WO2020240596A1

WO2020240596A1 - A process for the oxidation of fatty acids

Info

Publication number: WO2020240596A1
Application number: PCT/IN2020/050482
Authority: WO
Inventors: Amol Arvind Kulkarni; Dumbala Srinivasa REDDY; Paresh Ramesh ATHAWALE; Ranjit Shabu ATAPALKAR
Original assignee: Council Of Scientific & Industrial Research
Priority date: 2019-05-31
Filing date: 2020-05-30
Publication date: 2020-12-03
Also published as: US20220228086A1; EP3976005A1; EP3976005A4; CN113905725A

Abstract

The present invention discloses a process for the oxidation of fatty acids comprises reacting fatty acid with O₂ containing O₃ for a period of 0.1-60 min at a temp in the range of -78 to 30 deg C to obtain the corresponding products, wherein the conversion of the fatty acid is in the range of 80% to 100% and the process is catalyst free and co-oxidant free.

Description

A PROCESS FOR THE OXIDATION OF FATTY ACIDS

FIELD OF THE INVENTION/8

The present invention relates to a process for the oxidation of fatty acids. Particularly, the present invention relates to a process for the oxidation of oleic acid to afford azelaic acid.

BACKGROUND AND PRIOR ART OF THE INVENTION

Azelaic acid is a naturally occurring dicarboxylic acid produced by Malassezia furfur and found in whole grain cereals, rye, barley and animal products. Azelaic acid possesses antibacterial, keratolytic, comedolytic, and anti-oxidant activity. Azelaic acid is bactericidal against Proprionibacterium acnes and Staphylococcus epidermidis due to its inhibitory effect on the synthesis of microbial cellular proteins. Azelaic acid exerts its keratolytic and comedolytic effects by reducing the thickness of the stratum corneum and decreasing the number of keratohyalin granules by reducing the amount and distribution of filaggrin in epidermal layers. Azelaic acid also possesses a direct anti-inflammatory effect due to its scavenger activity of free oxygen radical. This drug is used topically to reduce inflammation associated with acne and rosacea.

Azelaic acid is conventionally synthesized in batch mode through oxidation of oleic acid with various oxidizing agents’ viz. H2O2, ozone, acetic anhydride etc. in the presence of a catalyst and solvent. Using ozone forces the reaction to be carried out at -78 °C over very long time. Article titled“Preparation, characterization, and theoretical studies of Azelaic acid derived from oleic acid by use of a novel Ozonolysis method” by Bilal Biswas et al. published in Research on Chemical Intermediates, 2012, 38(2):659-668 reports azelaic acid has been produced by Ozonolysis of oleic acid. The reaction was performed in a Batch bubbling reactor, with fine bubbles, at high temperature (150°C) without utilizing any catalyst or any solvent. Yield of the reaction was 20% after 2h. Production of azelaic acid was confirmed by use of FT- IR and 1H NMR spectroscopic data and high-performance liquid chromatography of both synthesized and reference Azelaic acid.

Article titled“Synthesis of azelaic acid from oleic acid with green oxidant H₂O₂ / H₂WO₄” by Zuhrina Masyithah et al. published in ARPN Journal of Engineering and Applied Sciences, 2017, Vol. 12, No. 24 reports The synthesis of Azelaic acid was carried out by oxidizing oleic acid (OA) with hydrogen peroxide (H₂O₂) as an oxidizer and tungstic acid (H₂WO₄) as a catalyst. This study was conducted to determine the correlation and significance of the effect of variable comparison to the resulting percent conversion of Iodine Number as well as to develop a more effective, selective and environmentally friendly process with HiC /thWC as oxidizer. The interactions effect of substrate mole ratio, percent catalyst, and temperature were observed to obtain maximum yield of azelaic acid by utilizing the Central Composite Design (CCD) and Response Surface Methodology (RSM). The results showed that all variables influenced the percent conversion of Iodine Number expressed by the value of coefficient of determination (R2 ) of 92.08% and the results of variance analysis showed that all models contribute significantly to the percent conversion resulted. The oxidative cleavage reaction was evidenced by the decrease of iodine number and the product of the reaction was analyzed by Fourier transform-infrared spectroscopy (FT-IR). The largest decrement of iodine number was recorded 99.12% and it was obtained on variation of substrate mole ratio of 1: 8 (OA/H2O2), 3% (wH₂W0₄/wt. OA) catalyst at temperature of 70 °C. From the results of biocompatibility analysis, the process of synthesis of azelaic acid is eco-friendly because the waste generated is environmentally friendly and the catalyst used can be recycled.

Prior arts disclose the oxidation of fatty acids with very long reaction time and with less yield. So, there is need to develop a process for the oxidation of fatty acids with less reaction time, recoverable or no catalyst and with high yield.

OBJECTIVES OF THE INVENTION

Main objective of the present invention is to provide a process for the oxidation of fatty acids. Another objective of the present invention is to provide a process for the oxidation of oleic acid to afford azelaic acid.

SUMMARY OF THE INVENTION

Accordingly, present invention provides a process for the oxidation of a fatty acid comprising i. reacting a fatty acid with O2 containing ozone for a period in the range of 2 to

60 minutes at a temp in the range of -78 deg C to 30 deg C to obtain a product, wherein the conversion of the fatty acid is in the range of 80% to 100% and said process is catalyst-free and co-oxidant-free.

In an embodiment of the present invention, said process is carried out in batch or continuous mode.

In another embodiment of the present invention, said fatty acid is oleic acid. In yet another embodiment of the present invention, said product is azelaic acid.

In yet another embodiment, present invention provides a process for the synthesis of azelaic acid by oxidation of oleic acid in batch mode comprising the steps of:

a) dissolving an oleic acid in a solvent to obtain a solution;

b) purging O2 containing O3 into the solution of step (a) at a temperature in the range of -15°C to 0°C for a time period in the range of 5 to 60 minutes to afford mixture of azelaic acid and nonanoic acid;

c) continuing purging of oxygen at a temperature in the range of -15 °C to 0°C for 30 minutes to remove traces of unreacted ozone, wherein the conversion of the oleic acid is in the range of 80 to 100%.

In yet another embodiment of the present invention, said solvent is selected from the group consisting of ethanol, methanol, acetone, isopropanol, n-butanol, dichloromethane, ethyl acetate and water alone or in combination thereof and said solvent is selected from dichloromethane and methanol or acetone and water in a ratio ranging between 0:20 to 20:0. In yet another embodiment, present invention provides a process for the synthesis of azelaic acid by oxidation of oleic in continuous mode comprising the steps of:

a) dissolving an oleic acid in a solvent to form oleic acid solution;

b) pumping O2 containing O3 in a flow reactor;

c) pumping the oleic solution of step (a) by keeping a gas phase to liquid phase flow rate ratio of 25 to 2500 and

d) continuing pumping of O2 containing O3 in a flow reactor without changing the flow ratio as mentioned in step (c) wherein temperature of the flow reactor is in the range of -10°C to 10°C to afford azelaic acid and nonanoic acid, wherein the conversion of oleic acid is in the range of 80% to 100%.

In yet another embodiment of the present invention, said solvent is selected from ethanol, methanol, acetone, isopropanol, n-butanol, ethyl acetate, dichloromethane and water alone or in combination thereof.

In yet another embodiment of the present invention, said solvent is selected from dichloromethane and methanol, isopropanol and water or acetone and water in the ratio ranging between 0:20 to 20:0.

In yet another embodiment of the present invention, the flow rate ratio of gas phase to liquid phase is 25:2500. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 : ¹ H NMR of azelaic acid in DMSO-d6.

Figure 2: 13C NMR of azelaic acid in DMSO-d6.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for the oxidation of fatty acids.

The present invention provides a process for the oxidation of fatty acids comprises reacting a fatty acid with O2 containing ozone (O3) for a period of 0.1-60 min at a temp in the range of - 78 to 30 deg C to obtain the corresponding products, wherein the conversion of the fatty acid is in the range of 80% to 100% and the process is catalyst free and co-oxidant free.

The process is carried out in batch or continuous (flow) mode.

The present invention provides a process for the oxidation of the oleic acid to afford azelaic acid wherein the reaction is carried out in batch or continuous (flow) mode.

The present invention provides a process for the synthesis of azelaic acid in batch mode comprising the steps of:

a) dissolving an oleic acid in a solvent to obtain a solution;

b) purging O2 containing O3 into the solution of step (a) at a temperature in the range of -15 °C to 0°C for a time period in the range of 5 to 60 minutes to afford mixture of azelaic acid and nonanoic acid and

c) continuing purging of oxygen at a temperature in the range of -15 °C to 0°C for 30 minutes to remove traces of unreacted ozone.

The solvent of step (a) is selected from the group consisting of ethanol, methanol, acetone, i- propanol, n-butanol, dichloromethane, ethyl acetate and water either alone or in combination thereof.

The solvent is selected from dichloromethane: methanol, acetone: water in the ratio of 0:20 to

20:0.

The conversion of oleic acid is in the range of 80% to 100%. The quantitative yield of mixture of azelaic acid and nonanoic acid is 100 %. (Refer Fig. 1 and

2)

Figure 1 depicts ^XH NMR of azelaic acid (200 MHz, DMSO-de ) d ppm 11.97 (s, 2 H), 2.10 - 2.34 (m, 4 H), 1.50 (t, 7=6.4 Hz, 4 H), 1.27 (br. s., 6 H).

Figure 2 depicts ¹³C NMR of azelaic acid (50 MHz, DMSO-d6) 174.8, 34.0, 28.8, 24.8.

From fig 1 and 2, it is observed that only azelaic acid peaks are observed.

The process for the synthesis of Azelaic acid in batch mode is carried out at different conditions. Results are summarized in following table 1:

Table 1

Entries 1 to 5 of table 1 show the comparative examples for the present invention. From the table 1, it is observed that catalyst and co-oxidant are used for oxidation of oleic acid and yield of azelaic acid and nonanoic acid is in the range of 80 to 93% but from entry 6 it is observed that oxidation of oleic acid is carried out without using catalyst and co-oxidant and gives 100% yield of azelaic acid and nonanoic acid.

The present invention provides a process for the synthesis of azelaic acid in continuous mode comprising the steps of:

a) dissolving an oleic acid in solvent to form oleic acid solution;

b) pumping O2 containing O3 in a flow reactor;

d) continuing pumping of O2 containing O3 in a flow reactor without changing the flow ratio as mentioned in step (c) wherein temperature of the flow reactor is in the range of -10°C to 10°C to afford azelaic acid and nonanoic acid. The solvent is selected from ethanol, methanol, acetone, isopropyl alcohol, n-butanol, ethyl acetate, dichloromethane and water alone or in combination thereof.

The solvent is selected from dichloromethane: methanol, isopropyl alcohol: water and acetone: water in the ratio of 0:20 to 20:0.

The conversion of oleic acid is in the range of 80% to 100%.

The quantity of O2 containing O3 is depending upon the quantity of oleic acid is taken.

The volume ratio of C containing O3: Oleic acid is 25:2500. The quantitative yield of mixture of azelaic acid and nonanoic acid is 100 %.( Refer Fig. 1 and

2).

From fig 1 and 2 it is observed that only azelaic acid peaks are appeared in 1H NMR and ¹³C NMR.

The process for the synthesis of azelaic acid in continuous mode is carried out at different conditions. Results are summarized in following table 2:

Table 2

In still yet another embodiment, the present invention provides impurity free, catalyst free and co-oxidant free process for the oxidation of fatty acids.

The present invention provides impurity free, catalyst free and co-oxidant free process for the oxidation of oleic acid to afford only product of azelaic acid and nonionic acid. No other impurity is formed. (Refer fig. 1 and 2)

From fig. 1 and 2, it is observed that only azelaic acid peaks are formed.

EXAMPLES

Following examples are given by way of illustration therefore should not be construed to limit the scope of the invention.

Example 1: Synthesis of azelaic acid with catalyst and co-oxidant

1 gm oleic acid was dissolved in dichlorome thane: methanol (1: 1) to form the solution of oleic acid. 5 mL acetic acid as a catalyst was added into the oleic acid solution. The temperature of the reaction mixture was set at -78°C andC containing O3 was purged into the oleic acid solution for 5 min. 5 ml H2O2 oxidant was added into the purged solution. The reaction mixture was stirred for 30 min. After completion of the reaction, work up procedure was followed to obtain mixture of azelaic acid and nonanoic acid. Azelaic acid and Nonanoic acid were separated and recovered by extraction and decantation method. It resulted in 90% yield mixture of azelaic acid and nonanoic acid.

Example 2: Synthesis of azelaic acid with catalyst and co-oxidant

0.5gm oleic acid was dissolved in acetone: water (95:5mL) to form the solution of oleic acid. 3 mL Me2S, 2 eq. as a catalyst was added into the oleic acid solution. The temperature of the reaction mixture was set at 0°C andC containing O3 was purged into the oleic acid solution for 5 min. 20ml (Jones reagent, i.e Cr0₃, aq. H2SO4_, Acetone and water mixture) oxidant was added into the purged solution. The reaction mixture was stirred for 3 hrs. After completion of the reaction, work up procedure was followed to obtain mixture of azelaic acid and nonanoic acid azelaic acid and nonanoic acid were separated and recovered by extraction and decantation method. It resulted in 93% yield mixture of azelaic acid and nonanoic acid.

Example 3: Synthesis of azelaic acid with catalyst and co-oxidant

lgm oleic acid was dissolved in acetone: water (95:5mL) to form the solution of oleic acid. 18 mg CuCl (5mol%), as a catalyst was added into the oleic acid solution. The temperature of the reaction mixture was set at 0°C andC containing O3 was purged into the oleic acid solution for 5 min. 1.2mL (30%H₂q₂) 1 eq. oxidant was added into the purged solution. The reaction mixture was stirred for 24 hrs. After completion of the reaction, work up procedure was followed to obtain mixture of azelaic acid and nonanoic acid. Azelaic acid and nonanoic acid were separated and recovered by extraction and decantation method. It resulted in 93% yield mixture of azelaic acid and nonanoic acid.

Example 4: Synthesis of azelaic acid with catalyst and co-oxidant

0.5gm oleic acid was dissolved in acetone: water (47.5:2.5mL) to form the solution of oleic acid, 18 mg CuCl (5mol%), as a catalyst was added into the oleic acid solution. The temperature of the reaction mixture was set at 0°C andC containing O3 was purged into the oleic acid solution for 10 min. 3 mL NaOCl (5mol%), 2eq. oxidant was added into the purged solution. The reaction mixture was stirred for 50 min. The reaction did not show any formation of the desired product.

Example 5: Synthesis of azelaic acid with catalyst

lgm oleic acid was dissolved in acetone: water (47.5:2.5mL) to form the solution of oleic acid, 18 mg CuCl (5mol%), as a catalyst was added into the oleic acid solution. The temperature of the reaction mixture was set at 0°C andC containing O3 was purged into the oleic acid solution for 10 min. Oxygen was purged for 30 min. After completion of the reaction, work up procedure was followed to obtain mixture of azelaic acid and nonanoic acid azelaic acid and nonanoic acid were separated and recovered by extraction and decantation method. It resulted in 83% yield mixture of azelaic acid and nonanoic acid. Example 6: Synthesis of azelaic acid with O2 containing O3

5gm oleic acid was dissolved in acetone: water (118.75:6.25mL) to form the solution of oleic acid. The temperature of the reaction mixture was set at 0°C andC containing O3 was purged into the oleic acid solution for 10 min. Oxygen was purged for 30 min. After completion of the reaction, work up procedure was followed to obtain mixture of azelaic acid and nonanoic acid. Azelaic acid and nonanoic acid were separated and recovered by extraction and decantation method. It resulted inl00% yield mixture of azelaic acid and nonanoic acid.

Example 7: Synthesis of azelaic acid in flow reactor

lgm oleic acid was dissolved in acetone: water mixture (95ml:5ml), O2 containing O3 and the oleic acid solution were pumped at the flow rate ratio of 400, in a flow reactor (volume = 20mL, inner diameter = 2mm, length 5m) at 0°C. The sample obtained from outlet was analyzed and analysis showed 81% azelaic acid and nonanoic acid (mixture).

Example 8: Synthesis of azelaic acid in flow reactor

2gm oleic acid was dissolved in acetone: water mixture (95ml: 5ml), O2 containing O3 and the oleic acid solution were pumped at the flow rate ratio of 400, in a flow reactor (volume = 20mL, inner diameter = 2mm, length 5m) at 0°C. The sample obtained from outlet was analyzed and analysis showed 93% azelaic acid and nonanoic acid (mixture).

Example 9: Synthesis of azelaic acid in flow reactor

5gm oleic acid was dissolved in acetone: water mixture (118.75:6.25 mL), O2 containing O3 and the oleic acid solution were pumped at the flow rate ratio of 400, in a flow reactor (volume = 20mL, inner diameter = 2mm, length 5m) at 0°C. The sample obtained from outlet was analyzed and analysis showed 93% azelaic acid and nonanoic acid (mixture).

Example 10: Synthesis of azelaic acid in flow reactor

1 gm oleic acid was dissolved in acetone: water mixture (95ml:5ml), O2 containing O3 and the oleic acid solution were pumped at the flow rate ratio of 100, in a flow reactor (volume = 20mL, inner diameter = 2mm, length 5m) at 0°C. The sample obtained from outlet was analyzed and analysis showed 92% azelaic acid and nonanoic acid (mixture). Example 11: Synthesis of azelaic acid in flow reactor

lgm oleic acid was dissolved in acetone: water mixture (95ml:5ml), O2 containing O3 and the oleic acid solution are pumped at the flow rate ratio of 50, in a flow reactor (volume = 20mL, inner diameter = 2mm, length 5m) at 0°C. The sample obtained from outlet was analyzed and analysis showed 80% azelaic acid and nonanoic acid (mixture).

Example 12: Synthesis of azelaic acid in flow reactor

lgm oleic acid was dissolved in acetone: water mixture (95ml:5ml), O2 containing O3 and the oleic acid solution are pumped at the flow rate ratio of 25, in a flow reactor (volume = 20mL, inner diameter = 2mm, length 5m) at 0°C. The sample obtained from outlet was analyzed and analysis showed less than 5% azelaic acid and nonanoic acid (mixture).

Example 13: Synthesis of azelaic acid in flow reactor

lgm oleic acid was dissolved in acetone: water mixture (45ml:5ml), O2 containing O3 and the oleic acid solution are pumped at the flow rate ratio of 100, in a flow reactor (volume = 20mL, inner diameter = 2mm, length 5m) at -10°C. The sample obtained from outlet was analyzed and analysis showed 87% azelaic acid and nonanoic acid (mixture).

Example 14: Synthesis of azelaic acid in flow reactor

lgm oleic acid was dissolved in acetone: water mixture (45ml:5ml), O2 containing O3 and the oleic acid solution are pumped at the flow rate ratio of 100, in a flow reactor (volume = 20mL, inner diameter = 2mm, length 5m) at 10°C. The sample obtained from outlet was analyzed and analysis showed 94% azelaic acid and nonanoic acid (mixture).

ADVANTAGES OF THE INVENTION

1. The yield of azelaic acid and nonanoic acid mixture is 100%.

2. Reaction is catalyst free.

3. Reaction is co-oxidant free.

4. Reaction is impurity free

5. Reaction time is in few seconds to few minutes, with 80-100% conversion of oleic acid to form azelaic acid and nonanoic acid.

Claims

We claim

1. A process for the oxidation of a fatty acid comprising

i. reacting a fatty acid with O2 containing ozone for a period in the range of 2 to

2. The process as claimed in claim 1, wherein said process is carried out in batch or continuous mode.

3. The process as claimed in claim 1, wherein said fatty acid is oleic acid.

4. The process as claimed in claim 1, wherein said product is azelaic acid.

5. A process for the synthesis of azelaic acid by oxidation of oleic acid in batch mode comprising the steps of:

a) dissolving an oleic acid in a solvent to obtain a solution;

6. The process as claimed in claim 5, wherein said solvent is selected from the group consisting of ethanol, methanol, acetone, isopropanol, n-butanol, dichloromethane, ethyl acetate and water alone or in combination thereof and said solvent is selected from dichloromethane and methanol or acetone and water in a ratio ranging between 0:20 to 20:0.

7. A process for the synthesis of azelaic acid by oxidation of oleic in continuous mode comprising the steps of:

a) dissolving an oleic acid in a solvent to form oleic acid solution;

b) pumping O2 containing O3 in a flow reactor;

8. The process as claimed in claim 7, wherein said solvent is selected from ethanol, methanol, acetone, isopropanol, n-butanol, ethyl acetate, dichloromethane and water alone or in combination thereof.

9. The process as claimed in claim 8, wherein said solvent is selected from dichloromethane and methanol, isopropanol and water or acetone and water in the ratio ranging between 0:20 to 20:0.

10. The process as claimed in claim 7, wherein the flow rate ratio of gas phase to liquid phase is 25:2500.