KR100460430B1 - Process for preparing 3-Isochromanone - Google Patents

Abstract

The present invention reacts o-tolylacetic acid with sulfyl chloride in the presence of a free radical initiator (e.g. AIBN) and then closes the ring of 2-chloromethylphenylacetic acid thus obtained with a base (e.g. potassium bicarbonate). It relates to a method for producing isochromonone.

Description

Process for preparing 3-Isochromanone

Example 1

O-tolylacetic acid (98% 750g, 4.89mol) and fluorobenzene in a 5 l jacketed vessel equipped with a mechanical stirrer, oil circulator, reflux condenser, nitrogen purge and outlet connected to caustic scrubber to remove hydrogen chloride vapor (1323 ml) was filled. The slurry is heated to the boiling point and the fluorobenzene is distilled off at atmospheric pressure (200 ml) to remove water. Additional fluorobenzene (100 ml) is added to the vessel and distilled until the water is completely removed. Cool the dry solution and stir overnight under nitrogen atmosphere.

Fluorobenzene and crystalline solid were reheated to 80 ° C. and AIBN (11.3 g) was added. Sulfuryl chloride (680.3 g, 4.89 mol at 97% concentration) was added over 4 hours using a peristaltic pump and the reaction solution was stirred at 80 ° C. for 1 hour. It was then cooled and left at ambient temperature under nitrogen atmosphere for 2 days. Small samples are separated from the mixture, diluted with more solvent and analyzed by GC. The reaction solution containing the crystalline material was reheated to 80 ° C. Additional sulfuryl chloride (68 g, 0.489 mol at 97% concentration) was charged and stirring continued at 80 ° C for 1 hour. GC analysis indicated that 23.5% of the starting material was present.

The reaction solution was cooled to about 45 ° C. and saturated potassium bicarbonate solution (908 g) was added slowly to avoid release of carbon dioxide too quickly. Potassium iodide (3.3 g) was added followed by a portion of solid potassium bicarbonate (430.5 g, 4.3 mol) to obtain a final pH of 7-8. Water (750 g) was added and the reaction mixture was stirred for 15 minutes to dissolve the inorganics and then settle. The aqueous and organic layers were separated and some residual organic material was extracted from the aqueous layer with fluorobenzene (2 × 500 g) at 60 ° C. and then the organic material was collected and cooled overnight.

Distillation at atmospheric pressure removed fluorobenzene (1058 g) from the organic material and charged with methyl cyclohexane (1075 g) while maintaining the organic solution at about 80 ° C. The crystals were then cooled once the crystallization had started and the temperature was lowered to about 2 ° C. Crystallized 3-isochromenone was isolated by filtration, washed with methylcyclohexane (300 g) and dried by aspiration: 453.7 g (436.91 g 100%) at a concentration of 96.3%; Yield 60.4%; Melting point 82.4-83.8 ° C.

Example 2

O-tolylacetic acid (50 g at 98% concentration, 0.326 mol) in fluorobenzene (76.7 g) was dried by azeotropic distillation and cooled to 60 ° C. AIBN (2.13 g, 0.013 mol) was added portionwise over 3 hours while maintaining a temperature of 60-62 ° C. followed by the addition of sulfuryl chloride (49.8 g, 0.358 mol at 97% concentration). A small amount of sample was separated from the mixture, diluted with more solvent and analyzed by GC. This indicated the presence of 10% o-tolylacetic acid starting material.

20% aqueous solution of potassium bicarbonate (60.6 g, 0.121 mol) was slowly added to the reaction mixture followed by potassium iodide (0.22 g) followed by solid potassium bicarbonate (20.95 g, 0.209 mol). Stirring was continued at 60 ° C. for 1 hour. Additional solid potassium bicarbonate (7.9 g) was added at 60 ° C and stirring continued for another 15 minutes. The reaction mixture was left to cool overnight to ambient temperature under nitrogen. It was then heated to 65 ° C. and the aqueous and organic layers separated. After washing the separator, the organic layer was diluted with a used fluorobenzene (50 ml) and azeotropically distilled to dryness. Cyclohexane was slowly added at 60-65 ° C. and then cooled to precipitate the product. The temperature was lowered to about 5 [deg.] C. and the solids were filtered and aspirated to dryness to afford 27.18 g (100 wt.%) Of 3-isochromanone (56.3% yield; melting point 79-80 [deg.] C.).

Example 3

A 1 l three-necked flask was charged with o-tolylacetic acid (150 g, 0.979 mol at 98% concentration) and fluorobenzene (280 ml). The contents were heated to remove water by azeotropic distillation and 50 ml of distillate was collected. After cooling under nitrogen the contents of the flask were heated to 78 ° C. and AIBN (2.25 g) was added. Sulfuryl chloride (204.3 g at 97% concentration, 1.468 mol) was added slowly over 3.5 hours under nitrogen while maintaining the temperature at 78-80 ° C. Sulfuryl chloride was added and stirring continued at 80 ° C. for 1 hour. The gases (SO ₂ and HCl) separated by water and caustic soda solution (120 g) were scrubbed. A small amount of sample was separated from the mixture, diluted with more solvent and analyzed by GC. This indicated the presence of 44.35% isochromenone and 54.78% mono and dibasic starting materials. The reaction mixture was stirred for additional 1 h at 80 ° C. and then cooled under nitrogen overnight. It was then reheated to 60 ° C. to redissolve the crystalline material and cooled to 45 ° C. Potassium iodide (0.66 g) was added followed by the slow addition of saturated sodium bicarbonate solution (165 ml) and solid sodium bicarbonate (143.4 g). The mixture was then heated to 60 ° C. and left stirring for 3 hours.

The aqueous and organic layers were separated at 60 ° C. Residual organics were extracted from the aqueous layer with fluorobenzene (2x100 ml) and collected as the main organic layer. Fluorobenzene (238 g) was removed from the organic material by distillation (50 ° C., greater than 200 mm Hg) and methyl cyclohexane (238 ml) was added at 60 ° C. After heating to 80 ° C., the clear organic solution was cooled to ambient temperature and at about 50 ° C. the product began to precipitate crystals. The final organic slurry was cooled to −10 ° C. using an ice / salt bath and kept at −10 −5 ° C. for 2 hours. The product was then filtered off and aspirated to dryness: 87.1 g (70.73 g 100%) at a 81.2% concentration; Yield 48.8%.

Example 4

This example illustrates the preparation of 3-isochromanone from 2-chloromethylphenylacetic acid recrystallized by different procedures.

O-tolylacetic acid (100 g) was slurried in fluorobenzene (153.4 g) under nitrogen and heated to reflux. An additional amount of fluorobenzene (100 ml) was then added to the reaction mixture and the solution was dried by azeotropic distillation at 85-90 ° C. under atmospheric pressure. The reaction mixture was then cooled to 80 ° C. and AIBN (2.14 g) was partially charged to the vessel. Sulfuryl chloride (105.55 g) was then added to the reaction mixture (maintained at 80-85 ° C.) refluxing over 3 hours while monitoring the reaction progress using ¹ H NMR. Analysis showed here about 80% conversion to 2-chloromethylphenylacetic acid. After the addition was complete the reaction mixture was slowly cooled to ambient temperature, finally 0-5 ° C. The precipitate was suction filtered, washed with n-hexane (70 g) and filtered and dried on a filter to give a fine off-white powder (75.73 g); ¹ H NMR (CDCl ₃ ) δ3.8 (s, 2H); 4.6 (s, 2 H); 7.2-7.5 (m, 4H) ppm; Melting point 114.5-117.1 ° C .; Quantitative yield 62.15%; % Concentration 95.7% by ¹ H NMR.

A 2-chloromethylacetic acid sample was recrystallized from toluene and filtered at high temperature to give a white solid having a concentration of 97.75%.

Reverse immersion work

2-chloromethylphenylacetic acid (97.75% concentration; 10 g) was dissolved in fluorobenzene (20.6 g) at 70 ° C. over about 20 minutes. The pH of the reaction mixture was 7-8 during the addition. The mixture was then separated at 60 ° C. and the lower aqueous layer was back extracted with fluorobenzene (10 ml). The collected fluorobenzene phases were then dried by azeotropic distillation at 85-90 ° C. Cyclohexane (20 g) was slowly added at 80 DEG C to give a colorless solution which was slowly cooled to ambient temperature. Cooling to 0-5 [deg.] C. gave a white precipitate which was filtered off, washed with n-nucleic acid (11.5 g), filtered and dried on a filter and naturally dried to constant weight (6.60 g); ¹ H NMR (CDCl ₃ ) δ 3.7 (s, 2H); 5.3 (s, 2H); 7.2-7.6 (m, 4H) ppm; Quantitative yield 83.9%; Chemical yield 94.8%; % Concentration 99.7% by quantitative HPLC.

Acid immersion work

At 70 ° C. 2-chloromethylphenylacetic acid (97.75% concentration; 10 g) was dissolved in fluorobenzene (12.6 g) and some aqueous hydrochloric acid (18% concentration; 6.45 g) was added. The reaction mixture was stirred at 70-80 ° C. for 30 minutes. Potassium bicarbonate solution (20% concentration; 10.15 g) was then added slowly, followed by the addition of solid potassium bicarbonate (6.7 g) in portions. This mixture was then separated at 60 ° C. and the lower aqueous layer was back extracted with fluorobenzene (10 ml). The collected fluorobenzene phases were then dried by azeotropic distillation at 85-90 ° C. The colorless solution obtained by the slow addition of cyclohexane (20 g) at 80 ° C. was slowly cooled to ambient temperature. The white precipitate obtained by cooling to 0-5 [deg.] C. was filtered, washed with n-hexane (11.5 g), filtered and dried on a filter and naturally dried to constant weight (6.45 g); ¹ H NMR (CDCl ₃ ) δ 3.7 (s, 2H); 5.3 (s, 2H); 7.2-7.6 (m, 4H) ppm; Quantitative yield 81.9%; Chemical yield 99.1%; % Concentration 99.61% by quantitative HPLC.

Example 5

This example illustrates the preparation of 3-isochromanone from 2-chloromethylphenylacetic acid in the form of a 'terminal chlorination' mixture by different procedures.

O-tolylacetic acid (101 kg; concentration of 97.5%) was slurried in fluorobenzene (137 kg) in a 454 l graduated glass vessel and the solution was heated to 80 ° C. Moisture content analysis of this solution showed less than 0.2%. Therefore, azeotropic drying was unnecessary. Over 30 minutes a meter pump was used to fill AIBN (2 kg) dissolved in fluorobenzene (25 kg). Sulfuryl chloride (64.5l; 108 kg; 98.5% concentration) was added to the reaction mixture (maintain temperature at 75-80 ° C.) over at least 4 hours. The addition was stopped twice and the bath was reheated to 68-75 ° C. At the end of the addition, a sample of the reaction mixture was taken to obtain a 'terminal chlorination' mixture.

Reverse immersion work

The sample of the 'terminal chlorination' mixture (100 ml; 0.2586 mol) was heated to 65-70 ° C. and alicoat of this solution was added to a stirred solution of potassium bicarbonate (20% concentration; 207.09 g) at 60 ° C. over 1.5 hours. It was. This mixture was then separated at 60 ° C. and the lower aqueous layer was back extracted with fluorobenzene (40 ml). The collected fluorobenzene phases were dried by azeotropic distillation at 85-90 ° C. The dark red solution obtained by the slow addition of cyclohexane (61.4 g) at 80 ° C was slowly cooled to ambient temperature. This was after adjusting the amount of fluorobenzene because some of the fluorobenzene was lost to air during the prolonged addition. The beige precipitate obtained by cooling again to 0-5 [deg.] C. was filtered, washed with n-hexane (26 g), filtered and dried over a filter and naturally dried to constant weight (19.99 g); ¹ H NMR (CDCl ₃ ) δ 3.7 (s, 2H); 5.3 (s, 2H); 7.2-7.6 (m, 4H) ppm; Quantitative yield 51.45%; Chemical yield 69.46%; % Concentration 98.51% by quantitative HPLC.

Another station immersion work

A sample of the 'terminal chlorination' mixture (100 ml; 0.2586 mol) was heated to 65-70 ° C. and stirred slurry of potassium bicarbonate in potassium bicarbonate solution (20% concentration; 48.54 g) at 60 ° C. over 30 minutes (32 g) Alicoat of this solution was added thereto. The end was filled with water (40 g). This mixture was then separated at 60 ° C. and the lower aqueous layer was back extracted with fluorobenzene (40 ml). The collected fluorobenzene phases were dried by azeotropic distillation at 85-90 ° C. The dark red solution obtained by the slow addition of cyclohexane (61.4 g) at 80 ° C was slowly cooled to ambient temperature. The beige precipitate obtained by cooling again to 0-5 [deg.] C. was filtered, washed with n-hexane (26 g), filtered and dried over a filter and naturally dried to constant weight (25.07 g); ¹ H NMR (CDCl ₃ ) δ 3.7 (s, 2H); 5.3 (s, 2H); 7.2-7.6 (m, 4H) ppm; Quantitative yield 61.43%; Chemical yield 69.15%; % Concentration 93.78% by quantitative HPLC.

Acid immersion work

The 'terminal chlorination' mixture sample (100 ml; 0.2586 mol) was heated to 65-70 ° C. and potassium iodide (0.18 g) was added in part. Potassium bicarbonate solution (20% concentration; 48.54 g) was added slowly followed by portion of solid potassium bicarbonate (32 g). The end was filled with water (40 g). This mixture was then separated at 60 ° C. and the lower aqueous layer was back extracted with fluorobenzene (40 ml). The collected fluorobenzene phases were dried by azeotropic distillation at 85-90 ° C. The dark red solution obtained by the slow addition of cyclohexane (61.4 g) at 80 ° C was slowly cooled to ambient temperature. The beige precipitate obtained by cooling again to 0-5 [deg.] C. was filtered, washed with n-hexane (26 g), filtered and dried over a filter and naturally dried to constant weight (25.07 g); ¹ H NMR (CDCl ₃ ) δ 3.7 (s, 2H); 5.3 (s, 2H); 7.2-7.6 (m, 4H) ppm; Quantitative yield 60.5%; % Concentration 93.60% by quantitative HPLC.

The present invention relates to a chemical process, and more particularly to a process for producing 3-isochromanones useful for the production of some agricultural products.

3-isochromenone is a well known compound and many methods for its preparation are described in the chemical literature. For example, this may be achieved by (i) 3-chloroperoxybenzoic acid (Syn. Com.) With acetic anhydride and hydrogen peroxide in sulfuric acid (Syn. Commun. 2 [1972], 139; Synthesis [1973], 107) or trifluoroacetic acid. Commun. 9 [1989], 829) was used to treat 2-indanone by Baeyer-Villiger oxidation or by treatment with (ii) (a) ethylchloroformate and (b) sodium borohydride in triethylamine From oxycarbonylmethylbenzoic acid (Chem. Pharm. Bull) 16 [1968], 492, 496) or (iii) isochromen-3-ol and chromium trioxide (Tet. Lett. [1973], 2359). Can be. It is also known to prepare 3-isochromanones by closing the ring by boiling o-tolylacetic acid with N-bromosuccinimide and then boiling 2-bromomethylphenylacetic acid together with potassium hydroxide in ethanol. (Zh.Org.Khim. [1973] 9 (10), 2145-9). The disadvantage of this method is that the halogen source is expensive and therefore unattractive on an industrial scale.

The first aspect of the invention

(a) reacting o-tolylacetic acid with sulfuryl chloride in the presence of a free radical initiator and

(b) treating the thus obtained 2-chloromethylphenylacetic acid with a base;

It is to provide a method for producing 3-isochromenone comprising a.

The method is represented by the following reaction scheme.

Step (a) of the process is conveniently carried out at a high temperature, suitably at 50-90 ° C., for example at 60-80 ° C., for example a halogenated aromatic hydrocarbon such as fluorobenzene or chlorobenzene or It is carried out in a solvent which is inert to aromatic hydrocarbons.

Sulfuryl chloride may be used in any amount, but efficiently using at least 1 mole of sulfuryl chloride per mole of o-tolylacetic acid (preferably molar excess of 1.5 moles or less per mole, for example 1.2 moles or less per mole). Is preferred. Generally about 1.1 mole of sulfylyl chloride is used per mole of o-tolyl acetic acid.

The free radical initiator may be a compound or a suitable source of light or heat in the form used to initiate free radical reactions such as peroxides, peracids or azo compounds. 2,2'-azobisisobutyronitrile (AIBN) is particularly suitable. The amount of AIBN used is generally 0.01-0.1 moles per mole of o-tolyl acetic acid, for example 0.01-0.05 moles.

For example, any suitable base such as an alkaline earth metal hydroxide such as alkali metal, sodium or potassium hydroxide may be used in step (b) of the process. However, it is an advantage of the present invention that it is possible to use mild bases such as alkali metal bicarbonates, for example potassium bicarbonate. In this case, it may be helpful to use a catalyst to assist in ring closure of 2-chloromethylphenylacetic acid. Thus, the amount of iodide catalysts, such as alkali metal iodide, generally potassium iodide, has been found to be particularly useful. In order to avoid problems associated with the crystallization of the product, it is preferred to treat the product of step (a) with a base at a temperature of 40-80 ° C., suitably 50-70 ° C., generally about 60 ° C.

The two steps of the process are novel and form part of the invention as independents.

Thus, a second aspect of the present invention provides a process for preparing 2-chloromethylphenyl acetic acid comprising reacting o-tolylacetic acid with sulfyl chloride in the presence of a free radical initiator.

The reaction is suitably carried out in halogenated aromatic hydrocarbon solvents, for example fluorobenzene solvents, at temperatures of 50-90 ° C., for example 60-80 ° C.

The amount of sulfyl chloride used is suitably 1-1.2 mol per mol of o-tolyl acetic acid. The free radical initiator is preferably 2,2'-azobisisobutyronitrile.

The o-tolylacetic acid starting material is a known compound which is commercially available.

A third aspect of the invention provides a process for the preparation of 3-isochromemanone comprising treating 2-chloromethylphenylacetic acid with a base.

The base is suitably alkali metal or alkaline earth metal hydroxides but preferably alkali metal bicarbonates, in particular potassium bicarbonate. In a preferred embodiment the process is carried out at a temperature of 40-80 ° C., more preferably 50-70 ° C., generally about 60 ° C., with a catalytic amount of alkali metal iodide, generally potassium iodide.

In this particular aspect of the invention the 2-chloromethylphenylacetic acid may be prepared by the process described in step (a) or by some other method. If prepared as described in step (a), it can be separated and recrystallized first if desired, or used directly in a 'one-pot' process.

In a typical one-pot process, the slurry of o-tolylacetic acid in fluoro- or chlorobenzene is distilled to remove any water and the temperature is lowered to 60-80 ° C. A chemical initiator (eg AIBN) is added followed by sulfuryl chloride over 3 or 4 hours. The reaction process is monitored by analyzing the reaction mixture samples at appropriate intervals using gas chromatography. At the end of the reaction, an aqueous solution of a base, preferably potassium bicarbonate, is slowly added and optionally an iodide catalyst and a solid base are added. Analytical samples are taken while stirring the reaction mixture at about 60 ° C. for about 1 hour. At the end of the reaction, the organic and aqueous layers are separated, the organic layer is dried by azeotropic distillation and the product precipitates upon cooling.

As a process of the invention, 3-isochromanone on an industrial scale using a low cost and convenient halogen source (sulfuryl chloride) for the preparation of moderate bases (potassium bicarbonate) and 2-halomethylphenylacetic acid intermediates for cyclization Can be prepared.

3-isochromanones are particularly useful as intermediates in the manufacture of agricultural products, in particular strobiliurin type fungicides, for example those described in EP-A-278595.

The present invention is illustrated by the following examples wherein:

NMR = nuclear magnetic resonance

HPLC = high performance liquid chromatography

s = single line m = polyline

g = grams kg = kilograms

GC = gas chromatography

ml = milliliters l = liters

mol = mol ℃ = degrees Celsius

AIBN = 2,2'-azobisisobutyronitrile mp = melting point

Claims (9)

(a) reacting o-tolylacetic acid with sulfuryl chloride in the presence of a free radical initiator; And (b) treating 2-chloromethylphenylacetic acid thus obtained with a base; Method of producing 3-isochromenone comprising a. A process for preparing 2-chloromethylphenylacetic acid comprising reacting o-tolylacetic acid with sulfyl chloride in the presence of a free radical initiator. The process according to claim 2, wherein the reaction is carried out in a halogenated aromatic hydrocarbon solvent at a temperature of 50-90 ° C. The process according to claim 2 or 3, wherein the amount of sulfyl chloride used is 1-1.2 moles per mole of o-tolyl acetic acid. The method of claim 2 or 3, wherein the free radical initiator is 2,2'-azobisisobutyronitrile. A method for preparing 3-isochromenone comprising treating 2-chloromethylphenylacetic acid with a base. 7. The method of claim 6, wherein the base is an alkali metal bicarbonate. 8. Process according to claim 6 or 7, characterized in that it is carried out at a temperature of 40-80 ° C. 8. The method of claim 6 or 7, wherein an alkali metal iodide is present.