EP1194412A1

EP1194412A1 - Method for producing 4,6-dichloropyrimidine with acid chlorides

Info

Publication number: EP1194412A1
Application number: EP00938784A
Authority: EP
Inventors: Franz-Josef Mais; Günther Cramm; Alexander Klausener; Guido Steffan
Original assignee: Bayer AG
Current assignee: Bayer Chemicals AG
Priority date: 1999-06-26
Filing date: 2000-06-13
Publication date: 2002-04-10
Also published as: CA2377089A1; WO2001000592A1; DE19929350A1; US6441170B1; AU5404600A; JP2003503393A

Abstract

The inventive 4,6-dichloropyrimidine is advantageously obtained from 4-chloro-6-methoxypyrimidine by reacting the same with an acid chloride in the presence of a hydrogen halide.

Description

Process for the preparation of 4,6-dichloropyrimidine with acid chlorides

The present invention relates to a process for the preparation of 4,6-dichloropyrimidine from 4-chloro-6-methoxypyrimidine. 4,6-dichloropyrimidine is a valuable one

Intermediate product for the production of crop protection products.

A number of processes are known for the preparation of 4,6-dichloropyrimidine, see for example WO 96/23776, EP-A-697 406, EP-A-745 593, WO 95/29166, DE-A-19 53 129 and GB 2 325 224. However, these procedures always use

4,6-Dihydroxypyrimidine assumed.

It is also known (see Res. Discl. N 391, 690-691 (1996)) that 4,6-dichloropyrimidine is reacted with a chlorinating agent of the formula 3PCI ₂ by reacting 4-chloro-6-methoxypyrimidine can. The chlorinating agent can be used as such or can be prepared in situ from a compound of the formula RP ^ O and phosgene. It also describes that 4-chloro-6-methoxypyrimidine does not react with phosphorus oxychloride. A disadvantage of this process is that, as a rule, only a very incomplete conversion can be achieved and therefore 4,6-dichloropyrimidine can only be obtained in low yields and low degrees of purity.

A process for the preparation of 4,6-dichloropyrimidine has now been found, which is characterized in that 4-chloro-6-methoxypyrimidine is reacted with an acid chloride in the presence of a hydrogen halide.

Suitable acid chlorides are organic and inorganic acid chlorides, for example PC1 ₃ , POCl ₃ , PC1 ₅ , R-PC1 ₂ , R-PC1 ₄ , R-POCl ₂ and R ₃ PC1 ₂ , where R represents optionally substituted Cg-C _j o Aryl or optionally substituted C _r C ₁₀ alkyl, acid chlorides of the formula R'-CO-Cl with R '= chlorine,

C _r C ₁₀ alkoxy, C ₆ -C ₁₀ aryloxy, -OCCI3, -CO-Cl, C ₅ -C _π heteroaryloxy with 1 to 3 heteroatoms from the group N, O and S, where the alkoxy, aryloxy and hetaryloxy radicals may optionally be substituted, and SOCI ₂ .

It is also possible to generate the required acid chloride in situ. For example, R3PCI2 can be made from R3P and chlorine or from R3P = O and a chlorinating agent, e.g. Generate PCI3, Phosgene or SOCI2.

As hydrogen halides e.g. Question: hydrogen chloride, hydrogen bromide and hydrogen iodine. Hydrogen chloride is preferred. The use of mixtures of hydrogen halides is also possible.

Hydrogen chloride can e.g. used as such in gaseous form or generated in situ from an excess of acid chloride and a protic compound. A wide variety of protic compounds come into question which do not cause any undesirable side reactions in the reaction mixture. Examples include: water, alcohols and organic and inorganic acids.

Gaseous hydrogen chloride is preferably added or generated in situ. Gaseous hydrogen chloride is particularly preferably used.

At least 1 mole of acid chloride per mole of 4-chloro-6-methoxypyrimidine is preferably used in the process according to the invention. It is preferred to use 1.1 to 20 mol, particularly preferably 1.5 to 10 mol, of acid chloride per mol of 4-chloro-6-methoxypyrimidine. If the acid chloride is also used as a solvent or as a starting substance for the in-situ generation of hydrogen halide, the preferred minimum amount of the acid chloride is of course correspondingly higher.

Furthermore, at least 1 mole of hydrogen halide is used per mole of 4-chloro-6-methoxypyrimidine. However, an excess of hydrogen halide is recommended to achieve a high turnover. It is preferred to use 1.1 to 25 moles of hydrogen halide, particularly preferably 2 to 10 moles of hydrogen halide, per mole of 4-chloro-6-methoxypyrimidine.

If you want to generate the above-mentioned amounts of hydrogen halide in situ from a protic compound and an acid chloride, the protic

The compound is used in amounts such that it produces the above-mentioned amounts of hydrogen halide, i.e. for example, to produce 1 mole of hydrogen chloride, e.g. 0.5 mol of water or 1.0 mol of methanol are used. In this case, it is also preferred to use additional amounts of acid chlorides, which are equivalent to the amounts of hydrogen chloride to be produced, for example to produce 1 mol of hydrogen chloride, additionally 0.33 mol of phosphorus oxychloride or additionally 0.5 mol of thionyl chloride.

If one works with an acid chloride which is liquid under the reaction conditions, the addition of a solvent can be dispensed with. In principle, solvents are suitable which do not negatively influence the reaction to be carried out. Examples of solvents are aliphatic solvents such as alkanes, cycloalkanes and haloalkanes, aromatic solvents such as benzene, toluene, xylenes, chlorobenzene, chlorotoluenes, dichlorobenzenes, benzotrifluoride and p-chlorobenzotrifluoride, where the aliphatic and aromatic solvents can optionally be further substituted, nitriles such as Acetonitrile and benzonitrile, N-containing solvents such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone and cyclic ureas and ethers and polyethers of all kinds.

The process of the invention can be used, for example, at temperatures in the. Carry out range 0 to 200 ° C, preferably at 20 to 175 ° C, particularly preferably at 30 to 150 ° C. The pressure is not critical. One can, for example, work at 0.1 to 50 bar, preferably at 0.5 to 5 bar. Working at normal pressure is particularly preferred. It is possible to use known catalysts from the field of chemical reactions with acid chlorides, for example amides such as dimethylformamide, amines such as pyridine, morpholine or 1,8-diazobicyclo [5.4.0] -undec-7-ene (= DBU) or phosphorus compounds such as Use triphenylphosphine or triphenylphosphine oxide. Such catalysts can, for example, in amounts of 0.1 to

10 mol%, based on the 4-chloro-6-methoxypyrimidine used. It is preferable to work without additions of catalyst.

The process according to the invention can be carried out in a wide variety of embodiments, for example batchwise, semi-continuously, continuously or batchwise in batches (for the latter see DE-A 195 31 299).

For example, 4-chloro-6-methoxypyrimidine can be introduced in solid or molten form, acid chloride and, if appropriate, solvent added, and either hydrogen halide introduced or a protic compound metered in at the desired reaction temperature. After the reaction has ended, the reaction mixture can be worked up in a manner known per se, for example

a) by watering down the reaction mixture and removing the 4,6-dichloropyrimidine,

b) by distillation of the entire reaction mixture,

c) by first re-chlorination of the used acid chloride with, for example, PCI3 / CI ₂ or PCI5 and subsequent distillation and

d) by direct extraction of the 4,6-dichloropyrimidine from the reaction mixture with a suitable solvent and subsequent distillation of the extract. A discontinuous operation in batches can be selected for the re-chlorination according to c). This can be done, for example, by adding 4-chloro-6-methoxypyrimidine and, for example, phosphorus oxychloride, heating to the reaction temperature, introducing hydrogen chloride gas, after a partial conversion, for example 25 to 60 mol%, the corresponding amount of PCI3 or a slight excess

(e.g. from 5 to 10 mol%) and introduces the corresponding amount of chlorine. Then the introduction of hydrogen chloride is continued, possibly interrupted again and again chlorinated with the amount corresponding to the conversion or a slight excess of PCI3 and chlorine. In carrying out the process according to the invention in this way, the reaction mixture contains after the

Conversion and a final re-chlorination with PCI ₃ / CI2 4,6-dichloropyrimidine only minor residues (generally less than 2 mol%) of 4-chloro-6-methoxypyrimidine, phosphorus oxychloride, PCI3 and hydrogen chloride. This mixture can be worked up simply by distillation. With this procedure it is possible, for example, to place the entire PCI3 at the beginning of the hydrogen chloride

Initiation or add to the first re-chlorination.

The process according to the invention represents a fundamentally new method for the production of 4,6-dichloropyrimidine. In contrast to the known literature, simple acid chlorides such as phosphorus oxychloride react directly with 4-chloro-6-methoxypyrimidine to give 4,6-dichloropyrimidine when in the presence of Hydrogen halide works.

The process according to the invention can be carried out technically without difficulty. The reaction of acid chlorides, in the simplest case phosphorus oxychloride, with 4-chloro-6-methoxypyrimidine to form 4,6-dichloropyrimidine is only possible by introducing a hydrogen halide, in the simplest case hydrogen chloride, or metering in a protic compound, in the simplest case water , When using liquid acid chlorides, you can work without solvents, which greatly simplifies the subsequent work-up. The method according to the invention also represents a significant advance about the in Res. Discl. The above-mentioned prior art is shown. The two examples given there show that there was only an incomplete conversion of 4-chloro-6-methoxypyrimidine into 4,6-dichloropyrimidine. This is particularly disadvantageous because 4,6-dichloropyrimidine and 4-chloro-6-methoxypyrimidine are very difficult to separate by distillation. Under the conditions according to the invention, in particular in the presence of hydrogen halide, the conversion occurs much faster and completely or almost completely.

Examples

example 1

90 parts by weight of phosphorus oxychloride and 10 parts by weight were placed in a stirred vessel

4-Chloro-6-methoxypyrimidine submitted. The mixture was heated to 100 ° C. with stirring and, at this temperature, 6 parts by weight of water were metered in uniformly rapidly over the course of 4 hours. The mixture was then stirred at 100 ° C. for 1 hour. After cooling to room temperature, 99.6 parts by weight of a reaction mixture were obtained, the HP LC analysis of which contained 4-chloro-6-methoxypyrimidine of 0.2% and 4,6-dichloropyrimidine of 9.3 parts by weight revealed. This corresponds to a yield of 4,6-dichloropyrimidine of 89.8% of theory.

Example 2

80 parts by weight of phosphorus oxychloride and 20 parts by weight of 4-chloro-6-methoxypyrimidine were placed in a stirred vessel. The mixture was heated to 80 ° C. with stirring. Thereafter, hydrogen chloride gas was introduced at a rate of 12 parts by weight per hour. After 20 hours, the introduction was stopped, cooled to room temperature and weighed out. 93.5 parts by weight of reaction mixture were obtained.

HPLC analysis showed 0.46% by weight of 4-chloro-6-methoxypyrimidine and 20.7% by weight of 4,6-dichloropyrimidine. This corresponds to a yield of 4,6-dichloropyrimidine of 93.8% of theory.

Example 3

80 parts by weight of phosphorus oxychloride, 20 parts by weight of 4-chloro-6-methoxypyrimidine and 2 parts by weight of N, N-dimethylformamide were stirred at 80.degree. 25 parts by weight of hydrogen chloride gas were introduced into this mixture at a uniform rate over the course of 6 hours. After cooling to room temperature, a reaction mixture was obtained in an amount of 87.2 parts by weight. The HPLC Analysis showed 0.17% by weight of 4-chloro-6-methoxypyrimidine and 23.3% by weight of 4,6-dichloropyrimidine, corresponding to a yield of 4,6-dichloropyrimidine of 98.4% of theory.

The reaction mixture was then extracted 6 times with 80 parts by weight of methylcyclohexane at 55 ° C. The combined extracts were spun in and thus 23.0 parts by weight of colorless crystal needles were obtained, which consisted of 4,6-dichloropyrimidine with an HPLC content of 96.9%.

Example 4

100 parts by weight of o-dichlorobenzene, 10 parts by weight of 4-chloro-6-methoxypyrimidine and 30 parts by weight of triphenyldichlorophosphorane were placed in a stirred vessel, heated to 100 ° C. and stirred. Then 20 parts by weight of hydrogen chloride gas were blown in uniformly quickly over the course of 4 hours. After that was on

Cooled at room temperature. This gave 141.0 parts by weight of the reaction mixture. Its HPLC analysis showed contents of 0.04% of 4-chloro-6-methoxypyrimidine and 7.02% of 4,6-dichloropyrimidine. This corresponds to a yield of 4,6-dichloropyrimidine of 96% of theory.

Example 5

100 parts by weight of o-dichlorobenzene, 2 parts by weight of triphenylphosphine oxide and 10 parts by weight of 4-chloro-6-methoxypyrimidine were placed in a stirred vessel. The mixture was then heated to 130 ° C. and 10 parts by weight of hydrogen chloride gas and 18 parts by weight of phosgene were blown in at a uniformly rapid rate over the course of 4 hours. It was then cooled to room temperature. This gave 108.5 parts by weight of the reaction mixture. Its HPLC analysis showed contents of 4-chloro-6-methoxypyrimidine of 0.08% and of 4,6-dichloφyrimidine of 9.37%. This corresponds to a yield of 4,6-dichloφyrimidine of 98.6%

Theory. Example 6

110 parts by weight of chlorobenzene, 46 parts by weight of phosphorus pentachloride and 28.9 parts by weight of 4-chloro-6-methoxypyrimidine were placed in a stirred vessel. The mixture was stirred at 100 ° C. and 20 parts by weight of hydrogen chloride gas were passed in uniformly over a period of 8 hours. The mixture was then cooled to room temperature, giving 175 parts by weight of the reaction mixture. Its HPLC analysis showed 0.15% 4-chloro-6-methoxypyrimidine and 16.55% 4,6-dichloφyrimidine. This corresponds to a yield of 4,6-dichloropyrimidine of 97.2% of theory.

Example 7

100 parts by weight of thionyl chloride, 30 parts by weight of phosphine oxide and 28.9 parts by weight of 4-chloro-6-methoxypyrimidine were placed in a stirred vessel. The mixture was then heated to 80 ° C. with stirring. At this temperature, 25 parts by weight of hydrogen chloride gas were passed in uniformly over a period of 4 hours. after cooling to room temperature, 130 parts by weight of a reaction mixture were obtained. Its HPLC analysis showed 0.30% 4-chloro-6-methoxypyrimidine and 22.61% 4,6-dichloropyrimidine, which is a yield of 4,6-dichloropyrimidine from

98.6% of theory.

Example 8

80 parts by weight of phosphorus oxychloride and 20 parts by weight were placed in a stirred vessel

4-Chloro-6-methoxypyrimidine submitted. The mixture was heated with stirring. to 80 ° C. and introduced 8 parts by weight of hydrogen chloride gas with stirring at a uniform rate over the course of 5 hours. Then 7.5 parts by weight of phosphorus trichloride were added and 3.3 parts by weight of chlorine were blown in at 80 ° C. in the course of 30 minutes. Now 8 parts by weight of hydrogen chloride gas were again in the course of 3

Initiated hours and then again 7.5 parts by weight of phosphorus trichloride added and 3.3 parts by weight of chlorine were added at 80 ° C over 30 minutes. Now, for the third time, 8 parts by weight of hydrogen chloride were introduced over the course of 3 hours, after which 7.5 parts by weight of phosphorus trichloride were again added, and another 3.3 parts by weight of chlorine were added at 80 ° C. over the course of 30 minutes. Then phosphorus oxychloride and residues of phosphorus trichloride were added

Distilled off normal pressure from the reaction mixture. This gave 99.2 parts by weight of a colorless distillate. The remaining residue of 24.0 parts by weight was distilled under vacuum (at 50 mbar). This gave 18.6 parts by weight of a colorless distillate consisting of 4,6-dichloφyrimidine. This corresponds to a yield of 90.2% of theory. The HPLC content was 99.8%. 4-chloro-6-methoxypyrimidine was no longer contained. The distillation residue was 5.1 parts by weight. According to a yield of 2.9% of theory, it contained a further 4,6-dichloropyrimidine.

Example 9

100 parts by weight of chlorobenzene, 28 parts by weight of 4-chloro-6-methoxypyrimidine and 10 parts by weight of dimethylformamide were placed in a stirred vessel. The mixture was heated to 100 ° C. with stirring and then 50 parts by weight of phosgene and 25 parts by weight of hydrogen chloride were passed in simultaneously over the course of 10 hours, and both were introduced uniformly rapidly. Then it was cooled to room temperature. 135.6 parts by weight of reaction mixture were thus obtained. Its HPLC analysis showed a content of 4,6-dichloφyrimidine of 18.7%, which corresponds to a yield of 85.1% of theory.

Claims

Patentansprttche

1. A process for the preparation of 4,6-dichloφyrimidine, characterized in that 4-chloro-6-methoxypyrimidine is reacted with an acid chloride in the presence of a hydrogen halide.

2. The method according to claim 1, characterized in that the acid chloride PC1 ₃ , POCI3, PC1 ₅ , R-PC1 ₂ , R-PCI ₄ , R-POCl ₂ and R ₃ PC1 ₂ , where R for optionally substituted Cg-Cio Aryl or optionally substituted C _r C ₁₀ alkyl, acid chlorides of the formula R'-CO-Cl with R '=

Chlorine, C _r C ₁₀ - alkoxy, C ₆ -C ₁₀ - aryloxy, -OCCl ₃ , -CO-Cl, C ₅ -C _{ι r} hetero-aryloxy with 1 to 3 heteroatoms from the group N, O and S, where the alkoxy, aryloxy and hetaryloxy radicals can optionally be substituted and SOCI _{2 is} used.

3. Process according to claims 1 and 2, characterized in that hydrogen chloride is used.

4. The method according to claim 3, characterized in that the chlorine-hydrogen is generated in situ from excess acid chloride and a protic compound.

5. Process according to Claims 1 to 4, characterized in that at least 1 mol of acid chloride and at least 1 mol of hydrogen halide are used per mol of 4-chloro-6-methoxypyrimidine.

6. Process according to Claims 1 to 5, characterized in that it is carried out at temperatures in the range from 0 to 200 ° C and pressures in the range from 0.1 to 50 bar.