DE102010007656B3 - Regioselective preparation of substituted N-(1H-pyrazolylmethyl) amide compound, comprises reacting hydrazinomethyl carboxylic acid amide derivative with diacetylene derivative - Google Patents

Abstract

Regioselective preparation of substituted N-(1H-pyrazolylmethyl) amide compound (I), comprises reacting hydrazinomethyl carboxylic acid amide derivative (II) with diacetylene derivative (III). Regioselective preparation of substituted N-(1H-pyrazolylmethyl) amide compound of formula (I), comprises reacting hydrazinomethyl carboxylic acid amide derivative of formula (R 3>-C(=O)-NH-CH 2-NH-NH 2) (II) with diacetylene derivative of formula (R 1>-CC-CC-R 2>) (III). R 1>, R 2>6-10C aryl (optionally substituted by halo), 1-4C alkyl (both optionally mono- or polysubstituted by 1-4C alkyl, 1-4C alkylsulfonyl, 1-4C alkoxy, 1-4C acyl, OH, trimethylsilyl, NO 2, CN, carbonyl, carboxyl or 1-5C carboxyalkyl), 3-8C cycloalkyl, preferably cyclopropyl or cyclobutyl, alkyl-aryl with 1-4C alkyl and 6-10C aryl, trialkylsilyl with 1-4C alkyl or H (preferred); and R 3>6-10C aryl (optionally substituted by halo), 1-20C alkyl (both optionally mono- or polysubstituted by 1-4C alkyl, 1-4C alkylsulfonyl, 1-4C alkoxy, 1-4C acyl, OH, trimethylsilyl, NO 2, CN, carbonyl, carboxyl or 1-5C carboxyalkyl), 3-8C cycloalkyl, alkyl-aryl with 1-4C alkyl and 6-10C aryl or H. [Image].

Description

wobei R¹ und R² unabhängig voneinander für H, C₁-C₄-Alkyl, C₃-C₈-Cycloalkyl, C₆-C₁₀-Aryl, Alkylaryl mit C₁-C₄-Alkyl- und C₆-C₁₀-Arylgruppen oder Trialkylsilyl, wobei Alkyl C₁-C₄-Alkyl sein kann, steht,
R³ für H, C₁-C₂₀-Alkyl, C₃-C₈-Cycloalkyl, C₆-C₁₀-Aryl oder Alkylaryl mit C₁-C₄-Alkyl- und C₆-C₁₀-Arylgruppen steht,
wobei die Alkyl- und Arylreste von R¹, R² und R³ gegebenenfalls einfach oder mehrfach mit C₁-C₄-Alkyl, C₁-C₄-Alkylsulfonyl, C₁-C₄-Alkoxy, C₁-C₄-Acyl, Hydroxyl, durch eine Trimethylsilyl-, Nitro-, Cyano-, Carbonyl-, Carboxyl- oder eine Carboxyalkylgruppe mit 1 bis 5 C-Atomen und die Arylreste von R¹, R² und R³ zusätzlich durch Halogen substituiert sein können, und außerdem die C₁-C₄-Alkylreste von R¹, R² und R³ linear oder verzweigt sein können, vorzugsweise stellen R¹ und R² ein Wasserstoffatom dar, C₃-C₈-Cycloalkyl ist beispielsweise Cyclopropyl oder Cyclobutyl,
dadurch gekennzeichnet, dass man die Hydrazinmethylcarbonsäureamide 2

wobei R³ oben genannte Bedeutung hat,
mit Diacetylenen der allgemeinen Formel 3

wobei R¹ und R² oben genannte Bedeutung haben,
zur Reaktion bringt.The present invention relates to a novel process for the regioselective preparation of N- (1H-pyrazolylmethyl) amides of general formula 1

where R ¹ and R ² independently of one another are H, C ₁ -C ₄ -alkyl, C ₃ -C ₈ -cycloalkyl, C ₆ -C ₁₀ -aryl, alkylaryl with C ₁ -C ₄ -alkyl and C ₆ -C ₁₀ -aryl or trialkylsilyl, where alkyl may be C ₁ -C ₄ -alkyl,
R ^{3 is} H, C ₁ -C ₂₀ -alkyl, C ₃ -C ₈ -cycloalkyl, C ₆ -C ₁₀ -aryl or alkylaryl having C ₁ -C ₄ -alkyl and C ₆ -C ₁₀ -aryl groups,
where the alkyl and aryl radicals of R ¹ , R ² and R ^{3 are} optionally mono- or polysubstituted by C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkylsulfonyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ - Acyl, hydroxyl, by a trimethylsilyl, nitro, cyano, carbonyl, carboxyl or a carboxyalkyl group having 1 to 5 carbon atoms and the aryl radicals of R ¹ , R ² and R ^{3 may be} additionally substituted by halogen, and furthermore, the C ₁ -C ₄ -alkyl radicals of R ¹ , R ² and R ^{3 may be} linear or branched, preferably R ¹ and R ^{2 represent} a hydrogen atom, C ₃ -C ₈ -cycloalkyl is, for example, cyclopropyl or cyclobutyl,
characterized in that the hydrazine methylcarboxamides 2

where R ^{3 has the} abovementioned meaning,
with diacetylenes of the general formula 3

where R ¹ and R ^{2 have the} abovementioned meaning,
brings to reaction.

In the DE-OS 10343277 describes the preparation of N- (1H-pyrazolylmethyl) amides by reaction of an acid amide, formaldehyde and an azole or by reacting an amide with 1-hydroxymethylazoles. The occurrence of mixtures of isomers with respect to the position of substituents of the azole is reported, but no information is given on the regioselectivity. Apparently, a mixture is formed with not insignificant proportions of isomers of 3- or 5-substituted azoles, according to which their ratio can not be controlled by the described method apparently. Therefore, there is a need for a process for the regioselective preparation of N- (1H-pyrazolylmethyl) amides.

It is off DE 10343277 It is known that the N- (1H-pyrazolylmethyl) amides are distinguished by a good nitrifying inhibiting or controlling action.

State of the art

From the DE 10 2008 057718.9 For example, there is known a process for preparing N- (1H-pyrazolylmethyl) amides from hydrazine methylcarboxamides and 1,3-dicarbonyl compounds. In this process, the substituted azoles are formed only with isomer ratios of up to 95: 5. This is preferably obtained 3-methyl isomer. This is also the only regioselective synthesis for N- (1H-pyrazolylmethyl) amides and the only process for preparing N- (1H-pyrazolylmethyl) amides by construction of the pyrazole skeleton.

It is known that the preparation of N- (1H-pyrazolylmethyl) amides has hitherto taken place in various ways.

Out DE 10343277 is the preparation of N- (1H-pyrazolylmethyl) amides known as a three-component reaction of the corresponding pyrazole, the corresponding acid amide and formaldehyde. In this method, however, both regioisomers are formed, information on isomer ratios are not available. These two are also the only processes for preparing N- (1H-pyrazolylmethyl) amides in which the carboxylic acid amide nitrogen atom is not further substituted.

For N- (1H-pyrazolylmethyl) amides substituted on the carboxylic acid amide nitrogen atom, the following reactions are known: The treatment of 3-acetyl-oxazolidin-5-ones with silicon-containing nucleophiles such as, for example, 1-trimethylsilanyl-1H-pyrazole gives the amidomethylated product (acetylpyrazole 1-ylmethyl-amino) -acetic acid, but only unsubstituted silylpyrazoles were used (Zh. Obsh. Khim., 1989, 1084-1099, ibid., 1984, 2397-2398) so that regioselective reactions were not investigated.

It is furthermore known that a further process is the reaction of chloromethylpyrazoles with the corresponding acid amides, but here too, either only 3,5-substituted or unsubstituted pyrazoles have hitherto been used, and thus no studies on regioselectivity have yet been carried out. (Can J. Chem. (1989), 67 (7), 1144-1147).

It is also known that the reaction of 1H-pyrazoles with chloromethylcarboxamides gives the corresponding N- (1H-pyrazolylmethyl) amides, but here again only 3,5-substituted pyrazoles were used ( EP 0048372 ; US 4322553 ), or information on regioselectivity is not available ( EP 23287 ).

Furthermore, regioselective syntheses of multiply substituted pyrazoles are described in the literature, but many of these syntheses and methods have weak points, eg. For example, expensive and difficult to handle reagents such as alkynyl lithium compounds are used (J. Chem. Soc. Perkin Trans. I, 2002, 207-210) or consuming reaction conditions required (microwave irradiation J. Het. Chem. (2007), 44 (5), 1195-1199; Synlett (2007), 704-708). Very often, many processes have limitations in the choice of solvents (fluorinated alcohols in J. Org. Chem. (2008), 73 (9), 3523-3529) or in the starting materials (only trifluoromethyl-substituted 1,3-diketones in J. Org. Chem. (2008), 73 (9), 3523-3529 and Synlett (2006), 3267-3270; only chiral benzyl hydrazines in WO 002007015999 ; 2,3-disubstituted acrylic acid derivatives and hydrazones formed therefrom EP 2133341 ).

In the DE 4137011 as well as the SU 237905 the synthesis of 3-methylpyrazole from diacetylene and hydrazine is described.

Armyanskii Khimicheskii Zhurnal (1977), 30 (4), 332-6 discloses the synthesis of 1,3 (5) -disubstituted and 1,3,5-trisubstituted pyrazoles from diacetylene or substituted and hydrazines, but the regioselectivity is linked to the presence of a β-hydroxyethyl radical on the hydrazine.

In Chemical Reports, 112 (8), 2829-36; In 1979, the formation of 1-methyl-3 (5) - (trimethylsilylmethyl) pyrazole described here both regioisomers - depending on the reaction conditions in different proportions - formed.

task

The present invention has for its object to develop a process for the preparation of N- (1H-pyrazolylmethyl) amides, which is characterized by a simple reaction of readily available, inexpensive starting materials and uncomplicated reaction with little technical effort, the disadvantages mentioned in accordance with State of the art does not have and the desired N- (1H-pyrazolylmethyl) amides in the highest possible yields and considerable Regioisomerenüberschüssen, preferably the 5-isomer is to be formed provides.

• 1. das Hydrazinmethylsäureamid 2 mit Diacetylenen der allgemeinen Formel 3 in Gegenwart eines Lösungsmittels bei Temperaturen von 0°C bis 110°C zur Reaktion gebracht wird, und
• 2. die gebildeten N-(1H-Pyrazolylmethyl)amide 1 nach den üblichen Methoden abgetrennt und gereinigt werden.

This object has been achieved according to the invention by the process according to Scheme 1 in that:

• 1. the Hydrazinmethylsäureamid 2 is reacted with diacetylenes of the general formula 3 in the presence of a solvent at temperatures of 0 ° C to 110 ° C, and
• 2. the resulting N- (1H-pyrazolylmethyl) amides 1 are separated and purified by the usual methods.

Description of the invention

It has surprisingly been found here that the N- (1H-pyrazolylmethyl) amides can be prepared in a technically simple manner in good yields and with excellent regioselectivities, although of the novel Hydrazinmethylcarbonsäureamiden the general formula 2 - the in DE 10 2008 057719.7 were not expected to give the desired pyrazoles regioselectively upon reaction with diacetylenes of general formula 3.

mit Diacetylen der allgemeinen Formel 3
wobei R¹ und R² unabhängig voneinander für H, C₁-C₄-Alkyl, C₃-C₈-Cycloalkyl, C₆-C₁₀-Aryl, Alkylaryl mit C₁-C₄-Alkyl- und C₆-C₁₀-Arylgruppen oder Trialkylsilyl, wobei Alkyl C₁-C₄-Alkyl sein kann, steht,
R³ für H, C₁-C₂₀-Alkyl, C₃-C₈-Cycloalkyl, C₆-C₁₀-Aryl oder Alkylaryl mit C₁-C₄-Alkyl- und C₆-C₁₀-Arylgruppen steht,
wobei die Alkyl- und Arylreste von R¹, R² und R³ gegebenenfalls einfach oder mehrfach mit C₁-C₄-Alkyl, C₁-C₅-Alkylsulfonyl, C₁-C₄-Alkoxy, C₁-C₄-Acyl, Hydroxyl, durch eine Trimethylsilyl-, Nitro-, Cyano-, Carbonyl-, Carboxyl- oder eine Carboxyalkylgruppe mit 1 bis 5 C-Atomen und die Arylreste von R¹, R² und R³ zusätzlich durch Halogen substituiert sein können, und außerdem die C₁-C₄-Alkylreste von R¹, R² und R³ linear oder verzweigt sein können, vorzugsweise stellen R¹ und R² ein Wasserstoffatom dar, C₃-C₈-Cycloalkyl ist beispielsweise Cyclopropyl oder Cyclobutyl, gemäß Schema 1 zur Reaktion gebracht wird: Schema 1:

wobei R¹ und R² unabhängig voneinander für H, C₁-C₄-Alkyl, C₃-C₈-Cycloalkyl, C₆-C₁₀-Aryl. Alkylaryl mit C₁-C₄-Alkyl- und C₆-C₁₀-Arylgruppen oder Trialkylsilyl, wobei Alkyl C₁-C₄-Alkyl sein kann, steht,
R³ für H, C₁-C₂₀-Alkyl, C₃-C₈-Cycloalkyl, C₆-C₁₀-Aryl oder Alkylaryl mit C₁-C₄-Alkyl- und C₆-C₁₀-Arylgruppen steht,
wobei die Alkyl- und Arylreste von R¹, R² und R³ gegebenenfalls einfach oder mehrfach mit C₁-C₄-Alkyl, C₁-C₄-Alkylsulfonyl, C₁-C₅-Alkoxy, C₁-C₅-Acyl, Hydroxyl, durch eine Trimethylsilyl-, Nitro-, Cyano-, Carbonyl-, Carboxyl- oder eine Carboxyalkylgruppe mit 1 bis 5 C-Atomen und die Arylreste von R¹, R² und R³ zusätzlich durch Halogen substituiert sein können, und außerdem die C₁-C₄-Alkylreste von R¹, R² und R³ linear oder verzweigt sein können, vorzugsweise stellen R¹ und R² ein Wasserstoffatom dar, C₃-C₈-Cycloalkyl ist beispielsweise Cyclopropyl oder Cyclobutyl.The process of the present invention comprises a step wherein a hydrazine methylcarboxylic acid amide of the general formula 2

with diacetylene of the general formula 3
where R ¹ and R ² independently of one another are H, C ₁ -C ₄ -alkyl, C ₃ -C ₈ -cycloalkyl, C ₆ -C ₁₀ -aryl, alkylaryl with C ₁ -C ₄ -alkyl and C ₆ -C ₁₀ -aryl or trialkylsilyl, where alkyl may be C ₁ -C ₄ -alkyl,
R ^{3 is} H, C ₁ -C ₂₀ -alkyl, C ₃ -C ₈ -cycloalkyl, C ₆ -C ₁₀ -aryl or alkylaryl having C ₁ -C ₄ -alkyl and C ₆ -C ₁₀ -aryl groups,
where the alkyl and aryl radicals of R ¹ , R ² and R ^{3 are} optionally mono- or polysubstituted with C ₁ -C ₄ -alkyl, C ₁ -C ₅ -alkylsulfonyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ - Acyl, hydroxyl, by a trimethylsilyl, nitro, cyano, carbonyl, carboxyl or a carboxyalkyl group having 1 to 5 carbon atoms and the aryl radicals of R ¹ , R ² and R ^{3 may be} additionally substituted by halogen, and furthermore, the C ₁ -C ₄ -alkyl radicals of R ¹ , R ² and R ^{3 can be} linear or branched, preferably R ¹ and R ^{2 represent} a hydrogen atom, C ₃ -C ₈ -cycloalkyl is, for example, cyclopropyl or cyclobutyl, according to the scheme 1 is reacted: Scheme 1:

where R ¹ and R ² independently of one another are H, C ₁ -C ₄ -alkyl, C ₃ -C ₈ -cycloalkyl, C ₆ -C ₁₀ -aryl. Alkylaryl having C ₁ -C ₄ -alkyl and C ₆ -C ₁₀ -aryl groups or trialkylsilyl, where alkyl may be C ₁ -C ₄ -alkyl,
R ^{3 is} H, C ₁ -C ₂₀ -alkyl, C ₃ -C ₈ -cycloalkyl, C ₆ -C ₁₀ -aryl or alkylaryl having C ₁ -C ₄ -alkyl and C ₆ -C ₁₀ -aryl groups,
where the alkyl and aryl radicals of R ¹ , R ² and R ^{3 are} optionally mono- or polysubstituted with C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkylsulfonyl, C ₁ -C ₅ -alkoxy, C ₁ -C ₅ - Acyl, hydroxyl, by a trimethylsilyl, nitro, cyano, carbonyl, carboxyl or a carboxyalkyl group having 1 to 5 carbon atoms and the aryl radicals of R ¹ , R ² and R ^{3 may be} additionally substituted by halogen, and furthermore, the C ₁ -C ₄ -alkyl radicals of R ¹ , R ² and R ^{3 may be} linear or branched, preferably R ¹ and R ^{2 represent} a hydrogen atom, C ₃ -C ₈ -cycloalkyl is, for example, cyclopropyl or cyclobutyl.

From Chemical Reports, 112 (8), 2829-36; In 1979, the formation of 1-methyl-3 (5) - (trimethylsilylmethyl) pyrazole from bis (trimethylsilyl) diacetylene and methylhydrazine is known, both regioisomers are formed since the primary attack on diacetyl-triple bond by both the primary and the primary secondary nitrogen atom can take place. For this reason, when using was Hydrazinmethylcarbonsäureamiden the general formula 2 for the reaction with diacetylene of the general formula 3 does not assume that the N- (1H-pyrazolylmethyl) amides of general formula 1 are formed hochregioselektiv.

Armyanskii Khimicheskii Zhurnal (1977), 30 (4), 332-6 describes the synthesis of 1,3 (5) -disubstituted and 1,3,5-trisubstituted pyrazoles from diacetylene or substituted representatives and 2-ethanolhydrazine, the regioselectivity is attributed to the presence of the hydroxyethyl radical. This forms a five-membered ring with the primary nitrogen atom of the hydrazine via a hydrogen bond, thus activating the secondary nitrogen atom of the hydrazine.

wobei R¹, R² und R³ oben genannte Bedeutung haben, die N-(1H-Pyrazolylmethyl)amide der allgemeinen Formel 1 regioselektiv gebildet werden.This activation possibility is not given to the present process according to the invention, so that it was not to be assumed that in the reaction of hydrazine-methylcarboxamides of general formula 2 with diacetylene of general formula 3

where R ¹ , R ² and R ^{3 have the} abovementioned meaning, the N- (1H-pyrazolylmethyl) amides of the general formula 1 are formed regioselectively.

In the DE 10 2008 057718.9 A process for the preparation of N- (1H-pyrazolylmethyl) amides is described, but in this case isomeric mixtures are obtained with a preference for the 3-isomer.

Surprisingly, it has now been found that in the reaction of Hydrazinmethylcarbonsäureamide the general formula 2 with diacetylene of the general formula 3, wherein R ¹ , R ² and R ^{3 have the} abovementioned meaning, the N- (1H-pyrazolylmethyl) amides of the general formula 1 exclusively be formed as a 5-isomer, so highly regioselective.

Since the hydrazine methylcarboxamides 2 are formaldehyde fully aminals, it could not be expected that the stability of the hydrazine methylcarboxamides 2 under the reaction conditions (see Houben-Weyl Bd Heterocyclization perform.

The reaction preferably takes place in a solvent. The solvent can be resorted to the usual known solvents. Aliphatic hydrocarbons (such as, for example, hexane), their singly or multiply halogenated representatives (such as, for example, methylene chloride), ethers (such as, for example, dioxane or tetrahydrofuran) or alcohols or polar aprotic solvents (such as eg Ethanol or acetonitrile), but also z. As water used.

Surprisingly, in this process, the N- (1H-pyrazolylmethyl) amides of general formula 1 are formed exclusively as 5-isomer, whereas in the process carried out according to the prior art both isomers are frequently formed ( DE 10343277 ).

The reaction time is not critical and can be chosen in a wider range depending on the batch size.

Diacetylene is conveniently prepared in the laboratory from 1,4-dichlorobut-2-one.

It has also been found that in the reaction of hydrazine methylcarboxamides 2 with diacetylenes of general formula 3 by the choice of temperature, the dosage, and the solvent, the yield can be controlled. Surprisingly, the temperature has the particular influence on the yield that the yield at lower temperatures, for. B. 5 ° C, is better than at higher.

The Hydrazinmethylcarbonsäureamide required as starting materials in carrying out the process according to the invention are generally defined by the formula 2.

In this formula, R ^{3 is} H, C ₁ -C ₂₀ -alkyl, C ₃ -C ₈ -cycloalkyl, C ₆ -C ₁₀ -aryl or alkylaryl having C ₁ -C ₄ -alkyl- and C ₆ -C ₁₀ - Aryl groups in which the alkyl and aryl radicals of R ^{3 are} optionally monosubstituted or polysubstituted by C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkylsulfonyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -acyl, hydroxyl, by a trimethylsilyl, nitro, cyano, carbonyl, carboxyl or a carboxyalkyl group having 1 to 5 carbon atoms and the aryl radicals of R ^{3 may be} additionally substituted by halogen. In addition, the C ₁ -C ₄ alkyl radicals can be linear or branched. C ₃ -C ₈ -cycloalkyl is, for example, cyclopropyl or cyclobutyl.

As can be seen from Table 1, only the 5-isomers are formed throughout. In previous syntheses ( DE-OS 10343277 . DE 10 2008 057718.9 ), only isomeric mixtures could be obtained, often only inseparable 1: 1 mixtures are often obtained. Thus, it has been possible with the present inventive method to produce N- (1H-pyrazolylmethyl) amides regioselectively in good yields.

The advantage of the process according to the invention is the exclusive formation of a regioisomer, so that additional purification steps necessary for the isomer separation are not necessary.

Following the reaction according to Scheme 1, the N- (1H-pyrazolylmethyl) amide 1 formed can be separated by the customary methods known to the skilled artisan. It has proven advantageous to isolate the product by evaporation of the solvent and then to purify it by crystallization or column chromatography.

With the aid of the process according to the invention, it is possible, starting from easily available or simply and inexpensively produced basic chemicals with little technical effort and uncomplicated reaction procedure, to prepare the N- (1H-pyrazoly-1-methyl) amides 1 in good yields and with high regioselectivities.

applications

Synthesis protocol for N- (1H-pyrazolylmethyl) -amide 1:

Tabelle 1: Synthese von N-(1H-Pyrazolylmethyl)amiden 1 R¹ R² R³ Temp. Ausbeute 3/5-Verhältnis H H Ph 60°C Keine Reaktion H H Ph 25°C 36% nur 5-Isomer H H Ph 5°C 48% nur 5-Isomer H H 4-MeO-Ph 5°C 45% nur 5-Isomer H H 4-NO₂-Ph 5°C 67% nur 5-Isomer ¹ bezogen auf den Umsatz des Hydrazinderivates, in der Reaktionslösung gemessen, Kalibrierung erfolgte mit Referenzsubstanzen, die NMR-Spektren stimmen mit denen von Referenzprodukten überein.In a at least 30 minutes with inert gas purged 3-necked stirred flask with reflux condenser, internal thermometer and provided with gas inlet funnel 4.91 g (40 mmol) of dichlorobutin in 96 percent strength. Alcohol (20 ml / g dichlorobutin) dissolved. With stirring at 78 ° C and constant passage of inert gas (at least 10 l / h) 400 mol% 40 percent. Sodium hydroxide added dropwise to the boiling 1.4-dichlorobut-2-in-ethanol solution. The diacetylene which escapes through the reflux condenser and is diluted with protective gas is passed through 2 washing bottles with dilute sodium hydroxide solution. The thus produced and diluted with inert gas diacetylene is slowly introduced into an ethanolic solution of the corresponding Hydrazinmethylcarbonsäureamids 2 (40 mmol). To avoid Diacetylenverlusten a dry ice intensive cooler is used. After completion of the introduction, the mixture is stirred at room temperature. The solvent is removed under vacuum. Optionally, it is recrystallized or purified by column chromatography.

Table 1: Synthesis of N- (1H-pyrazolylmethyl) amides 1 R ¹ R ² R ³ Temp. yield 3/5 ratio H H Ph 60 ° C No reaction H H Ph 25 ° C 36% only 5-isomer H H Ph 5 ° C 48% only 5-isomer H H 4-MeO-Ph 5 ° C 45% only 5-isomer H H 4-NO ₂ -Ph 5 ° C 67% only 5-isomer ¹ based on the conversion of hydrazine derivative, measured in the reaction solution, calibration was carried out with reference substances, the NMR spectra are consistent with those of reference products.

Claims (3)

Process for the regioselective preparation of N- (1H-pyrazolylmethyl) amides of general formula 1

where R ¹ and R ² independently of one another are H, C ₁ -C ₄ -alkyl, C ₃ -C ₈ -cycloalkyl, C ₆ -C ₁₀ -aryl, alkylaryl with C ₁ -C ₄ -alkyl and C ₆ -C ₁₀ -aryl or trialkylsilyl, wherein alkyl may be C ₁ -C ₄ -alkyl, R ^{3 is} H, C ₁ -C ₂₀ -alkyl, C ₃ -C ₈ -cycloalkyl, C ₆ -C ₁₀ -aryl or alkylaryl with C ₁ -C ₄ -alkyl and C ₆ -C ₁₀ -aryl groups, where the alkyl and aryl radicals of R ¹ , R ² and R ^{3 are} optionally mono- or polysubstituted with C ₁ -C ₄ -alkyl, C ₁ - C ₄ alkylsulfonyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ acyl, hydroxyl, by a trimethylsilyl, nitro, cyano, carbonyl, carboxyl or a carboxyalkyl group having 1 to 5 carbon atoms and the aryl radicals of R ¹ , R ² and R ^{3 can} additionally be substituted by halogen, and furthermore the C ₁ -C ₄ -alkyl radicals of R ¹ , R ² and R ^{3 can be} linear or branched, preferably R ¹ and R ² is a hydrogen atom, C ₃ -C ₈ cycloalkyl is, for example, cyclopropyl or cyclobutyl, characterized gekennzeichn in that the hydrazine methylcarboxamides 2

where R ^{3 has the} abovementioned meaning, with diacetylene of the general formula 3

where R ¹ and R ^{2 have the} abovementioned meaning, brings to reaction. A method according to claim 1, characterized in that one carries out the reaction in a solvent, in particular dichloromethane or dioxane or tetrahydrofuran. Method according to one of claims 1 to 2, characterized in that one carries out the reaction at temperatures of 0 ° C to 110 ° C.