Piperonal synthesis

[demorol]

I've done some more searching on Espacenet and again found two interesting patents about Piperonal synthesis. Here they are.

A process for preparing piperonal

Patent US4157333

Abstract
A process for preparing piperonal which compriss the steps of reacting 1,2-methylenedioxybenzene with an N-alkylformanilide and a condensing agent comprising one or more compounds selected from the groups consisting of phosgene, phosphorus oxychloride, phosphorus oxybromide, thionyl chloride, thionyl bromide, sulfuryl chloride, sulfuryl bromide, phosphorus trichloride and phosphorus pentachloride and then hydrolizing the resulting reaction product.

Preparation process for piperonal

Patent US5095128

Abstract
Preparation process for piperonal by decarboxylating oxidation of 3,4-methylenedioxymandelic acid by nitric acid in aqueous medium in the presence of HCl.

Life without chemistry would be a mistake.

[demorol]

Some more patents were found on Espacenet. But unfortunately no abstacts are available.

Process for preparing piperonal

Patent GB1591268

Process for the Preparation of Methylenedioxybenzene, 1,3-benzoxathiole and derivatives thereof

Patent GB1097270

Life without chemistry would be a mistake.

[Rhodium]

US4157333 = GB1591268

Entropy just isn't what it used to be.

[pHarmacist]

Here is a patent that describes preparation of imidiate pre-cursor (3,4-methylenedioxymandelic acid) used in preparation of piperonal as described above by demorol:

Abstract:

Disclosed is a process for preparing 3,4-methylenedioxymandelic acid by reacting 1,2-methylenedioxybenzene with glyoxylic acid in the presence of a strong acid, characterized in that the reaction is carried out in the presence of at least one selected from the group consisting of an aprotic organic solvent and 100 to 1200 ml of an organic acid per kg of 1,2-methylenedioxybenzene.

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 DEG 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 DEG 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 DEG 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%.


Patent: EP1229031 (Sorry, I can't make a link to it, that's the reason I pasted the procedure above)
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[pHarmacist]

Abstract:

The present invention relates to a process for producing piperonal, more specifically to a process for producing a high quality piperonal with high yield by using 1,2-methylenedioxybenzene as a starting material and without taking 3,4-methylenedioxymandelic acid which is an intermediate in the course of the reaction as a crystal.

Example 1


In a flat bottom separable flask having an inner volume of 7 liters, 500.0 g (4.09 mol) of 1,2-methylenedioxybenzene and 250 ml of 4-methyl-2-pentanone were charged under nitrogen atmosphere, and the mixture was cooled to -5 DEG C while stirring. Then, a mixture comprising 833.4 g (4.44 mol) of a 40% by weight aqueous glyoxylic acid solution and 857.8 g (8.40 mol) of 96% by weight sulfuric acid was gradually added dropwise, and then, the mixture was stirred at -5 DEG C for 21 hours.

Then, 3000 ml of 4-methyl-2-pentanone was added, and 1030.0 g(16.9 mol) of 28% by weight aqueous ammonia was gradually added to the mixture while maintaining the liquid temperature to -10 to 5 DEG C to effect neutralization. After the neutralization, the mixture was heated to 80 DEG C, and 3,4-methylenedioxymandelic acid was extracted in a 4-methyl-2-pentanone layer (an organic solvent layer). At this time, the reaction mixture was separated into two layers of an organic solvent layer and an aqueous layer.

Then, the aqueous layer was removed, and the organic solvent layer was concentrated (2200 ml of 4-methyl-2-pentanone was removed). After concentration, the reaction mixture in a slurry state was transferred to a round bottom separable flask with an inner volume of 20 liters, and cooled to 10 DEG C while stirring under nitrogen atmosphere. Thereafter, 1746.7 g (2.78 mol) of 10% by weight nitric acid was gradually added dropwise, and the temperature of the mixture was raised to 50 DEG C and the mixture was stirred at the temperature for one hour.

After completion of the reaction, the mixture was cooled to 25 DEG C, 140 ml (1.00 mol) of a 25% by weight aqueous sodium hydroxide solution was added to the mixture to make up the whole reaction mixture weak basic (pH=7.9). Subsequently, 4-methyl-2-pentanone layer (an organic solvent layer) and an aqueous layer were separated, and the organic solvent layer was analyzed by gas chromatography, then no 1,2-methylenedioxy-4-nitrobenzene which is a by-product was detected. Also, when it was analyzed by high performance liquid chromatography, a conversion of 1,2-methylenedioxybenzene was 97%, and a yield of piperonal was 78% (in terms of mole).


Example 2


In a flat bottom separable flask having an inner volume of 500 ml, 50.0 g (409.4 mmol) of 1,2-methylenedioxybenzene and 50 ml of acetic acid were charged under nitrogen atmosphere, and then, the mixture was cooled to 0 DEG C while stirring. Then, a mixture of 83.4 g (450.6 mmol) of a 40% by weight glyoxylic acid aqueous solution and 85.8 g (839.8 mmol) of 96% by weight sulfuric acid was gradually added dropwise, and then, the mixture was stirred at 5 DEG C for 21 hours.

Then, 200 ml of ethyl acetate was added to the mixture, and then, 102.0 g (1677 mmol) of 28% by weight aqueous ammonia was gradually added to the mixture while maintaining the liquid temperature to -10 to 5 DEG C to effect neutralization. After the neutralization, the mixture was heated to 60 DEG C, and the 3,4-methylenedioxymandelic acid was extracted in an ethyl acetate layer (an organic solvent layer). At this time, the reaction mixture was separated into two layers of an organic solvent layer and an aqueous layer.

Then, the aqueous layer was removed, and the organic solvent layer was concentrated (ethyl acetate was completely removed by distillation), 173 ml of water and 160 ml of toluene were newly added to the concentrate, and the mixture was cooled to 0 DEG C while stirring under nitrogen atmosphere. Then, 33.9 g (328.2 mmol) of 61% by weight nitric acid was gradually added dropwise, and the temperature of the mixture was raised to 40 DEG C, and the mixture was stirred at the temperature for one hour.

After completion of the reaction, the mixture was cooled to 0 DEG C, 80 ml (0.57 mol) of a 25% by weight aqueous sodium hydroxide solution was added to the mixture to make up the whole reaction mixture weak basic (pH=7.9). Subsequently, the toluene layer and the aqueous layer were separated, and the toluene layer was analyzed by gas chromatography, no 1,2-methylenedioxy-4-nitrobenzene which is a by-product was detected. Also, when it was analyzed by high performance liquid chromatography, a conversion of 1,2-methylenedioxybenzene was 97%, and a yield of the piperonal was 80% (in terms of mole).


Pat #: EP1253147
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