CS199788B1 - Process for preparing 6-hydroxy-2-thio-4-pyrimidincarboxylic acid - Google Patents

Description

The present invention relates to a process for the preparation of 6-hydroxy-2-thio-4-pyrimidinecarboxylic acid of the formula I

which is also referred to in the literature as 2-thio-4-uracil-carboxylic acid, also referred to as 4-carboxy-2-thiouracil or briefly as thioorotic acid (hereinafter thioorotic acid).

The substance attracted more attention only after it was recognized that the mercapto group could easily be exchanged for a hydroxyl group, thereby making it a physiologically and pharmacologically active orotic acid. Even now, thioorotic acid is of greatest importance as an intermediate for the production of orotic acid.

The known processes for the preparation of thioorotic acid are based on thiourea and diethyl ester of oxaleacetic acid, respectively. from sodium diethyloxalacetate. The simpler the starting materials, the more varied the ways of performing chemical incidents. M.BACHSTEZ (Ber. 64. 322 (1931)) chose the same path for his procedure using thiourea,

199 788

1A9 788 has been shown to be viable for the preparation of uracilecarboxylic acid (orotic acid) from urea and diethyloxal acetate (yield 23% based on diethyloxalacetate). Also K.A.CHIKVADZE et al. (ž. chim. J4, 161 (1964)) followed in their work a procedure that was successfully applied in the synthesis from orotic acid (yield 42%) .These authors worked with thiourea and oxoacetic acid monoethyl ester and their procedure was analogous to the procedure U.S. Pat.

937 175 or in GB Pat. No. 800 709 for the synthesis of orotic acid from urea and oxoacetic acid mono ethyl ester. H. VANDERHAEGHE (Bull.Soc.Chim.Belg. 62, 611 (1953)) was the first to use diethyloxalacetate sodium salt for the synthesis of thioorotic acid and first worked in an aqueous-alkaline medium (32% yield on sodium salt). M.J.E.ERNSTING and W.TH.NAUTA (Rec.trav.chim.Payes-Bas 5? 7 (1953)) achieved remarkable results. They worked in absolute alcohol, using sodium ethanolate as a condensing agent, starting with oxaloacetic acid ester in addition to thiourea. The authors present in their work a reaction scheme from which it can be seen that the synthesis process proceeds through a thioorotic acid ester which is not isolated. The yield is reported to be 68.5% (based on the ester used).

J.MIKSCH and L.BAUER (GB Pat. 820 147; DE Pat. 1039519) used a water-alkaline medium for their method and are based on thiourea and sodium diethyloxalacetate. According to the authors, the best results can be obtained in the pH range of 7 to 10 (NaHCO 3 or NagCO 3 were used to adjust the pH), and in the temperature range of 50 to 100 ° C. The procedure which runs through the thioorotic acid intermediate ester must be carried out in a concentrated solution.

The reported yield is 75% based on the sodium salt.

It has now been found that thioorotic acid can be prepared in high yields while at the same time highly pure in a simple and short process by cyclizing thiourea and sodium diethyl oxalacetate in an aqueous-alkaline environment at temperatures ranging from 25 to 60 ° C. preferably from 35 to 50 ° C, that is, in a temperature range that has so far been out of consideration in the preparation of thioorotic acid. Diethyl oxalate can also be used as the starting material of the synthesis, i.e. the sodium salt of diethyl oxalate can be prepared first and converted without further isolation with thiourea to the final product. Furthermore, it has been found that in order for the reaction to proceed well, it is necessary to have sufficient alkali in the reaction mixture. It is not enough that the alkalinity of the environment is expressed by the highest pH scale value. It is preferred to express the amount of the alkaline reagents in molar multiples and refer to the amount of diethyl oxalate used. It has been found that 1 mol of diethyl oxalate requires at least 2.5 mol. 3 times the amount of the alkaline agent, preferably 3 to 3.5 times. Suitable alkali reagents are alkali metal (sodium, potassium), alkali metal (sodium, potassium) alcoholate with alkyls containing 1 or 2 carbon atoms, and alkali metal hydroxide (sodium, potassium) or a mixture thereof. When working with the sodium salt of diethyl oxalacetate as the starting material, the amount used for the actual preparation of the sodium salt is included in the total amount of alkaline reagent used, even if an excess of the alkaline reagent is taken to prepare the sodium salt of diethyl oxalacetate. Thus, even in this case, the sum of all alkaline agents is expressed as at least 2.5 moles relative to diethyl oxalate. but preferably 3 to 3.5 times. The above-mentioned alkaline agents cannot be included

199 799 sodium bicarbonate or sodium carbonate. Thus, it will be appreciated that the reaction of the present invention is conducted in an extremely stable alkaline medium, and that under these conditions a thioorotic acid product is formed - as the sodium salt, which is soluble in the aqueous-alkaline medium. It has been found that a strongly alkaline environment has no detrimental effect on the reaction components, since under the conditions specified herein, the main reaction proceeds at an order of magnitude higher than the rates of unwanted side reactions such as decomposition of thiourea or oxaloacetate in alkaline medium. The process is characterized by the ease and speed at which the pyrimidine ring closes. The reaction itself, which lasts approximately 20 to 30 minutes, is accompanied by a slight heat generation. The rest of the time devoted to the cyclization reaction is richly dimensioned for the reactants to be comminuted and dissolved. Advantageously, distillation of the organic solvent used can be carried out already during the cyclization and the total synthesis time can be shortened.

The process is not sensitive to concentration and can therefore be carried out at a suitable dilution. The process, on the other hand, requires thiourea to be added to the reaction mixture in a gentle manner. It is sufficient if the thiourea is added before the alkaline agent or when it is added simultaneously with the alkaline agent. If an alkali metal hydroxide is used as the alkaline agent, which is advantageous for achieving low raw material costs, it must be added in the form of a dilute solution and, in addition, it is advantageously added slightly pre-cooled (-10 ° C to + 20 ° C). ). If these principles are respected, this creates the preconditions for achieving a high yield in the synthesis process.

The preparation of the thioorotic acid according to the invention is carried out by mixing the sodium salt of diethyl oxalacetate or a mixture of said salt with an excess of an alkali metal alcoholate with alkyls containing 1 or 2 carbon atoms with water, thiourea and an alkali metal hydroxide solution (sodium). (potassium), taking care that the temperature of the thiourea dosing medium is in the temperature range of -10 ° C to 25 ° C and that the temperature of the alkali metal hydroxide solution to be added is between -10 ° C and +20 ° C. The order of addition of the components can also be altered by first combining the thiourea with an alkali hydroxide solution and then adding the two components adjusted to a temperature of -10 ° C to + 20 ° C simultaneously. After addition of the thiourea and the alkali metal hydroxide solution, the mixture is maintained at a temperature of 25 ° C to 60 ° C, preferably at 35 ° C to 50 ° C, for about 2 hours. The mixture is then acidified with a mineral acid such as hydrochloric acid and the product is isolated and dried,

The yields are about 70 to 75% of theory based on the starting sodium salt. If it is based on diethyloxallate, it is prepared according to MS. No. 1991-789, first sodium dialkyl oxalate acetate. This salt is isolated, mixed with the other ingredients and proceeded as described above in this paragraph. It is advantageous in this case already during heating, i.e. during the cyclization reaction of thiourea and oxaloacetate, or immediately thereafter to distil off the organic solvent used in the preparation of the sodium salt of diethyl oxaloacetate.

The yields are from 70 to 74% based on diathyloxalate.

In the same manner as described above, the corresponding pyrimidines can also be converted

IBS 788 thiourea, respectively. substituted thiourea with sodium diethyl oxalate or derivatives thereof.

The following examples illustrate but do not limit the methods of the present invention. In particular, they show different ways of adding alkaline agents during the synthesis process, the ratio of these reagents to each other, and the ratio of their total to diethyl oxalate. The same is true when starting from the sodium salt of diethyl oxalacetate in the synthesis process. It is clear from the examples that the total amount of alkaline reagents in both cases is clearly defined when expressed in relation to diethyl oxalate. This simplicity gas; wherein the actual preparation of diethyl oxalate acetate sodium from diethyl oxalate can be carried out in virtually 100% yield, i.e. said salt contains one whole equivalent of an alkaline agent (sodium) relative to the starting diethyl oxalate. (The reaction mixture optionally contains an excess of alkaline reagent). The examples show the relative proportions of all the components, including the dilution with water, and can be used to observe a variety of methods for the gentle addition of thiourea and alkali hydroxides to the reaction mixture.

Finally, the examples illustrate at which stage of the process it is preferable to distill off the organic solvent used.

Example 1

193.7 g (0.92150 mol) of sodium diethyloxalacetate (prepared from 1 mol of diethyloxallate) was mixed with 108 g (2 moles) of sodium methoxide and a cooled solution of 20 g NaOH (0.5 mol) was added in one portion. ) in 360 ml of water (-6 ° C) to which 92 g (1.2 mol) of thiourea are added just prior to addition. Then 500 ml of water (about 18 ° C) is added rapidly and the reaction mixture is rapidly heated to 35 ° C with a pre-heated water bath. After reaching 35 ° C, the hot bath is removed and the mixture is allowed to react spontaneously. Within about 15 minutes, the temperature rises to 39 to 41 ° C, then rapidly heated to 50 ° C and maintained at that temperature for about 50 minutes. After this time, the mixture was diluted with 250 mL of water and acidified slowly at 70 ° C with 310 mL conc. hydrochloric acid. The precipitated product is filtered off with suction and washed with water. Mp 322 ° C (dec.). By reprecipitation, the melting point no longer changes. Yield 119.65 g, i.e. 0.69483 mol. This corresponds to 75.4% of the theory based on diethyl oxalacetate sodium (or 69.48% of the theory based on diethyl oxalate from which the sodium salt was prepared). Orothic acid was prepared from thioorotic acid in a yield of 98% of theory.

This crude product was converted to the pure pharmacopoeial form in a yield of 97.5 to 98%,

Example 2

200 g (0.95147 mol) of sodium diethyl oxalate acetate (this amount of sodium salt was prepared from 1 mol of diethyl oxalate) was mixed with 27 g (0.5 mol) of sodium methoxide and 76 g (1 mol) of thiourea. Then 500 ml of 18 ° C water are added all at once, stirred and immediately and a solution of 80 g of NaOH (2 moles) in 360 ml of water cooled to -10 ° C is added. After stirring, the mixture is warmed to 35 ° C (pre-transported hot bath) over 2 minutes and allowed to exotherm. After about 20 minutes, when the temperature rose to 39 ° C, it was heated to 50 ° q _and at room temperature

199 789 at this temperature was maintained for 2 hours. Finally, when the reaction mixture is diluted with 250 ml of water, it is acidified at 70 DEG C. with 310 ml of conc. hydrochloric acid and the product is filtered off with suction and washed with water.

Yield 118.05 g, i.e. 0.68554 mol. This corresponds to 72.05% of the theory based on the sodium salt of diethyl oxaloacetate (or 68.55% of the theory based on the diethyl oxalate from which the sodium salt was prepared). Product quality as in Example 1.

Example 3

From 146.1 g (1 mol) of diethyl oxalate ae was prepared according to the procedure of US. Certificate No.

199,789 sodium diethyloxalacetate. (46 g sodium metal was used; toluene was used from organic solvents). To the solidified reaction mass, which in addition to the sodium salt of diethyl oxalacetate, also contains an excess of sodium methoxide (1 mol), is added 250 ml of water and the water bath in which the flask and the mixture is immersed is rapidly heated. Upon reaching about 60-80 ° C in the bath, the solidified mixture is generally released from the walls and agitated. At this point, the reaction mixture, which was heated to 35 to 40 ° C during the described operation, was rapidly cooled by an external cold bath to 20 ° C. At this temperature, a cooled (-10 ° C) solution of sodium hydroxide is added to the reaction mixture, namely 60 g (1.5 mol) in 360 ml of water, to which 92 g (1.2 mol) of thiourea is added immediately before the addition. . After stirring, the reaction mixture was quickly warmed to 35 ° C from 7 ° C and stirred at this temperature for 1 hour. Initially, this temperature is maintained at a constant level by gentle cooling through an ice bath. Said time of 1 hour is sufficient for the initially solidified mixture to dissolve and react. Then toluene is distilled off azeotropically under gentle vacuum. The operation takes about 1 hour and the temperature of the mixture rises to 65-70 ° C. During or after the distillation, the mixture is diluted with 250 ml of water, then heated to 70 ° C and acidified slowly with 310 ml of conc. hydrochloric acid.

The precipitated product is filtered off with suction, washed with water and dried.

Yield 127.85 g, i.e. 0.74245 mol. This corresponds to 74.25% of theory based on the starting diethyl oxalate. Product quality as in Example 1.

Example 4

From 146.1 g (1 mol) of diethyl oxalate was prepared according to the procedure of Cs. Certificate No.

199 789 diethyloxalacetate sodium, (23 g sodium metal was worked up; toluene was used from organic solvents).

To the solidified reaction mass, which is essentially sodium diethyloxalacetate, 250 ml of water are added and the water bath is rapidly heated in which the flask and the mixture are immersed. After reaching about 60-80 ° C in the bath, the solidified mixture is generally released from the walls and the mixture is stirred evenly. At this point, it is rapidly cooled to 10 ° C and 77 g (1.01 mol) of thiourea are added to the mixture at this temperature. Immediately thereafter, a pre-cooled (+1 ° C) sodium hydroxide solution, namely 80 g (2 moles) of NaOH in 360 ml of water, was added to the mixture. After stirring, the reaction mixture rapidly warmed to 35 ° C from 6 ° C. The cyclization was carried out at 35 ° C (1 hour) and at 50 ° C (also 1 hour) for a total of 2 hours. The first phase of cyclization at 35 ° C proceeds with continuous heat release, so it is necessary to cool slightly.

After completion of the cyclization, the mixture is diluted with 500 ml of water and then distilled off under a slight vacuum

199 798 toluene. At the end of this operation, the mixture was acidified with 260 ml conc. hydrochloric acid, the precipitated product is filtered off with suction, washed with water and dried.

Yield 121.2 g, i.e. 0.70383 mol. This corresponds to 70.38% of theory based on diethyl oxalate used. Product quality as in Example 1.

Example 5

From 148.1 g (1 mole) of diethyl oxalate was prepared according to the procedure of US. Certificate No.

199,789 sodium diethyloxalacetate, (69.0 g of sodium metal was worked up; toluene was used from organic solvents).

To the solidified reaction mass, which, in addition to the sodium salt of diethyl oxalacetate, also contains an excess of sodium methoxide (2 moles), 350 ml of water are added and the water bath is rapidly heated in which the flask and the mixture are immersed. After reaching about 60-60 ° C in the bath, the solidified mixture is generally released from the walls and the mixture is begun to stir. At this point, the reaction mixture, now about 40 ° C warm, was rapidly cooled by an external cold bath to 24 ° C. At this temperature, 92 g (1.2 mol) of thiourea are added, followed immediately by 260 ml of water (14.5 ° C), and the mixture is rapidly heated to 35 ° C. Cyclization is performed by keeping the mixture at 35 ° C (2 hours) and 50 ° C (1.5 hours). After cyclization, toluene is distilled off under a slight vacuum, the mixture is diluted with 500 ml of water and acidified at 260 DEG C. with 260 ml of conc. hydrochloric acid. The precipitated product is filtered off with suction, washed with water and dried.

Yield 125.4 g, i.e. 0.72822 mol. This corresponds to 72.82% of theory based on diethyl oxalate. Product quality as in Example 1.

Example 6

From 146.1 g (1 mole) of diethyl oxalate was prepared according to the procedure of US. Certificate No.

199 789 diethyl oxalacetate sodium. (34.5 g of sodium metal was used; toluene was used from organic solvents).

To the solidified reaction mass, which, in addition to the sodium salt of diethyl oxalacetate, also contains an excess of sodium methoxide (0.5 mol), 250 ml of water are added and the water bath in which the flask is immersed is rapidly heated. After reaching about 60-80 ° C (bath temperature), the solidified mixture is generally released from the walls and agitated. At that point, the hot bath was replaced with an ice bath and the flask contents were cooled to 20 ° C. At this temperature, a cooled (-5 ° C) solution of potassium hydroxide is added to the reaction mixture, namely 112.5 g (2 moles) of KOH in 360 ml of water, to which 92 g (1.2 moles) is added immediately before the addition. thioureas. Follow the same procedure as in Example 3.

Yield 123.40 g, i.e. 0.71661 mol. corresponds to 71.66% of theory based on the starting diethyl oxalate. Product quality as in Example 1.

Claims (4)

1. A process for the preparation of 6-hydroxy-2-thio-4-pyrimidinecarboxylic acid from diethyl oxalate via the sodium diethyl oxalate acetate cyclization process of this salt with thiourea in aqueous alkali. 199789, characterized in that at least 2.5 times the alkaline reagent, preferably 3 to 3.5 times, including the reagent used for the preparation of the sodium salt, are used per 1 mol of diethyl oxalate for the reaction, wherein the cyclization reaction is carried out at a temperature of 25 to 60 ° C, preferably in a temperature range of 35 to 50 ° C. t 2. A process according to claim 1, wherein the alkali is an alkali metal, an alkali metal alcoholate and alkyls containing 1 or 2 carbon atoms, an alkali metal hydroxide, or mixtures thereof. 3. Process according to claim 1, characterized in that thiourea is added as a reaction component in the temperature range of -10 ° C to +25 ° C. 4. The process of claim 1, wherein the alkali metal hydroxide is added to the reaction mixture in the form of a dilute solution at a temperature of -10 ° C to +20 ° C after the addition of the thiourea or simultaneously with the thiourea.