HK1031871B - Process for preparing heterocyclic compounds - Google Patents

Description

Process for preparing heterocyclic compounds

Technical Field

The present invention relates to a novel process for the preparation of known heterocyclic compounds by alkylation of suitable precursors.

Background

Such alkylation reactions carried out in aprotic solvents are known (EP A20235725).

It is also known to prepare unsaturated heterocyclic compounds by alkylating unsubstituted ring nitrogen atoms in alcohols (EP a 20259738).

In these cases, the product needs to be subsequently purified to achieve sufficient purity; moreover, the yields obtained with the known processes are insufficient.

Disclosure of Invention

It has now been found that compounds of the general formula (I)

Wherein

R¹Represents a hydrogen atom or an alkyl group,

a represents an ethylene group which may be substituted by an alkyl group, or a trimethylene group which may be substituted by an alkyl group,

x represents an oxygen or sulphur atom or a group of formula

Wherein

R³Represents a hydrogen atom or an alkyl group, and

z represents an optionally substituted 5-or 6-membered heterocyclic group containing at least two hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, or represents an optionally substituted 3-or 4-pyridyl group,

can be prepared by reacting a compound of formula (II)

Wherein

A and X are each as defined above

With compounds of the formula (III)

Wherein

R¹And Z are each as defined above, and

M¹represents halogen or a group-OSO₂-M²

Wherein

M²Represents lower alkyl, aryl or OM³，

Wherein

M³Represents a lower alkyl group or an alkali metal,

in the presence of a protic solvent, if appropriate in the presence of a base, and then crystallizing with an alcohol.

The process of the present invention avoids the purification step of recrystallization, which is necessary in the prior art to date and requires a reduced one-step operation.

Surprisingly, the process of the invention gives a much higher yield than the prior art process.

Although the reaction of the compound of formula (III) with the compound of formula (II) is carried out in a protic solvent in the process according to the invention, contrary to what was expected, no ether formation in the Wlliamson reaction (see textbook on organic chemistry) was observed.

In the general formulae I, II and III,

R¹preferably represents a hydrogen atom or C₁-C₃Alkyl, particularly preferably a hydrogen atom;

a preferably represents a group which may be independently substituted by C₁-C₃Alkyl-substituted ethylene or trimethylene groups, particularly preferably ethylene;

x preferably represents an oxygen atom or a sulfur atom, particularly preferably a sulfur atom;

z preferably represents a halogenated 5-or 6-membered heterocycle containing 2 heteroatoms selected from oxygen, sulphur and nitrogen atoms or represents a halogenated 3-or 4-pyridyl group, particularly preferably a halogenated thiazolyl or 3-pyridyl group, very particularly preferably a 2-chloro-pyridin-5-yl group;

m preferably represents Cl, Br, tosyl or OSO₂OK, particularly preferably Cl or Br.

Particularly preferred compounds of the formula (I) are those of the following general formula (Ia)

The compound can be prepared by reacting a compound of the formula

With a compound of the formula

And reacting to prepare the compound.

In the terminology relating to alkyl, alkoxy, alkylthio or alkylsilyl, the term "lower" represents C₁-C₆Preferably C₁-C₄-alkyl, -alkoxy, -alkylthio or-alkylsilyl.

Particularly suitable polar protic solvents are water and alcohols or mixtures of water and alcohols. If the solvent used is an alcohol (and preferably an alcohol), the compounds of the general formula (I) can be obtained directly in the modification, which is advantageous for their use as plant protection agents and to give the desired purity.

Examples of alcohols which may be mentioned are:

primary alcohols, such as methanol, ethanol, propanol, butanol, 2-methyl-1-propanol, 1-pentanol, benzyl alcohol,

secondary alcohols, such as isopropanol, sec-butanol, 2-pentanol, tertiary alcohols, such as tert-butanol.

Particularly preferred solvents are alcohols which are not or only partially miscible with water, such as isobutanol or n-butanol or pentanol, n-butanol being particularly preferred.

If appropriate, the process can be carried out in the presence of a base. Examples of bases which may be mentioned are: alkali metal hydroxides and alkaline earth metal hydroxides, e.g. NaOH, KOH, Ca (OH)₂Alkali metal carbonates or bicarbonates, e.g. Na₂CO₃，Li₂CO₃，K₂CO₃，Cs₂CO₃Or NaHCO₃And KHCO₃. Preferably K₂CO₃NaOH and KHCO₃Particularly preferably K₂CO₃。

The compounds of the general formula (II) can be used in solid or dissolved form with alkali metal or alkaline earth metal salts.

If the reaction is carried out in water or a water/alcohol mixture, the process can be carried out at a pH in the range from 8 to 13.

The catalyst used may be a phase transfer catalyst, if appropriate a quaternary ammonium halide, such as tetrabutylammonium chloride or the like.

The process can be carried out over a wide temperature range, for example between 30 ℃ and 100 ℃, preferably between 50 ℃ and 80 ℃. The reaction is preferably carried out at atmospheric pressure; however, it may be carried out under reduced pressure or increased pressure.

In the practice of this process, for example, 1mol of a compound of the formula (II) is reacted with 1 to 1.3mol, preferably 1 to 1.1mol, of a compound of the formula (III) at pH8-9 and in a polar solvent, such as butanol, in the presence of 0.6 to 2mol, preferably 1 to 1.3mol, of a base, such as potassium carbonate, and, if appropriate, in the presence of a catalyst, such as tetrabutylammonium chloride.

The reaction can also be carried out at the reaction temperature with the corresponding amount of compound of the formula (III) in dissolved or suspended form at the initial addition of the alkali metal salt or alkaline earth metal salt of the compound of the formula (II).

The compounds of the general formulae (II) and (III) are known and are disclosed in EP0235725 (which is incorporated herein by reference).

Compounds of the general formula (I) are suitable, for example, as insecticides (EP A20235752, EP A20259738).

Detailed Description

The following examples illustrate the subject matter of the invention, but do not limit the invention in any way.

Example 1

0.3mol of 2-cyanoiminothiazolidine and 0.315mol of 2-chloro-5-chloro-methylpyridine are dissolved in 240g of n-butanol, and the solution is heated to 80 ℃. At this temperature, 0.36mol of potassium carbonate are metered in and the mixture is stirred for 2 hours at 80 ℃. After cooling (to 65 ℃ C.), 250g of water are added and the aqueous and organic phases are separated. The organic phase is then stirred at 50 ℃ for 3 hours and subsequently cooled to 3 ℃ over 3 hours. Filtering the precipitated product and drying; 62.3g (83% of theory) are obtained. M.P.: 135 ℃ is adopted.

Example 2

0.3mol of 2-cyanoiminothiazolidine and 0.315mol of 2-chloro-5-chloro-methylpyridine and 0.015mol of tetrabutylammonium bromide are suspended in water and the suspension is heated to 60 ℃. The pH of the reaction mixture was continuously maintained at 8 to 8.5 with NaOH. After 2 hours at 60 ℃ the aqueous and organic phases were separated at this temperature and the organic phase was diluted with 200ml butanol and stirred for 3 hours at 50 ℃. The mixture was cooled to 3 ℃ over 3 hours and the precipitated product was filtered by suction; 55.5g (72% of theory) are obtained.

Example 3

39.3g of 97% strength 2-cyanoiminothiazolidine (< ═ 0.3mol) were dissolved in 250g of 80% strength n-butanol (containing 20% water) and mixed with 26.7g of 45% strength aqueous sodium hydroxide (0.3 mol). The resulting pale green solution was mixed at 65 ℃ with 49.5g of 95% strength 2-chloro-5-chloromethylpyridine (0.29 mol). After 3.5 hours of reaction, 190g of water were added and the phases were separated. 60g of n-butanol/water are distilled off from the organic phase. The organic phase was then cooled to 50 ℃. Seed crystals were added and cooling continued to 0 ℃. At this temperature, the mixture was stirred for 3 hours to crystallize. Filtration and drying gave 61.8g of product having a purity of 96% (87% of theory).

Claims (4)

1. Process for the preparation of compounds of the general formula (I)

Wherein

R¹Represents a hydrogen atom or C₁-C₃An alkyl group, a carboxyl group,

a represents ethylene which may be substituted by C₁-C₃Alkyl is substituted or represents a group which may be substituted by C₁-C₃An alkyl-substituted trimethylene group, a trimethylene group,

x represents an oxygen or sulphur atom,

z represents a halogenated 5-or 6-membered heterocyclic ring containing at least two heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms, or represents a halogenated 3-or 4-pyridyl group,

characterized in that a compound of formula (II)

Wherein

A and X are as defined above

With compounds of the formula (III)

Wherein R is¹And Z are each as defined above and

M¹represents Cl, Br, tosyl or OSO₂-OK，

In the presence of an alcohol selected from the group consisting of isobutanol, n-butanol or pentanol, and in the presence or absence of a base.

2. A process according to claim 1, characterized in that a compound of formula (II) in which A represents an ethylene group and X represents a sulfur atom is reacted with R¹Represents hydrogen, Z represents 2-chloro-pyridin-5-yl, M¹Reacting a compound of formula (III) representing Cl or Br.

3. A process for the preparation of a compound of formula (Ia) according to claim 1,

characterized in that a compound of the general formula (IIa) is reacted with a compound of the general formula (IIIa)

4. A process according to any one of claims 1-3, characterized in that n-butanol is used.