Process for preparation of pyrazole carboxylic acid amides

Abstract

The invention relates to a method for separating a solution mixture, characterized in that the solution mixture comprises a base, an organic solvent, water and a compound of formula (I), comprising distilling the solution mixture wherein a phase separator is present downstream of the distillation.

Description

[0001] The present invention relates to a process for the preparation of a pyrazole carboxylic acid amide, in particular 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (9-dichloromethylene-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-yl)-amide, more particularly to a process for the isolation of a solution mixture originating from its preparation.

[0002] The compound 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (9-dichloromethylene-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-yl)-amide and its microbiocidal properties are described, for example, in WO 2007 / 048556.

[0003] The preparation of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (9-dichloromethylene-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-yl)-amide is known from WO 2007 / 048556.

[0004] The compound can be prepared according to schemes 1 and 4 by a) reacting a compound of formula A

[0005] with a compound of formula B

[0006] in the presence of an alkyl nitrite, to a compound of formula C

[0007]

[0008] b) hydrogenating the compound of formula C in the presence of a suitable metal catalyst to a compound of formula D

[0009]

[0010] c) ozone treatment of the compound of formula D and subsequent treatment with a reducing agent to a compound of formula E

[0011]

[0012] d) reacting the compound of formula E in the presence of triphenylphosphane / tetrachloromethane to 2,9-dichloromethylene-5-nitro-benzonorbornadiene of formula F

[0013]

[0014] e) hydrogenating the compound of formula F in the presence of a metal catalyst to 2,9-dichloromethylene-5-amino-benzonorbornadiene of formula G

[0015]

[0016] f) and reacting the compound of formula G with a compound of formula H

[0017]

[0018] to 3-difluoromethyl-l-methyl-lH-pyrazole-4-carboxylic acid (9- dichloromethylene- 1,2,3,4-tetrahydro- 1,4-methano-naphthalen-5-yl)-amide.

[0019] More precisely, in the above described process for preparing 3-difluoromethyl-l- methyl-lH-pyrazole-4-carboxylic acid (9-dichloromethylene-l,2,3,4-tetrahydro-l,4- methano-naphthalen-5-yl)-amide (compound of formula (I)), xylene is used as solvent for the reaction, followed by crystallization. In order to recycle xylene, the solution has to be purified by removing water and triethylamine (TEA). As a result, there is a loss of part of the xylene during distillation.

[0020] For cost and environmental reasons, such losses should be reduced as low as possible. It is therefore an object of the present application to provide a novel process for improving the recovery of such organic solvents.

[0021] According to the present application, there is therefore provided a process for separating a solution mixture, characterized in that the solution mixture comprises a base, an organic solvent, water and a compound of formula (I)

[0022]

[0023] The process comprises distilling the solution mixture, wherein a phase separator is present downstream of the distillation.

[0024] According to a preferred embodiment of the present application, the base is triethylamine, pyridine, 2,6-dimethylpyridine, NaOH, KOH, sodium acetate, potassium carbonate, sodium carbonate, sodium bicarbonate, or potassium bicarbonate.

[0025] According to a preferred embodiment of the present application, the organic solvent is tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethyl ether, tert-butyl methyl ether, methyl ethyl ketone, ethyl acetate, methyl acetate, an aromatic hydrocarbon, or an aliphatic hydrocarbon.

[0026] According to a preferred embodiment of the present application, the organic solvent is an aromatic or aliphatic hydrocarbon.

[0027] According to a preferred embodiment of the present application, the organic solvent is toluene, xylene, benzene, hexane, pentane or petroleum ether.

[0028] According to a preferred embodiment of the present application, there is at least one condenser, preferably two condensers, downstream of the distillation.

[0029] According to a preferred embodiment of the present application, there are two condensers downstream of the distillation.

[0030] According to a preferred embodiment of the present application, the phase separator is located downstream of the condensers.

[0031] According to a preferred embodiment of the present application, the recovery of the organic solvent is increased by at least 15%, preferably at least 18%, more preferably at least 20% and most preferably at least 25% compared to the case where no phase separator is used.

[0032] According to a preferred embodiment of the present application, the distillation is operated in batch mode.

[0033] According to a preferred embodiment of the present application, the content of the organic solvent in the solution mixture is from 65 to 75 wt%, preferably from 67 to 73 wt%, more preferably from 69 to 71 wt% relative to the total weight of the solution mixture.

[0034] According to a preferred embodiment of the present application, the content of the compound of formula (I) in the solution mixture is from 15 to 25 wt%, preferably from 17 to 23 wt%, more preferably from 19 to 21 wt% relative to the total weight of the solution mixture.

[0035] According to a preferred embodiment of the present application, the content of the base in the solution mixture is from 3 to 7.5 wt%, preferably from 3.5 to 7.3 wt%, more preferably from 3.9 to 7.1 wt% relative to the total weight of the solution mixture.

[0036] According to a preferred embodiment of the present application, the content of the water in the solution mixture is from 0.3 to 4.5 wt%, preferably from 0.4 to 4.3 wt%, more preferably from 0.5 to 3.8 wt% relative to the total weight of the solution mixture. BRIEF DESCRIPTION OF DRAWINGS

[0037] Figure 1 is a general flow chart for the production of a compound of formula (I).

[0038] Figure 2 is a prior art method for the production of a compound of formula (I) without using a phase separator.

[0039] Figure 3 is the method of the present application for the production of a compound of formula (I) by using a phase separator.

[0040] Preferred embodiments

[0041] As Figure 1 indicated in the introduction, the desired compound is produced by a series of reactions involving the use of an organic solvent, a base and water. After the reaction, a solution mixture will be present comprising the base, the organic solvent, water and the compound of formula (I) (identified in the Figure 1 introduction as "product"). The volatile components, such as for example the base and / or the organic solvent, will be separated from the solution mixture by distillation. And the desired compound will be recovered by crystallization, filtration, drying and storage.

[0042] The distillation for separating such volatile components will preferably be operated in batch mode, as Figure 2 and Figure 3 indicated. Figure 2 The main difference between the Figure 3 and the present application is the use of a phase separator after the distillation operation.

[0043] Such distillation can be performed in continuous, semi-continuous or batch, preferably batch mode. In case of batch distillation, two product streams are obtained, first a mixture of the organic solvent (such as xylene) and the base (such as triethylamine) having a water content of less than 0.05 wt.%, and then a product stream consisting mainly of the organic solvent (such as xylene).

[0044] Generally, the operating conditions of the distillation will be such that the separation of the base, the organic solvent and water is facilitated, in particular the distillation is operated under vacuum conditions such as 200 to 400 mbar, preferably 250 to 350 mbar (absolute pressure). The reflux ratio of the distillation will be 1 to 5.

[0045] The function of the phase separator is mainly to separate water from the organic phase.

[0046] The resulting mixture recovered from the distillation can be recycled to the specific step for producing the compound of formula (I).

[0047] Preparation example:

[0048] Example 1 (comparative)

[0049] In the distillation unit Figure 2 , there are two fractions

[0050] 1. 1000 kg of a first fraction in receiver 1 as organic waste, which contains TEA (196 kg), xylene (706 kg) and 98 kg of water.

[0051] 2. About 1255 kg of high purity xylene (TEA content <= 0.3 wt.%, water content <= 0.05 wt.%) in receiver 2 and recycled back into the process as second fraction.

[0052] There is a substantial loss of solvent in the first fraction.

[0053] Example 2 (present invention)

[0054] In the improved distillation unit ( Figure 3 ) After that, a new phase separator was implemented in the system, which could remove most of the water during distillation. As a result, more xylenes and TEA were recovered in the second fraction with a water content of <= 0.05 wt.%.

[0055] The new distillation method has been implemented in the factory

[0056] 1. Most of the water (78 kg) was removed via a phase separator to receiver 1 (the same vessel used for the first fraction).

[0057] 2.647 kg of the first fraction, which contained TEA (176 kg), xylene (373 kg) and 20 kg of water, was placed in receiver 1 as organic waste.

[0058] 3. About 1608 kg of a mixture of xylene and TEA (water content <= 0.05 wt.%)

[0059] As a second fraction, it is present in receiver 2 and is recycled back into the process.

[0060] The recovery of organic solvents was improved by up to 28%.

Claims

1. A method for separating a mixture of solutions, characterized in that, The solution mixture comprises a base, an organic solvent, water and a compound of formula (I) The method comprises subjecting the solution mixture to a distillation, wherein a phase separator is present downstream of the distillation.

2. The method of claim 1, wherein, The base is triethylamine, pyridine, 2,6-lutidine, NaOH, KOH, sodium acetate, potassium carbonate, sodium carbonate, sodium bicarbonate, or potassium bicarbonate.

3. The method of the method according to any of the preceding claims, characterized in that, The organic solvent is tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethyl ether, tert-butyl methyl ether, methyl ethyl ketone, ethyl acetate, methyl acetate, an aromatic hydrocarbon, or an aliphatic hydrocarbon.

4. The method of the method according to any of the preceding claims, characterized in that, The organic solvent is an aromatic or aliphatic hydrocarbon.

5. The method of the method according to any of the preceding claims, characterized in that, The organic solvent is toluene, xylene, benzene, hexane, pentane or petroleum ether.

6. The method of the method of any of the preceding claims, characterized in that, At least one condenser, preferably two condensers, are present downstream of the distillation.

7. The method of the method of any of the preceding claims, characterized in that, Two condensers are present downstream of the distillation.

8. The method of the method of claim 6 or 7, characterized in that, The phase separator is located downstream of the condensers.

9. The method of the method of any of the preceding claims, characterized by, The recovery of the organic solvent is increased by at least 15%, preferably at least 18%, more preferably at least 20% and most preferably at least 25% compared to the case where the phase separator is not used.

10. The method of the method of any of the preceding claims, characterized by, The distillation is operated in batch mode.

11. The method of the method of any of the preceding claims, characterized by, The content of the organic solvent in the solution mixture is 65 to 75 wt%, preferably 67 to 73 wt%, more preferably 69 to 71 wt% relative to the total weight of the solution mixture.

12. The method of the method of any of the preceding claims, characterized in that, The content of the compound of formula (I) in the solution mixture is 15 to 25 wt%, preferably 17 to 23 wt%, more preferably 19 to 21 wt% relative to the total weight of the solution mixture.

13. The method of the method of any of the preceding claims, characterized by, The content of the base in the solution mixture is 3 to 7.5 wt%, preferably 3.5 to 7.3 wt%, more preferably 3.9 to 7.1 wt% relative to the total weight of the solution mixture.

14. The method of the method of any of the preceding claims, characterized by, The content of water in the solution mixture is 0.3 to 4.5 wt%, preferably 0.4 to 4.3 wt%, more preferably 0.5 to 3.8 wt% relative to the total weight of the solution mixture.

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