DE3135574A1 - "METHOD FOR PRODUCING 5-ISOPROPYL-4-METHYL-6-HYDROXYPYRIMIDINE" - Google Patents

Description

Dr. F. Zumstein Sr. - Dr. E.; A4? Manr »-: Ώτ: Β..Κ-oenigsberger Dipl.-Phys. R. Holzbauer - Dipl.-Ing * F. Klingseisen -Dr.-F. Zumstein jun.

PATENT LAWYERS

80OO Munich 2 · BrauhausstraQe 4 · Tetefon Sommel no. 22 5341 - Telegram Zumpat Telex 529979

(J

CIBA-GEIGY AG ⁷ '5-13055 / CGC 925 / = « Basel, Switzerland)

procedure for the production of 5-isopropyl-4-methyl-6-hydroxypyrimidine

The present invention relates to a process for the preparation of 2-isopropyl-4-methyl-6-hydroxypyrimidine.

2-isopropyl-4-methyl-6-hydroxypyrimidine, hereinafter referred to as oxypyrimidine, is a valuable intermediate for the production of esters of thiophosphoric acid, which are excellent insecticides and have acaricidal effects. Such thiophosphoric acid esters are described, for example, in US Pat. No. 2,754,243. One of those connections , namely O, O-diethy1-0- (2-isopropy1-4-methy1-6-pyrimidy1) -

(D thiophosphate is sold under the name DIAZINON. Since the product is manufactured and sold in large quantities, any improvement in the process for the manufacture of oxypyrimidine is of economic importance.

The technically most important process for the production of Oxypyrimidine comprises three stages. In the first stage, isobutyronitrile is mixed with a lower alkanol, for example methanol or ethanol, and hydrogen chloride converted to the corresponding imino isobutyrate hydrochloride. This is then done in the second stage. Reaction with ammonia converted into the amidine hydrochloride of isobutyric acid, which in the third stage in the reaction with a Acetoacetic acid alkyl ester in a ring-closing reaction which yields oxypyrimidine. This procedure can be carried out by the following reaction equations being represented:

step 1

/ CH-GN + ROH £ 5 ± -> / C
GH ₃ CH ₃ OR

Isobutyronitrile isobutyric acid iminoester hydrochloride

Level 2

^CH 3 /NH.HC1 ^CH 3 /

/ ΪΗ-gC + NH,> / ^CH " ^C C

GH ₃ OR CH ₃ T) IH

Isobutyranidine hydrochloride

level 3

CH "

^X - "^ + CH _n -S-CH ₀ -S-OR> _Λ ^ CH-V _y i-0H

/ ^ ₃ -C-CH ₂ COR> / ^CH \ /

CH, m, 1. OH CH- TST

^{J z} ©

2 H

Oxypyrimidine

This process is carried out with water as the solvent. One A variant of this process is described in US Pat. No. 4,014,879.

Some alternative methods of making oxypyrimidine have also been proposed. For example, oxypyrimidine can according to Japanese Patent 557,103 starting from ß-acylaminocrotonamide, which in turn from the ß-aminocrotonamide which can be produced by reacting diketene and ammonia and acid anhydride or acid halide is obtained. After a

in Japanese Patent Application Sho 48-39,492 Oxypyrimidine can be obtained by reacting β-aminocrotonamide and an alkyl isobutyrate.

Following the procedure described in US Pat. No. 4,018,771 Isobutyric acid amide reacted with diketene to form N-acetoacetylbutyric acid amide, which upon further reaction with ammonia yields oxypyrimidine. According to another described in U.S. Patent 4,052,396 Process is formed by reacting isobutyronitrile with diketene and hydrogen chloride and further reacting the oxypyrimidine Obtained intermediate product with ammonia. Finally, oxypyrimidine can can also be prepared by the process described in US Pat. No. 4,052,397 by first reacting diketene converted with ammonia into ß-aminocrotonamide and this then in the presence of sodium isobutylate with isobutyric acid isobutyl ester implements.

However, these processes were capable of the 3-step process mentioned at the beginning not to be replaced, especially since the production of isobutyric acid iminoester hydrochloride carried out in the first stage of this process This was significantly improved by the fact that isobutyronitrile, hydrogen chloride and methanol were continuously added in methanolic solution reacted in the presence of excess hydrogen chloride. This process is described in U.S. Patent 4,111,976. In the second However, the third and third stage still uses water as the solvent for the preparation of the amidine (stage 2) and for the ring closure (Level 3) used.

The sole use of water as a solvent makes a big one Excess of alkyl acetoacetate is necessary, which is preferably about 30%. This excess is necessary to get through Compensate for losses of alkyl acetoacetate resulting from hydrolysis. Attempts have already been made to obtain the required excess

Acetoacetic acid alkyl ester by reducing the ring closure reaction in a two-phase, from water and one with water immiscible organic solvent existing reaction medium carried out in the presence of a phase transfer catalyst. However, the application of these two-phase solvent systems has in practice brought no advantages in terms of yield.

It has now been found that when carrying out the aforementioned Process in water required excess of Äcetoessigsäurealkylester without any adverse effect on the yield substantially can be reduced if the reaction of the isobutyric acid iminoester according to step 2 and the subsequent reaction of the amidine with the Äcetessigsäurealkylester according to stage 3 in the presence of a lower one Alkanols, such as methanol, or ethanol, performs. The inventive Process for the preparation of 2-isopropyl-4-methyl-6-hydroxypyrimidine is therefore characterized in that one is an isobutyric acid imino ester hydrochloride the formula

^CH 3

> HC (
CH ₃

> HC (

O-alkyl

in which alkyl is methyl or ethyl, under alkaline conditions in a reaction medium consisting of water and a lower alkanol from the group consisting of methanol and ethanol and that up to Contains 75% by weight of water, to the corresponding isobutyramidine hydrochloride the formula

3 _χ / NH'HCl

ch /

implemented and this immediately afterwards in the same reaction

medium under strongly alkaline conditions with excess acetoacetic acid alkyl ester the formula

, -C-CH ₀ -C-

GH ₃ -C-CH ₂ -CO-alkyl

in which alkyl has the meaning given above to 2-isopropyl-4-methyl-6-hydroxypyrimidine implements.

The alkanol is usually in an amount of 50-800 ml per MbI imino isobutyrate hydrochloride used. It is preferable to use 150-250 ml of alkanol per mole of imino isobutyrate hydrochloride.

The ratio of alkanol to water is preferably 4: 1 Parts by weight. Among the alkanols which can be used according to the invention, methanol is preferred. The use of a Reaction medium proved in which the quantitative ratio of methanol to Water is 4: 1 parts by weight. The use of pure methanol as the reaction medium is particularly preferred.

When imino isobutyrate hydrochloride is reacted with ammonia, the reactants are used essentially in equimolar amounts. In general, it is advantageous to use the ammonia in an excess of 5-10 mol%. The reaction of Isobuttersäureiminoester hydrochloride and ammonia can be carried out at a temperature of 0-40 ⁰ C. The reaction is preferably carried out in the temperature range from 15-25.degree.

The implementation of isobutyric acid iminoester hydrochloride with ammonia is expediently carried out in such a way that a solution of ammonia in the alkanol used and the isobutyric acid iminoester hydrochloride are initially charged enters under cooling. During the introduction of the isobutyric acid iminoester hydrochloride, the pH of the reaction mixture becomes s kept in the range of 8.5 to 9.0 by the addition of alkali hydroxide. Sodium hydroxide is the primary alkali hydroxide and potassium hydroxide. These alkali hydroxides can be added to the reaction mixture as concentrated aqueous solutions or as solutions

-f-1.

be added in the alkanol used. As a concentrated aqueous Solutions are in particular 50% sodium hydroxide solution and 50% potassium hydroxide solution suitable.

The conversion of the isobutyramidine hydrochloride to the oxypyrimidine takes place without isolation of the amidine immediately afterwards in the same reaction medium. Isobutyramidine hydrochloride and Alkyl acetoacetate is advantageously used in a molar ratio of 1: 1.05 to 1: 1.10.

The reaction of the isobutyramidine hydrochloride with the alkyl acetoacetate may be conveniently carried out at temperatures between 25 ° and 60 ⁰ C. The reaction is preferably carried out at 40-45 ° C. The reaction of the isobutyramidium hydrochloride with the alkyl acetoacetate is usually carried out in a pH range of 11.0-12.0. Carrying out the reaction in This pH range is set at the beginning of the reaction by adding alkali metal hydroxide, in particular sodium hydroxide or potassium hydroxide, and is maintained during the reaction by adding further proportions of alkali metal hydroxide In the form of a concentrated aqueous solution or in the form of a solution in the alkanol used. Particularly suitable concentrated aqueous solutions are 50% sodium hydroxide solution and 50% potassium hydroxide solution. After the reaction has ended, the reaction mixture is diluted with water and the low-boiling solutions Fractions separated by distillation from the resulting aqueous solution of oxypyrimidine potassium salt, the oxypyrimidine is deposited by neutralization, filtered and dried. In this way, the oxypyrimidine is obtained in a yield of 90-94% of theory.

According to a preferred embodiment, the inventive Process carried out in such a way that the isobutyric acid

iminoester hydrochloride at 15-25 ° C in a solution of 1.05 mol of ammonia per mole of isobutyric acid iminoester hydrochloride in methanol and the reaction mixture is added so much 50% sodium hydroxide solution that a pH of 8 during the entire reaction is maintained from 5 to 9.0 and then the formed isobutyramidine hydrochloride at 25-40 ⁰ C with 1.05-1.10 mol Acetessigsäuremethy! ester reacted to oxypyrimidine per mole isobutyramidine hydrochloride and during this reaction by adding 50% -iger sodium hydroxide solution maintains a pH value of 11.5-12.0.

The process of the invention is illustrated by the following examples explained in more detail- At the same time, examples of the known process in which water is used as the reaction medium are given for comparison will. Examples 1 and 2 show the production of imino isobutyrate hydrochlorides described, which are required as starting materials. Example 1 essentially corresponds to the procedure according to U.S. Patent 4,111,976.

Example 1 : Production of isobutyric acid / minomethyl ether hydrochloride

311 g (9.7 mol) of dry methanol are in a stirrer, thermo? meter, gas inlet tube, addition funnel, condenser and a calcium chloride drying tube equipped 2 liter flask. The methanol is first saturated with cooling at 15-25 ⁰ C and hydrogen chloride, are then added followed by 4 hours 622 g (9.0 mol) Isobutyranitril, wherein the discharge is constantly continued by hydrogen chloride. The reaction temperature is kept at 15-25 ° C. After the addition of the isobutyranitrile is complete, the introduction of hydrogen chloride is continued for a further 10 minutes. The reaction mixture is then stirred at 15-25 ° C. for a further 1 hour. 1700-1800 g of a viscous smoking liquid are obtained in this way, which is stored under cooling.

Example 2 ; Production of isobutyric acid iminoethyl ester hydrochloride

A mixture of 373.2 g (5.4 mol) of isobutyranitrile and 268.7 g (5.8 MbI) of anhydrous ethanol is added to a 2-liter flask equipped with a stirrer, thermometer, condenser, gas inlet tube and calcium chloride drying tube with cooling 15-25 ^C C saturated with hydrogen chloride. When no more hydrogen chloride is absorbed, the mixture is stirred for a further 1 hour at 15-25 ° C. 1100-1200 g of fuming, viscous product are obtained, which is stored with cooling.

Example 3: Production of oxypyrimidine in water with a 10% excess Acetoacetic acid methyl ester

In a 2-liter flask, 97.0 g (1.67 mol) are introduced 29.3% aqueous ammonia and 225 ml of water and cooled to 0 ⁰ C. Then, the aliquot Isobuttersäureiminomethylester hydrochloride, corresponding to 1.59 mol Isobutyranitril, for 20 minutes is added, the temperature being maintained at 15-25 ⁰ C. During the addition of the imino ester hydrochloride, the pH of the reaction mixture falls. As soon as the pH value has dropped to 9.0, 50% sodium hydroxide solution is added continuously in order to keep the pH value between 8.5 and 9.0. After the addition of the isobutyric acid iminomethyl ester hydrochloride has ended, the reaction mixture is stirred at 20-25 ° C. for 1 hour. The reaction mixture is then ^{cooled to 0 °} C. and first 89.0 g (1.11 mol) of 50% strength sodium hydroxide solution and then 203.0 g (1.75 mol; 10% excess) methyl acetoacetate are added over the course of 15 minutes. During the addition of the methyl acetoacetate, 50% sodium hydroxide solution is added at the same time in order to keep the pH at 12.0. When the addition of the methyl acetoacetate is complete, the reaction mixture is 1 1/2 hours

Stirred at 25-4O ° C to complete the reaction.

The reaction mixture is then added by adding aqueous hydrochloric acid adjusted to pH 6.0, cooled and filtered. The product is dried in vacuo. Ea 241.0 g of crude product are thus obtained, which is 80.6% Contains 2-isopropyl-4-methyl-6-hydroxypyrimidine. The filtrate (1595 g) contains another 0.9% product, making the overall yield 86.2% ". amounts to.

Example 4 ; Production of oxypyrimidine in water with a 30% excess of acetates

Acetic acid methyl ester

As described in Example 3, 1.88 mol isobutyric acid iminomethyl ester, 114.4 g (1.97 mol) of 29.3% strength aqueous ammonia and 250 ml of water converted to isobutyramidine hydrochloride. The following Ring closure is achieved with 284.0 g (2.44 mol; 30% excess) methyl acetoacetate carried out with the simultaneous addition of 112.8 g (1.41 mol) of 50% sodium hydroxide solution. Then the reaction mixture neutralized and filtered and the product obtained dried. 376.0 g of crude product are obtained, which is 69.8% of 2-isopropyl-4-methyl-6-hydroxypyrimidine contains. The filtrate (1626 g) contains more 0.65% oxypyrimidine, so that an overall yield of 95.4% of theory results.

Example 5 : Production of oxypyrimidine in methanol with 5% excess of acetates

Acetic acid methyl ester

26.3 g (1.54 mol) of anhydrous ammonia are dissolved in 290 ml of methanol.

1.46 mol of isobutyric acid iminomethyl ester hydrochloride are added to this solution entered and as described in Example 3, to isobutyramidine hydrochloride implemented. 178.0 g (1.52 mol; 5% excess) of methyl acetoacetate are added to the mixture obtained with cooling registered. Then, with further cooling, the pH of the mixture is adjusted to 11.7 by rapidly adding 50% sodium hydroxide solution. The temperature rises to 40-45 ° C. and is there for 1-1.5 hours held. 50% sodium hydroxide solution must be added periodically, to keep the pH of the reaction mixture at 11.7.

After the reaction has ended, 800 ml of water are added and the low-boiling components are added up to a transition temperature of 99.degree separated by distillation. The contents of the reactor are then neutralized, cooled and the product filtered off. After drying will be 215.2 g of 92.4% oxypyrimidine and 1233 g of filtrate were obtained that still Contains 0.38% oxypyrimidine. The total yield of 2-isopropyl-4-methyl-6-hydroxypyrimidine is 91.6% of theory.

Example 6 : Production of oxypyrimidine in methanol with a 10% excess Methyl acetoacetate

As described in Example 5, there are 24.0 g (1.41 mol) of ammonia, 281 ml of methanol and 1.44 mol of isobutyric acid iminomethyl ester hydrochloride converted to isobutyramidine hydrochloride. Then 183.9 g (1.58 mol; 10% excess) methyl acetoacetate are added and converted to oxypyrimidine as described in Example 5. 217.9 g of a 90.7% strength oxypyrimidine and 1236 g of filtrate are obtained, which contains an additional 0.34% oxypyrimidine. The total yield of oxypyrimidine amounts to 93.1% of theory.

Example 7 : Production of oxypyrimidine in ethanol with 5% excess of acet

methyl acetate

Example 5 is made using 29.12 g (1.71 mol) ammonia, 298 ml of ethanol and 1.53 mol of iminoethyl isobutyrate hydrochloride repeated. After conversion to the amidine, 185.8 g (1.60 mol; 5% excess) methyl acetoacetate are obtained in the ring closure reaction used. 212.0 g of 93.9% strength oxypyrimidine and 1380 g of filtrate are obtained which contain 0.36% of oxypyrimidine. The total yield of oxypyrimidine is 87.6% of theory.

Example 8 :

Continuous production of oxypyrimidine in methanol under Verwen- 'extension of a multi-stage reactor

The one used for the continuous production of oxypyrimidine Multi-stage reactor consists of three independent units: 1) a cooling circuit upstream of the multi-stage reactor, which consists of a consists of a small continuously stirred tank reactor, a heat exchanger for cooling the reactor and a circulation pump; 2) the multistage reactor itself and 3) a downstream of the multistage reactor. th larger continuously stirred tank reactor. Every unit is equipped with suitable temperature and pH measuring instruments.

During operation, the reactants are pumped into the continuously stirred tank reactor of the cooling circuit is metered in. Comes from the continuously stirred tank reactor of the cooling circuit the reaction mixture via an overflow into the multistage reactor, from where it continues through another overflow into the downstream stirred tank reactor comes. The product is withdrawn from this after a suitable residence time.

The cooling circuit and the first stage of the multi-stage reactor are charged with methanol, which is circulated through the heat exchanger in order to set the temperature to 25 ^° C. Then a solution of isobutyramidine hydrochloride (prepared according to Example 5) at a rate of 1.0 mol per hour, Äcetoessigsäuremethylester at a rate of 1.05 mol per hour (5% excess) and 50% sodium hydroxide solution in the for Adjustment of a pH value of 11.7 required amount metered into the cooling circuit. A temperature of 39-45 ° C. is maintained in the multi-stage reactor and a pH of 11.3-12.0 is maintained by adding further sodium hydroxide solution. In the downstream continuously stirred tank reactor, the temperature is kept at 42 ° C. and the pH value at 11.7. The residence time in the downstream continuously stirred tank reactor is 1.5 hours. The distillation, neutralization and filtration are carried out as described in the previous examples. The yield of oxypyrimidine is 88-90% of theory.

Claims (14)

Claims 1. Process for the preparation of 2-isopropyl-4-methyl-6-hydroxypyrimidine, characterized in that one is an isobutyric acid imino ester hydrochloride the formula ^CH 3 JIH-HCl CH ₃ O -alkyl in which alkyl is methyl or ethyl, under alkaline conditions in a reaction medium consisting of water and a lower alkanol from the group consisting of methanol and ethanol and that up to Contains 75% by weight of water, to the corresponding isobutyramidine hydrochloride the formula ^CH 3 /
CH- _C /
CH ₃ TIH and this immediately afterwards in the same reaction medium under strongly alkaline conditions with excess acetoacetate the formula , -C-CEL-C-O-i CH ₃ -C-CH ₂ -CO-alkyl
in which alkyl has the meaning given above. 2. The method according to claim 1, characterized in that 150-250 ml of alkanol per mole of isobutyric acid iminoester hydrochloride used. 3. The method according to claim 1, characterized in that the quantitative ratio of alkanol to water in the reaction medium used 4: 1 parts by weight. 4. The method according to claim 1, characterized in that as Alkanol methanol used. 5. The method according to claim 1, characterized in that one Reaction medium consisting of methanol and water used, in which the quantitative ratio of methanol to water is 4: 1 parts by weight. 6. The method according to claim 1, characterized in that methanol used as a reaction medium. 7. The method according to claim 1, characterized in that the · Ammonia is used in an excess of 5-10 MbI.%. 8. The method according to claim 1, characterized in that the reaction of isobutyric acid imino ester hydrochloride with ammonia in the temperature range of 15-25 ⁰ C is carried out. 9. The method according to claim 1, characterized in that during the implementation of isobutyric acid iminoester hydrochloride with ammonia maintains a pH of 8.5-9. 10. The method according to claims 1 and 7, characterized in that 50% aqueous sodium hydroxide solution or potassium hydroxide solution is used as the alkali metal hydroxide. 11. The method according to claim 1, characterized in that the Isobutyramidine hydrochloride and the alkyl acetoacetate in one Mol. Ratio of 1: 1.05-1: 1.10 used. 12. The method according to claim 1, characterized in that one carries out the reaction of the isobutyramidine hydrochloride with the alkyl acetoacetate at a temperature of 25-45 ⁰ C. 13. The method according to claim 1, characterized in that the Implementation of the isobutyramidine hydrochloride with the alkyl acetoacetate in a pH range of 11.5-12.0. 14. The method according to claim 1, characterized in that one enters the Isobuttersäureiminoester hydrochloride at 15-25 ⁰ C in a solution of 1.05 moles of ammonia per mole Isobuttersäureiminoester hydrochloride in methanol and adding to the reaction mixture as much 50% sodium hydroxide solution that during the entire reaction a pH of 8.5-9 is maintained and then the isobutyramidine hydrochloride formed reacts at 25 ~ 40 ° C with 1.05-1.10 mol of methyl acetoacetate per mol of isobutyramidine hydrochloride and during this Implementation by adding 50% sodium hydroxide solution maintains a pH of 11.5-12.0.