EP1554255A1

EP1554255A1 - Method for the production of 2-amino-4-chloro-6-alkoxypyrimidines

Info

Publication number: EP1554255A1
Application number: EP03775230A
Authority: EP
Inventors: Sylvia Huber; Thomas GÜTHNER; Wolfgang Moser; Doris Krammer
Original assignee: Degussa GmbH
Current assignee: Evonik Operations GmbH
Priority date: 2002-10-26
Filing date: 2003-10-24
Publication date: 2005-07-20
Also published as: US20060035913A1; DE10249946B4; DE10249946A1; JP2006512305A; WO2004037795A1

Abstract

The invention relates to a method for producing 2-amino-4-chloro-6-alkoxypyrimidines by reacting 2-amino-4,6-dichloropyrimidine with an alkali alcoholate or a mixture of alkali hydroxides and an alcohol in a polar aprotic solvent (mixture), whereupon the solvent is distilled off to > 30 percent and the product is precipitated by adding water during or following the distillation process. The inventive method, in which especially acetone is used as a polar aprotic solvent and which can be carried out at temperatures between 5 and 60 DEG C, allows 2-amino-4-chloro-6-alkoxypyrimidines and above all 2-amino-4-chloro-6-methoxypyrimidine to be produced in a particularly economical and environmentally friendly manner while obtaining high yields and a very distinctive purity.

Description

Process for the preparation of 2-amino-4-chloro-6-alkoxypyrimidines

description

The present invention relates to a process for the preparation of 2-amino-4-chloro-6-alkoxypyrimidines.

2-Amino-4-chloro-6-methoxypyrimidine (ACMP) is an important intermediate in the synthesis of highly active herbicides and various active pharmaceutical ingredients. Most of the time, ACMP is reacted with sulfonyl isocyanates or sulfonyl carbamide acid phenyl esters and can therefore also be found in numerous sulfonyl urea herbicide derivatives (e.g. DE-PS 43 04 864,

EP-A 246 984, BR 8303322, CN 1277195, CN 1171197, DE-OS 197 07580, US 5,723,409, DE-PS 43 41 454, EP-A 464 838, US 4,699,647, EP-B 238 070, EP-B 232 067, US 4,656,273, EP-A 156 521, EP-A 161 905, DE-OS 31 51 450). ACMP is also used as an intermediate in active pharmaceutical ingredients; so z. B. in diabetes (cf. WO 01/36 416) or anti-cancer drugs (Zhenghou Daxue, Ziran Kexueban (2000), 32 (2), 87-88). The use of 2-amino-4-chloro-6-ethoxypyrimidine has been described, for example, in connection with the synthesis of herbicides (EP-A 101 308, JP 62111982, Huaxue Shiji (1999) 21 (2), 73-75) and 2 -Amino-4-chloro-6-n-propoxypyrimidine is, for example used as an intermediate in the synthesis of active pharmaceutical ingredients (J. Chem. Med. (1986 19 (5) 676-81).

Several processes for the preparation of 2-amino-4-chloro-6-methoxy-pyrimidine are already known from the literature. The industrially available 2-amino-4,6-dichloropyrimidine (ADCP) with sodium methylate (Rose et al., J. Chem. Soc, 1946, 81, 84) or methanol and sodium hydroxide or potassium hydroxide or else potassium carbonate in methanol is usually used implemented as a solvent (Kitani et al., Nippon Kagaku Zasshi, 74, 1953, 624). Indeed In the known reaction methods of ADCP in methanol or other solvents with methylate or with sodium or potassium hydroxide and methanol, between 4 and 6% by weight of the starting material remain in the product, which only have to be removed by complex purification steps such as recrystallization or distillation and which thus becomes a

Reduce yields. With the known methods, yields of only about 70% are achieved.

The reaction of 2-amino-4,6-dichloropyrimidine with sodium ethylate (J.Chem.Soα, 1946, 81, 84) or propylate (J. Med.

Chem, 29, 5, 1986, 676-681) or the reaction with

Potassium hydroxide and ethanol (Nippon Kagaku Zasshi, 74, 1953, 624; Chem.

Abstr. 1954, 13693) to the corresponding 2-amino-4-chloro-6-ethoxy or propoxypyrimidine. However, satisfactory yields are also not possible with these processes.

ACMP can also be prepared starting from the N-cyano-cyanoacetimido methyl ester by reaction with a hydrogen halide (cf. JP 01016770). However, the yield in this process is only 60%.

The reaction of 2,4-dichloro-6-methoxy-pyrimidine with ammonia is also known (Gabriel et al., Chem. Ber., 36, 1903, 3383). However, the problem here is the lack of selectivity of the reaction and the insufficient availability of the raw material.

It has been shown that 2-amino-4-chloro-6-alkoxypyrimidines and especially the ACMP cannot be produced in the required purity under economical conditions using the processes known hitherto. The object of the present invention was therefore to provide a process by which 2-amino-4-chloro-6-alkoxypyrimidines can be reacted with an alkali metal alcoholate or a Mixture of alkali metal hydroxides and an alcohol can be prepared without disturbing amounts of 2-amino-4,6-dichloropyrimidine remaining as a starting material in the product.

This object was achieved by the process according to the invention, in which the reaction takes place in a polar aprotic solvent or solvent mixture, the solvent or solvent mixture is then distilled off to> 30% and the product is precipitated by adding water during or after the distillation.

Surprisingly, it has been shown in the process according to the invention that 2-amino-4-chloro-6-alkoxypyrimidines from 2-amino-4,6-dichloropyrimidine in a purity of> 98% and with ADCP contents of <0.2% by weight. % are obtained in an economical and environmentally friendly manner, the desired products regularly being obtained in yields> 95%.

It has proven to be advantageous to use a C 1 -C 4 alcohol and very particularly preferably methanol as the obligatory alcohol component, whereby in particular the known ACMP is obtained.

According to the invention, the ADCP and the corresponding alkali alcoholate are used in a preferred molar ratio of 1: 1 to 1.5 and particularly preferably 1: 1.05 to 1.10.

The process according to the invention is carried out in a polar aprotic

Solvent (mixture) carried out, but it is by no means limited to special solvents within this framework. From the series of polar aprotic solvents, those have proven to be particularly suitable which are selected from the group of ketones, amides or nitriles and acetone, methyl ethyl ketone, dimethylimidazolidinone, cyclohexanone, dimethylformamide, N-methylpyrrolidone, acetonitrile and / or their are particularly preferred Mixtures used. Acetone can be regarded as a particularly preferred solvent due to its well-known low toxicity and the simple work-up of the mother liquor formed.

The reaction at temperatures between 5 and 60 ° C and particularly preferably between 15 and 40 ° C results in a particularly good selectivity of the process according to the invention.

The selectivity of the reaction necessary for the product is achieved above all by reaction at low temperatures below about 20 ° C. and a limitation of the alcoholate or the mixture of alkali metal hydroxide / alcohol. 2-Amino-4,6-dichloropyrimidine is generally initially introduced into the solvent and then the alcoholate, for example methylate, or the alkali metal hydroxide and the alcohol, for example methanol, are metered in.

For the subsequent reaction phase, the invention provides for the mixture to be heated to a higher temperature after the addition of the reactants, particularly preferably to temperatures between 20 and 60 ° C. and in particular to temperatures between 25 and 45 ° C. If necessary, the reaction can thus be completed after the addition and after-reaction time have ended.

Subsequently, in the process according to the invention,> 30% of the solvent is distilled off, it being considered preferable to distill off the solvent by more than about 50% and particularly preferably by about 75 to 95%. With this distillation step, not only is the solvent largely removed, but also, as a rule, excess alcohol is advantageously removed, which additionally improves the yield.

The distillate can be recycled without any problems, which advantageously means that the amount of waste generated in the process according to the invention is extremely low. The product is then precipitated according to the present invention by adding water. The water can be added in the form of several portions during the distillation or after the distillation step, which the invention also takes into account.

According to the invention, the procedure of adding in portions during the distillation is preferred, since more solvent can be distilled off in this way and higher yields can be achieved as a result.

The salt formed in the reaction can either be separated off, for example by filtration from the polar aprotic solvent (acetone) before adding water, and / or the salt can be dissolved in the mother liquor by adding water, which is preferred according to the invention. The product itself is usually isolated by filtration and then dried in vacuo after washing with water.

In addition, depending on the quality of the raw material 2-amino-4,6-dichloropyrimidine used, a cleaning step with activated carbon can be carried out according to the invention. The addition takes place after the reaction and preferably before and / or during the distillation and it is preferably additionally stirred for about another hour under the conditions of the after-reaction, that is to say for example at temperatures between 20 and 60 ° C. In this case, the activated carbon is then filtered off together with the salt even before the distillation, which advantageously means that all impurities from the raw material, in particular colored compounds or other disruptive by-products, e.g. B. 2-Amino-4-methoxy-6- ^(4, ^6, -dimethoxypyrimidin-2'-ylamino) pyrimidine, are almost completely separated. Through this activated carbon cleaning step a pure white product can be obtained, which further demonstrates its quality.

With the process according to the invention, 2-amino-4-chloro-6-alkoxypyrimidines and in particular the ACMP can be obtained in a particularly economical and environmentally friendly manner in high yields and with a very pronounced purity.

The present invention relates to a process for the preparation of 2-amino-4-chloro-6-alkoxypyrimidines by reacting the 2-amino-4,6-dichloropyrimidine with an alkali metal alcoholate or a mixture of alkali metal hydroxides and an alcohol, in which the reaction in a polar aprotic solvent (mixture) is carried out, then the solvent is distilled off to> 30% and the product is precipitated by adding water during or after the distillation. With this

Processes in which acetone, in particular, is used as the polar aprotic solvent and which can be carried out at temperatures between 5 and 60 ° C., can be 2-amino-4-chloro-6-alkoxypyrimidines and especially 2-amino-4-chlorine -6-Methoxypyrimidine in a particularly economical and environmentally friendly manner in high yields and at the same time very distinctive purity.

The following examples demonstrate these advantages of the method according to the invention.

Examples

Example 1 (Invention)

1,000 ml of acetone were placed in the reaction vessel and then 32.8 g of ADCP 97.6% (195 mmol) were introduced. The temperature of the suspension was set to 17 ° C. and then within approx. 37.44 g of sodium methylate solution 30% (0.208 mol) were added dropwise at 17 ° C. in the course of 3.5 hours. The mixture was stirred at this temperature for 1 hour and then heated to 30 ° C. for two hours. 0.8 g of activated carbon was added to the still warm suspension and stirred for about 1 hour. The activated carbon and the sodium chloride formed were then filtered off. 700 ml of acetone were distilled off from the filtrate in vacuo and the distillation residue was then mixed with 500 ml of water. After cooling to 7 ° C., the product was filtered off and washed once with 50 ml of water. After drying in vacuo at 50 ° C., 29.67 g of ACMP remained (yield 95.3%, purity 99.3% compared to the external standard via HPLC; residual content ADCP <0.2% by weight).

Example 2 (Invention)

1,000 ml of acetone were placed in the reaction vessel and then 32.8 g of ADCP 97.6% (195 mmol) were introduced. The temperature of the suspension was set to 17 ° C. and then 37.44 g of 30% strength sodium methylate solution (0.208 mol) were added dropwise at 17 ° C. in the course of 3.5 hours. The yellow suspension was stirred for a further 1 hour at this temperature and then heated to 30 ° C. for two hours. 500 ml of acetone were then distilled off from the suspension in vacuo up to 43 ° C., 600 ml of water were added in portions during the distillation and distillation was continued. After cooling to 7 ° C., the product was filtered off and washed twice with 50 ml of water. After drying, 30.09 g of ACMP remained (yield 96.7%, purity 99.8% compared to the external standard via HPLC; residual content ADCP <0.2% by weight). Example 3 (Invention)

250 ml of dimethyl formate were placed in the reaction vessel and then 41 g of ADCP 97.6% (244 mmol) were introduced. The temperature of the suspension was set to 17 ° C. and then 46.8 g of 30% strength sodium methylate solution (0.260 mol) were added dropwise at 17 ° C. in the course of 3.5 hours. The suspension was stirred for a further 1 hour at this temperature and then heated to 30 ° C. for two hours. Then 1 g of activated carbon was added to the batch and stirring was continued at 30 ° C. for 1 h. After the filtration, 500 ml of water was added to the filtrate and cooled to 7 ° C. The product was then filtered off and washed twice with 50 ml of water. After drying, 36.84 g of ACMP remained (yield 94.6%, purity 97.10% compared to the external standard via HPLC; residual content ADCP <0.2% by weight).

Example 4 (comparison)

500 ml of methanol were introduced and 82 g of ADCP and potassium carbonate were added at room temperature. The mixture was heated and refluxed for 2 hours, which made the reaction suspension less fluid. After cooling, 370 ml of methanol were distilled off and 250 ml of water were added to the residue. After stirring for 1 hour at room temperature, the product was filtered off and washed three times with 75 ml of water each time. After drying in vacuo, 75.82 g of product remained (95% of theory, ACMP content 93.5% according to HPLC, compared to the external standard; residual ADCP content 4.5% by weight). Example 5 (comparison)

500 ml of methanol and 82 g of ADCP were introduced and cooled to 17 ° C. 90 g (0.5 mol) of sodium methylate solution (30%) were then metered in over the course of 3.5 h, and the mixture was then heated and refluxed for 1 h to complete the reaction. After cooling, 495 ml of methanol were distilled off and 250 ml of water were added to the residue. After stirring for 1 hour at room temperature, the product was filtered off and washed three times with 75 ml of water each time. After drying in vacuo, 77.31 g of product remained (97% of theory; ACMP content 94.5% according to HPLC compared to the external standard; residual ADCP content 4.2% by weight).

Claims

Expectations

1. A process for the preparation of 2-amino-4-chloro-6-alkoxypyrimidines by reacting the 2-amino-4,6-dichloropyrimidine with an alkali metal alcoholate or a mixture of alkali metal hydroxides and an alcohol, characterized in that the reaction is carried out in a polar aprotic solvent or solvent mixture takes place, the solvent or solvent mixture is then distilled off to> 30% and the product is precipitated by adding water during or after the distillation.

2. The method according to claim 1, characterized in that a C 1 -C 4 alcohol, in particular methanol, is used as the alcohol component.

3. The method according to any one of claims 1 or 2, characterized in that the molar ratio of 2-amino-4,6-dichloropyrimidine and the alkali metal alcoholate is 1: 1 to 1.5, and particularly preferably 1: 1.05 to 1.10 ,

4. The method according to any one of claims 1 to 3, characterized in that the polar aprotic solvent is selected from the group consisting of ketones, amides or nitriles and in particular from the group consisting of acetone, methyl ethyl ketone, dimethylimidazolidinone, cyclohexanone, dimethylformamide, N- Methyl pyrrolidone, acetonitrile and mixtures thereof.

5. The method according to any one of claims 1 to 4, characterized in that the reaction takes place at temperatures between 5 and 60 ° C and particularly preferably between 15 and 40 ° C.

6. The method according to any one of claims 1 to 5, characterized in that the mixture is heated to a higher temperature after the addition of the reactants, particularly preferably to temperatures between 20 and 60 ° C and in particular between 25 and 45 ° C.

7. The method according to any one of claims 1 to 6, characterized in that more than 50% and particularly preferably 75 to 95% of the solvent is distilled off.

8. The method according to any one of claims 1 to 7, characterized in that activated carbon is added to the reaction mixture before or / and during the distillation.

9. The method according to any one of claims 1 to 8, characterized in that the salts formed are separated and / or brought into solution by adding water.