Preparation of 4-haloalkylnicotinamides

Abstract

A process for preparing 4-haloalkylnicotinamides of the formula (I) where R1 is (C1-C4-haloalkyl, which comprises subjecting one or more 3-((C1-C4)-haloalkyl-3-oxo-1-alkenylamino)nitriles of the formula (II), (III) and/or (IV) R1—C(O)—CH=CH—NH—CH=CH—CN  (II) R1—C(O)—CH=CH—NH—CH(ZR2)—CH2—CN  (III) R1—C(O)—CH=CH—NH—CH(Hal)—CH2—CN  (IV) where R1 is as defined above; R2 is the same or different and is (C1-C6)-alkyl and Z is the same or different and is O, S or NR1, to a ring-closing reaction and simultaneous hydrolysis in the presence of a strong acid. The compounds of the formula (I) are useful as intermediates for preparing pesticides.

Description

The present invention relates to a process for preparing 4-haloalkyinicotinamides.

4-Haloalkylnicotinamides are useful starting materials for preparing pesticides, as described, for example, in WO-A 98/57 969, EP-A 0 580 374 and WO-A 01/70692.

These compounds can be prepared in two stages from 4-haloalkylnicotinic acids whose synthesis is described, for example, in EP-A 0 744 400, or by hydrolysis of 4-haloalkylnicotinonitriles, see, for example, WO-A 02/048111.

Surprisingly, a simple process has now been found for preparing 4-haloalkylnicotinamides, especially trifluoromethyinicotinamide, by cyclization and hydrolysis of 3-(haloalkyl-3-oxo-1-butenylamino)acrylonitriles in the presence of a strong acid.

The invention therefore provides a process for preparing 4-haloalkylnicotinamides of the formula (I)
where

• • R¹ is (C₁-C₄)-haloalkyl,
    which comprises subjecting
  • one or more 3-((C₁-C₄)-haloalkyl-3-oxo-1-alkenylamino)nitriles of the formula (II), (III) and/or (IV)
    R¹—C(O)—CH=CH—NH—CH=CH—CN  (II)
    R¹—C(O)—CH=CH—NH—CH(ZR²)—CH₂—CN  (III)
    R₁—C(O)—CH=CH—NH—CH(Hal)—CH₂—CN  (IV)
    where
  • R¹ is as defined above;
  • R² is the same or different and is (C₁-C₆)-alkyl and
  • Z is the same or different and is O, S or NR¹,
    to a ring-closing reaction and simultaneous hydrolysis in the presence of a strong acid.

The process according to the invention enables the preparation of the nicotinamide derivatives (I) from the nitrile derivatives (II-IV) in only one step and is additionally particularly simple to carry out. This is particularly surprising because it is known that the hydrolysis of 4-trifluoromethylnicotinonitrile to the amide is only achieved by heating to 120-140° C. for 8 h in concentrated H₂SO₄.

“(C₁-C₄)-Haloalkyl” is an alkyl group in which one or more hydrogen atoms are replaced by the same number of identical or different halogen atoms, preferably chlorine or fluorine, such as the trifluoromethyl, the 1-fluoroethyl, the 2,2,2-trifluoroethyl, the chloromethyl, the fluoromethyl, the difluoromethyl and the 1,1,2,2-tetrafluoroethyl group.

The symbols in the formulae (I) to (IV) are preferably defined as follows:

• • R¹ is preferably CF₂H, CFCl₂, CF₂Cl, CF₃, C₂F₅ or C₃F₇, more preferably CF₃.
  • R² is preferably (C₁-C₄)-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, more preferably methyl or ethyl, most preferably methyl.
  • Z is preferably O or NR¹.
  • Hal is F, Cl, Br or I, preferably Cl or Br.

The starting materials, 3-(haloalkyl-3-oxo-1-alkenylamino)acrylonitrile derivatives (II) or enamines of the formulae (III) and (IV), are known and can be prepared, for example, as described in WO-A 02/048111.

The cyclization to the 4-haloalkylnicotinamides (I) takes place in the presence of a strong acid, preferably having a pK_a value of below 0.5. During the cyclization in the strongly acidic medium, the transformation of the nitrile group also takes place.

Particularly preferred acids are H₂SO₄, SO₃, oleum, phosphoric acid, polyphosphoric acids, perfluoroalkanesulfonic acids, such as trifluoromethylsulfonic acid, methanesulfonic acid and p-toluenesulfonic acid, and very particular preference is given to H₂SO₄ and polyphosphoric acid, special preference to H₂SO₄.

It is also possible to use acid mixtures.

Depending on the compound, acid and further reaction conditions used, the ratio of the compound(s) (II), (III) and/or (IV) to acid can vary within a wide range.

In general, the amount of acid used is from 4 to 30 parts by weight, preferably from 6 to 15 parts by weight, per part by weight of compound (II)-(IV).

Depending on the compound used and other reaction conditions, the reaction temperature can vary within wide limits. In general, it is in the range from 0° C. to +40° C., and the reaction time is typically from 0.1 to 6 h, preferably from 3 to 5 h.

The reaction conditions also vary in a manner familiar to those skilled in the art, depending on whether a compound of the formula (II), (III) or (IV) is used.

The reaction can be carried out in a solvent. The components (II-IV) and the acid can be initially charged separately in the solvent and these solutions/suspensions reacted together, or one of the components is initially charged in the solvent and the other component is added.

Preferred solvents are halogenated hydrocarbons such as methylene chloride or chloroform, ethers such as diethyl ether or diisopropyl ether, and SO₂. The amount of solvent used can vary within wide limits and depends, for example, on which starting material is used. It is generally up to 30 parts by weight, preferably from 6 to 15 parts by weight, per part by weight of compound (II)-(IV).

The workup can be effected by known methods familiar to those skilled in the art, for example by dilution with water and filtration or extraction of the product.

Depending on the nature of the cyclization reagent (e.g. SO₃, oleum, concentrated H₂SO₄), aqueous workup is strictly necessary to release the amide from its precursor, if necessary, and to isolate it.

The compound (I), in particular 4-trifluoromethylnicotinamide, finds use, for example, as an intermediate in the preparation of crop protection agents, in particular pesticides, such as insecticides.

It is particularly suitable for further conversion to compounds, as described in WO-A 98/57969, EP-A 0 580 374 and WO-A 01/07692. These documents, in particular the compounds of the formula (I) in each case and the exemplary embodiments, are explicitly incorporated herein by reference.

The invention also provides a process for preparing insecticidally active 4-haloalkylnicotinic acid derivatives, in particular 4-trifluoromethylnicotinic acid derivatives, according to WO-A 98/57969, EP-A 0 580 374 and/or WO-A 01/70692, by preparing the above-described compounds of the formula (I), subjecting these to a ring-closing reaction, optionally hydrolyzing them and further reacting them by processes described in the documents cited to give the insecticidally active end compounds.

The content of German patent application 102 23 274.1, from which this application claims priority, and of the enclosed abstract is hereby incorporated by reference.

The invention is illustrated by the examples which follow, without being limited by them.

EXAMPLE NO. 1

4-Trifluoromethylnicotinamide

A three-neck flask was initially charged under N₂ with 100 ml of H₂SO₄ (d 1.8) and the solution was cooled to 10° C.

30 g (0.5 mol) of N-(2-cyanovinyl)-4,4,4-trifluoro-3-keto-1-butenylamine were added at this temperature within 1 h.

Subsequently, the mixture was stirred at room temperature (RT) for 3-5 h. The reaction mixture was added to 300 g of ice, the pH adjusted to 3-4 using 40% by weight NaOH and the product extracted using ethyl acetate. The solvent was removed under reduced pressure.

27 g (90%) of the amide were obtained, m.p.: 166-167° C.

¹⁹F NMR δ: −60.0 (singlet) ppm.

EXAMPLE NO. 2

4-Trifluoromethylnicotinamide

The procedure of example 1 was repeated, except using polyphosphoric acid instead of H₂SO₄. The reaction mixture was heated to 40° C. for 4 h and 24 g (80%) of the product having a melting point of 165° C. were obtained.

EXAMPLE NO. 3

4-Difluoromethylnicotinamide

The procedure of example 1 was repeated, except that N-(2-cyanovinyl)-4,4-difluoro-3-keto-1-butenylamine was used instead of N-(2-cyanovinyl)-4,4,4-trifluoro-3-keto-1-butenylamine.

Yield 65%. m.p.: 124-125° C.

Claims

1. A process for preparing 4-haloalkylnicotinamides of the formula (I) where

R1 is (C1-C4)-haloalkyl,

which comprises subjecting

one or more 3-((C1-C4)-haloalkyl-3-oxo-1-alkenylamino)nitriles of the formula (II), (III) and/or (IV)

R1—C(O)—CH=CH—NH—CH=CH—CN (II)

R1—C(O)—CH=CH—NH—CH(ZR2)—CH2—CN (III)

R1—C(O)—CH=CH—NH—CH(Hal)-CH2—CN (IV)

where

R1 is as defined above;

R2 is the same or different and is (C1-C6)-alkyl and

Z is the same or different and is O, S or NR1,

to a ring-closing reaction and simultaneous hydrolysis in the presence of a strong acid having a pKa value of below 0.5.

2. The process as claimed in claim 1, wherein R1 in the formula (I) is CF2H, CFCl2, CF2Cl, CF3, C2F5 or C3F7.

3. The process as claimed in claim 2, wherein R1 in the formula (I) is CF3.

4. The process as claimed in claim 1, carried out in the presence of one or more acids selected from the group consisting of H2SO4, SO3, oleum, phosphoric acid, polyphosphoric acids, perfluoroalkanesulfonic acids, methanesulfonic acid and p-toluenesulfonic acid is used.

5. The process as claimed in claim 4, carried out in the presence of H2SO4.

6. The process as claimed in claim 1, carried out in a solvent.

7. The process as claimed in claim 2, carried out in the presence of one or more acids selected from the group consisting of H2SO4, SO3, oleum, phosphoric acid, polyphosphoric acids, perfluoroalkanesulfonic acids, methanesulfonic acid and p-toluenesulfonic acid.

8. The process as claimed in claim 3, carried out in the presence of one or more acids selected from the group consisting of H2SO4, SO3, oleum, phosphoric acid, polyphosphoric acids, perfluoroalkanesulfonic acids, methanesulfonic acid and p-toluenesulfonic acid.

9. The process as claimed in claim 7, carried out in the presence of H2SO4.

10. The process as claimed in claim 8, carried out in the presence of H2SO4.

11. The process as claimed in claim 2, wherein the reaction is carried out in a solvent.

12. The process as claimed in claim 3, wherein the reaction is carried out in a solvent.

13. The process as claimed in claim 4, wherein the reaction is carried out in a solvent.

14. The process as claimed in claim 5, wherein the reaction is carried out in a solvent.

15. The process as claimed in claim 7, wherein the reaction is carried out in a solvent.

16. The process as claimed in claim 8, wherein the reaction is carried out in a solvent.

17. The process as claimed in claim 9, wherein the reaction is carried out in a solvent.

18. the process as claimed in claim 10, wherein the reaction is carried out in a solvent.