Field of the invention

The present invention relates to an improved synthesis of curcuminoids. More specifically, such an improved process of the present invention is to provide curcuminoids in a composition similar to natural curcuminoids in good yield and high purity.

Background of the invention

Curcuminoids are the yellow colored pigments of the Turmeric. Curcuminoids are a mixture of closely related three components, curcumin (I), demethoxycurcumin (II) and bisdemethoxycurcumin (III). The major component is curcumin and its complete chemical name, is ( IE, 6E)-1, 7-bis (4-hydroxy-3-methoxyphenyl)-l, 6-heptadiene-3, 5- dione (I).

Curcuminoids are reported to posses various potential medicinal uses such as antitumor activity, antioxidant, antiarthritic, antiamyloid and anti-inflammatory properties (Alternative Medicine Review, Sept, 2001).

Number of commercially viable processes for the manufacture of curcumin (I) have been reported in the literature via the condensation of acetylacetone with vanillin in the presence of boron reagents, particularly boric anhydride and an amine. Some of the prior art is noted below.

The US Patent 3,194,841 describes the condensation of vanillin with acetylacetone in the presence of trialkylborate and boric anhydride to give curcumin with yields ranging from 16 to 70%. According to US Patent 3,194,841 patent, the process for the preparation of trialkylborate employs a large molar excess, for example, 7 molar equivalents, of the expensive and high boiling butanol solvent, which is difficult to remove after completion of the reaction.

DE 1282642 patent provides curcumin through the reaction of vanillin in Dimethyl sulfoxide (high boiling aprotic solvent) with acetylacetone in the presence of boric anhydride and a secondary amine or its acetate at a temperature of about 80 to 90° C followed by usual work up and purification to give curcumin in purity > 99 % but with low yield of 25%.

DE 1280849 patent describes the reaction of vanillin with acetylacetone in presence of boron anhydride a secondary amine or its acetate at high temperatures ranging from 100 to 170° C followed by usual work up and purification to obtain curcumin with low yields ranging from 19 to 28%.

The US Patent 5,679,864 provides curcumin by sequential steps of reacting the acetyl acetone in a chemically inert, highly polar, aprotic solvent with a suitable boron complexing agent and then adding an aromatic aldehyde and catalytic amount of primary or secondary amine to provoke aldol condensation.

According to this US Patent 5,679,864, addition of water scavenger is needed to remove the water formed during the condensation step otherwise reaction does not proceed thus the yields of curcumin are substantially reduced. Suitable scavengers for this purpose mentioned are C1-5 alkyl borates and C1-5 alkyl phosphates and mixtures thereof.

Another class of water reactive compounds which are mentioned in this patent are ketals such as 2, 2-dimethoxy propane.

According to WO2007/110168, curcumin is obtained by condensation of acetyl acetone with vanillin in a highly polar, aprotic solvent, in the presence of equimolar or nearly equimolar amount of boric acid and a catalytic amount of an aliphatic or araliphatic amine, at a temperature in the range of 50-85 C, at reduced pressure of 10-100 mbar, under concomitant removal of reaction water by azeotropic distillation. Curcumin obtained by this process is in about 66-69% yield with purity more than 90%.

Simultaneous removal of the reaction water by azeotropic distillation under vacuum, particularly during the key condensation step and throughout the reaction makes the process economically unattractive.

All the above mentioned patents involve either the prior addition of costly reagent boric anhydride or formation of boron complex reacting the acetyl acetone in a chemically inert, highly polar, aprotic solvent with a suitable boron complexing agent. Simultaneous addition of water scavenger i.e. trialkylborate takes place to remove the water formed during the condensation step.

The US Patent 5,679,864 provides a method for producing the natural curcuminoids, but, uses boric anhydride and also polar aprotic solvent, dimethylacetamide, thus precluding the manufacture in an economical way.

The inventors claimed that polar aprotic solvent is needed to make the reaction successful. Further, the process led to the product in dark orange color that is not acceptable.

As there is no economical process for obtaining the natural curcuminoids in commercial scale, the present inventors have developed a process that is economical and scalable to produce the three curcuminoids mixture in a single step. The major difficulties encountered with the preparation of curcumin /cucrminoids in the prior art experiments are that the reaction does not proceed without the usage of costly reagent, boric anhydride. From an economic point of view, the process has to be efficient enough to prevent the reagents costs and energy from becoming prohibitive. Subsequent to these early inventions, significant changes have been made in the present invention in order to avoid this expensive reagent boric anhydride or azeotropic distillations under vacuum.
In order to overcome the disadvantages of the prior art, the present inventors set the reaction conditions in such a way that the trialkylborate acts as boron complexing agent, polar aprotic solvent and water scavenger so that the reaction proceeds without using boric anhydride or polar aprotic solvent or additional water scavengers.

According to the present invention, a work-up process is devloped to obtain natural orange-yellow colour to the curcuminoids mixture. The present process is suitable to obtain pure curcumin I also.

Summary of the invention

The main object of the present invention is to provide an improved process for the preparation of curcuminoids mixture in good yield and high purity without the usage of costly reagent, boric anhydride. The trialkylborate reagent, which serves multiple functions of forming boron complex with acetylacetone, acts as polar aprotic solvent and as scavenger of water formed during the course of the reaction.

Yet another object of the present invention is to provide the process that avoids the use of polar aprotic solvent and obtain the product, curcuminoids, in the natural yellowish-orange colour.

Detailed Description

The present invention relates to an improved synthesis of curcuminoids. More specifically, such an improved process of the present invention is to provide curcuminoids in a composition similar to natural curcuminoids in good yield and high purity.

According to the present invention curcuminoids are prepared by the following process steps :

a. reacting the mixture of vanillin and p-hydroxybenzaldehyde with acetyl acetone in trialkylborate in presence of n-butyl amine without any other organic solvent.

b. heating the reaction mixture for 5-10 h.

c. treating the reaction mixture with aqueous acetic acid.

d. adjusting the pH in the range of 5 to 8 by treating with alkaline metal carbonate solution to remove dark orange color.

e. purification of the product by re-crystallization from ethyl acetate and/or aqueous methanol

The trialkyl borate is preferably trimethyl borate or tri(n-butyl)borate. The trialkyl borate used in the reaction serve as an aprotic solvent, as a scavenger of water which is generated during the reaction and as borate complex forming reagent with acetyl acetone to form the desired product.

The reaction mixture is heated in the range of 40° C to 100° C to reflux, preferably, in the range of 55-65° C for 8 h. The dark orange color of the reaction mixture is removed by the treatment with alkaline metal carbonate solution to a pH between 5 and 8, preferably 6 to 7.

The alkaline metal carbonate solution used is lithium carbonate, sodium carbonate or potassium carbonate solution, preferably, potassium carbonate solution.

Finally the product is purified by re-crystallization from ethyl acetate and/or aqueous methanol. The curcuminoids obtained by this process is in good yield with high purity.

The following examples are for illustrative purpose of the invention but not limitative to the scope thereof.

Example-1: Preparation of curcuminoids

To a mixture of trimethylborate (1750.0 mL, 15.60 mol), acetylacetone (210.0 mL, 2.05 mol), in a 10000 mL RB flask at room temperature, was added vanillin (425.0 g, 2.80 mol),p-hydroxybenzaldehyde (75.0 g, 0.62 mol) and n-butylamine (50.5 mL, 0.51 mol). The reaction mixture was heated to reflux and maintained for 7.0 h and cooled to 40oC. Aqueous acetic acid (50%, 1000 mL) was added to the reaction mixture and refluxed for 2.5 h. The reaction mixture was cooled to room temperature and stirred for another 2.0 h and the dark red solid obtained was filtered, washed with water (200 mL) and then the solid was suspended in a mixture of ethyl acetate (2000 mL) and water (2000 mL), under stirring. Adjusted the pH of the solution to 8.0 with aqueous potassium carbonate solution (50%, prepared by dissolving 250 g of potassium carbonate in 250 mL of water) and the solid remained was filtered , the filtrate was kept aside. The solid was extracted with hot ethyl acetate (2500 mL) and filtered again and the solid was washed with additional 500 mL of ethyl acetate. The combined filtrate was taken in a separatory funnel and the water layer was discarded. The organic layer was extracted with water (1 x 500 mL) again and the organic layer was separated and concentrated up to 10 % and kept the solution for crystallization overnight, The crystallized solids were filtered and washed with aqueous methanol (70 %, 400 mL) and dried the solids for 4.0 h at 80-90 C to get the yellowish-orange coloured curcuminoids (yield: 270-320 g) HPLC analysis of curcuminoids: CurcuminI : 75.0-85.0% CurcuminII : 15.0-25.0%
CurcuminIII : 0.1-3.0%

Example-2: Preparation of curcuminoids

To a mixture of trimethylborate (500.0 mL, 4.48 mol ), acetylacetone (105.0 mL, 1.02 mol ), in a 5000 mL RB flask at room temperature, was added vanillin (212.5 g, 1.40 mol), p-hydroxybenzaldehyde (37.5g, 0.31mol) and n- butylamine (25.5 mL, 0.26 mol). The reaction mixture was heated to reflux and maintained for 8.0 h and cooled to 40C. Aqueous acetic acid (50%, 500 mL) was added to the reaction mixture and refluxed for 2.5 h. The reaction mixture was concentrated under vaccum to remove methanol, water and acetic acid to a syrapy mass. The residue was cooled to 40C and added a mixture of ethyl acetate (2500 mL) and water (1250 mL), under stirring. Adjusted the pH of the solution to 7.5-8.0 with aqueous potassium carbonate solution (50%, prepared by dissolving 220.0g of potassium carbonate in 220.0 mL of water) and the solid remained was filtered and washed with further quantity (250 mL) of ethyl acetate. The filtrate was taken in a separatory funnel and washed with water (500 mL) and the organic layer was separated and concentrated up to 15-20 % and kept the solution for crystallization overnight at 20 C, The crystallized solids were filtered and washed with aqueous methanol (70%, 500 mL) and dried the solids for 4.0 h at 70-80C to get the yellowish-orange coloured curcuminoids (yield: 164-180 g)
HPLC analysis of curcuminoids: CurcuminI : 75.0-85.0%
CurcuminII : 15.0-25.0%
Curcuminlll : 0.1-3.0%

Example-3: Preparation of curcuminoids

To a mixture of tributylborate (155.0 mL, 0.58 mol), acetylacetone (10.1 mL, 0.1 mol), in a 500 mL RB flask at room temperature, was added vanillin (20.5 g, 0.14 mol),p-hydroxybenzaldehyde (3.6 g, 0.03 mol), and n-butylamine (2.45 mL, 0.025 mol). The reaction mixture was heated to 60 C and maintained for 7.0 h and cooled to 40 C.

Aqueous acetic acid (50%, 50 mL) was added to the reaction mixture and refluxed for 2.5 h. The reaction mixture was cooled to room temperature and stirred for another 2.0 h and the solid obtained was filtered, washed with water (50 mL) and then the solid was suspended in a mixture of ethyl acetate (100 mL) and water (100 mL). Adjusted the pH of the solution to 8 with aqueous potassium carbonate solution (50%, prepared by dissolving 12 g of potassium carbonate in 12 mL of water) and the solid remained was filtered , the filtrate was kept aside. The solid was extracted with hot ethyl acetate (150 mL) and filtered again and the solid was washed with additional 50 mL of ethyl acetate.

The combined filtrate was taken in a separatory funnel and the water layer was discarded. The organic layer was extracted twice with water (2 x 25 mL) and the organic layer was separated and concentrated up to 10 % and kept the solution for crystallization overnight,

The crystallized solids were filtered and washed with aqueous methanol (70%, 50
mL) and dried the solids for 4.0 h at 85-95 C to get the yellowish-orange coloured curcuminoids (yield: 9.0-11.0 g)

HPLC analysis of curcuminoids : Curcumin I : 75.0 - 85.0%)
CurcuminII : 15.0-25.0%
Curcumin III : 0.1-3.0%

Example-4: Preparation of curcumin I

To a mixture of tributylborate (155.0 mL, 0.58 mol) and acetyl acetone (10.1 mL, 0.10 mol), in a 1000 mL RB flask at 40-45°C, was added successively vanillin (25.0 g, 0.16 mol) and n-butylamine (2.45 mL, 0.025 mol). The reaction mixture was heated at 60 C for 8 h and cooled to room temperature. Aqueous acetic acid (10%, 250 mL) was added and heated to reflux and maintained for 1 h and then cooled to 20 C. The solid separated was filtered, washed with water. The crude product was re-crystallized from aqueous acetone (50%, 100 mL) by heating the solution at 50-55° C for 1 h. After this period, the solution was cooled to room temperature and the yellowish-orange solid formed was filtered, washed with 50% aqueous acetone (50 mL) and the product was dried under vacuum, yield: 60-75 %, purity by HPLC 99.1%.

Example-5: Preparation of curcumin I

To a mixture of trimethylborate (64.1mL, 0.58 mol) and acetyl acetone (10.1 mL, 0.10 mol), in a 1000 mL RB flask at 40-45°C, was added successively vanillin (25.0 g, 0.16 mol) and n-butylamine (2.45 mL, 0.025 mol). The reaction mixture was heated at 60 C for 8 h and cooled to room temperature. Aqueous acetic acid (10%, 250 mL) was added and heated to reflux and maintained for 1 h and then cooled to 20°C. The solid separated was filtered, washed with water. The crude product was re-crystallized from aqueous acetone (50%, 100 mL) by heating the solution at 50-55C for 1 h. After this period, the solution was cooled to room temperature and the yellowish-orange solid formed was filtered, washed with 50% aqueous acetone (50 mL) and the product was dried under vacuum, yield: 30-50 %, purity by HPLC 99.8 %.

Example-6: Preparation of curcuminoids

To a mixture of trimethylborate (9.0 L, 80.67 mol), acetyl acetone (1.9 L, 18.62 mol ), in a 100 L glass reactor, at room temperature, was added vanillin (3.75 Kg, 24.37 mol),p-hydroxy benzaldehyde (0.75 Kg, 6.15 mol) and n-butylamine (0.45 L, 4.56 mol). The reaction mixture was heated to reflux and maintained for 8.0 h and cooled to 40°C.

Aqueous acetic acid (50%, 9.0 L) was added to the reaction mixture and refluxed for 2.5 h. The reaction mixture was concentrated under vacuum to remove methanol, water and acetic acid to a syrupy mass. The residue was cooled to 40C and added a mixture of ethyl acetate (45 L) and water (22.5 L), under stirring. Adjusted the pH of the solution to 7.5-8.0 with aqueous potassium carbonate solution (50%, prepared by dissolving 3.0 Kg of potassium carbonate in 3.0 L of water) and the solid remained was filtered and washed with further quantity (10.0 L) of ethyl acetate. The filtrate was separated and organic layer was washed with water (10.0 L) and the organic layer was concentrated up to 15-20% and kept the solution for crystallization overnight at 20°C, The crystallized solids were filtered and washed with aqueous methanol (70 %, 3.0 L) and dried the solids for 4.0 h at 70-80°C to get the yellowish-orange colored curcumirioids (yield: 2.1-2.5 Kg).

The residual solvent of ethyl acetate was reduced to below 100 ppm when treated with two volumes of aqueous acetic acid.

HPLC analysis of curcuminoids: Curcumin I : 75.0 - 85.0%
CurcuminII : 15.0-25.0%
Curcumin III : 0.1-3.0%

Example-7: Preparation of curcuminoids

To a mixture of trimethylborate (220 L, 1971.5 mol), acetyl acetone (45.4 Kg, 454.0 mol ), in a 3.0 KL SS reactor at room temperature, was added vanillin (92.0 Kg, 605.2 mol), p- hydroxybenzaldehyde (18.4 Kg, 150.8 mol) and n-butylamine (8.4 Kg, 115.0 mol). The reaction mixture was heated to reflux and maintained for 8.0 h and cooled to 40° C. Aqueous acetic acid (50%), 220 L) was added to the reaction mixture and refluxed for 2.5 h. The reaction mixture was concentrated under vacuum to remove methanol, water and acetic acid to a syrupy mass. The residue was cooled to 40°C and added a mixture of ethyl acetate (1100 L) and water (550 L), under stirring. Adjusted the pH of the solution to 6.5-7.0 with aqueous potassium carbonate solution (50%), prepared by dissolving 106 Kg of potassium carbonate in 106 L of water) and the solid remained was filtered and washed with further quantity (110 L) of ethyl acetate. The filtrate was separated and organic layer was washed with water (110 L) and the organic layer was concentrated up to 15-20% and kept the solution for 12 h to crystallize product at 18-20C, The crystallized solids were filtered and washed with aqueous methanol (70%, 100 L) and dried for 4.0 h at 70-80°C to get the yellowish-orange colored curcuminoids (yield: 60.0 - 65.0 Kg). The residual solvent of ethyl acetate was reduced to below 100 ppm when treated with two volumes aqueous acetic acid.

HPLC analysis of curcuminoids: Curcumin I : 75.0 — 85.0%
CurcuminII : 15.0-25.0%
Curcumin III : 0.1-3.0%

WE CLAIM:

1. A process for the preparation of curcuminoids mixture which comprises the following steps :

a. reacting the mixture of vanillin and p-hydroxybenzaldehyde with acetyl acetone in trialkylborate in presence of n-butyl amine without any other organic solvent;

b. heating the reaction mixture for 5-10 h;

c. treating the reaction mixture with aqueous acetic acid;

d. adjusting the pH in the range of 5 to 8 by treating with alkaline metal carbonate solution to remove dark orange color;

e. purification of the product by re-crystallization from ethyl acetate and/or aqueous methanol

2. The process as claimed in claim 1, wherein the trialkyl borate is preferably trimethyl borate or tri(n-butyl)borate.

3. The process as claimed in claim 1, wherein in step (b), the reaction mixture is heated in the range of 40 C to 100 C for 8 h.

4. The process as claimed in claim 1, wherein in step (b), the reaction mixture is heated in the range of 55°C to 65° C for 8 h.

5. The process as claimed in claim 1, wherein the dark orange color of the reaction mixture is removed by the treatment with alkaline metal carbonate solution to a pH between 5 and 8, preferably 6 to 7.

6. The process as claimed in claim 4, wherein the alkaline metal carbonate solution is lithium carbonate, sodium carbonate or potassium carbonate solution, preferably, potassium carbonate solution.

7. The process as claimed in claim 1, wherein the organic solvent residues of the product is reduced by treating with aqueous acetic acid followed by vacuum drying.