KR820001888B1 - Process for preparing n-alkyl-benzothiazolone derivatives - Google Patents

Abstract

Title compds.(I; R1 = H, Cl, Br, F, Me; R2 = C1-5 alkyl) were prepd. by reaction of II(X = Cl, Br, F) with KOH in the presence of a base to give III or by alkylation of I(R2 = H) with alkyl halides or sulfates. Thus II(R1 = Cl; X = Br) reacted with MeOH in the presence of NaOH to give III(R2 = Me), which was refluxed with Et3N+CH2PhCl- and PhMe to give I(R1 = Cl; R2 = Me).

Description

Method for preparing N-alkylbenzothiazolone derivative

N- of formula (I) via an alkoxy benzothiazole derivative of formula (III) or a benzothiazolone derivative of formula (IV) as an intermediate from 2-halogenobenzothiazole derivative of formula (II) which is a starting material of the present invention It relates to a process for preparing alkylbenzothiazolone derivatives.

In the above formulas

R ₁ is hydrogen, chlorine, bromine, a fluorine atom, or a methyl group;

R ₂ is an alkyl group having 1-5 carbon atoms;

X is a chlorine, bromine or fluorine atom.

More specifically, the present invention is 2-reaction of 2-halogeno-benzothiazole derivative (II) in the presence of a basic condensate with a lower alkanol of formula (V) to obtain an alkoxybenzothiazole derivative (III) and a derivative (III). ) Is thermally displaced in the presence of a catalyst such as a tertiary amine, a salt thereof, a quaternary ammonium salt, or a dialkyl sulfate, or hydrolyzed to a 2-halogenobenzothiazole derivative (II) to obtain a benzothiazolone derivative (IV). A method of synthesizing high purity and high yield N-alkylbenzothiazolone derivative (I) by reacting this derivative (IV) with an alkylating agent of formula (VI) or (iii) in the presence of an aqueous alkali metal hydroxide solution will be.

R ₂ OH (Ⅴ) R ₂ Y (Ⅵ)

(R ₂ O) ₂ SO ₂ (Ⅶ)

Wherein R ₂ is as defined above and Y is a chlorine, bromine, iodine atom.

The N-alkylbenzothiazolone derivatives (I) according to the invention are useful as non-medical fungicides as is known.

According to the known techniques these compounds are prepared by (1) alkylating the benzothiazolone derivatives in the presence of a strong base such as sodium hydrate in a non-aqueous solvent or (2) N-alkylating the 2-alkylthiobenzothiazole derivatives Or by pyrolyzing (4) 2-nitrosoamino-3-alkylbenzothiazole derivatives or (3) reacting 2-mercaptoaniline derivatives with phosgene.

However, the use of expensive and dangerous sodium hydride requires special operating conditions, and the production of complex by-products that induce low yields requires purification such as recrystallization to obtain high purity products. do. Other methods of carrying out analogous reactions of these homologues are also known but will be described in detail later, and satisfactory results cannot be obtained when these methods are used in the compounds of the present invention.

As a result of much research on the synthesis of the N-alkylbenzothiazolone derivative (I), the inventors have found a method for producing the target compound by an industrially advantageous method with high purity and high yield unlike the conventional method. Thus, the present invention has been attained.

The present invention is specifically described in detail in the following reaction steps.

Step A: 20-halogenobenzothiazole (II) is reacted with an alkanol (V) in the presence of a methahalogenating agent to prepare 2-alkoxy-benzothiazole derivative (III).

Similar methods for preparing 2-alkoxybenzothiazoles are described in the literature below.

W. H. Davis et al., J Chem Soc., 304 (1942)

H. Glman et al., J Am Chem Soc 74, 1081 (1952)

J. K Elwood et al., J. Org chem., 32, 2956 (1967)

This reaction consists of reacting 2-halogenobenzothiazole with an alkali metal alkoxide previously prepared from alcohol and alkali metal in anhydrous alcohol to produce 2-alkoxybenzothiazole.

However, the publicization of this method involves many difficulties: when preparing alkali metal alkoxides from alkali metals and alcohols, the reaction between alkali metals and alcohols is very exothermic and the alkali metal reacts rapidly with water to ignite and burn. And explosive properties. Care should be taken. Therefore, the alcohol must be completely water-free and dehydration and purification of the alcohol is essential to recover and reuse the alcohol. After all, this method has many problems in operation and safety besides that alkali metal is not cheap.

In general, the synthesis of ethers from alcohols and halogen compounds is well known as the Willimson reaction (Shin Jikken Kagaku Koza, Vol 14 (1), 568 (1977)). Most ethers are synthesized by the reaction between alkyl halides and alkoxides.

Alternatives to the Williamson reaction, ie, reaction of an alkyl halide with an alcohol in the presence of a base are also known. However, most of them require strong bases such as sodium amide, barium oxide, silver oxide, sodium hydride, or special solvents (e.g., potassium carbonate, triethylamine, sodium hydroxide) that are limited to allow the reaction to proceed sufficiently if they are used. : Aprotic polar solvents such as dimethyl sulfoxide, dimethylformamide, dimethoxyethane, tetrahydrofuran) are required. In fact 2-halogeno-benzothiazole cannot be readily converted to its methoxy derivative in methanol in the presence of triethyl amine. These special bases and solvents are not industrially suitable for safety and economics.

It is also known that 2-halogenobenzothiazole is readily hydrolyzed by alkali to produce 2-hydroxybenzothiazole (benzothiazolone). It is consequently considered that the formation of 2-hydroxy compounds as by-products is inevitable when 2-halogenobenzothiazoles are treated with alkali metal hydroxides, especially in the presence of water.

For example, 2-6-dibromo-7-nitro-benzothiazole is converted to a low yield (34.2%) of 2-methoxy compound by sodium methoxide in a non-aqueous system and as a by-product due to incomplete removal of moisture from the reaction system. It is reported that significant amounts of 2-hydroxy compounds are produced (R. O Elderfield et al., J. Org. Chem 18, 1092 (1953)).

Further studies have been made to solve the problems caused in the production of 2-alkoxybenzothiazole derivatives (III). The present inventors have found that the halogenobenzothiazole derivatives (II) are very mild in the presence of basic condensing agents (e.g. alkalis). The target derivative (III) was easily obtained in high yield by reaction with a metal hydroxide, an alkali metal carbonate and a heterocyclic secondary amine) alcohol.

The basic condensing agent used in the process of the present invention is also effective in the presence of water and 2-hydroxycompound benzo, which is a hydrolysis by-product of the 2-halogeno benzothiazole derivative (II) which is to be produced in large quantities in conventional methods. It was found that the production of thiazolone (IV) is limited to 1% or less and the desired 2-alkoxy compound is produced almost quantitatively.

It is very important that the 2-alkoxybenzothiazole derivative (III) is readily converted to N-alkylbenzothiazolone derivatives useful as non-medical fungicides by thermal potential in the presence of a suitable catalyst, as described in Process B below.

As essential basic condensing agents used in the present invention as dehydrohalogenating agents, alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate) and bicyclic tertiary amines [1, 5- Diazabicyclo [3.4.0] Nonen-5 (DBN), 1,5-diazabicyclo [5.4.0] Undecene-5 (DBU), 1,4-diazabicyclo [2.2.2] octane (DABCO ), 2-dimethylamino-1-pyrroline and 5-methyl-1 azabicyclo [3.3.0] octane].

The amount of base condensing agent per mole of 2-halogenobenzothiazole derivative is in the range of at least about 1.0 mole and is substantially 1.1-2.0 moles.

As the reaction solvent, alcohol, one of reagents and / or other solvents which do not interfere in principle and which are stable under the reaction conditions may be used. Solvents include, for example, aliphatic hydrocarbons (e.g. hexane, heptane), aromatic hydrocarbons (e.g. benzene, toluene, xylene), halogenated aromatic hydrocarbons (e.g. chlorobenzene, dichlorobenzene) and ethers (e.g. diethyl ether, diisopropyl ether). ) Is included.

Water-miscible solvents in the solvent can be used as a mixture with water and dehydration and purification are not particularly necessary to recover them. If a water-immiscible solvent is used, the base is not soluble therein and the reaction can be carried out in two phases consisting of an aqueous phase and an organic phase together with an aqueous solution of the base.

The reaction temperature is arbitrarily selected depending on the reagent and the solvent, but in general, the reaction is carried out under mild conditions between approximately room temperature (about 20 ° C.) and the reflux temperature of the solvent.

Step B: N-alkylbenzo characterized in that the 2-alkoxybenzothiazole derivative (III) obtained in step A is subjected to a thermal potential in the presence of a catalyst such as a tertiary amine, a salt thereof, a quaternary ammonium salt, or a dialkylsulfate. Process for preparing thiazolone derivative (I).

It is known to produce N-methylbenzothiazolone via 2-methoxybenzothiazole by thermal potential without solvent (W. H. Davis et al., J. chem Soc., 304 (1942)). It is also reported in the literature that iodine has no effect as a catalyst.

This method is a mandatory operation of dislocations and requires long heating at high temperatures and does not have any disadvantages in terms of yield, safety and energy consumption for doing this on an industrial scale.

3-methyl-4-bromobenzothiazolone can be obtained by heating 2-methoxy-4-bromobenzothiazole at 160 ° C. for 5 hours and the reaction can also be carried out in an inert solvent such as nitrobenzene or dichlorobenzene. May be reported. However, the yield is only about 86.7% and the use of catalysts is not described in the literature.

The results of a wider study to overcome the above shortcomings suggest that the target N-alkylbenzothiazolone derivative (I) is transposed in the presence of a catalyst such as a tertiary amine, salt thereof, quaternary ammonium salt or dialkylsulfate. It was found that it can be easily obtained almost quantitatively under very mild conditions.

The tertiary amine used in the present invention may be arbitrarily selected. For example, aliphatic tertiary amines such as triethylamine, tri-n-propylamine, tri-n-butylamine, N, N, N ', N'-tetramethylethylenediamine, N, N-diethyl Benzylamine, N, N-aromatic tertiary amines, e.g., N, N-dimethylaniline, N, N-diethylaniline, and tertiary amines with nitrogen-containing heterocyclic rings (e.g. pyridine, 1,5-diazabi Cyclo [3.4.0] nonene-5 (DBN), 1,5-diazabicyclo [5.4.0] undecene-5 (DBU), etc. Aliphatic tertiary amines in terms of reaction rate and amount used. Preference is given to using relatively strong bases such as, DBN and DBU These tertiary amines are also used as reaction solvents at the same time.

Tertiary amines can also be used as free amines as well as salts such as their hydrochloride hydrobromide and sulfates.

The amount of secondary amines or salts thereof varies from a catalytic amount of optionally about 1/1000 moles of 2-alkoxybenzothiazole derivative (III) to an excess of reaction medium. It is preferable to use 5/1000 moles or more of relatively strong bases such as aliphatic tertiary amines, DBN and DBU to reduce the reaction time to 1 hour or less.

Any of the quaternary ammonium salts used in the present invention can be used.

Such as tetra-n-butylammonium bromide, tetra-n-butylammonium chloride, tetra-n-butylammonium iodide, tetra-n-butylammonium hydroxide, triethylbenzeneammonium chloride, triethylbenzylammonium bromide, tri Ethylbenzylammonium iodide, trimethylbenzylammonium chloride, n-cetylpyridinium bromide, tetra-n-butylammonium hydrogen sulphate and tetra-n-butyl ammonium perclate.

The amount of quaternary ammonium based on 2-alkoxybenzothiazole derivative (III) is optionally wide. It is desirable to increase the amount to increase the reaction rate at the same temperature. In practice, satisfactory effects are obtained in the range of 1 / 1000-1 / 10 mole per mole of the derivative (III), in particular in the range of 1/101 / 1000-2 / 100 mole.

Tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, triethylbenzylammonium chloride, triethylbenzylammonium bromide, triethylbenzylammonium iodide, and Preference is given to using 5/1000 moles or more selected from trimethylbenzylammonium chloride. In this case, the reaction time can be reduced to less than 1 hour.

Methods of using dialkylsulfates to produce N-alkylbenzothiazolone derivatives are known (W. A. Soxton, J, chem. Soc., 470 (1939)). The method consists of N-alkylating 2-methylthiobenzothiazole with at least equimolar amounts of dimethylsulfate and then heating and hydrolyzing the resulting 2-methylthiobenzothiazole dimethylsulfate with aqueous sodium hydroxide solution. This method is fundamentally different from the method of the present invention in that a 2-methylthio compound is used as a starting material and hydrolysis of the methylthio group is carried out after N-methylation. It is also necessary to use at least equimolar amounts of dimethylsulfate as the alkylating agent.

In the process of the present invention, the inventors unexpectedly found that 2-alkoxybenzothiazole derivative (III) is almost quantitatively transposed under very mild conditions in the presence of a catalytic amount of dialkylsulfate.

Dialkyl sulfates used in the present invention include, for example, diethyl sulfate and diethyl sulfate. Among these sulfates, dimethylsulfate shows a greater effect. The amount of dialkylsulfate based on 2-alkoxybenzothiazole derivative (III) is optionally wide. If the temperature conditions are the same, increasing the amount increases the reaction rate. However, substantially 1 / 100-1 / 10 mole per mole of 2-alkoxybenzothiazole derivative is sufficient.

The thermal potential in the presence of a catalyst of a 2-alkoxybenzothiazole derivative (eg tertiary amines, salts thereof, quaternary ammonium salts, dialkylsulfate) can be carried out in the presence or absence of a solvent. As organic solvents, aprotic organic solvents can be used, but for example halogenated hydrocarbons (e.g. monochlorobenzene, dichlorobenzene) as well as 2-alkoxybenzothia such as aromatic hydrocarbons (e.g. toluene, o-, m-, p-xylene) It is preferred to be a solvent having high solubility for the sol derivative.

The reaction temperature is optionally at least 100 ° C. or no melting point of the N-alkylbenzothiazolone derivatives when no solvent is present. But generally it is in the range of 100-150 ℃. If present, the reaction is carried out under relatively mild conditions near the reflux temperature of the solvent.

Step C: Hydrolyzing the 2-halogenobenzothiazole derivative (II) to obtain a benzothiazolone derivative (IV), which is then catalyzed with a lower alkyl halide (VI) or dialkyl sulfate (X). A process for the preparation of an N-alkylbenzothiazolone derivative (I) consisting of reacting in the presence of an alkali metal hydroxide aqueous solution using a um compound.

Intermediate benzothiazolone derivatives (IV) can be obtained by known methods. (R. C. Elderfield et al., J. Org. Chem. 18, 1092 (1953)). For example, 4-chlorobenzothiazolone is relatively low in yield (46.2%) but can be obtained by reacting 2-bromo-4-chloro benzothiazole with 10% aqueous sodium hydroxide solution under reflux for 1.5 hours. However, the yield of this reaction can be increased to 89% by using a water / dioxane (1: 1) mixed solvent according to the method improved by the inventor.

Known methods for direct N-methylation of analogous compounds are as follows.

(1) A method comprising reacting a benzothiazolone compound with methyl halide or dimethyl sulfate in a two-phase solvent system of chloroform and 25-30% aqueous potassium hydroxide solution (Hunter et al., J. Chem. Soc. 1755 (1935) ).

(2) A method consisting of reacting a benzoxazolone compound with methyl halide or dimethylsulfate in an alcohol solution of potassium hydroxide (Close et al., J. Am. Chem. Soc., 71, 1265 (1949)).

(3) A method (ibid) consisting of reacting a benzoxazolone compound in an alcohol solution of a metal alkoxide.

However, in the method (1), the conversion is poor because the reaction is performed in the two-phase system of the organic phase and the aqueous phase, and besides, the hydrolysis of the dialkyl sulfate proceeds as usual, so a large amount of dialkyl sulfate must be used to increase the conversion of the reaction.

Methods (2) and (3) have been studied in detail by Close et al. And the yield in method (2) is extremely poor regardless of the reaction in a homogeneous system when the solvent is methanol. Even when the solvent is a high boiling cellosolve (glycolmonoethyl ether), the yield is never satisfactory at only 62-76%.

The inventors also found that the conversion was not good by performing N-methylation using cross as a method using methanol as a solvent, and also found a new fact that the longer reaction time was accompanied by an undesirable side reaction to increase the conversion. . As a result, the inventors were unable to obtain the desired N-methyl compound in high yield (Comparative Example 1).

Method (3) demonstrates that by replacing potassium hydroxide with an alkali metal alkoxide, the yield was significantly increased, for example, from 80 to 95%.

With the use of alkali metal alkoxides essential in the process, the process has many problems in terms of operating conditions, stability and economics. As a result, the industrialization of this method involves many difficulties.

Recently, 4-chlorobenzothiazolone was reacted with sodium hydroxide in xylene under reflux for 1 hour by Vematsu et al., Followed by reaction with dimethyl sulfate for 2 hours to prepare 3-methyl-4-chlorobenzothiazolone. This has been reported (Japanese Patent Application (vnexamined) No. 90261/78).

However, the 3-methyl-4-chloro-benzothiazolone yield was only 77.6%.

Huemasu et al. Proposed that the N-alkylation reaction can be carried out under three combinations of the following solvents and bases.

(1) Solvent: Benzene, Toluene, Xylene, etc .:

Base: potassium-t-butoxide, sodium methoxide, sodium hydride, etc.

(2) Solvent: Methanol, Ethanol, etc.

Base: sodium methoxide, sodium ethoxide, sodium hydroxide potassium hydroxide

(3) Solvent: water, water soluble organic solvent

Base: sodium hydroxide, potassium hydroxide, etc.

Combination (I) has the following disadvantages: the base is too expensive, the solvent must be anhydrous and the base must be handled under non-aqueous conditions to prevent changes in activity. When (2) and (3) are combined, the conversion of N-alkylation is low, and when the reaction time is long, the thiazolone ring is decomposed to produce a by-product (see Control Example 1).

As a result of the research to overcome these disadvantages, the inventors have used the benzothiazolone derivative (IV) as an onium compound as a catalyst to react the N-alkylbenzothiazolone derivative of the target under a relaxed condition by reacting with an alkylating agent in an aqueous alkali metal hydroxide solution ( It was found that I) can be obtained in high yield.

Onium compounds include, for example, quaternary ammonium compounds, quaternary phosphonium compounds and sulfonium compounds. Typical onium compounds include, for example, tetra-n-butylammonium bromide, tetra-n-butylammonium chloride, tetra-n-butylammonium hydrogensulfate, triethylbenzylammonium chloride, triethylbenzylammonium hydroxide, 3-phenoxy Benzyltriethylammonium bromide, trimethylbenzylammonium chloride, tetramethylphosphonium iodide, tetra-n-butylphosphonium bromide, ethyl-2-methylpentadecyl-2-methylundecylsulfoniummethyl sulfate and the like.

The amount of onium compound based on the benzothiazolone derivative (IV) is wide. However, considering yields and economics, about 1 / 5-1 / 200 moles per mole of derivative are substantial, with 1 / 20-1 / 100 moles being preferred.

The amount of alkali metal hydroxides (eg sodium hydroxide, potassium hydroxide) is optionally at least 1 mole per mole of benzothiazolone derivative (IV). However, considering economics, 1.1-1.5 moles is sufficient.

The concentration of the alkali metal hydroxide aqueous solution varies from the low concentration to the saturated concentration, but more preferable results are obtained at relatively low concentrations, for example, up to about 10 W / W.

The amount of alkylating agent (eg alkylhalide, dialkylsulfate) is at least 1 mole per mole of benzothiazolone derivative (IV), but 1.1-1.5 moles is sufficient to complete the reaction.

This reaction can be carried out in the presence or absence of an organic solvent. If an organic solvent is used, an aprotic organic solvent which is essentially insoluble in water is preferable.

These aprotic organic solvents are aliphatic or aromatic hydrocarbons (e.g. n-hexane, cyclohexane, benzene, toluene, o-, m-, p-xylene) and halogenated hydrocarbons (e.g. dichloromethane, dichloroethane, chloroform, carbon tetrachloride, Monochlorobenzene).

The reaction temperature is optionally 0 ° C. or higher. Generally, however, the reaction proceeds under mild conditions near the reflux temperature of the room temperature-solvent.

The invention is illustrated in more detail by the following examples which, of course, do not limit the invention.

All orders were determined by gas chromatography.

Process A

Example 1

2-bromo-4-chlorobenzothiazole (6.21 g, 0.025 mol) and 94% sodium hydroxide (1.57 g, 0.037 mol) were added to methanol (100 cc) and the mixture was heated to reflux for 30 minutes. After cooling, water (100 cc) was added to the reaction solution, followed by ice cooling. The precipitated crystals were filtered off and washed with water to obtain 4.68 g of 2-methoxy-4-chlorobenzothiazole.

Yield 93.8%, pure bath 99.3%, melting point 55-57 ° C.

Example 2

2, 4-dichlorobenzothiazole (10.21 g, 0.05 mol) and 94% sodium hydroxide (8.30 g, 0.075 mol) were added to a 50 V / V% water / methanol mixed solvent (150 cc) and the compound was heated under reflux for 30 minutes. . After cooling, water (100 cc) was added to the reaction solution and ice-cooled. The precipitated crystals are filtered off and washed with water to give 9.22 g of 2-methoxy-4-chlorobenzo thiazole.

Yield 92.4%, purity 100%, melting point 55-57 ° C.

Example 3

A mixture of 2-bromo-4-chloro-benzothiazole and 2,4-dichlorobenzothiazole (5 g, 0.023 mol) and 1, 5-diazabicyclo [5.4.0] undecene-5 (DBU) ( 3.8 g, 0.025 mole) was added to methanol (80 cc) and the mixture was heated at reflux for 4 h. After cooling, water (150 cc) was added to the reaction solution and ice-cooled. The precipitated crystals were filtered off and washed twice with water to obtain 4.23 g of 2-methoxy-4-chlorobenzothiazole.

Yield 92.5%, purity 98.5%, melting point 55-57 ° C.

Example 4

A mixture of 2-bromo-4-chlorobenzothiazole and 2,4-dichlorobenzothiazole (20.87 g, 0.1 mol) and 48.5% aqueous sodium hydroxide solution (17.28 g, 0.21 mol) were added to toluene (150 cc) and methanol (16.12 g, 0.5 mole) was added dropwise thereto at room temperature. After the addition was completed, the reaction solution was heated to 50 ° C. and maintained at 50 ° C. for 4 hours. After cooling, the toluene layer was washed three times with water, and the solvent was removed under reduced pressure to obtain 19.92 g of 2-methoxy-4-chlorobenzothiazole as a pale yellow viscous liquid (solidified after cooling).

Yield 99.8%, purity 96.0%, melting point 54-56 ° C.

Example 5

A mixture of 2-bromo-4-methylbenzothiazole (11.41 g, 0.05 mole) and 94% sodium hydroxide (2.34 g, 0.055 mole) in methanol (100 cc) was heated at reflux for 4 hours.

Methanol was evaporated and the residue was dissolved in chloroform and the chloroform solution was washed twice with water. The solvent was removed under reduced pressure to obtain 8.86 g of 2-methoxy-4-methylbenzothiazole as a pale yellow viscous liquid (solidification after cooling).

Yield 98.5%, purity 97.8%, melting point 40-42 ° C.

Example 6

A solution of a mixture of 2-bromo-4-chlorobenzothiazole and 2,4-dichlorobenzothiazole (20.87 g, 0.1 mol) and 94% sodium hydroxide (4.68 g, 0.11 mol) in 95% ethanol (200 cc) Was heated at reflux for 1 h. After cooling, water (250 cc) was added to the reaction solution, followed by ice cooling. Precipitated crystals were filtered and washed with water to obtain 19.86 g of 2-ethoxy-4-chlorobenzothiazole.

Yield 92.9%, purity 98.9%. Melting point 43-45 ° C.

Example 7

A solution of n-propanol (100 cc) of a mixture of 2-bromo-4-chlorobenzothiazole and 2,4-dichlorobenzothiazole (11.30 g, 0.05 mol) and 94% sodium hydroxide (2.34 g, 0.055 mol) It was heated to reflux for 1 hour. Water was added and alcohol was azeotropically distilled with water. The resulting oily substance was extracted with chloroform and the chloroform layer was washed with water. The solvent was evaporated under reduced pressure to obtain 11.12 g of 2-n-propoxy-4-chlorobenzothiazole as a yellow viscous liquid.

Yield 97.7%, purity 98.9%, boiling point 106-108 ° C / 0.12mmHg

Example 8

In a mixture of 2-bromo-4-chlorobenzothiazole and 2,4-dichlorobenzothiazole (11.30 g, 0.05 mol) and 94% sodium hydroxide (2.34 g, 0.055 mol) in n-amyl alcohol (100 cc) The solution was heated at reflux for 1 hour, water was added and alcohol was azeotropically distilled with water. The resulting oily substance was extracted with chloroform and the chloroform layer was washed with water. The solvent was removed under reduced pressure to give 12.07 g of 2-n-amyloxy-4-chlorobenzothiazole as a yellow viscous liquid.

Yield 94.3%, purity 97.5%, boiling point 124-126.5 ° C / 0.3mmHg, melting point 28 ° C

Example 9

A mixture of 2-bromo-4-chlorobenzothiazole and 2,4-dichlorobenzothiazole (11.30 g, 0.05 mol) and 94% sodium hydroxide (2.34 g, 0.055 mol) in isopropanol (100 cc) was refluxed Under heating for 1 hour.

Water was added and alcohol was azeotropically distilled with water. The resulting oily substance was extracted with chloroform and the chloroform layer was washed with water. The solvent was removed under reduced pressure to obtain 10.92 g of 2-isopropoxy-4-chlorobenzothiazole as a yellow viscous liquid.

Yield 95.9%, purity 97.7%, boiling point 95-96 ° C / 0.2mmHg

Example 10

Mixture reflux in a mixture of 2-bromo-4-chlorobenzothiazole and 2,4-dichlorobenzothiazole (11.30 g, 0.05 mol) and 94% sodium hydroxide (2.34 g, 0.055 mol) in isobutanol (100 cc) Under heating for 1 hour.

Water was added and alcohol was azeotropically distilled with water. The resulting oily substance was extracted with chloroform and the chloroform layer was washed with water. The solvent was removed under reduced pressure to obtain 11.70 g of 2-isobutoxy-4-chlorobenzothiazole as a yellow viscous liquid.

Yield 96.8%, purity 97.2%, boiling point 103.5-105 ° C / 0.15mmHg

Example 11

2-chlorobenzothiazole (8.48 g, 0.05 mol) and 48% aqueous sodium hydroxide solution (4.78 g, 0.055 mol) were added to toluene (40 cc), and methanol (8.09 g, 0.25 mol) was added dropwise at room temperature. After the addition was complete the reaction mixture was heated to 70 ° C. and maintained at 70 ° C. for 4.5 hours. After cooling, the toluene layer was washed three times with water and the solvent was removed under reduced pressure to obtain 8.17 g of 2-methoxybenzothiazole as a pale yellow viscous liquid (solidification after cooling).

Yield 98.9%. Purity 96.8%, Melting Point 31-33 ° C.

Comparative Example 1

A mixture of 2-bromo-4-chlorobenzothiazole (6.2 g, 0.025 mol) and triethylamine (2.8 g, 0.028 mol) in methanol (80 cc) was heated at reflux for 10 hours. The reaction solution was sampled and the conversion to 2-methoxy-4-chlorobenzothiazole was measured by gas chromatography 20% to obtain a conversion rate.

Process B

Example 12

A mixture of 2-methoxy-4-methylbenzothiazole (2.69 g, 0.015 mol) and tetra-n-butylammonium bromide (97 mg, 3 × 10 ^-4 mol) was heated at 130 ° C. for 40 minutes with stirring. After cooling, the reaction was dissolved in chloroform and the chloroform layer was washed with water. The solvent was removed under reduced pressure to obtain 2.65 g of 4-methyl-N-methyl-benzothiazolone as pale yellow crystals.

Yield 98.5%, purity 99.0%. Melting point 122-124 ℃

Example 13

Triethylbenzylammonium chloride (230 mg, 0.001 mol) was added to a solution of toluene (8 g) of 2-methoxy-4-chlorobenzothiazole (4.00 g, 0.02 mol) and the mixture was heated at reflux for 5 hours. After cooling, the toluene layer was washed with water and the solvent was removed under reduced pressure to obtain 3.90 g of 4-chloro-N-methylbenzothiazolone as white crystals.

Yield 97.5%, Purity 99.1%, Melting Point 130-132 ℃

Example 14

A mixture of 2-methoxy-4-chlorobenzothiazole (5.00 g, 0.025 mol) and tetra-n-butylammonium bromide (162 mg, 5x10 ^-4 mol) was heated at 140 ° C. for 10 minutes with stirring. After cooling the reaction was dissolved in chloroform and the chloroform layer was washed with water. The solvent was evaporated under reduced pressure to obtain 4.88 g of 4-chloro-N-methylbenzothiazolone as white crystals.

Yield 97.6%, purity 98.8%, melting point 130-132 ° C

Example 15-19

The reaction was carried out in the same manner as in Example 14 except changing both or only one of the catalysts and their amounts. The results are shown in Table 1.

TABLE 1

Example 20

A mixture of 2-methoxy-4-chlorobenzothiazole (3.00 g, 0.015 mol) and tri-n-butylamine (14 mg, 7.5 × 10 ^-5 mol) was heated at 140 ° C. for 1 hour with stirring. After cooling, the reaction was dissolved in chloroform and the chloroform layer was washed with 2% aqueous hydrochloric acid solution and water. The solvent was removed under reduced pressure to give 2.92 g of 4-chloro-N-methylbenzothiazolone as white crystals.

Yield: 97.3%, purity 99.9%. Melting point 132-133 ℃

Example 21

A mixture of 2-methoxy-4-chlorobenzothiazole (3.00 g, 0.015 mol) and triethylamine (7 mg, 7 × 10 ^-5 mol) was heated at 140 ° C. for 30 minutes while stirring. After cooling, the reaction was dissolved in chloroform and the chloroform was washed with 2% aqueous hydrochloric acid solution and water. The solvent was removed under reduced pressure to give 3.00 g of 4-chloro-N-methylbenzothiazolone as white crystals.

Yield: 100%, purity 99.3%. Melting point 130-132 ℃

Example 22

Of 2-methoxy-4-chlorobenzothiazole (3.00 g, 0.015 mole) and 1,5-diazabicyclo [[5.4.0] undecene-5 (DBU) (12 mg, 7.5 × 10 ⁻⁵ mole) 0.0375 mol) was dissolved in an aqueous solution (100 cc), and tetra-n-butylammonium bromide (0.24 g, 7.5x10 ^-4 mol) and toluene ( ⁴⁰ cc) were added thereto. Diethylsulfate (5.78 g, 0.0375 mol) was added dropwise at room temperature and the mixture was stirred at room temperature for 1 hour before the phases were separated. The toluene layer was washed once with water and the solvent was removed under reduced pressure to obtain 5.24 g of 4-chloro-N-ethylbenzothiazolone as white crystals.

Yield 98.1%, purity 98.5%. Melting Point 96-98.5 ℃

Example 23

A mixture of 4-chloro-2-methoxybenzothiazole (3.00 g, 0.015 mol) and dimethylsulfate (95 mg, 7.5 × 10 ^-4 mol) was heated at 150 ° C. for 3 hours with stirring. After cooling the reaction was dissolved in chloroform and the chloroform layer was washed with an aqueous solution saturated with sodium carbonate and washed with water. The solvent was evaporated under reduced pressure to obtain 2.99 g of 4-chloro-N-methylbenzothiazolone as white crystals.

Yield 99.7%, purity 99.0%, melting point 130-132 ° C

Example 24

A mixture of 2-methoxy-4-chlorobenzothiazole (2.00 g, 0.01 mol) and tetra-n-butylammonium bromide (64 mg, 2 × 10 ^-4 mol) was heated at 100 ° C. for 90 minutes with stirring. After cooling, the reaction was dissolved in chloroform and the chloroform layer was washed with water. The solvent was evaporated under reduced pressure to obtain 1.98 g of 4-chloro-N-methylbenzothiazolone as white crystals.

Yield 99.0%, purity 99.7%, melting point 130-132 ° C

Example 25

A mixture of 2-methoxybenzothiazole (2.00 g, 0.012 mol) and tetra-n-butylammonium bromide (24 mg, 7 × 10 ^-5 mol) was heated at 120 ° C. for 2.5 hours with stirring. After cooling the reaction was dissolved in chloroform and the chloroform layer was washed with water. The solvent was evaporated under reduced pressure to obtain 1.85 g of N-methylbenzothiazolone as white crystals.

Yield 92.5%, Purity 96.0%, Melting Point 73-75 ℃

Example 26

A mixture of 2-ethoxy-4-chlorobenzothiazole (2.14 g, 0.01 mol) and tetra-n-butylammonium bromide (64 mg, 2 × 10 ^-4 mol) was heated at 150 ° C. for 3 hours with stirring. After cooling the reaction was dissolved in chloroform and the chloroform layer was washed with water. The solvent was evaporated under reduced pressure to obtain 2.06 g of 4-chloro-N-ethylbenzothiazolone as pale yellow crystals.

Yield 96.3%, purity 97.5%, melting point 94-98 ° C

Example 27

A mixture of 2-n-propoxy-4-chlorobenzothiazole (2.28 g, 0.01 mol) and tetra-n-butylammonium bromide (64 mg, 2 × 10 ^-4 mol) is heated at 150 ° C. for 7 hours with stirring did. After cooling the reaction was dissolved in chloroform and the chloroform layer was washed with water. The solvent was evaporated under reduced pressure to obtain 2.16 g of 4-chloro-Nn-propylbenzothiazolone as a pale yellow viscous liquid (cold solidification).

Yield 94.7%, purity 96.0%, melting point 40-45 ° C, boiling point 108-109 ° C / 0.2mmHg

Example 28

A mixture of 2-n-amyl-4-chlorobenzothiazole (2.56 g, 0.01 mol) and tetra-n-butylammonium bromide (64 mg, 2 × 10 ^-4 mol) was heated at 150 ° C. for 10 hours with stirring. After cooling the reaction was dissolved in chloroform and the chloroform layer was washed with water. The solvent was evaporated under reduced pressure to obtain 2.39 g of 4-chloro-Nn-amylbenzothiazolone as a yellow viscous liquid.

Yield 93.4%, Purity 93.6%, Boiling Point 124-125 ° C / 0.16mmHg

Process C

Example 29

4-chlorobenzothiazolone (9.28 g, 0.05 mole) was dissolved in an aqueous solution (220 ml) of sodium hydroxide (3.19 g, 0.075 mole) and tetra-n-butyl ammonium bromide (0,48 g, 0.0015 mole) and toluene (80 ml) Added here. Methyl iodide (11.21 g, 0.075 mol) was added dropwise at room temperature and the mixture was stirred at room temperature for 30 minutes, warmed at 50 ° -60 ° C for 1 hour, cooled and the phases separated. The toluene layer was washed once with water and the solvent was removed under reduced pressure to yield 9.58 g of 4-chloro-N-methyl benzothiazolone as pale yellow crystals.

Yield 96.0%, Purity 99.3%, Melting Point 130-132 ℃

Example 30

4-chlorobenzothiazolone (9.28 g, 0.05 mole) was dissolved in an aqueous solution (220 ml) of sodium hydroxide (3.19 g, 0.075 mole) and tetra-n-butylammonium bromide (0.48 g, 0.0015 mole) and toluene (80 ml) Added here. Dimethyl sulfate (9.40 g, 0.075 mol) was added dropwise at room temperature, then the mixture was stirred at room temperature for 1 hour and the phases were separated. The toluene layer was washed once with water and the solvent was removed under reduced pressure to obtain 9.80 g of 4-chloro-N-methylbenzothiazolone as pale yellow crystals.

Yield 98.2%, purity 98.2%, melting point 130-132 ° C

Example 31

4-chlorobenzothiazolone (9.28 g, 0.05 mole) was dissolved in an aqueous solution (220 ml) of sodium hydroxide solution (3.15 g, 0.075 mole) and benzyltriethylammonium chloride (0.34 g, 0.0015 mole) and toluene (80 ml) were excited here. Added to. Dimethyl sulfate (9.40 g, 0.075 mol) was added dropwise at room temperature and the mixture was stirred at room temperature for 4 hours and the phases separated. The toluene layer was washed once with water and the solvent was removed under reduced pressure to obtain 8.97 g of 4-chloro-N-methylbenzothiazolone as pale yellow crystals.

Yield 90.3%, Purity 96.7%, Melting Point 129-131 ° C

Example 32

4-chlorobenzothiazolone (9.28 g, 0.05 mol) is dissolved in an aqueous solution (500 ml) of sodium hydroxide (3.19 g, 0.075 mol), tetra-n-butylammonium bromide (0.48 g, 0.0015 mol) and ethylene dichloride ( 300 ml) was added here. Dimethylsulfate (9.40 g, 0.075% mol) was added dropwise at room temperature and the mixture was stirred at room temperature for 1 hour and then the phases were separated. The ethylene chloride layer was washed once with water and the solvent was removed under reduced pressure to obtain 9.37 g of 4-chloro-N-methylbenzothiazolone as pale yellow crystals.

Yield 93.9%, Purity 98.7%, Melting Point 130-132 ℃

Example 33

4-Methylbenzothiazolone (4.13 g, 0.025 mole) was dissolved in an aqueous solution (100 cc) of sodium hydroxide (1.60 g, 0.0375 mole), and tetra-n-butylammonium bromide (0.24 g, 7.5 x 10 ^-4 mole) and toluene 40 cc was added. Dimethyl sulfate (4.70 g, 0.0375 moles) was added dropwise at room temperature, then the mixture was stirred at room temperature for 1 hour and the phases were separated. The toluene layer was washed once with water and the solvent was evaporated under reduced pressure to obtain 4.31 g of 4-methyl-N-methylbenzothiazolone as white crystals.

Yield 96.2%, Purity 98.8%, Melting Point 122-124 ° C

Example 34

4-fluorobenzothionezolone (4.23 g, 0.025 mole) was dissolved in an aqueous solution (100 cc) of sodium hydroxide (1.60 g, 0.0375 mole) and tetra-n-butylammonium bromide (0.24 g, 7.5 x 10 ^-4 mole) Toluene (40 cc) was added to this. Dimethylsulfate (4.70 g, 0.0375 mol) was added dropwise at room temperature and the mixture was stirred at room temperature for 1 hour and the phases were separated. The toluene layer was washed once with water and the solvent was evaporated under reduced pressure to yield 4.47 g of 4-fluoro-N-methylbenzothiazolone as white crystals.

Yield 97.6%, purity 98.7%, melting point 121.5-123.5 ° C

Example 35

4-bromobenzothiazolone (5.75 g, 0.025 mole) was dissolved in an aqueous solution (100 cc) of sodium hydroxide (1.60 g, 0.0375 mole) and tetra-n-butylammonium bromide (0.24 g, 7.5 x 10 ^-4 mole) Toluene (40 cc) was added. Dimethyl sulfate (4.70 g, 0.0375 mol) was added dropwise at room temperature and the mixture was stirred at room temperature for 1 hour before the phases were separated. The toluene layer was washed once with water and the solvent was removed under reduced pressure to obtain 6.00 g of 4-bromo-N-methylenebenzothiazolone as white crystals.

Yield 98.3%, purity 99.0%, melting point 138-140 ° C

Example 36

4-chlorobenzothiazolone (4.64 g, 0.025 mol) to sodium hydroxide (1.60 g, potassium hydroxide (4.95 g, 0.075 mol) and 4-chlorobenzothiazolone (9,28 g, 0.05 mol) in methanol (100 ml) After dissolving, methyl iodide (11.21 g, 0.075 mol) was added dropwise at room temperature After stirring under reflux for 3 hours, a sample was taken and the conversion rate was determined by gas chromatography, resulting in 4-chlorobenzothiazolone 50 as a starting material. % Remained unreacted, after which 8.78 g (0.133 mole) of potassium hydroxide and 25.71 g (0.072 mole) of methyl iodide were added in three portions under reflux for 7 hours until the starting material disappeared completely. Water (200 ml) was added to the reaction solution The separated crystals were filtered, washed with water and dried to give 7.49 g of a reddish orange crystal (melting point 65-67 ° C.).

NMR and elemental analysis showed that this product was not the desired 4-chloro-N-methylbenzothiazolone but N-methyl-N- (2-chloro-6-methylthiophenyl) carbamate produced by decomposition of the thiazole ring. It turned out as follows.

Elemental analysis;

Theoretical C 48.9% H 4.9% N 5.7% S 13.0% Cl 14.4%

Found 49.3 4.6 6.1 12.7 14.1

Example 37

Benzothiazolone (3.78 g, 0.025 mole) was dissolved in an aqueous solution (100 cc) of sodium hydroxide (1.60 g, 0.0375 mole), tetra-n-butylammonium bromide (0.24 g, 7.5 x 10 ^-4 mole) and toluene ( ⁴⁰ cc) Added here. Dimethyl sulfate (4.70 g, 0.0375 mol) was added dropwise at room temperature and the mixture was stirred at room temperature for 1 hour before the phases were separated. The toluene layer was washed once with water and the solvent was removed under reduced pressure to obtain 4.14 g of N-methylbenzothiazolone as white crystals.

Yield 100%, Purity 97.7%, Melting Point 70-73.5 ° C

Control Example 1

The mixture was heated for 40 minutes with stirring at 140 ° C. After cooling the reaction was dissolved in chloroform and the chloroform layer was washed with 2% aqueous hydrochloric acid solution and water. The solvent was evaporated under reduced pressure to obtain 2.95 g of 4-chloro-N-methylbenzothiazolone as white crystals.

Yield 98.3%, purity 98.5%, melting point 129-132 ° C

Claims (1)

Structural formula (I) using a catalyst from the 2-halogenobenzothiazole derivative of formula (II) to the 2-alkoxybenzothiazole derivative of formula (III), or the intermediate of the benzothiazolone derivative of formula (IV) A process for preparing an N-alkylbenzothiazolone derivative.

In the above formulas R ₁ is a hydrogen atom, a chlorine atom, a bromine atom, a fluorine atom, or a methyl group R ₂ is a C ₁ -C ₅ alkyl group, X is a chlorine, bromine or fluorine atom.