HU200999B - Process for producing n-methyl-(2,3-dihydro-2,2-dimethyl-7-benzofuranyl)-carbamate - Google Patents

Abstract

N-methyl-(2,3-di:hydro -2,2-di:methyl-7-benzofuranyl)-carb amate is prepd. through a hitherto not known intermediate, (2,3-di:hydro-2,2-di -methyl-7-benzo-furanyl-(chloro-methyl)carbonate. The intermediate is prepd. from 2,3-di:hydro-2,2- di:methyl-7-benzo-furanol and chloro-methyl-chloro formate in an inert gas atmosphere, in an organic solvent or in an organ solvent water mixt.. An organic base and/or a quaternary ammonium and/or a phase-change catalyst. - The intermediate reacts with methylamine and/or a methylamine salt either in the original reaction mix or following isolation.

Description

The present invention relates to a process for the preparation of N-methyl- (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) -carbamate and its novel intermediate, (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) - (chloro). -methyl) carbonate. In our process, 2,3-dihydro-2,2-dimethyl-7-benzofuranol is reacted with (chloromethyl) - (chloroformate) to give (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) - chloromethyl carbonate which is reacted with methylamine or a salt thereof to give N-methyl- (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) carbamate.

Carbofuran became known in 1965 as Nmethyl- (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) carbamate as an insecticide, nematicide and acaricide (FLMcEwen, AC Davis, J. Econ. Entomol ., 1965, 58, 369, U.S.A. 3,474,170). Since then its use has been widespread in plant protection. As a result, several processes have been developed for its production, which fall into three groups. The starting materials for each of these processes

2,3-Dihydro-2,2-dimethyl-7-benzofuranol is used, with differences in the reaction partners and the way in which it is converted to the final product.

In a large group of processes, 2,3-dihydro-2,2-dimethyl-7-benzofuranol is reacted with methyl isocyanate to produce the carbamate (NL 64.07.316; NL 65.00.340; DE 2.461.129). The reaction is usually carried out in the presence of triethylamine or another organic base, without solvent or in diethyl ether, usually at room temperature (DE 2,309,379).

A process using a reaction temperature of 65 ° C is also known (NL 64.07.316). 173,437. s. According to Hungarian Patent Specification

2,3-Dihydro-2,2-dimethyl-7-benzofuranol is reacted with methyl isocyanate for 6 hours at a temperature of 25-30 ° C in isopropyl alcohol solvent to give Carbofuran in a yield of 74%.

Cooling of the exothermic coupling reaction is accomplished by recirculation of an inert solvent (e. Cation exchange resins containing free tertiary amino or quaternary ammonium groups are also used to catalyze the reaction, which advantageously improves the yield (DE 2.461.129).

In another group of processes, the use of the extremely dangerous and difficult to produce methyl isocyanate is attempted by reacting the starting phenolic hydroxyl group compound with a primary amine and phosgene (DE 2.618.853). According to another method, the reaction is carried out in a toluene solution under a nitrogen atmosphere in a yield of 73% (U.S. Pat. No. 4,272,441). In one embodiment of these processes, the phenolic hydroxyl group is first reacted with phosgene to form chloroformate in the presence of a tertiary base and then acylated to give Carbofurant (US 3,547,955).

In a third group of procedures, they attempt to avoid the use of both methyl isocyanate and phosgene (because of its hazardousness).

Carbamoylation is carried out with N- (methylamino) carbonyl saccharin (DE 3.040.633; US 4,315,861). The disadvantage of these processes is that the alkali-glazed carbamoylating agent is difficult and inexpensive to produce.

In our research to overcome the drawbacks of known processes, we have developed a new synthesis route for the production of Carbofuran. Our process is based on the recognition that when 2,3-dihydro-2,2-dimethyl-7-benzofuranol (chloromethyl) - (chloroformate) is reacted in a solvent medium, optionally in a stream of gas, in the presence of a base, a compound (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) (chloromethyl) carbonate not previously described in the literature, which is further reacted with methylamine or its salt either in the reaction mixture or after separation in a solvent medium, and as a result, Carbofuran can be produced with good yield and purity.

If the carbonate is first prepared and subsequently reacted with the methylamine or its salt, the reaction conditions (solvent, base, temperature) may be similar to the carbonate preparation but may be different. For example, in the second step, when an aqueous solution of methylamine is used, the solvent can be petroleum ether and the reaction is carried out in a petroleum ether-water biphasic system.

In both reaction steps, the same organic base can be used, but different (eg triethylamine, pyridine). If the carbonate is not prepared from the reaction mixture, the reaction proceeds in the second step in an organic solvent and aqueous two-phase system.

The process is carried out using known preparative and separation methods, and the product is obtained by simple operations, with sufficient purity and in favorable yield.

The process is illustrated by the following examples, which are not limited to the scope of the patent.

Example 1 Preparation of (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) (chloromethyl) carbonate with a dm ³ stirrer, 350 g of dichloromethane and 27.1 g of methylene chloride are added to a round-bottomed flask equipped with a thermometer. chloromethyl) - (chloroformate). While stirring, the mixture was cooled to 0 ° C and a mixture of 22 g of triethylamine and 100 g of dichloroethane and 32.8 g of 2,3-dihydro-2,2-dimethyl-7-benzofuranol was added dropwise with cooling. hours, ensuring that the temperature does not rise above + 5 'C. The reaction mixture was then stirred for a further 100 minutes while allowing to warm to room temperature.

The precipitated solid triethylammonium chloride was removed by filtration and washed with 50 g of dichloromethane. The combined organic phases were washed three times with 60 g of saturated sodium bicarbonate solution and then three times with 60 cm ^{3 of} distilled water. The dichloromethane is then distilled off in vacuo.

The residue was fractionated by vacuum distillation to remove 42.0 g of (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) (chloromethyl) carbonate, b.p. 152-153 ° C.

Yield: 81.1% of 2,3-dihydro-2,2-dimethyl-7-benzofuranol.

-2HU 200999 Β

Example 2 Preparation of 2,3-dihydro-2,2-dimethyl-7-benzofuranyl (chloro-methyl) carbonate

Into a 500 cm ³ round-bottomed flask equipped with a stirrer, a thermometer and an addition funnel, 150 g of carbon tetrachloride and 27.1 g of (chloromethyl) - chloroformate are weighed. The solution was cooled to 0 ° C and a solution of 32.8 g of 2,3-dihydro-2,2-dimethyl-7-benzofuranol, 17 g of pyridine and 50 g of carbon tetrachloride was added dropwise with stirring over 45 minutes without increasing the temperature to + 5 ° C. Above 'C. The mixture was stirred for an additional hour while allowing to warm to room temperature.

The precipitated solid was removed by filtration and the filtrate was washed three times with 50 cm ^{3 of} water. The carbon tetrachloride is then distilled off. 39.3 g of (23-dihydro-2,2-dimethyl-7-benzofuranyl) - (chloromethyl) carbonate are isolated by fractional vacuum distillation of the residue.

Yield for benzofuranol: 76.5%.

Example 3 Preparation of (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) (chloromethyl) carbonate

Into a 500 cm ³ round-bottomed flask equipped with stirrer, thermometer and addition funnel were added 150 g of carbon tetrachloride and 27.1 g of (chloromethyl) -chloroformate, and the solution was cooled to -20 ° C. While stirring and cooling, 25 g of pyridine are added dropwise and 32.8 g of 2,3-dihydro-2,2-dimethyl-7-benzofuranol and 50 g of carbon tetrachloride are added dropwise over 45 minutes while maintaining the temperature below -10 ° C. The reaction mixture was stirred for a further 60 minutes, allowing it to warm to room temperature.

The precipitated solid pyridine salt is removed by filtration and the filtrate is washed three times with 50 cm ^{3 of} distilled water. The carbon tetrachloride is then distilled off. 39.8 g of (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) (chloromethyl) carbonate are isolated by fractional vacuum distillation of the residue.

Yield: 76.3% for benzofuranol.

Example 4 Preparation of (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) (chloromethyl) carbonate In a dm ³ round-bottomed flask fitted with a stirrer, a thermometer and a separatory funnel, 100 g of dioxane and 27.1 g were added. (chloromethyl) - (chloroformate).

Then, 32.8 g of 2,3-dihydro-2,2-dimethyl-7-benzofuranol and 200 g of dioxane were weighed into a 500 cm ³ round-bottomed flask equipped with stirring, addition funnel and gas evacuation tube, and 5.8 g of 20 g were added in portions. Sodium hydride containing 40% paraffin oil (4.6 g pure sodium hydride). The addition is accompanied by gas evolution. After the evolution of gas has ceased, the suspension is added under cooling and stirring to a solution of (chloromethyl) (chloroformate) and dioxane over 45 minutes, ensuring that the temperature does not rise above + 5 ° C. After stirring at room temperature for an additional hour, 200 cm @ ^{3 of} water and 200 cm @ ^{3 of} dichloromethane are added, after 5 min the two phases are separated and the organic phase is washed with 100 cm @ ^{3 of} water and after drying the dioxane and dichloromethane. methane is distilled off. Fractional distillation of the residue afforded 41.5 g of (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) (chloromethyl) carbonate.

Yield: 80.8% (based on benzofuranol).

Example 5 Preparation of 2,3-Dihydro-2,2-dimethyl-7-benzofuranyl (chloromethyl) carbonate

Into a 250 cm ³ three-necked round-bottom flask equipped with a thermometer, a dropping funnel and a mechanical stirrer was added 16.42 g (0.1 mol) of 2,3-dihydro-2,2-dimethyl-7-benzofuranol, 17.17 g (0.06 mol). sodium carbonate decahydrate, 1 g of Adogen 464 phase transfer catalyst is ^R / (methyl trialkyl (C8-Clo) ammonium chloride 15) / 50 cm ³ of benzene and 50 ^cm3 of water.

The biphasic system was cooled to 0-5 ° C with ice-water cooling and a solution of 15.38 g (0.119 mol) of (chloromethyl) - (chloroformate) in 30 cm <^{3> of} benzene was added dropwise over 30 minutes, so that the temperature does not rise above 5 'C. After stirring for a further 45 minutes, the phases are separated off, with the elimination of nitrogen gas. The aqueous phase was extracted twice with 30 cm ^{3 of} benzene.

The combined benzene phases are washed three times with 30 cm <^{3> of} water, dried over anhydrous calcium chloride, filtered and the benzene is distilled off in vacuo. The residue is fractionated by vacuum distillation to isolate (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) - (chloromethyl) carbonate. Yield: 14.86 g, boiling point: 126 ° C / 266 Pa. Yield: 57.9% based on 2,3-dihydro-2,2-dimethyl-7-benzofuranol. According to gas chromatography analysis, the target product content is:

94.2%.

Example 6 Preparation of (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) (chloromethyl) carbonate

16.42 g (0.1 mol) of 2,3-dihydro-2,2-dimethyl-7-benzofuranol, 1 g of Adogen ^R 464 phase transfer catalyst were charged into a 250 cm ³ four-necked flask fitted with a thermometer, two dropping funnels and a mechanical stirrer. cm ³ benzene and 30 cm ³ water.

The biphasic system was cooled with ice water to 0-5 ° C and a solution of 15.38 g (0.119 mol) of (chloromethyl) - (chloroformate) in 30 cm ^{3 of} benzene was added dropwise to one of the dropping funnels, while , A solution of 8 g (0.12 mol) of sodium hydroxide in 50 cm ^{3 of} water at 25 ° C for 25 minutes. Stir for an additional 40 minutes and then separate. The aqueous phase was extracted twice with 30 cm ^{3 of} benzene. The combined benzoic phases were washed three times with 30 cm <^{3> of} water, dried over anhydrous calcium chloride, and the desiccant was filtered off and concentrated in vacuo.

The residue is fractionated by vacuum distillation to isolate (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) (chloromethyl) carbonate. Yield: 17.40 g, b.p. 130-133 ° C. Analysis by gas chromatography65 showed that the target product content was 98.7%.

-3HU 200999 Β

6

Example 7

Preparation of N-methyl- (2,3-dihydro-2,2-dimethyl-7-benzofuran-1) -carbamate

Into a 250 cm round-bottomed flask with stirring, add 20 g of petroleum ether, boiling in 120 ° C, to a vigorously stirred mixture of 5 and 5.13 g of (23-dihydro-2,2-dimethyl-7-benzofuranyl) (chloromethyl) carbonate at room temperature. A mixture of 15 g of a 12.5% aqueous solution of methylamine and 10 g of water. After stirring for one and a half hours, the precipitated solid was filtered, washed first with water, then with petroleum ether, and then dried.

2.93 g of N-methyl- (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) - (chloromethyl) carbamate of melting point 148-149 C. ^E (2,3-dihydro Yield: 66.2% based on 15 Ro-2,2-dimethyl-7-benzofuranyl) (chloromethyl) carbonate.

& example

Preparation of N-methyl- (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) carbamate

Into a 250 cm ³ round-bottomed flask with stirring and addition funnel, add 5.13 g of (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) - (chloro-methyl) carbonate, 4.05 g of methyl ammonium chloride. , 10 g of petroleum ether (120 ° C, 25 boiling point) and 10 g of water. To the vigorously stirred mixture, a solution of 2.4 g of sodium hydroxide in 15 g of water is added dropwise at room temperature. After stirring for two hours, the precipitated solid was filtered off, washed with water and petroleum ether and dried.

3.06 g of N-methyl- (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) -chloromethyl-ka Tbamate are obtained, m.p. 149-152 'C.

Yield: 69.2% (based on starting benzofuranyl carbonate).

Example 9

Preparation of N-methyl- (2,3-dihydro-2,2-dimethyl-7-benzofuran-1) -carbamate 40

250 cm ^3, stirrer and an addition funnel was charged with 5.13 g (2.3 dihidro2.2--dimethyl-7-benzofuranyl) - (chloromethyl) carbonate tót, 4.0 g of methyl chloride and 10 g of water. To the vigorously stirred mixture was added dropwise a mixture of 6.1 g of triethylamine and 10 g of petroleum ether (boiling point 120 ° C) for 45 minutes. After stirring for two hours, the solid is filtered off, washed with water and then with petroleum ether and dried. 3.67 g of N-methyl- (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) carbamate are obtained, m.p. 148-150 ° C. Yield:

82.9% (based on starting benzofuranyl carbonate).

Example 10 55

N-methyl- (2,3-dihydro-2,2-dimethyl-7-benzofuranylmethyl

l) - Chloromethyl carbamate

5.13 g of (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) - (chloro-60-methyl) carbonate are weighed into a 250 cm ³ round-bottomed flask with stirring, addition funnel and gas inlet. Pour petroleum ether (C) was added. Methylamine gas was bubbled through the solution at 50 g / h for 1 hour.

After the bubbling ceased, the suspension was stirred for an additional 65 hours, then the precipitated solid was filtered, washed with water and petroleum ether, and then dried.

3.75 g of N-methyl- (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) carbamate are obtained, m.p. 151-152 ° C.

Yield: 84.7% (based on benzofuranyl carbonate).

Example 11

Preparation of N-methyl- (2,3-dihydro-2,2-dimethyl-7-benzofuran-1) -carbamate

Into a 250 cm ³ round-bottomed flask with stirring and addition funnel, add 5.13 g of (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) (chloromethyl) carbonate and 10 g of methylene chloride, followed by 0 '. Cool to C.

Then, 15 g of a 12.5% solution of methanol in methanol is added dropwise so that the temperature is kept below 15 ° C. After stirring for half an hour, the solid was collected by filtration, washed with water and then with methylene chloride, and then dried. 4.43 g of N-methyl- (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) carbamate are obtained, m.p. 150-151 ° C.

Yield: 93.2% based on starting benzofuranyl carbonate.

Example 12

Preparation of N-methyl- (2,3-dihydro-2,2-dimethyl-7-benzofuran-1) -carbamate

250 ^cm3, thermometer, dropping funnel and mechanical stirrer was charged with three-necked flask equipped cent 13.55 g (0.105 mol) of (chloromethyl) (chloroformate) and 100 cm ³ of dichloromethane. The solution was cooled with stirring to 0-5 ° C and 16.42 g (0.1 mol) of 2,3-dihydro-2,2-dimethyl-7-benzofuranol, 10.63 gh (0.105 mol) of triethyl was added dropwise over 90 minutes. amine and 40 cm ^{3 of} dichloromethane. The reaction mixture was stirred for an additional 100 minutes while the temperature was raised to 25 ° C. The precipitated solid triethylammonium chloride was removed by filtration and washed with 20 cm ^{3 of} dichloromethane.

The combined dichloromethane phases are washed twice with 30 cm @ 3 of sodium bicarbonate and the dichloromethane is distilled off in vacuo.

To the crude product obtained above was added methyl ammonium chloride (20.0 g, 0.296 mole) and water (50 cm ³ ), and 30.37 g (0.3 mole) of triethylamine and 50 cm ^{3 (} 50 ml) were added dropwise to the resulting emulsion with stirring over 45 minutes. ³ A mixture of petroleum ether boiling at 120 ° C. After stirring for two hours, the precipitated solid was filtered off, washed with water and petroleum ether. 15.23 g of N-methyl- (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) carbamate are obtained, m.p. 149-150 ° C. The yield of starting 2,3-dihydro-2,2-dimethyl-7-benzofuranol was 68.8%.

Example 13

Preparation of N-methyl- (2,3-dihydro-2,2-dimethyl-7-benzofuran-1) -carbamate

13.55 g (0.105 mol) of (chloromethyl) (chloroformate) and 20 cm @ ^{3 of} hot petroleum ether (120 cm @ 3) are weighed into a 250 cm3 ^three -necked flask fitted with a thermometer, a dropping funnel and a mechanical stirrer. The solution is stirred at 0-5 ° C

Cool and add dropwise over 45 minutes 16.42 g (0.1 mol) of 23-dihydro-2,2-dimethyl-7-benzofuranol,

A mixture of 10.63 g (0.105 mol) of triethylamine and 10 cm ^{3 of} petroleum ether. The reaction mixture was stirred for an additional 100 minutes while allowing the temperature to rise to room temperature. The solid tri-ethyl ammonium chloride was removed by filtration and washed with 15 cm ³ of petroleum ether. To the combined organic phases were added methyl ammonium chloride (20.0 g, 0.296 mol) and water (50 mL), and a mixture of triethylamine (30.37 g, 0.3 mol) and petroleum ether (10 cm ³ ) was added dropwise to the resulting emulsion with stirring over 45 minutes. Stirring is continued for 125 minutes, the precipitated solid is filtered off, washed with water and petroleum ether. 10.72 g of N-methyl- (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) carbamate are obtained, m.p. 148-150 ° C. Yield: 48.4% based on 2,3-dihydro-2,2-dimethyl-7-benzofuranol.

Claims (1)

PATIENT PERSONALITY Process for the preparation of N-methyl- (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) carbamate, comprising: - 2,3-dihydro-2,2-dimethyl-7-benzofuranol in an organic solvent or organic solvent aqueous medium, optionally in an inert gas stream, in the presence of a base and optionally a phase transfer catalyst at -35 ° C to 40 ° C (chloromethyl) chloroformate) - (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) - (chloromethyl) carbonate so produced, optionally after recovery from the reaction mixture in an organic solvent or organic solvent-aqueous medium in the presence of an organic and / or inorganic base It is reacted with methylamine and / or its salt at a temperature of from -35 ° C to 40 ° C finally, N-methyl- (2,3-dihydro-2,2-dimethyl-7-benzofuranyl) -carbamate is recovered from the reaction mixture in a known manner.