (2-ethoxy-4-butylsulfinylphenyl) -1H-imidazo [4,5-b] pyridine, m.p. 187-188 ° C;

2- (2-fluoro-5-methylsulfinylphenyl) -1H-imidazo [4,5-b-] pyridine, m.p. 191-192 ° C;

2- (2- (2-ethylsulfinylethoxy) -4-methoxyphenyl) -1H-imidazo [4,5-b] pyridine, m.p. 188-189 ° C;

2- [2- (2-methylsulfinylethoxy) -4-methoxyphenyl] -1H-imidazo [4,5-b] pyridine, m.p. 231-232 ° C,

2- (2- (3-methylsulfinylpropoxy) -4-methoxyphenyl] -1H-imidazo [4,5-b] pyridine, m.p. 133-134 ° C,

2- (2- (3-ethylsulfinylpropoxy) -4-methoxyphenyl] -1H-imidazo [4,5-b] pyridine, m.p. 127-128 ° C,

2- (2- (2-methylsulfinylethoxy) -4-methylsulfinylphenyl) -1H-imidazo [4,5-b] pyridine, m.p. 193-194 ° C;

2- (2- (2-methylsulfinylethoxy) -4-methylphenyl) -1H-imidazo [4,5-b] pyridine, m.p. 191-192 ° C;

2- (2- (2-methylsulfinylethoxy) -4-chlorophenyl) -1H-imidazo [4,5-b] pyridine, m.p. 221-222 ° C;

2- [2-methoxy-4- (2-methylthiulfinyl-ethoxy) -phenyl] -1H-imidazo [4,5-b] pyridine, m.p. 205-206 ° C,

2- [2-methoxy-4- (2-ethylsulfinylethoxy) phenyl] -1H-imidazo [4,5-b] pyridine, m.p. 215-217 ° C,

2- [2-methoxy-4- (3-methylsulfinylpropoxy) phenyl] -1H-imidazo [4,5-b] pyridine, m.p. 179-180 ° C;

2- [2-methoxy-4- (3-ethylsulfonylpropoxy) phenyl] -1H-imidazo [4,5-b] pyridine, m.p.

2- [2- (2-methylsulfinylethoxy) -5-methylmercaptophenyl] -1H-imidazo [4,5-b] pyridine, m.p. 191-192 ° C;

8- (2-ethoxy-4-methylsulfinylphenyl) purine hydrochloride, m.p. 220-221 ° C (dec.),

8- [4-methoxy-2- (2-methylsulfinylethoxy) phenyl] purine, mp 228-229 ° C,

2- [2- (2-phenylsulfinylethoxy) -4-methoxyphenyl] -1H-imidazo (> 4,5-b) pyridine, m.p. 185-186 ° C,

2- [2- (2-benzylsulfinylethoxy) -4-methoxyphenyl] -1H-imidazo [4,5-b] pyridine, m.p. 194-195 ° C;

2- [2- (2- (4-chlorophenylsulfinyl / ethoxy) -4-methoxyphenyl] -1H-imidazo] 4,5-b] pyridine, m.p. 172-173 ° C,

2- [2- (2- (4-methylphenylsulfinyl / ethoxy) -4-methoxyphenyl] -1H-imidazo (4,5-b) pyridine, m.p. 110-122 ° C;

2- (2- (2- (4-methoxyphenylsulfinyl / ethoxy) -4-methoxyphenyl) -1H-imidazo (4,5-b) pyridine, m.p. 200 DEG-201 DEG C .;

2- (2- (2- (2-methoxyphenylsulfinyl / ethoxy) -4-methoxyphenyl) -1H-imidazo [4,5-b (pyridine) mp 131-133 ° C,

2- [2- (2- (3,4-dimethoxyphenylsulfinyl / ethoxy) -4-methoxyphenyl] -1H-imidazo [4,5-b] pyridine, m.p. 157-159 ° C,

2- (2- (2- / 2-methyl-4,5-dimethoxyphenylsulfinyl / ethoxy) -4-methoxyphenyl) - N -imidazo [4,5-b] pyridine, m.p. C,

2- [2- (274-nitrophenylsulfinyl / ethoxy) -4-methoxyphenyl] -1H-imidazo] 4,5-b] pyridine, m.p. 203-204 ° C,

2- [2- (272,4-dimethoxyphenylsulfinyl / ethoxy) -4-methoxyphenyl] -1H-imidazo [4,5-b] pyridine, m.p. 179-180 ° C.

Claims (6)

OBJECT OF THE INVENTION A process for the preparation of imidazole-4,5-b] pyridines and -pyrimidines of the general formula I in which R1 represents an alkyl, alkoxy, alkylmercapto- or alkylsulphinyl group containing from 1 to 4 carbon atoms or a halogen atom, R @ 6 is C1 -C4 alkylsulfinyl or C2 -C3 alkoxy substituted in the end position with C1 -C4 alkylsulfinyl, C7 -C9 aralkylsulfinyl, phenylsulfinyl or mono-, di- or trisubstituted C 1 -C 3 alkyl, C 1 -C 3 alkoxy and / or halogen, or nitrophenylsulphinyl, optionally mono- or disubstituted C 1 -C 3 alkyl, C 1 -C 3 alkoxy carbon and / or halogen atoms, and X is CH or N, as well as their ta-tautomers and their physiologically tolerable addition salts with inorganic or organic acids, characterized in that X and R 1 are as defined above and R 3 is C 1 -C 4 alkyl or C 2 -C 3 alkoxy substituted in the end position by C 1 -C 4 alkyl, C 7 -C 9 aralkyl mercapto, phenyl mercapto optionally mono-, di- or trisubstituted (C 1 -C 3) alkyl, (C 1 -C 3) alkoxy and / or halogen, or nitrophenylmercapto optionally mono- or disubstituted with (C 1 -C 3) alkyl, (C 1 -C 3) alkoxy and / or or a halogen atom, oxidized in the solvent with bromine or its addition compounds, and optionally converting the compound of formula I so obtained into a 1H-tautomer or a physiologically tolerable salt with an inorganic or organic acid. 2. A process according to claim 1 wherein the solvent is an aqueous or non-aqueous solvent. 3. Process according to claims 1 and 2, characterized in that the reaction is carried out at a temperature between -10 and 80 [deg.] C, preferably between 15 and 30 [deg.] C. 4. Process according to claim 1, characterized in that the reaction is carried out at a pH in the range from 0 to 10, preferably from 3 to 8. 5. A process according to any one of claims 1 to 4, wherein the reaction is carried out in the presence of a carboxylate, carbonate, hydrogen phosphate or dihydrogen phosphate anion. 6. A process according to any one of claims 1 to 5, wherein the oxidation is carried out by treatment with bromine or sodium hypobromite.