Process for the preparation of 4-haloalkylnicotinonitriles

Process for the preparation of 4-haloalkylnicotinonitriles

The invention relates to a process for the preparation of 4־haloalkyl-3־pyridinecarbonitriles (4-haloalkylnicotinonitriles) and their further reaction.to give 4-haloalkylnicotinic acid derivatives having insecticidal activity.

4-Haloalkylnicotinamides are useful starting substances for the preparation of pesticides, such as are described, for example, in WO-A 98/57 969, EP-A 0 580 374 and DE-A100 14 006.

These compounds can be prepared in the two stages from 4-haloalkylnicotinic acids, whose synthesis is described, for example, in EP-A 0 744 400.

A simple process has surprisingly now been found for the preparation of 4-haloalkylnicotinonitriles (I), from which 4-haloalkylnicotinic acids can be obtained in one step by hydrolysis.

The invention therefore relates to a process for the preparation of a compound having the formula (I):

<img file="IL156359A_D0001.tif" />

(I) wherein R^F is (C1 -C₄)-haloalkyl, said process comprising:

(a) reacting a 3-amino-1-haloalkyl-2-propen-1-one having the formula (II):

R^f-C(O)-CH=CH-NH₂ (II) wherein R^F is defined as above, in a condensation reaction with at least one compound having a formula selected from the group consisting of (III), (IV), (V), (VI) and (VII):

<td> (R¹ Z)CH=CH—CN</td><td> (I״)</td>

<td> (R¹ Z)₂CH-CH2 -CN</td><td> (IV)</td>

<td> Hal-CH=CH—CN</td><td> (V)</td>

<td> Hal2-CH-CH₂ CN</td><td> (VI)</td>

<td> HC^C-CN</td><td> (VII)</td>

wherein R¹ is alkyl, Hal is Cl or Br and each Z is, independently, 0, S, NR¹ or OCO, to afford at least one compound having a formula selected from the group consisting of (VIII), (IX) and (X):

R^F—C(0)—CH=CH—NH—CH=CH—CN (VIII)

R^F—C(0)—CH=CH—NH—CH(ZR¹)—CH2—CN (IX)

R^F—C(0)—CH=CH—NH—CH(Hal)—CH₂—CN (X) wherein R^F, R¹, Z and Hal are as defined above; and (b) subjecting the reaction product of step (a) to a ring closure reaction to afford the corresponding compound having the formula (I).

2a

Preferably, the symbols in the formulae (I) - (X) have the following meaning:

R^f is preferably CH₂F, CFCI₂, CF₂CI, CF₃ or C₂F₅, particularly preferably CF₃.

R¹ is preferably (C1־C₄)־alkyl. such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, particularly preferably methyl or ethyl, very particularly preferably methyl.

Z is preferably 0 or NR¹.

Hal is preferably F or Cl.

The invention also relates to the use of 4־haloalkylnicotinonitriles as intermediates for the preparation of plant protection agents, in particular pesticides, such as insecticides.

The invention furthermore relates to a process for the preparation of 4-haloalkyl* nicotinamides (XI),

<img file="IL156359A_D0002.tif" />

(XI) where R^F has the meanings indicated above and where the 4-haloalkylnicotinonitrile (I)

R^F

<img file="IL156359A_D0003.tif" />

(I) obtained according to the above process is hydrolyzed.

A particular.economic advantage compared with the known synthesis from the acid lies in the fact that by the process according to the invention no activated acid derivative, such as, for example, an acid chloride, is necessary and no reaction with ammonia has to be carried out.

The invention furthermore relates to compounds of the formulae (VIII), (IX) and (X) and their salts,

R״-C(O)-CH=CH-NH-CH=CH-CN (VIII)

R^F-C(O)-CH=CH-NH-CH(OR²)-CH₂-CN (IX)

R^F-C(O)-CH=CH־NH־CH(Hal)־CH₂-CN (X) .

where R^F, Z and Hal have the meanings indicated above and R² is ah alkyl group. The formulae (VIII), (XI) and (X) in this case include all stereoisomers of the compounds, such as (Z) and (E) isomers on the double bonds, e.g. the (Z,Z), (Z,E), (E,Z) and (E,E) isomers of the compound (VIII) and in each case the (Z) and (E) :some's of the compounds (IX) and (X).

R² is preferably a linear or branched alkyl group having 1 to 6 carbon atoms, for example methyl, ethyl, n־propyl, iso-propyl, n-butyl or tert-butyl; methyl and ethyl are preferred, methyl is particularly preferred.

The invention likewise provides for the use of compounds of the formula (VIII), (IX) and/or (X) as intermediates for the preparation of plant protection agents, in particular pesticides, such as insecticides.

4-Amino-l,1,1-trifluoro-3-buten-2-one (II), as a preferred starting material, is known and can be prepared, for example, as described in EP-A 0 744 400, by reacting an acid halide of the formula (XII),

CF3-COX (XII) in which X is a halogen atom, with a compound of the formula (XIII)

CH₂=CHOR³ (XIII) in which R³ is an alkyl group, to give a compound of the formula (XIV),

R^F-C(O)-CH=CH(OR) (XIV) from which, by reaction with ammonia, compound (II) is obtained.

Compounds of the formulae (III) to (VII) are known. They are commercially obtainable or can be prepared by known methods familiar to the person skilled in the art, such as are described, for example, in J. Chem. Soc; 1969,406-408; Bull. Soc. Chim. Fr. 1948, 594 and J. Org. Chem; 29,1964,1800-1808.

R³ is preferably a linear or branched alkyl group having 1 to 6, preferably 1 to 4, carbon atoms, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl or tert-butyl; methyl and ethyl are preferred, methyl is particularly preferred.

According to the invention, compound (II) is reacted in a condensation reaction with one or more compounds of the formulae (III) and (VII) to give compound (VIII), (IX) and/or (X).

The condensation of compound (II) with one or more compounds (III) to (VII) and the subsequent ring closure reaction are shown in the following scheme:

R^F-C-GH=CH-NH.

וו

Ο + compounds (lll)-(Vll)

H ZR¹

I I

R^F-C-CH=CH-N-CH-CH₂-CN

II (IX) and/or

H Hal

I I

R^F-C-CH=CH-N-CH-CH_Q-CN

II ² . (X)

R^F-C-CH=CH-NH-CH=CH-GN

II (VIII)

Ring closure:

(VIII), (IX) and/or (X)

<img file="IL156359A_D0004.tif" />

The condensation of (11) with (III) - (VII) is preferably carried out under reduced pressure (particularly preferably at a pressure in.the range from 5-150 mbar, very particularly preferably 10 -100 mbar). At the same time, the .preferably lpw_:boi^ components are distilled off from the reaction mixture and in this process makes possible complete reaction of both starting materials. The vacuum is advantageously selected such that the boiling point of the eliminated compound R¹ZH, such as CH₃OH, EtOH, BuOH, is below, preferably 50 to 10^sC, below the reaction temperature, and the boiling point of the solvent is above, preferably 50 to 150°C above, the reaction temperature. As the same time, the formation of by-products is largely suppressed, and the reaction rate increases.

The ratio of the two components (II) and (III) to (VII) in the reactions can vary to.a large extent-depending on the compound employed and further reaction conditions.

Customarily, the molar ratio of the components (II): (III) to (VII) is 1.01.2:1־, preferably

1.02-1.06:1.

Depending on the compound employed, the reaction temperature and the other reaction conditions can be varied within wide limits. In general, the reaction temperature is in the range from -20°C - +100°C, preferably 0°C - + 30°C and the reaction time is customarily 0.5 to 12 h, preferably from 1 to 6 h.

The reaction conditions also vary, depending on which compound of the formula (III) to (VII) is employed.

Reaction with compounds of the formula (Ill)/(V):

The reaction temperature is preferably from -10 to +75 °C. For efficient conversion, the׳ reaction is expediently carried out in the presence of a base. Suitable bases are, for example, alkali metal hydrides, such as NaH or KH, alkyllithium compounds, such as n-butyllithium, or t-butyllithium, alkali metals, such as sodium or potassium, alkali metal hydroxides, such as NaOH or KOH, alkoxides, such as Na methoxide, Na ethoxide, K methoxide or K t-butoxide, or basic heterocycles, such as pyridine or quinoline. Alkali metal hydrides are preferred, NaH and K t-butoxide are particularly preferred. The bases can be employed individually or as a mixture. The amount of the base'employed can vary within wide limits, depending on what is employed as a compound of the formula (III) or (V), whether and in which solvent the reaction is carried out and the further reaction conditions. In general, 1.0 ' to 1.2 equivalents of base, preferably 1.05 to

1.1 equivalents by weight of base, are employed per mole of compound of the formula (ii).

The reaction is preferably carried out in a solvent. In this process, the components (II) can be introduced into the solvent and these solutions reacted with (III) or (V) together with base.

'

Preferred solvents are polar aprotic solvents, such as Ν,Ν-dimethylformamide or acetonitrile, halogenated hydrocarbons, such as methylene chloride or chloroform, ethers such as diethyl ether, dimethoxyethane or tetrahydrofuran, alcohols, such as methanol or ethanol, or basic heterocycles, such as pyridine or quinoline. Polar aprotic solvents are preferred; Ν,Ν-dimethylformamide (DMF) and dimethoxyethane (DME) are particularly preferred. Mixtures of the solvents mentioned can also be employed. The amount of the solvent employed׳ can very within wide limits and depends, for example, on whether and which base is added. In general, the amount of the solvent used is 1 to 30, preferably 4 to 15, parts by weight per part by weight of the compound (III) or (V).

The preparation of compounds of the formula (VIII) by reaction of the compound of the formula (II) with a compound of the formulae (IV), (VI) and/or (VII) is carried out in two stages, the compound of the formula (IX) or (X) firstly being formed with elimination of alcohol or elimination of H־Hal and then in a second stage a further alcohol molecule or H־Hal molecule being eliminated, which leads to the compound of the formula (VUI),

In all reactions, instead of the pure compounds the salts can also be employed or obtained, depending on the reaction procedure.

By way of example, the reaction, below with compound (IV) as a second component is illustrated:

1st stage

Base

R^F-C-CH=CH־NH2-r(R¹Z)2CHCH₂CN ----------*־

II 0 (II)(IV)

H ZR¹R171-II ^K Rr.c-CH=CH-N-CH-CH,-CN

II

Ο (IX)

2nd stage

-R1ZH R^F־C־CH=CH-NH-CH=CH-CN ־־־^ H ⁰ (VIII)

In orderto obtain the compounds of the formula (IX) and/or (X) in pure form, the condensation reaction is preferably carried out at low temperatures, preferably from 10 to 0°C, the reaction time is then preferably 0.2 to 4 h. For the further reactions to give compounds of the formula (VIII), the reaction must be carried out at higher temperatures, preferably 20 to +25°C, the reaction time for this second stage preferably

1Ό being 3 to 10h.

For a given reaction, the person skilled in the art can select suitable reaction conditions in a simple manner, it being possible to combine the general and preferred ranges . indicated as desired.

. If the condensation reaction is carried out in the presence of a base which contains an alkali metal, the compounds (VIII), (IX) and/or (X) form alkali metal salts which, under certain circumstances, can be present in the reaction product. In such cases, a neutralization step is added to the condensation reaction, the reaction product being 20 treated, for example, with a mineral acid, such as hydrochloric acid or sulfuric acid.

Working-uptakes place by'methods'which are known and familiar to the person skilled in the art, such as extraction by shaking, washing and drying.

The compound (VIII) has the following tautomers and isomerizes rapidly, in particular in the dissolved state:

RF-C-CH=CH-NH-CH=CH-CN

II

----RF-C-CH=CH-N=CH-CH₂-CN

----־״ R^F־C=CH־CH=N־CH=CH־CN

OH

Accordingly, the isolated compound (VIII) can contain a compound of the formula (VIII)':

R^f-C(O)־CH=CH-N=CH-CH2-CN (VIII)'

Correspondingly, the compound (IX) has the following tautomers:

H ZR

RF-C-CH=CH-N־CH־CH₂-CN

H ,0

ZR

R^F-C=CH־CH=N-CH-CH,־CN

I

OH

The formulae (VIII), (IX) and (X) include all these tautomers and salts of the compounds.

2nd stage

-R1ZK R^F-C־CH=CH־NH־CH=CH־CN —* II ⁰ (VIII)

In order to obtain the compounds of the formula (IX) and/or (X) in pure form, the condensation reaction is preferably carried out at low temperatures, preferably from 10 to 0°C, the reaction time is then preferably 0.2 to 4 h. For the further reactions to give compounds of the formula (VIII), the reaction must be carried out at higher temperatures, preferably 20 to +25°C, the reaction time for this second stage preferably being 3 to 10 h.

For a given reaction, the person skilled in the art can select suitable reaction conditions in a simple manner, it being possible to combine the general and preferred ranges indicated as desired.

If the condensation reaction is carried out in the presence of a base which contains an alkali metal, the compounds (VIII), (IX) and/or (X) form alkali metal salts which, under certain circumstances, can be present in the reaction product. In such cases, a neutralization step is added to the condensation reaction, the reaction product being treated, for example, with a mineral acid, such as hydrochloric acid or sulfuric acid.

Working-up takes place by methods which are known and familiar to the person skilled in the art, such as extraction by shaking, washing and drying.

The compound (VIII) has the following tautomers and isomerizes rapidly, in particular in the dissolved state:

RF-C־CH=CH-NH-CH=CH’CN

II 0

----*־ R^f-C-CH=CH־N=CH-CH₂-CN

----־״ R^F-C=CH־CH=N-CH=CH־CN

---------------- I

OH

Accordingly, the isolated compound (VIII) can contain a compound of the formula (VIII)׳:

R^f-C(O)-CH=CH-N=CH-CH₂־CN (VIII)'

Correspondingly, the compound (IX) has the following tautomers:

H ZR

CN־CH-CH₂־N־R^f-C-CH=CH II 0,

ZR

----- RF-C=CH-CH=N־CH-CH₂-CN

------------ II

The formulae (VIII), (IX) and (X) include all these tautomers and salts of the compounds.

The ring closure reaction of the compounds (VIII), (XI) and/or (X) to give the compound (I) is advantageously carried out in a solvent. Alcohols are preferred, particularly preferably primary (C1-C6)־alcohols; methanol and ethanol, in particular methanol, are very particularly preferred. Mixtures of the solvents mentioned can also be employed.

The compounds (VIII), (IX) and/or (X) can in this case be introduced into the solvent, or the solvent is added to the reaction mixture.

The amount of the solvent employed for the ring closure reaction can vary within wide limits, depending on the starting compound and reaction conditions. In general, it is 1 to 30, preferably 4 to 15, parts by weight per part by weight of compound (VIII) or (IX) and/or (X).

The ring closure reaction of the compounds (VIII), (IX) and/or (X) is advantageously carried out in an alcohol as solvent and in the presence of a preferably weak base to give the intermediates (XV), (XVI) and/or (XVII). On subsequent acidification, compound (I) is formed:

(VIII), (IX) and/or (XI)

<img file="IL156359A_D0005.tif" />

Here, R^F is (C1-C4)-haloalkyl, preferably CF3, and R¹ is a, preferably straight-chain, (Cr C₆)־, preferably (C1־C₄) -, in particular (C1-C2)־, alkyl radical and M is H⁺ or a monovalent cation, such as Na⁺, K⁺, Li⁺, 1/2Ca²⁺, 1/2Mg²⁺, HN((C1-C4)-alkyl)₃⁺.

It is is automatically understood here that the nature of the radical M depends on the base used and its strength.

Suitable bases are, for example, alkali metal carbonates, hydrogencarbonates and acetates, such as the corresponding Li, Na, K and Cs salts, alkaline earth metal carbonates and hydrogencarbonates, such as the corresponding Mg and Ca salts, alkali metal hydrides, such as NaH and KH, alkyllithium compounds, such as n-butyl5 lithium, alkali metals, such as Na and K, alkali metal hydroxides, such as NaOH and KOH, alkali metal alkoxides, such as NaOMe, NaOEt, KOMe and KOtBu, basic heterocycles, such as pyridine, 4-N,N-dimethylaminopyridine and quinoline, □r ammonia.

Alkali metal and alkaline earth metal carbonates, hydrogencarbonates and acetates, such as Li₂CO₃, Na₂CO3, NaHCO3, K₂CO3, CaCO₃ and MgCO3, are preferred. Li₂CO3, Na₂CO₃ and K₂CO₃ are particularly preferred, Li₂CO₃ and K₂CO₃ are very particularly preferred. By means of the two last-mentioned bases, it is possible in particular to increase the selectivity of the reaction in the direction of the desired final product (I).

The bases can be employed individually or as a mixture. In general, 0.05 to 1 equivalent, preferably 0.1 to 0.8 equivalent, of base are employed per mole of compound of the formula (VIII), (IX) and/or (X). The base can optionally be filtered off after the reaction and employed again.

The activity and selectivity of the base can be controlled by phase-transfer catalysts (PTCs). Suitable PTCs are typically crown ethers, cryptands, quaternary ammonium, phosphonium and onium compounds. Examples which may be mentioned are 12־ crown-4,15-crown-5,18-crown6־, dibenzo-18-crown-6, dicyclohexyl-18־crown-6, 25 tetrabutylammonium chloride and bromide, tetrabutylphosphonium chloride and bromide. 18-Crown6־ is preferred. The PTC is customarily employed in an amount from 1 to 10, preferably 1 to 5 mol%, based on the compound (VIII), (IX) and/or (X).

The intermediates of the formula (XV) and (XVI) and/or (XVII) can be isolated according to customary methods known to the person skilled in the art, for example by removing the solvent and washing the residue.

The invention likewise relates to these compounds.

It is preferred, however, to react to the intermediates of the formula (XII), (XV) and/or (XVII) by treating with acid to give compound (I) without prior isolation.

Strong acids are preferred here, such as aqueous or gaseous HCI, HBr, K₂SO4 and CF3C00H. The pH of the reaction mixture is in general adjusted to 1 to 2, which is customarily achieved by use of 0.1 to 1 equivalent of acid, based on the theoretical amount of compound (I).

The hydrolysis of the nitrile (I) to give the acid amide (XI) can be carried out according to methods which are known and familiar to the person skilled in the art, such as are described, for example, in Houben Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry].

.

. In a further, preferred variant of the process according to invention, the synthesis of the compounds (I) and (XI) is carried out in a one-pot reaction, i.e. without intermediates of the formula (VIII) to (X) and/or (XII) being isolated.

The compounds (I) and (XI) are used, for example, as intermediates in the preparation of plant protection agents, in particular pesticides, such as insecticides.

In particular, they are suitable for further reaction to give compounds such as are described in WO-A 98/57969, EP-A.0 580 374 and DE 100 14 006.8. In these documents, reference is hereby expressly made in particular to the compounds of the respective formula (I) and the working examples; they are incorporated by reference as part of this description.

The invention also provides a process for the preparation of 4-trifluoromethylnicotinic 30 acid derivatives having insecticidal activity according to WO-A 98/57969, EP-A 0 580

374 and/or DE 100 14 006.8,4-trifluoromethylnicotinonitrile being prepared as described above, optionally hydrolyzed and additionally reacted further in the processes described in the cited documents to give the final compounds of the respective formula (I) having insecticidal activity.

The invention also provides a process for preparing compounds of the formula (XVIII) in which an amide (XI) obtained according to the invention is reacted with a halogenating agent to give (XIX), if appropriate as a salt, which, by reaction with R⁴R⁵S/base and, if appropriate, subsequent oxidation, gives the compounds (XVIII),

<img file="IL156359A_D0006.tif" />

Halogenating . agent --------------->.

<img file="IL156359A_D0007.tif" />

if approprate, oxidizing agent

W) (XIX)

<img file="IL156359A_D0008.tif" />

⁽⁰⁾π (XVIII) where the symbols and indices are as defined below:

n isOorl;

m IsOorl;

R⁴,R⁵ are identical or different R⁶, -C(=W)R⁷, -C(=NOR⁷)R⁷, -C(=NNR⁷₂)R⁷,

-C(=W)0R⁷, -C(=W)NR⁷2, -OC(=W)R⁷, -OC(=W)OR⁷, -NR⁷C(=W)R⁷,

-N[C(=W)R⁷]2, -NR⁷C(=W)OR⁷, -C(=W)NR⁷-NR⁷2, -C(=W)NR⁷NR⁷[C(=W)R⁷], -NR⁷-C(=W)NR⁷2, -NR⁷־NR⁷C(=W)R⁷, ־NR⁷-N[C(=W)R⁷]2, -N[(C=W)R⁷]-NR⁷2, -NR⁷-NR⁷[(C=W)WR⁷], -NR⁷[(C=W)NR⁷2], -NR⁷[C=NR⁷)R⁷, -NR⁷(C=NR⁷)NR⁷2, -O-NR⁷2, -O-NR⁷(C=W)R⁷,

-SO₂NR⁷2, -NR⁷SO2R⁷, -SO2OR⁷, -OSO2R⁷, ־OR⁷, -NR⁷2, -SR⁷, -SiR⁷3, -PR⁷2, -P(=W)R⁷, -sor⁷, -so2r⁷, -pw2r⁷2, -pw₃r⁷2;

or

R⁴ and R⁵ together with the sulfur to which they are attached form a three- to eightmembered saturated or unsaturated, preferably carbocyclic ring system which is unsubstituted br mono- or polysubstituted, preferably by radicals R^b, and which may contain 1 to 4 further heteroatoms, it being possible for two or more of the substituents to form one or more further ring systems;

W isOorS;

R⁶ are identical or different (Ci-C^-alkyl, (C₂־C₂0)־alkenyl, C2־C20)־alkynyl, (C3-C_B)-cycloalkyl, (C₄-C₈)-cycloalkenyl, (C_B־C10)־cycloalkynyl, aryl or heterocyclyl; where the radicals mentioned may be unsubstituted or mono- or polysubstituted, preferably by radicals R⁸;

R⁷ are identical or different H or R⁶.

The invention furthermore provides a process for preparing the formulae (XX) and (XXI)

<img file="IL156359A_D0009.tif" />

(XX)

<img file="IL156359A_D0010.tif" />

(XXI) where the oxadiazole and the oxazole ring are unsubstituted or substituted and R^F is as defined above, by reacting (XXII)

<img file="IL156359A_D0011.tif" />

(XXII) obtained by hydrolysis of (I) prepared according to the invention, if appropriate in the form of an activated derivative, for example the acid chloride, with unsubstituted or substituted compounds (XXIII) or (XXIV)

HO

N H-N—.

L or >

η₂νή oh (XXIII) (XXIV) where in the case of the compound (XXIV) the alcohol function is oxidized prior to cyclization.

The invention furthermore provides a process for preparing compounds of the formula (XXV)

---NR⁷R⁶ ( J' (XXV) where

R^f is as defined above and

R⁵R⁷ are H or unsubstituted or substituted alkyl, alkenyl, alkynyl or cycloalkyl groups or else together form a ring system which may contain one or more N, S or 0 atoms;

which comprises activating, if appropriate, (XXII)

<img file="IL156359A_D0012.tif" />

(XXII) obtained according to the invention, followed by reaction with HNR°R⁷.

Reference is expressly made to the contents of the German patent applications

100 61 967.3,101 20 819.7 and 101 44 411.7, whose priority the present application 5 claims, and the attached abstract; it is hereby incorporated by reference as part of this description.

The invention is further explained by the following examples, without being restricted thereby.

Example 1

Isomer mixture of 3-(4,4,4-trifluoro-3-oxo-1 -butenyl)־2־propenenitrile |_na three-necked flask, 61.6 g (0.55 mol) of potassium tert-butoxide were introduced into 250 ml of di methoxyethane under N₂and the solution was cooled to 0°C.

1.5 4-Amino-1,1,Ttrifluoro-3-buten2־-orie, 69.5 g (0.5 mol), was added dropwise at this temperature in the course of 30 min and then 60.3 g (0.525 mol) of

3,3-dimethOxypropioriitrile were added dropwise. The :mixture wasthen stirred at 30°C for 3-4 h. The reaction mixture was added to ice and acidified to pH 3-4 using HOI. The precipitate was filtered off and washed with water.

71 g of product (75 %), mp: 123-126 °C.

¹⁹F NMR 5: -77.6 (4 singlets) ppm.

,Example 2

4־Trifluoromethyl-3-pyridinecarbonitrile

In a three-necked flask, 19 g (0.1 mol) of 3-(4_l4,4-trifluoro-3-oxo-1-butenyl) 2־propenenitrile were dissolved in 200 ml of methanol and 1 g of U₂CO₃ was added. The reaction mixture was heated under reflux for 4 - 6 h, cooled to 30°C and 10 ml of aqueous HOI were added. The reaction mixture was stirred for 2 h, the methanol was 30 removed in vacuo and the product was extracted with diethyl ether. I he solvent was removed and 4-trifluoronicotinonitrile was purified by vacuum distillation. 14 g .(81 %) of the product of bp 80 ⁰C/18 mbar were obtained.

זו

NMR'¹H(CDCI3) δ :8.87(5,1 Η), 8.81 (d, 1Η, ³J₍h.h)= 5 Hz), 7.51 (d,1H)ppm.

NMR¹⁹F δ: -64.5.(5, CF3) ppm.

Example 3

4-Trifluoromethyl-3־pyridinecarbonitrile־

The reaction was carried out as described in Example 2, but instead of Li₂CO₃1 g of

K₂CO₃ was taken.

Yield 75%.

Example 4

4־Trifluoromethyl-3-pyridinecarbonitrile

The reaction was carried out as described in Example 2, but instead of Li₂CO₃1 g of

15. sodium acetate was taken.

Yield 64%.

Examples

4-Hydroxy-6־methoxy-4-(trifluoromethyl)־1,4,5,6־tetrahydro-3-pyridinecarbonitrile

In a three-necked flask, 1.9 g (0.01 mol) of 3-(4,4,4-trifluoro-3-oxo-1butenyl)-2-propenenitrile were dissolved in 20 ml of methanol under N₂ and 0.2 g of NaOMe were added. The reaction mixture was stirred at RT for 10-14 h and the methanol was then largely removed in vacuo. 50 ml of dry diethyl ether were added.

The product was purified by recrystallisation from ethyl acetate.

1.5 g of product were obtained as a white solid. M.p. 121-123’C.

.1H NMR (CD3OD) (ABX spin system) 1.72 dd (Ha), 1.91 dd (H_B), 3.22 (5,3H), 4.52 dd (1H),.6.88 (s,1H) ppm.

The product reacted with HCI at RT to give 4־tnfluoromeihyl-3-pyrioinsCarbonitrile Yield 95%.

Example 6

Isomer mixture of 3־methoxy־3־(Z and E)-4,4,4-trifluoro־3־oxo־1־butenyl)propionitrile

In a three-necked flask, 61.6 g (0.55 mol) of potassium tert-butoxide were introduced into 250 ml dimethoxyethane under N₂ and the solution was cooled to 0°C. 4-Amino1,1,1-trifluoro-3-buten־2־one, 69.5 g (0.5 mol), was added dropwise at this temperature in the course of 30 min, and 43.5 g (0.525 mol) of 3־methoxypropionitrile were then added dropwise. The mixture was then stirred at 510°־C for 34־ h. The reaction mixture was added to ice and acidified to pH 34־ using HCI. The product was extracted with diethyl ether, dried and the solvent was removed in vacuo.

g were obtained (74%), oil.

¹⁹F NMR δ: 77.5־ (s); 77.6 (s) ppm.

Example 7

Isomer mixture of 3־4,4,4)־trifluoro־3־oxo-1-butenylamino)acrylonitrile

In a 11 four-necked flask having a thermometer, KPG stirrer, dropping funnel with bubble counter, descending condenser with cooled (10°־C) receiver and vacuum 20 connection, 117 g of potassium tert-butoxide were introduced into 700 ml of DMF under

N2 and the solution was cooled to 0°C. 142 g of 4-amino-1,1,1-trifluoro-3-buten-2-one were added dropwise at this temperature in the course of 30 min. After addition was complete, 117 g of 3,3-dimethoxypropiononitrile were added dropwise at this temperature. The dropping funnel was removed, and the pressure in the system was slowly reduced to 20-25 mbar.

The mixture was then heated at 30-35°C for 3-5 h and stirred under a vacuum of 2025 mbar, the low-boiling products (methanol, tert-butanol) simultaneously being removed in vacuo and condensed in the receiver.

The reaction mixture was added to 1000 g of ice with 40 ml of HCI (d 1.19) at 010°־C and, if necessary, adjusted to pH 23־ using HCI. After 1 h, the precipitate was filtered off, washed with ice water and the product was dried. 175 g (92 %) of 3-(4,4,4-trifluoro3-oxo-1-butenyl)acrylonitrile were obtained as an isomer mixture of 4 stereoisomers.

M. p.: 120-126°C. Purity 99%

Example 8 (comparative example)

Isomer mixture of 3-(4,4,4־trifluoro-3-oxo-1־butenylamino)acrylonitrile

The reaction was carried out as described in Example 1, but at normal pressure.

Yield 71%. Purity 93%.

Example 9

3-(4,4,4-T rifluoro-3-oxo-1 -butenylamino)acrylonitrile

The reaction was carried out as described in Example 1, but NaOMe was taken as the base.

Yield 86%.

Example 10 !

Isomer mixture of 3-(4,4,4-trifluoro-3-oxo-1 -butenylamino)acrylonitrile . The reaction was carried out as described in Example 1, but NaOtBut was taken as the base.

Yield 89%.

Example 11

4-Trifluoromethylnicotinonitrile

In a three-necked flask, 19 g (0.1 mol) of 3-(4,4,4-trifluoro-3-oxo-1-butenyl)acrylonitrile were dissolved in 200 ml of a methanol and 0.5 g of Li₂CO₃ was added. The reaction mixture was heated under reflux for 10 h. Methanol was removed in vacuo and 30 ml of

HCI were added. After 1 h, the product was extracted, the solvent was removed and

4-trifluoromethylnicotinonitrile was purified by vacuum distillation.

14.5 g (84 %) of the product of b.p. 80°C/18 mbar were obtained.

NMR ¹H (CDCI3) δ : 9.35 (s), 8.0 (d, 1H, ³J_(H,h)=5 Hz), 7.8 (d,1 H, =CH), 3.8 (s, 2H); 2.2 (s, 3H) ppm.

NMR ¹⁹F δ: 64.5 ־ (s, CF₃) ppm.

Example 12

Preparation of 3-(4,4,4-trifluoro-3-oxo-1 -butenylaminojacrylonitrile

Tubular reactor: 60 cm glass tube of internal diameter 4 cm, having a heatable jacket, half-filled with glass balls, cooled receiver and vacuum connection with cold trap. Preparation of reaction mixture.

N-Methylpyrrolidinone (NMP) (800 ml) was cooled to 0°C and 69.5 g of 4,4,4-trifluoro15 1 -aminobut-2-en-3-one, 92 g of 30 % NaOMe in methanol and 60 g of 3,3dimethoxypropionitrile were slowly added successively at this temperature. This mixture was transferred to the receiver.

Reaction procedure

The tubular reactor was fully filled with NMP, the jacket was heated to 80-85°C and a vacuum of 30-35 mbar was applied. The reaction mixture was added uniformly to the tubular reactor from the receiver within 1 h. The reaction time was 7-8 min at 80-85°C, methanol being condensed in the cold trap. After addition was complete, a further 120 ml of NMP were added dropwise in order to displace the reaction mixture completely from the reactor. The reaction mixture was added to ice water and HCI and, if necessary, adjusted to pH 2-3 using HCL The precipitated product was filtered off and washed with water.

g (90 %)־of 3-(4,4,4-trifluoro-3-oxo-1-butenyl)acrylonitrile having the purity w.w %

99 % as an isomer mixture of 4 stereoisomers were obtained.

M. p.: 124-126°C.