FIELD OF THE INVENTION

[0001] The present invention relates to a process for the purification of para- methallylpyrocatechol and to the preparation of flavor and fragrance compounds from para-methallylpyrocatechol.

BACKGROUND OF THE INVENTION

[0002] In catechol-based processes for preparing 2,3-dihydro-2,2-dimethyl-7- hydroxybenzofuran, an intermediate to the insecticide/nematicide, carbofuran, catechol is reacted with methallyl chloride to produce 2-methallyloxyphenol and ortho-methallylpyrocatechol. The phenol/pyrocatechol mixture is subjected to thermal rearrangement and cyclization forming 2,3-dihydro-2,2-dimethyl-7- hydroxybenzofuran. A by-product of this thermal rearrangement and cyclization process is para-methallylpyrocatechol, formed in a weight % of about 25% to about 30%, which does not cyclize to form 2,3-dihydro-2,2-dimethyl-7- hydroxybenzofuran, has no commercial use, and is discarded as a waste material. It would be most beneficial to find a commercial process to purify para- methallylpyrocatechol from the reaction tars and use it for the preparation of useful products.

SUMMARY OF THE INVENTION

[0003] The present invention provides a process for the purification of para- methallylpyrocatechol and the use of para-methallylpyrocatechol as an intermediate to certain flavor and fragrance compounds.

DETAILED DESCRIPTION OF THE INVENTION

[0004] The present invention provides a process for the purification of para- methallylpyrocatechol and the use of para-methallylpyrocatechol as an intermediate to certain flavor and fragrance compounds.

[0005] In catechol-based processes for preparing 2,3-dihydro-2,2-dimethyl-7- hydroxybenzofuran, an intermediate to the insecticide/nematicide, carbofuran, catechol is reacted with methallyl chloride to produce 2-methallyloxyphenol (MOP) and ortho-methallylpyrocatechol (3-MAC), Step 1 below. The phenol/pyrocatechol mixture is subjected to Clasien thermal rearrangement and cyclization forming 2,3- dihydro-2,2-dimethyl-7-hydroxybenzofuran (7-Hydroxy), Step 2 below. A byproduct of this thermal rearrangement and cyclization process is para- methallylpyrocatechol (4-MAC), formed in a weight % of about 25% to about 30%, which does not cyclize to form 2,3-dihydro-2,2-dimethyl-7-hydroxybenzofuran, has no commercial use, and is discarded as a waste material. In Step 2, MOP and 3- MAC are placed into an autoclave along with xylene and a catalytic amount of aluminum isopropoxide. The mixture is heated for about four hours, the autoclave is then cooled and the reaction mixture diluted and stirred with a 2% aqueous sodium sulfate solution. The mixture is allowed to separate and the organic phase is removed. The xylene is removed from the organic phase by distillation under reduced pressure leaving an oily residue. This residue is subjected to distillation, collecting the fraction at 99°C to 100°C at 2.5-3 mmHg, which is 7-Hydroxy. The remaining residue (Crude 4-MAC) would usually be treated as a waste material.

Step 1:

(

(3-MAC) Step 2:

(3-MAC)

[0006] A process has now been discovered to isolate para-methallylpyrocatechol from the tarry residue remaining after 7-Hydroxy is removed from the reaction mixture.

[0007] The process of the present invention to purify para-methallylpyrocatechol comprises:

a) heating the residue from the Claisen rearrangement and cyclization of 2- methallyloxyphenol and ortho-methallylpyrocatechol and subsequent distillation removal of 2,3-dihydro-2,2-dimethyl-7-hydroxybenzofuran, under reduced pressure; b) collecting the distillate at 110°C to 120°C at a pressure of 1.2 to 1.5 mmHg; c) dissolving the distillate in heptanes at an elevated temperature;

d) cooling the solution to crystallize para-methallylpyrocatechol;

e) collecting the para-methallylpyrocatechol by filtration; and

f) drying the para-methallylpyrocatechol.

[0008] The para-methallylpyrocatechol obtained by the process of this invention has a purity of at least 95%.

[0009] In another embodiment the present invention provides a method of preparation of certain flavors and fragrances using para-methallylpyrocatechol as an intermediate. [0010] Heliotropin, the common name for l,3-benzodioxazole-5-carboxaldehyde, is an aromatic aldehyde that has a floral odor commonly described as being similar to that of vanillin and cherry. It is used as flavoring and in perfume. Para- methallylpyrocatechol can be used as a starting material in the process to prepare heliotropin as described in Scheme 1 below.

Scheme 1:

Step A

(4-MAC) Compound 1

Step B

Compound 1

Compound 2

Step C

Oxidant

Compound 2

Solvent

Heliotropin [0011] In Scheme 1, Step A, the reaction of 4-MAC and methylene chloride in the presence of a base in a solvent produces 5-(2-methyl-2-propen-l-yl)-l,3- benzodioxazole, Compound 1. In this Step the base can be an aqueous or nonaqueous hydroxide, for example potassium or sodium hydroxide or an organic base, for example l,8-diazabicyclo[5.4.0]undec-7-ene. The solvent can be dimethyl sulfoxide, triethyl amine, an alcohol such as butanol, 1 ,4-dioxane, water or an ether such as bis(2-methoxyethyl) ether, depending on the base used.

[0012] In Step B, heating Compound 1 with a base in the presence of a glycol forms 5-(2-methyl-l-propene-l-yl)-l,3-benzodioxazole, Compound 2. In this step, the base is preferably a hydroxide, for example potassium hydroxide. Preferably the glycol is a polyethylene glycol (PEG 300), is added to catalyze the isomerization of Compound 1 to Compound 2. Solvents such as water or an alcohol, for example, n- butanol can be present.

[0013] In Step C, oxidation of Compound 2 in the presence of an acid solvent produces heliotropin. Preferably the oxidant is potassium chromate and the acid solvent is sulfuric acid.

[0014] Another use for para-methallylpyrocatechol is as a starting material for helional, the common name for alpha- methyl- 1, 3 -benzodioxazole-5-propanal, an aromatic aldehyde that has a floral odor commonly described as being similar to that of new mown hay and is used in perfume. The process to prepare helional is described in Scheme 2 below.

Scheme 2:

Step A

Compound 1 Compound 3

Step B

Catalyst

Solvent

Compound 3

Helional

[0015] In Scheme 2, Step A, Compound 1 is treated with an oxidant in a solvent to prepare 3-(l,3-benzodioxol-5-yl-methyl)-3-methyl-2-oxirane, Compound 3. The oxidant is preferably 3-chloroperbenzoic acid and the preferred solvent is methylene chloride.

[0016] In Step B, Compound 3 and a catalyst are stirred in a solvent to yield helional. Preferred catalyst/ solvent combinations are zinc chloride/1, 4-dioxane; boron trifluridediethyl etherate/1, 4-dioxane; copper (II) tetrafluoroborate/ methlyene chloride; indium (III) chloride/tetrahydrofuran; and bismuth (III) 1,1,1- trifluoromethane sulfonic acid/methylene chloride.

[0017] In addition, other flavors and fragrances can be made using para- methallylpyrocatechol as a starting material. These include: protocatechuic aldehyde, the common name for 3,4-dihydroxybenzaldehyde, which is a phenolic aldehyde, a compound released from cork stoppers into wine and can be used as a precursor in the synthesis of; vanillin (4-hydroxy-3-methoxybenzaldehyde), ethyl vanillin (4-hydroxy-3-ethoxybenzadehyde), veratric aldehyde (3,4- dimethoxybenzaldehyde), veratric alcohol (3,4-dimethoxybenzyl alcohol), and veratric acid (3,4-dimethoxybenzoic acid). Para-methallylpyrocatechol can also be used as a starting material for the preparation of certain pharmaceuticals such as epinephrine, dopamine and L-DOPA.

[0018] Unless otherwise specified in the examples, ambient temperature means a temperature of about 15°C to about 20°C. The following examples serve only to illustrate the invention and should not be interpreted as limiting since further modifications of the disclosed invention will be apparent to those skilled in the art. All such modifications are deemed to be within the scope of the invention as defined in the claims.

Example 1

This Example Sets Forth a Method of Preparing and Purifying Para- methallylpyrocatechol

Step A

[0019] A mixture of 90.0 grams of catechol, 38.4 grams of potassium carbonate, 79.1 grams of methallyl chloride and 319.0 grams of a 1:1 mixture of methyl isobutyl ketone and water was added to a stainless steel 1000 mL autoclave reactor. The reactor was sealed and heated to 130°C with stirring. After two hours the reactor was allowed to cool to ambient temperature. The reactor was vented, opened and the contents poured into a lOOOmL flask. A 2% aqueous sodium sulfate solution (140.0grams) was added to the flask with stirring. The mixture was heated to 70°C and the pH of the mixture was adjusted to between 3 and 4 with dilute hydrochloric acid. After 30 minutes, stirring was stopped and the phases were allowed to separate. The organic phase was separated and diluted with 215.0 grams of a 2% aqueous sodium sulfate solution and this mixture was subjected to azeotropic distillation removing the material which distilled at 40°C to 48° at 140mmHg. Xylene (250 grams) was added to the pot residue and the mixture was stirred at a temperature of between 30°C and 40°C for 30 minutes. Stirring was stopped and the phases were allowed to separate. The organic phase was removed and diluted with xylene until a total weight of 387 grams was obtained. This organic phase was extracted four times using 118.3 grams of a 2% aqueous sodium sulfate solution each time. Remaining water was removed by azeotropic distillation under a pressure of 55 mmHg, leaving 338 grams of a xylene solution containing 2- methallyloxyphenol (MOP) and ortho-methallylpyrocatechol (3-MAC).

Step B

[0020] Into a stainless steel 1000 mL autoclave reactor was placed a mixture of 338 grams of the xylene, MOP and 3-MAC mixture from Step A and 0.34 gram of aluminum isopropoxide. The reactor was sealed and heated to 180°C with stirring. After about four hours the reactor was cooled to ambient temperature using cool water. The reactor was vented, opened and the contents poured into a lOOOmL flask. This organic mixture was extracted three times using 118.3 grams of a 2% aqueous sodium sulfate solution each time. Trioctylamine (0.34 gram) was added to the washed organic mixture and the xylene removed by distillation under reduced pressure leaving a residue. The residue was subjected to wiped film distillation collecting the distillate at 99°C to 100°C at 1 mmHg (7-Hydroxy). The residue was subjected to fractional distillation collecting the fraction at 99°C to 100°C at 1 mmHg (7-Hydroxy). The pot residues from the wiped film and fractional distillation were saved for Step C.

Step C

[0021] Pot residues from several preparations of 7-Hydroxy, as prepared in Steps A and B above, were combined to give a total of 1450 grams. This material was placed into a 3 liter round bottom flask and subjected to vacuum distillation, collecting the fraction at 110°C to 120°C at a pressure of 1.2 to 1.5 mmHg. The distillate, 751 grams, contained 60.2% by weight para-methallylpyrocatechol. A portion of the distillate (250 grams) was placed into a 3 liter three necked round bottom flask, equipped with a high performance mechanical stirrer and a thermometer, to which 2500 iriL of mixed heptanes was added. The temperature of the stirred mixture was increased to 55°C, forming a clear solution. The solution was allowed to cool to ambient temperature and stirred for about 18 hours. A solid had formed which was collected by filtration. The filter cake was rinsed with 300 mL of mixed heptanes and then dried under reduced pressure to yield 116 grams of para-methallylpyrocatechol as an off-white solid, melting point 63-65°C, and purity by gas Chromatography area % of 96.3%. Mass spectrophotometer analysis:

164(M ⁺ ), 149 (M ⁺ , -methyl), 123 (M ⁺ -CH (CH ₃ )=CH ₂ ). H NMR (CDC13, 300 MHz): 1.63 (s, CH ₃ , 3H), 3.17 (S, CH ₂ , 2H), 4.69 (s, =CH ₂ , 1H), 4.77 (s, =CH ₂ , 1H), 5.59 (s, OH, 2H), 6.59-6.78 (m, Ph, 3H).

IR (KBr): 3253, 1618, 1604, 1518, 1446, 1369, 1349, 1280, 1259, 1212, 1187, 1109, 950, 901.

Example 2

The Preparation of Heliotropin from Para-methallylpyrocatechol

Step A Preparation of 5-(2-methyl-2-propen- 1-yl)- 1 ,3-benzodioxole

[0022] Into a 1 liter 3-neck round bottom flask equipped with a stir bar,

thermometer, dropping funnel and condenser was added 16 grams of solid potassium hydroxide, 215 grams of dimethyl sulfoxide and 15 grams of water. The mixture was stirred and heated to 92°C. A solution of 20 grams of para- methallylpyrocatechol in 25 grams of dimethyl sulfoxide and 30 grams of methylene chloride was added slowly and after complete addition the mixture was stirred at 95°C for three hours. The mixture was cooled and diluted with 500 grams of water. The mixture was extracted three times with 100 gram portions of methylene chloride. The extracts were combined and washed with 100 grams of an aqueous 1% sodium hydroxide solution followed by three, 25 gram portions of water. The washed extract was concentrated under reduced pressure and purified by column chromatography on silica gel to yield 21 grams of 5-(2-methyl-2-propen-l-yl)-l,3- benzodioxole as an oil. The NMR was consistent with the proposed structure. H NMR (CDCI ₃ , 300MHz): 1.66 (s, CH3, 3H), 3.22 (s, CH2, 2H), 4.73-4.79 (d, CH2, 2H), 5.92 (s, CH2, 2H), 6.61-6.74 (m, Ph, 3H).

Step B Preparation of 5-(2-methyl-l-propen-l-yl)-l,3-benzodioxole

[0023] A stirred mixture of 35 grams of 5-(2-methyl-2-propen-l-yl)-l,3- benzodioxole, 3.5 grams of potassium hydroxide and 3.5 grams of polyethylene glycol (PEG 300) was heated to 120°C for 2.5 hours. The mixture was distilled under reduced pressure collecting the fraction at 90°C at a pressure of 2.0 mmHg and purified by column chromatography on silica gel to yield 30 grams of 5-(2- methyl-l-propen-l-yl)-l,3-benzodioxole as an oil. The NMR was consistent with the proposed structure. H NMR (CDCI ₃ , 300MHz): 1.83 (s, CH3, 3H), 1.87 (s, CH3, 3H), 5.92 (s, CH2, 2H), 6.17 (s, CH, 1H), 6.62-6.78 (m, Ph, 3H). Gas chromatography analysis, area %, indicated a purity of 90%.

Step C Preparation of Heliotropin

[0024] To a stirred mixture of 3.8 grams of 5-(2-methyl-l-propen-l-yl)-l,3- benzodioxole, 18.0 grams of sulfuric acid and 1.0 gram of ammonium sulfate was added portion wise, 6.0 grams of potassium chromate, while maintaining a reaction temperature of less than 60°C. Upon complete addition, the mixture was stirred at 45 °C for one hour and 1.0 gram of potassium chromate was added. The mixture was stirred at 45 °C for forty minutes, cooled and diluted with 100 rriL of water. The mixture was extracted with 50 rriL of methylene chloride. The organic extract was washed with water then was concentrated under reduced pressure to yield 0.5 gram of oil. Gas chromatography analysis of the oil indicated 65% by weight heliotropin and 15% by weight 5-(2-methyl-l-propen-l-yl)-l,3-benzodioxole. Analysis by GC- MS and the main peak analysis result shows EI-MS( (M-l) 149, 121, 91, 63) which is identical to heliotropin standard graph. Other impurity peak shows EI -MS (M 176) which is 5-(2-methyl-l-propen-l-yl)-l,3-benzodioxole.

[0025] It has been discovered that the addition of a small amount of polyethylene glycol (PEG 300 or PEG 800) or polyethylene glycol methyl ether (PEG 300DM) to the reaction mixture of 5-(2-methyl-2-propen-l-yl)- 1,3-benzodioxole, (2-propene isomer), and base catalyzes the isomerization to form 5-(2-methyl-l-propen-l-yl)- 1,3-benzodioxole, (1-propene isomer). This reaction proceeds quicker when glycol is added. Table 1 below summarizes experiments with and without glycol wherein the Area is gas chromatography area % of a sample of the reaction mixture taken at the time indicated.

TABLE 1

Isomerization of 2-Porpene Isomer to 1-Propene Isomer

* A continuation of Control 1 experiment wherein after 4 hours at 170°C, the reaction temperature was decreased to 130°C and 0.3 gm of PEG-300 was added.

** A continuation of 2A wherein after 2 hours and additional 0.2 gm of PEG-300DM was added.

[0026] As can be seen from the data in Table 1, the 1-propene isomer is formed slowly by the treatment of the 2-propene isomer with a base, however, the speed of the reaction is dramatically increased by the addition of a glycol, especially with the addition of PEG-300. Example 3

The Preparation of Helional from Para-methallylpyrocatechol

Step A Preparation of 3-(l,3-benzodioxol-5-yl-methyl)-3-methyl-2-oxirane

[0027] To a stirred solution of 9.0 grams of 5-(2-methyl-2-propen-l-yl)-l,3- benzodioxole (prepared as in Example 2, Step A) in 100 grams of methylene chloride was added portion wise, 12.0 grams of meta-chloroperbenzoic acid, while maintaining a reaction temperature of about 35°C. After complete addition, the mixture was stirred at 35°C for two hours. The reaction mixture was filtered and the filter cake rinsed with 10 mL of methylene chloride. The combined filtrate was extracted twice with 100 gram portions of an aqueous 5% sodium sulfate solution followed by two 50 mL portions of water. The organic phase was concentrated under reduced pressure and the residue purified by column chromatography on silica gel to yield 9.0 grams of 3-(l,3-benzodioxol-5-yl-methyl)-3-methyl-2-oxirane as an oil. H NMR (CDC1 ₃ , 300MHz): 1.27 (s, CH3, 3H), 2.60-2.65 (m, CH2, 2H), 2.72-2.83 (m, CH2, 2H), 5.94 (s, CH2, 2H), 6.64-6.76 (m, Ph, 3H).

Step B Preparation of Helional

[0028] A mixture of 1.0 gram of 3-(l,3-benzodioxol-5-yl-methyl)-3-methyl-2- oxirane, 0.004 gram of bismuth (III) 1,1,1-trifluoromethane sulfonic acid and 10 grams of methylene chloride was stirred at 20°C to 25 °C for two hours. The reaction mixture was extracted twice with water. Analysis of the organic phase by gas chromatography indicated 48% methylene chloride and 45% helional. The organic phase was evaporated under reduced pressure and the residue purified by column chromatography to yield helional as an oil, H NMR (CDCI ₃ , 300MHz): 1.07-1.10 (d, CH3, 3H), 2.50-2.65 (m, CH2, 2H), 2.97-3.03 (m, CH, 1H), 5.93 (s, CH2, 2H), 6.60-6.75 (m, Ph, 3H), 9.70 (s, CHO, 1H);

C NMR (CDCI ₃ , 300MHz): 204.3, 147.7, 146.1, 132.4, 121.9, 109.3, 108.2, 100.9, 48.2, 36.4, 13.1). [0029] While this invention has been described with an emphasis upon preferred embodiments, it will be obvious to those of ordinary skill in the art that variations in the preferred devices and methods may be used and that it is intended that the invention may be practiced otherwise than as specifically described herein.

Accordingly, this invention includes all modifications encompassed within the spirit and scope of the invention as defined by the claims that follow.