FRAGRANCE SYNTHESIS…Floralozone and lysmeral

Floralozone

67634-15-5

4-ethyl-a,a-dimethylbenzene propanal; p-ethyl-a,a-dimethylhydrocinnamic aldehyde; a,a-dimethyl-p-ethylphenyl-propanal; 3-(p-ethylphenyl)-2,2-dimethylpropionaldehyde; Florazone; 3-(4-ethylphenyl)-2,2-dimethylpropanal

LYSMERAL

CAS No:80-54-6

CAS Name:Benzenepropanal, 4-(1,1-dimethylethyl)-.alpha.-methyl-

Synonyms p-Tert. Butyl-alpha-methyldihydrocynnamic aldehyde / Lilestralis / Lilial / Lilialdehyde

A current process for producing an aromatic aldehyde compound is shown in Scheme I, wherein production of 4-tert-butyl-phenyl-formaldehyde is critical. The final step of the process requires hydrogen-reduction with palladium on carbon catalyst under high pressure. Use of noble metal as catalyst results in high cost of production. Patent NO. WO2007045641 owned by Badische Anilin- and Soda-Fabrik Corp. (BASF) aims at improving the final step for hydrogen-reduction of the above process. However, the reaction pressure is so high as 30 Bar, leading to difficulties in its industrialization.

Figure US20120264981A1-20121018-C00002

Givaudin Corporation discloses a process for producing an aromatic aldehyde inBull. Soc. Chem. Fr., p 1194 in 1961, as shown in Scheme II. The process utilizes great amounts of TiCland BF3-Et2O as catalyst. However, it has a yield less than 10%. Moreover, one of the raw materials, 2-methylpropenal, is rare and difficult to be obtained, and TiClis easy to be hydrolyzed. Therefore, the process cannot be industrialized and will cause three wastes, that is, waste water, waste gas and industrial residue, leading to environmental pollutions.

Figure US20120264981A1-20121018-C00003

DE2627112 discloses a process for producing an aromatic aldehyde compound as shown in Scheme III. Although its yield is higher than 80%, one of the raw materials, 2-methylpropenal, is extremely rare and high-priced, resulting in the limitation of the process in industrial application. A process published in Journal of Molecular Catalysis A: Chemical, 231(1-2), 61-66 (2005) is a modification of the above process and achieves a theoretical production rate of 95%. However, the modified process requires use of 4-tert-butyliodobenzene as raw material, rare elements as catalyst, and ion liquid for reaction, and has a reaction time more than 24 hours, which leads to its low efficiency and failure in industrial application.

Figure US20120264981A1-20121018-C00004

DE2851024 discloses a process for producing an aromatic aldehyde compound, as shown in Scheme IV. The process requires a great amount of AlCl3, and has problems of three wastes and corrosion of manufacturing equipments. Furthermore, the known Vilsmeier reaction also has problems of three wastes and has a yield of only 35%. A process published in Organic Preparations and Procedures International, 14(1-2), p 2-20 is a modification of the above process. However, the modified process still requires hydrogen-reduction as a final step and utilizes noble metal as catalyst, contributing to its high production cost.

Figure US20120264981A1-20121018-C00005

To overcome the shortcomings, the present invention provides a process for producing an aromatic aldehyde compound that requires no hydrogen-reduction under high pressure with expensive and complicated manufacturing equipments and will not cause pollution to environment to mitigate or obviate the aforementioned problems.

Example-1 Preparation of Compound 1

Compound 1 was obtained by Route 1 and experimental protocols as follows.

Figure US20120264981A1-20121018-C00010

50 grams (0.37 mol) of tert-butylbenzene, 12.3 grams (0.40 mol) of paraformaldehyde and 100 mL of acetic acid were mixed in a flask. 109.6 grams of hydrogen bromide (HBr) in 33% (w/w) acetic acid solution was slowly added into the flask dropwise within 30 minutes and then heated to 120° C. and stirred for 7.5 hours. Samples were obtained and extracted with water and dichloromethane. Organic phase was obtained and subjected to thin-layer chromatography (TLC) for tracing reaction. Until reactants were consumed, 200 mL of water was added into the reaction mixture and then extracted with 200 mL dichloromethane for three times. Organic phases were collected, concentrated and distilled under a condition of a temperature of 165˜170° C. and a pressure of 4.8˜5.5×10−1 torr to obtain distilled fractions. 73.02 grams of compound 1 was obtained with a yield of 86.3%.

Example-2 Preparation of Phase Transfer Catalyst 1 (PTC 1)

Phase transfer catalyst 1 (PTC 1) was obtained by Route 2 and experimental protocols as follows.

Figure US20120264981A1-20121018-C00011

10 grams (220.1 mmol) of compound 1 was dissolved in 200 mL of anhydrous ethanol, followed by adding 14.31 grams (242.1 mmol) of trimethylamine, refluxing for 2 hours and standing overnight. Precipitate was obtained by filtration and rinsed with anhydrous ethanol for three times to obtain a solid, which was dried and ready for use as PTC 1 in the following examples.

Example-3 Preparation of Compound 2

Compound 2 was obtained by Route 3 and experimental protocols as follows.

Figure US20120264981A1-20121018-C00012

50 grams (0.47 mol) of ethylbenzene, 15.56 grams (0.52 mol) of paraformaldehyde and 100 mL acetic acid were mixed in a flask. 138.6 grams of hydrogen bromide in 33% (w/w) acetic acid solution was slowly added into the flask dropwise within 30 minutes and then heated to 120° C. and stirred for 7.5 hours. Samples were obtained and extracted with water and dichloromethane. Organic phase was obtained and subjected to TLC for tracing reaction. When the reaction was finished, 200 mL of water was added and extracted with 200 mL dichloromethane for three times. Organic phases were collected, concentrated and distilled under a condition of a temperature of 151˜156□ and a pressure of 4.2˜4.8×10−1 torr to obtain distilled fractions. 81.66 grams of compound 2 was obtained with a yield of 86.9%.

Example-4 Preparation of Phase Transfer Catalyst 2 (PTC 2)

Phase transfer catalyst 1 (PTC 2) was obtained by Route 4 and experimental protocols as follows.

Figure US20120264981A1-20121018-C00013

10 grams (251.2 mmol) of compound 2 was dissolved in 200 mL of anhydrous ethanol, followed by adding 16.33 grams (276.3 mmol) of trimethylamine, refluxing for 2 hours and standing overnight. Precipitate was obtained by filtration and rinsed with anhydrous ethanol for three times to obtain a solid, which was dried and ready for use as PTC 2 in the following examples.

Comparative Example-1

The present example was performed by the following experimental protocols to produce lysmeral.

2.3 grams (57.7 mmol) of sodium hydroxide, 0.33 grams (0.88 mmol) of tetrabutylammonium iodide, 7.5 mL water, 4.2 mL toluene, 1 mL tetrahydrofuran (THF) were mixed in a flask and then heated to 70˜75° C. Mixture of 10 grams (44.0 mmol) of compound 1 and 3.55 grams (61.2 mmol) of propanal was slowly added into the flask dropwise within 2 hours while the reaction mixture was vigorously stirred. When addition was finished, the reaction mixture was stirred at 70-75° C. for 3 hours and traced by gas chromatography (GC). Until reactants were consumed, 30 mL water was added for extraction to obtain an organic phase. The organic phase was dehydrated with anhydrous sodium sulfate, filtered and concentrated by vacuum distillation. 4.84 grams of lysmeral was obtained with a yield of 53.8%.

Example-5 Preparation of Lysmeral

The present invention was performed according to the following Route 5 and experimental protocols to obtain lysmeral.

Figure US20120264981A1-20121018-C00014

2.3 grams (57.7 mmol) of sodium hydroxide, 0.26 grams (0.88 mmol) of PTC 1, 7.5 mL of water, 4.2 mL of toluene, 1 mL of THF were mixed in a flask and then heated to 70-75° C. Mixture of 10 grams (44.0 mmol) of compound 1 and 3.55 grams (61.2 mmol) of propanal was added into the flask dropwise within 2 hours while the reaction mixture was vigorously stirred. While addition was finished, the reaction mixture was stirred at 70-75° C. for 3 hours and traced by GC. When the reaction stopped, 30 mL water was added for extraction to obtain an organic phase. The organic phase was dehydrated with anhydrous sodium sulfate, filtered and concentrated by vacuum distillation. 7.43 grams of lysmeral was obtained with a yield of 82.6% and verified to have a purity of 97.27% by GC analysis.

Results of analysis by NMR are shown as follows:

1H NMR (CDCl3) □δ 9.73 (t, 1H, J=6.851), 7.34 (ddd, 1H, J=8.032, J=3.716, J=0.000), 7.13 (ddd, 1H, J=8.032, J=3.732, J=0.000), 7.11 (ddd, 1H, J=8.032, J=3.716, J=0.000), 7.32 (ddd, 1H, J=8.032, J=3.732, J=0.000), 2.6 (dd, 2H, J=6.945, J=6.851), 3.0 (tq, 1H, J=6.945, J=6.911), 1.32 (m, 9H), 1.1 (d, 3H, J=6.911).

Results of Comparative Example-1 and Example-5 were shown in Table 1, demonstrating the yields of lysmeral were affected by catalyst and temperature. Table 1 illustrated that reactions with PTC 1 had higher yields than those with tetrabutylammonium iodide.

TABLE 1
reaction temperature phase transfer catalyst yield
20~25° C. tetrabutylammonium iodide no reaction
PTC 1 no reaction
50~60° C. tetrabutylammonium iodide 50.9%
PTC 1 63.1%
70~75° C. tetrabutylammonium iodide 53.8%
PTC 1 82.6%
0.02 equivalent of phase transfer catalyst was used herein.

Comparative Example-2

The present example was performed by the following experimental protocols to produce floralozone.

2.63 grams (65.8 mmol) of sodium hydroxide, 0.37 grams (1.0 mmol) of tetrabutylammonium iodide, 7.5 mL of water, 4.2 mL of toluene, 1 mL of THF were mixed in a flask and then heated to 70˜75° C. Mixture of 10 grams (50.2 mmol) of compound 2 and 5.03 grams (69.8 mmol) of isopropanol was added into the flask dropwise while the reaction mixture was vigorously stirred. When addition was finished, the reaction mixture was stirred at 70-75° C. for 3 hours and traced by GC. When the reaction stopped, 30 mL water was added for extraction to obtain an organic phase. The organic phase was dehydrated with anhydrous sodium sulfate, filtered and concentrated by vacuum distillation. 5.17 grams of floralozone was obtained with a yield of 54.1%.

Example-6 Preparation of Floralozone

The present invention was performed according to the following Route 6 and experimental protocols to obtain floralozone.

Figure US20120264981A1-20121018-C00015

2.63 grams (65.8 mmol) of sodium hydroxide, 0.27 grams (1.0 mmol) of PTC 2, 7.5 mL of water, 4.2 mL of toluene, 1 mL of THF were mixed in a flask and then heated to 70˜75° C. Mixture of 10 grams (50.2 mmol) of compound 2 and 5.03 grams (69.8 mmol) of isopropanal was added into the flask dropwise while the reaction mixture was vigorously stirred. When addition was finished, the reaction mixture was stirred at 70-75° C. for 3 hours and traced by GC. When the reaction stopped, 30 mL of water was added for extraction to obtain an organic phase. The organic phase was dehydrated with anhydrous sodium sulfate, filtered and concentrated by vacuum distillation. 7.92 grams of floralozone was obtained with a yield of 82.8% and verified to have a purity of 95.76% by GC analysis.

Results of analysis by NMR are shown as follows:

1H NMR (CDCl3) □δ 9.62 (m, 1H), 7.15 (ddd, 4H, J=8.026, J=3.500, J=1.319), 2.8 (m, 2H), 2.6 (q, 2H, J=7.486), 1.2 (m, 9H).

Results of Comparative Example-2 and Example-6 were shown in Table 2, demonstrating the yields of floralozone were affected by catalyst and temperature. Table 2 illustrated that reactions with PTC 2 had higher yields than those with tetrabutylammonium iodide.

TABLE 2
reaction temperature phase transfer catalyst yield
20~25° C. tetrabutylammonium iodide no reaction
PTC 2 no reaction
50~60° C. tetrabutylammonium iodide 51.7%
PTC 2 64.6%
70~75° C. tetrabutylammonium iodide 54.1%
PTC 2 82.8%
0.02 equivalent of phase transfer catalyst was used herein.

Here’s a greener process for making fragrance components. Y.-C. Lee and co-inventors improved the process for making aldehydes that are used as fragrances in soaps, detergents, and cosmetics. Compounds specifically covered are floralozone (1) and lysmeral (2).

Current processes for preparing the compounds require a high-pressure hydrogenation step that the inventors believe is unsuitable for industrial use. The new process begins with the preparation of a phase-transfer catalyst (PTC) that is used to make the desired aldehydes.

The first sequence in the figure shows the synthesis of PTC compounds 5a and 5b by the reaction of alkylbenzene 3a or 3b with HCHO and HBr in HOAc. Intermediate 4a is isolated in 86.9% yield after vacuum distillation; it is then treated with NMe3 to produce PTC compound 5a. The PTC is isolated as a solid, but its yield and purity are not reported.

PTC compound 5b is similarly prepared by way of 4b, isolated in 86.3% yield. The PTCs are used to prepare aldehydes 1 and 2.

In the synthesis of 1, shown the second sequence, compound 4a reacts with isobutyraldehyde in a two-phase mixture of water and toluene that contains PTC 5a. Compound 1 is isolated in 82.8% yield with 95.8% purity by GC. A comparative preparation of 1 that uses n-Bu4NI as the catalyst yields only 54.1% product.

The same procedure, shown in the third sequence, is used to produce lysmeral. Bromide6 and propionaldehyde react in the presence of PTC 5b to produce 2 in 82.6% yield and 97.3% purity (GC).

The process uses inexpensive reagents. In contrast to earlier processes, it does not require high pressures or produce hazardous wastes. (UFC Corp. [Taipei]. US Patent 8,362,303, January 29, 2013;

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