Method of producing substituted pyrimidine derivatives
The present invention relates to a new method of producing specifically substituted 4-chloropyrimidine derivatives.
In Helv. Chim. Acta 72, 744 (1989), a method of producing bis-(4,6-dichloropyrimidin-2-yl)- disulphide is described. According to this method, 2-thiobarbituric acid is reacted together with phosphorus oxychloride (POCI3) and N,N-diethylaniline in a ratio of 2:1, whereby the desired product is obtained in almost quantitative yield.
In J. Org. Chem. 26, 792 (1961), the production of 4,6-dichloro-2-(methylthio)pyrimidine by reacting 2-(methylthio)-4,6-pyrimidinediol and phosphorus oxychloride without solvents, and at reflux temperature, is described. The desired product is obtained in a yield of 16.6%.
J. Org. Chem. 27, 1462 (1962) describes the production of 4,6-dichloro-2-(methylthio)- pyrimidine by means of chlorination of 2-methylthio-4-chloro-6-pyrimidinol with phosphorus oxychloride in the presence of dimethylaniline.
J. Am. Chem. Soc. 76, 2899 (1954) describes the production of bis-(2,4-dimethoxy)-6- pyrimidine)disulphide starting with 2,4-dimethoxy-6-pyrimidinethiole using hydrogen peroxide in dioxane in 73% yield.
Furthermore, DE-A-4429466, EP-A-0697406 and EP-A-0747 364 describe the production of 2,4,6-trichloropyrimidine by means of chlorination of barbituric acid, using excess phosphorus oxychloride, in the presence of a tertiary amine.
All these described methods use, as the chlorination or oxidation agents, phosphorus chlorides such as phosphorus oxychloride, phosphorus trichloride or phosphorus penta- chloride or the desribed phosphorus chlorides in combination with chlorine or thionyl chloride as additional optimising variants, or hydrogen peroxide. However, the yields and purities of the products obtained from these methods are frequently unsatisfactory. In addition, when using phosphorus chlorides as chlorination and oxidation agents, various phosphate salts are produced as waste material, which is a
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problem in respect of large-scale production methods, especially from an ecological point of view.
Also, chlorination with phosphorus oxychloride very often leads to thermally unstable intermediate stages, which impair safety of the production method.
Surprisingly, it has now been found that specifically substituted 4-chloropyrimidine derivatives can be easily produced particularly advantageously in high purity, economically and ecologically, avoiding the disadvantages of the described methods, from (thio)barbituric acid derivatives, by effecting chlorination or oxidation with a chlorination agent other than phosphorus chlorides, in the presence of catalysts in an inert reaction medium.
An object of the present invention is thus a method of producing 4-chloropyrimidine derivatives of formula I
Ri is chlorine, CH3S- or a radical ; and
R2 is chlorine or CH3O-, by chlorination of a compound of formula II
wherein R
3 signifies OH or CH
3O- and R4 signifies OH, CH
3S- or SH, in the presence of an inert solvent and at least one catalyst.
The chlorination agents suitable for chlorination of the compound of formula II are e.g. phosgene, diphosgene, chlorine and thionyl chloride. Phosgene and diphosgene are preferred in particular.
These chlorination agents are conveniently employed in an excess of 2 to 3 molar equivalents, based on the compound of formula II.
The chlorination reaction of the compound of formula II is effected by passing the chlorination agent into the reaction mixture at a reaction temperature of 0° to 200°C, depending on the reaction medium employed.
The inert organic solvents suitable for reacting the compound of formula II to the compound of formula I are, for example, aliphatic or aromatic hydrocarbons, such as dichloromethane, 1 ,1 ,2,2-tetrachloroethane, methylcyclohexane, benzene, toluene, the isomeric xylenes ortho-, meta- and para-xylene, chlorobenzene and the isomeric 1 ,2-dichlorobenzenes 1 ,2-, 1 ,3- and 1 ,4-dichlorobenzene; ethers such as tetrahydrofuran and dioxane, and mixtures of these solvents. Especially preferred are benzene, toluene, xylenes, chlorobenzene, dichlorobenzenes, methylcyclohexane, tetrahydrofuran and dioxane, as well as mixtures of these solvents. Particularly preferred are toluene, xylenes, chlorobenzene and dichlorobenzenes.
The reaction of the compound of formula II with the above-described chlorination agents advantageously takes place in the presence of at least one catalyst having the effect of accelerating and standardising the chlorination reaction. The catalyst in question may be phosphines and phosphine oxides, especially triphenylphosphine and triphenylphosphine oxide or copolymer-bound phosphines and phosphine oxides. If desired, phase transfer catalysts may be additionally added as further catalysts, especially quaternary ammonium salts, e.g. tetraalkylammonium halides, for example tetrabutylammonium chloride or Aliquat as a dissolving intermediary between the (partly) dissolved educt of formula II and the chlorination agent triphenylphosphine dichloride formed in situ, with the effect of further accelerating the reaction. Further phase transfer catalysts suitable for the above chlorination reaction are described e.g. in Synthesis 1973, 441-456 and in Angew. Chem. Int. Ed. Engl. 13, 170-179 (1974).
Each of these two types of catalyst is used in amounts of 1 to 10 mol%, especially 5 mol%, based on the compound of formula II.
If two mols of the compound of formula II, wherein R3 is OH or CH3O- and R» is SH, are used as the starting compound for the chlorination reaction according to the invention, then one mol of the 2-pyrimidinyl disulphide of formula la
wherein R
2 is chlorine or CH
3O-, are obtained. Reaction scheme 1 illustrates this reaction.
Reaction scheme 1
CI
l,: R3 Z SH CH3°"' lb: R2 = Cl' CH3°'
The compound of formula lb, in which R2 signifies CH3O-, is new. It therefore likewise forms an object of the present invention.
In a preferred variant of the chlorination reaction according to the invention, a compound of formula II is placed in pure toluene, xylene, chlorobenzene or dichlorobenzene in the presence of 1 to 10 mol% of triphenylphosphine or triphenylphosphine oxide and 1 to 10 mol% of a quaternary ammonium salt, both based on the compound of formula II, at a reaction temperature of 0° to 25°C, this reaction mixture is heated until just below the reflux
temperature of the solvent used, and chlorinated at this temperature by passing in phosgene, diphosgene, chlorine orthionyl chloride until the compound of formula II has completely reacted. After cooling the reaction mixture, the crude product obtained can either be used directly for further reactions, or can be prepared in pure form by distilling the solvent and purifying in conventional manner, e.g. by recrystallisation. The yields are generally in the range of 20 to > 90% of theory.
In an especially preferred variant of the chlorination reaction according to the invention, a compound of formula II, wherein R3 is OH or CH3O- and R is CH3S-, is placed in pure toluene, xylene, chlorobenzene or dichlorobenzene in the presence of 1 to 10 mol% of triphenylphosphine or triphenylphosphine oxide and 1 to 10 mol% of tetrabutylammonium chloride, both based on the compound of formula II, at a reaction temperature of 0° to 25°C, this reaction mixture is subsequently heated until just below the reflux temperature of the solvent used, and chlorinated at this temperature by passing in phosgene, diphosgene, chlorine or thionyl chloride until the compound of formula II has completely reacted.
The compounds of formula I which are preferably produced by the method according to the invention are bis-(4,6-dichloro-2-pyrimidinyl)-disulphide, bis-(4-chloro-6-methoxy-2- pyrimidinyO-disulphide, 2-methylmercapto-4,6-dichloropyrimidine, 2-methylmercapto-4- chloro-6-methoxypyrimidine and 2,4,6-trichloropyrimidine, especially 2-methylmercapto-4,6- dichloropyrimidine and 2-methylmercapto-4-chloro-6-methoxypyrimidine.
The starting compounds of formula II, as well as all the chlorination agents and catalysts employed, are known or may be produced by known methods. For example, EP-A-0529 631 describes the production of disodium thiobarbiturate and 2-(methylthio)-disodium barbiturate by reacting thiourea, malonic acid dimethyl ester and sodium methanolate, followed by methylation with methyl bromide. DE-OS-2412 854 describes the production of 2-methylthio-4-hydroxy-6-methoxypyrimidine from 2-methylthio-4,6-dihydroxypyrimidine by means of methylation with dimethylsulphate (DMS) in the presence of a base, and 2- methylthio-4,6-dihydroxypyrimidine from thiobarbituric acid by means of methylation with DMS in the presence of a base.
The method according to the invention is distinguished from known methods in that
1 ) instead of the conventional phosphorus (oxy)chlorides or phosphorus (oxy)chlorides in combination with chlorine or thionyl halides, other chlorination agents are used, and therefore no phosphates or phosphoric esters are obtained as waste material.
2) chlorination is effected in the presence of at least one catalyst, which thereby a) accelerates the reaction and b) standardises the chlorination reaction by reducing the amount of undesired by-products, and
3) the products are obtained in an inert reaction medium which is suitable for further reactions.
The advantages of the present process over the known processes are therefore:
1 ) it is particularly suitable for large-scale applications with substantially more favourable balance of waste e.g. in respect of phosphates.
2) it avoids the usage of complex separation and purification steps,
3) it is possible to further process the formed 4-chloropyrimidine derivatives of formula I in a one-pot process without changing the solvents and thereby reduce the solvent residues and the need for complex apparatus.
4) the process has higher thermal safety and
5) it is possible to use polymer-bound phosphines and phosphine oxides with simplified separation of these catalysts after the reaction has been carried out.
The 4-chloropyrimidine derivatives of formula I which are produced according to the invention are used especially as intermediates in the production of 7-[(4,6-dimethoxy- pyrimidin-2-yl)thio]-3-methylphthalide, as described for example in EP-B-0 447506 .
In a first reaction step, therefore, the 4-chloropyrimidine intermediates of formula I which are produced according to the invention
wherein Ri is a radical and R
2 is chlorine or CH
3O-, are reacted with
an excess of 2 to 6 molar equivalents of alkali metal methylate in methanol, based on the compound of formula I, and the obtained 4,6-dimethoxy-2-pyrimidinethiole or the alkali metal salts thereof is or are reacted firstly with a methylation agent such as dimethylsulphate (DMS), then with an oxidation agent such as peroxides, for example hydrogen peroxide, in acetic acid and in the presence of alkali metal tungstate, or chlorine, and the obtained 4,6-dimethoxy-2-(methylsulphonyl)pyrimidine is reacted with 7-mercapto- 3-methyiphthalide.
In a subsequent reaction step, therefore, the 4-chloropyrimidine intermediates of formula I which are produced according to the invention
wherein Ri is CH
3S- and R
2 is chlorine orCH
3O-, are reacted with a small excess (ca. 5-10 mol%) of alkali metal methylate in methanol and subsequently with an oxidation agent such as peroxides, for example hydrogen peroxide in acetic acid, and in the presence of alkali metal tungstate, or chlorine, and the obtained 4,6-dimethoxy-2-(methylsulphonyl)pyrimidine is reacted with 7-mercapto-3-methylphthalide.
The above process variants for the production of 7-[(4,6-dimethoxypyrimidin-2-yl)thio]-3- methylnaphthalide are illustrated in the following reaction schemes 2 and 3.
Reaction scheme 2
CH,0 OCH,
SO,CH,
CH,0 rv OCH,
R
OCH,
Cleavage of the disulphide derivative of formula la to the 4,6-dimethoxy-2-pyrimidinethiole or to the alkali metal salt thereof, in which M+ is an alkali metal ion such as a sodium or potassium ion, in reaction scheme 2, advantageously takes place with an excess of 2 to 6 molar equivalents of alkali metal methylate, such as sodium methylate in methanol at temperatures of 10° to 80°C.
The methylation of 4,6-dimethoxy-2-pyrimidinethiole or the alkali metal salt thereof with dimethylsulphate (DMS) to the intermediate 4,6-dimethoxy-2-methylthiopyrimidine (reaction scheme 2) conveniently takes place in an aqueous-basic medium, optionally in the presence of a polar organic solvent, such as alcohols, at temperatures of 0° to 40°C. The subsequent oxidation, e.g. with hydrogen peroxide in above solvents or in organic acids, such as alkanecarboxylic acids, for example acetic acid, and optionally in the presence of alkali metal tungstate, such as sodium tungstate, or with chlorine gas, yields the 4,6- dimethoxy-2-methylsulphonyl)pyrimidine. Methylation and oxidation reactions of this kind are described for example in DE-A-2412 854, DE-A-3324399, EP-A-0 033 195, Z. Chem. 17(392), 63 (1977), Chem. Soc. 16(6), 489 (1995) and J. Org. Chem. 26, 792 (1961).
The subsequent reaction of the formed 4,6-dimethoxy-2-(methylsulphonyl)pyrimidine with 7-mercapto-3-methylphthalide (reaction scheme 2) conveniently takes place in an inert organic solvent such as ethers, ketones, nitrites and amides, for example tetrahydrofuran, butanone, acetonitrile and N,N-dimethylformamide, at temperatures of 0° to 160°C. Substitution reactions of this kind are described e.g. in EP-A-0447506.
According to reaction scheme 3, the 4-chloropyrimidine derivative of formula I is firstly reacted with alkali metal methylate in methanol, then with an oxidation agent, and the 4,6- dimethoxy-2-(methylsulphonyl)pyrimidine obtained undergoes a substitution reaction with the 7-mercapto-3-methylphthalide.
The first reaction step according to reaction scheme 3, namely the reaction of the compound of formula I with an alkali metal methylate in methanol is effected analogously to the manner described e.g. in J. Org. Chem. 27, 1462 (1962), EP-A-0547411 and J. Am. Chem. Soc. 76, 2899 (1954). The subsequent oxidation of the 4,6-dimethoxy-2- methylthiopyrimidine thus formed, and the substitution reaction in the presence of 7- mercapto-3-methylphthalide, are effected analogously to the manner already described for reaction scheme 2.
The following examples further illustrate the method according to the invention.
Example P1 : Preparation of 4.6-dichloro-2-methylthiopyrimidine 8.5 g (1 molar equivalent) of 2-methylthiobarbituric acid is placed in 150 g of xylene and mixed with 1.3 g (5 mol%) of triphenylphosphine oxide and additionally with 1.3 g (5 mol%) of tetrabutylammonium chloride. Afterwards, heating is effected until just below the reflux temperature, and 19.8 g of phosgene passed in, until reaction of the educt is complete (ca. 2 molar equivalents). The phosgene is removed from the reaction mass by passing in nitrogen, and the mass is subsequently cooled. The organic phase is extracted once with water and the salts removed, the solvent is distilled off and the intermediate product 4,6- dichloro-2-methylthiopyrimidine is obtained as a yellow to brown oil. Upon cooling, the desired title compound crystallises. Yield 80% of theory.
Example P2: Preparation of 4.6-dimethoxy-2-fmethylsulphonyl)pyrimidine 8.5 g (1 molar equivalent) of 2-methylthiobarbituric acid is placed in 150 g of xylene and mixed with 1.3 g (5 mol%) of triphenylphosphine oxide and additionally with 1.3 g (5 mol%) of tetrabutylammonium chloride. Afterwards, heating is effected until just below the reflux temperature, and 19.8 g of phosgene passed in, until reaction of the educt is complete (ca. 2 molar equivalents). The phosgene is removed from the reaction mass by passing in nitrogen, and the mass is subsequently cooled. The organic phase is extracted once with water and the salts removed. The solvent is dried by evaporating under vacuum for a short time, and reacted with 22.5 g (2.5 molar equivalents) of sodium methylate (30%) at 50°C to form 4,6-dimethoxy-2-methylthiopyrimidine. Subsequently, 0.83 g (5 mol%) of sodium tungstate and 0.7 g (5 mol%) of tetrabutylammonium chloride are added to the reaction mixture obtained, and mixed at 85°C with 2 molar equivalents of hydrogen peroxide. The product precipitates during oxidation and may be isolated from the reaction mixture by filtration at 0°C.