Title of Invention

"PROCESS FOR PREPARATION OF 3,4-METHYLENEDIOXYMANDELIC ACID"

Abstract Disclosed is a process for preparing 3,4-methylenedioxymandelic acid by reacting 1,2-methylenedioxybenzene with glyoxylic acid in the presence of sulfuric acid, characterized in that the reaction is carried out in the presence of an aprotic organic solvent.
Full Text Summary of the invention
The present invention relates to a process for preparing 3.4-methylenedioxymandelic acid by
reacting 1.2-methylenedioxybenzene with glyoxylic acid in the presence of sulfuric acid.
characterized in that the reaction is carried out in the presence of an aprotic organic solvent.
The present invention relates to a process for preparing 3.4-methylenedioxymandelic acid by
reacting 1.2-methylenedioxybenzene with glyoxylic acid in the presence of sulfuric acid.
characterized in that the reaction is carried out in the presence of an aprotic organic solvent.
Brief description of the accompanying drawings
Fig. 1 is a drawing showing one example of a reaction apparatus used in a process of the present invention.
Best mode for earning out the invention
The strong acid used in the reaction of the present invention includes inorganic acids such as sulfuric acid and phosphoric acid, and organic acids having a pKa of 3 or less such as methanesulfonic acid, and preferably an inorganic acid, more preferably sulfuric acid is used. These strong acids are used in the form of 70 % by weight or more aqueous solution. The amount of the strong acid used is preferably 0.50 to 3.00 mol. more preferably 1.00 to 2.50 mol. per mol of 1.2-methylenedioxybenzene.
Glyoxylic acid used in the reaction of the invention can be used not only in the form of solid (monohydrate) but also in the form of 40 % by weight or more aqueous solution. The amount of glyoxylic acid used is preferably 0.8 to 3.0 mol. more preferably 1.0 to 2.0 mol. per mol of 1.2-methylenedioxybenzene.
The aprotic organic solvent used in the reaction of the present invention is not particularly limited insofar as it is stable under acidic conditions and does not inhibit the reaction, and examples thereof include ethers such as diethyl ether, diisopropyl ether, dibutyl ether and tetrahydrofuran; ketones such as acetone. 2-butanone. 2-pentanone, 3-pentanone. 4-methyl-2-pentanone. cyclopentanone and cyclohexanone; carboxylic acid esters such as ethyl formate, isopropyl formate, butyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, methyl propionate, ethyl propionate, isopropyl propionate and butyl propionate, amides such as N.N-dimethylformamide. N.N-dimethylacetamide. hexamethyl phosphoric triamide and l-methyl-2-pyrrolidone; urea or analogues thereof such as 1.3-dimethyl-2-imidazolidone; carbonic acid esters such as dimethyl carbonate and diethyl carbonate: and sulfoxides such as dimethyl sulfoxide.
The amount of the aprotic organic solvent used is preferably 100 to 2000 ml, more preferably 100 to 1000 ml. per kg of 1.2-methylenedioxybenzene. These organic solvents may be used singly or in combination thereof.
The organic acid used in the reaction of the present invention is not particularly limited insofar as it is stable under acidic conditions and does not inhibit the reaction, and examples thereof include aliphatic carboxylic acids such as formic acid, acetic acid, propionic
acid, n-butyric acid, isobutyric acid and n-valeric acid; and halogenated aliphatic carboxylic acids such as trifluoroacetic acid and dichloroacetic acid, and preferably an aliphatic carboxylic acid, more preferably acetic acid is used. These organic acids may be used singly or in combination thereof.
The amount of the organic acid used is 100 to 1200 ml, preferably 100 to 1000 ml and more preferably 100 to 500 ml, per kg of 1,2-methylenedioxybenzene. When the amount of the organic acid used is less than 100 ml, there is the problem that the ability of the reaction solution to be stirred is significantly worsened, and the temperature of the solution is partially increased to cause formation of byproducts, thus reducing the selectivity of the desired product, while if the amount of the organic acid is greater than 1200 ml, there is the problem that the reaction rate is significantly reduced, the reaction requires a longer time, and the selectivity of the desired product is lowered.
The reaction of this invention is carried out, for example, according to a method of adding glyoxylic acid and a strong acid to a mixture of 1,2-methylenedioxybenzene and an aprotic organic solvent and/or an organic acid (100 to 1200 ml per kg of 1,2-methylenedioxybenzene) in an atmosphere of an inert gas such as nitrogen or argon. The reaction temperature at this time is preferably -20 to 10°C, more preferably -10 to 5°C. The reaction is carried out usually at normal pressure but may also be carried out under pressure or under reduced pressure if necessary. The reaction time is usually 1 to 100 hours, preferably about 3 to 75 hours.
After the reaction is finished, the resulting product is neutralized by adding, e.g., a suitable amount of a base, then, extracted with a suitable solvent, separated and purified by general techniques such as column chromatography, distillation and recrystallization.
Examples
Next, the present invention is described in more detail by reference to the Examples, which are not intended to limit the scope of the present invention. Incidentally, the selectivity of 3,4-methylenedioxymandelic acid formed was calculated on the basis of the amount (in terms of moles) of 1,2-methylenedioxybenzene consumed.
Example 1
A flat bottom separable flask with an internal volume of 500 ml as shown in Fig. 1 was charged with 50.0 g (0.409 mol) of 1,2-methylenedioxybenzene and 25 ml of 4-methyl-2-pentanone (the amount of the organic solvent used was 500 ml per kg of 1,2-methylenedioxybenzene) in a nitrogen atmosphere, and the mixture was cooled to -5°C with stirring. In Fig. 1, the reference numeral 1 denotes a motor, 2 denotes a thermometer, and 3 denotes a stirring blade, respectively. Then, a mixture of 83.4 g (0.450 mol) of a 40 % by weight aqueous glyoxylic acid solution and 85.8 g (0.839 mol) of 96% by weight

sulfuric acid was added dropwise thereto, and the mixture was stirred at -5°C for 21 hours. Incidentally, the mixture could be stirred smoothly during the reaction.
Thereafter, the reaction solution was neutralized by adding 102.0 g (1.67 mol) of 28 % by weight aqueous ammonia little by little. Then, 100 ml of 2-butanone was added, then the mixture was heated to 60°C, and the formed 3,4-methylenedioxymandelic acid was extracted into a 2-butanone layer (an organic layer). Analysis of the organic layer by high performance liquid chromatography indicated that the conversion of 1,2-methylenedioxybenzene was 95%, and the selectivity of 3,4-methylenedioxymandelic acid was 92%. Examples 2 to 4
The reaction was carried out in the same manner as in Example 1 except that the organic solvent used, the reaction temperature and the reaction time in Example 1 were changed. The results are shown in Table 1.
Table 1
(Table Removed)

MDB: 1,2-Methylenedioxybenzene MDMA: 3,4-Methylenedioxymandleic acid
Comparative Example 1
The reaction was carried out in the same manner as in Example 2 except that the organic solvent in Example 2 was not added. The reaction solution was made highly viscous during the reaction to permit only a part of the solution around the stirring blade to be stirred, thus failing to sufficiently stir the whole of the solution. As a result, the conversion of 1,2-methylenedioxybenzene was 94%, and the selectivity of 3,4-methylenedioxymandelic acid was 77%. Example 5
A flat bottom separable flask with an internal volume of 7 L as shown in Fig. 1 was charged with 500.0 g (4.09 mol) of 1,2-methylenedioxybenzene and 250 ml of 4-methyl-2-pentanone (the amount of the organic solvent used was 500 ml per kg of 1,2-methylenedioxybenzene) in a nitrogen atmosphere, and the mixture was cooled to -10°C with stirring. Then, a mixture of 833.7 g (4.05 mol) of

40% by weight aqueous glyoxylic acid and 857.5 g (8.39 mol) of 96% by weight sulfuric acid was added slowly dropwise thereto, and the mixture was stirred at -5°C for 23 hours. Incidentally, the mixture could be stirred smoothly during the reaction.
Thereafter, the reaction solution was neutralized by adding 1030.0 g (16.93 mol) of 28 % by weight aqueous ammonia little by little. Then, 3000 ml of 4-methyl-2-pentanone was added, then the mixture was heated to 80°C, and the formed 3,4-methylenedioxymandelic acid was extracted into a 4-methyl-2-pentanone layer (an organic layer). Analysis of the organic layer by high performance liquid . chromatography indicated that the conversion of 1,2-methylenedioxybenzene was 95%, and the selectivity of 3,4-methylenedioxymandelic acid was 90%. Example 6
A flat bottom separable flask with an internal volume of 500 ml was charged with 50.0 g (0.409 mol) of 1,2-methylenedioxybenzene and 20 ml of acetic acid (the amount of acetic acid used was 400 ml per kg of 1,2-methylenedioxybenzene) in a nitrogen atmosphere, and the mixture was cooled to 0°C with stirring. Then, a mixture of 83.4 g (0.450 mol) of 40% by weight aqueous glyoxylic acid solution and 85.8 g (0.839 mol) of 96 % by weight sulfuric acid was added dropwise thereto, and the mixture was stirred at 0°C for 9 hours. Incidentally, the mixture could be stirred smoothly during the reaction.
Thereafter, the reaction solution was neutralized by adding 102.0 g (1.68 mol) of 28 % by weight aqueous ammonia little by little. Then, 100 ml of 2-butanone was added, then the mixture was heated to 60°C, and the formed 3,4-methylenedioxymandelic acid was extracted into a 2-butanone layer (an organic layer). Analysis of the organic layer by high performance liquid chromatography indicated that the conversion of 1,2-methylenedioxybenzene was 95%, and the selectivity of 3,4-methylenedioxymandelic acid was 91%. Examples 7 to 12
The reaction was carried out in the same manner as in Example 6 except that the amount of acetic acid used for 1,2-methylenedioxybenzene, the reaction temperature and the reaction time in Exampte 6 were changed. The results are shown in Table 2. Comparative Examples 2 to 3
The reaction was carried out in the same manner as in Example 6 except that the amount of acetic acid used for 1,2-methylenedioxybenzene was outside the scope of the present invention, and the reaction temperature and the reaction time in Example 6 were changed. The results are also shown in Table 2.
Table 2
(Table Removed)



1) An amount of acetic acid used relative to 1,2-methylenedioxybenzene
MDB: 1,2-Methylenedioxybenzene MDMA: 3,4-Methylenedioxymandleic acid
Industrial Applicability
According to the present invention, there can be provided an
industrially preferable process for preparing 3,4-
methylenedioxymandelic acid, which can produce 3,4-
methylenedioxymandelic acid in high selectivity by reacting 1,2-
methylenedioxybenzene with glyoxylic acid and which can be also
applied to the reaction in a large scale.





We claim:
1. A process for preparing 3,4-methylenedioxymandelic acid by reacting 1,2-methylenedioxybenzene with glyoxylic acid in the presence of sulfuric acid, characterized in that the reaction is carried out in the presence of 100-2000ml of at per kg of 1,2 methylenedioxybenzene and 100-1200 ml of said acid per kg of 1, 2 dimethydioxybenzene aprotic organic solvent.
2. The process for preparing 3,4-methylenedioxymandelic acid as claimed in Claim 1, wherein the amount of the strong acid to be used is 0.50 to 3.00 mol per mol of 1,2-methylenedioxybenzene.
3. The process for preparing 3,4-methylenedioxymandelic acid as claimed in Claim 1, wherein the amount of the strong acid to be used is 1.00 to 2.50 mol per mol of 1,2-methylenedioxybenzene.
4. The process for preparing 3,4-methylenedioxymandelic acid as claimed in Claim 1, wherein the amount of the glyoxylic acid to be used is 0.8 to 3.0 mol per mol of 1,2-methylenedioxybenzene.
5. The process for preparing 3,4-methylenedioxymandelic acid as claimed in Claim 1, wherein the amount of the glyoxylic acid to be used is 1.0 to 2.0 mol per mol of 1,2-methylenedioxybenzene.
6. The process for preparing 3,4-methylenedioxymandelic acid as claimed in any one of Claims 1 to 5, wherein the aprotic organic solvent is selected one or more from the group consisting of ethers, ketones, carboxylic acid esters, amides, ureas and carbonic acid esters.
7. The process for preparing 3,4-methylenedioxymandelic acid as claimed in any one of Claims 1 to 5, wherein the aprotic organic, solvent is selected one or more from the group consisting of diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, acetone, 2-butanone, 2-pentanone, 3-pentanone, 4-methyl-2-pentanone, cyclopentanone, cyclohexanone, ethyl formate, isopropyl formate, butyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, methyl propionate, ethyl propionate, isopropyl propionate, butyl propionate, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethyl phosphoric triamide, l-methyl-2-pyrrolidone, l,3-dimethyl-2-imidazolidone, dimethyl carbonate, diethyl carbonate and dimethyl sulfoxide.
8. The process for preparing 3,4-methylenedioxymandelic acid as claimed in any one of Claims 1 to 7, wherein the aprotic organic solvent is used in an amount of 100 to 1000 ml per kg of 1,2-methylenedioxybenzene.
9. The process for preparing 3,4-methylenedioxymandelic acid as claimed in any one of Claims 1 to 8, wherein the reaction is carried out at a reaction temperature of-20 to 10°C.
10. A process for preparing 3,4-methylenedioxymandelic acid by reacting 1,2-methylenedioxybenzene with glyoxylic acid in the presence of sulfuric acid substantially as herein described with reference to the foregoing examples and as illustrated by the accompanying drawings.

Documents:

in-pct-2002-329-del-abstract.pdf

in-pct-2002-329-del-assignment.pdf

in-pct-2002-329-del-claims.pdf

in-pct-2002-329-del-complete specification (granded).pdf

in-pct-2002-329-del-correspondence-others.pdf

in-pct-2002-329-del-correspondence-po.pdf

in-pct-2002-329-del-description (complete).pdf

in-pct-2002-329-del-drawings.pdf

in-pct-2002-329-del-form-1.pdf

in-pct-2002-329-del-form-13.pdf

in-pct-2002-329-del-form-19.pdf

in-pct-2002-329-del-form-2.pdf

in-pct-2002-329-del-form-3.pdf

in-pct-2002-329-del-form-5.pdf

in-pct-2002-329-del-gpa.pdf

in-pct-2002-329-del-pct-210.pdf

in-pct-2002-329-del-pct-301.pdf

in-pct-2002-329-del-pct-304.pdf

in-pct-2002-329-del-pct-306.pdf

in-pct-2002-329-del-pct-308.pdf

in-pct-2002-329-del-pct-332.pdf

in-pct-2002-329-del-pct-409.pdf

in-pct-2002-329-del-petition-137.pdf

in-pct-2002-329-del-petition-138.pdf


Patent Number 244828
Indian Patent Application Number IN/PCT/2002/00329/DEL
PG Journal Number 52/2010
Publication Date 24-Dec-2010
Grant Date 21-Dec-2010
Date of Filing 26-Mar-2002
Name of Patentee UBE INDUSTRIES LTD.
Applicant Address 1978-96, OAZA KOGUSHI, UBE-SHI, YAMAGUCHI 755-8633, JAPAN.
Inventors:
# Inventor's Name Inventor's Address
1 HARDA KATSUMASA, 1978-5, OAZA KOGUSHI, UBE-SHI, YAMAGUCHI 755-8633, JAPAN.
2 SHIRAI MASASHI 1978-5, OAZA KOGUSHI, UBE-SHI, YAMAGUCHI 755-8633, JAPAN.
3 SHBIA KOJI 1978-5, OAZA KOGUSHI, UBE-SHI, YAMAGUCHI 755-8633, JAPAN.
PCT International Classification Number C07D 317/60
PCT International Application Number PCT/JP00/07103
PCT International Filing date 2000-10-13
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 290774/1999 1999-10-13 Japan
2 326116/1999 1999-11-16 Japan