JPH1087624A - Production of 2-chloro-5-chloromethylpyridine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially and inexpensively produce 2-chloro-5- chloromethylpyridine useful as a producing intermediate of a medicine or an agrochemical by chlorinating 2-alkoxy-5-methylpyridines. SOLUTION: The objective 2-chloro-5-chloromethylpyridine of the formula II is obtained by affecting a molecular chlorine to 2-alkoxy-5-methylpyridines of the formula I [R<1> is a lower alkyl, a (substituted) lower alkenyl, etc.] and affecting an acid chloride and/or phosphorus chloride. The starting material of the formula I is obtained by producing 5-methyl-2-sulfonylpyridines by reacting sulfonylcyanide of the formula III with 1-acyloxy-2-methyl-1,3-butadiene of the formula IV and affecting an alcoholic salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing 2-chloro-5-chloromethylpyridine, which is useful as a raw material for producing pharmaceuticals and agricultural chemicals.

[0002]

2. Description of the Related Art As a general method for producing 2-chloro-5-chloromethylpyridine useful as an intermediate for producing pharmaceuticals and agricultural chemicals, a method obtained by chlorination of 2-chloro-5-methylpyridines [DE -3630046 (EP-A-0260485), JP-B-7-94441, JP-A-5-230024, JP-A-5-230025 (EP-A-055
7967)] is known. 2-chloro-5 as the raw material
-Methylpyridines are tetrahedron letters (Tetr
ahedron Letters, 1971, p. 2807).
3-methylpyridine N-oxide obtained by oxidizing -methylpyridine is converted into a chemistry of heterocyclic compound (Chemistry of Heterocyclic Compound).
ounds, vol. 14, supplementary volume 2, 1974). Therefore, 2-chloro-5-chloromethylpyridine is produced from 3-methylpyridine through three steps, and the yield is low when the whole steps are counted.

[0003] 2-Chloro-5-chloromethylpyridine has also been prepared by direct chlorination of 3-methylpyridine [USP-5247093 (WO94 / 13640), USP-4577027, U.S. Pat.
SP-4564681]. However, the reaction requires a high temperature of 300 ° C. to 500 ° C. and the yield is low, so that it cannot be used as an industrial production method.

[0004] In the method described in EP-A-0393453, 3-dichloromethylpyridine obtained by chlorination of 3-methylpyridine is converted to 2-methoxy-5-methoxymethylpyridine, and further acid chloride and / or phosphochloride is added. 2-chloro-5-chloromethylpyridine is produced by chlorination with a substance. In any of these methods, 2-chloro-5-chloromethylpyridine is produced from 3-methylpyridine through three steps, so that the overall yield is low.

[0005] As another raw material for producing 2-chloro-5-chloromethylpyridine, 2-chloro-chloroform described in EP-A-0477828 is used.
Although 5-hydroxymethylpyridine is mentioned, low production efficiency is a problem due to the production method by microbial conversion. That is, until now, there has been no method capable of industrially and inexpensively producing 2-chloro-5-chloromethylpyridine, which is useful as an intermediate for producing pharmaceuticals and agricultural chemicals.

[0006]

An object of the present invention is to provide a method for industrially and inexpensively producing 2-chloro-5-chloromethylpyridine, which is useful as an intermediate for producing pharmaceuticals and agricultural chemicals. Aim.

[0007]

Means for Solving the Problems The present inventors have conducted various studies to achieve the above object, and as a result,
The action of molecular chlorine on the alkoxy-5-methylpyridines, followed by the action of acid chlorides and / or phosphorus chlorides to selectively produce 2-chloro-5-chloromethylpyridine; and 2-alkoxy-5
It has been found that 2-chloro-5-chloromethylpyridine can be selectively produced by reacting -chloromethylpyridines with acid chlorides and / or phosphorus chlorides, thereby completing the present invention.

That is, the present invention provides the following general formula:

[0009]

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(Wherein R ¹ represents a lower alkyl group, a halogenated lower alkyl group, a cycloalkyl group, an optionally substituted alkenyl group, or an optionally substituted aralkyl group) Reacting molecular chlorine on -5-methylpyridines, and then reacting with an acid chloride and / or a phosphochloride,
The following formula (II)

[0011]

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And a method for producing 2-chloro-5-chloromethylpyridine.

Further, the present invention provides a compound represented by the following general formula (III):

[0014]

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(Wherein, R ¹ represents a lower alkyl group, a cycloalkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group); (IV)

[0016]

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(Wherein R ³ represents an acyloxy group) by reacting with 1-acyloxy-2-methyl-1,3-butadiene represented by the following general formula (V):

[0018]

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(Wherein, R ² represents a lower alkyl group, a cycloalkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group) Is further added to the obtained 5-methyl-2-sulfonylpyridine represented by the above general formula (V), wherein R ¹ OM (where R ¹ is a lower alkyl group, a halogenated lower) Represents an alkyl group, a cycloalkyl group, an optionally substituted alkenyl group, or an optionally substituted aralkyl group, and M represents an alkali metal atom, an alkaline earth metal atom, or an optionally substituted ammonium). By reacting an alcohol salt represented by the following formula (I):

[0020]

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(Wherein R ¹ represents a lower alkyl group, a halogenated lower alkyl group, a cycloalkyl group, an alkenyl group which may be substituted, or an aralkyl group which may be substituted) -5-methylpyridines, and then the resulting 2-alkoxy-5
Reacting molecular chlorine on methylpyridines,
Formula (II) below characterized by reacting an acid chloride and / or a phosphorus chloride

Embedded image And a method for producing 2-chloro-5-chloromethylpyridine.

Further, the present invention provides a compound represented by the following general formula (VI):

Embedded image (Wherein, R ¹ represents a lower alkyl group, a halogenated lower alkyl group, a cycloalkyl group, an optionally substituted alkenyl group, or an optionally substituted aralkyl group.) The following formula (II), wherein an acid chloride and / or a phosphorus chloride is allowed to act on chloromethylpyridines.

Embedded image And a method for producing 2-chloro-5-chloromethylpyridine.

[0023]

DESCRIPTION OF THE PREFERRED EMBODIMENTS In the above formula, examples of the lower alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, a pentyl group and a hexyl group. A halogenated lower alkyl group such as a 2,2,2-trifluoroethyl group,
2,2,3,3-tetrafluoropropyl group and the like. Examples of the cycloalkyl group include a cyclopentyl group, a cyclohexyl group, and a cyclooctyl group. Examples of the lower alkenyl group include an allyl group, a 1-propenyl group, and the like. These are a lower alkyl group such as a methyl group and an ethyl group, a lower alkoxy group such as a methoxy group and a propoxy group, a fluorine atom, a chlorine atom, and a bromine atom. May be appropriately substituted by a halogen atom, a cyano group, a nitro group, or the like. Examples of the aryl group include a phenyl group and a naphthyl group, and these may be appropriately substituted with the above substituent. Examples of the aralkyl group include a benzyl group and a phenethyl group, and these may be appropriately substituted with the above substituent.

The method for producing 2-chloro-5-chloromethylpyridine of the present invention is shown in the following scheme.

[0025]

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(Wherein R ¹ , R ² and R ³ are the same as above)

The 2-alkoxy-5-methylpyridines represented by the above general formula (I), which are the starting materials in the first method of the present invention, are prepared from Journal of Chemical Society, Parkin Transaction I (Journal o).
f Chemical Society PerkinTransaction I, 1984, 1
839) can be produced by the method described,
The 5-methyl-2-sulfonylpyridines represented by the above general formula (V) have the general formula: R ¹ OM (where R ¹ is a lower alkyl group, a halogenated lower alkyl group, a cycloalkyl group, Represents a good lower alkenyl group or an optionally substituted aralkyl group, and M is an alkali metal atom, an alkaline earth metal atom, or an optionally substituted ammonium salt. it can.

Examples of the alcohol as a raw material of the alcohol salt represented by the general formula R ¹ OM include lower alkyl alcohols such as methanol, ethanol and propyl alcohol; 2,2,2-trifluoroethanol;
A halogenated lower alkyl alcohol such as 3,3-tetrafluoropropyl alcohol, an optionally substituted lower alkenyl alcohol such as allyl alcohol and isopropenyl alcohol, cyclohexanol, and a substituted benzyl alcohol and a substituted such as p-fluorobenzyl alcohol Aralkyl alcohol which may be used. Alcohol salts include alkali metal salts,
Examples thereof include an alkaline earth metal salt and an ammonium salt which may be substituted.

The alkali metal salts include lithium salts, sodium salts and potassium salts, and the alkaline earth metal salts include magnesium salts and calcium salts. Examples of the ammonium salt include ammonium salts, alkyl ammonium salts such as ethyl ammonium salt, dialkyl ammonium salts such as dibutyl ammonium salt, trialkyl ammonium salts such as trimethyl ammonium salt, tetraalkyl ammonium salts such as tetrabutyl ammonium salt, and benzyl. Aralkyl ammonium salts such as ammonium salts, aralkyl ammonium salts such as dibenzyl ammonium salts, aralkyl alkyl ammonium salts such as benzyl methyl ammonium salts, aralkyl dialkyl ammonium salts such as benzyl dimethyl ammonium salts, and aralkyls such as benzyl trimethyl ammonium salts Trialkylammonium salts. Of these, an alkali metal salt is preferably used, and a sodium salt is more preferable.

In the reaction, a solvent can be used. As the solvent, alcohols corresponding to alcohol salts can be used. Further, any solvent can be used as long as it does not participate in the reaction. For example, hydrocarbons such as hexane and octane, dichloromethane, 1,2
-Halogenated hydrocarbons such as dichloroethane, ethers such as diethyl ether and tetrahydrofuran, and aromatic hydrocarbons such as toluene and xylene. In addition, the reaction is generally carried out at 20 ° C to 120 ° C,
More preferably, the reaction is performed at 60 to 80 ° C.

The chlorinating agent used for the chlorination with molecular chlorine may be any chlorinating agent which generates molecular chlorine (chlorine radical) under radical generating conditions. In this respect, chlorine or sulfuryl chloride is preferred. The chlorinating agent is preferably added continuously or sequentially during the reaction.

In order to generate molecular chlorine, a radical initiator can be used. Examples of such a radical initiator include nitriles such as 2,2′-azobis (isobutyronitrile) and 1,1′-azobis (cyclohexanecarbonitrile), and peroxides such as benzoyl peroxide and acetyl peroxide. Can be The radical initiator can be added continuously or sequentially before and / or during the reaction. The amount of the radical initiator to be added is 0.001 to 3.0 equivalents, preferably 0.05 to 1.0 equivalent. Further, molecular chlorine can be generated by light irradiation or the like.

This reaction is preferably carried out in a solvent, and any solvent may be used as long as it does not take part in the reaction. For example, acetonitrile, carbon disulfide,
Dichloromethane, chloroform, carbon tetrachloride, 1,2-
Halogenated hydrocarbons such as dichloroethane and 1,1,2,2-tetrachloroethane; aromatic hydrocarbons such as acetic acid, chlorobenzene and dichlorobenzene; nitrogen-containing aromatic hydrocarbons such as pyridine; and hydrocarbons such as hexane. These can be used as a mixture.

The reaction is preferably carried out at a temperature from 20 ° C. to the reflux temperature of the solvent, more preferably from 60 ° C. to 120 ° C.

Examples of the acid chloride used for chlorination with an acid chloride and / or phosphorus chloride include phosphorus oxychloride, thionyl chloride, oxalyl chloride and the like. Examples of phosphorus chloride include phosphorus pentachloride, phosphorus trichloride and the like. Is mentioned. The acid chloride and / or phosphorus chloride can be added continuously or sequentially before and / or during the reaction. The addition amount of the acid chloride and / or the phosphorus chloride is 1 equivalent to 20 equivalents, more preferably 2 equivalents to 10 equivalents.

In this reaction, a solvent can be used. The above-mentioned acid chloride and / or phosphorus chloride can be used as a solvent, but any other solvent that does not participate in the reaction can be used, for example, halogenated hydrocarbons such as tetrachloroethane and carbon tetrachloride, toluene, And substituted aromatic hydrocarbons such as chlorobenzene.

In the present reaction, the presence of hydrogen chloride is preferred, and hydrogen chloride can be added continuously or sequentially before and / or during the reaction. The addition amount of hydrogen chloride may be a saturation amount with respect to the solvent, but is preferably 1 equivalent to 1 equivalent.
It is 0 equivalent.

This reaction is preferably carried out in a closed system such as in a sealed tube, but can also be carried out in an open system. In addition, the reaction is preferably performed at 20 ° C to 200 ° C, more preferably 60 ° C to 150 ° C.

The starting material sulfonyl cyanide (III) in the second method of the present invention is more organically synthesized than the corresponding sodium sulfinate.
Synthesis, vol. 57, p. 88, 1977). The other starting material, 1-acyloxy-2-
Methyl-1,3-butadiene (IV) is, for example, industrial and engineering chemistry.
(Industrial and Engineering Chemistry, Vol. 41, No. 12,
2920, 1949).

The sulfonyl cyanide (II)
Specific examples of I) include lower alkane sulfonyl cyanide such as methanesulfonyl cyanide and propane sulfonyl cyanide, cycloalkane sulfonyl cyanide such as cyclohexane sulfonyl cyanide and cyclooctane sulfonyl cyanide, benzene sulfonyl cyanide, and p-
Examples include allensulfonyl cyanide such as toluenesulfonyl cyanide, and arylalkanesulfonyl cyanide such as phenylmethanesulfonyl cyanide.

The 1-acyloxy-2-methyl-1,3-butadiene represented by the general formula (IV) to be subjected to the reaction includes an acetoxy group, a propanoyloxy group, a butanoyloxy group and a benzoyloxy group. And the like.

The reaction between the sulfonyl cyanide represented by the general formula (III) and 1-acyloxy-2-methyl-1,3-butadiene represented by the general formula (IV) is carried out under Diels-Alder reaction conditions. The reaction can be carried out in the presence or absence of a polymerization inhibitor. In this reaction, once a Diels-Alder adduct is formed, the elimination reaction proceeds under the reaction conditions to obtain 5-methyl-2-sulfonylpyridine represented by the general formula (V). Conceivable.

Examples of the polymerization inhibitor include phenols such as 4-methoxyphenol and 2,6-di-tert-butyl-4-methylphenol; hydroquinones such as hydroquinone and di-tert-butylhydroquinone; 1-naphthol; 2
Naphthols such as naphthol, and catechol;
Catechols such as pt-butyl catechol are exemplified. The addition amount of the polymerization inhibitor is preferably from 1 / 100,000 to 1/100, more preferably from 1 / 10,000 to 1/100 of the weight of the diene.

In the reaction, a solvent can be used. Any solvent can be used as long as it does not participate in the reaction. Examples thereof include hydrocarbons such as hexane and octane, halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane, and ethers such as ethyl ether and tetrahydrofuran. And aromatic hydrocarbons such as toluene and xylene.

In general, the reaction is preferably carried out at a temperature of from 20 ° C to 120 ° C, more preferably from 60 ° C to 100 ° C.

The third starting material of the present invention, 2-alkoxy-5-chloromethylpyridines (VI), is described, for example, in Journal of Organic Chemistry (Jour).
nal ofOrganic Chemistry, 56, 15, 4636, 1991
Year) or the Journal of Medical
Chemistry (Journal of Medicinal Chemistry, 34 volumes,
1028, 1991).

Specific examples of 2-alkoxy-5-chloromethylpyridines (VI) to be subjected to the reaction include 5-chloromethyl-2-methoxypyridine, 5-chloromethyl-
2-ethoxypyridine, 5-chloromethyl-2-propoxypyridine, 5-chloromethyl-2,2,2-trifluoroethoxypyridine, 5-chloromethyl-2,2,
3,3-tetrafluoropropoxypyridine, 2-benzyloxy-5-chloromethylpyridine, and 5-chloromethyl-2-p-fluorobenzyloxypyridine.

[0048]

The present invention will be described in more detail with reference to the following examples. The present invention is not limited by these.

Example 1 Synthesis of 5-methyl-2-phenylsulfonylpyridine

[0050]

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At room temperature, 4-methoxyphenol (5.2 mg,
0.04 mmol) was added to 1-acetoxyisoprene (17.3 g,
0.14mol) to benzenesulfonyl cyanide (14.4g, 85.7mm
ol) and stirred at 80 ° C. for 1 hour. After adding a saturated aqueous solution of sodium hydrogen carbonate to the reaction solution to make it alkaline and allowing it to cool to room temperature, the resulting solid was washed twice with water (200 ml), subsequently with diethyl ether (200 ml), and the solvent was removed under reduced pressure. By distillation, 5-methyl- having the following physical properties is obtained.
2-Phenylsulfonylpyridine was converted to a white solid (19.0 g, 8
1.5 mmol, yield 95%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.40 (s, 3H,
-CH ₃ ), 7.52-7.60 (m, 3H, Ar-H), 7.70 (dd, 1H, J =
1.8 and 8.6Hz, H-4), 8.03-8.07 (m, 2H, Ar-H), 8.09
(d, 1H, J = 8.6Hz, H-3), 8.49 (d, 1H, J = 1.8Hz, H-
6) CIMS (m / z): 234 (M ⁺ +1), 169 (M ⁺ -SO ₂ ) Melting point: 118 ° C to 120 ° C

Example 2 Synthesis of 2-methoxy-5-methylpyridine

[0054]

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At room temperature, methanol (100 ml) was added to a solution of 5-methyl-2-phenylsulfonylpyridine (100 g, 0.43 mol) in toluene (100 ml), and sodium methoxide (46.0 g, 0.85 mol) was added. The mixture was refluxed for 2 hours. After allowing the reaction solution to cool to room temperature, the resulting solid was separated by filtration, and the solvent was distilled off from the obtained filtrate. The obtained residue was subjected to vacuum distillation, and 2-methoxy-5-methylpyridine having the following physical properties as a fraction at 63 ° C to 65 ° C (18 mmHg) was obtained as a colorless liquid
(47.7 g, 0.39 mol, 91% yield).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.23 (s, 3H,
-CH ₃ ), 3.90 (s, 3H, -OCH ₃ ), 6.65 (d, 1H, J = 8.4Hz,
H-3), 7.36 (dd, 1H, J = 1.1 and 8.4Hz, H-4), 7.96
(d, 1H, J = 1.1Hz, H-6)

Example 3 Synthesis of 2-chloro-5-chloromethylpyridine

[0058]

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2-methoxy-5-methylpyridine (10.0
g, 81.3 mmol) in carbon tetrachloride (150 ml) was added with 2,2′-azobis (isobutyronitrile) (67.0 mg, 0.41 mmol) and heated under reflux for 5 minutes. Chlorine (per minute)
The mixture was heated under reflux for 2 hours while adding 2,2′-azobis (isobutyronitrile) (67.0 mg, 0.41 mmol) every 15 minutes. The reaction solution was poured into ice (100 g) with heating, and a saturated aqueous solution of sodium hydrogen carbonate (50 ml) was added to make the solution alkaline. The organic layer was separated, the aqueous layer was washed with carbon tetrachloride (20 ml × 3), and this was added to the previous organic layer. The obtained organic layer was washed with saturated saline (200 ml), dried over anhydrous sodium sulfate, and then carbon tetrachloride was distilled off. The obtained residue was subjected to distillation under reduced pressure to collect a starting material, 2-methoxy-5-methylpyridine, to obtain a residue (3.8 g). Conversion by gas chromatography analysis was 21%.

At room temperature, hydrogen chloride (0.3 ml per second) was passed through a solution of the obtained distillation residue (2.0 g) in phosphorus oxychloride (10 ml) for 5 minutes, and the mixture was stirred at 120 ° C. for 2 hours in a sealed tube. After allowing the reaction solution to cool to room temperature, phosphorus oxychloride was distilled off under reduced pressure, and the obtained residue was poured into ice (100 g), sodium carbonate was added until alkaline, and the mixture was extracted with methylene chloride (40 ml × 5). . The obtained organic layer was washed with saturated saline (200 ml), dried over anhydrous sodium sulfate, and methylene chloride was distilled off.
The obtained residue was subjected to column chromatography (hexane / ethyl acetate = 5/1) to give 2-chloro-5-chloromethylpyridine having the following physical properties as a white semi-solid (640 mg,
4.0 mmol). This corresponds to 44% of the starting 2-methoxy-5-methylpyridine conversion.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.57 (s, 2H,
-CH _2- ), 7.35 (d, 1H, J = 8.1Hz, H-3), 7.50 (dd, 1H,
J = 2.3 and 8.1Hz, H-4), 8.40 (d, 1H, J = 2.3Hz, H
-6) EIMS (m / z): 161 (M ⁺ ), 126 (M ⁺ -Cl) Example 4 Synthesis of 2-chloro-5-chloromethylpyridine

[0062]

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At room temperature, hydrogen chloride (0.3 ml per second) was passed through a solution of 5-chloromethyl-2-methoxypyridine (1.02 g, 6.5 mmol) in phosphorus oxychloride (3 ml) for 20 seconds.
Stirred at C for 1 hour. After allowing the reaction solution to cool to room temperature, ice (10
0 g), sodium carbonate was added until the mixture became alkaline, and the mixture was extracted with methylene chloride (40 ml × 5). The obtained organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 2-chloro-5-chloromethylpyridine as a white semi-solid (784 mg, 4.
8 mmol, yield 74%).

[0064]

Industrial Applicability According to the production method of the present invention, 2-chloro-5-chloromethylpyridine useful as an intermediate for producing pharmaceuticals and agricultural chemicals can be produced industrially and at low cost.

Claims (3)

[Claims] 1. A compound represented by the following general formula (I): (Wherein R ¹ represents a lower alkyl group, a halogenated lower alkyl group, a cycloalkyl group, an optionally substituted lower alkenyl group, or an optionally substituted aralkyl group.) -Methylpyridines with molecular chlorine, then acid chloride and / or
Or a compound represented by the following formula (II): A method for producing 2-chloro-5-chloromethylpyridine represented by the formula: 2. The following general formula (III): (Wherein R ² represents a lower alkyl group, a cycloalkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group), and a sulfonyl cyanide represented by the following general formula (IV) Embedded image (In the formula, R ³ represents an acyloxy group.)
By reacting with acyloxy-2-methyl-1,3-butadiene, the following general formula (V) is obtained. (Wherein R ² represents a lower alkyl group, a cycloalkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group), to produce a 5-methyl-2-sulfonylpyridine compound represented by the formula: The obtained general formula (V)
5-methyl-2-sulfonylpyridines represented by
General formula: R ¹ OM (wherein, R ¹ represents a lower alkyl group, a halogenated lower alkyl group, a cycloalkyl group, an optionally substituted lower alkenyl group, or an optionally substituted aralkyl group, and M represents an alkali. A metal atom, an alkaline earth metal atom, or an optionally substituted ammonium) to react with an alcohol salt represented by the following general formula (I): (Wherein, R ¹ represents a lower alkyl group, a halogenated lower alkyl group, a cycloalkyl group, an optionally substituted alkenyl group, or an optionally substituted aralkyl group.) Producing methylpyridines, then reacting the obtained 2-alkoxy-5-methylpyridines with molecular chlorine, and then reacting acid chlorides and / or phosphorus chlorides.
The following formula (II): A method for producing 2-chloro-5-chloromethylpyridine represented by the formula: 3. The following general formula (VI): (In the formula, R ¹ represents a lower alkyl group, a halogenated lower alkyl group, a cycloalkyl group, an optionally substituted alkenyl group, or an optionally substituted aralkyl group.)
Wherein an acid chloride and / or a phosphorus chloride is allowed to act on 2-alkoxy-5-chloromethylpyridines represented by the following formula (II): A method for producing 2-chloro-5-chloromethylpyridine represented by the formula: