EP1529036A1

EP1529036A1 - Method for producing highly pure crystalline 4-amino-5,6-dimethoxypyrimidine

Info

Publication number: EP1529036A1
Application number: EP03763777A
Authority: EP
Inventors: Thomas GÜTHNER; Doris Krammer; Bernd Braml
Original assignee: Degussa GmbH
Current assignee: Evonik Operations GmbH
Priority date: 2002-07-12
Filing date: 2003-07-09
Publication date: 2005-05-11
Also published as: DE10231496A1; DE10231496B4; AU2003250930A1; WO2004007466A1

Abstract

The invention relates to a method for producing highly pure crystalline 4-amino-5,6-dimethoxypyrimidine by: a) reacting 4-amino-6-chloro-5-methoxypyrimidine with methanol and with a base at a temperature ranging from 20 to 100 °C, whereby: b) the methanolic solvent is entirely or partially replaced by water; c) the aqueous or aqueous/methanolic solution is extracted using t-butyl methyl ether, and; d) the extracted product is crystallized out of the t-butyl methyl ether. It has been surprisingly shown that an extremely pure and crystalline 4-amino-5,6-dimethoxypyrimidine can be produced with a high yield by using t-butyl methyl ether as an extracting agent. In addition, the method can be carried out in a comparatively technically simple manner.

Description

Process for the preparation of high-purity, crystalline 4-amino-5,6-dimethoxypyrimidine

description

The present invention relates to a process for the preparation of high-purity, crystalline 4-amino-5,6-dimethoxypyrimidine, starting from 4-amino-6-chloro-5-methoxypyrimidine.

4-Amino-5,6-dimethoxypyrimidine is a valuable intermediate in the production of active pharmaceutical ingredients, in particular bactericidal sulfadoxine (cf. H. Bretschneider et. Al., Monthly Chem. 96 (1965) 1661).

There is essentially one chemical route for the preparation of 4-amino-5,6-dimethoxypyrimidine, namely the reaction of 4-amino-6-chloro-5-methoxypyrimidine with a reagent which is capable of supplying methylate as a nucleophile, i.e. usually a mixture of methanol and a suitable base. Corresponding regulations are known from the literature, e.g. V. A. Zasosov et. al. Pharm. Chem. J. (Engl. Transl.) 6, 3, 160 (1972), A. Grüssner et. al., monthly Chem. 96, 1677 (1965), CH 405322, GB 946488 and FR 1343491.

As reagents and reaction conditions for the implementation of

4-Amino-6-chloro-5-methoxypyrimidine to 4-amino-5,6-dimethoxypyrimidine are mentioned, for example: a solution of sodium metal in methanol, a solution of sodium methylate in methanol or a solution of sodium hydroxide in methanol. For safety and economic reasons, the use of an alkali hydroxide in methanolic solution is to be regarded as preferred. According to the prior art, the reaction mixture obtained is freed from methanol, taken up in water and extracted with an organic solvent.

The following are mentioned as solvents: dichloromethane, diethyl ether, diisopropyl ether and ethyl acetate. All of these solvents have the following significant disadvantages: dichloromethane is a highly environmentally hazardous substance and may only be handled in specially equipped systems. Diethyl ether and diisopropyl ether are solvents which, due to their slight peroxide formation after exposure to oxygen, have often led to accidents and should therefore be avoided. Ethyl acetate is a relatively safe solvent. When extracting from the basic, e.g. However, NaOH-containing reaction solution hydrolyzes it to ethanol and acetate and prevents trouble-free phase separation, which is why its use also poses problems.

A particularly pure 4-amino-5,6-dimethoxypyrimidine is desired for further processing to the pharmaceutical active ingredient sulfadoxine. As can be seen from the melting points, the processes described, however, provide clearly varying, in some cases significantly lower melting points.

The process according to CH 405 322 yields a 4-amino-5,6-dimethoxypyrimidine with a melting point of 92 to 93 ° C., purified by recrystallization from diisopropyl ether and subsequent two-time sublimation. Before the sublimations, the melting point is 88 to 89 ° C. According to H. Bretschneider et al. a product with a melting range of 86 to 91 ° C was obtained from ethyl acetate, which melted after sublimation at 89 to 91 ° C, after sublimation again at 90 to 92 ° C. VA Zasosov obtained a product with a melting point of 85 to 88 ° C from dichloromethane. According to the prior art, there has so far been no process for producing a high-purity 4-amino-5,6-dimethoxypyrimidine characterized by a melting point of> 90 ° C., with the exception of sublimation, which is technically very complex and requires special apparatus.

The present invention was therefore based on the object of a technically and economically feasible process for the preparation, isolation and purification of 4-amino-5,6-dimethoxypyrimidine by a) reacting 4-amino-6-chloro-5-methoxypyrimidine with methanol and to develop a base that does not have the disadvantages of the prior art, but rather can deliver high-purity 4-amino-5,6-dimethoxypyrimidine in conventional apparatus and without additional effort.

The object of the invention was achieved in that b) the methanolic solvent was completely or partially replaced by water, c) the aqueous or aqueous-methanolic solution was extracted with t-butyl methyl ether and d) the extracted product was crystallized from t-butyl methyl ether.

Surprisingly, it has been shown that t-butyl methyl ether is capable of delivering 4-amino-5,6-dimethoxypyrimidine, which is extremely pure compared to the prior art, in high yield, the process being comparatively simple to carry out industrially. In addition, the product is obtained in crystalline form and can be separated off or processed very well (for example by filtration).

In the process according to the present invention, 4-amino-6-chloro-5-methoxypyrimidine is assumed, which, for example, according to known method from 4,6-dichloro-5-methoxypyrimidine is obtained by reaction with ammonia. The starting material can be used in dried form or as a moist, in particular water-moist, filter cake.

The 4-amino-6-chloro-5-methoxypyrimidine is dissolved or suspended in methanol and reacted with the addition of a base.

In particular, an alkali methylate or alkali hydroxide is used as the base. Preferred bases are e.g. Sodium methylate, potassium methylate, solid sodium hydroxide, solid potassium hydroxide, aqueous sodium hydroxide solution in the concentration range from 25 to 70% by weight, preferably from 30 to 65% by weight, more preferably from 45 to 55% by weight, and / or aqueous potassium hydroxide solution Concentration range 20 to 60 wt .-%, preferably from 30 to 55 wt .-%, more preferably from 40 to 50 wt .-%. Aqueous sodium hydroxide solution is particularly preferred, in particular as a 50% by weight solution.

The reaction can take place under increased or reduced pressure. "Increased pressure" means that the pressure is greater than atmospheric pressure, e.g. can be increased by 0.5 bar to 10 bar, preferably by 1 to 8 bar, more preferably 2 to 5 bar, in relation to atmospheric pressure. "Reduced pressure" means that the pressure is lower than atmospheric pressure. The pressure is e.g. from 0.9 bar to 0.2 bar, preferably from 0.7 to 0.3 bar, more preferably from 0.5 to 0.4 bar. The reaction is particularly preferably carried out at atmospheric pressure.

The reaction temperature in step a) can be 20 to 100 ° C, preferably 40 to 80 ° C, more preferably 50 to 75 ° C, particularly preferably 65 to 70 ° C. It is preferred that the reaction be under Boiling conditions at atmospheric pressure and a resulting temperature of 65 to 70 ° C is carried out.

1.0 to 5.0 mol of base can be used per 1 mol of 4-amino-6-chloro-5-methoxypyrimidine. A base amount of 1.5 to 3.5 mol, more preferably 1.8 to 2.5 mol, is preferably used. On the one hand, the amount of base should be minimized for economic reasons, on the other hand, an excess of base with by-products (e.g. hydroxypyrimidines) can keep in solution. It is particularly preferred to work with a base amount of 1.05 to 2.0 moles.

Methanol is preferably used as a solvent and reactant, the amount being mainly determined by the stirrability. Preferably 300 to 800 ml of methanol are used per 1 mol of 4-amino-6-chloro-5-methoxypyrimidine, more preferably 400 to 650 ml of methanol are used.

At the end of the reaction, the methanolic solvent is completely or partially replaced by water in stage b). This can be done by completely distilling off or evaporating off the methanol and redissolving the product in water or by adding water before or during the distillation. A volume of water corresponding to the volume of methanol removed can be added. However, more or less water can be added than the volume of methanol removed.

After the distillation has ended, the mixture preferably contains less than or equal to 10% by weight of methanol, more preferably less than or equal to 8% by weight, particularly preferably less than or equal to 5% by weight of methanol. In particular, there is no methanol after the distillation or there are only traces of methanol or, for example, amounts of 1% by weight to 4 % By weight, preferably 1.5% by weight to 3.5% by weight and more preferably 2 to 3% by weight.

It is to be regarded as essential to the invention that the mixture obtained is extracted in step c) with t-butyl methyl ether. This is a comparatively safe solvent with an extremely low tendency to form peroxides, low toxicity and a high ignition temperature. The extraction is carried out at a preferred temperature of 10 to 55 ° C., in particular 25 to 50 ° C., with an amount sufficient to dissolve the 4-amino-5,6-dimethoxypyrimidine present, preferably 200 to 2000 ml, more preferably 250 ml to 1,500 ml, in particular 300 to 800 ml of t-butyl methyl ether per mole of 4-amino-6-chloro-5-methoxypyrimidine used.

After phase separation has been carried out, the aqueous phase is extracted 1 to 5 times, preferably 2 to 4 times, with further t-butyl methyl ether to increase the yield, the amount of solvent used depending on the batch size. For example. For each mole of 4-amino-6-chloro-5-methoxypyrimidine used, e.g. 50 ml to 1500 ml, preferably 1 50 ml to 1250 ml, more preferably 250 ml to 1000 ml and even more preferably 500 to 750 ml of t-butyl methyl ether.

To remove coloring and / or slimy impurities, the combined organic phases can optionally be treated with activated carbon, which is preferably separated off in a subsequent filtration.

In the final stage d), the extracted product is crystallized from t-butyl methyl ether. For this purpose, the combined organic phases can be partially evaporated, so that preferably 50 to per mole of 4-amino-6-chloro-5-methoxypyrimidine used 300 ml, more preferably 100 to 200 ml, in particular 50 to 100 ml of t-butyl methyl ether remain in the residue. Then is preferably cooled to -20 to 25 ° C, preferably to -10 to 10 ° C, the precipitated 4-amino-5,6-dimethoxypyrimidine is filtered off and dried.

Very high yields of 92 to 99%, for example 94 to 96%, of a high-purity, crystalline 4-amino-5,6-dimethoxypyrimidine with a melting point of> 90 ° C., in particular 90 to 93 ° C., are obtained. It is preferred that the melting point is> 91 ° C, more preferably> 92 ° C. The yields are in particular ≥ 93%, more preferably> 95%, even more preferably> 98%. The contents, determined by gas chromatography, are> 99.5%, in particular ≥ 99.7%, more preferably> 99.8% and can be up to 99.9 to 99.99% or more.

This highly pure product enables better product quality when processed into active pharmaceutical ingredients, especially sulfadoxine, and prevents the formation of unwanted by-products.

The following examples are intended to explain the process according to the invention.

Example 1 :

951 g (4.0 mol) of dry 4-amino-6-chloro-5-methoxypyrimidine were placed in 2500 ml of methanol and warmed to 65.degree. Then 512 g (6.4 mol) of 50% aqueous sodium hydroxide solution were metered in over the course of 2 hours. The mixture was heated under gentle reflux (70 ° C) for a further 3 hours. Then the methanol was largely distilled off, replaced with 2500 ml of water, and the remaining methanol was distilled off in vacuo. The methanol content was <1% by weight. The resulting solution was mixed at 40 ° C. with 4000 ml of t-butyl methyl ether, stirred and left to separate the phases. The organic phase was separated. The aqueous phase was extracted a further 3 times with 1000 ml each of t-butyl methyl ether.

The combined organic phases were treated with 20 g activated carbon and filtered.

Then 5970 ml of t-butyl methyl ether were distilled off, the suspension obtained was cooled to 0 ° C. and suction filtered. After drying at 40 ° C. in vacuo, 598.9 g of crystalline 4-amino-5,6-dimethoxypyrimidine were obtained. The yield was 96.5%. The product had a melting point of 90.3 to 91.4 ° C, the purity determined by GC was 99.93%.

Example 2

98.3 g of crude 4-amino-6-chloro-5-methoxypyrimidine with a water content of 1 6.9% by weight (0.51 mol) became analogous to Example 1 with 66.7 g (0.83 mol) 50 % sodium hydroxide solution in 260 ml of methanol. The extraction was carried out first with 306 g, then 3 times with 76.5 g each of t-butyl methyl ether. The combined organic extracts were decolorized with 0.5 g activated carbon.

After distilling off the excess t-butyl methyl ether, crystallization, filtration and drying, 75.3 g of crystalline 4-amino-5,6-dimethoxypyrimidine were obtained. The yield was calculated to be 95.3%. The melting point was 90.8 to 91.9 ° C, the purity determined by GC was 99.9%. Example 3 (not according to the invention)

15.95 g (0.1 mol) of 4-amino-6-chloro-5-methoxypyrimidine were reacted with 10.4 g (0.13 mol) of 50% sodium hydroxide solution in 100 g of methanol at 65 ° C. for 4 hours. The mixture was evaporated to dryness and taken up in 100 ml of water. The solution obtained (pH 14) was extracted 4 times with 100 ml of ethyl acetate. This showed a very poor phase separation due to the progressive hydrolysis of the ethyl acetate. The organic extracts were washed with water, dried with sodium sulfate and decolorized with activated carbon. Then 350 g of ethyl acetate were distilled off, cooled, crystallized, the product was filtered off and dried.

12.9 g (83%) of 4-amino-5,6-dimethoxypyrimidine with a melting range of 85.8 to 88.2 ° C. were obtained.

Example 4 (not according to the invention)

15.95 g (0.1 mol) of 4-amino-6-chloro-5-methoxypyrimidine were reacted with 10.4 g (0.13 mol) of 50% sodium hydroxide solution in 100 g of methanol at 65 ° C. for 4 hours. The mixture was evaporated to dryness and taken up in 100 ml of water. The solution obtained (pH 14) was extracted 4 times with 100 ml of t-butyl methyl ether. The organic extracts were decolorized and then completely evaporated at 90 ° C. A product melt formed which crystallized on cooling.

15.3 g (99%) of 4-amino-5,6-dimethoxypyrimidine were obtained. The melting range was 80.9 to 87.3 ° C. A content determination by means of GC showed 97.4% purity.

Claims

Expectations

1 . Process for the preparation of high-purity, crystalline 4-amino-5,6-dimethoxypyrimidine by a) reacting 4-amino-6-chloro-5-methoxypyrimidine with methanol and a base in the temperature range from 20 to 100 ° C, characterized in that b) all or part of the methanolic solvent

Replaces water, c) the aqueous or aqueous-methanolic solution is extracted with t-butyl methyl ether and d) the extracted product is crystallized from t-butyl methyl ether.

2. The method according to claim 1, characterized in that an alkali metal methylate or an alkali metal hydroxide is used as base in stage a).

3. The method according to claim 1 or 2, characterized in that sodium hydroxide, solid or as sodium hydroxide solution, is used as the base.

4. The method according to any one of claims 1 to 3, characterized in that the reaction a) is carried out at 40 to 80 ° C.

5. The method according to any one of claims 1 to 4, characterized in that 1, 0 to 5.0, preferably 1, 05 to 2.0 moles of base per mole of 4-amino-6-chloro-5-methoxypyrimidine are used.

6. The method according to any one of claims 1 to 5, characterized in that 300 to 800 ml of methanol are used as the solvent per mole of 4-amino-5,6-dimethoxypyrimidine.

7. The method according to any one of claims 1 to 6, characterized in that in step b) so much water is added that the methanol content is reduced to <5 wt .-%.

8. The method according to any one of claims 1 to 7, characterized in that the extraction step c) is carried out with t-butyl methyl ether at 10 to 55, in particular at 25 to 50 ° C.

9. The method according to any one of claims 1 to 8, characterized in that in step c) 300 to 800 ml of t-butyl methyl ether per mole of 4-amino-6-chloro-5-methoxypyrimidine used.

10. The method according to any one of claims 1 to 9, characterized in that the solution of 4-amino-5,6-dimethoxypyrimidine obtained in step c) is partially evaporated in step d), crystallized and filtered.

1 1. The method according to claim 10, characterized in that the solution from stage a) is partially evaporated so far that 50 to 100 ml of t- per mole of 4-amino-6-chloro-5-methoxypyrimidine used

Butyl methyl ether remain in the residue.

12. The method according to any one of claims 1 to 1 1, characterized in that stage d) is carried out at temperatures from -20 to 25 ° C, in particular -10 to 10 ° C.