Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2001-08-20
2004-01-06
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S299000, C544S302000, C514S270000, C514S271000
Reexamination Certificate
active
06673925
ABSTRACT:
The present invention relates to a new method of producing specifically substituted thiobarbituric acid derivatives.
J. Org. Chem. 26, 792 (1961) describes the possible pyrimidine derivatives which are substituted in the 2-, 4- and 6-positions by hydrogen, hydroxy, amino and thiole groups, it describes the possibility of obtaining them synthetically and their ability to be used in the preparation of further derivatives.
For example, the synthesis of 4,6-dichloro-2-(methylthio)pyrimidine from thiobarbituric acid by means of methylation with dimethylsulphate (DMS) in a basic medium with subsequent chlorination of the 2-(methylthio)-4,6-pyrimidinediol, formed as an intermediate, with phosphorus oxychloride is described on the one hand, and on the other hand the substitutability of the chlorine atoms in the 4- and 6-positions of the pyrimidine ring using sodium hydrogen sulphide in ethanol to form the corresponding 4,6-pyrimidinethiole.
EP-A-0 529 631 discloses the production of 2-(methylthio)-disodium barbiturate from thiourea and malonic acid dimethyl ester in the presence of sodium methanolate, and the methylation of the disodium thiobarbiturate formed as an intermediate, with methyl bromide.
J. Am. Chem. Soc. 76, 2899 (1954) describes on the one hand the production of bis-(2,4-dimethoxy-6-pyrimidinyl)-disulphide from 2,4-dimethoxy-6-pyrimidinethiole using hydrogen peroxide in dioxane, and on the other hand the cleavage thereof by reduction with lithium aluminium hydride in absolute ether to form the corresponding 2,4-dimethoxy-6-pyrimidinethiole in a yield of 76%.
In Helv. Chim. Acta 72, 744 (1989), the production of bis-(4,6-dichloropyrimidin-2-yl)-disulphide from 2-thiobarbituric acid with phosphorus oxychloride and N,N-diethylaniline is described, and it is pointed out therein at the same time that the disulphide formed cannot be converted into the monomeric uracil derivative either by acid- or base-catalysed hydrolysis or by reductive hydrolysis.
EP-A-0 547 411 discloses the production of 4,6-dialkoxy-2-alkylmercapto-pyrimidines by cyclising cyanimidates in the presence of hydrogen halide to form 4,6-dialkoxy-2-halopyrimidine and reacting the latter compound with sodium thiolate.
DE-A-2 412 854 describes the production of 2-alkylthio-4-methoxy-6-hydroxypyrimidine by means of methylation of 2-alkylthio-4,6-dihydroxypyrimidine using dimethylsulphate.
Helv. Chim. Acta 72, 738 (1989) describes, in a two-stage process, the selective basic hydrolysis of the chlorine substituent in 2-position of 2,4,6-trichloropyrimidine and the subsequent nucleophilic substitution of the remaining chlorine substituents in 4- and 6-position with methanol.
Furthermore, DE-A-4 408 404 and DE-A-2 248 747 describe the conversion of 2-hydroxy-4,6-dialkoxypyrimidine with phosphorus oxychloride and with catalytic amounts of amine hydrochloride or with phosphorus pentachloride to form 2-chloro-4,6-dialkoxypyrimidine.
All these described methods of producing specifically substituted (thio-)barbituric acid derivatives are partly complex in operation via several reaction steps, since on the one hand certain substituents at defined positions of the pyrimidine ring have practically the same reactivity and cannot therefore be substituted selectively, or on the other hand they are sluggish in reaction towards nucleophilic reagents or even have remarkable stability, and, if at all, they only react under extreme reaction conditions, such as in a pressurised container and at elevated temperatures (see e.g. J. Org. Chem. 26, 794 (1961) and Helv. Chim. Acta 72, 745 (1989). The observed product yields and product purities are consequently frequently unsatisfactory for large-scale production methods. In addition, the isolation and purification processes are uneconomical and are linked with complex apparatus.
It has surprisingly now been found that specifically substituted 4,6-dimethoxy-2-thiobarbituric acid, 4,6-dimethoxy-2-sodium thiobarbiturate and 4,6-dimethoxy-2-methylthiopyrimidine can be easily produced in high yield and purity, economically and ecologically, most advantageously in a one-pot process, avoiding the above-described disadvantages of the disclosed methods, directly from bis-(4,6-disubstituted) 2-pyrimidine disulphides, by hydrogenolysing the latter compound and methylating the hydrogenolysis product directly without isolation either with an alkali metal alcoholate or with a methylation reagent, and then reacting the thiomethylation product with an alkali metal alcoholate.
An object of the present invention is thus a method of producing thiobarbituric acid derivatives of formula I
wherein
R
1
is SH, S
−
M
+
or CH
3
S—, and M
+
is an alkali metal ion, by hydrogenolysis of a compound of formula II
wherein R
2
is chlorine or CH
3
O—, with
a) a hydrogenolysis agent in the presence of an inert solvent and by a direct reaction of the hydrogenolysis product with an alkali metal methylate in methanol, or
b) with a hydrogenolysis agent in the presence of an inert solvent and in the presence of a methylation reagent, and subsequently with an alkali metal methylate in methanol.
The hydrogenolysis agents which are suitable for the hydrogenolytic cleavage of the compound of formula II are e.g. boron hydrides, diborane, alkali metal aluminium hydrides and hydrogen. Of these, those that are especially suitable are alkali metal borohydrides, diborane, lithium aluminium hydride and hydrogen in the presence of a noble metal catalyst.
Particularly suitable hydrogenolysis agents are alkali metal borohydrides and hydrogen in the presence of a noble metal catalyst, especially sodium borohydride and hydrogen in the presence of palladium or platinum.
These hydrogenolysis agents are conveniently used in equimolar amounts or in a slight excess of 5-15 mol %, based on the compound of formula II.
The hydrogenolysis reaction of the compound of formula II according to variant a) or b) is carried out at a reaction temperature of 0° to 60° C.
The solvents that are suitable for the hydrogenolysis reaction of the compound of formula II according to variant a) or b) are e.g. ketones, amides, nitriles, aliphatic hydrocarbons, ethers, alcohols, alcohol-water mixtures and mixtures of these solvents. Preference is given to acetone, N,N-dimethylformamide (DMF), 1-methyl-2-pyrrolidone (NMP), acetonitrile, dioxane, tetrahydrofuran, methanol and methanol-water mixture.
Particularly preferred are acetone, N,N-dimethylformamide, methanol, dioxane and tetrahydrofuran.
A further characteristic of the method according to the invention is that the hydrogenolysis according to variant a) or b) takes place continuously, i.e. as a ‘one-pot reaction’ without isolation of intermediate products.
The hydrogenolysis product of formula IV which is formed directly according to variant a)
wherein R
1
is SH or S
−
M
+
; M
+
is an alkali metal ion and R
2
is defined as given for formula I, is unstable and is not isolated.
The hydrogenolysis product of formula III which is formed directly according to variant b)
wherein R
2
is defined as given for formula I, is stable and may be isolated if required.
Reaction scheme 1 illustrates these reactions.
If diborane or hydrogen is used as the hydrogenolysis agent in the presence of a noble metal catalyst, then according to variant a) a compound of formula IV, in which R
1
is SH, is obtained as the primary unstable hydrogenolysis product. If an alkali metal borohydride or alkali metal aluminium hydride is used as the hydrogenolysis agent, then according to variant a) a compound of formula IV, in which R
1
is S
−
M
+
and M
+
is an alkali metal ion, is obtained as the primary unstable hydrogenolysis product.
In a preferred variant a) of the hydrogenolysis reaction according to the invention, the compound of formula II in dry methanol, N,N-dimethylformamide or acetonitrile is mixed at 15° to 35° C. with a small excess of 5-10 mol % of sodium borohydride as required, then stirred for 0.5 to 3 hours and afterwards at the same reaction temperature a small excess o
Passafaro Marco
Rapold Thomas
Urwyler Bernhard
Hamilton Thomas
Shah Mukund J.
Syngenta Crop Protection Inc.
Truong Tamthom N.
LandOfFree
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