Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF CURCUMIN

Abstract

57) Abstract:- The invention disclosed in this apphcations relates to a process for the preparation of curcumin comprising the steps of reacting vanillin with acetyi'dcetonedifluoroboronite in the presence of a base catalyst, isolating the l,7-diai'yl-l,6-heptadiene-3,5-dionedifluoroboronite formed and decomposing it with an aqueous alcohol followed by purification and isolating the product in high purity.

Full Text

Field of the invention The invention relates to a process for the preparation of curcumin. Curcumin has variety of uses such as antibacterial, anti-inflammatory, anticancer and antioxidant agents . Curcuminoids are characteristic yellow coloring components of turmeric, Curcuma fonga and of other Curcuma species. Chemically they are phenolic diarylheptanoids having diverse physiological activities including antibacterial, anti-inflammatory, anticancer and antioxidant activities. The most important constituent of commercial value is curcumin. The major processes known in the prior art for the preparation of curcumin are the following i) Pabon's route (H. J. J. Pabon Rec. Trav. Chim. 1964 83, 379) This route involves the reaction of vanillin and acetylacetone in the presence of boric oxide, trialkyl borate and a primary amine. The synthetic strategy of Pabon was followed in the route followed by Graf which process omitted the use of trialkylborate ( reference may be made to E. Graf, Ger. Pat. 1,280,849, 24-10-1968; Ger. Pat. 1,282,642,14-11-1968). This process employs an expensive reagent namely Boric oxide and involves heating at 80 - 130^ i) Stieglitz's commercial synthesis of curcumin (A. Stieglitz and O. Horn, Ger. Pat. 859,145, 11-12-1952). In this process use is made to carboxy methoxy feruloyi chloride which is reacted with aluminum chloride in carbon disulphide. The resulting product is hydrolysed to get curcumin In this process the starting material Is very expensive and the work up of the product involves cumbersome procedure because it involves steam distillation. Further the resulting product is a mixture of curcumin isomers. This process is rarely used now. It is felt that there is a necessity to develop and improved process using inexpensive reagents and relatively mild reaction conditions. Therefore the main objective of the present invention is to provide a process for the preparation of curcumin which is simple Another objective of the present invention is to provide an improved process for the preparation of curcumin using relatively mild conditions resulting in enormous savings making the process economical Yet another objective of the present invention is to provide an improved process for the preparation of curcumin which can be extended to other curcominoids and l,7-diaryl-l,6-diene'3,5-dione heptanoids in general. In the course of our work on Curcuma longa (turmeric) we have observed that curcumin is always obtained with two other curcuminoids, viz. desmethoxycurcumin and bisdesmethoxycurcumin which can be separated only by colunnn chromatography. Further the yield of mixed curcuminoids is only 4-6% and involves handling of large quantities of raw material such as which is finally to be discarded. Under the circumstances we explored the possibilities of developing other routes for the preparation of curcumin. We felt that use of an inexpensive substitute to boric oxide may be beneficial. The purpose of the use of boric oxide in the process of preparation of curcumin is mainly to block the active methylene group of acetylacetone from reacting with aryl aldehyde, thereby forming undesired by products such as arylidene derivatives. While studying the cliemical properties of curcumlnoids, we observed for the first time that they react with borontrifluoride to form difluoroboronites which can be cleaved to get back the original compounds. This observation prompted us to use the acetylacetone difluoroboronite In the place of acetylacetone and boric oxide previously used in the process for the preparation of curcumlnoids. We also observed that Borontrifluoride etherate (BF3-Et20) and acetylacetone are both commercially available and the boronite complex can be easily prepared (vide G.T. Morgan and R,B. Turnstall, J, Chem. Soc, 1924,125, 1963) and can be stored and used whenever required. Accordingly, the present Invention provides an Improved process for the synthesis of curcumin which comprises a) treating vanillin in ethyl acetate or chloroform solution with acetylacetonedifluoroboronite, b) adding a base catalyst under stirring at room temperature. c) distilling off the solvent, d) adding water and acidifying with IN hydrochloric acid under stirring, e) cooling, filtering, washing with water and drying the resulting product, f) refluxing the product from step (e) with 80% aqueous methanol or aqueous ethanol after adjusting the pH to 5.5, g) reducing the volume of the aqueous alcoholic solution, h) filtering the separated product from step (f) and washing with water, i) dissolving the product in aq. alkali and extracting with chloroform, j) Acidifying the alkali layer, filtering and drying the said product. In a preferred ennbodlment of the invention 1 mole of acetylacetone-difluoroboronite Is used for 2 moles of vanillin. The ethyl acetate or chloroform used for dissolution of vanillin may be 250-300 ml for each mole of aldehyde used. The base catalyst employed for each mole of aldehyde may be A7-butylamine, morpholin and the like. The amount of the catalyst employed may be n-butylamine (0.08 to 0.1 mole) for each mole of aldehyde or 0.14 to 0.16 mole or morpholin. The catalyst may be added In small quantities at a time over a period of 35 to 45 min. The stirring after addition of base catalyst may be continued for a period In the range of 3-4 hrs. Acidification may be done with the addition of IN HCI drop-wise until a pH of 2-3 is reached. The aqueous methanol or ethanol used may preferably be 80% (20 ml of water for 80 ml of methanol or ethanol) and the refluxing, after adjustment of pH to ca. 5.5 with 1% NaOH, is for a period of 3-4 hrs. when the deep red color of the solution turns orange. Reduction of the volume of aq. methanol or aq. ethanol is to an extent of 2/3 the original volume. Dissolution of the separated product is done in 5% sodium hydroxide or potassium hydroxide and the volume used is about 10 ml per each gram of the product. Extraction of the alkali solution may be done with chloroform twice using 1/3 of the volume of alkali solution each time and rejecting the chloroform extract. Acidification of tine alkali layer is done under continuous stirring at 5-10°C with cone, hydrociiloric acid added in small lots until the pH comes to 2-3. The resulting curcumin is obtained in an yield of 75-78% with a purity of ca 99%with n-butylamine as base catalyst and ca. 98% with morpholin as base catalyst. The invention is disclosed in detail in the following Examples which are provided by way of illustration only and therefore should not be construed to limit the scope of the Invention. Example 1 Vanillin (9.5 g) was dissolved in ethyl acetate (50 ml) in a 3-necked RB flask equipped with a mechanical stirrer, a reflux condenser and a stopper. Acetyl-acetonedifiuoroboronite (4.65 g) was added in small lots over a period of 5 minutes under stirring at room temperature. Stirring was continued for 10 more minutes before adding n-butylamine (0.625 ml) in small quantities over a period of 40 minutes under stirring. After the addition was completed stirring was continued for 4 hrs at room temperature. The solvent was distilled off from the reaction mixture and water (50 ml) was added. 1 N hydrochloric acid was added drop-wise under stirring until the pH of 2-3 is reached. The reaction mixture was cooled to about 20°C and the solid filtered, washed with water and dried (11.4 g). The above product was dissolved in 80% aq. methanol (2 l)(methanol 1600 ml + 400 ml water) the pH adjusted to 5.5 by the drop-wise addition of 1% aqueous NaOH and refluxed under vigorous stirring for 3 Va hr. Water (200 ml) was added and the volume reduced to about 650 ml by distillation under slight reduced pressure. The resulting suspension was cooled to 15'^C under stirring and the solid filtered, washed with water and dried (9.0 g) The product was dissolved in 5% aq. potassium hydroxide (90 ml). The all Example 2 Vanillin (1.9 g) was dissolved in ethyl acetate (8 ml) in a glass stoppered conical flask placed on a magnetic stirrer. Acetylacetonedifluoroboronite (0.93 g) was added in small lots over 5 min. under stirring at room temperature followed by the addition of n~butylamine (0.125 ml) over a period of 35 min. After the addition was completed stirring was continued for 3 Vz hrs at room temperature. The solvent was distilled off from the reaction mixture and water (10 ml) was added. IN HCI was added drop-wise under stirring until a pH of 2-3 is reached. The reaction mixture was cooled to about SCC and filtered, washed with water and dried (yield 2.24 g). The above product was dissolved in 80% aq. ethano! (425 ml) (ethanol 340 ml + water 85 mi) the pH adjusted to 5.5 by the drop-wise addition of L% aqueous NaOH and refluxed under vigorous stirring for 3 hr. Water (50 ml) was added and the volume reduced to about 150 ml by distillation under slight reduced pressure. The resulting suspension was cooled to 15°C under stirring and the solid filtered, washed with water and dried (1.8 g). The product was dissolved in 5% aq, sodium hydroxide (20 ml). The alkali solution was immediately extracted with chloroform (2 x 5ml). The chloroform layer was discarded. The alkali layer was immediately cooled to 10°C and acidified to pH 2-3 with cone, hydrochloric acid added drop-wise under stirring . The precipitated yellow solid curcumin was filtered, washed free from acid with water and dried, m.p. 181 - 82°C (1.76 g; yield 77%). Purity 99.5 % (HPLC). Example 3 Vanillin (3.8 g) was dissolved in ethyl acetate (20 ml) in a stoppered conical flask placed on a magnetic stirrer. Acetylacetonedifluoroboronite (1.86 g) was added in small lots over 5 min. under stirring at room temperature followed by the addition of morpholin (0.4 mi) over a period of 40 min. After the addition was completed stirring was continued for 4 hrs at room temperature. The solvent was distilled off from the reaction mixture and water (20 ml) was added. IN HCl was added drop-wise under stirring until the pH of 2-3 is reached. The reaction mixture was cooled to about 20°C, filtered, washed with water and dried (yield 4.6 g). The above product was dissolved in 80% aq. methanol (900 ml), the pH adjusted to 5.5 by the drop-wise addition of 1% aq. NaOH and refluxed under vigorous stirring for 4 hrs. Water (100 ml) was added and the volume reduced to about 350 ml by distillation under slight reduced pressure. The resulting suspension was cooled to 15°C under stirring, the solid filtered and washed with water and dried (3.6 g). The product was dissolved in 5% aq. KOH (40 ml). The alkali solution was immediately extracted with chloroform (2 X 12 ml). The alkali layer was Immediately cooled to 10°C and acidified to pH 2-3 with cone. HCI, added drop-wise under continuous stirring. The precipitated yellow solid curcumin was filtered, washed free from acid with water and dried, m.p. 176 - 78°C (3.55 g ; yield 77.6 %). Purity 97.8% (HPLC). Example 4 Vanillin (1.9 g) was dissolved in ethyl acetate (8 ml) in a conical flask placed on a magnetic stirrer. Acetylacetonedifluoroboronite (0.93 g) was added in small lots over 5 min. under stirring at room temperature followed by the addition of morpholin (0.12 ml) over a period of 40 min. After the addition was completed stirring was continued for 4 hrs at room temperature. The solvent was distilled off from the reaction mixture and water (10 ml) was added. IN HCI was added drop-wise under stirring until a pH of 2-3 is reached. The reaction mixture was cooled to about 20°C and filtered, washed with water and dried (yield 2.16 g). The above product was dissolved in 80% aq. ethanol (425 ml) (ethanol 340 ml + water 85 ml) the pH adjusted to 5.5 by the drop-wise addition of 1% aqueous NaOH and refluxed under vigorous stirring for 3 hr. Water (50 ml) was added and the volume reduced to about 150 ml by distillation under slight reduced pressure. The resulting suspension was cooled to 15°C under stirring and the solid filtered, washed with water and dried (1.8 g). The product was dissolved in 5% aq. sodium hydroxide (20 ml). The alkali solution was immediately extracted with chloroform (2 x 5mt). The chloroform layer was discarded. The all Example 5 Vanillin (4.95 g) was dissolved in chloroform (25 ml) in a 3-neci Then the solvent was distilled off from the reaction mixture and water (25 ml) was added. IN HCl was added drop-wise under stirring until the pH of 2-3 is reached. The reaction mixture was cooled to about 20°C and the 50lid filtered, washed with water and dried (5.75 g). The above product was dissolved in 80% aq. methanol (1050 ml), the pH adjusted to 5.6 by the drop-wise addition of 1% aq. NaOH and refluxed under vigorous stirring for 4 hrs. Water (120 ml) was added and the volume reduced to 300 ml by distillation under mild vacuum. The resulting suspension was cooled to 15°C under stirring and the solid filtered and washed with water and dried (4.6 g). The product was treated with 5% aq. sodium hydroxide (45 ml) and the alkali solution was immediately extracted with chloroform (2 x 15 ml). The alkali layer was immediately cooled to 5°C and acidified to pH 2-3 by the addition of cone, hydrochloric acid added drop-wise under stirring. The precipitated yellow solid curcumin was filtered, washed free from acid with water and dried, m.p. 179 - 81°C (4.4 g ; yield 76.2 %). Purity, 99.2% (HPLC). Example 6 Vanillin (1.9 g) was dissolved in chloroform (8 ml) in a glass stoppered conical flask placed on a magnetic stirrer. Acetylacetonedifluoroboronite (0.93 g) was added in small lots over 5 min. under stirring at room temperature. Stirring was continued for 5 more minutes before adding n-butylamine (0.130 ml) over a period of 40 min. After the addition was completed stirring was continued at room temperature for 4 hrs. The solvent was distilled off from the reaction mixture and water (10 ml) was added. IN HCI was added drop-wise under stirring until a pH of 2-3 is reached. The reaction mixture was cooled to about 20°C and filtered, washed with water and dried (yield 2.30 g). The above product was dissolved in 80% aq. ethanol (425 ml) (ethanol 340 ml + water 85 ml) the pH adjusted to 5.5 by the drop-wise addition of 1% aqueous NaOH and refluxed under vigorous stirring for 3 hr. Water (50 ml) was added and the volume reduced to about 150 ml by distillation under slight reduced pressure. The resulting suspension was cooled to 15°C under stirring and the solid filtered, washed with water and dried (1.9 g). The product was dissolved In 5% aq. sodium hydroxide (20 ml). The alkali solution was immediately extracted with chloroform (2 % 5ml). The chloroform layer was discarded. The alkali layer was immediately cooled to WC and acidified to pH 2-3 with cone, hydrochloric acid added drop-wise under stirring . The precipitated yellow solid curcumin was filtered, washed free from acid with water and dried, m.p. 181 - 82°C (1.72 g; yield 75.2%). Purity 98.8 % (HPLC). Example 7 Vanillin (9.5 g) was dissolved in chloroform (45 ml) in a 3-necl The solvent was distilled off from the reaction mixture and water (50 ml) was added. 1 N hydrochloric acid was added drop-wise under stirring until the pH of 2-3 is reached. The reaction mixture was cooled to about 20'C and the solid filtered, washed with water and dried (11.4 g). The above product was dissolved in 80% aq. methanol (2 ))(methanol 1600 ml + 400 ml water) the pH adjusted to 5.5 by the drop-wise addition of 1% aqueous NaOH and refluxed under vigorous stirring for 3 Vi hr. Water (200 ml) was added and the volume reduced to about 650 ml by distillation under slight reduced pressure. The resulting suspension was cooled to 15°C under stirring and the solid filtered, washed with water and dried (9.0 g) The product was dissolved in 5% aq. potassium hydroxide (90 ml). The alkali solution was immediately extracted with chloroform (2 x 25 ml). The chloroform layers were discarded. The alkali layer was immediately cooled to 5°C and acidified to pH 2-3 with the addition of cone, hydrochloric add in small volumes under stirring. The precipitated yellow solid curcumin was filtered, washed free from acid with water and dried, m.p. 177-79°C (yield 8.72 g, yield 76.4%). Purity 98.2% (HPLC). Example 8 Vanillin (3.8 g) was dissolved in chloroform (20 ml) in a stoppered conical flask placed on a magnetic stirrer. Acetylacetonedifluoroboronite (1.86 g) was added in small lots over 5 min. under stirring at room temperature. Stirring was continued for 5 more minutes before addition of morpholin (0.42 ml) over a period of 45 min. After the addition was completed stirring was continued for 4 hrs at room temperature. The solvent was distilled off from the reaction mixture and water (20 ml) was added. IN HCI was added drop-wise under stirring until the pH of 2-3 is reached. The reaction mixture was cooled to about 20°C, filtered, washed with water and dried (yield 4.6 g). The above product was dissolved in 80% aq. methanol (900 mi), the pH adjusted to 5.5 by the drop-wise addition of 1% aq. NaOH and refluxed under vigorous stirring for 4 hrs. Water (100 ml) was added and the volume reduced to about 350 mi by distillation under slight reduced pressure. The resulting suspension was cooled to IB^C under stirring, the solid filtered and washed with water and dried (3.6 g). The product was dissolved in 5% aq. KOH (40 ml). The alkali solution was immediately extracted with chloroform (2 X 12 mi). The alkali layer was immediately cooled to 10°C and acidified to pH 2-3 with cone. HCI, added drop-wise under continuous stirring. The precipitated yellow solid curcumin was filtered, washed free from acid with water and dried, m.p. 178 - 80°C (yield 75.4%). Purity 98.5% (HPLC). Advantages of the invention: 1. Curcumin obtained is of high purity and can be used in pharmaceutical, food and cosmetic industries. 2. The yield of curcumin is about 70 to 75% 3. The process Is simple and does not involve the use of costly reagents. 4. The intermediate curcumin difluoroboronite is stable and can be isolated to be used in the next step whenever required. 5. The process can be scaled up for industrial use. 6. Solvents used can be recovered and / or recycled in the operation. 7. The process can be extended for the preparation of various other curcuminoids. 8. The process is not only economical but also environmentally safe. We claim: 1. An improved process for the preparation of curcumin which comprises: a) Reacting vanillin in ethyl acetate or chloroform solution with a b) adding a base catalyst under stirring at room temperature, c) distilling off the solvent, d) adding water and acidifying with IN hydrochloric acid under stirring, e) cooling, filtering, washing with water and drying the resulting product, f) refluxing the product from step (e), with 80% aqueous methanol or aqueous ethanol after adjusting the pH to 5.5, g) reducing the volume of the aqueous alcoholic solution, h) filtering the separated product from step (f), and washing with water, i) dissolving the product In aq. alkali and extracting with chloroform, j) Acidifying the alkali layer, filtering and drying the said product. 2. A process as claimed In claim 1 wherein the solvent such as selected from ethyl acetate, chloroform is used . 3. A process as claimed in claims 1 & 2 wherein the base catalyst employed is selected from n- butylamine or morpholln. 4. A process as claimed in claims 1 to 3 wherein the amount of base catalyst used is In the range of 0.08 to 0.1 mole of n-butylamine per each mole of vanillin or 0.14 to 0.16 mole of morpholin for each mole of vanillin. 5. A process as claimed in claims 1 to 4 wherein the reaction time ranges from 3-4 hours after the addition of the base catalyst. 6. A process as claimed in claims 1 to 5 wherein IN HCI is added drop-wise under stirring until a pH of 2-3 is reached. 7. A process as claimed in claims 1 to 6 wherein the alcohol used is 75-80% aq. methanol or ethanol and the voiume is adjusted to 200-220 ml per each gram of the product formed (in Ic) 8. A process as claimed in claims 1 to 7 wherein the duration of refluxing is in the range of 3-4 hours. 9. A process as claimed in claims 1 to 8 wherein the distillation of solvent is effected to the extent of 2/3rd the volume under mild vacuum. 10. A process as claimed in claims 1 to 9 wherein the dissolution of 1 gm of the product is effected in ca. 10 ml of 5% aq NaOH or KOH. 11. A process as claimed in claims 1 to 10 wherein the extraction of alkali solution with chloroform is done twice using l/3rd of the volume of alkali solution each time. 12. A process as claimed In claims 1 to 11 wherein the acidification is done at a temperature in the range of 5-10°C with addition of cone, hydrochloric acid drop-wise under stirring until the pH reaches 2-3. 13. An improved process for the preparation of curcumin substantially herein described with reference to the Examples.

Documents:

876-mas-2001 abstract.pdf

876-mas-2001 claims.pdf

876-mas-2001 correspondence others.pdf

876-mas-2001 correspondence po.pdf

876-mas-2001 description (complete).pdf

876-mas-2001 form-1.pdf