HU195196B - Process for production of halogenated uracil derivatives - Google Patents

Abstract

Hydrogenated uracil cpds. (I) R is 1-4C atom alkyl gp. are prepd. from sodium salts of uracil derivs. of type (II). R is unchanged by chlorination in aq. sodium hydroxide medium with 1.01-1.1 mole aq. sodium hypochlorite 0-5 secs., pref. 0.1-1 secs. at 0-25 deg.C. Perfect mixing prior to reaction is essential. - Uracils are important bioactive cpds. in the construction of nucleic acids and as active agents in plant protecting and growth regulating agents.

Description

The present invention relates to a novel process for the preparation of halogenated uracil derivatives of formula I, wherein R is a C 1 -C 4 alkyl group, from uracil derivatives of formula II, wherein R is as defined for formula I - by chlorination in aqueous sodium hydroxide solution with sodium hypochlorite so that the sodium salt of the uracil derivative (II), wherein R is as defined above, in an aqueous sodium hypochlorite at 0-25 ° C. The reaction is carried out at a temperature of from 0.1 to 5, preferably from 0.1 to 1 second.

In the formulas I and II, R as a C 1-4 alkyl group is any straight or branched chain group such as methyl, ethyl, η-propyl, i-propyl, η-butyl, sec-butyl , tert-butyl or i-butyl.

Uracil derivatives are important bioactive compounds: building blocks of nucleic acids and various pesticides, such as herbicides, fungicides, growth regulators, and active ingredients.

One of their important groups, the 3-alkyl-5-halo-6-methyluracils of the formula (I), in which R is a (C1-C4) -alkyl group, exhibits enhanced herbicidal activity. This beneficial biological effect occurs * when the uracil ring is in position 5 with halogen, primarily chlorine.

·. substituted.

I

3-Alkyl-6-methyluracil can be chlorinated in many ways. The most common method is the use of elemental chlorine in aqueous or organic media, such as acetic acid, which is particularly advantageous in the place where chlorine gas is produced. A disadvantage, however, is the highly toxic nature of chlorine, its propensity for oxidative side reactions. For this reason, the reaction requires very careful design. Such a procedure is disclosed in U.S. Patent No. 3,352,862. U.S. Pat.

Sulfuryl chloride, which is also commonly used, is a mild chlorinating agent, but gaseous products such as hydrochloric acid and sulfur dioxide produce a corrosive effect similar to chlorine gas, resulting in a significant increase in its molecular weight and relatively high unit cost. This chlorination process is accomplished by the process described in U.S. Patent 3,480,631.

It is most advantageous from an operational point of view when using an aqueous solution of sodium hypochlorite as the chlorinating agent. There is no gas evolution in the reaction which would require a separate absorber. Because of their low corrosion, they can work in iron hardware. Addition of the reaction components and processing of the reaction mixture is much simpler compared to the previous processes. The chlorination can be carried out in a homogeneous phase because the weakly acidic uracil derivative is dissolved in a strongly alkaline aqueous solution such as alkali metal hydroxide. Upon completion of chlorination, the product precipitates from the neutralized reaction mixture 2. Such a preparation is disclosed in German Patent No. 1,803,167, for example, where the sodium salt of 3-tert-butyl-6-methyluracil is chlorinated in aqueous solution with 16% molar solution of 10% aqueous sodium hypochlorite at 30 ° C and 45 ° C. ° C. The reaction mixture is inoculated with the slurry from the previous preparation and the precipitated product is filtered off after adjusting the pH to 7. Production is 87.5% of theory.

In our experiments, the reaction temperature of the uracil derivative and the sodium hypochlorite was lowered to 0-25 ° C and the stoichiometric molar ratio of the sodium hypochlorite was maintained to 90-95%. rises to. Such conditions can easily be achieved in a laboratory apparatus of 1 liter or less.

However, in the case of batch-scale production (1000-fold increase), depending on the mixing conditions of the autoclave used (mixer shape, flow breaker, rpm, etc.), the chlorination yield is still significantly reduced (40-50%) compared to laboratory results. In a laboratory review of the process, it was found that the production of the main reaction over a period of seconds is reduced by consecutive oxidation side reactions at approximately one order of magnitude. Increasing the reaction temperature causes a significant decrease in production only above 40 ° C, but even at lower temperatures (0-10 ° C) the final product is oxidized to fractional molecules (carbon dioxide, ammonia, etc.) by sodium hypochlorite. Oxidation Jeha is enriched with spade at the end of chlorination. Thus, for example, production is improved by allowing 1-2% of the unreacted uracil derivative in the product.

In order to suppress the oxidation side reactions, experiments were carried out using an operational solution which reduces the total mixing time to one second and continuously feeds the starting uracil derivative in the mixing zone and ensures that the reactant and chlorinating agent are present in equimolar concentrations. In spite of the homogeneous phase, the main reason for the decrease in production is the decrease of the relative mixing efficiency due to the high volume. There is a significant gradient of sodium hypochlorite concentration at the site of administration of the chlorinating agent. It is well known that the total mixing time (interruption of the concentration gradient) of intermittent autoclaves with conventional mixing of several m ^{3 is} such that a gradient of high concentration of sodium hypochlorite in the autoclave at the injection site creates favorable conditions for overoxidation.

The starting uracil derivative is in excess and the reactive components

The equimolarity of -2195196 can be achieved momentarily by mixing an aqueous solution of the two reactants with a high-efficiency liquid-liquid mixing unit such as centrifugal pumps, injectors, and flow mixers. The most easily available of these is the centrifugal pumps, which perform instant mixing of miscible liquid phases.

In one industrially feasible embodiment, the reaction is carried out in a continuous reactor equipped with an agitator for intensive mixing. In such an adiabatic reaction, the aqueous solution of the components is cooled so that the reaction heat does not damage the product. This embodiment requires two cooled dosing tanks and a reaction mixture collecting tank in addition to the mixing unit. Equimolarity of the reactants is assured by mass flow meters (e.g., rotameter).

The chlorination can be accomplished under substantially simpler industrial conditions by recirculating the aqueous solution of the sodium salt of the reactant uracil derivative through a high-capacity centrifugal pump and adding sodium hypochlorite at a constant rate before the pump. In this case, the pump capacity should be chosen so that the initial uracil derivative is in excess at the point of mixing until a maximum conversion of at least 90% is achieved. This can be achieved by rotating the uracil derivative solution with a suction pump at least 10 times during the addition of the sodium hypochlorite solution while maintaining a constant mass flow. This embodiment provides equivalent to laboratory results, equivalent to equimolar dosing, i.e. 90-94%.

Thus, the realization of the present invention is that the virtually equimolar instantaneous mixing of the starting uracil compound and the sodium hypochlorite ensures high production, regardless of the size of the embodiment, and thus there is no obstacle to scale-up in the industrial realization.

The following examples illustrate the process of the present invention.

Example 1

3-tert-butyl-5-chloro-6-methyluracil

A solution of 164 kg of 3-tertiary-butyl-6-methyluracil (0.90 kmol) and 43 kg of sodium hydroxide (1.075 kmol) in 1440 liters of water cooled to 10 ° C in a 2000 liter tank with a dosing pump and 612 liters of sodium hypochlorite solution (120 g of sodium - hypochlorite / liter of solution) (0.98 kmol) (for example by means of a venturi tube mixing element having mixing Re-number of more than 10 ⁵ at) administered in a 1000 liter tank metering pump over 2 hours through hydrodynamic mixer steady pace Let's conceive a 3000 liter mixed car4. The reaction mixture was cooled with water until the final temperature was 23-25 ° C. The reaction mixture was then concentrated to pH 5 to 6 with concentrated aqueous hydrochloric acid, the slurry cooled to 15 ° C, centrifuged, washed with cold water and dried. Thus 185.5 kg

3-tert-butyl-5-chloro-6-methyluracil was obtained.

Melting point: 174-175 ° C.

The yield is 95% of theory.

Example 2

3-tert-Butyl-5-chloro-6-methyluracil

In a 3000 liter stirred reactor, a solution of 164 kg of 3-tert-butyl-6-methyluracil and 43 kg of sodium hydroxide in 1440 liters of water was circulated with a Vo-520 centrifugal pump at 10-11 m ³ / h (transport height 15-17 m) and a metering pump. 612 liters of sodium hypochlorite solution (120 g of sodium hypochlorite / liter) are added to the pressure port of the centrifugal pump evenly over 2 hours. The reaction mixture was cooled to 15-20 ° C. The pH of the reaction mixture was then adjusted to 5 to 6 with concentrated aqueous hydrochloric acid, the slurry was centrifuged at 15 ° C, washed with cold water and dried. 182 kg of 3-tert-butyl-5-chloro-6-methyluracil are obtained.

Melting point: 174-175 ° C.

The yield is 93% of theory.

Example 3

3-tert-Butyl-5-chloro-6-methyl uracil

The operating conditions, starting materials, and reaction conditions described in Example 2 were used except that 80% of the sodium hypochlorite solution was added at the rate described in Example 2 and then the last 20% of sodium hypochlorite was added to one third. In the same manner as in Example 2, 185.5 kg of 3-tert-butyl-5-chloro-6-methyluracil are obtained.

Production is 95% of theory.

4. Control Example

3-tert-butyl-5-chloro-6-methyluracil

A 3,000 liter Lampart apparatus equipped with an Anker stirrer (60 rpm) equipped with a flow breaker is charged with aqueous alkaline 3-tert-butyl-6-methyluracil as in Example 2 and cooled to 5-10 ° C. 120 g / l sodium hypochlorite solution is added continuously from the vessel over a period of 1 hour, with a maximum of 2% (about 750 liters) of unreacted starting uracil derivative. The reaction mixture was worked up as in Example 2.

83.5 kg of 3-tert-butyl-5-chloro-6-methyluracil were obtained.

The production is 43% of theory.

Example 5

3-tert-Butyl-5-chloro-6-methyluracil 1 L round-bottomed flask fitted with a KPG swivel blade (revolution:

-3195196

400 rpm) with a rotary blade fitted with a 6 x 1.5 cm / cm thermometer and a addition funnel, a solution of 91 g (0.5 mol) of 3-tert-butyl-6-methyluracil and 24 g of sodium hydroxide in 800 ml of water. While cooling, sodium hypochlorite solution was slowly added dropwise at 15-20 ° C so that the unreacted starting uracil derivative remained at a maximum of 2% (about 340 mL of 120 g / L solution) containing 0.55 molar sodium hypochlorite. The reaction mixture was worked up as described in Example 2.

101 g of 3-tert-butyl-5-chloro-6-methyluracil were obtained.

Production is 93% of theory.

6. Control Example

3-tert-butyl-5-chloro-6-methyluracil

The apparatus and starting materials described in Example 5 were used except that the agitator speed was set to 100 rpm. The required amount of sodium hypochlorite is about 450 ml (0.73 mol). The reaction was carried out as described in Example 5.

52 g of 3-tert-butyl-5-chloromethyl-uracil are obtained.

The production is 48% of theory.

Example 7

3-sec-Butyl-5-chloro-6-methyluracil A solution of 91 g of 3-sec-butyl-6-methyluracil and 24 g of sodium hydroxide in 800 ml of water was added to the mixing apparatus described in Example 6 and cooled to 15 340 ml of sodium hypochlorite solution was added dropwise at 20 ° C. The processing is the same as in Example 6.

99 g of 3-sec-butyl-5-chloro-6-methyluracil are thus obtained.

M.p. 153-155 ° C.

Yield 91.5% of theory.

Claims (1)

A process for the preparation of halogenated uracil derivatives of formula I wherein R is C 1 -C 4 alkyl from uracil ²⁰ derivatives of formula II wherein R is as defined in formula I, aqueous sodium hydroxide by chlorination with crosslinked sodium hypochlorite, characterized in that one (II) in ²⁰ uracil derivative of formula - wherein R is as defined above - from 1.01 to 1.1 mol of the sodium salt with aqueous sodium hypochlorite 0-25 ° C The reaction is carried out at a rate of 0.1-5 seconds, preferably 0.1-1 seconds.