KR100244881B1 - Method for the preparation of 2-chloro-5-methyl-pyridines - Google Patents

Abstract

The present invention relates to a novel process for the preparation of 2-chloro-5-methyl-pyridine (I) of formula (I) and to novel intermediates for the preparation thereof.

The process of the present invention comprises reacting 3-methyl-pyridine 1-oxide of formula (II) with organic nitrogen base A and an electrophilic compound, optionally in the presence of a diluent, to obtain a compound of formula (III) This compound (III) is then optionally separated or optionally further purified in the form of the intermediate, and in the second step the compound of formula (III) is reacted with a chlorinating agent at a temperature of 10 ° C to 150 ° C.

2-Chloro-5-methyl-pyridine prepared according to the invention is used as an intermediate of pharmaceuticals and pesticides.

Description

[Name of invention]

Method for preparing 2-chloro-5-methyl-pyridine

Detailed description of the invention

The present invention relates to a novel process for the preparation of 2-chloro-5-methyl-pyridine and to novel intermediates for the preparation thereof.

2-Chloro-5-methyl-pyridine is known to be obtained by reacting 3-methyl-pyridine-1-oxide with phosgene in the presence of triethylamine. (See Example 3 of EP-A 439,745). However, the yield of 2-chloro-5-methyl-pyridine obtained by this method is usually unsatisfactory and the product is always obtained in a mixture with a significant amount of 2-chloro-3-methyl-pyridine.

According to the present invention, in the first step, 3-methyl-pyridine 1-oxide of formula (II) is reacted with organic nitrogen base A and an electrophilic compound, optionally in the presence of a diluent, to give a compound of formula (III) This compound (III) is optionally separated into coarse intermediate forms or optionally further purified, and in the second step, the compound of formula (III) is optionally subjected to from 10 ° C. to optionally in the presence of alkyl chloride and optionally in the presence of a diluent. Characterized by reacting with a chlorinating agent at a temperature of 150 ° C., a novel process for preparing 2-chloro-5-methyl-pyridine of formula (I) was found.

Where

A represents an organic nitrogen base,

Represents an anion formed from an electrophilic compound.

Surprisingly, 2-chloro-5-methyl-pyridine of formula (I) can be obtained by the process according to the invention in high yield, with significantly improved isomeric purity compared to known methods. Unreacted intermediates of the general formula (III0) can be reused in the process according to the invention. Thus, the process according to the invention significantly improves the state of the art.

When trimethylamine is used as the organic nitrogen base A in the first step and phosgene is used as the electrophilic compound and the chlorinating agent in the first and second steps, respectively, the reaction process of the process according to the present invention is represented by the following scheme. Can represent:

Starting compounds of formula (II) are already known (see J. AM. Chem. Soc. 76 (1954), 1286-1291).

Formula (III) provides a general definition of the adduct formed in the first step of the process according to the invention.

In general formula (III)

A is preferably tri- (C ₁ -C ₄ -alkyl) -amine, N, N-di- (C ₁ -C ₄ -alkyl) -benzylamine, N, N-di (C ₁ -C _4- Alkyl) -cyclohexylamine and optionally an organic nitrogen base selected from the group consisting of mono-, di-, or tri-substituted pyridine by C ₁ -C ₄ -alkyl,

Preferably represents chloride or C ₁ -C ₄ -alkylcarboxylate ions.

In general formula (III)

A is more preferably trimethylamine, triethylamine, tripropylamine, tributylamine, N, N-dimethylbenzylamine, N, N-diethylbenzylamine, N, N-diethylcyclohexylamine, N, N-diethylcyclohexylamine or pyridine optionally monosubstituted or disubstituted with methyl or ethyl,

Represents chloride or acetate ions.

Adducts of general formula (III) have not been known in the literature so far and are novel chemical compounds which form the subject matter of this patent application.

The first step of the invention is carried out using organic nitrogen base A. The preferred or more preferred meaning of A can be selected in the definition of the general formula (III) compound. Trimethylamine is the most particularly preferred organic nitrogen base for the process according to the invention.

Electrophilic compounds are also used in the first step of the process according to the invention. Preferred electrophilic compounds for the process according to the invention are, for example, acetyl chloride, propionyl chloride, acetic anhydride, propionic anhydride, benzoyl chloride, benzotrichloride, phosgene, oxalyl chloride, benzenesulfochloride, P-toluenesulfonyl Acid chlorides such as chloride, phosphorus (III) chloride, phosphoryl chloride (phosphoryl oxychloride), phosphorus chloride (V), thionyl chloride, sulfuryl chloride, dichloromethylene- demethylammonium chloride, cyanuric chloride and chlorotrimethylsilane And anhydrides.

Phosgene, thionyl chloride, sulfuryl chloride, benzenesulfonyl chloride and P-toluene sulfonyl chloride are particularly preferred electrophilic compounds for the process according to the invention.

The second step of the process according to the invention is carried out using a chlorinating agent. Preferred chlorinating agents for the process according to the invention are, for example, acetyl chloride, benzoyl chloride, phosgene, oxalyl chloride, benzosulfochloride, phosphorus (III) chloride, phosphoryl chloride, phosphorus (V), thionyl chloride, sulf Compounds capable of providing chloride ions to other reactants, such as furyl chloride, hydrogen chloride, tetraethylammonium chloride, tetrabutylammonium chloride and benzyltriethylammonium chloride.

Phosgene and hydrogen chloride are particularly preferred chlorinating agents for the second step of the process according to the invention.

The second step of the process according to the invention is optionally carried out in the presence of alkyl chloride. Preferred alkyl chlorides are methyl chloride, ethyl chloride, propyl chloride and butyl chloride, and preferably methyl chloride.

The first step of the process according to the invention is preferably carried out using a diluent. Suitable diluents are practically all inert organic solvents. These are preferably halogenated optionally such as pentane, hexane, heptane, cyclohexane, petroleum ether, benzine, ligroin, benzene, toluene, xylene, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene Aliphatic and aromatic hydrocarbons, diethyl and dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether, ethers such as tetrahydrofuran and dioxane, ketones such as acetone, methyl-ethyl, methyl-isopropyl and methyl-isobutyl ketone Esters such as methyl and ethyl acetate, for example nitriles such as acetonitrile and propionitrile, for example dimethyl sulfoxide, tetra as well as amides such as dimethylformamide, dimethylacetamide and N-methyl-pyrrolidone Methylene sulfone and hexamethylphosphate triamide.

The second step of the process according to the invention is also optionally carried out in the presence of a diluent. In addition to water, suitable diluents are practically all inert organic solvents. These preferably include alcohols such as methanol, ethanol, n- and i-propanol, carboxylic acids such as formic acid, acetic acid and propionic acid as well as the solvents mentioned above for the first step of the process according to the invention.

When trimethylamine is used as the organic nitrogen base, the first step of the process according to the invention is generally carried out in the temperature range of -50 ° C to + 120 ° C, preferably -30 ° C to + 80 ° C. When using an organic nitrogen base other than trimethylamine, the use temperature is generally between -30 ° C and + 100 ° C, preferably between -15 ° C and + 10 ° C.

The first step of the process according to the invention is generally carried out at atmospheric pressure. However, it is also possible to carry out under elevated or reduced pressure, generally between 0.1 and 100 bar.

When carrying out the first step of the process according to the invention, generally 1 to 10 moles, preferably 2 to 5 moles of organic nitrogen base per mole of 3-methyl-pyridine 1-oxide of formula (II), and 1 to 10 moles, preferably 1 to 5 moles of the electrophilic compound are used.

In a preferred embodiment of the first step of the process according to the invention, 3-methyl-pyridine 1-oxide of formula (II) is first introduced into the diluent, and after cooling, the organic nitrogen base and then The electronic compound is weighed while stirring and slowly added.

After the reaction is completed, the more volatilized components are optionally distilled off under reduced pressure. The crude intermediate, consisting mainly of adducts of general formula (III), can be purified in a general manner, for example using column chromatography, or used in crude form in the second step.

Preferably, the intermediate is used by itself without optionally removing the diluent in the second step.

The second step of the process according to the invention is generally carried out at temperatures of 10 ° C to 150 ° C, preferably 20 ° C to 120 ° C, in particular 30 ° C to 110 ° C.

The second step of the process according to the invention is generally carried out at atmospheric pressure. However, it is also possible to carry out under elevated or reduced pressure, generally from 0.01 to 200 bar.

Post-treatment can be carried out in a conventional manner. For example, the crude material is immersed in an organic solvent that is not actually miscible with water, washed with water and dried. After the organic solvent is carefully removed by distillation under reduced pressure, a residue containing the product of formula (I) is obtained.

2-Chloro-5-methyl-pyridine obtained by the process according to the invention is known as an intermediate for pharmaceuticals (see DE-A (Republic of Germany) No. 2812585), but it is also an intermediate for pesticides. It can also be used as (see DE-A (German Federal Republic Publication No. 2630046)).

Production Example

Example 1

First step:

90 g (0.825 mole) of 3-methyl-pyridine 1-oxide are initially introduced in 540 mL of methylene chloride and the mixture is cooled to 0 ° C. 195 g (3.3 mol) trimethylamine are added by condensation at this temperature. After passing 245 g (2.63 mol) of phosgene through the mixture, the temperature is maintained at 0 ° C. by vigorous cooling. After the reaction is complete, excess phosgene is removed under a water pump at 20 ° C. The remaining residue is purified using column chromatography (silica gel; eluent: methylene chloride / methanol, volume ratio 10: 1.5).

H NMR spectra give 188 g of the product mixture, found to contain 102 g (66% of theory) of trimethyl- (5-methyl-pyridin-2-yl) -ammonium chloride.

NMR data: ¹ H NMR (300 MHz, D ₆ -DMSO) δ / ppm = 2.41 (3H, singlet); 3.64 (9H, singlet); 8.06 (2H, AB- system, ^J AB = 8.4 Hz); 8.5 (1H, single line)

2nd step:

The 15 g product mixture obtained in the first step is heated to 100 ° C. At this temperature, the phosgene vapor is passed through the melt for six hours, the melt gradually becoming viscous. Finally excess phosgene is removed by means of a nitrogen stream. The current is then treated with 100 ml of methylene chloride, washed twice with water, dried over sodium sulfate and filtered. The solvent is carefully distilled from the filtrate under a water pump.

2.43 g of a mixture of 2-chloro-5-methyl-pyridine and 2-chloro-3-methyl-pyridine in a 44: 1 ratio are obtained (analysis by gas chromatography). This corresponds to 28.2% yield of theory for 3-methyl-pyridine 1-oxide used in the first step. Unreacted intermediates of formula III can be recovered by evaporation of the combined aqueous phases. The yield of 2-chloro-5-methyl-pyridine corresponds to 90% of theory for the reaction intermediate.

Example 2

90 g (0.825 mole) of 3-methyl-pyridine 1-oxide are initially introduced into 540 mL of methylene chloride and the mixture is cooled to 0 ° C. At this temperature, 195 g (3.3 mol) of trimethylamine are condensed and added. 245 g (2.65 moles) of phosgene are then passed through the mixture and the temperature is maintained at 0 ° C. by vigorous cooling. After completion of the reaction, the mixture is evaporated to dryness in vacuo. The crude product obtained is made stirrable by heating to 100 ° C. and adding a small amount of acetonitrile. At this temperature, the phosgene stream is passed through the mixture for 10 hours, which gradually becomes viscous. Dilute sodium hydroxide solution is added while cooling until the pH is 7-8. The mixture is extracted four times with methylene chloride. The combined organic phases are dried over sodium sulfate, then filtered and evaporated under water vacuum.

28.8 g (27.4% of theory) of a mixture of 2-chloro-5-methylpyridine and 2-chloro-3-methylpyridine in a 47: 1 ratio are obtained (analyzed by gas chromatography). Unreacted intermediates of formula III can be recovered by evaporation of the aqueous phase.

Example 3

90 g (0.825 mole) of 3-methyl-pyridine 1-oxide are initially introduced into 540 mL of methylene chloride and the mixture is cooled to 0 ° C. 334 g (3.3 mol) of trimethylamine are added by condensation at this temperature. 245 g (2.63 mol) of phosgene are passed through the mixture and the mixture is kept at 0 ° C. by vigorous cooling. After the reaction is complete, excess phosgene is removed under a water pump at 20 ° C. The remaining residue is purified using column chromatography (silica gel; eluent: methylene chloride / methanol, volume ratio, 10: 1.5).

^One H-NMR spectrum yields 173 g of product mixture found to contain 104 g (55% of theory) of triethyl- (5-methyl-pyridin-2-yl) -ammonium chloride.

¹ H-NMR (300 MHz, CDCl ₃ )

δ / ppm = 1.20 (9H, triplet, J = 7.2 Hz), 2.44 (3H, singlet), 4.14 (6H, quartet, J = 7.2 Hz), 7.98 (1H, multiplet, ^J AB = 8.4 Hz ), 8.34 (1H, quartet, J = 0.9 Hz), 8.63 (1H, doublet, ^J AB = 8.7 Hz).

Example 4

19.5 g (0.331 moles) of trimethylamine are condensed at -10 ° C and added to a solution of 8.8 g (0.0807 moles) of 3-methyl-pyridine 1-oxide in 100 ml methylene chloride at -5 ° C. 6.9 ml (0.097 mol) of thionyl chloride in 10 ml methylene chloride are then added dropwise over 30 minutes at the same temperature. During the dropping, the temperature is kept below 0 ° C. The resulting yellow solution is thawed and then stirred overnight at room temperature.

A golden solution is obtained, which is evaporated in a rotary evaporator at 20-25 ° C. ¹ H-NMR affords 24.5 g greasy solid which is found to contain about 14.5 g (96% of theory) of trimethyl- (5-methyl-pyridin-2-yl) -ammonium chloride.

¹ H-NMR (300 MHz, D ₆ -DMSO)

delta / ppm = 2.41 (3H, singlet); 3.64 (9H, single line), 8.06 (2H, AB-system, ^J AB = 8.4 Hz), 8.5 (1H, single line)

Example 5

20.5 g (0.348 mole) of trimethylamine are condensed at -10 ° C and then added to a solution of 8.8 g (0.0807 mole) of 3-methyl-pyridine 1-oxide in 110 ml methylene chloride at -5 ° C. Then a solution of 21.3 ml (0.2421 mol) of sulfuryl chloride in 20 ml methylene chloride is added dropwise at the same temperature. A fine white precipitate is obtained, liberated to room temperature over 1 hour and stirred for an additional 2 hours at this temperature. The precipitate is completely dissolved during this time. The resulting golden solution is allowed to stand overnight and then evaporated in a rotary evaporator.

48.7 g of a greasy solid which was found to contain 11.6 g (77% of theory) of trimethyl- (5-methyl-pyridin-2-yl) -ammonium chloride by ¹ H-NMR.

Example 6

109 g (1.0 mole) of 3-methyl-pyridine 1-oxide are initially introduced into 800 ml of 1,2-dichloroethane and the mixture is cooled to -30 ° C. 130 g (2.2 moles) of trimethylamine are condensed at this temperature and 212 g (1.2 moles) of benzene sulfochloride are introduced over 2 hours with continuous cooling. Then cooling is stopped and the reaction mixture is stirred at 20 ° C. for 15 h. The mixture is then heated to 35 ° C. and hydrogen chloride is introduced at this temperature until thin layer chromatography confirms that the reaction is complete (time: about 32 hours). The mixture is worked up by adjusting the alkali pH value with 20% sodium hydroxide solution and extracting the solution with dichloromethane. The organic phase is dried over sodium sulfate and filtered. The solvent is carefully distilled from the filtrate under water vacuum.

Gas chromatography gives 136 g of crude product, which is analyzed to contain 78% 2-chloro-5-methylpyridine.

Yield: 84% of theory

Claims (14)

In the first step, 3-methyl-pyridine 1-oxide of formula (II) is reacted with organic nitrogen base A and an electrophilic compound in the presence or absence of a diluent to obtain a compound of formula (III), A process for preparing 2-chloro-5-methyl-pyridine of formula (I), characterized by reacting a compound of formula (III) with a chlorinating agent at a temperature of 10 ° C. to 150 ° C. in two steps: In the above formula, A represents an organic nitrogen base, Represents an anion formed from an electrophilic compound. The compound of claim 1, wherein the organic nitrogen base A is tri- (C ₁ -C ₄ -alkyl) -amine, N, N-di- (C ₁ -C ₄ -alkyl) -benzylamine, N, N-di- A compound selected from the group consisting of (C ₁ -C ₄ -alkyl) -cyclohexylamine, and pyridine mono-, di-, or trisubstituted or unsubstituted by C ₁ -C ₄ -alkyl, Acid chloride or anhydride, wherein the chlorinating agent is a compound capable of providing chloride ions to other reactants. The organic nitrogen base A of claim 1, wherein the organic nitrogen base A is trimethylamine, triethylamine, tripropylamine, tributylamine, N, N-dimethylbenzylamine, N, N-diethylbenzylamine, N, N-dimethylcyclohexyl An electrophilic compound is selected from the group consisting of amines, N, N-diethylcyclohexylamine, and pyridines mono- or di-substituted or unsubstituted by methyl or ethyl, the electrophilic compounds being acetyl chloride, propionyl chloride, acetic anhydride, anhydrous Propionic acid, benzoyl chloride, benzotrichloride, phosgene, oxalyl chloride, benzene sulfochloride, p-toluenesulfonyl chloride, phosphorus chloride (III), phosphoryl chloride (phosphoryl chloride), phosphorus chloride (V), thionyl chloride , A compound selected from the group consisting of sulfuryl chloride, dichloromethylene dimethylammonium chloride, cyanuric chloride and chlorotrimethylsilane, Topical agents include acetyl chloride, benzoyl chloride, phosgene, oxalyl chloride, benzosulfochloride, phosphorus (III) chloride, phosphoryl chloride, phosphorus (V), thionyl chloride, sulfuryl chloride, hydrogen chloride, tetraethylammonium chloride, tetra Wherein said compound is selected from the group consisting of butylammonium chloride and benzyltriethylammonium chloride. The compound of claim 1, wherein the organic nitrogen base is trimethylamine, and the electrophilic compound is a compound selected from the group consisting of phosgene, thionyl chloride, sulfuryl chloride, benzenesulfonyl chloride and p-toluene-sulfonyl chloride, chlorine The topical agent is phosgene or hydrogen chloride. 5. The process according to claim 1, wherein trimethylamine is used as the organic nitrogen base A and the first reaction step is carried out at temperatures between −50 ° C. and + 120 ° C. 6. 5. The process according to claim 1, wherein the first reaction step is carried out at a temperature between −30 ° C. and + 100 ° C., using an organic nitrogen base other than trimethylamine. 6. The process according to any one of claims 1 to 4, wherein the second reaction step (chlorination reaction) is carried out at a temperature of 20 ° C to 120 ° C. The method according to any one of claims 1 to 4, characterized in that 1 to 10 moles of organic nitrogen base A and 1 to 10 moles of electrophilic compound are used per mole of 3-methyl-pyridine 1-oxide (II). How to. The method according to any one of claims 1 to 4, characterized in that 2 to 5 moles of organic nitrogen base A and 2 to 5 moles of electrophilic compound are used per mole of 3-methyl-pyridine 1-oxide (II). How to. 5. The organic nitrogen base A according to claim 1, wherein in the first step 3-methyl-pyridine 1-oxide (II) is first introduced into an inert organic diluent and cooled, first followed by organic nitrogen base A and then The method is characterized in that the electrophilic compound is measured while stirring and slowly added thereto. Compound of general formula (III): In the above formula, A represents an organic nitrogen base, Represents an anion formed from an electrophilic compound. The compound of claim 11, wherein A is tri- (C ₁ -C ₄ -alkyl) -amine, N, N-di- (C ₁ -C ₄ -alkyl) -benzylamine, N, N-di- (C ₁ An organic nitrogen base selected from the group consisting of -C ₄ -alkyl) -cyclohexylamine, and pyridine mono-, di-, or trisubstituted or unsubstituted by C ₁ -C ₄ -alkyl, Is a compound of formula (III) representing chloride or C ₁ -C ₄ -alkyl carboxylate ions. The compound of claim 11, wherein A is trimethylamine, triethylamine, tripropylamine, tributylamine, N, N-dimethylbenzylamine, N, N-diethylbenzylamine, N, N-dimethylcyclohexylamine, N , N-diethylcyclohexylamine or pyridine mono- or di-substituted or unsubstituted by methyl or ethyl, Is a compound of formula (III) representing chloride or acetate ions. The method of claim 1, further comprising separating or purifying Compound (III) in crude intermediate form prior to the second step.