EP3464283A1 - Method for producing heterocyclic compounds - Google Patents

Abstract

The invention relates to a method for producing compounds of formula (I), in which R¹, A, X and Z have the meaning given in the description, by reacting compounds of formula (II) or the salts thereof with 2-chloro-5-chloromethylpyridine in a non-polar aliphatic or aromatic solvent in the presence of a phase transfer catalyst.

Description

 Process for the preparation of heterocyclic compounds

The present invention relates to a novel process for the preparation of known heterocyclic compounds of the formula I.

It is known to produce unsaturated, heterocyclic compounds by the alkylation of unsubstituted ring material atoms which can be carried out, inter alia, in alcohol (EP 0 259 738) or in only partially water-miscible alcohols (and EP 1 252 159).

EP 1024140 describes the reaction of compounds of the formula (II)

with 2-chloro-5-chloromethylpyridine in the presence of protic solvents

As protic solvents in particular alcohols are proposed. Mention is also made of the addition of phase transfer catalysts such as tetrabutylammonium bromide. However, in Example 2 shown (page 5) EP 1024140 only 72% d. Theory of the product, which is clearly not enough for a process on an industrial scale.

In all these cases, therefore, the yield achieved is only unsatisfactory. A subsequent purification of the product is therefore necessary to achieve sufficient purity and therefore very expensive. There was therefore an urgent need for an improved process which makes it possible to produce the desired product of the formula I in a manner which is simple to carry out industrially and yet at higher yields.

SUMMARY

One aspect of the present invention relates to a process for the preparation of compounds of the formula (I)

in which

R 1 represents a hydrogen atom or an alkyl group, preferably a C 1 -C 4 -alkyl group,

A is an ethylene group which may be substituted by alkyl, preferably C 1 -C 4 -alkyl, or a trimethylene group which may be substituted by alkyl, preferably C 1 -C 4 -alkyl,

X is an oxygen or sulfur atom or the groups

- LH or -CH-R ³ , in which represents a hydrogen atom or an alkyl group, preferably a C 1 -C 4 alkyl group, and

Z denotes an optionally substituted 5- or 6-membered heterocyclic group which contains at least two heteroatoms selected from oxygen, sulfur and nitrogen atoms, or denotes an optionally substituted 3- or 4-pyridyl group, characterized in that compounds of the formula (II )

(Π) or salts thereof of the formula (Ha),

n

(IIa) in which

A and X have the meanings given above, n depending on the counterion (M ^{n +} ) can be one or two,

M ^{n +} ammonium (n = 1), alkali (n = 1) or alkaline earth metal cation (n = 2), in a nonpolar aliphatic or aromatic organic solvent in the presence of a phase transfer catalyst, preferably an ammonium salt, more preferably a quaternary ammonium salt, with 2 -Chloro-5-chloromethylpyridine.

A preferred embodiment relates to a method according to the invention, wherein the phase transfer catalyst is an ammonium salt of the formula - N-R5 anion

R6 wherein R4, R5, R6 is hydrogen or a Ci-Ci ₂ alkyl group, or benzyl or alkylbenzyl stand, preferably a Ci-Ci ₂ -alkyl group (for clarity, is in -N (-NR4R5R6) ^"1" the well-known shorthand notation for a methyl group, (-NR4R5R6) ^"1" is the short notation of (Me-NR4R5R6) ⁺ ), and

Anion ^"is OH, chloride, bromide, iodide or cyanide; or

R4

R ₇ - N-R 5 An ion

R6 wherein R4, R5, R6 is hydrogen or a Ci-Ci ₂ alkyl group, or benzyl or - alkylbenzyl (preferably C ₁₂ - alkylbenzyl) are provided and R7 is a Ci-Ci ₂ alkyl group, or - benzyl or alkylbenzyl is , preferably a Ci-Ci ₂ alkyl group are, and anion ^"OH, chloride, bromide, iodide or cyanide is, preferably represents chloride.

A preferred embodiment relates to a process according to the invention, in which the organic-soluble quaternary ammonium salt is Aliquat 336 (methyltri-n-octylammonium chloride).

A preferred embodiment relates to a process according to the invention in which the solvent is selected from benzene, toluene, xylene, mixtures thereof or hexane, cyclohexane, methylcyclohexane and mixtures thereof.

A preferred embodiment relates to a process according to the invention, wherein the solvent is toluene.

A preferred embodiment relates to a method according to the invention, wherein M ^{+ represents} a Na ⁺ ion. A preferred embodiment relates to a process according to the invention, wherein the compound of the formula (I) is the compound of the formula (Ia)

(Ia), characterized in that compounds of the formula (IIb)

(IIb) in the presence of a base, preferably NaOH, or salts thereof of the formula (He),

(IIc) where n is, depending on the counterion, M ^{n +} one or two and M ^{n + is} an ammonium (n = 1), an alkali (n = 1) or an alkaline earth metal cation (n = 2), preferably a Na ⁺ ion, in Presence of a phase transfer catalyst as described herein with 2-chloro-5-chloromethylpyridine. It will be understood by those skilled in the art that all embodiments described herein may be combined with each other but, of course, combinations that conflict with the laws of nature are excluded.

Surprisingly, it has now been found that a significantly better yield can be achieved, especially when using non-polar solvents such as aliphatic or aromatic hydrocarbons and the use of a suitable phase transfer catalyst.

Compounds of the formula (I)

With

is a hydrogen atom or an alkyl group, preferably a Ci-C / t-alkyl group, is an ethylene group which may be substituted by alkyl, preferably by a Ci-C / t-alkyl, or a trimethylene group, which is alkyl, preferably by a C ₁ -C 4 alkyl, may be substituted, represents an oxygen or sulfur atom or the groups or -CH-R ³ , in which

R ^{3 is} a hydrogen atom or an alkyl group, preferably a Ci-C / t-alkyl group, and

Z is an optionally substituted 5- or 6-membered heterocyclic group containing at least two heteroatoms selected from oxygen, sulfur and nitrogen atoms, or denotes an optionally substituted 3- or 4-pyridyl group, obtained by reacting compounds of the formula (II ) or ammonium, alkali or alkaline earth metal salts of the compound of formula IIa

n

(IIa) in which n, depending on the counterion (M ^{n +} ), can be one or two,

M ^{n +} = ammonium (n = 1), alkali (n = 1) or alkaline earth cation (n = 2), and

A and X have the meanings given above,

in the presence of an organically soluble phase transfer catalyst with 2-chloro-5-chloromethylpyridine of the formula (ΠΙ).

(ΙΠ) Surprisingly, the abovementioned compounds can be prepared in a simpler manner, that is to say in a smaller number of process steps and in significantly better yields, by the process according to the invention.

In a preferred embodiment, in the general formulas (I) and (II) and (IIa), the variables (insofar as they occur in one of the three formulas)

R ^{1 is} preferably hydrogen or a C ¹ -C ³ -alkyl group, more preferably hydrogen;

A is preferably an ethylene or trimethylene group, which may each be substituted by a C 1 -C 3 -alkyl group, particularly preferably an ethylene group;

X is preferably an oxygen or sulfur atom or the group

L H particularly preferred for an oxygen atom or the group

-L H

Z preferably represents a halogenated, 5- or 6-membered heterocyclic group which contains 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen or a halogenated 3- or 4-pyridyl group, more preferably a halogenated thiazolyl or 3-pyridyl group , most preferably 2-chloro-pyrid-5-yl.

A very particularly preferred embodiment is directed to a process for preparing a compound of formula (Ia),

by reacting the compound of formula (IIb)

(IIb) is obtained with an inorganic base and in the presence of a nonpolar aliphatic or aromatic organic solvent, preferably an aromatic hydrocarbon such as toluene or xylene, and by subsequent reaction with 2-chloro-5-chloromethylpyridine, particularly preferably, wherein the reaction in the presence a phase transfer catalyst, or by reacting the compound of formula (IIc)

(IIc) where n is, depending on the counterion, M ^{n +} 1 or two and M ^{n + is} an ammonium (n = 1), an alkali metal (n = 1) or an alkaline earth metal cation (n = 2), preferably a Na ⁺ ion.

Preferred inorganic bases are ammonium-containing bases, or alkali or alkaline earth metal, particularly preferably NaOH.

As solvents, it is possible to use all nonpolar aliphatic or aromatic solvents or mixtures thereof.

Examples of aromatic solvents which may be mentioned are: benzene, toluene or xylene or mixtures thereof; Hexane, cyclohexane, methylcycolohexane or mixtures thereof; and mixtures of aliphatic and aromatic solvents. Particularly preferred is toluene.

To improve the conversions and yields in addition phase transfer catalysts such as

R4

¹ +

 - N-R5 anion

wherein R4, R5, R6 is hydrogen or a Ci-Ci ₂ alkyl group or benzyl or alkylbenzyl (methyl-N (R4, R5, R6) ⁺ anion ^" , or

R4

 I.

 R N-R5 anion

 I

R6 wherein R4, R5, R6 is hydrogen or a Ci-Ci ₂ alkyl group, or benzyl or alkylbenzyl stand and R7 is a Ci-Ci ₂ alkyl group, or benzyl or alkylbenzyl group, preferably a C ₁ -C ₁₂ - alkyl group stands,

 (IIa)

And anion ^" for OH, chloride, bromide, iodide, or cyanide, particularly preferably chloride is used.

Especially preferred phase transfer catalysts are organic löslische quaternary ammonium salts, particularly preferred quaternary Ci-Ci ₂ alkyl ammonium halide salts, particularly preferably C ₁ -C ₁₂ - alkyl ammonium chloride salts, such as Aliquat 336 (methyl-tri-n-octylammonium chloride).

In the presence of water, the process is carried out in a pH range between 6 and 14. The range is preferably between pH 10 and pH 13. The reaction may be carried out at temperatures of 10 ° C to 130 ° C such as 15 ° C to 130 ° C, optionally in vacuo or under pressure. Preference is 40 to 80 ° C.

The reaction is conveniently carried out under atmospheric pressure, but it is also possible to work under reduced or elevated pressure.

In the practice of the process, for example, 1 mole of the 2-chloro-5-chloro-methylpyridine with 0.95 to 3 moles of the compounds of formula (II), preferably 1.0 to about 2.5 moles, in a solvent such Toluene is preferably reacted in the presence of a Katlaysators such as methyltrioctylammonium chloride (Aliquat 336).

When using water in a two-phase system is preferably carried out at pH 8 -13.

The reaction time is between 0.1 and 12 hours, preferably 1 to 5 hours.

After completion of the reaction, by simply cooling below the reaction temperature, for. To 10 ° C or less, such as in the range of -10 ° C to 10 ° C, in the range of 0 ° C to 10 ° C or below 10 ° C as in the range of 0 ° C to 9 ° C, and Filtration the product to be isolated.

Alternatively, the phases can also be separated first. The separation of the organic phase takes place at 50 ° C to 120 ° C, preferably at 40 to 80 ° C. The mixture is then cooled as described above and the precipitated active ingredient is isolated, washed and optionally recrystallized.

The compounds of the formula (I) are suitable, for example, for use as insecticides (EP A2 0235 752, EP A2 0259 738).

The following examples illustrate the subject matter of the invention without limiting it in any way.

example 1

0.501 mole of CCMP (2-chloro-5-chloromethylpyridine) was placed in 260 g of toluene together with 5 g of Aliquat 336 (methyltri-n-octylammonium chloride) and heated to 70 ° C. For this purpose, 250 g of a 29.8% solution of 2-cyaniminothiazolidine Na salt (0.5 mol) in water were metered in for 1 h. Thereafter, stirring was continued until complete conversion of Cyaniminothiazolidins. The mixture was then cooled to 10 ° C and filtered.

The solid obtained was then washed twice with 70 g of 10 ° C cold toluene. After drying in vacuo 119 g of the 98.5% active ingredient were thus obtained (92.5% of theory, mp 136-137 ° C).

Example 2

12 moles of CCMP (2-chloro-5-chloromethylpyridine) were charged in 1207 g of toluene together with 71 g of Aliquat 336 (methyltri-n-octylammonium chloride) and heated to 60 ° C. Within 2 h, 11.6 moles of a 29.8% strength solution of 2-cyanoiminothiazolidine Na salt in water were metered in for this purpose. Thereafter, stirring was continued until complete conversion of Cyaniminothiazolidins. The mixture was then cooled to 10 ° C and filtered.

The solid obtained was washed once with 1600 g of 10 ° C cold toluene and 2000 g of water. After drying in vacuo, 2820 g of the 99.8% active substance were obtained (95% of theory). Example 3 Comparative Experiment in Butanol Instead of Toluene

0.501 mol of CCMP (2-chloro-5-chloromethylpyridine) were initially charged in 260 g of 1-butanol together with 5 g of Aliquat 336 (methyltri-n-octylammonium chloride) and heated to 70.degree. Within one hour, 250 g of a 29.8% solution of 2-Cyaniminothiazolidin-Na salt (0.5 mol) were metered into water for this purpose. Thereafter, until the complete conversion of Cyaniminothiazolidins was stirred. The mixture was then cooled to 10 ° C and filtered.

The resulting solid was then washed twice with 70 g of 10 ° C cold 1-butanol / toluene (1: 1 mixture). After drying in vacuo 88.1 g of the only 97.8% active ingredient were thus obtained (68.2% of theory).

Example 4 (comparative experiment to EP 11024140)

0.615 mol of potassium carbonate and 0.3 mol of 2-cyaniminothiazolidine were suspended in 100 ml of n-butanol and stirred at 60 ° C for 1 h. Within 2 h were then added at 70 ° C, 0.315 mol of 2-chloro-5-chloromethylpyridine / 2-chloro-5-methylpyridine (CCMP / CMP, 23% CCMP in the mixture) suspended in 100 ml of n butanol and 2 h at 72 ° C stirred. After cooling to 65 ° C then 400 g of water were added and the phases were separated. Thereafter, the organic phase was stirred for 3 h at 50 ° C and then stirred for 18 h at 5 ° C. Precipitated product was filtered off and dried; 59.6 g (78% of theory). Example 4 Comparison Test to EP 11024140 with Phase Transfer Catalyzer

0.3 mol of 2-cyaniminothiazolidine and 4.2 g of tetrabutylammonium bromide were suspended in 300 ml of water and heated to 70 ° C. This was followed by the addition of 0.315 mol of CMP / CCMP mixture. The pH of the reaction mixture was kept continuously at 8 to 8.5 with NaOH. After a reaction time of 2 hours at 60 ° C., a phase separation was then carried out at this temperature and the organic phase was diluted with 150 ml of butanol and stirred. Within 3 h was cooled to 3 ° C and precipitated product filtered off with suction; 58.5 g (76% of theory) were thus obtained.

Claims

Patent claims: 1. Process for the preparation of compounds of formula (I) in which Rl represents a hydrogen atom or an alkyl group, preferably a C ₁ -C4 alkyl group, A represents an ethylene group, which can be substituted by alkyl, preferably Ci-C t-alkyl, or a trimethylene group, which can be substituted by alkyl, X represents an oxygen or sulfur atom or the groups R3 represents a hydrogen atom or an alkyl group, preferably a C ₁ -C4 alkyl group, and an optionally substituted 5- or 6-membered heterocyclic group containing at least two heteroatoms selected from oxygen, sulfur and nitrogen atoms, or one optionally substituted 3- or 4-pyridyl group, 1 characterized in that compounds of the formula (II) (Π) or their salts of the formula (Ha), n (IIa) in those A and X have the meanings given above, n can be one or two depending on the counterion (M ⁿ⁺ ), M ⁿ⁺ represents ammonium (n=1), alkali metal (n=1) or alkaline earth metal cation (n=2), in a non-polar aliphatic or aromatic organic solvent in the presence of a phase transfer catalyst, preferably an ammonium salt, more preferably a quaternary ammonium salt, with 2 -Chloro-5-chloromethylpyridine reacts. 2. The method according to claim 1, wherein the phase transfer catalyst is an ammonium salt formula R4 — N-R5 anion R6 in which R4, R5, R6 represent hydrogen or a Ci-Ci ₂ alkyl group or -benzyl or -alkylbenzyl, and Anion ^" stands for OH, chloride, bromide, iodide or cyanide; or R4 I. R N—R5 anion I R6 where R4, R5, R6 represent hydrogen or a Ci-Ci2-alkyl group or -benzyl or -alkylbenzyl and R7 represents a Ci-Ci ₂ -alkyl group or -benzyl or -alkylbenzyl, preferably a Ci-Ci ₂ -alkyl group stands, and anion ^" stands for OH, chloride, bromide, iodide or cyanide, preferably stands for chloride. 3. The method according to claim 1 or 2, wherein the organically soluble quaternary ammonium salt is Aliquat 336 (methyl-tri-n-octylammonium chloride). 4. Process according to one of claims 1 to 3, in which the solvent is selected from benzene, toluene, xylene, mixtures thereof or hexane, cyclohexane, methylcyclohexane and mixtures thereof. 5. The method according to any one of the preceding claims, wherein the solvent is toluene. 6. The method according to any one of the preceding claims, wherein M ⁺ represents a Na ⁺ ion. 7. A process for the preparation of compounds of formula (I) according to any one of the above claims, wherein the compound of formula (I) is the compound of formula (Ia). (Ia) characterized in that compounds of the formula (IIb) (IIb) in the presence of a base, preferably NaOH, or its salts of the formula IIc, (IIc) where n is 1 or two depending on the counterion M ⁿ⁺ and M ⁿ⁺ is an ammonium (n=1), an alkali metal (n=1) or an alkaline earth metal cation (n=2), preferably a Na ⁺ ion, in Presence of a phase transfer catalyst according to one of claims 1 to 3 with 2-chloro-5-chloro - reacted with methylpyridine.