WO2015155713A1

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Publication number: WO2015155713A1
Application number: PCT/IB2015/052557
Authority: WO
Inventors: Giovanni Meazza; Pierangelo MEREGHETTI; Laura Sillani; Daniele Forgia; Paolo Bellandi
Original assignee: Isagro S.P.A.
Priority date: 2014-04-09
Filing date: 2015-04-08
Publication date: 2015-10-15

Abstract

A process is described for the synthesis of pyrazoles having general formula (I) comprising the following steps: a) a mixture comprising an alkyl-hydrazine having formula (II) RNH-NH₂and a compound having general formula (III) Rx₁ -X₁ -Rx-X₂-Rx₂, b) the mixture obtained in step a) is reacted with a compound having formula (IV), obtaining a 1,3,4-substituted pyrazole having general formula (I), according to the reaction scheme 1.

Description

PROCESS FOR THE REGIOSELECTIVE SYNTHESIS OF 1,3,4-SUBSTITUTED PYRAZOLES

The present invention relates to a new process for the regio selective synthesis of 1,3,4- substituted pyrazoles.

In particular, the present invention relates to a process for the regioselective synthesis of derivatives of l-alkyl-3-difluoromethyl-4-pyrazolecarboxylic acids.

1,3,4-substituted pyrazoles are used as intermediates in the pharmaceutical industry, as described, for example, in Pharmaceuticals (2012), vol.5, pages 317-324, WO 2004/4039365, US 2012/0122907, US 2013/0012715, US 2006/0079562, or in the agrochemical industry, as described for example in US 5,747,518, WO 93/11117, WO 2012/084812.

The use of 1,3-disubstituted 4-pyrazolecarboxylic acids are of particular applicative interest. These compounds are normally prepared by the cyclization of suitable derivatives of acrylic acid with monosubstituted hydrazines, as indicated in reaction scheme A:

wherein Y represents oxygen or sulphur, Q represents a leaving group, such as for example an alkoxyl, Z represents in general an alkoxycarbonyl group, R_a and R represent the desired substituents in position 1 and 3 of the pyrazole.

As can be seen from the reaction scheme indicated above, the disadvantage of this method consists in the fact that significant quantities of 1,4,5-substituted pyrazole regioisomer are generally formed.

In addition to lowering the yields in the 1,3,4-substituted product, the lack of regio selectivity requires the separation of the two regioisomers, considerably increasing the production process costs of the desired compound.

The Australian Journal of Chemistry (1983), vol. 36, pages 135- 147, for example, describes the reaction between methylhydrazine and ethyl 2-(ethoxymethylidene) -3- oxobutanoate in diethyl ether, which leads to the formation of ethyl 1,3 -dimethyl- lH-pyrazole-4- carboxylate in a mixture with 10% of the 1,4,5-substituted regioisomer and an overall yield in the two isomers of 94%.

When R_a represents an alkyl group, the preparation of 1,3,4-substituted pyrazoles can also be effected by reaction between a suitable derivative of acrylic acid and hydrazine, followed by an alkylation reaction with a compound having formula R_a-LG, wherein LG represents a leaving group such as, for example, a halogen, in order to introduce the alkyl group onto the nitrogen atom in position 1, as indicated in reaction scheme B:

scheme B

As can be seen, however, also in this case, the N-alkylation reaction of pyrazoles is not regio selective and leads to the formation of mixtures of the two pyrazole isomers, as described, for example, in the Australian Journal of Chemistry (1983), vol. 36, pages 135- 147, in which the reaction of ethyl 3 -methyl- lH-pyrazole-4-carboxylate with methyl iodide in ethanol leads to the formation of ethyl l,3-dimethyl- lH-pyrazole-4-carboxylate in a 1 : 1 mixture with the 1,4,5- substituted regioisomer.

The Applicant has surprisingly found that, for particular meanings of the groups Ra, Rb, Y, Z and Q, a 1,3,4-substituted pyrazole can be obtained with an extremely high regioselectivity with respect to the 1,4,5 isomer (higher than 95:5), by reacting the acrylic derivative with a mixture comprising a monosubstituted alkyl-hydrazine and a suitable organic compound containing at least two heteroatoms selected from oxygen, nitrogen and sulphur.

An object of the present invention therefore relates to a process for the synthesis of pyrazoles having general formula (I)

Q

(I) comprising the following steps:

a) a mixture comprising an alkyl-hydrazine having formula (II) and a compound having general formula (III) is prepared

[ RNH-NH₂ Rx^-Rx-Xg-Rxg ]

(II) (III)

b) the mixture obtained in step a) is reacted with a compound having formula (IV), obtaining a 1,3,4-substituted pyrazole having general formula (I), according to the reaction scheme 1

reaction scheme 1

[ RNH-NH₂ Rx₁ -X₁-Rx-X₂-Rx₂ ] +

(II) (III) (IV)

(I) (HI) wherein in said formulae:

R represents a Ci-C₄ alkyl group;

Ri represents a Ci-C₄ alkyl group or a Ci-C₄ haloalkyl group;

R₂ represents a Ci-C₄ alkyl group;

Xi and X₂, equal to or different from each other, represent an oxygen atom, a sulphur atom, or a N-RN group;

Rxi, R_x2, RN_, equal to or different from each other, represents a Ci-C₄ alkyl group, a C₂-C₄ alkoxyalkyl group; or R_xi and R_x2 together, represent a C₂ alkylene (ethylene); when both Xi and X₂ represent a N-RN group, both R together represent a C₂ alkylene (ethylene);

R_x represents a Ci-C₂ alkylene, optionally substituted by one or more groups selected from Ci-C₄ alkyl groups, Ci-C₄ alkoxyl groups, a C₆-Cio aryl group substituted in vicinal positions by R_Xi-Xi- and Rx₂-X₂- groups, equal to or different from each other, a tetrahydrofuranyl group substituted in vicinal positions or in positions 2,5 by Rxi-Xi- and Rx₂- X₂- groups, equal to or different from each other.

Examples of a Ci-C₄ alkyl group are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl.

Examples of a Ci-C₄ haloalkyl group are difluoromethyl, trifluoromethyl, 1,1- dichloroethyl, 1,1,1-trifluoroethyl, 1,1,2,2-tetrafluoropropyl, 1,1,1,2,2-pentafluoropropyl, 1,1- dichlorobutyl, 1,1-difluorobutyl.

Examples of a Ci-C₄ alkoxyl group are methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy.

Examples of a C₂-C₄ alkoxyalkyl group are methoxy-methyl, methoxyethyl, methoxypropyl, ethoxyethyl.

Examples of a Ci-C₂ alkylene are methylene, ethylene.

Examples of a C₆-Cio aryl group are phenyl, naphthyl.

Among the pyrazoles having general formula (I) that can be prepared with the process of the present invention, those in which:

- R represents a methyl group;

- Ri represents a Ci-C₄ alkyl group

are preferred.

As previously indicated, the process, object of the present invention takes place in two consecutive steps.

In step a) for the preparation of the mixture, the alkyl-hydrazine (II) and the compound having formula (III) are kept in a mixture, optionally in the presence of a solvent, for a minimum time that can vary in relation to the compounds having formula (II) and (III) used, the temperature at which the mixture is maintained, the solvent possibly used.

The solvent that can be used in step a) of the process is preferably an aromatic hydrocarbon such as toluene, xylene, benzene, or tetrahydrofuran, preferably toluene.

The mixture is normally maintained, under stirring or possibly without stirring, at a temperature within the range of 10°C to 30°C, preferably from 15°C to 25°C, for a minimum time ranging from 6 to 24 hours, preferably from 12 to 18 hours, before proceeding with the subsequent step b) of the process according to the present invention. The compounds having formula (II) and (III) are used in a molar ratio that can vary from an equimolar ratio of 1 : 1, to a ratio in which the product having formula (III) is in a molar ratio of 1.5: 1 with respect to the alkyl -hydrazine (II).

In step b) of the process according to the present invention, the mixture of compounds having formula (II) and (III) is reacted with the compound having formula (IV), preferably in the same solvent possibly used for the preparation of the mixture of compounds (II) and (III).

In step b), the temperature of the reaction mixture is normally maintained within the range of 10 to 30°C.

Step b) of the process can be carried out by adding the mixture of compounds (II) and (III), possibly dissolved in a suitable solvent, to the compound having formula (IV), possibly dissolved in a suitable solvent.

Or step b) can be carried out by adding compound (IV), possibly dissolved in a suitable solvent, to the mixture of compounds (II) and (III), possibly dissolved in a suitable solvent.

Step b) of the process is preferably carried out by adding the compound having formula (IV) possibly dissolved in a suitable solvent to the mixture of compounds (II) and (III), kept under bland stirring and possibly dissolved in a suitable solvent.

More preferably, the mixture of compounds (II) and (III) and the compound having formula (IV) are dissolved in the same solvent.

The solvent that can be used in step b) of the process is preferably an aromatic hydrocarbon such as toluene, xylene, benzene, or tetrahydrofuran, preferably toluene.

Both step a) and step b) are normally carried out at atmospheric pressure, but can also be carried out, independently of each other, at a lower or higher pressure than atmospheric pressure.

The compounds having formula (II) and (IV) are generally used in a molar ratio that can vary from 0.9: 1 to 1.1 : 1, and are preferably used in a substantially equimolar ratio.

The molar ratio between the compounds having formula (II) and (III) is extremely important for obtaining a high regio selectivity in the process according to the present invention which comprises the condensation/cyclization reaction of alkyl-hydrazines (II) with compounds having formula (IV).

It is surprising, in fact, that if the compounds having formula (III) are used in a large excess with respect to the alkyl-hydrazines (for example as reaction solvents), the selectivity that can be obtained in the formation of the pyrazole compound having general formula (I) is lower, as can be seen from the following comparative examples 3 and 5.

If the compounds (II) and (IV), on the other hand, are reacted without the compound having formula (III), in a reaction solvent selected from those indicated above, a lower regio selectivity is still obtained, as can be seen from the following comparative example 2.

Once the reaction of step b) of the process according to the present invention has been completed, the pyrazoles having formula (I) can be isolated and purified according to methods known in the practice of organic chemistry, on both a laboratory scale and in industrial plants. The reaction mixture of step b), for example, can be concentrated at reduced pressure, thus enabling the recovery and recycling of the solvent and compound having formula (III), whereas the residue can be purified or hydrolyzed directly to l-alkyl-3-difluoromethyl-4- pyrazolecarboxylic acid, which can be obtained in a high yield and high purity by crystallization.

The compounds having formula (II) and (III) used for the process according to the present invention are generally products available on the market.

The preferred compound having formula (II) in the process according to the present invention is methyl-hydrazine.

Examples of compounds having formula (III) which can be used in the process according to the present invention are: dimethoxy-methane, 1,2-dimethoxy-propane, 2,2-dimethoxy- propane, 1,2-dimethoxy-ethane, 1,1-diethoxy-ethane, 1,2-diethoxy-ethane, 1,4-dioxane, bis-(2- methoxyethyl)ether, poly(ethyleneglycol)-dimethylether, 1,2-dimethoxy-benzene, 2,5- dimethoxy-tetrahydrofuran, Ν,Ν,Ν',Ν'-tetramethylethylene-diamine, 1,4-diazobicyclooctane, tris(3,6-dioxo-heptyl)amine, N-methyl-morpholine, 1,3-dithiane.

Preferred compounds having formula (III) in the process according to the present invention are compounds having formula (III) wherein Xi and X₂ both represent an oxygen atom.

Compounds having formula (III) which are even more preferred are: 1,2-dimethoxy- ethane, 1,2-dimethoxy-propane, 2,2-dimethoxy-propane, 1,2-diethoxy-ethane, 1,4-dioxane, 1,2- dimethoxy-benzene, 2,5-dimethoxy-tetrahydrofuran.

The compounds having formula (IV) can be prepared according to what is described, for example, in "Organic and Biomolecular Chemistry" (2009), vol. 7, pages 2182-2186. Examples of compounds having formula (IV) that can be used in the process according to the present invention are methyl 2-(methoxymethylidene)-4,4-difluoro-3-oxo-butanoate, ethyl 2- (methoxymethylidene)-4,4-difluoro-3-oxo-butanoate, methyl 2-(ethoxymethylidene)-4,4- difluoro-3-oxo-butanoate, ethyl 2-(ethoxy-methylidene)-4,4-difluoro-3-oxo-butanoate, trifluoroethyl 2-(ethoxymethylidene)-4,4-difluoro-3-oxo-butanoate, propyl 2-

(ethoxymethylidene)-4,4-difluoro-3-oxo-butanoate, butyl 2-(ethoxymethylidene)-4,4-difluoro-3- oxo-butanoate.

Preferred compounds having formula (IV) are methyl 2-(ethoxymethylidene)-4,4- difluoro-3-oxo-butanoate, ethyl 2-(ethoxymethylidene)-4,4-difluoro-3-oxo-butanoate, butyl 2- (ethoxymethylidene)-4,4-difluoro-3-oxo-butanoate.

The compound having formula (IV) which is particularly preferred is ethyl 2- (ethoxymethylidene)-4,4-difluoro-3-oxo-butanoate.

There are numerous advantages of the process according to the present invention.

In addition to allowing compounds having formula (I) to be obtained with a high yield and regioselectivity, the process is carried out with operative procedures that can be very easily effected in both laboratories and in industrial plants. Furthermore, it is not necessary to operate at temperatures that require energy consumption for heating or cooling the reaction mixture, nor is it necessary to use aggressive agents such as acids or bases for carrying out the reaction of phase b) or for processing the mixture obtained to complete the same.

By operating under the conditions described in the present invention, the ester derivatives of 3-difluoromethyl-l-methyl-4-pyrazolecarboxylic acid, which is an extremely important intermediate for the synthesis of products having a high fungicidal activity used in the agrochemical field, can be obtained with high yields and a high purity.

The following examples are provided hereunder for illustrative and non-limiting purposes of the present invention.

EXAMPLE 1

Preparation of ethyl 3-(difluoromethyl)-l-methyl-lH-pyrazole-4-carboxylate (1-1) in the presence of 1,2-dimethoxyethane.

Methyl-hydrazine (0.71 ml) is dripped into a solution of 1,2-dimethoxyethane (2.1 ml) in 9.0 ml of toluene and the mixture is left under moderate stirring for a night (18 hours) at room temperature. The mixture is then cooled to 10°C and ethyl 2-(ethoxymethylidene)-4,4-difluoro- 3-oxo-butanoate (3.0 g), dissolved in 4.5 ml of toluene, is then added. The mixture is left to react at room temperature for two hours.

At the end of the reaction, the mixture is evaporated under vacuum. 2.49 g of a solid product (yield 90%) are obtained, with a regioselectivity of 98.3% (GC-mass analysis).

EXAMPLE 2 (comparative)

Preparation of (1-1) (without 1,2-dimethox ethane)

Ethyl 2-(ethoxy-methylidene)-4,4-difluoro-3-oxo-butanoate (3.0 g) dissolved in 4.5 ml of toluene is added to a solution of methyl-hydrazine (0.71 ml) in 9 ml of toluene, cooled to 10°C. The mixture is left under stirring at room temperature for two hours.

At the end of the reaction, the mixture is evaporated under vacuum. 2.45 g of a raw product are obtained in the form of a solid, containing a mixture 88: 12 of the two isomers ethyl l-methyl-3-difluoromethyl-lH-pyrazole-4-carboxylate and ethyl l-methyl-5-difluoromethyl-lH- pyrazole-carboxylate.

EXAMPLE 3 (comparative)

Preparation of (1-1) in the presence of 1,2-dimethoxyethane as solvent

A solution of methyl-hydrazine (0.71 ml) in 10 ml of 1,2-dimethoxyethane is kept under moderate stirring at room temperature for 18 hours. The whole mixture is then cooled to 10°C, 2- (ethoxy-methylidene)-4,4-difluoro-3-oxo-butanoate (3.0 g) dissolved in 4.5 ml of toluene is added and left under stirring at room temperature for two hours.

At the end of the reaction, the mixture is evaporated under vacuum. 2.5 g of a residue of raw product are obtained, consisting of a mixture 87.6: 12.4 of the two isomers ethyl l-methyl-3- difluoromethyl-lH-pyrazole-4-carboxylate and ethyl l-methyl-5-difluoromethyl-lH-pyrazole-4- carboxylate.

EXAMPLE 4

Preparation of (1-1) in the presence of 2,2-dimethoxypropane.

Methyl-hydrazine (0.48 ml) is added to a solution of 2,2-dimethoxypropane (1.66 ml) in 3.0 ml of toluene and the mixture is left under moderate stirring for 8 hours. The solution is then cooled to 10°C and ethyl 2-(ethoxymethylidene)-4,4-difluoro-3-oxo-butanoate (2.0 g), dissolved in 1.5 ml of toluene, is then added. The mixture is left under stirring at room temperature for 12 hours.

The mixture is then concentrated under vacuum to give a raw residue of 1.65 g of product (1- 1), with a regioselectivity of 96.5% with respect to the 1,5-substituted isomer.

EXAMPLE 5 (comparative)

Preparation of (1-1) in the presence of 2,2-dimethoxypropane as solvent

Ethyl 2-(ethoxy-methylidene)-4,4-trifluoro-3-oxo-butanoate (2.0 g) is added dropwise to a solution of 1-methyl-hydrazine (0.48 ml) in 11 ml of 2,2-dimethoxypropane, cooled to 10°C; the mixture is kept under stirring at room temperature for 12 hours.

GC-mass analysis of the product obtained at the end of the reaction confirms the presence of a mixture 89.8: 10.2 of the two isomers ethyl l-methyl-3-difluoro methyl- lH-pyrazole-4- carboxylate and ethyl l-methyl-5-difluoromethyl-lH-pyrazole-carboxylate.

EXAMPLE 6

Preparation of (1-1) in the presence of 1,2-dimethox ethane, and with xylene or tetrahydrofuran as solvent.

Following the procedure described in Example 1, the compound (1- 1) was prepared starting from the mixture (methylhydrazine + 1,2-dimethoxyethane) and ethyl 2- (ethoxymethylidene)-4,4-difluoro-3-oxobutanoate, alternatingly using xylene and tetrahydrofuran as solvents, instead of the toluene adopted in Example 1.

A selectivity of 98.2% was obtained using xylene as solvent.

A selectivity of 97.4% was obtained using tetrahydrofuran as solvent.

EXAMPLE 7

Following the procedure described in Example 1, various compounds having formula (III) were used in substitution of dimethoxyethane.

Table 1 indicates the compounds having formula (III) and the solvents used, the temperature range of step b), the regioselectivities obtained.

Table 1

Compound having formula (III) Solvent rs ( )*

1 , 1 -dimethoxymethane toluene 95.8

Bis(2-methoxyethyl)ether toluene 97.0 1,4-dioxane toluene 98.4

2, 5 -dimethoxy tetrahydrofuran toluene 98.4

Ν,Ν,Ν',Ν' -tetramethylethylen-diamine toluene 95.1

1 ,2-dimethoxybenzene toluene 98.0

1 ,2-diethoxyethane toluene 98.8

Poly(ethyleneglycol)dimethylether toluene 95.3

Tris(3,6-dioxaheptyl)amine toluene 96.8 l,4-diazobicyclo[2.2.2]octane toluene 95.3

N-methylmorpholine toluene 97.1

1,3-dithiane toluene 95.1 rs (%) represents the regioselectivity in the isomer (I).

Claims

1. Process for the synthesis of pyrazoles of general formula (I)

R (I)

comprising the following steps:

a) a mixture comprising an alkyl-hydrazine of formula (II) and a compound of general formula (III) is prepared

[ RNH-NH₂ Rx -I -X -Rx-X₂-Rx₂ ]

(II) (III)

b) the mixture obtained in step a) is reacted with a compound of formula (IV) to form a 1,3,4-substituted pyrazole of general formula (I), according to the reaction scheme 1

scheme 1

[ RNH-NH₂ Rx_rX_rRx-X₂-Rx₂ ] +

(II) (III) (IV)

(I) (HI)

wherein in said formulas:

R represents a Ci-C₄ alkyl group;

Ri represents a Ci-C₄ alkyl group or a Ci-C₄ haloalkyl group;

R₂ represents a Ci-C₄ alkyl group;

Xi and X₂, equal to or different from each other, represent an oxygen or sulphur atom, or a N-RN group;

R_xi, R_X2, R_N, equal to or different from each other, represents a Ci-C₄ alkyl group, a C₂-C₄ alkoxyalkyl group; or R_xi and R_x2 together, represent a C₂ alkylene (ethylene); when both Xi and X₂ represent a N-R_N group, both R together represent a C₂ alkylene (ethylene);

- R_x represents a Ci-C₂ alkylene, being optionally substituted by one or more groups selected from Ci-C₄ alkyl groups, Ci-C₄ haloalkyl groups, a C₆-Cio aryl group substituted in vicinal positions by Rxi-Xi- and Rx₂-X₂- groups equal to or different from each other, a tetrahydrofuranyl group substituted in vicinal or in 2,5 positions by R_Xi-Xi- and Rx₂-X₂- groups equal to or different from each other.

2. Process according to claim 1, wherein step a) is carried out at a temperature maintained in the range of from 10°C to 30°C, preferably from 15°C to 25°C and step b) is carried out at a temperature maintained in the range of from 10°C to 30°C.

3. Process according one or more of the preceding claims, wherein step a) and/or step b) are carried out in a solvent selected among toluene, xylene, benzene, tetrahydrofuran, preferably toluene.

4. Process according to one or more of the preceding claims, wherein compound of formula

(II) is methyl-hydrazine.

5. Process according to one or more of the preceding claims, wherein compound of formula

(III) is selected among those in which Xi and X₂ represent an oxygen atom.

6. Process according to one or more of the preceding claims 1-4, wherein compound of formula (III) is selected among dimethoxy-methane, 1,2-dimethoxy-ethane, 1,1-diethoxy-ethane, 1,2-diethoxy-ethane, 1,2-dimethoxy-propane, 2,2-dimethoxy-propane, 1,4-dioxane, bis-(2- methoxyethyl)ether, poly(ethylenglycol)dimethylether, 1,2-dimethoxy-benzene, 2,5-dimethoxy- tetrahydrofuran, Ν,Ν,Ν',Ν'-tetramethylethylen-diamine, 1,4-diazobicyclooctane, tris(3,6-dioxo- heptyl)amine, N-methyl-morpholine, 1,3-dithiane, preferably among 1,2-dimethoxy-ethane, 1,2- dimethoxy-propane, 2,2-dimethoxy-propane, 1,2-diethoxy-ethane, 1,4-dioxane, 1,2-dimethoxy- benzene, 2,5-dimethoxy-tetrahydrofuran.

7. Process according to one or more of the preceding claims, wherein compound of formula (II) and compound of formula (III) are present in a molar ratio ranging from 1 : 1 to 1 : 1.5.

8. Process according to one or more of the preceding claims, wherein compound of formula (II) and compound of formula (IV) are present in a molar ratio ranging from 0.9: 1 to 1.1 : 1, preferably in equimolar ratio.

9. Process according to one or more of the preceding claims, wherein compound of formula (TV) is selected among methyl 2-(methoxymethylidene)-4,4-difluoro-3-oxo-butanoate, ethyl 2- (methoxymethylidene)-4,4-difluoro-3-oxo-butanoate, methyl 2-(ethoxymethylidene)-4,4- difluoro-3-oxo-butanoate, ethyl 2-(ethoxymethylidene)-4,4-difluoro-3-oxo-butanoate, trifluoroethyl 2-(ethoxymethylidene)-4,4-difluoro-3-oxo-butanoate, propyl 2-

(ethoxymethylidene)-4,4-difluoro-3-oxo-butanoate, butyl 2-(ethoxymethylidene)-4,4-difluoro-3- oxo-butanoate, preferably selected among methyl 2-(ethoxymethylidene)-4,4-difluoro-3-oxo- butanoate, ethyl 2-(ethoxymethylidene)-4,4-difluoro-3-oxo-butanoate, butyl 2- (ethoxymethylidene)-4,4-difluoro-3-oxo-butanoate, more preferably is ethyl 2- (ethoxymethylidene)-4,4-difluoro-3-oxo-butanoate.

10. Process according to one or more of the preceding claims, wherein compound of formula (I) is ethyl 3-(difluoromethyl)-l-methyl- lH-pyrazole-4-carboxylate.

11. Process according to one or more of the preceding claims, wherein the mixture of compound (II) and compound (III) is maintained, under stirring or possibly in absence of stirring, for a minimum time ranging of from 6 to 24 hours, preferably from 12 to 18 hours, before being submitted to the following step b).