HU195798B - Process for producing benzofuranyl-carbamate derivatives - Google Patents

Abstract

Benzo-furanyl-carbamate intermediates i.e. complexes of 3 moles of 2,3-di:hydro-2,2-dimethyl 7-dibenzo-furanol and its ion and 1 mole of an alkali metal-ion are prepd. from (a) 2,3-dihydro-2,2-dimethyl 7-benzo-furanol and an alkali carbonate 1:0.25-0.3 in aq. and/or solvent medium or (b) 2,3-dihydro-2,2-dimethyl 7-benzo-furanol and an alkali-hydroxide 1:0.2-0.3 in aq. and/or solvent medium, or (c) 2,3-dihydro-2,2 dimethyl 7-benzo-furanol-alkali salt:alkali hydrogen carbonate 1:0.75. - An alternative prepn. of benzo-furanyl-carbamate derivs. (II) comprise reactions between the preceding intermediates and known reagents suitable for the introduction of carbonoyl gps. of general formula -CO-N(CH3)-R1, R1 is a H atom or a gp. of general formula (III). R2 is a substd. alkyl gp., R3 an alkyl gp. Both R2 and R3 can be selected to form a morpholinyl or piperidinyl gp. with the use of the adjacent N atom.

Description

The present invention relates to a process for the preparation of 2,3-dihydro-2,2-dimethylbenzofuran-7-yl carbamates by complexation from 2,3-dihydro-2,2-dimethyl-7-benzofuranol containing a mixture of compounds having a phenolic hydroxyl group as a contaminant. , by carbamoylation after removal of impurities and complex decomposition.

Variable substituents in the general formulas herein are designated as follows:

-R or an ion thereof benzofuranol -R ¹ represents a hydrogen atom or a group of formula III in which -R ² or C 1-6 alkyl -R ³ or C 1-6 alkyl, -R ² and R ³ together are morpholino- or piper

forms a dino ring.

2,3-Dihydro-2,2-dimethyl-7-benzofuranol (IV) (hereinafter "benzofuranol") is a valuable intermediate for the preparation of various biologically active products, in particular for the synthesis of the carbamates of formula II. These compounds are used as active ingredients in insecticidal compositions. (German Patent Nos. 1,493,646, 173,457 and 170,494, etc.)

There are several processes in the literature for the preparation of the carbamates of formula II which differ in the manner of preparation of the benzofuranol or in the conditions of the carbamoylation reaction.

Benzofuranol is prepared according to one of the known processes for its preparation by rearrangement of o-metallyloxy-phenol and cyclization of the resulting o-metal-methyl-pyrocatechin. The result of the ring closure is a mixture of substances which, in addition to many by-products, also contains 2,3-dihydro-2,2-dimethyl-7-benzofuranol. Thus, U.S. Patent No. 1,403,952. French patent specification 48%; European patent application 65-70% production Promise.

The quality of the benzofuranol used plays an important role in the carbamoylation reaction.

Therefore, benzofuranol useful for carbamoylation must be purified, in particular by distillation. thus they can get rid of low boiling point decomposition products and tar high molecular weight impurities. The starting materials and by-products present - due to their near boiling points - can only be removed in the laboratory in a very good fractionator. Examples of such by-products, which are always present in crude or pre-purified benzofuranol, are: o-metallyloxy-phenol, o-methyl-pyrocatechin, o-bis-methyloxy-oxybenzene, p-methyl-pyrocatechin, pyrocatechin (USG No. 2,925,763). British Patent Application Serial No. 2,035,322). In addition, the reaction products of these compounds at high temperatures of cyclization.

Purification difficulties are the main reason that the carbamoylation reactions starting from benzofuranol could not be carried out in sufficient yield, although it is known that methyl isocyanate, for example, can be added in good yield to other compounds containing phenolic hydroxyl.

The present invention relates to a process for the preparation of 2,3-dihydro-2,2-dimethylbenzofuran-7-ylcarbamates of formula II by carbamoylation, which comprises as an impurity a mixture of 2-40% by weight of a mixture of compounds having mainly a phenolic hydroxyl group. 2,3-Dihydro-2,2-dimethyl-7-benzofuranol or an alkali salt thereof is formed into a complex of the formula I in which Mat) is an alkali metal ion and R is 2,3-dihydro-2,2-dimethyl-7 benzofuranol - by one of the following methods:

the. ) reacting benzofuranol (IV) containing said impurity in the presence of water and / or an organic solvent with 0.25 to 1 mol of alkali metal carbonate per mole (IV), or

b. ) reacting benzofuranol (IV) containing said impurity in the presence of water and / or an organic solvent with 0.2 to 0.3 mol of alkali metal hydroxide (IV), or

c. ) reacting an aqueous and / or organic solvent solution of an alkali salt of benzofuranol (IV) containing the above impurity with 0.75 mol of an alkali metal bicarbonate of the alkali salt of compound (IV) to obtain the complex of formula (I), optionally by filtration then separating the impurities with water and / or organic solvent or releasing it therefrom by heating with water and / or organic solvent and optionally acidifying to pH 2-3 with an aqueous solution of 1-15% inorganic acid (IV benzofuranol of formula (I) at a temperature of 20-100 ° C in the presence of an aprotic organic solvent and optionally water, from 3.6 to 4.24 moles of the complex of formula (I), from 0.9 to 1.1 moles of benzofuranol of formula (IV); 06 moles of methyl isocyanate, methyl carbamoyl chloride in the reaction mixture, or the compound of formula (V) wherein X is halogen and R 1 is hydrogen or a group of formula III wherein R 2 is C 1 -C 6 alkyl and R 3 is C 1 -C 6 alkyl, or R 1 and R 4 are taken together to form a morpholine or piperidine ring and the resulting carbamoyl halide. The carbamate derivative (II) is isolated from the reaction mixture.

In the first step of the process of the present invention, an alkali complex is prepared. As a secondary material, mixtures of benzofuranol of various purities or pre-purified benzofuranol containing from 60 to 98% by weight of gas chromatography can be used.

The benzofuranol-alkali complex according to variant (a) of our process is preferably formed in a heterogeneous phase in the presence of solid alkali carbonate. The fact that only the complex is selectively precipitated from the other phenolic hydroxyl-containing compounds under the reaction conditions is particularly surprising.

Water-immiscible solvents, especially non-polar solvents such as benzene, toluene, xylene, carbon tetrachloride, are preferably used for complexation. Saturated apolar solvents such as petroleum ether, petroleum, cyclohexane and the like are particularly well suited.

Although the reaction takes place with both sodium carbonate and potassium carbonate, it is preferred to use anhydrous potassium carbonate.

From the benzofuranol complexes, the free benzofuranol can be liberated by acid treatment or by water treatment only and / or heat treatment. For concentrated solutions, acid treatment is the preferred solution.

According to the present invention, benzofuranol liberated from the benzofuranol-alkyl complex is found to be more than 99% pure by thin layer chromatography and gas chromatography.

This allows the carbamate-forming reaction to be carried out without excess carbamoylating agent, under advantageous conditions. Carbamoylating reagents include alkyl isocyanate, carbamoyl halide X-CO-Nf R 4 -CH 3, or phosgene and alkylamine, preferably methylamine. When methyl isocyanate is used for carbamoylation, it is preferable to first contact the complex with an aqueous solution of water or an inorganic acid in a water-immiscible solvent and, if desired, carry out the reaction in an organic solvent after removal of the aqueous phase. For carbamoylation, solvents can be used in which the carbamate end product is poorly soluble, since there is no need for crystallization from impurities. However, if a solvent in which the carbamate is freely soluble is used, the mother liquor of the reaction can be recycled for further reactions, which causes an additional increase in yield due to the presence of a small amount of impure benzofuranol in the mother liquor.

According to the present invention, it has been possible to obtain extremely high purity benzofuranol, which enables the active compounds of the general formula (II) to be obtained from the complex or the benzofuranol thus purified in higher yields or higher purities than before.

The following examples illustrate our process in more detail:

Examples

Example 1

To 16.4 g (0.1 mol) of 98% 2,3-dihydro-2,2-dimethyl-7-benzofuranol in 100 ml of xylene was added 13.8 g (0.1 mol) of anhydrous potassium carbonate with stirring. the reaction mixture is stirred for 2-3 minutes. The solid was filtered off and washed with 10 mL xylene. On standing, the mother liquor crystallized out of an off-white sparkling material which, after an hour, was filtered off and dried. 19.2 g of an off-white solid are obtained which is 2,3-dihydro-2,2-dimethyl-7-benzofuranol-potassium complex by elemental analysis and IR. Mp 171-173 ° C.

Calculated: C, 69.13; H, 6.81; K: 5.62%;

0: 18.44%.

Found: C, 69.03; H, 6.84%; K: 5.68%;

0: 18.30%.

Example 2

To a mixture of 13.8 g of anhydrous potassium carbonate and 75 ml of cyclohexane are added dropwise with stirring 16.4 g of 81%

A solution of 2,3-dihydro-2,2-dimethyl-7-benzofuranol (0.08 mol) in cyclohexane (20 ml) was added. A thick gray-white solid precipitates, which, after stirring for 30 minutes, is filtered, washed with cyclohexane and dried. 26.9 g of an off-white substance are obtained which, by analytical determination, have the same potassium carbonate and potassium bicarbonate

Contains 13.1 g of 2,3-dihydro-2,2-dimethyl-7-benzofuranol-potassium complex. (The latter is 99% of the calculated amount.)

Example 3

1.4 g of solid chemically pure potassium hydroxide (0.025 mol), 16.4 g of benzofuranol (0.1 mol) and 20 ml of tap water are stirred at 20 ° C for 2 hours. A white solid precipitates which is filtered off, washed with cold water and dried. After drying, the material is covered with 2 x 10 mL of cyclohexane and filtered again.

16.2 g of material is obtained, which is the same complex as the product of Example 1.

Example 4

6.91 g of anhydrous potassium carbonate (0.05 mol) in 30 ml of tap water and 16.4 g of benzofuranol (0.1 mol) are stirred for 2 hours at 20 ° C. A white solid precipitates which is filtered off, washed with cold water, dried and then covered with cyclohexane. Filtration gave 16.0 g of white material which was identical to the complex product obtained in Example 1.

Example 5

In each case, the procedure of Example 3 was followed except that 1.0 g of solid sodium hydroxide (0.025 mol) was used instead of potassium hydroxide. 15.7 g of white material are obtained which is an 2,3-dihydro-2,2-dimethyl-7-benzofuranol-sodium complex based on elemental analysis and IR. M.p .: 124 'C.

Calculated: C, 70.77; H, 7.13; 0, 18.86.

Na: 3.39 Found: C: 70.79%, H: 7.11%, 0: 18.84%,

Na: 3.38%.

Example 6

The procedure of Example 4 was repeated except that 5.3 g of anhydrous sodium carbonate (0.05 mole) was used instead of potassium carbonate to give 15.5 g of a white solid, which was obtained as a complex from Example 5. equivalent to.

Example 7

To a solution of 1.40 g (0.025 mol) of solid, potassium hydroxide in solid and 40 g of methanol is added dropwise at 20 DEG C. 16.4 g of 2,3-dihydro-2,2-dimethyl-7-benzofuranol (0.1 mol) and 20 ml of methanol solution. After stirring for 10 minutes, the reaction mixture was concentrated on a film evaporator. The resulting solid was washed with cyclohexane, the filtrate dried, covered with cold water, filtered and the filtrate dried. The product was 16.1 g, identical to the material obtained in Example 1.

Example 8 A mixture of solid sodium hydroxide (0.1 mol), water (40 ml) and benzofuranol (0.1 mol) (16.4 g) was stirred for half an hour at 20 ° C. A greenish solution (an aqueous solution of the benzofuranol sodium salt) was added to which 6.3 g of solid sodium bicarbonate (0.075 mol) were added and, after stirring for 2 hours, the white precipitate was isolated as in Example 7. The product was 15.4 g of white material, identical in all to the product of Example 5.

Example 9

A mixture of 5.3 g of anhydrous sodium carbonate (0.05 mol), 30 ml of tap water and 16.4 g of benzofuranol (containing 95% / 2% pyrocatechin) is stirred for 2 hours at 20 ° C. A white solid precipitates. At this time, xylene (20 mL) was added to the reaction mixture and the mixture was kept at an internal temperature of 60-70 ° C for 1 hour. The solid dissolves. The upper xylene layer was separated. It is extracted with 4 ml of 1: 1 dilute hydrochloric acid and the xylene phase is concentrated. 16.2 g remain, which is distilled off in vacuo. The product is 15.5 g of 2,3-dihydro-2,2-dimethyl-7-benzofuranol, which is 99.8% pure by gas chromatography. It does not contain pyrocatechin impurities.

Example 10

A mixture of 5.0 g of solid sodium hydroxide (0.125 mol) in 40 ml of tap water and 16.4 g of 70% 2,3-dihydro-2,2-dimethyl-7-benzofuranol (0.07 mol) was stirred for 15 minutes. We keep it at 'C. A greenish-black solution was obtained, to which 20 ml of xylene was added and stirred for 10 minutes. The emulsion mixture and the lower aqueous layer (this is an aqueous solution of the sodium salt of 2,3-dihydro-2,2-d: methyl-7-benzofuranol) are placed in a separatory funnel and separated. To the aqueous phase was added xylene (20 mL) and a stirred solution of 10.5 g of solid sodium bicarbonate (0.125 mol) and 2,3-dihydro-2,2-dimethyl-7-benzofuranol sodium complex was added with stirring. Keep at an internal temperature of 60-70 ° C for one hour. The reaction mixture was transferred to a separatory funnel and the upper xenol phase containing benzofuranol was separated off, extracted with 4 ml of 1: 1 hydrochloric acid and the xylene phase was evaporated. 11.8 g of an oil are obtained which is distilled off in vacuo. The product was 10.5 g

2,3-dihydro-2,2-dimethyl-7-benzofuranol, which is 99.7% pure by gas chromatography.

Example 11

To a stirred mixture of 13.8 g of anhydrous potassium carbonate and 75 ml of petroleum ether are added dropwise a mixture of 16.4 g of 81% of 2,3-dihydro-2,2-dimethyl-7-benzofuranol and 20 ml of petroleum ether in 30 minutes. After stirring for an additional 30 minutes, the precipitated solid is filtered off, washed with petroleum ether and dried. The resulting greyish-white material (26.8 g) was stirred at room temperature with a mixture of 30 mL of water and 50 mL of xylene. The pH of the mixture was adjusted to pH 2-3 with 10% hydrochloric acid and after 1 hour the material was dissolved. At this time, the xylene layer was separated and evaporated. 12.6 g of a tan oil are left, which is 99% pure by gas chromatography and thin layer chromatography (95% of the calculated amount),

Example 12

26.9 g of the compound prepared in Example 2 (containing 16.15 g of potassium complex of 2,3-dihydro-2,2-dimethyl-7-benzofuranol) are added with 100 ml of toluene. It is heated to 95100 ° C and 40 ml of a solution of 8.05 g (0.085 mol) of methyl carbamoyl chloride in toluene are passed through a dropping funnel over 2 hours to the liquid level. The reaction mixture was stirred at this temperature for a further 3 hours. The solid salts were filtered off while hot and the clear toluene solution allowed to cool. 2,3-Dihydro-2,2-dimethylbenzofuran-7-yl-N-methylcarbamate is precipitated as a white solid. Filter, wash with toluene, dry. The product was treated with 15.0 g (85%) of 2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethyl carbamate.

Mp 152-154 ° C. The toluene mother liquor contains 15% unreacted 2,3-dihydro-2,2-dimethyl-7-benzofuranol.

Example 13

To the material prepared in Example 2 (27.1 g (13.9 g of 2,3-dihydro-2,2-dimethyl-7-benzofuranol-potassium complex)) was added 120 ml of toluene. The solution was heated to 90-95 ° C with parallel addition

9.9 g of phosgone (0.1 mol) and 2.5 g (0.085 mol) of monomethylamine are added over 5 hours. After stirring for another hour at 80 ° C, the solid salts were filtered hot and the clear toluene solution allowed to cool. Upon cooling, a white crystalline material precipitates. Filter, wash with toluene, dry. 15.6 g of 2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethyl carbamate (88%) are obtained. Mp 152-154 ° C. The toluene mother liquor contains 10% unreacted 2,3-dihydro-2,2-dimethyl-7-benzofuranol.

Example 14

To 27.2 g of the potassium complex of 2,3-dihydro-2,2-dimethylbenzofuranol (13.9 g) prepared in Example 2, 50 ml of chloroform and 80 ml of water are added. and a solution of 18.9 g (0.08 mol) of N- (di-n-butyl) -arainesulfenyl] -N-methylcarbamoyl fluoride in 50 ml of chloroform is added dropwise over a further 2.5 hours. The chloroform solution was washed with water (2.times.30 ml), dried over sodium sulfate and concentrated to give 28 g (86.5%) of a yellow oil which was purified by chromatography (23.8 g, 73%). (5%) 2,3-Dihydro-2,2-dimethylbenzofuran-7-yl-N- [di (n-butyl) aminosulfenyl] -N-methylcarboxylate.

Calculated: C, 63.12; H, 8.48; N, 7.36.

Found: C, 63.15; H, 8.46; N, 7.21.

example

26.8 g of the material prepared in Example 2 (containing 13.2 g of 2,3-dihydro-2,2-dimethyl-7-benzofuranol potassium complex) are dissolved in 30 ml of water and 35 ml of ethyl acetate with stirring. . The pH is adjusted to 2-3 by addition of 10% hydrochloric acid. After stirring for one hour, the aqueous phase is separated off, 0.1 g of triethylamine is added to the organic phase and 4.2 g (0.08 mol) of pure methyl isocyanate are added dropwise over 30 minutes with gentle cooling. After stirring at room temperature for 20 hours at 20-25 ° C, heat the salt to boiling point and allow the solution to cool. A white crystalline solid precipitates which is filtered off with ice and washed with ethyl acetate. The white product 2,3-dihydro-2,2-dimethylbenzofuran-7-yl] methylcarbamate was 16.0 g (90.2%).

Op: 154-155 C.

Example 16

In all cases, the procedure of Example 14 was repeated except that 4.2 g (0.02 mole) of morpholinosulfenyl was replaced by N- [di (n-butyl) aminosulfenyl] -N-methylcarbamoyl fluoride. N-methylcarbamoyl chloride is used. The product was 5.8 g (85.7%) of 2,3-dihydro-2,2-dimethylbenzofuran-7-yl-N-morpholinosulfenyl-N-methylcarbam.

Mp 80-81 ° C.

Example 17

In all cases, the procedure of Example 14 was repeated except that 3.84 g (0.02 mole) of piperidine sulfenyl was replaced by N- [di (n-butyl) aminosulfenyl] -N-methylcarbamoyl fluoride. N-methylcarbamoyl fluoride is used. This gave 5.7 g (84.8%) of 2,3-dihydro-2,2-dimethylbenzofuran-7-yl-N-piperidinesulfenyl-N-methylcarbamate as a thick oil. Analysis: Calculated: C, 60.69; N, 8.33; H, 7.19. Found: C, 59.52; N, 7.94; H, 7.24.

Example 18 Comparative Example

Purification of 2,3-dihydro-2,2-dimethyl-7-benzofuranol by vacuum distillation.

The 81% 2,3-dihydro-2,2-dimethyl-7-benzofuranol used in Example 2 was subjected to vacuum fractionation.

Precursor: 12 g (64-79 ° C / 50 Pa)

Main Spirit: 110 g (79-80 ° C / 50 Pa)

Residue: 32 g

The distillates and the residue obtained by distillation are analyzed by gas chromatography

-511

The content of 2.3-dihydro-2,2-dimethyl-7-benzofuranol is as follows:

Distillate: 70.1%

Spirits: 95%

Remaining: 40%

The precursor can be recycled once to the next fraction, the residue is no longer dense tar.

110 g of 95% pure 2,3-dihydro-2,2-dimethyl-7-benzofuranol obtained as the main distillate, based on 2,3-dihydro-2,2-dimethyl-7-benzofuranol in the 81% mixture , Corresponding to a yield of 8% by weight of the spirit.

EXAMPLE 2 2,3-Dihydro-2,2-dimethyl-7-benzofuranol in the above mixture of 81% purity can be recovered in pure form by the same method as in the thousand minutes.

Example 19 Comparative Example

16.4 g (0.095 mole) of the material purified by distillation according to Example 18 having a

2.3-Dihydro-2,2-dimethyl-7-benzofuranol is dissolved in 95% ethyl acetate in 40 ml, triethylamine (0.12 g) is added and neat methyl isocyanate (5.49 g, 0.1045 mol) is added dropwise. At -25 ° C for 30 minutes. After stirring for 2 hours at 2025C, the reaction mixture is heated to reflux and refluxed for 10 minutes. After cooling, a white crystalline solid precipitates, which is filtered off and washed with ethyl acetate. The white product 2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethylcarbamate 17.9 g (85.3%) m.p. 151-153 ° C, 2.3% phenolic carbamic acid contains ester impurities.

Claims (1)

Process for the preparation of 2,3-dihydro-2,2-dimethylbenzofuran-7-ylcarbamates of general formula (II) by carbamoylation, characterized in that 2-4% by weight of a mixture of compounds having mainly a phenolic hydroxyl group is used as impurity. to form a complex of formula (I) wherein Mef1 is an alkali metal ion and R is 2,3-dihydro-2,2-dimethyl-7-hydroxy-2-dimethyl-7-benzofuranol or an alkali salt thereof; Benzofuranol by one of the following methods: the. ) reacting benzofuranol (IV) containing said impurity in the presence of water and / or an organic solvent with 0.25 to 1 mol of alkali metal carbonate per mole of the compound (IV), or b. ) reacting benzofuranol (IV) containing said impurity in the presence of water and / or an organic solvent with 0.2 mol / l to 0.3 mol of alkali metal hydroxide per liter (IV), or c. ) reacting an aqueous and / or organic solvent solution of the alkali metal salt of benzofuranol (IV) containing the above impurity with 0.75 mol of alkali metal hydrogencarbonate per alkali salt of the compound (IV) to obtain the resulting compound of formula (I), optionally separated by filtration followed by removal of impurities with water and / or organic solvent or by liberating it with water and / or organic solvent by snow bleaching and optionally by acidification of 1 to 15% by weight of aqueous solution of inorganic acid to a pH of 2-3 to 3Φ (IV) benzofuranol of formula (I) in the presence of an aprotic organic solvent and optionally water, at a temperature of from 20 to 100 ° C, from 3.6 to 4.24 moles per complex of formula (I), from 0.9 to 1.06 per cent of benzofuranol of formula (IV) of methyl isocyanate, methyl carbamoyl chloride prepared in the reaction mixture, or a compound of formula (V) wherein X is halogen and R 1 is hydrogen or a ceoport of formula III wherein R 1 is C 1 -C 6 alkyl and R 3 is C 1 -C 6 alkyl, or R 2 and R 3 are reacted with a morpholine or piperidinyl ring to form the The carbamate derivative of the formula (I) is isolated from the reaction mixture.