DD201902A5 - A NEW METHOD FOR THE PRODUCTION OF IMIDAZO / 4,5-B / PYRIDINES AND PYRIMIDINES - Google Patents

Abstract

The invention relates to a process for the preparation of imidazo (4,5-b) pyridines and pyrimidines. The aim of the invention is an improved process with which the desired compounds are obtained in high yield and high purity. According to the invention, imidazo (4,5-b) -pyridines and -pyrimidines of the general formula I where R 1 is an alkyl, alkoxy, alkylmercapto or alkylsulfinyl group or a halogen atom, R 2 is an alkylsulfinyl group or an alkoxy group terminally substituted by an alkylsulfinyl group, aralkylsulfinyl group or optionally substituted phenylsulfinyl group, and X represents the CH group or a nitrogen atom, prepared in such a way that a corresponding mercapto compound is oxidized with bromine or its addition compounds.

Description

Berlin, the 24 _β 3.1982

AP C 07 D / 234 957/6 59 943/12

Process for the preparation of imidazo / "4,5-bj-pyridines and -pyrimidines

the invention

The invention relates to a novel process for the preparation of imidazo-4,5-b3-pyridines and -pyrimidines.

Charak ^ _tjBTis: tik of the known technical solutions

In GB-PS 1,445,824 and the European Offenlegungsschriften _e 0 022 495 and 0 _{s e} 024 _like 290 is u a _e already / 4,5-bJ-pyridines, a process for preparing imidazo and pyrimidines of the general formula

in the

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

R _{2 is} an alkylsulfinyl group having 1 to 4 carbon atoms or an alkoxy group having 2 or 3 carbon atoms terminated by an alkylsulfinyl group having 1 to 4 carbon atoms, an aralkylsulfinyl group having 7 to 9 carbon atoms, and optionally

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by alkyl groups I to 3 carbon atoms, alkoxy groups having 1 to 3 carbon atoms and / or halogen atoms mono-, di- or trisubstituted phenylsulfinyl group or an optionally substituted by alkyl groups having 1 to 3 carbon atoms, alkoxy groups ¹ having 1 to 3 carbon atoms and / or halogen atoms mono- j or disubstituted nitrophenylsulfinyl group, and

X denotes the CH group or a nitrogen atom, of which IH-tautomers and of their physiologically tolerated salts with inorganic or organic acids are described, which is 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 , these impurities necessitate extensive purification for the preparation of a pharmaceutical grade product.

Further, from the manuals of Organic Chemistry (C. Ferri, Reactions of Organic Synthesis, Publisher: G, Thieme (1978); Kharasch and Meyers: The Chemistry of Organic Sulfur Compounds, Vol. 1, 157-159 (1951)) , 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. , B »Cleavage of the carbon-sulfur bond, formation of carbon-bromine bonds and / or bromination of the aromatic.

b 24.3 * 1982

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the invention

The aim of the invention is to provide an improved process for the preparation of Imidazo f4,5-b3 - pyridines and -pyriraidinen, with the excellent yields in high purity can be achieved.

The invention has for its object to find new starting compounds and novel process steps for the preparation of imidazo £ 4,5 - ^] - pyridines and pyrimidines.

Surprisingly, now. found that the compounds of general formula I aer in greater purity and in excellent yields by oxidation of a compound of general formula

(ID

in the

X and R are as defined above and R _{3 is} an alkylmercapto group having 1 to 4 carbon atoms or

  an alkoxy group having 2 or 3 carbon atoms which is terminal by an alkylmercapto group having 1 to 4

; Carbon atoms, an aralkylmercapto group having from 7 to 9 carbon atoms, a mono-, di- or trisubstituted phenylmercapto group optionally substituted by alkyl groups having from 1 to 3 carbon atoms, alkoxy groups having from 1 to 3 carbon atoms and / or halogen atoms, or optionally alkyl groups having from 1 to 3 carbon atoms, Alkoxy groups having 1 to 3 carbon atoms and / or halogen atoms mono- or di-substituted Nitrophenylmercaptogruppe "is replaced with bromine or its addition compounds.

The oxidation is preferably carried out 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, ethyl formate, ethyl acetate, dimethylformamide, dimethyl sulfoxide or hexamethyl-phosphoric triamide, at temperatures between -10 and 80 ⁰ C, but preferably at temperatures between 15 and 30 ° C, carried out in a pH range of 0 to 10. However, the reaction is particularly advantageous in a pH range of 3 to 8, suitably in the presence of a buffer, for example in the presence of a carboxylate anion, for example

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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 carbonates such as sodium bicarbonate or disodium carbonate, with bromine or with a hypobromite, z, B. sodium hypobromite carried out.

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

The starting materials used in the process are mostly known from the literature or can be prepared analogously to the process described in GB-PS 1,445,824 methods, namely or by ring closure of a corresponding 5,6-diaminopyrimidine, 2,3-diamino-pyridine.

Embodiment Example *

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

iReference Example I

j 2- (2-methoxy-4-methylsulfinylphenyl) -iH-imidazo £ 4,5-b / pyridine

6., 6.g 2- (2-Methoxy-4-methylmercapto-phenyl) -iH-imidazo / M, 5-b / pyridine are dissolved in 100 ml of chloroform and at -15 to -20 ⁰ C for 5 hours a solution of 2.96 g of 3-chloro-peroxybenzoic acid in 600 ml of chloroform was added dropwise. It is then extracted by shaking with a dilute sodium carbonate solution, the chloroform phase dried and concentrated. The residue is purified over a silica gel column (eluent: chloroform / methanol = 9: 1). The addition of ethereal hydrochloric acid to a methanolic solution of the base gives the yellow hydrochloride. Yield: 2.3 g (33.6% of theory), Melting point of the base: 154-155 ⁰ C.

Reference Example II

2- (2-methoxy-4-methylsulfinyl-phenyl) -1H-imidazo / 4,5-b? Pyridine hydrochloride

A solution of 135.6 g (0..5 mol) of 2- (2-methoxy-4-methylmercapto-phenyl) -ih-imidazo ^ 4/5-b-pyridine in 600 ml of 80% acetic acid is added with 57 g of 30 % hydrogen peroxide and allowed to stand for 2 days at laboratory temperature. After addition of 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 stopped, the reaction mixture poured onto 3 1 of ice water, .with conc. Ammonia adjusted to pH 9 and extracted 3 times with chloroform. The combined extracts are dried and concentrated in vacuo. According to a thin-layer chromatographic comparison, the crude product contains about 3.% starting material, 4% sulfonone and 2% further unknown impurities.

After purification over 4,000 g of silica gel (eluent: chloroform + 3% acetone), after precipitation from acetone, 72.2 g (50.3% of theory) of the desired product of melting point 198 are obtained.

199 ° C received. The product contains according to thin-layer chromatography: (silica gel prefabricated plates 60 F .. 254 from E .. Merck, Dam s-tadt, system: chloroform / ethanol (85/15)) 0.1% sulfide, 0.5% sulfonate and 0.85% unknown compounds as impurities «

example 1

2- (2-methoxy-4-methylsulfinylphenyl) -1H-i midazoZ4,5-b_7 pyridine

i

To a suspension of 229.8 g of 2- (2-methoxy-4-methylmercaptophenyl) -iH-imidazo / 4,5-bipyridine χ 0.5 CH ₃ OH and 72.1 g of sodium acetate in 1.5 1 glacial acetic acid with vigorous stirring 41.1 ml of bromine, dissolved in 150 ml of glacial acetic acid, added dropwise at a temperature between 20 and 25 C. Subsequently, the Reaktiorisgemisch is poured onto about 1 kg of ice and acidified with conc. Ammonia at about 2 5 ° C adjusted to pH 9. The aqueous phase is extracted 3 times with a total of 3 1 chloroform. After drying the organic phase with magnesium sulfate and treating with activated carbon, the solvent is removed to a remainder of 200 g and the

γ incipient crystallization by addition of 40 ml of methanol and

ν ο

Heating to about 40-45 C prevented. The precipitated with 1.2 1 acetone product is filtered off, dissolved in a mixture of 300 ml of methanol and methylene chloride at 40 ° C and precipitated after concentration in vacuo to a residual solvent of about 150 g again with 1 1 of acetone. It is filtered off with suction and washed with a mixture .... of 200 ml of acetone and 300 ml of η-hexane. Yield: 175, t g of melting point 2O1-2O2 ° C.

After concentrating the mother liquor and by adding acetone, one obtains a further 36.3 g of the melting point 2OO-2O1 ° C. Total yield: 211.4 g (92% of theory).

£ O ί * Ό «J -I

The product thus obtained contains, according to the thin layer chromatogram (silica gel plates 60 F 254 from E. Merck, Darmstadt;! System chloroform / ethanol (35/15) 5 0.05 and 0.25% SuIfön I 'unknown impurities!.

Example 2

• 2 - '(2-Methoxv-4-methylsul- finyl-phenvl) -1H-imidazoZ.'4,5-b7pvridine

^! To a Lösung'von 5.4 g (0.02 mol) of 2- (2-methoxy-4-methylmercapto-phenyl) -iH-imidazo £ 4,5-b7pyridine in 30 ml of 50% acetic acid is within 20 minutes under Stirring at room temperature, a solution is added dropwise, which is prepared as follows: To 6 g of sodium hydroxide in 50 ml of water are added dropwise with stirring and ice water cooling 4.8 g = 1.5 ml (0.03 mol) of bromine. After completion of the reaction is acidified with further cooling with 45 ml of glacial acetic acid. """" _C;

The resulting reaction mixture is stirred for 5 minutes, diluted with 100 ml of water, acidified with conc. Adjust ammonia to pH 8 and shake for 3 χ with ethyl acetate. Then 3 χ is extracted with chloroform, the extract dried over magnesium sulfate, the solvent removed in vacuo and the honey-like residue dissolved in 100 ml of acetone. The sulfoxide begins to crystallize out immediately. The white product is filtered off with suction, washed with acetone and then with η-hexane and dried, yield: 4.8 g (83.6% of theory), melting point: 2OO-2O2 ° C.

4 α J /

Example 3

8- (2-methoxy-4-methylsulfinyl-phenyl) -purin

Werderfreak given to a suspension of 250.2 g of 8- (2-methoxy-4-phenyl methylmercaptc) purine hydrochloride in 1.4 1 50% acetic acid 142.0 g of anhydrous sodium acetate and stirred for 20 minutes mtemperatur "at Rau. then, under vigorous stirring, a solution of 127.9 g bromine in 120 ml of glacial acetic acid is added dropwise within an hour. The temperature rises to 27 C from 22 C to ⁰ After completion of the addition of bromine for 10 minutes then nachgerühr with saturated potassium carbonate to a pH. Value of 7.5 and stirred at room temperature After about one hour, a precipitate begins to crystallize out

It is allowed to stand overnight, filtered off with suction, washed with cold water, and dried in vacuo at 50 ^° C. For purification, the substance 2 χ is dissolved in about 1 l of water at 50 ° C., treated with activated charcoal and added 1O ⁰ C slowly crystallized, followed by drying at 70 ⁰ C in vacuo over phosphorus pentoxide.

Yield: 167 g (72 % of theory),

melting point

236-238 ⁽

The same compounds were prepared as in Examples 1 to 3 above:

2- (2-methoxy-4-ethylsulfinyl-phenyl) -IH-imidazo / 4,5-b7pyridinhydrochlorid

Melting point: 122-123 ° C

LOH Ό J / υ

2- (2-Methoxy-5-methylsulfinylphenyl) -iH-imidazo / 4,5-bpyridine Melting point: 211-212 ° C

2- (2-Ethoxy-5-methylsulfinylphenyl) -1H-imidazo £ 4,5-b / pyridine mp. 199-200 ° C

2- (2-Ethoxy-4-ethylsulfinylphenyl) -iH-imidazo ^ i, 5-b7pyridine Melting point: 167-168 ° C

2- (2-Methoxy-4-propylsulfinylphenyl) -iH-imidazo ^ _4,5-b / pyridine Melting point: 182-183 ° C

2- (2-Ethoxy-4-propylsulfinyl-phenyl) -iH-imidazo _ / _ 4, 5-b / pyridine Melting point: 182.5-183.5 ° C (dec.)

2- (2-ethoxy-4-butylsulfinyl-phenyl) -IH-imidazo ^ 4,5-b / pyridine mp: 1'87-188 ⁰ C

2- (2-Fluoro-S-methylsulfinylphenyl) -1H-imidazo / 4,5-b / pyridine Melting point: 191-192 ° C

2 ~ l_2- (2-ethylsulfinyl-ethoxy) -4-methoxy-phenyl / -1H-imidazo / 4,5-b7-pyridine Melting point: 188-189 ° C

2- / 2- (2-methylsulfinyl-ethoxy) -4-methoxyphenyl / -1H-imidazo- β, 5-b7pyridine, m.p .: 231-232 ° C

2- / 2- (3-methylsulfinyl-propoxy) -4-methoxy-pheny3 ^ / - 1H-imidazo / 4,5-b7pyridin

Melting point: 133-134 ° C

2 ~ 12- (3-ethylsulfinyl-propoxy) -4-methoxyphenyl ^ / -1H-imidazo- β, 5-b7pyridine Melting point: 127-128 ° C

ζ YES yb /

-ΙΟΙ2- ^ - (2-Methylsulfinyl-ethoxy) -4-methylsulfinyl-phenyl 17-1H-: imidazo / 4,5-b / pyridine delting point: 193-194 ° C

...... - 2-JIlr- (2-methylsulfinyl-ethoxy) -4-methylphenyl / -1H-imidazo- β, 5-b7pyridine m.p .: 191-192 ° C

-2- £ 2- (2-methylsulfinyl-ethoxy) -4-chloro-phenyl-7-1H-imidazo / 4,5-i. ipyridine. "Melting point: 221-222 ° C

^; 2- / j2-Methoxy-4- (2-methylsulfinyl-ethoxy) -phenyl-IH-imidazo- β, 5-b7pyridine 'Melting point: 2O5-2O6 ° C

2 - ^ _ 2-Methoxy-4- (2-ethylsulfinyl-ethoxy) -phenyv-IH-imidazo-Zi '5-b7pyridine' '' '. Melting point: 215-217 ° C

2 - ^ _ 2-Methoxy-4- (3-methylsulfinyl-propoxy) -phenyl / -1H-imidazo- 1 $, 5-b / pyridine Melting point: 179-18O ⁰ C

2 - / _ 2-methoxy-4- (3-ethylsulfinyl-propoxy) -phenylZ-IH-imidazo 14, 5-b7pyridin Melting point: 166-167 ° C

2- 12- (2-methylsulfinyl-ethoxy) -5-methylmercapto-phenyl / -IH -...... imidazo /! , 5-b7pyridine Melting point: 191-192 ° C

8- (2-ethoxy-4-methylsulfinylphenyl) purine hydrochloride Melting point: 22O-221 ° C (dec.)

8- / 4-Methoxy-2- (2-methylsulfinyl-ethoxy) -phenyl / -purine Melting point 228-229 ° C

-12- (2-phenylsulfinylethoxy) -4-methoxy-phenyl / -iH-imidazo

Melting point: 18 5-186 ° C

2 ~ [2 " (2-Benzylsulfinylethoxy) - ^ - methoxy-phenyl-IH-imidazo- η (Λ ~, 5-b / pyridine) Melting point: 194-195 ° C

2- (2- (4-chlorophenylsulfinyl) ethoxy) -4-methoxyphenyl / -1H-imidazo / 4,5,3o-7-pyridine Melting point: 172-173 ° C

.2- / 2- {2- (4-Methylphenylsulfinyl) -ethoxy) -4-methoxyphenyl / -1H-imidazo ^, 5-b7-pyridine "... ·

Melting point: -11O-122 ° C - "" "

2- [2- (2- (4-Methoxyphenylsulfinyl) -ethoxy) -4-methoxyphenyl] -1 H , 5-b "7-pyridine

Melting point: 2CX) -2O1 ° C

2- / 2- (2- (2-methoxyphenylsulfinyl) -ethoxy) -4-trimethoxyphenyl / 1H, 5-b / pyridine

Melting point: 131-133 ° C

2- / J, - (2- {3,4-Dimethoxyphenylsulfinyl) ethoxy) -4-methoxyphenyl / -IH-imidazo ^ _4,5-b / pyridine Melting point: 157-159 ° C

2- / 2- (2- (2-methyl-4,5-dimethoxyphenylsulfinyl) ethoxy) _-4-f 5-methi7 ii7pyridin

Melting point: 172-173 ° C

2- [2- (2 - (4-Nitrophenylsulfinyl) -ethoxy) -4-methoxy-phenyl / 1H-imidazo / 5,1-b / pyridine m.p .: 2O3-2O4 ° C

'2- / 2- (2- (2,4-Dimethoxyphenylsulfinyl) ethoxy) -4-methoxyphenyl / 4,5- ^ / pyridine

Melting point: 179-180 ° C

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or organic acids, characterized in that a compound of general formula

(II)

in the

X and R are as defined above and R _{3 is} an alkylmercapto group having 1 to 4 carbon atoms or an alkoxy group having 2 or 3 carbon atoms terminated by an alkylmercapto group having 1 to 4 carbon atoms, an aralkyl racercapto group having 7 to 9 carbon atoms, optionally substituted by alkyl groups 1 to 3 carbon atoms ,. Alkoxy groups and / or halogen atoms mono-, di- or tri-substituted phenylmercapto or optionally substituted by alkyl groups having 1 to 3 carbon atoms, alkoxy groups having 1 to 3 carbon atoms and / or halogen atoms mono- or disubstituted nitrophenylmercapto is substituted, in a solvent with bromine or whose addition compounds is oxidized, and, if desired, converting a compound of general formula I or its tautomer obtained in this way into a physiologically tolerated salt with an inorganic or organic acid *

Claims (6)

24.3.1982 AP C 07 D / 234 957/6 - 13 - 59 943/12 Claim for invention 1. A process for the preparation of imidazo / 4,5-bJ-pyridines and -pyrlmidines of the general formula in the - R _{1 is} an alkyl, alkoxy, alkylmercapto or alkylsulfinyl group each having 1 to 4 carbon atoms or a halogen atom, R "is an alkylsulfinyl group having 1 to 4 carbon atoms or an alkoxy group having 2 or 3 carbon atoms terminated by an alkylsulfinyl group having 1 to 4 carbon atoms, an aralkylsulfinyl group having 7 to 9 carbon atoms, optionally substituted by alkyl groups having 1 to 3 carbon atoms, alkoxy groups having 1 to 3 carbon atoms and / or halogen atoms mono-, di- or tri-substituted phenylsulfinyl or optionally substituted by alkyl groups having 1 to 3 carbon atoms, alkoxy groups having 1 to 3 carbon atoms and / or halogen atoms mono- or disubstituted nitrophenylsulfinyl, and X denote the CH group or a nitrogen atom, as well as their IH tautomers and their physiologically acceptable salts with inorganic 24,3.1982 AP C 07 D / 234 957/6 - 15 - 59 943/12 2. The method according to item 1, characterized in that an aqueous or anhydrous solvent is used as the solvent. Process according to items 1 and 2, characterized in that the reaction is carried out at temperatures between -10 and 80 ° C, but preferably at temperatures between -15 and 30 ^° C. 4. The method according to the items 1 to 3, characterized in that the reaction in a pH range of 0 to 10 , but preferably in a pH range of 3 to 8, is performed. 5. Method according to items 1 to 4, characterized in that the reaction in the presence of a buffer, for. B, in the presence of a carboxylate, carbonate hydrogen phosphate or dihydrogen phosphate anion, is performed » 6. Process according to items 1 to 5 _X, characterized in that the oxidation is carried out with bromine or sodium hypobromite »