DE1695336A1 - 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.

From the synthesis of purine derivatives from 4-amino-5-arylazopyrimidine derivatives it is known 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 74, 411 (1952)] or ethyl orthoformate together with Acetic anhydride [Journal of Organic Chemistry 25th? 148 (1960) J, to cause the formation of the imidazole ring can be obtained. Similar procedures are used for the synthesis of adenine and xanthine known [Journal of the Chemical Society, 386 (1934), Journal

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of the American Chemical Society 75, 263 (1953), ibid. 21 »533 (1949) f Pharmaceutical Bulletin (Tokyo) 3.ι ²² 4 (1955) etc.] For example, a process for the preparation of adenine is known in which one 4 , 6-diamino-5-arylazopyrimidine reduced catalytically with Raneynickel [Journal of the Chemical Society, 386 (1943)] or with zinc [Journal of the American Chemical Society 21 »533 (1949)], the 4.5s, 6- Triaminopyrimidine 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 21,535 (1949)] in order to bring about the formation of the imidazole ring.

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

It is also known from German Patent 834 105 to obtain xanthine derivatives by reducing 5-ionitroso-4-imino-2,6-diketo-hexahydropyrimidine derivatives to formamide derivatives without isolating the intermediate compound. From "Japanese Patent Publication ¹ » No. 526/57 it is also known to reduce a 4-amino-5-arylazouracil compound with formamide or catalytically with Raney nickel in the presence of formamide or ammonium formate and then to ring-close the reduced compound From the literature it can be seen that the yield of the reaction process;} e

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in the manner of the pyrimidine compound to be reduced, the in its substituents and the reduction conditions, such as temperature, pressure and solvent, especially if the pyrimidine compound occurs in tautomeric forms, fluctuates, so that reliable conclusions can be drawn from a pyrimidiri starting compound to other pyrimidine starting compounds cannot be drawn. This also applies to those from German Patent 834 105 and the "Japanese Patent Publication "No. 526/57 known uracil derivatives. A method for producing a Purine derivatives of the general formula

j!

N ",

found in the I ^ H, the NH ₂ ^ OH-, SH-, a lower alkyl, lower alkylamino, acylamino, lower alkylmercapto or lower alkoxy radical, X "O =, HH = or S = and Rjj a may mean lower alkyl radical in the 1- or 3-position, which is characterized in that one is a 4-amino-5-arylazopyrinddine of the general formula

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in which Υ «, X ₂ and R _{2 have} the meaning given above, R. hydrogen or a lower alkyl, the OH,

»A lower alkoxy, halogen, nitro, sulfo or X '

Carboxyisubstituent, and η means 0, 1, 2 or 3, reduced continuously in a single reaction stage and without isolation of the intermediate and cyclized to form the imidazole ring, the reduction being carried out by the action of a reducing agent at at least ambient temperature and with the formation of the imidazole ring a temperature of at least 100 ⁰ C by means of at least one cyclizing agent selected from formamide, lOrmamidin, formic acid "lower alkyl formates,

'

- ammonium formate, di- (LOW.) - ^ LOW iminoäthern alkoxymethyl-^ alkanoates, lower Alkylfor, lower alkyl orthoformates, combinations of lower alkyl orthoformates and acetic anhydride, 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 alkylorthoformiateny ammonia and salts of lower organic acids

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The uninterrupted reaction, i.e. .. the reduction and the cyclization to form the iniidazole ring advantageously in one and the same reactant carried out. The reduction "Is preferably with Using at least one reducing agent from sulfur compounds with reducing properties, reducing metals, reducing metal salts, metal hydrides and Hydrazines ". The reaction is carried out continuously in one step, i.e. without isolation of the intermediate.

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 Exposed to reducing agent 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 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 2, B. Nitrogen, carried out, and purirido derivatives of a sufficiently high level can also be used

2 03 B! Ö / l 162

then obtained v / ground if the procedure is carried out in air Furthermore, there is no disadvantage if you during add a diluent to the reaction ", and if one continues 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 ₉ propanol, butanol? Hexanol, cyclohexanol, FurfurylalkoholjTetrahydrofurfurylalkohol, benzyl alcohol, ethylene glycol, propylene glycol and G-lycerin} ethers such as butyl ether, amyl ether, anisole ₇ phenetol, tetrahydrofuran, the dioxanes, the Äthylenglykoldialkyläther that Propylenglykoldialkylather that PoIyäthylenglykoldialkyläther (such zBdie Diäthylenglykoldialkyläther and Triäthylenglykoldialkyläther) and the Polypropylenglykoldialkyläther (such as the di- and tripropylene glycol dialkyl ethers) f alcohol ethers, such as the various "Cellosolve" solvents, the "carbols", the polyethylene glycols (such as diethylene glycol and triethylene glycol), the polypropylene glycols (such as eg di- and tripropylene glycol), the Polyäthylenglykolmonoalkylather (such as di- and ζ.B.die Triäthylenglykolmonoalkyläther) and the poly ~ propylenglykolmonoalkyläther (such as the di- and Tripropylenglykolmonoalkyläther) ι ketones such as "cyclohexanone and Dibujylketonj esters such as Mebnylformiat, MethylA3etat ₅ methyl

BAD OTlGINAL 2 0 9 8 18/1 1 R 2

orthoformate, methyl propionate, ethyl formate, ethyl acetate, ethyl thoformate, ethyl propionate, butyl et at _t butyl fo-rmate, ethyl lactate, the ethylene glycol monocarboxylic acid esters, the ethylene glycol diarboxylic acid esters, the propylene glycol esters, the propylene glycol esters, the dihylene carboxylic acid esters, the dihylene glycol glycol esters, the dihylene carboxylic acid esters, the dihyleneglycolic acid esters, the dihylene glycol esters, the dihylene carboxylic acid esters, the dihydric carboxylic acid esters, the ethyl propionate, the butyl acid and the triethylene glycol - and tri propylenglykoldicarbonsäureester that Propylenglykolmonocarbonsäureester, di- and Tripropylenglykolmonocarbonsäureester that Äthylenglykolmonoalfcyläthermonocarbonsäureester, di- and Triäthylenglykolmonoalkyläthermonocarbonsäureester that Propylenglykolmonoalkylätheimonocarbonsäureester and di- and Tripropylenglykolmonoalkyläthermonocarbonsäureester {nitrites, such as ■ capronitrile, acetonitrile and benzonitrile | the morpholine} acid amides, such as formamide and NjN-dimethylformamidi organic acids such as formic acid and hydrocarbons such as benzene, toluene and xylene.

The reducing agents which can be used in the process according to the invention include sulfur compounds with reducing properties, such as, for example, the dithionites (such as, for example, sodium dithionite), the thiosulfates (such as, for example, ammonium thiosulfate, lithium thiosulfate, sodium thiosulfate, potassium thiosulfate, calcium thiosulfate, magnesium thiosulfate and barium thiosulfate), the sulfites (such as, for example, , Potassium sulfite, sodium sulfite, lithium sulfite, calcium sulfite, magnesium sulfite, barium sulfite, ammonium hydrogen sulfite, - sodium hydrogen sulfite, potassium hydrogen sulfite, sodium pyrosulfite and potassium pyrosulfite), the sulfides (such as ammonium sulfide, lithium sulfide _p sodium

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sulfide, potassium sulfide, magnesium sulfide, calcium sulfide and barium sulfide), the hydro sulfides (such as affimonium sulfide, sodium hydrosulfide, potassium hydrosulfide, calcium hydrosulfide and earium hydrosulfide), the polysulfides, (such as ammonium pentasulfide, potassium pentasulfide, potassium pentasulfide, potassium pentasulfide * , Potassium trisulfide, bayium trisulfide, ICalium disulfide »anuaonium polysulfide, KatriuBipolysulfid and Kaliimipolysulfid) | the organic Dithionites (such as Pormaldehydnatriumsulfoxylatäihydrat, ßongalit) and the organic sulfites (such as Formaldehydnatriumhydrogensulfit) ι reducing metals (such, B 'Zinfc _t tin, Raney * - nickel alloy and Raneynicfcel as it is obtained from this alloy "Raneykobaltlegierung and! Raney cobalt, as it is obtained from this alloy, palladium and aluminum amalgam), reducing metal salts [such as tin (II) chloride and titanium (III) chloride] and hydrides (such as sodium borohydride, calcium hydride, sodium hydride and titanium hydride )? and hydrazines (such as * hydrazine sulfate, hydrazine hydrochloride and hydrazine * -

™ hydrate).

To the "in the inventive method" Cyclisierungsmitteln useful for the preparation of the imidazole ring include iormamid, Pormamidin, formic acid, the Ameisensäureester, ammonium formate, the Dialkoxymethylester of organic acids such as Diäthoxymethylessigsäureesterf Formiminoester- (lOrmimidoester) derivatives, such as _e Äthylformiminoester, Ortho-

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Formic acid esters, mixtures or combinations of an orthoformic acid ester with ammonia, mixtures "or combinations of an orthoformic acid ester with a ketene compound, e.g. Ketene or diethyl ketene »mixtures or combinations of one Orthoformic acid ester with a jfitril derivative * such as e.g. Acetonitrile »and mixtures or combinations of an orthoformic acid ester with ammonia and a salt of a lower organic one Acid. However, if a solvent is used during the reduction, it will act as a cyclizing agent capable of, such as formamide, formic acid or a formic acid ester, so 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 (approx. 15-3 ° 0). But what if they are done at a higher temperature? you can manage with a smaller amount of reducing agent than when working at a lower temperature. The reduction can be carried out, for example, in formamide using sodium dithionite or sodium formaldehyde sulfoxylate (Rongalit). If the reduction is to be carried out catalytically using a reducing agent, it is preferable to carry out the reduction by heating in an airtight vessel under an elevated hydrogen pressure. The processing performed in the second stage Imidazölringbildung is performed at a temperature above 100 ⁰ G best.

The purine derivatives obtained in this way provide very important starting materials for the production of chemical

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see seasonings and medicines.

example

3.4 g ö-

oxo-5- (p-chlorophenylazo) pyrimidine were suspended in 50 ecm of ethylene glycol dimethyl ether. The suspension was then charged to the hydrogenation vessel together with 20 to 25 g of Raney-Niekel. In embodiments of the reduction by shaking the reaction mixture at 140 to 15O ⁰ C under hydrogen pressure (initial pressure of 100 atmospheres) hydrogen absorption was easily achieved. After the hydrogen absorption ceased, the reaction liquid was cooled, and 3.0 g of ethyl orthoformate and 60 cc of acetone saturated with ketene were added. After heating the reaction mixture in a closed vessel at 150 to 170 ⁰ C for 4 hours with stirring, the reaction mixture was cooled and the deposited precipitate was filtered off. The precipitate was dissolved in an alkali and then neutralized with an acid, with 1.5 g of 6 Acetylamino-2,3-dihydro-3-methyl-2-oxopurine were obtained.

"- Claims -

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Claims (4)

P a ΐ e η t a ns ρ r ü c h e: 1, process for the preparation of a purine derivative of general formula Y. Ro - - it - ι Xn H in which Y ₁ H, the NHg-, OH-, SH-, a lower alkyl, lower alkylamineQ _t acylamino, lower alkylmercapto or lower alkoxy radical * X ₂ 0-, IiH = or S = and R ₂ a lower alkyl radical in the 1- or 3-position "can mean" characterized in that a ^ -amino-S-arylazopyrimidine of the general formula in which Y ^, X ₂ and Ep have the meaning given above, E ₁ , hydrogen or a lower alkyl, which is OH, a lower alkoxy, halogen, nitro, sulfo or carboxyl substituent, and η 0 , 1, 2 or 3 means, continuously reduced in a single Eeaktionsstufe and without isolation of the intermediate and to the formation of the imidazole ring 209818 / H62 eyclisiert, which comprises carrying out the reduction by the action of a reducing agent at at least ambient temperature and give the imidazole ring at a temperature of at least 1QO ⁰ C with the aid of at least one cyclizing agent selected from formamide, formamidine, formic * lower alkyl formates, ammonium, di- (LOW. ) -alkoxymethyl-lower alkanoates, lower alkyl formimino ethers, α lower alkyl orthoformates, combinations of lower alkyl orthoformates and acetic anhydride, combinations of lower alkyl orthoformates and ammonia, combinations of lower alkyl orthoformates and ketene, combinations of lower alkyl orthoformates and nitrile forms and combinations of lower alkyl orthoformates and ammonia and salts of lower organic acids. 2. The method according to claim 1, characterized in that that one has the uninterrupted reaction in one and the same ™ inert solvent. 3. The method according to claim 1, characterized in that the water formed during the reaction with the help a solvent is distilled off, which with water an azeo- . forms a tropic mixture. 4. The method according to claim 1, characterized in that that one can see the continuous reaction in one atmosphere of an inert gas. Dr.Ye/Wr 209818/1162