DE1695335A1 - Process for the preparation of purine derivatives - Google Patents

Description

Separation from patent application K 54 420 IVd / 12p

The invention relates to a new process for the preparation of purine derivatives.

It is known from the synthesis of purine derivatives from 4-amino-5-arylazopyrimidine derivatives that, for example, hypoxanthine can be obtained by reducing 4-amino-5-arylazo-6-hydroxypyrimidine with sodium dithionite [Yakagaku Zasshi 77 »687 (1957)], isolation of the 4,5-diamino-6-hydroxypyrimidine obtained and treatment of this compound with a formylating agent such as formic acid [Journal of the American Chemical Society JA * 411 (1952)] or ethyl orthoformate together with acetic anhydride [Journal of Organic Chemistry 25_, 148 (1960 )] to cause the formation of the imidazole ring can be obtained. Similar procedures are used for the synthesis of adenine and xanthine

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[Journal of the Chemical Society, 386 (1934), Journal of the American Chemical Society 75, 263 (1953), ibid. JJ., 533 (1949), Pharmaceutical Bulletin (Tokyo) 2 »224 (1955), etc.]. For example, a process for the preparation of adenine is known in which 4,6-diamino-5-arylazopyrimidine is catalytically treated with Raneynickel [Journal of the Chemical Society, 386 (1943)] or with zinc [Journal of the American Chemical Society 71, 533 ( 1949)]

^ reduced, the 4,5,6-triaminopyrimidine obtained isolated and then this compound in formamide [Journal of the American Chemical Society 25, 263 (1953)] or in formamide and formic acid [Journal of the American Chemical Society Tl. » 535 (1949)] to cause the formation of the imidazole ring.

However, the above methods have the disadvantage that they require a plurality of steps and that, for example, the 4,5,6-triaminopyrimidine obtained as an intermediate is colored is because it is subject to air oxidation during isolation. It is also from German patent specification 834 105

P known, xanthine derivatives by reduction of 5 ~ isonitroso ~ 4-

imino-2,6-diketohexahydropyrimidine derivatives to formamide derivatives without isolating the interconnections. From the "Japanese Patent Publication" No. 562/57 it is also known a 4-amino-5-arylazouracil compound with formamide or to reduce catalytically with Raney nickel in the presence of formamide or ammonium formate and then to subject the reduced compound to the ring closure. The reaction should take place run under high pressure. From literature

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K

It can be seen that the yield of the reaction process varies depending on the nature of the pyrimidine compound to be reduced, the substituents it contains and the reduction conditions such as temperature, pressure and solvent, especially when the pyrimidine compound occurs in tautomeric forms, so that reliable conclusions can be drawn from one pyrimidine starting compound cannot be drawn onto other pyrimidine starting compounds. This also applies to the uracil derivatives known from German Patent 834 105 and "Japanese Patent Publication" No. 526/57.

There has now been a method of making a purine derivative the general formula

r ²

, N
HN

found in which Y ₂ O =, NH = or S = * and R ₂ can mean a lower alkyl group in the 1- or 3-position, which is characterized by the fact that a 4-amino-5-arylazopyrimidine of the general formula

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in which Y and R _{p have} the meaning given above, X _{1 is} the hydrazine, a lower alkylhydrazo, arylhydrazo or semicarbazide radical, R- is hydrogen or a lower alkyl-, the OH-, a lower alkoxy-, halogen-, the nitro, sulfo or carboxyl substituent is »and η O _{9 means} 1» 2 or 3, continuously reduced at atmospheric pressure in a single reaction stage and without isolation of the intermediate and cyclized to form the imidazoIring, the reduction being carried out by the action of a reducing agent at least ambient temperature and at ambient pressure and where the imidazole ring formation is carried out at a temperature of at least 100 ⁰ G and at ambient pressure with the aid of at least one cyclizing agent of formamide, formamidine, formic acid, lower alkyl formates, ammonium formate, di- (lower) - alkoxymethyl-low .-alkanoates, lower alkyl formimino ethers, lower alkyl orthoformates, combinations of lower alkyl orthoformate en and acetic anhydride, combinations of lower alkyl orthoformates and ammonia, combinations of lower alkyl orthoformates and ketene, combinations of lower alkyl orthoformates and nitriles

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and combinations of lower alkyl orthoformates, ammonia and salts of lower organic acids.

The continuous reaction, d.lu the reduction and the Cyclization to form the imidazole ring are advantageous carried out in one and the same reactant. The reduction is preferably done with the help of at least a reducing agent of sulfur compounds with ^

reducing properties, reducing metals, reducing metal salts, metal hydrides and hydrazines. The conversion takes place uninterruptedly in one stage, ie. without isolation of the intermediate. The whole stage is carried out under mild reaction conditions to produce drastic conditions such as are working under pressure using hydrogenation or using special equipment, etc., are avoided.

In detail, according to the invention, the starting material which is a 4-amino-5-arylazopyrimidine is preferred in solution in a solvent with stirring and at a suitable temperature of the action of a suitable Reducing agent exposed to reduce the arylazo group, after which the mixture - without the intermediate product too isolate - with further stirring with or without addition of a suitable cyclizing agent (to form the imidazole ring) is heated to form the imidazole ring (and thus the

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Purine nucleus) and in this way the corresponding Obtain purine derivative in high yield.

The method according to the invention is preferably carried out in an inert atmosphere, such as nitrogen, however, purine derivatives of sufficiently high purity can be obtained even when the process is carried out in air will. Furthermore, there is no disadvantage if a diluent is added during the reaction and if one continues to do so a solvent is used, with the aid of which the water formed during the reaction is distilled off azeotropically leaves.

A wide variety of inert solvents which do not inhibit the reaction are suitable as solvents or diluents. These include alcohols such as ethanol, propanol, butanol, hexanol, cyclohexanol, furfuryl alcohol, tetrahydrofurfuryl alcohol, benzyl alcohol, ethylene glycol, propylene glycol and glycerine; Ethers such as butyl ether, amyl ether, anisole, phenetol, tetrahydrofuran, the dioxanes, the ethylene glycol dialkyl ethers, the propylene glycol dialkyl ethers, the polyethylene glycol dialkyl ethers (such as the diethylene glycol dialkyl ethers (such as the diethylene glycol dialkyl ethers) and the triethylene glycol dialkyl ethers (such as, for example, the diethylene glycol dialkyl ethers (such as the di-propylene glycol dialkyl ethers) and the alcohols such as, e.g. various ^M Cellosolve ^M solvents, the "carbitols", the polyethylene glycols (such as diethylene glycol and triethylene glycol), the polypropylene glycols (such as di- and

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Tripropylene glycol), the polyethylene glycol monoalkyl ethers (such as e.g. the di- and triethylene glycol monoalkyl ethers) and the polypropylene glycol monoalkyl ethers (like ss.B. the di- and tripropylene glycol monoalkyl ethers) f Ketones such as cyclohexanone and dibutyl ketone esters such as methyl formate, methyl acetate, methyl orthof ormiate, methyl propionate, ethyl formate, ethyl acetate, Ethyl orthoformate, ethyl propionate, butyl acetate, butyl formate, Ethyl lactate, the ethylene glycol monoarboxylic acid ester, the ethylene glycol dicarboxylic acid ester, the di- and triethylene glycol! monocarboxylic acid esters, the di- and triethylene glycol dicarboxylic acid esters, the propylene glycol dicarboxylic acid esters, the di- and tripropylene glycol dicarboxylic acid esters, the propylene glycol monocarboxylic acid esters, the di- and tripropylene glycol monocarboxylic acid esters, the Äthylenglykolmonoalkyläthermonocarbonsäureester, the di- and Triethylene glycol monoalkyl ether monocarboxylic acid ester, the propylene glycol monoalkyl ether monocarboxylic acid ester and the di- and tripropylene glycol monoalkyl ether monocarboxylic acid estersj nitriles, such as capronitrile, acetonitrile and benzonitrile, the morpho | line} acid amides such as formamide and N, K-dimethylformamide; organic acids such as formic acid; and hydrocarbons such as benzene, toluene and xylene.

The reducing agents which can be used in the process of the invention include sulfur compounds with reducing agents Properties such as dithionites (such as sodium dithionite), thiosulfates (such as ammonium thiosulfate, Lithium thiosulphate, sodium thiosulphate, potassium thiosulphate,

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Calcium thiosulphate, magnesium thiosulphate and barium thiosulphate), the sulfites (such as ammonium sulfite, potassium sulfite, sodium sulfite, Lithium sulfite, calcium sulfite, magnesium sulfite, barium sulfite, Ammonium bisulfite, sodium bisulfite, Potassium hydrogen sulfite, sodium pyrosulfite and potassium pyrosulfite), the sulfides (such as ammonium sulfide, lithium sulfide, sodium sulfide, Potassium sulfide, magnesium sulfide, calcium sulfide and Barium sulfide), the hydrosulfides (such as ammonium hydrosulfide, Sodium hydrosulfide, potassium hydrosulfide, calcium hydrosulfide and Barium hydrosulphide), the polysulphides (such as ammonium pentasulphide, Sodium pentasulphide, potassium pentasulphide, barium pentasulphide, Sodium tetrasulfide, potassium tetrasulfide, potassium trisulfide, barium trisulfide, potassium disulfide, ammonium polysulfide, sodium polysulfide and potassium polysulphide), the organic dithionites (such as formaldehyde sodium sulphoxylate dihydrate, rongalite) and the organic sulfites (such as formaldehyde sodium hydroxide hydrogen sulfite) reducing metals (such as zinc, tin, Raney nickel alloy and Raney nickel as obtained from this alloy, Eaney cobalt alloy and Raney cobalt as it is obtained from this alloy, palladium and aluminum amalgam) f reducing metal salts [such as stannous chloride and titanium (III) chloride] j hydrides (such as sodium borohydride, Calcium hydride, sodium hydride and titanium hydride); and hydrazines (such as hydrazine sulfate, hydrazine hydrochloride and hydrazine hydrate).

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The cyclizing agents which can be used in the process according to the invention for the production of the imidazole ring include formamide, formamidine, formic acid, the formic acid esters, ammonium formate, the dialkoxymethyl esters of organic acids, v / ie, for example diethoxymethyl acetic acid esters, formimino ester (pormimido ester) derivatives, such as ethyl acetate. Mixtures or combinations of an orthoformic acid ester with ammonia, mixtures or combinations of an Λ orthoformic acid ester with a ketene compound, such as, for example. Ketene or diethyl ketene, mixtures or combinations of an orthoformic acid ester with a nitrile derivative, such as, for example, acetonitrile, and mixtures or combinations of an orthoformic acid ester with ammonia and a salt of a lower organic acid. However, if during the reduction, a solvent is used, fä which is able to act as a cyclizing agent, such as, "B. Formamide, formic acid or a formic acid ester, it is not always necessary to add a cyclizing agent after the reduction. "

The reduction carried out in the first stage can be carried out at room temperature (about 15-30 ^° C.). However, if they are carried out at a higher temperature, a smaller amount of reducing agent will result from al3 when working at a lower temperature. The reduction can be carried out, for example, in formamide using sodium dithiotite or sodium formaldehyde sulfoxylate (Rongalit). If the reduction is carried out catalytically using a re-

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If you want to carry out reducing agent, it is preferable to carry out the reduction by heating in an airtight vessel under an increased hydrogen pressure. The imidazole ring formation carried out in the second stage is carried out at a temperature above 100 ^° C. when testing.

The purine derivatives obtained in this way are very important starting materials for the production of P chemical seasonings and medicines.

In the following example, the reactions were carried out _{under ambient pressure, ie under atmospheric pressure 9.}

example

3.2 g of 4-amino-2-ethylhydrazino-1,6-dihydro-5- (p-nitrophenylaz-o) -6-mercapto-3Hnethylpyridin were suspended in 30 ecm Ν, Ν-dimethylformamide, and the temperature of the mixture was kept at 110 to 130 ^{° C. with stirring.} At this temperature, 5 to 10 g of sodium thiosulphate were added in small portions over the course of 20 minutes. After the addition, the temperature was maintained for a further 10 minutes. The mixture was cooled and a mixture of 15 ecm of ethyl orthoformate, 25 ecm of 20% methanolic ammonia and 5 g of ammonium acetate was added. After heating at 150 to 180 ⁰ C in a closed vessel for 2 hours under stirring, the reaction liquid was concentrated ness. 40 to 50 ecm of a 2 normal aqueous

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Sodium hydroxide was added to the reaction liquid, and the insolubles were filtered off. The filtrate was neutralized with acetic acid and the deposited precipitate was filtered off, 1.3 g of 2-amino-3 »6-dihydro-6-mercapto-3-methylpurine being obtained.

- patent claims -

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Claims (4)

K 770 -12- claims: 1. Process for the preparation of a purine derivative of general formula in which Y ₂ O =, NH = or S = and R ₂ can mean a lower alkyl group in the 1- or 3-position, characterized in that a 4-amino-5-arylazopyrimidine of the general formula ψ in which Y ₂ and Rp have the meaning given above, X ^ denotes the hydrazine, a lower alkylhydrazo, arylhydrazo or the semicarbazide radical, R .. hydrogen or a lower alkyl, the OH-, a lower alkoxy, Halogen, the nitro, sulfo or carboxyl substituent, and η 0, 1, 2 or 3 is reduced at atmospheric pressure continuously in a single reaction stage and without isolation of the intermediate and cyclized to form the imidazole ring, the reduction being effected by action one 209818/1161 K 770 Performs reducing agent at at least ambient temperature and at ambient pressure and give the imidazole ring at a temperature of at least 100 ⁰ C and at ambient pressure using at least one cyclizing agent selected from Formamidj formamidine, formic acid, lower alkyl formates, ammonium, di- (LOW.) - alkoxymethyl lower alkanoates, lower alkyl formimino ethers, lower alkyl orthoformates, combinations of lower alkyl orthoformates and acetic anhydride, g combinations of lower alkyl orthoformates and ammonia, combinations of lower alkyl orthoformates and ketene, combinations of lower alkyl orthoformates and nitriles and combinations of lower alkyl orthoformates, ammonia and salts organic acids existing group. 2. The method according to claim 1, characterized in that the uninterrupted reaction in one and the same inert solvent carries out. λ 3. The method according to claim 1, characterized in that that the water formed during the reaction is distilled off with the aid of a solvent which is azeotropic with water Mixture forms. 4. The method according to claim 1, characterized in that one dafl the continuous reaction in an atmosphere of a inert grass. Dr.Ve/Wr 209818/1161