CN1318393C

CN1318393C - Process for the preparation of 4-haloalkylnicotinonitriles

Info

Publication number: CN1318393C
Application number: CNB2005100966412A
Authority: CN
Inventors: S·帕杰诺克; H·M·M·巴斯蒂亚安斯
Original assignee: Bayer CropScience AG
Current assignee: Bayer CropScience AG
Priority date: 2000-12-13
Filing date: 2001-12-12
Publication date: 2007-05-30
Anticipated expiration: 2021-12-12
Also published as: ZA200304586B; DE10061967A1; CN1736982A

Abstract

Preparation of 4-haloalkyl-nicotinonitriles (I) comprises reacting a 3-amino-1-haloalkyl-2-propenone (II) with a nitrile (III) selected from 3,3-disubstituted propionitriles, 3-substituted acrylonitriles and propiolonitrile, and cyclizing the obtained 3-oxo-haloalkenylamino-substituted nitrile (IV). Intermediates (IV) are new compounds. Also new are tetra- or dihydropyridine derivative intermediates (XV)-(VII). Preparation of 4-haloalkyl-nicotinonitriles of formula (I) comprises: (a) reacting a 3-amino-1-haloalkyl-2-propenone of formula R-C(O)-NH-CH=CH-NH2 (II) with a nitrile (III) of formula Q-CH=CH-CN (IIIa), Q2-CH-CH2-CN (IIIb) or H-CC-CN (IIIc); and (b) cyclizing the obtained alkenylamino-substituted nitrile (IV) of formula R-C(O)-NH-CH=CH-NH-CH=CH-CN (IVa) or R-C(O)-NH-CH=CH-NH-CH(Q)-CH2-CN (IVb). R = 1-4C haloalkyl; Q = Cl, Br or -YR1; R1 = alkyl; and Y = O, S, NR1 or OCO; provided that the two Q groups in (IIIb) are both Cl and/or Br or both -YR1. Independent claims are also included for: (1) preparation of 4-haloalkyl-nicotinamides of formula (XI), by hydrolyzing (I) obtained by the above method; (2) intermediates (IVa) and (IVb) as new compounds; and (3) new tetra- or dihydropyridine derivative intermediates of formula (XV)-(XVII). R2 = 1-6C alkyl; and M = H or monovalent cation.

Description

Process for preparing 4-haloalkyl nicotinonitriles

The present application is a divisional application filed on the filing date of 12.12.2001, entitled "method for producing 4-haloalkyl nicotinonitriles" with the filing number of 01820484.8.

The invention relates to a method for producing 4-haloalkyl-3-pyridinecarbonitriles (4-haloalkylnicotinonitriles) and their further reaction to give 4-haloalkylnicotinic acid derivatives having insecticidal activity.

4-haloalkyl-nicotinamides can be used as starting materials for the preparation of pesticides, as described, for example, in WO-A98/57969, EP-A0580374 and DE-A10014006.

These compounds can be prepared in two steps from 4-haloalkylnicotinic acids, the synthesis of which is described, for example, in EP-A-0744400.

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

The invention therefore relates to a process for preparing 4-haloalkyl nicotinonitriles (I),

wherein

R^FIs halo (C)₁-C₄) Alkyl, preferably CF₃，

Wherein

a) 3-amino-1-haloalkyl-2-propen-1-one

R^F-C(O)-CH＝CH-NH₂ (II)

In a condensation reaction with a compound of one of the formulae (III) to (VII),

(R¹Z)CH＝CH-CN (III)

(R¹Z)₂CH-CH₂-CN (IV)

Hal-CH＝CH-CN (V)

Hal₂CH-CH₂CN (VI)

HC≡C-CN (VII)，

wherein R is¹Is alkyl, Hal is Cl or Br and Z, equal or different, is O, S, NR¹Or an OCO (oxygen-containing organic compound),

to give a compound of the formula (VIII), (IX) and/or (X),

R^F-C(O)-CH＝CH-NH-CH＝CH-CN (VIII)

R^F-C(O)-CH＝CH-NH-CH(ZR¹)-CH₂-CN (IX)

R^F-C(O)-CH＝CH-NH-CH(Hal)-CH₂-CN (X)

wherein R is^F、R¹Z and Hal have the same meanings as above,

and reaction products

b) A ring closure reaction is carried out.

The symbols in formulae (I) to (X) preferably have the following meanings:

R^Fpreferably CH₂F、CFCl₂、CF₂Cl、CF₃Or C₂F₅Particularly preferably CF₃。

R¹Is preferably (C)₁-C₄) Alkyl radicals, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, particularly preferably methyl or ethyl, very particularly preferably methyl.

Z is preferably O or NR¹。

Hal is preferably F or Cl.

The invention also relates to the use of 4-haloalkyl nicotinonitriles as intermediates for the production of plant protection agents, in particular pesticides, for example insecticides.

The invention also relates to a method for producing 4-haloalkylnicotinamide (XI),

R^Fis halo (C)₁-C₄) Alkyl and

wherein

a) 3-amino-1-haloalkyl-2-propen-1-one

R^F-C(O)-CH＝CH-NH₂ (II)

(R¹Z)CH＝CH-CN (III)

(R¹Z)₂CH-CH₂-CN (IV)

Hal-CH＝CH-CN (V)

Hal₂CH-CH₂CN (VI)

HC≡C-CN (VII)

wherein R is¹Is alkyl, Hal is Cl or Br and Z is O, S, NR¹Or OCO, where, in the case of formula (IV), the two Z radicals can assume the abovementioned meanings independently of one another,

to form a compound of formula (VIII), (IX) and/or (X),

R^F-C(O)-CH＝CH-NH-CH＝CH-CN (VIII)

R^F-C(O)-CH＝CH-NH-CH(ZR¹)-CH₂-CN (IX)

R^F-C(O)-CH＝CH-NH-CH(Hal)-CH₂-CN (X)

wherein R is¹Z and Hal have the same meanings as above,

and reaction products

b) The ring-closure reaction is carried out,

and also

c) The 4-haloalkyl nicotinonitrile (I) obtained is hydrolysed.

A particular economic advantage compared with the known processes of acid synthesis is that the process according to the invention does not require activated acid derivatives, such as acid chlorides, and does not require a reaction with ammonia.

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

R^F-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)

wherein R is^FZ and Hal have the abovementioned meanings and R²Is an alkyl group.

In this case, formulae (VIII), (XI) and (X) include all stereoisomers of the compounds, such as the (Z) and (E) isomers at the double bond, for example the (Z, Z), (Z, E), (E, Z) and (E, E) isomers of compound (VIII) and the various (Z) and (E) isomers of compounds (IX) and (X). R²Preferably a straight-chain or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl; methyl and ethyl groups are preferred, and methyl groups are particularly preferred.

The invention also relates to the use of compounds of the formulae (VIII), (IX) and/or (X) as intermediates for the preparation of plant protection agents, in particular pesticides, for example insecticides.

4-amino-1, 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-A0744400 by reacting an acyl halide of the formula (XII),

CF₃-COX (XII)

wherein X is a halogen atom, and X is a halogen atom,

reacting with a compound with a molecular formula (XIII),

CH₂＝CHOR³ (XIII)

wherein R is³Is an alkyl group, and is,

producing a compound of formula (XIV),

R^F-C(O)-CH＝CH(OR) (XIV)

compound (II) is obtained by its reaction with ammonia.

The compounds of the formulae (III) to (VII) are known. They are commercial products or can be prepared by known methods familiar to the expert, see for example j.chem.soc; 1969, 406-; bill, soc, chim, fr, 1948, 594, and j, org, chem; 29, 1964, 1800-1808.

R³Preferably a linear or branched alkyl group containing 1 to 6, preferably 1 to 4, carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl; methyl and ethyl groups are preferred, and methyl groups are particularly preferred.

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

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

and/or

Closed loop:

(VIII), (IX) and/or

The condensation reaction of (II) with (III) to (VII) is preferably carried out under reduced pressure, particularly preferably at 5 to 150 mbar, very particularly preferably at 10 to 100 mbar. At the same time, preferably low-boiling components are removed from the reaction mixtureDistilled off, complete reaction of the two starting materials being achieved here. The degree of vacuum is advantageously chosen so that the compound R to be removed¹ZH (e.g. CH)₃OH, EtOH, BuOH) below the reaction temperature, preferably from 50 to 10 c, and solvents above the reaction temperature, preferably from 50 to 150 c. The formation of by-products is largely suppressed and the reaction rate is increased.

The ratio of the two components (II) to (III) to (VII) in the reaction can vary within wide limits, depending on the compounds used and the other reaction conditions. The molar ratio of the components (II) to (III) to (VII) is generally 1.0-1.2: 1, preferably 1.02-1.06: 1.

The reaction temperature can vary within wide limits depending on the compounds used and the other reaction conditions. In general, the reaction temperature is in the range of-20 ℃ to +100 ℃, preferably 0 ℃ to +30 ℃ and the reaction time is usually 0.5 to 12 hours, preferably 1 to 6 hours. The reaction conditions may also vary depending on the compounds of formulae (III) to (VII) used.

Reaction with a compound of formula (III)/(V):

the reaction temperature is preferably from-10 to +75 ℃. For efficient reaction, the reaction is purposefully 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 tert-butyllithium, alkali metals, such as sodium or potassium, alkali metal hydroxides, such as NaOH or KOH, alkoxides, such as methanol Na, ethanol Na, methanol K or tert-butanol K, or basic heterocycles, such as pyridine or quinoline. Preference is given to alkali metal hydrides, particular preference to NaH and tert-butanol K. The bases can be used individually or as a mixture. The amount of base used may vary within wide limits depending on what base is used for the compound of formula (III) or (V), whether and in which solvent the reaction is carried out and other reaction conditions. In general, from 1.0 to 1.2 equivalents by weight of base, preferably from 1.05 to 1.1 equivalents by weight, are used per mole of compound of formula (II).

The reaction is preferably carried out in a solvent. Component (II) may be initially added to a solvent, and this solution is reacted with (III) or (V) together with a base.

The solvent is preferably a polar aprotic solvent, for example N, N-dimethylformamide or acetonitrile, a halogenated hydrocarbon, for example dichloromethane or chloroform, an ether, for example diethyl ether, dimethoxyethane or tetrahydrofuran, an alcohol, for example methanol or ethanol, or a basic heterocycle, for example pyridine or quinoline. Polar aprotic solvents are preferred, with N, N-Dimethylformamide (DMF) and Dimethoxyethane (DME) being particularly preferred. Mixtures of the solvents mentioned may also be used. The amount of solvent used can vary within wide limits, for example depending on whether and which base is added. In general, the amount of solvent used is from 1 to 30, preferably from 4 to 15 parts by weight per part by weight of compound (III) or (V).

The compounds of the formula (VIII) are prepared by reacting a compound of the formula (II) with a compound of the formula (IV), (VI) and/or (VII) in two steps, in which first the compound of the formula (IX) or (X) is formed in the course of dealcoholation or removal of H-Hal and then the other alcohol molecules or H-Hal molecules are removed in a second step, so that the compound of the formula (VIII) is formed.

In all reactions, instead of pure compounds, salts or, depending on the reaction step, salts can also be used.

This reaction is illustrated below using compound (IV) as the second component:

first step of

Second step of

In order to obtain pure compounds of formula (IX) and/or (X), the condensation reaction is advantageously carried out at low temperatures, preferably from-10 to 0 ℃ and preferably for a period of 0.2 to 4 hours. For the further reaction to give compounds of formula (VIII), the reaction must be carried out at relatively high temperatures, preferably from 20 to +25 ℃ and the reaction time in the second step is preferably from 3 to 10 hours.

For a given reaction, the skilled worker can select suitable reaction conditions in a simple manner, wherein the abovementioned general and preferred ranges can be combined arbitrarily.

If the condensation reaction is carried out in the presence of a base comprising an alkali metal, the compounds (VIII), (IX) and/or (X) form alkali metal salts which may in some cases be present in the reaction product. In this case, the condensation reaction is followed by a neutralization step in which the reaction product is treated with a mineral acid, such as hydrochloric acid or sulfuric acid.

The treatment is carried out by known methods familiar to the expert, for example by extraction with shaking, washing and drying.

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

thus, the isolated compound (VIII) comprises a compound of formula (VIII)':

R^F-C(O)-CH＝CH-N＝CH-CH₂-CN (VIII)′

accordingly, compound (IX) has the following tautomer:

formulae (VIII), (IX) and (X) include all such tautomers and salts of such 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, with (C) being particularly preferred₁-C₆) Primary alcohols, more particularly methanol and ethanol, especially methanol. Mixtures of the solvents mentioned may also be used.

Here, the compounds (VIII), (IX) and/or (X) may be added to the solvent beforehand or the solvent may be added to the reaction mixture.

The amount of solvent used in the ring-closure reaction can vary within wide limits, depending on the starting compounds and the reaction conditions. The solvent is generally used in an amount of 1 to 30, preferably 4 to 15 parts by weight per part by weight of the compound (VIII) or (IX) and/or (X).

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

wherein R is^FIs halo (C)₁-C₄) Alkyl, preferably CF₃，R¹Preferably linear (C)₁-C₆) -, preferably (C)₁-C₄) -, in particular (C)₁-C₂) -alkyl, M is H⁺Or monovalent cations, e.g. Na⁺、K⁺、Li⁺、1/2Ca²⁺、1/2Mg²⁺，NH((C₁-C₄) -alkyl groups)₃ ⁺。

It is self-evident here that the nature of the radical M depends on the base used and on its strength.

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

Preference is given to alkali metal and alkaline earth metal carbonates, bicarbonates and acetates, e.g. Li₂CO₃、Na₂CO₃、NaHCO₃、K₂CO₃、CaCO₃And MgCO₃. Particularly preferred is Li₂CO₃、Na₂CO₃And K₂CO₃More particularly, Li is preferable₂CO₃And K₂CO₃. The selectivity of the reaction towards the desired end product (I) can be increased in particular by the latter two bases.

The bases may be used individually or as a mixture. In general, from 0.05 to 1 equivalent, preferably from 0.1 to 0.8 equivalent, of base is used per mole of compound of the formula (VIII), (IX) and/or (X), the base optionally being filtered off after the reaction and reused.

The activity and selectivity of the base can be controlled by a phase transfer catalyst (PTK). Suitable PTKs are typically crown ethers, hole ligands, quaternary ammonium-, * -and onium compounds. For example, known 12-crown-4, 15-crown-5, 18-crown-6, dibenzo-18-crown-6, dicyclohexyl-18-crown-6, tetrabutylammonium chloride and bromide, tetrabutyl * chloride and bromide *. 18-crown-6 is preferred. PTK is generally used in amounts of from 1 to 10, preferably from 1 to 5, mol%, based on compounds (VIII), (IX) and/or (X).

The intermediate products of the formulae (XV) and (XVI) and/or (XVII) can be isolated in accordance with customary methods familiar to the person skilled in the art, for example by removing the solvent and washing off the residue.

These compounds are also a subject of the present invention.

However, it is preferred that the intermediates of formula (XII), (XV) and/or (XVII) are not isolated beforehand but are treated with an acid to give compound (I).

Preference is given here to strong acids, e.g. aqueous or gaseous HCl, HBr, H₂SO₄And CF₃COOH. The pH of the reaction mixture is generally adjusted to 1 to 2, which is generally achieved by using 0.1 to 1 equivalent of acid, based on the theoretical amount of compound (I).

The hydrolysis of the nitrile (I) to give the amide (XI) can be carried out in accordance with known methods familiar to the expert, see for example Houben Weyl, Methoden der organischen Chemie (methods of organic chemistry).

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

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

Which are particularly suitable for further reactions to give compounds as described, for example, in WO-A98/57969, EP-A0580374 and DE 10014006.8. These documents, in particular the compounds of formula (I) and the examples, are incorporated herein by reference; they are incorporated herein by reference as part of this specification.

The present invention also relates to a process for the preparation of 4-trifluoromethylnicotinic acid derivatives with insecticidal activity according to WO-A98/57969, EP-A0580374 and/or DE10014006.8, 4-trifluoromethylnicotinonitrile as described above, optionally hydrolyzed and further reacted as described in the cited documents to give the final product of formula (I) with insecticidal activity.

The invention also relates to a method for producing compounds of the formula (XVIII), in which the compounds according to the invention are obtainedThe amide (XI) of (a) is reacted with a halogenating agent to form (XIX), which may be in the form of a salt, by reaction with R⁴R⁵S/base reaction, if appropriate with subsequent oxidation, to give the compound (XVIII),

wherein the signs and indices have the following meanings:

n is 0 or 1;

m is 0 or 1;

R⁴，R⁵are the same or different and are R⁶，-C(＝W)R⁷，-C(＝NOR⁷)R⁷，

-C(＝NNR⁷ ₂)R⁷，-C(＝W)OR⁷，-C(＝W)NR⁷ ₂，-OC(＝W)R⁷，-OC(＝W)OR⁷，-NR⁷C(＝W)R⁷，-N[C(＝W)R⁷]₂，-NR⁷C(＝W)OR⁷，-C(＝W)NR⁷-NR⁷ ₂，-C(＝W)NR⁷-NR⁷[C(＝W)R⁷]，-NR⁷-C(＝W)NR⁷ ₂，-NR⁷-NR⁷C(＝W)R⁷，-NR⁷-N[C(＝W)R⁷]₂，-N[(C＝W)R⁷]-NR⁷ ₂，-NR⁷-NR⁷[(C＝W)WR⁷]，-NR⁷[(C＝W)NR⁷ ₂]，-NR⁷(C＝NR⁷)R⁷，-NR⁷(C＝NR⁷)NR⁷ ₂，-O-NR⁷ ₂，-O-NR⁷(C＝W)R⁷，-SO₂NR⁷ ₂，-NR⁷SO₂R⁷，-SO₂OR⁷，-OSO₂R⁷，-OR⁷，-NR⁷ ₂，-SR⁷，-SiR⁷ ₃，-pR⁷ ₂，-P(＝W)R⁷，-SOR⁷，-SO₂R⁷，-PW₂R⁷ ₂，-PW₃R⁷ ₂；

Or

R⁴And R⁵Together with the sulfur atom to which they are attached form a three-to eight-membered, saturated or unsaturated, optionally once or more than once, preferably substituted by a group R⁸Substituted, preferably carbocyclic ring systems optionally containing 1 to 4 further heteroatoms, wherein two or more of these substituents optionally form one or more further ring systems;

w is O or S;

R⁶same or different is (C)₁-C₂₀) -alkyl, (C)₂-C₂₀) -alkenyl, (C)₂-C₂₀) -alkynyl, (C)₃-C₈) -cycloalkyl, (C)₄-C₈) -cycloalkenyl (C)₈-C₁₀) -cycloalkynyl, aryl or heterocyclyl; wherein the above radicals are optionally substituted one or more times, preferably radicals R⁸Substitution;

R⁷same or different and is H or R⁶。

In addition, the invention also relates to a method for preparing the compounds with the formulas (XX) and (XXI),

wherein the diazole and oxazole rings are optionally substituted, R^FIn the same sense as above, by hydrolysis from (I) prepared according to the invention,

it is also possible to prepare activated derivatives, for example by reacting the acid chloride form of (XXII) with optionally substituted compounds (XXIII) or (XXIV),

or

Wherein in the case of compound (XXIV), the alcohol function is oxidized before ring closure.

Furthermore, the invention relates to a process for preparing compounds of the formula (XXV),

wherein,

R^Fin the same sense as above and

R⁶R⁷is H or optionally substituted alkyl, alkenyl, alkynyl or cycloalkyl or together form a ring system which may also contain one or more N, S or O atoms;

wherein (XXII) obtained according to the invention,

optionally activated, and then reacted with HNR⁶R⁷And (4) reacting.

The present application expressly refers to the contents of german patent application nos. 10061967.3, 10120819.7 and 10144411.7, and the accompanying abstract, which are the basis for their priority; which is incorporated herein by reference as part of this specification.

The invention is further illustrated by the following examples, without being limited thereto.

Example 1

Isomeric mixtures of 3- (4, 4, 4-trifluoro-3-oxo-1-butenylamino) -2-propenenitrile

In a three-necked flask, 61.6 g (0.55 mol) of potassium tert-butoxide are added in advance to N₂250 ml of dimethoxyethane were added and the solution was cooled to 0 ℃. 69.5 g (0.5 mol) of 4-amino-1, 1, 1-trifluoro-3-buten-2-one and then 60.3 g (0.525 mol) of 3, 3-dimethoxypropionitrile are added dropwise at this temperature over 30 minutes. The mixture was then stirred at 30 ℃ for 3-4 hours. The reaction mixture was added to ice and acidified with HCl to pH 3-4. The precipitate was filtered off and washed with water. 71 g (75%) of product are obtained, mp: 123 ℃ and 126 ℃.¹⁹F NMR. delta.: -77.6(4 singlet) ppm.

Example 2

4-trifluoromethyl-3-pyridinecarbonitrile

In a three-necked flask, 19 g (0.1 mol) of 3- (4, 4, 4-trifluoro-3-oxo-1-butenylamino) -2-acrylonitrile are dissolved in 200 ml of methanol, and 1 g of Li is added₂CO₃. The reaction mixture was heated to reflux for 4-6 hours, cooled to 30 ℃ and 10 ml of aqueous HCl was added. The reaction mixture was stirred for 2 hours, methanol was removed under vacuum and the product was extracted with ether. The solvent was removed and the 4-trifluoromethyl nicotinonitrile was purified by vacuum distillation. 14 g (81%) of the product with a bp of 80 ℃/18 mbar are obtained.

NMR¹H(CDCl₃)δ：8.87(s，1H)，8.81(d，1H，³J_(H，H)＝5Hz)，7.51(d，1H)ppm。NMR¹⁹Fδ：-64.5(s，CF₃)ppm。

Example 3

4-trifluoromethyl-3-pyridinecarbonitrile

The reaction was carried out as described in example 2, but with 1 gK₂CO₃In place of Li₂CO₃. The yield was 75%.

Example 4

4-trifluoromethyl-3-pyridinecarbonitrile

The reaction was carried out as described in example 2, but replacing Li by 1 g of sodium acetate₂CO₃. The yield was 64%.

Example 5

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-1-butenylamino) -2-propenenitrile in the presence of N₂Then dissolved in 20 ml of methanol and 0.2 g of NaOMe are added. The reaction mixture was stirred at RT for 10-14 hours, and then methanol was removed as much as possible under vacuum. 50 ml of anhydrous ether was added. The product was purified by recrystallization from ethyl acetate. 1.5 g of product are obtained as a white solid. mp: 121 ℃ and 123 ℃.¹HNMR(CD₃OD) (ABX spin System) 1.72dd (H)_A)，1.91dd(H_B)，3.22(s，3H)，4.52dd(1H)，6.88(s，1H)ppm。

The product was reacted with HCl at RT to give 4-trifluoromethyl-3-pyridinecarbonitrile. The yield was 95%.

Example 6

Isomeric mixtures of 3-methoxy-3- (Z and E) -4, 4, 4-trifluoro-3-oxo-1-butenylaminopropionitrile

In a three-necked bottle, N is preliminarily set₂61.6 g (0.55 mol) of potassium tert-butoxide are added to 250 ml of dimethoxyethane and the solution is cooled to 0 ℃. 69.5 g (0.5 mol) of 4-amino-1, 1, 1-trifluoro-3-buten-2-one and then 43.5 g (0.525 mol) of 3-methoxypropionitrile are added dropwise over 30 minutes at this temperature. The mixture was then stirred at 5-10 ℃ for 3-4 hours. The reaction mixture was added to ice and acidified with HCl to pH 3-4. The product is extracted with diethyl ether, dried and removed under vacuumAnd (4) removing the solvent. 81 g (75%) of oil were obtained.¹⁹F NMRδ：-77.5(s)：77.6(s)ppm。

Example 7

Isomeric mixtures of 3- (4, 4, 4-trifluoro-3-oxo-1-butenylamino) acrylonitrile

In a1 liter four-necked flask equipped with thermometer, KPG stirrer, dropping funnel with bubble counter, downflow condenser with cooled (-10 ℃) receiver and vacuum connection₂Next 117 g of potassium tert-butoxide are added to 700 ml of DMF and the solution is cooled to 0 ℃. At this temperature 142 g of 4-amino-1, 1, 1-trifluoro-3-buten-2-one are added dropwise over 30 minutes. After the end of the dropwise addition, 117 g of 3, 3-dimethoxypropionitrile 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 is then stirred at 30-35 ℃ and 20-25 mbar vacuum for 3-5 hours, the low boilers (methanol, tert-butanol) being removed simultaneously in vacuum and condensed in a receiver.

The reaction mixture is added to 1000 g of ice containing 40 ml of HCl (d1.19) at 0-10 ℃ and, if necessary, adjusted to a pH of 2-3 using HCl. After 1 hour, the precipitate was filtered off, washed with ice water and the product was dried. 175 g (92%) of 3- (4, 4, 4-trifluoro-3-oxo-1-butenylamino) acrylonitrile are obtained as a mixture of 4 stereoisomers. mp: 120 ℃ and 126 ℃. Purity of 99%

Example 8 (comparative example)

Isomeric mixtures 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. The yield was 71%. The purity was 93%.

Example 9

3- (4, 4, 4-trifluoro-3-oxo-1-butenylamino) acrylonitrile

The reaction was carried out as described in example 1, but with NaOMe as base. The yield was 86%.

Example 10

Isomeric mixtures of 3- (4, 4, 4-trifluoro-3-oxo-1-butenylamino) acrylonitrile

The reaction was carried out as described in example 1, but with NaOtBut as base. The yield was 89%.

Example 11

4-trifluoromethyl nicotinonitrile

In a three-necked flask, 19 g (0.1 mol) of 3- (4, 4, 4-trifluoro-3-oxo-1-butenylamino) acrylonitrile are dissolved in 200 ml of methanol and 0.5 g of Li is added₂CO₃. The reaction mixture was heated to reflux for 10 hours. The methanol was removed under vacuum and 30 ml of HCl was added. After 1 hour, the product was extracted, the solvent was removed, and 4-trifluoromethyl nicotinonitrile was purified by vacuum distillation. 14.5 g (84%) of a product with a bp of 80 ℃/18 mbar are obtained. NMR¹H(CDCl₃)δ：9.35(s)，8.0(d，1H，³J_(H，H)＝5Hz)，7.8(d，1H，＝CH)，3.8(s，2H)；2.2(s，3H)ppm。NMR¹⁹Fδ：-64.5(s，CF₃)ppm。

Example 12

Preparation of 3- (4, 4, 4-trifluoro-3-oxo-1-butenylamino) acrylonitrile

A tubular reactor: an internal diameter of 4cm, a heating mantle, half-filled glass spheres, a cooling receiver, and a vacuum-connected 60cm long glass tube with a cold trap.

Preparation of the reaction mixture.

N-methylpyrrolidone (NMP) (800 ml) is cooled to 0 ℃ and 69.5 g of 4, 4, 4-trifluoro-1-aminobut-2-en-3-one, 92 g of a 30% NaOMe solution in methanol and 60 g of 3, 3-dimethoxypropionitrile are added slowly in succession at this temperature with stirring. This mixture was transferred to a receiver.

Reaction step

The tube reactor was filled with NMP, the mantle heated to 80-85 ℃ and a vacuum of 30-35 mbar applied. The reaction mixture was added uniformly from the receiver to the tubular reactor over 1 hour. The reaction time was 7-8 minutes at 80-85 ℃ with methanol condensed in a cold trap. After complete addition, a further 120 ml of NMP were added dropwise to completely drain the reaction mixture from the reactor. The reaction mixture was added to ice water and HCl, adjusted to pH 2-3 using HCl if necessary. The precipitated product was filtered off and washed with water. 88 g (90%) of w.w% 3- (4, 4, 4-trifluoro-3-oxo-1-butenylamino) acrylonitrile with a purity of 99% were obtained as a mixture of isomers with 4 stereoisomers. mp: 124 ℃ and 126 ℃.

Claims

1. A compound of formula (VIII), (IX) or (X),

R^F-C(O)-CH＝CH-NH-CH＝CH-CN (VIII)

R^F-C(O)-CH＝CH-NH-CH(ZR¹)-CH₂-CN (IX)

R^F-C(O)-CH＝CH-NH-CH(Hal)-CH₂-CN (X)

wherein

R^FIs halo C₁-C₄An alkyl group;

R¹is C₁-C₆An alkyl group;

z is O, S or OCO and

hal is Cl or Br.