TW201835036A - Method for preparation of 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol - Google Patents

Abstract

The invention discloses a method for the preparation of 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol with high selectivity with respect to the content of the isomer 1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-ol, wherein ethyl 4,4,4-trifluoroacetoacetate is reacted with methyl hydrazine in the presence of 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol: ethyl 4,4,4-trifluoroacetoacetate and methyl hydrazine are brought into contact in the presence of 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol and are reacted in the presence of 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol.

Description

Method for preparing 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol

The invention relates to a method for preparing 1-methyl-3-(trifluoromethyl) with high selectivity relative to the content of the isomer 1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-ol. a method of -1H-pyrazole-5-ol, wherein ethyl 4,4,4-trifluoroacetate and methylhydrazine are in 1-methyl-3-(trifluoromethyl)-1H-pyrazole Reaction in the presence of -5-alcohol: 4,4,4-trifluoroacetic acid ethyl acetate and methyl hydrazine in the presence of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol The next contact is carried out and the reaction is carried out in the presence of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol.

If not stated otherwise, the following abbreviations are used:

ETFAA 4,4,4-trifluoroacetic acid ethyl acetate, a compound of formula (3);

3-MTP 1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-ol, a compound of formula (2), isomer;

5-MTP 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol, a compound of formula (1).

5-MTP can be used as an intermediate in the production of pharmaceuticals and agricultural chemicals such as herbicides such as pyroxasulfone.

Lee et al, J. Heterocyclic Chem. 1990, 27, 243-245 discloses a process for the preparation of 5-MTP: methyl hydrazine is added to a mixture of ETFAA and water at room temperature. After the reaction subsided, the mixture was kept at reflux for 2 hours. The yield was 24.2 g (49%) 5-MTP and 4.2 g (8%) 3-MTP with a selectivity of 6:1.

EP 1 767 528 A1 and EP 1990 336 A1 each disclose the same process of preparing 5-MTP by dissolving ETFAA in 2 equivalents of acetic acid, adding methylhydrazine aqueous solution at 10 ° C for 1 hour, and then applying the solution at room temperature. It was stirred for 1 hour and then stirred at 80 ° C for 5 hours. The yield was 86.5%. The repetition of Reference Example 1 shows that the selectivity as described in Comparative Example 1 of the present invention is 96:4.

Dai et al, J. Agric. Food Chem. 2008, 56, 10805-10810 on page 10806, in the last paragraph at the bottom of the right column, discloses 1-methyl-5-hydroxy-3-(trifluoromethyl)pyridinium. Synthesis of azole (6). For the repetition of this example, see Comparative Example 2 herein, which shows the low yield of 5-MTP in the crude product and the high ratio of 5-MTP:3-MTP.

The preparation of 2-methyl-5-trifluoromethyl-2H-pyrazol-3-ol is disclosed in paragraph [577] of US 2011 / 0071150 A1. For the repetition of this example, see Comparative Example 1 herein, which shows the low yield of 5-MTP in the crude product and the high ratio of 5-MTP:3-MTP.

There is a need for a process for the preparation of 5-MTP which provides 5-MTP with higher yields and higher selectivity than is known in the art and does not require the use of stoichiometric or even higher amounts of acetic acid. Better filtration and washing behavior are also desired. This method also does not require the addition of a solvent.

Unexpectedly, by reacting ETFAA with methyl hydrazine in the presence of 5-MTP already present, and from the beginning of the reaction, selectivity can be improved and the yield is high. It is not necessary to use stoichiometric or even higher amounts of acetic acid, so the cost of this method is significantly lower compared to the method disclosed in Reference Example 1 of EP 1 767 528 A1 and EP 1 990 336 A1, respectively.

5-MTP is obtained in the form of a large crystal which allows for rapid and efficient filtration and washing, in addition to crystals having a sheet-like shape, wherein the prior art provides needle crystals. This improvement leads to better filtration and washing behavior.

The subject of the invention is a process for the preparation of a compound of formula (1);

The method includes step ST1;

ST1 comprises the reaction REAC1 of the compound of formula (3) with methylhydrazine;

among them,

REAC1 is carried out in the presence of a compound of formula (1);

The compound of the formula (3) and methylhydrazine are contacted in the presence of the compound of the formula (1) and reacted in the presence of the compound of the formula (1).

The compound of the formula (1), the compound of the formula (2) and the compound of the formula (3) may take various tautomeric forms depending on, for example, a solvent or a pH, and thus their structural formulas include any respective tautomeric forms.

Preferably, the compound of formula (1) is at least 0.1 times, more preferably at least 0.5 times, even more preferably at least 0.75 times, especially at least 1 time, more particularly at least 2 times, even more, the molar amount of the compound of formula (3) In particular, at least 3 times, in particular at least 3.5 times, the amount of moles is present.

Preferably, methyl hydrazine is used as an aqueous solution; more preferably methyl hydrazine is used in an aqueous solution of 30 to 50% (w/w), and even more preferably 35 to 45% (w/w).

Preferably, the molar amount of methyl hydrazine is from 0.9 to 1.5 times, more preferably from 0.95 to 1.25 times, even more preferably from 0.98 to 1.15 times the molar amount of the compound of formula (3).

The purpose of using substoichiometric amounts of methyl hydrazine is to avoid residual highly toxic methyl hydrazine in the final product and any waste stream.

REAC1 can be carried out in the presence of acid ACID1. ACID1 is preferably used as a catalyst in REAC1. The compound of formula (3) and methylhydrazine can be contacted in the presence of acid ACID1 and can be reacted in the presence of ACID1.

Preferably, ACID1 is selected from the group consisting of sulfuric acid, acetic acid, trifluoroacetic acid, H ₃ PO ₄ , methanesulfonic acid, formic acid, polymeric sulfonic acid resins, and mixtures thereof; more preferably, ACID 1 is selected from the group consisting of sulfuric acid, acetic acid, trifluoroacetic acid, H ₃ PO ₄ , methanesulfonic acid, polymeric sulfonic acid resin and mixtures thereof; even more preferably, ACID 1 is selected from the group consisting of sulfuric acid, acetic acid, trifluoroacetic acid, polymeric sulfonic acid resins, and mixtures thereof.

The polymeric sulfonic acid resin is preferably an acidic cation exchange resin, more preferably a strongly acidic cation exchange resin, for example, for heterogeneous acid catalysis.

Preferably, the polymeric sulfonic acid resin has an average molecular weight of from 1000 to 1,000,000 D; and/or preferably from 1 to 15, more preferably from 1 to 11.6, even more preferably from 1 to 10, especially from 1 to 8, more particularly 1 per kg of resin. Up to 7 equivalents of acid sites concentration; and/or preferably 1 to 650, more preferably 1 to 560, even more preferably 1 to 450, especially 1 to 350, more particularly 50 to 650, even more particularly An acid value of from 1 to 560, particularly from 50 to 450, more particularly from 50 to 350; and/or preferably from 4 to 800 mesh, more preferably from 4 to 400 mesh.

The concentration of the acid center is determined by Master Test Method MTM 0232, Edition 1.4, © Rohm and Haas Company, 1998, wherein the catalyst volatility is determined by Master Test Method MTM 0126, Edition 1.6, ©Rohm and Haas Company, 2000.

The acid number is determined according to DIN EN ISO 3682. Further explanation of the acid value and its relationship with the acid center concentration can be found in "BASF Handbuch Lackiertechnik", Artur Goldschmidt and Hans-Joachim Streitberger, Vincentz Verlag, 2002, ISBN 3-87870-324-4, chapter 2.3.2.2 (Chapter 272). To 273 pages). According to the teachings therein, an acid center concentration of 1 equivalent per kilogram is equal to an acid value of 56, so an acid center concentration of 4.7 equivalents per kilogram is equal to an acid value of 263.

In particular, the polymeric sulfonic acid resin is selected from the group consisting of sulfonated polystyrene resins, sulfonated polystyrene resins crosslinked with divinylbenzene, and poly(2-propenylamino-2-methyl-1-propanesulfonic acid) .

The sulfonated polystyrene resin crosslinked with divinylbenzene is also known as a divinylbenzene-styrenesulfonic acid copolymer.

An example of a polymer sulfonic acid resin is Amberlyst® 15 DRY.

Preferably, the molar amount of any ACID1 used in the process is from 0.001 to 0.25 times, more preferably from 0.005 to 0.2 times, even more preferably from 0.005 to 0.15 times, especially 0.005, of the molar amount of the compound of formula (3). To 0.125 times, more specifically 0.01 to 0.125 times, even more particularly 0.05 to 0.125 times.

In another preferred embodiment, the molar amount of any ACID1 used in the method is from 0.001 to 0.25 times, more preferably from 0.005 to 0.25 times, even more preferably from 0.01 to 0.25 times the molar amount of the compound of formula (3). In particular, it is from 0.01 to 0.2 times, more particularly from 0.05 to 0.2 times, even more particularly from 0.05 to 0.15 times, especially from 0.05 to 0.125 times.

Preferably, the amount of acetic acid in the REAC1 is not more than 1 equivalent, more preferably not more than 0.5 equivalent, even more preferably not more than 0.25 equivalent, especially not more than 0.2 equivalent, more particularly not more than 0.15 equivalent, even more specifically not more than 0.125 equivalent, based on The molar amount of the compound of formula (3) is calculated; more preferably, ACID1 is not more than 1 equivalent in REAC1, more preferably not more than 0.5 equivalent, even more preferably not more than 0.25 equivalent, especially not more than 0.2 equivalent, more particularly not exceeding 0.15 equivalents, even more specifically no more than 0.125 equivalents, based on the molar amount of the compound of formula (3).

In a preferred embodiment, ACID1 is not added to REAC1.

In a more preferred embodiment, no acid is added to REAC1.

In a preferred embodiment, REAC1 is performed in the absence of ACID1.

In a more preferred embodiment, REAC1 is carried out in the absence of an acid.

Preferably, the compound of formula (3) and methylhydrazine are contacted in the presence of a compound of formula (1) and reacted in the presence of a compound of formula (1).

Preferably, the reaction temperature TEMP1REAC in REAC1 is at least 40 ° C, more preferably at least 50 ° C, even more preferably at least 60 ° C, especially at least 70 ° C, more particularly at least 80 ° C, even more particularly at least 100 ° C, in particular at least 110 °C.

Preferably, the TEMP1REAC is up to 180 ° C, more preferably up to 170 ° C, even more preferably up to 160 ° C, especially up to 150 ° C.

Any upper limit of TEMP1REAC can be combined with any lower limit of TEMP1REAC; preferably TEMP1REAC is 40-180 ° C, more preferably 50-180 ° C, even more preferably 50-170 ° C, especially 60-160 ° C, especially 70-150 ° C Even more preferably from 80 ° C to 150 ° C, especially from 100 to 150 ° C, more particularly from 110 to 150 ° C.

Preferably, in REAC1, the compound of formula (3) and methylhydrazine are contacted at temperature TEMP1CONT and reacted at TEMP1REAC.

Preferably, TEMP1CONT has the same value and range as TEMP1REAC.

Preferably, REAC1 is carried out at a pressure of from 0.1 to 10 bar, more preferably from 0.1 to 5 bar, even more preferably from 0.5 to 5 bar, especially from 0.5 to 2.5 bar.

The pressure of REAC1 can be adjusted depending on the selected TEMP1CONT, the selected TEMP1REAC, and the boiling point of the reaction mixture formed when the compound of formula (3) is contacted with methylhydrazine.

Preferably, the reaction time TIME1REAC of REAC1 is from 0.1 second to 12 hours, more preferably from 1 second to 8 hours, preferably from 10 seconds to 6 hours, even more preferably from 10 seconds to 4 hours.

Preferably, ST1 may comprise distillation DIST1 carried out during or after REAC1, wherein the ethanol is distilled off; more preferably, ethanol and water are distilled off in DIST1.

Preferably, the distilled ethanol is ethanol formed during REAC1.

Water may be added to the reaction mixture during or after DIST1.

REAC1 can be carried out in the presence of the solvent SOLV1.

SOLV1 is preferably selected from the group consisting of ethyl acetate, butyl acetate, acetonitrile, valeronitrile, _C1-8 alcohols, and mixtures thereof.

More preferably, SOLV1 is selected from the group consisting of butyl acetate, valeronitrile, C _4-8 alcohols, and mixtures thereof;

Even more preferably, SOLV1 is selected from the group consisting of butyl acetate, valeronitrile, C _4-6 alcohols, and mixtures thereof.

Preferably, REAC1 is carried out in an aqueous medium.

Preferably, REAC1 is performed without the addition of SOLV1.

More preferably, REAC1 is carried out without adding a solvent.

When REAC1 is carried out without adding a solvent, the only solvent present in REAC1 is ethanol formed during REAC1.

Even more preferably, REAC1 is carried out in an aqueous medium and no solvent other than water is added.

Preferably, when REAC1 is carried out in an aqueous medium, methylhydrazine is used as an aqueous solution; more preferably, when REAC1 is carried out in an aqueous medium and methylhydrazine is used as an aqueous solution, the water present during REAC1 is from A Water based on aqueous solution; that is, no additional water is added.

ST1 may contain an anti-solvent ANTSOLV1.

REAC1 can be carried out in the presence of ANTSOLV1.

ANTSOLV1 is preferably a solvent which promotes precipitation of the compound of the formula (1), that is, (1) for the compound of the formula (1), ANTSOLV1 preferably has low solubility; more preferably, ANTSOLV1 has low solubility for the compound of the formula (1) at a low temperature at which crystallization occurs, And it has high solubility at high temperatures such as distillation or reactive distillation.

ANTSOLV1 is preferably selected from the group consisting of ACID1, chlorobenzene, xylene, mesitylene, dichlorobenzene, 1,2-dichloroethane and mixtures thereof; more preferably, ANTSOLV1 is selected from the group consisting of ACID1, xylene, dichlorobenzene, 1, A group consisting of 2-dichloroethane and mixtures thereof; even more preferably, ANTSOLV1 is selected from the group consisting of ACID1, xylene, dichlorobenzene, and mixtures thereof.

Preferably, in the case where ANTSOLV1 is different from ACID1, the amount of ANTSOLV1 is from 0.1 to 10 times, more preferably from 0.25 to 5 times, even more preferably from 0.25 to 2.5 times the weight of the compound of formula (3).

Preferably, in the case where ANTSOLV1 is ACID1, the molar amount of ANTSOLV1 used is 0.001 to 0.25 times, more preferably 0.005 to 0.2 times, even more preferably 0.005 to 0.15 times the molar amount of the compound of the formula (3), In particular, it is from 0.005 to 0.125 times, more particularly from 0.01 to 0.125 times, even more particularly from 0.05 to 0.125 times.

It is also possible to use ANTSOLV1 only after REAC1, which can be used to increase the separation yield, especially in crystallization. Therefore, the crystallization after REAC1 is preferably carried out in the presence of ANTSOLV1, or the crystallization which has occurred during REAC1 can be enhanced by adding ANTSOLV1 after REAC1.

After ST1, the compound of formula (1) can be isolated and purified by methods well known to those skilled in the art. These include, for example, cooling, crystallization, filtration, post-filtration washing and drying.

The product crystallizes after REAC1, during or after DIST1, or during or after cooling.

The compound of the formula (1), the compound of the formula (2) and the compound of the formula (3) are known compounds which are commercially available and/or can be produced according to known methods.

Preferably, REAC1 is performed in a continuous manner.

For the purpose of continuous reaction, any continuous working device CONTDEV can be used, such as a ring device LOOPDEV, a microreactor, a reactive distillation column or a continuously stirred reaction vessel.

Typically, loop reactors include static mixing devices.

LOOPDEV is preferably a loop reactor.

ANTSOLV1 can be added before or during or after REAC1, or before or during DIST1.

In the case where both REAC1 and DIST1 occur simultaneously (for example, if the CONTDEV is a reactive distillation column or a continuously stirred reaction vessel may be the case), ANTSOLV1 may have been added before or during REAC1. Otherwise, if DIST1 only occurs after REAC1, then it is preferable to add ANTSOLV1 only after REAC1.

Static mixing devices, such as static mixers, are well established and widely used in all areas of chemical process technology. The static mixing device is characterized in that only the medium to be mixed is moved compared to the dynamic mixing device. The liquid or gas is only mixed by pumping energy, while the geometrically determined mixing elements in the static mixing device remain in place. Companies such as Fluitec, Seuzachstrasse, 8413 Neftenbach, Switzerland, or Sulzer Ltd, Neuwiesenstrasse 15, 8401 Winterthur, Switzerland are well known as suppliers of static mixing equipment.

Microreactors are also known as microstructured reactors, where chemical reactions occur in the limits of typical lateral dimensions below about 1 mm; the most typical form of this limitation is microchannels. The microreactor is a continuous flow reactor. They have been successfully applied to the laboratory, pilot and production scale. For example, the Fraunhofer Institute for Chemical Technology ICT, Joseph-von-Fraunhofer Strasse 7, 76327 Pfinztal, Germany, develops and supplies such a microreactor. The microreactor can include a mixing unit, a residence unit, and a feed and discharge device.

Preferably, the static mixing device has the form of a tube comprising means for providing an obstacle to the flow of the three components and thereby achieving a mixture of the three components.

Preferably, the microreactor comprises microchannels arranged in a manner that achieves mixing.

Reactive distillation columns are well known in the art and may include feed and discharge units, outlet means for low boiling and high boiling materials, means for heating and cooling, with separate boiling points for separation A column of material means (which is known in the art, such as packing or plates).

Continuously stirred reaction vessels are well known in the art and may include reaction vessels, agitators, means for heating and cooling, feed means and discharge means.

The compound of the formula (1), the compound of the formula (3) and the methyl group can be fed to the CONTDEV alone or in any premixed form, for example, a premix of the compound of the formula (1) and the compound of the formula (3). The feed is fed while the methyl hydrazine is fed separately or as a premix of all three components.

Preferably, in the case of using a static mixing device, the DELTAP is from 1 to 10 bar, more preferably from 1 to 5 bar, even more preferably from 1 to 4 bar, especially from 1.5 to 4 bar.

Preferably, in the case of using a continuously operating microreactor, the DELTAP is from 5 to 100 bar, more preferably from 5 to 50 bar.

In CONTDEV, a compound of formula (1) is present.

The compound of formula (3) and methylhydrazine were fed into LOOPDEV and the reaction mixture REACMIX was provided in LOOPDEV.

LOOPDEV includes a mixing device MIXDEV and a device CONVDEV for transporting REACMIX;

The exit of the MIXDEV is connected to the entrance of the CONVDEV, and the exit of the CONVDEV is connected to the entrance of the MIXDEV, thereby forming a loop.

Preferably, the CONVDEV is a pump.

Preferably, the LOOPDEV comprises a device HEATDEV for heat exchange.

Preferably, the LOOPDEV comprises a device HOLDUPDEV, which is a holding device for controlling the dwell time.

In addition, LOOPDEV includes an outlet that directs the product stream to the next device, ultimately providing separation.

More preferably, the exit of the HEATDEV is connected to the entrance of the MIXDEV, the exit of the MIXDEV is connected to the entrance of the HOLDUPDEV, the exit of the HOLDUPDEV is connected to the entrance of the CONVDEV, and the exit of the CONVDEV is connected to the entrance of the HEATDEV.

Preferably, the exit is located after the CONVDEV, more preferably between the CONTDEV and the HEATDEV.

Preferably, the two component compounds of formula (3) and methyl hydrazine are fed into LOOPDEV between HEATDEV and MIXDEV.

The two component compounds of formula (3) and methylhydrazine can be fed into LOOPDEV in any spatial order relative to the flow direction of REACMIX in LOOPDEV. The compound of the formula (3) and methylhydrazine may also be previously mixed to give a mixture, which may then be fed to the LOOPDEV in the form of the mixture.

Preferably, the compound of formula (3) and methyl hydrazine are separately fed into LOOPDEV.

The residence time RESTIME in the circulation is defined by

The unit of VOLTOT is [L], and the unit of FLOWTOT is [L/H]. Set FLOWTOT as needed to select RESTIME.

Preferably, the residence time RESTIME of REACMIX in LOOPDEV is from 10 seconds to 6 hours.

Usually the time of the mixture in the loop is also TIME1REAC, ie TIME1REAC corresponds to RESTIME. The higher the TEMP1REAC, the shorter the RESTIME you can choose.

Preferably, the RESTIME is from 15 minutes to 6 hours for a TEMP1REAC of 80 to 100 °C.

Preferably, for a TEMP1REAC of 100 to 120 °C, the RESTIME is from 5 minutes to 3 hours.

Preferably, the RESTIME is from 1 minute to 1 hour for a TEMP1REAC of 120 to 140 °C.

Preferably, the RESTIME is from 10 seconds to 30 minutes for a TEMP1REAC of 140 to 160 °C.

The upper limit of the amount of the compound of formula (1) present during REAC1 depends on the conversion and yield of REAC1. For example, if the conversion is 90%, it is apparent that the molar amount of the compound of the formula (1) present in the REAC1 may be up to 9 times the molar amount of the compound of the formula (3), and in the case where the conversion is 99.9%, The molar amount of the compound of the formula (1) present in the REAC1 may be up to 999 times the molar amount of the compound of the formula (3).

Therefore, the upper limit of the molar amount of the compound of the formula (1) which is present during REAC1 may preferably be up to 50 times, more preferably up to 100 times, even more preferably up to 500 times or even higher than the molar amount of the compound of the formula (3). .

A non-limiting illustration of a LOOPDEV that can be used as a loop reactor is schematically illustrated in Figure 1, and in turn comprises a static mixer (1), a holding device (2), a circulation pump (3) and a heat exchanger (4) The outlet of the heat exchanger is connected to the inlet of the static mixer to form a loop reactor.

Feed 1 is a compound of formula (3) and feed 2 is methyl hydrazine and vice versa.

Feed 1 and feed 2 are pumped into the loop, which in the scheme of Figure 1 is carried out between the heat exchanger and the static mixer. The holding device is not mandatory, but in production, in order to better control the RESTIME and the amount of REACMIX in the LOOPDEV, it is preferred to have a holding device and the holding device can also be used to have any exhaust gas that may form during operation. Export.

An outlet (d) is installed between the circulation pump and the heat exchanger, and the outlet directs the product stream to the next unit (e), which ultimately provides separation.

When REACMIX circulates in LOOPDEV and both feeds are running, it represents a constant input to the loop reactor, by measuring the level of the reaction mixture in the holding device (LI in Figure 1) and by respectively, as shown in Figure 1 The outlets are adjusted by adjusting the outlet to maintain a constant level in the holding device as shown in (c) and (d).

The average RESTIME is adjusted by setting the desired ratio of the two feeds or by setting the level of the reaction mixture in the holding device or by both methods.

TEMP1REAC can be measured between the circulation pump and the heat exchanger.

Preferably, in the case of a batch reaction, the compound of formula (1) is present starting from REAC1. This can be carried out by adding a compound of the formula (3) and methylhydrazine to the compound of the formula (1), which may be a pure compound of the formula (1) or it may be from a previous batch Sub-production is the product of the reaction of a compound of formula (3) with methylhydrazine, which was carried out in the presence or absence of a compound of formula (1). The compound of formula (1) is preferably present in REAC1 in the form of the reaction mixture of the previous batch.

Preferably, in the case where REAC1 is carried out as a continuous reaction, the compound of formula (1) is either present in the CONTDEV from the beginning, or it is formed by a continuous reaction and thus is present in the CONTDEV.

Preferably, the CONTDEV is initially filled with water and is preferably filled with a compound of formula (1) at a desired temperature. Then start feeding.

The initially present compound of formula (1) may be a pure compound of formula (1) or it may be the product of a previous reaction from a compound of formula (3) and methyl hydrazine, or a compound of formula (1) Exist in the presence or absence. The compound of formula (1) is preferably present in REAC1 in the form of the previously reacted reaction mixture.

A non-limiting illustration of a possible apparatus using a reactive distillation column, including a reactive distillation column (4) and a crystallizer (6), is schematically illustrated in FIG.

Feed 1 is a compound of formula (3) and feed 2 is methyl hydrazine and vice versa.

The inlet of the feed is understood to be merely illustrative, and the exact point of entry into the tower may vary. Feed 1 and feed 2 can enter the column at the same height or at different heights.

The water and ethanol exit the column at a higher level than the feed, preferably at the top of the column, the compound of formula (1) exits the column at a lower point than the feed, preferably exits the column at the bottom of the column.

The compound of formula (1) preferably leaves the column in the form of a mixture with water, and then preferably the mixture is fed to a crystallizer.

SOLV1 or ANTSOLV1 can be fed into the column, into the crystallizer or both. Preferably, ANTSOLV1 is used to promote crystallization of the compound of formula (1) in a crystallizer.

Water and any solvent can also be separated in the crystallizer, preferably by distillation.

The separation (5) of the compound of the formula (1) after crystallization is preferably carried out in a conventional manner, for example by filtration, washing and drying.

Example

In the following examples, the following applies if not specified:

The selectivity is the ratio of the compound of the formula (1): the compound of the formula (2). The selectivity was determined by ¹ H-NMR and ¹⁹ F-NMR.

HPLC:

Column: YMC-Pack ODS-A (250mm x 4.6mm x 5 microns), YMC Europe GmbH, 46539 Dinslaken, Germany

Gradient elution: eluent A 0.1% H ₃ PO ₄ + 10% v/v acetonitrile, eluent B acetonitrile

At 40 ° C: starting at A: B is 94.4: 5.6; within 50 minutes to A: B is 33.3: 66.7

UV detector at 230 nm

External standard for HPLC: 5-MTP (Sigma-Aldrich, 97.0% by NMR)

NMR Reference:

¹ H-NMR: TMS delta 0 ppm

¹³ C-NMR: DMSO-d ₆ δ 39.51 ppm

¹⁹ F-NMR: 1,4-difluorobenzene δ-120.89 ppm

Particle size distribution:

d _xx,3 :xx = percentage of sample, 3 = volume %

Comparative Example 1

Reference example 1 of EP 1 767 528 A1 is repeated.

The yield was 85.8%.

The selectivity is 95.2:4.8.

Embodiment 1 and Embodiment 2

Type of microreactor: The microreactor is a Lonza Flowplate® Lab Microreactor Multiinjection SZ, 1701-1642 distributed by EHRFELD Mikrotechnik BTS GmbH, Mikroforum Ring 1, 55234 Wendelsheim, Germany

Stream 1:

A mixture of ethyl 4,4,4-trifluoroacetate (1 eq.) and a mixture of MIXTRIPLE containing 5-MTP (4 equivalents, in the absence of 3-MTP) 31 wt% / water 60 wt% / EtOH 9 wt% , where wt% is calculated based on the total weight of MIXTRIPLE

Flow rate: 4.1 g / min

Stream 2:

40% by weight of methylhydrazine solution

Flow rate: 0.13 g / min

Total flow: 4.23 g / min

Stream 1 and stream 2 are mixed in a microreactor.

Microreactor temperature: see Table 1

The selectivity of the sample sampled from the microreactor outlet was measured.

Comparative Example 2

An example of the preparation of 2-methyl-5-trifluoromethyl-2H-pyrazol-3-ol in paragraph [577] of US2011/0071150A1 is repeated.

7.8 g of an off-white solid were obtained in a yield of 86.5%, which indicated that the yield of 89% (8 g) as described in [577] was reasonably repeated.

19F NMR analysis showed that the 5-MTP yield was 74.4% and the 5-MTP: 3-MTP selectivity was 92.5: 7.5 in the off-white solid, much lower than the ones shown in Examples 1 and 2.

Comparative Example 3

Repeat the synthesis of 1-methyl-5-hydroxy-3-(trifluoromethyl)pyrazole from Dai et al., J. Agric. Food Chem. 2008, 56, 10805-10810 at the bottom of the bottom right column on page 10806. The example of 6) is followed by evaporation of the solvent.

In this iteration, after evaporation of the solvent and before recrystallization, 16.1 g of a yellow solid was obtained which represents a crude yield of 97%.

¹⁹ F NMR analysis showed that the yield of 5-MTP was 67.6% in the yellow solid, and the selectivity of 5-MTP:3-MTP was 86.9:13.1, which was lower than the selectivity shown in Examples 1 and 2. Much more.

The yellow solid was then recrystallized from ethanol to give 4.2 g, which afforded 25.5%.

¹⁹ F NMR analysis showed that the selectivity of 5-MTP:3-MTP was 98.6:1.4 in the yellow solid.

The comparative example shows that the Dai synthesis method produces a product with a high content of 3-MTP, and only recrystallization increases the ratio of 5-MTP:3-MTP to values in the range of Examples 1 and 2. This additional recrystallization step increases the cost of the process, and furthermore the undesired high content of 3-MTP reduces the corresponding yield of 5-MTP desired in the product obtained directly from the reaction prior to any recrystallization.

figure 1

(1)‧‧‧Static mixer

(2) ‧‧‧holding device

(3) ‧ ‧ Circulating pump

(4) ‧ ‧ heat exchangers

figure 2

(4) ‧‧‧Reactive distillation tower

(5)‧‧‧5-MTP separator

(6)‧‧‧ Crystallizer

1 is a non-limiting illustration of a LOOPDEV that can be used as a loop reactor, in accordance with the present invention;

Figure 2 is a non-limiting illustration of a possible apparatus for using a reactive distillation column in accordance with the present invention.

Claims (6)

A method of preparing a compound of formula (1); The method comprises the step ST1; ST1 comprises the reaction REAC1 of the compound of the formula (3) with methylhydrazine; Wherein REAC1 is carried out in the presence of a compound of formula (1); a compound of formula (3) is contacted with methylhydrazine in the presence of a compound of formula (1) and reacted in the presence of a compound of formula (1); The amount is present in an amount at least 0.1 times the molar amount of the compound of formula (3). The method of claim 1, wherein REAC1 is carried out in the presence of acid ACID1; ACID1 is preferably selected from the group consisting of sulfuric acid, acetic acid, trifluoroacetic acid, H ₃ PO ₄ , methanesulfonic acid, formic acid, polymeric sulfonic acid resins, and mixtures thereof; The molar amount of ACID1 is 0.001 to 0.25 times, more preferably 0.005 to 0.2 times, even more preferably 0.005 to 0.15 times, especially 0.005 to 0.125 times, more particularly 0.01 to 0.125, of the molar amount of the compound of the formula (3). Times, even more particularly 0.05 to 0.125 times. The method of claim 1, wherein REAC1 is carried out without acid. The method of one or more of claims 1 to 3, wherein: the reaction temperature TEMP1REAC of REAC1 is at least 40 °C. The method of one or more of claims 1 to 4, wherein: REAC1 is carried out without adding a solvent. The method according to one or more of claims 1 to 5, wherein: REAC1 is followed by an anti-solvent ANTSOLV1; ANTSOLV1 is preferably selected from the group consisting of ACID1, chlorobenzene, xylene, mesitylene, dichlorobenzene, 1,2- Dichloroethane and mixtures thereof; ACID1 as defined in claim 2.