WO2018154097A1

WO2018154097A1 - Method for preparation of 1-methyl-3-(trifluoromethyl)-1h-pyrazol-5-ol

Info

Publication number: WO2018154097A1
Application number: PCT/EP2018/054620
Authority: WO
Inventors: Christoph Taeschler; Christophe Girard; Sandro TONAZZI; Daniel Polenske; Stefan Garms; Christoph Escher; Andreas Lorenz; Sonja BINER; Mareile VON DER GRUEN; Herbert KUEHBERGER; Jonas ZURBRIGGEN; Dieter IN-ALBON; Beat Lutz
Original assignee: Lonza Ltd
Priority date: 2017-02-27
Filing date: 2018-02-26
Publication date: 2018-08-30
Also published as: TW201835036A

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 PREPARATION OF 1 -ME TH YL-3-(TRIFLUOROME TH YL)- 1 H-

PYRAZOL-5-OL

The invention discloses a method for the preparation of l-methyl-3-(trifluoromethyl)-lH- pyrazol-5-ol with high selectivity with respect to the content of the isomer l-methyl-5-

(trifluoromethyl)-lH-pyrazol-3-ol, wherein ethyl 4,4,4-trifluoroacetoacetate is reacted with methyl hydrazine in the presence of l-methyl-3-(trifluoromethyl)-lH-pyrazol-5-ol: ethyl 4,4,4-trifluoroacetoacetate and methyl hydrazine are brought into contact in the presence of 1- methyl-3-(trifluoromethyl)-lH-pyrazol-5-ol and are reacted in the presence of l-methyl-3- (trifluoromethyl)- 1 H-pyrazo 1-5 -ol.

BACKGROUND OF THE INVENTION

The following abbreviations are used, if not otherwise stated:

ETFAA ethyl 4,4,4-trifluoroacetoacetate, compound of formula (3);

3-MTP l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-ol, compound of formula (2), the isomer;

5-MTP l-methyl-3-(trifluoromethyl)-lH-pyrazol-5-ol, compound of formula (1).

5-MTP is useful as an intermediate in the production of pharmaceutical and agricultural chemicals, such as herbicides such as pyroxasulfone. Lee et al, J. Heterocyclic Chem. 1990, 27, 243-245, discloses a method for preparation of 5-MTP: Methyl hydrazine is added at room temperature to a mixture of ETFAA and water. After the reaction has subsided, the mixture is held at reflux for 2 h. The yield is 24.2 g (49%) of 5-MTP and 4.2 g (8%) of 3-MTP, selectivity of 6 : 1.

EP 1 767 528 Al and EP1 990 336 Al both disclose in an identical Reference Example 1 a method for preparation of 5-MTP: ETFAA is dissolved in 2 eq of acetic acid, at 10 °C aqueous methyl hydrazine is added over 1 h, then the solution is stirred for 1 h at room temperature and then for 5 h at 80 °C. Yield is 86.5%. Repetition of this Reference Example 1 showed a selectivity of 96 : 4 as described in the Comparative Example 1 of instant invention.

Dai et al, J. Agric. Food Chem. 2008, 56, 10805-10810, discloses on page 10806 in the last paragraph at the bottom of the right column the Synthesis of l-Methyl-5-hydroxy-3-

(triftuoromethyl)pyrazole (6). A repetition of the example, see herein under Comparative Example 2, revealed a low yield of 5-MTP in the crude product together with a high ratio of 5-MTP : 3-MTP. US 2011/0071150 Al reveals in [577] the preparation of 2-Methyl-5-trifluoromethyl-2H- pyrazol-3-ol. A repetition of this example, see herein under Comparative Example 1, revealed a low yield of 5-MTP in the crude product together with a high ratio of 5-MTP : 3-MTP.

There was a need for a method for preparation of 5-MTP which provides 5-MTP in high yield and in higher selectivity then known from the prior art and that does not require the use of acetic acid in stoichiometric or even higher amounts. Also better filtration and washing behavior was desired. Also the method should not require the addition of a solvent.

Unexpectedly, by reacting the ETFAA with the methyl hydrazine already in the presence of 5-MTP, and this from the very beginning of the reaction, the selectivity can be enhanced and the yield is high. The use of acetic acid in stoichiometric or even higher amounts is not required, thereby the costs of the method are significantly lower compared to the method disclosed in Reference Example 1 of EP 1 767 528 Al and of EP1 990 336 Al respectively. 5-MTP is obtained in form of large crystals, which allows for fast and effective filtration and washing, furthermore the crystals have platelet like shape, where the prior art provides the crystals in form of needles. This improvement results in better filtration and washing behavior.

SUMMARY OF THE INVENTION

Subject of the invention is a method for the preparation of compound of formula (1);

the method comprises a step ST1;

ST1 comprises a reaction REAC1 of compound of formula (3) with methyl hydrazine;

wherein

REAC1 is done in the presence of compound of formula (1);

compound of formula (3) and methyl hydrazine are brought into contact in the presence of compound of formula (1) and are reacted in the presence of compound of formula (1).

DETAILED DESCRIPTION OF THE INVENTION

Compound of formula (1), compound of formula (2) and compound of formula (3) can adopt various tautomeric forms, depending for instance on solvent or on pH, therefor their formulae comprise any respective tautomeric form.

Preferably, compound of formula (1) is present in a molar amount of at least 0.1 times, more preferably of at least 0.5 times, even more preferably of at least 0.75 times, especially of at l ast 1 times, more especially of at least 2 times, even more especially of at least 3

Preferably, methyl hydrazine is used as an aqueous solution;

more preferably, methyl hydrazine is used as an aqueous solution of from 30 to 50 % (w/w); even more preferably of from 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, of the molar amount of compound of formula (3). The aim of using methyl hydrazine in sub stoichiometric amounts is to avoid having residual methyl hydrazine, which is highly toxic, in the final product and in any waste streams.

REAC1 can be done in the presence of an acid ACIDl . ACIDl is preferably used as a catalyst in REAC1. Compound of formula (3) and methyl hydrazine can be brought into contact in the presence of an acid ACIDl and can be reacted in the presence of ACIDl .

preferably, ACIDl is selected from the group consisting of sulfuric acid, acetic acid, trifluoro acetic acid, H3PO4, methane sulfonic acid, formic acid, polymeric sulfonic acid resin, and mixtures thereof;

more preferably, ACIDl is selected from the group consisting of sulfuric acid, acetic acid, trifluoro acetic acid, H3PO4, methane sulfonic acid, polymeric sulfonic acid resin, and mixtures thereof;

even more preferably, ACIDl is selected from the group consisting of sulfuric acid, acetic acid, trifluoro acetic acid, polymeric sulfonic acid resin, 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 such as used in heterogeneous acid catalysis. Preferably, the polymeric sulfonic acid resin has an average molecular weight of from 1000 to 1000000 D; and/or

preferably, a concentration of acid sites of from 1 to 15, more preferably of from 1 to 1 1.6, even more preferably of from 1 to 10, especially of from 1 to 8, more especially of from 1 to 7 equivalents per kg resin; and/or

preferably, an acid number of from 1 to 650, more preferably of from 1 to 560, even more preferably of from 1 to 450, especially of from 1 to 350, more especially of from 50 to 650, even more especially of from 1 to 560, in particular of from 50 to 450, more in particular of from 50 to 350; and/or

preferably, a particle size of from 4 to 800 mesh, more preferably 4 to 400 mesh.

The concentration of acid sites is determined by the Master Test Method MTM 0232, Edition 1.4, ©Rohm and Haas Company, 1998, wherein the CATALYST VOLATILES are determined by the Master Test Method MTM 0126, Edition 1.6, ©Rohm and Haas Company, 2000. The acid number is determined according to DIN EN ISO 3682. For further explanation of the acid number and for its relation to the concentration of acid sites see "BASF Handbuch Lackiertechnik", Artur Goldschmidt and Hans- Joachim Streitberger, Vincentz Verlag, 2002, ISBN 3-87870-324-4, chapter 2.3.2.2 (pages 272 to 273). According to the teaching therein, an concentration of acid sites of 1 equivalents per kg equals an acid number of 56, therefore a concentration of acid sites of 4.7 equivalents per kg equals an acid number of 263.

Especially, the polymeric sulfonic acid resin is selected from the group consisting of sulfonated polystyrene resins, sulfonated polystyrene resins cross linked with divinyl benzene and poly(2-acrylamido-2-methyl-l-propanesulfonic acid).

Sulfonated polystyrene resins cross linked with divinyl benzene are also called

divinylbenzene-styrenesulfonic acid copolymer.

One example for a polymeric sulfonic acid resin is Amberlyst® 15 DRY.

Preferably, the molar amount of any ACID1, that is used in the method, 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 from 0.005 to 0.125 times, more especially from 0.01 to 0.125 times, even more especially from 0.05 to 0.125 times, of the molar amount of compound of formula (3).

In another preferred embodiment, the molar amount of any ACID 1 , that is 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, especially from 0.01 to 0.2 times, more especially 0.05 to 0.2 times, even more especially from 0.05 to 0.15 times, in particular from 0.05 to 0.125 times, of the molar amount of compound of formula (3).

Preferably, acetic acid is not present in REAC1 in an amount over 1 eq, more preferably over 0.5, even more preferably over 0.25 eq, especially over 0.2 eq, more especially over 0.15 eq, even more especially over 0.125 eq, based on the molar amount of compound of formula (3);

more preferably, ACID1 is not present in REAC1 in an amount over 1 eq, more preferably over 0.5, even more preferably over 0.25 eq, especially over 0.2 eq, more especially over 0.15 eq, even more especially over 0.125 eq, based on the molar amount of compound of formula (3).

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

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

In a preferred embodiment, REACl is done in the absence of ACID1.

In a more preferred embodiment, REACl is done in the absence of an acid.

Preferably, compound of formula (3) and methyl hydrazine are brought into contact in the presence of compound of formula (1) and are reacted in the presence of compound of formula (1).

Preferably, the reaction temperature TEMPIREAC of in REACl is at least 40 °C, more

preferably at least 50 °C, even more preferably at least 60 °C, especially at least 70 °C, more especially at least 80°C, even more especially at least 100°C, in particular at least 110°C.

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

Any of the upper limit of TEMPIREAC can be combined with any of the lower limit of

TEMPIREAC;

preferably, TEMPIREAC is from 40 to 180°C, more preferably from 50 to 180°C, even more preferably from 50 to 170°C, especially from 60 to 160°, especially from 70 to 150°C, even more especially from 80 to 150°C, in particular from 100 to 150°C, more in particular from 110 to 150°C.

Preferably, in REACl compound of formula (3) and methyl hydrazine are brought into

contact at a temperature TEMPICONT and are reacted at TEMPIREAC.

Preferably, TEMPICONT has the same values and ranges as TEMPIREAC.

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

The pressure of REACl can be adjusted according to the chosen TEMPICONT, to the chosen TEMPIREAC and to the boiling point of the reaction mixture that is formed when compound of formula (3) and methyl hydrazine are brought into contact. Preferably, the reaction time TIMEIREAC of REACl is from 0.1 sec to 12 h, more preferably from 1 sec to 8 h, preferably from 10 sec to 6 h, even more preferably from 10 sec to 4 h. Preferably, ST1 can comprise a distillation DIST1 that is done during or after REACl,

wherein ethanol is distilled off;

more preferably, in DIST1 ethanol and water are distilled off.

Preferably the ethanol, that is distilled off, is the ethanol that is formed during REACl . During or after DIST1 water can be added to the reaction mixture.

REACl can be done in the presence of a solvent SOLVl .

SOLVl is preferably selected from the group consisting of ethyl acetate, butyl acetate,

acetonitrile, valeronitrile, C_1-8 alkohols, and mixtures thereof.

more preferably, SOLVl is selected from the group consisting of butyl acetate, valeronitrile,

C4-8 alkohols, and mixtures thereof;

even more preferably, SOLVl is selected from the group consisting of butyl acetate,

valeronitrile, C4-6 alkohols, and mixtures thereof. Preferably, REACl is done in aqueous medium.

Preferably, REACl is done without the addition of SOLVl .

More preferably, REACl is done without the addition of a solvent.

When REACl is done without the addition of a solvent, then the only solvent, that is present in REACl, is the ethanol that is formed during REACl .

Even more preferably, REACl is done in aqueous medium and without the addition of a solvent other than water.

Preferably, when REACl is done in aqueous medium, then the methyl hydrazine is used as an aqueous solution;

more preferably, when REACl is done in aqueous medium and the methyl hydrazine is used as an aqueous solution, then the water that is present during REACl is the water from the aqueous methyl hydrazin; that is no additional water is added.

ST1 can comprise the addition of an anti solvent ANTSOLV1.

REACl can be done in the presence of ANTSOLV1. ANTSOLVl is preferably a solvent which facilitates the precipitation of compound of formula (1), that is (1) ANTSOLVl has preferably a low solubility for compound of formula (1); more preferably ANTSOLVl has a low solubility for compound of formula (1) at low temperature, when the crystallization should take place, and a high solubility at high temperature, when for example a distillation or a reactive distillation takes place.

ANTSOLVl is preferably selected from the group consisting of ACIDl, chloro benzene, xylene, mesitylene, dichloro benzene, 1,2-dichloro ethane, and mixtures thereof;

more preferably, ANTSOLVl is selected from the group consisting of ACIDl, xylene,

dichloro benzene, 1 ,2-dichloro ethane, and mixtures thereof;

even more preferably, ANTSOLVl is selected from the group consisting of ACIDl, xylene, dichloro benzene, and mixtures thereof.

Preferably, in case that ANTSOLVl is different from ACIDl, then the ANTSOLVl is used in an amount of from 0.1 to 10 times, more preferably from 0.25 to 5 times, even more preferably from 0.25 to 2.5 times, of the weight of compound of formula (3).

Preferably, in case that ANTSOLVl is ACIDl, the ANTSOLVl is used in a molar amount of 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 from 0.005 to 0.125 times, more especially from 0.01 to 0.125 times, even more especially from 0.05 to 0.125 times, of the molar amount of compound of formula (3).

It is also possible to use ANTSOLVl only after REACl, this can be done for improvement of yield in the isolation, especially in crystallization. Therefore preferably a crystallization after REACl is done in the presence of ANTSOLVl, or a crystallization that took place already during REAC 1 can be enhanced by the addition of ANTSOLV 1 after REAC 1.

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

The product crystallizes after REACl, during or after DIST1, or during or after a cooling.

Compound of formula (1), compound of formula (2) and compound of formula (3) are known compounds which are commercially available and/or can be produced according to known methods. Preferably, REAC1 is done in a continuous way.

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

Usually, a loop reactor comprises a static mixing device.

LOOPDEV is preferably a loop reactor.

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

In case that REAC1 and DIST1 take place simultaneously, which can be the case for example if CONTDEV is a reactive distillation column or a continuous stirred reaction vessel, then ANTSOLV1 can be added already before or during REAC1. Otherwise, if DIST1 takes place only after REAC1, then preferably ANTSOLV1 is added only after REAC1.

Static mixing devices, e.g. static mixers, are well established and widespread in all fields of chemical process technology. It is characteristically for static mixing devices, that, in contrast to dynamic mixing devices, only the media to be mixed are in motion. The liquids or gases are mixed by pump energy only, while the geometrically strong defined mixing elements in the static mixing devices remain in position. Companies such as Fluitec, Seuzachstrasse, 8413 Neftenbach, Switzerland, or Sulzer Ltd, Neuwiesenstrasse 15, 8401 Winterthur, Switzerland, are well known suppliers among others of such static mixing devices.

Micro reactors, also called microstructured reactors, are devices in which chemical reactions take place in a confinement with typical lateral dimensions below 1 mm; the most typical form of such confinement are microchannels. A micro reactor is a continuous flow reactor. They have been successfully applied in lab, pilot and production scale. E.g. the Fraunhofer Institute for Chemical Technology ICT, Joseph-von-Fraunhofer Strasse 7, 76327 Pfmztal, Germany, develops and offers such micro reactors. Micro reactors can comprise a mixing unit, a residence unit and feed and exit devices.

Preferably, the static mixing device has the form of a tube containing means that present obstacles for the flow of the three components and thereby effecting the mixing of the three components. Preferably, the micro reactor contains micro channels which are arranged in such a way as to effect the mixing.

Reactive distillation columns are well known in the art, they can comprise feed and exit

devices, the exit devices for low and high boiling substances, means for heating and cooling, a column with means for separation of substances with different boiling points, which are well known in the art, such as packings or plates.

Continuous stirred reaction vessels are well known in the art, they can comprise a reaction vessel, stirrer, means for heating and cooling, feed devices and exit devices. The three components compound of formula (1), compound of formula (3) and methyl

hydrazine can be fed into CONTDEV either separately or in any premixed form such as a premix of compound of formula (1) with compound of formula (3) while methyl hydrazine is fed separately, or as a premix of all three components. Preferably, in case that a static mixing device is used, then 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 case that a continuously working micro reactor is used, then DELTAP is from 5 to 100 bar, more preferably from 5 to 50 bar.

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

Compound of formula (3) and methyl hydrazine are fed into LOOPDEV providing a reaction mixture REACMIX in LOOPDEV.

LOOPDEV comprises a mixing device MIXDEV and a device CONVDEV for conveyance of REACMIX;

the outlet of MIXDEV is connected to the inlet of CONVDEV and the outlet of CONVDEV is connected to the inlet of MIXDEV, thereby the loop is formed.

Preferably CONVDEV is a pump.

Preferably, LOOPDEV comprises a device HEATDEV for heat exchange.

Preferably, LOOPDEV comprises a device HOLDUPDEV, which is a hold up device for control the residence time.

Furthermore LOOPDEV comprises an outlet, the outlet leads the product stream into the next device, which provides ultimately for isolation. More preferably,

the outlet of HEATDEV is connected to the inlet of MIXDEV,

the outlet of MIXDEV is connect to the inlet of HOLDUPDEV,

the outlet of HOLDUPDEV is connected to the inlet of CONVDEV,

the outlet of CONVDEV is connected to the inlet of HEATDEV.

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

Preferably, the two components compound of formula (3) and methyl hydrazine are fed into

LOOPDEV between HEATDEV and MIXDEV.

The two components compound of formula (3) and methyl hydrazine can be fed into

LOOPDEV in any spatial sequence with respect to the direction of the flow of

REACMIX in LOOPDEV. Compound of formula (3) and methyl hydrazine can also be premixed resulting in a mixture and then can be fed into LOOPDEV in form of said mixture.

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

LOOPDEV. The residence time RESTIME in the loop is defined by

(total volume VOLTOT of all devices of the loop)

(total flow FLOWTOT of the feed streams)

The unit of VOLTOT is [liter], the unit of FLOWTOT is [liter/h]. RESTIME is chosen by setting FLOWTOT as desired.

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

Usually the time that the mixture is in the loop is also TIME IRE AC, that is TIME IRE AC corresponds to RESTIME. The higher TEMPIREAC is, the shorter RESTIME can be chosen.

Preferably, for a TEMPIREAC of 80 to 100°C RESTIME is 15 min to 6 h.

Preferably, for a TEMPIREAC of 100 to 120°C RESTIME is 5 min to 3 h. Preferably, for a TEMP IRE AC of 120 to 140°C RESTIME is 1 min to 1 h.

Preferably, for a TEMP IRE AC of 140 to 160°C RESTIME is 10 sec to 30 min.

The upper limit of the amount of compound of formula (1) that is present during REAC1, depends on the conversion and the yield of RE AC 1. For example if the conversion is 90% then obviously the molar amount of compound of formula (1) present in REAC1 can be up to 9 times of the molar amount of compound of formula (3), in case of a conversion of 99.9%, the molar amount of compound of formula (1) present in REAC1 can be up to 999 times of the molar amount of compound of formula (3).

Therefore the upper limit of the molar amount of compound of formula (1), that is present during REAC1, can be preferably up to 50 times, more preferably up to 100 times, even more preferably up to 500 times, or even more, of the molar amount of compound of formula (3). An non- limiting illustration for a possible LOOPDEV as a loop reactor is shown

schematically in FIG 1 and comprises sequentially a static mixer (1), a hold up 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, thereby forming the loop reactor.

Feed 1 is compound of formula (3), Feed 2 is methyl hydrazine, or vice versa.

The feeds Feed 1 and Feed 2 are fed via pumps into the loop, in the scheme of FIG 1 this is done between the heat exchanger and the static mixer. The hold up device is not mandatorily required, but in production it is preferably to have a hold up device in order to have a better control of RESTIME and of the amount of REACMIX in LOOPDEV, and a hold up device can also be used to have an outlet of any waste gas that can form during operation.

Between the circulation pump and the heat exchanger an outlet (d) is installed, the outlet leads the product stream into the next device (e), which provides ultimately for isolation. When REACMIX circulates in LOOPDEV and the two feeds are running, representing a constant input into the loop reactor, the outlet is regulated by measuring the level of reaction mixture in the hold up device (LI in FIG 1) and by maintaining a constant level in the hold up device by regulating the outlet respectively, as illustrated by (c) and (d) in FIG 1.

The average RESTIME is adjusted by setting a desired rate of the two feeds or by setting the level of the reaction mixture in the hold up device or by both measures. TEMP IRE AC can be measured between the circulation pump and the heat exchanger.

Preferably, in case of a batch reaction, compound of formula (1) is present from the beginning of REAC1. This is can be done by adding compound of formula (3) and methyl hydrazin to compound of formula (1), this compound of formula (1) can be pure compound of formula (1) or it can be a product from a previous batch that was produced be a reaction of compound of formula (3) and methyl hydrazine, this previous batch was done either in the presence of compound of formula (1) or not. Compound of formula (1) is preferably present in REAC1 in form of the reaction mixture of said previous batch.

Preferably, in case that REAC1 is done as a continuous reaction, compound of formula (1) is either present from the beginning in CONTDEV, or it is formed by the continuous reaction and thereby becomes present in CONTDEV.

Preferably, CONTDEV is initially filled with water and preferably with compound of formula (1) at the desired temperature. Then the feeds are started.

This initially present compound of formula (1) can be pure compound of formula (1) or it can be a product from a previous reaction of compound of formula (3) and methyl hydrazine, the previous reaction was done either in the presence of compound of formula (1) or not.

Compound of formula (1) is preferably present in REAC1 in form of the reaction mixture of said previous reaction.

A non-limiting illustration for a possible set up using a reactive distillation column is shown schematically in FIG 2 and comprises the reactive distillation column (4) and a crystallizer (6).

Feed 1 is compound of formula (3), Feed 2 is methyl hydrazine, or vice versa.

The entrance of the feeds is to be understood as being displayed only schematically, the exact point of entry into the column can vary. Feed 1 and Feed 2 can enter the column on the same height or on different heights.

Water and ethanol are leaving the column at a higher point than the feeds, preferably at the top of the column, compound of formula (1) is leaving the column at a lower point than the feeds, preferably at the bottom of the column.

Compound of formula (1) leaves the column preferably in form of a mixture with water, this mixture is then preferably fed into a crystallizer. SOLVl or ANTSOLVl can be fed into the column, into the crystallizer or into both.

Preferably ANTSOLVl is used for facilitating the crystallization of compound of formula (1) in the crystallizer.

Water and any solvent can also be separated in the crystallizer, preferably by distillation. Isolation (5) of compound of formula (1) after crystallization is preferably done in a conventional way, such as by filtration, washing and drying.

Examples

In the examples the following applies, if not otherwise stated:

Selectivity is the ratio of compound of formula (1) : compound of formula (2). Selectivity is determined by ^!H- and with ¹⁹F-NMR.

HPLC:

Column: YMC-Pack ODS-A (250 mm x 4.6 mm x 5 micro meter), YMC Europe GmbH,

46539 Dinslaken, Germany

Gradient elution: Eluent A 0.1 % H3P04 + 10 %v/v acetonitrile, Eluent B acetonitrile At 40 °C: Start at 94.4 : 5.6 A : B; over 50 min to 33.3 : 66.7 A : B

UV detector at 230 nm

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

NMR referencing:

Ή-NMR: TMS delta 0 ppm

1³C-NMR: DMSO-d₆ delta 39.51 ppm

¹⁹F-NMR: 1,4-Difiuorobenzene delta -120.89 ppm

Particle size distribution:

d_xx,3 : xx = percentage of the sample, 3 = volume %

Comparative Example 1

Reference Example 1 of EP 1 767 528 Al was repeated.

Yield was 85.8 %.

Selectivity was 95.2 : 4.8.

Example 1 and Example 2

Type of microreactor: The microreactor was a Lonza Flowplate® Lab Microreactor

Multiinjection SZ, 1701-1642, distributed by EHRFELD Mikrotechnik BTS GmbH, Mikro forum Ring 1, 55234 Wendelsheim, Germany

Stream 1 :

Mixture of Ethyl 4,4,4-trifluoroacetoacetate (1 eq) with a mixture MIXTRIPLE, MIXTRIPLE contained of 5-MTP (4 eq, no 3-MTP present) 31 wt-% / water 60 wt-% / EtOH 9 wt-%, with the wt-% being based on the total weight of MIXTRIPLE Flow Rate: 4.1 g / min

Stream 2:

Aqueous methyl hydrazine 40 wt-%

Flow Rate: 0.13 g / min

Total Flow Rate: 4.23 g / min

Stream 1 and stream 2 were mixed in the microreactor.

Temperature of microreactor: See Table 1

Selectivity was measured of a sample taken from the outlet of the microreactor. Comparative Example 2

The example in [577] of US 2011/0071150 Al for the preparation of 2-Methyl-5- trifluoromethyl-2H-pyrazol-3-ol was repeated.

7.8 g of an off-white solid were obtained, which represents a yield of 86.5 %, which shows a fair repetition of the yield of 89% (8 g) as stated in [577].

¹⁹F NMR analysis revealed in this off- white solid a yield of 74.4% of 5-MTP, and a selectivity for 5-MTP : 3-MTP of 92.5 : 7.5, which is considerably lower than the selectivity shown in Examples 1 and 2.

Comparative Example 3

The example in 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, for the synthesis of l-Methyl-5-hydroxy-3- (triftuoromethyl)pyrazole (6) was repeated until after the evaporation of the solvent. In this repetition, after said evaporation of the solvent and before the recrystallization, 16.1 g of a yellow solid were obtained, which represents a crude yield of 97%.

1⁹F NMR analysis revealed in this yellow solid a yield of 67.6% of 5-MTP, and a selectivity for 5-MTP : 3-MTP of 86.9 : 13.1, which is considerably lower than the selectivity shown in Examples 1 and 2.

The yellow solid was then recrystallized from ethanol to afford 4.2 g, which represents a yield of25.5%.

¹⁹F NMR analysis revealed in this yellow solid a selectivity for 5-MTP : 3-MTP of 98.6 : 1.4. The comparative example shows, that the synthesis of Dai results in a product with a high content of 3-MTP, and only a recrystallization reduces the ratio of 5-MTP : 3-MTP to a value in the range of Examples 1 and 2. This additional recrystallization step adds costs to the process, and furthermore the high content of undesired 3-MTP reduces the respective yield of the desired 5-MTP in the product as obtained directly from the reaction before any recrystallization.

Claims

1. A method for the preparation of compound of formula (1);

the method comprises a step ST1;

wherein

REAC1 is done in the presence of compound of formula (1);

compound of formula (3) and methyl hydrazine are brought into contact in the presence of compound of formula (1) and are reacted in the presence of compound of formula (1); compound of formula (1) is present in a molar amount of at least 0.1 times of the molar

amount of compound of formula (3).

2. Method according to claim 1, wherein

REAC1 is done in the presence of an acid ACIDI;

ACIDI is preferably selected from the group consisting of sulfuric acid, acetic acid, trifluoro acetic acid, H3PO4, methane sulfonic acid, formic acid, polymeric sulfonic acid resin, and mixtures thereof;

the molar amount of ACIDI 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 from 0.005 to 0.125 times, more especially from 0.01 to 0.125 times, even more especially from 0.05 to 0.125 times, of the molar amount of compound of formula (3).

3. Method according to claim 1, wherein

REAC1 is done in the absence of an acid.

4. Method according to one or more of claims 1 to 3, wherein

the reaction temperature TEMPIREAC of in REACl is at least 40 °C.

5. Method according to one or more of claims 1 to 4, wherein

REACl is done without the addition of a solvent.

6. Method according to one or more of claims 1 to 5, wherein

an anti solvent ANTSOLVl is added after REACl ;

ANTSOLVl is preferably selected from the group consisting of ACIDl, chloro benzene, xylene, mesitylene, dichloro benzene, 1,2-dichloro ethane, and mixtures thereof; with ACID as defined in claim 2.