FIELD OF THE INVENTION

The present invention relates to a process for the preparation of metal nicotinates and complexes thereof.

BACKGROUND AND PRIOR ART

Chromium is associated with a low-molecular weight organic complex termed glucose tolerance factor (GTF) that acts with insulin in promoting normal glucose utilization. Brewer's yeast, which is rich in GTF, has been shown to improve glucose tolerance, lower serum cholesterol and triglycerides in some elderly subjects, and to reduce insulin requirements in some diabetics. Glucose tolerance is usually impaired in protein-calorie malnutrition and some cases have shown a dramatic response to trivalent chromium. Purified extract from Brewer's yeast containing chromium, nicotinic acid, glycine, glutamic acid and cystine has been shown to have GTF activity (Toepfer, et al., "Chromium Foods in Relation to Biological Activity", J. Agric. Food Chem, Vol 21, p. 69, 1973). A synthesis procedure to prepare complexes with a similar composition having GTF activity has also been reported (Toepfer, et al, "Preparation of Chromium-Containing Material of Glucose Tolerance Factor Activity from Brewer's Yeast Extracts and by Synthesis", J. Agric Food Chem., Vol 25, p. 162, 1977).

US4923855 and US5194615 describe the synthesis of metal nicotinates, particularly, Chromium compounds, possessing GTF (Glucose Tolerance Factor) activity, starting from Nicotinic acid, where the sodium salt of nicotinic acid is first produced by reacting nicotinic acid with sodium hydroxide and subsequently adding a trivalent chromium salt solution to it.

US5536838 discloses a novel synthesis of a chromium amino acid nicotinate complex which has glucose tolerance factor activity in which nicotinic acid is dissolved in an aqueous solvent, followed by glycine, glutamic acid and cystine and chromium chloride.

After completion of the reaction, the pH is adjusted with a base and the reaction mixture is freeze dried.

US7022853 describes a single pot synthesis of metal nicotinate compounds starting from beta-picoline, in which, beta-picoline is oxidized using a mixture of sulphuric acid and nitric acid and neutralized. Then to the neutralized mass, a solution of trivalent chromium salt is added to produce chromium nicotinates.

Alternatively, US4242257 discloses a material exhibiting GTF activity, which is obtained by complexing cobalt with Nicotinamide in the ratio of 1:2, followed by acidification of the complex and reduction with glutathione.

SUMMARY OF THE INVENTION

The present invention relates to a process for preparing metal nicotinate complex, said process comprising: mixing an alkali or an alkaline-earth metal base or salt with an aqueous nicotinamide solution; wherein an alkali or an alkaline-earth metal base or salt and aqueous nicotinamide solution are mixed in a ratio of 1:1; refluxing the above mixture for 6-12 hours; adjusting pH to 6.5-8.0 to obtain a solution of metal salt of nicotinic acid; co-adding the solution of the metal salt of nicotinic acid and a solution of a transition metal salt in the molar ratio range of 3:1 to 2:1, to a reactor containing a solvent selected from water, a solution of a metal salt of an amino acid or an organic acid, at 60-80°C for a period of 1 to 2 hours; and stirring the solution at 60-70°C for 1 hour to obtain metal nicotinate complex.

BRIEF DESCRIPTION OF THE DRAWING

A full and enabling disclosure of the method of present invention, including the best mode thereof, to one of ordinary skill in the art, is set forth more particularly in the remainder of the specification, including reference to the accompanying figure, in which: Figure 1 shows the schematic representation of the process for the preparation of meta nicotinate complex. Figure 2 shows the schematic representation of the process for the preparation of metal nicotinate amino acid or organic acid complex. Figure 3 Shows the FTIR spectra of the chromium tri nicotinate complex which contains the peaks, between 4000 to 600 cm"1. And particular peaks at 3412, 2364, 1620, 1559, 1411, 1378, 1162, 1093, 1056, 842, 758, 702, 591 and 520 cm"1 characterized the typical chromium-nicotinate complex,

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for preparing metal nicotinate complex, said process comprising: mixing an alkali or an alkaline-earth metal base or salt with an aqueous nicotinamide solution; wherein an alkali or an alkaline-earth metal base or salt and aqueous nicotinamide solution are mixed; refluxing the above mixture for 6-12 hours; adjusting pH to 6.5-8.0 to obtain a solution of metal salt of nicotinic acid; co-adding the solution of the metal salt of nicotinic acid and a solution of a transition metal salt to a reactor containing a solvent selected from water, a solution of a metal salt of an amino acid or an organic acid, at 60-80°C for a period of 1 to 2 hours; and stirring the solution at 60-70°C for 1 hour to obtain metal nicotinate complex.

An embodiment of the present invention is a process for preparing metal nicotinate complex, said process comprising: mixing an alkali or an alkaline-earth metal base or salt with an aqueous nicotinamide solution; wherein an alkali or an alkaline-earth metal base or salt and aqueous nicotinamide solution are mixed in a ratio of 1:1; refluxing the above mixture for 6-12 hours; adjusting pH to 6.5-8.0 to obtain a solution of metal salt of nicotinic acid; co-adding the solution of the metal salt of nicotinic acid and a solution of a transition metal salt in the molar ratio range of 3:1 to 2:1, to a reactor containing a solvent selected from water, a solution of a metal salt of an amino acid or an organic acid, at 60-80°C for a period of 1 to 2 hours; and stirring the solution at 60-70°C for 1 hour to obtain metal nicotinate complex.

An embodiment of the present invention is to provide a process for preparing metal nicotinate complex which further comprises filtering the solution of the metal nicotinate complex; and drying the metal nicotinate complex to obtain pure metal nicotinate complex.

Yet another embodiment of the present invention is to provide a process for preparing metal nicotinamide complex wherein the ratio of solution of the metal salt of nicotinic acid to solution of transition metal salt to solvent is in the range of 3: 1 ; 6 to 2 : 1: 2.

Another embodiment of the present invention is to provide a process for preparing metal nicotinate complex which is carried out in a single reactor. In this process, nicotinamide is first hydrolyzed by using an alkali or alkaline earth metal base or salt, by giving sufficient heat and time to the reaction system for complete hydrolysis. The ammonia gas liberated during the hydrolysis is absorbed in a scrubber containing chilled water and the aqueous ammonia solution obtained is used for other application.

Yet another embodiment of the present invention is to provide a process for preparing metal nicotinate complex, wherein the alkali or an alkaline-earth metal base or salt is added as an aqueous solution.

Still another embodiment of the present invention is to provide a process for preparing metal nicotinate complex where, the alkali or alkaline earth metal is selected from its hydroxide, carbonate and bicarbonate.

Yet another embodiment of the present invention is to provide a process for preparing metal nicotinate complex, wherein the alkali or alkaline earth metal hydroxide is selected from sodium hydroxide, potassium hydroxide, magnesium hydroxide and calcium hydroxide.

Further embodiment of the present invention is to provide a process for preparing metal nicotinate complex, wherein the carbonate or bicarbonate is selected from sodium carbonate or bicarbonate, potassium carbonate or bicarbonate, magnesium carbonate or bicarbonate and calcium carbonate or bicarbonate.

The completion of hydrolysis is indicated by the absence of ammonia in the reaction mass. After the completion of hydrolysis the solution containing alkali or alkaline earth metal salt of nicotinic acid is co-added along with a solution of transition metal salt, in to a reactor containing a solvent selected from water, a solution of metal salt of amino acid or an organic acid, at an appropriate addition rate and at an elevated temperature, to form colour metal nicotinate-amino acid or organic acid complexes at faster rate and with improved yield and purity.

One embodiment of the present invention is to provide a process for preparing metal nicotinate complex, wherein the transition metal salt is selected from chloride, oxide, carbonate and sulphate salts of iron, cobalt, nickel, manganese, copper, chromium and zinc.

Another embodiment of the present invention is to provide a process for preparing metal nicotinate complex, wherein the amino acid is selected from alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamine, glutamic acid, glycine, histidine, hydroxyproline, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, praline, serine, threonine, tryptophan, tyrosine, and valine or combination thereof.

Further embodiment of the present invention is to provide a process for preparing metal nicotinate complex, wherein the organic acid is selected from acetic acid, benzoic acid, butyric acid, fumaric acid, lactic acid, levulinic acid, mucic acid, succinic acid, tartaric acid, citric acid and oxalic acid or a combination thereof.

The metal to nicotinic acid ratio in the complex usually ranges from 1:1 to 1:3, where as the ratio of metal to amino acid in the complex, usually ranges from 1:1 to 1:4 and the ratio of metal to organic acid in the complex, usually ranges from 1:1 to 1:4.

EXAMPLES

The following examples are given by way of illustration of the present invention and should not be construed to limit the scope of present disclosure. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are intended to provide further explanation of the claimed subject matter.

Example-1

Preparation of chromium trinicotinate complex 50.0g (0.4093 moles) of nicotinamide is dissolved in 200ml of de-ionized water and added to it a solution of 25.0g(0.625 moles) of sodium hydroxide in 100ml water. The mixture is refluxed for 6 hours for complete hydrolysis, cooled to room temperature and adjusted the pH of the solution to 6.5 - 8.0, preferably, 7.0 -7.5 with concentrated hydrochloric acid (Solution-A). 36.5g (0.1369 moles) of chromium chloride hexahydrate is dissolved in 200ml of de-ionised water to obtain a solution of chromium chloride (Solution-B).

Solution-A and solution-B are simultaneously added (co-addition), under stirring, at 60-70°C at an appropriate addition rate, into a reaction flask containing 100ml of de-ionised water, during a period of 1 hour. The green colour of the solution-B disappears and a purple colour complex formation is observed. After the addition is over, the reaction mass is stirred at 60-70°C for another hour. Then the reaction mixture is cooled to room temperature and filtered, washed with excess of water. The purple gray, wet solid is then dried at 90-100°C till a constant weight about 48.Og of chromium trinicotinate complex with 9.2% estimated chromium content is obtained. Refer to Figure 1

Example - 2

Preparation of Chromium dinicotinate glycinate 50g (0.4093 moles) of nicotinamide is dissolved in 200 ml of de-ionised water and is placed in a RB flask fitted with mechanical stirrer, thermo well and reflux condenser. A solution of 16.375g (0.4093 moles) of sodium hydroxide in 100ml of de-ionised water is added to the nicotinamide solution. The contents of the flask are refluxed for 10-12 hours for complete hydrolysis, (SOLUTION -A).

In another beaker a solution is prepared by dissolving 54.53g (0.2047 moles) of chromium chloride hexahydrate in 200ml of de-ionized water, (SOLUTION-B).

In another reaction flask, fitted with thermowell and a mechanical stirrer, a solution of amino acid is prepared by dissolving 15.35g (0.2047moles) of glycine and 8.188g (0.2047moles) of sodium hydroxide in 100ml of de-ionised water, (SOLUTION-C).

Then, the solution-A & Solution-B are simultaneously added to the reaction flask containing solution-C (co-addition), under stirring, at an appropriate addition rate at a temperature of about 60-80°C, over a period of 2 hours. During the addition, the green colour of chromium chloride disappears immediately and a purple colour complex formation is observed. After addition of solutions-A and B to solution-C, the reaction mass is stirred at 60 -70°C for another 1 hour to obtain a reaction mass of Chromium dinicotinate glycinate. Then the reaction mass is cooled, filtered and dried at 80-90°C to get 46.0 g of light purple crystalline powder of Chromium dinicotinate glycinate (chromium content = 12.83%). Refer to Figure 2

Example - 3

Preparation of Chromium dinicotinate Lactate

100g (0.82 moles) of nicotinamide is dissolved in 400 ml of de-ionised water and is placed in a RB flask fitted with a mechanical stirrer, a thermowell and a reflux condenser. A solution of 32.8 g (0.82 moles) of sodium hydroxide in 200ml of de-ionised water is added to the nicotinamide solution. The contents of the flask are refluxed for 10 - 12 hours for complete hydrolysis, (SOLUTION -A).

In an another beaker, a solution is prepared by dissolving 109.0g (0.4094 moles) of chromium chloride hexahydrate in 400ml of de-ionized water, (SOLUTION-B).

In an another reaction flask, fitted with a thermowell and a mechanical stirrer, a solution of alkali salt of organic acid is prepared by dissolving 41.0 g (0.4094 moles) of lactic acid (of 90% purity) and 16.4 g (0.4094 moles) sodium hydroxide in 200ml of de-ionised water, (SOLUTION-C).

Then, the solution-A & Solution-B are simultaneously added to the reaction flask containing solution-C (co-addition), under stirring, (at an appropriate addition rate, so that there is no large molar excess of any of the solutions A & B in the reaction vessel) at a temperature of about 60-80°C, over a period of 2 hours. During the addition, the green colour of chromium chloride disappears immediately and a purple to purple gray colour complex formation is observed. After the addition of solutions-A and B to solution-C, the reaction mass is stirred at 60-70°C for another 1 hour to obtain a reaction mass of Chromium dinicotinate Lactate. Then the reaction mass is cooled, filtered and dried at 80 - 90°C to get 51.0 g of light purple to purple gray crystalline powder of Chromium dinicotinate Lactate (chromium content = 13.45%). Refer to Figure 2

Example - 4

Preparation of chromium trinicotinate complex

Into a 750 L glass lined reactor, charged 300 L of water and under stirring, charged 50 kg of nicotinamide and continue agitation for another 20 to 30 minutes. Once the dissolution is complete, charge 25 kg of sodium hydroxide in to the reactor, under agitation. The temperature of the reaction mass rises to 40 to 50°C on its own accord.

Then the reaction mass is refluxed for 10 to 12 hours for complete hydrolysis. The
completion of hydrolysis is indicated by the cessation of ammonia gas evolution. The
solution is cooled to room temperature and the pH of the solution is adjusted to 6.5 - 8.0,
preferably, 7.0 -7.5 with concentrated hydrochloric acid (Solution I).

Dissolved 36.5 kg of chromium chloride hexahydrate in 200 L of water, in a separate vessel (Solution-II).

The solution-I and solution -II were simultaneously added ( co-addition), under stirring, at 60 - 70°C at an appropriate addition rate, into a reaction flask containing 100 L of water, during a period of 2 hours. The green color of the solution-II disappears and a purple color complex formation is observed. After the addition is over, the reaction mass is stirred at 60 - 70°C for another hour. Then the reaction mixture is cooled to room temperature and filtered, washed with excess of water. The purple gray, wet solid is then dried at 90 -100°C till constant weight. About 49.5 kg of chromium trinicotinate complex was obtained as dried product with moisture content less than 2.0%. The chromium content was analyzed by Atomic Absorption Spectroscopy and the content was found to be 12.3%. Refer to Figure 1

The product obtained is subjected to FTIR and NMR analysis and the findings are apprehended below.

FTIR spectra: The FTIR spectra (figure 3) of the chromium tri nicotinate sample were found to contain the following peaks, between 4000 to 600 cm-1. 3412, 2364, 1620, 1559, 1411, 1378, 1162, 1093, 1056, 842, 758, 702, 591 & 520 cm-1, depicting a typical chromium - nicotinate complex.

NMR spectra: Proton NMR of the chromium tri nicotinate was taken in D20. But no signals were obtained, since the solubility of the chromium nicotinate in D20 is very poor.

Advantages

1. The present invention provides a simple process for the preparation of metal nicotinate or its organic or amino acid complexes.

2. The present invention does not employ corrosive reagents such as sulphuric acid or nitric acid in the preparation of metal nicotinate or its organic or amino acid complexes.

claim:

1. A process of preparing metal nicotinate complex, said process comprising:

i. mixing an alkali or an alkaline-earth metal base or salt with an aqueous nicotinamide solution; wherein said alkali or alkaline-earth metal base or salt and the aqueous nicotinamide solution are mixed in a ratio of 1; 1;

ii. refluxing the above mixture for 6-12 hours;

iii. adjusting pH to 6.5-8.0 to obtain a solution of metal salt of nicotinic acid;

iv. co-adding the solution of the metal salt of nicotinic acid and a solution of a transition metal salt in the molar ratio range of 3:1 to 2:1, to a reactor containing a solvent selected from water, a solution of a metal salt of an amino acid or an organic acid, at 60-80°C for a period of 1 to 2 hours; and

v. stirring the solution at 60-70°C for 1 hour to obtain metal nicotinate complex.

2. The process as claimed in any of the claim 1 further comprises:

i. filtering the solution of the metal nicotinate complex; and

ii. drying the metal nicotinate complex to obtain pure metal nicotinate complex.

3. The process as claimed in claim 1, wherein the ratio of the solution of the metal salt of nicotinic acid, the solution of the transition metal salt and solvent is in the range of 3: 1 : 6 to 2 : 1: 2.

4. The process as claimed in claim 1, wherein the alkali or an alkaline-earth metal base or salt is added as an aqueous solution.

5. The process as claimed in claim 1, wherein the alkali or alkaline earth metal is selected from its hydroxide, carbonate and bicarbonate.

6. The process as claimed in claim 5, wherein the alkali or alkaline earth metal hydroxide is selected from sodium hydroxide and potassium hydroxide.

7. The process as claimed in claim 5, wherein the alkali or alkaline earth metal carbonate or bicarbonate is selected from sodium carbonate or bicarbonate and potassium carbonate or bicarbonate.

8. The process as claimed in claim 1 wherein the transition metal salt is selected from chloride, oxide, carbonate and sulphate salts of iron, cobalt, nickel, manganese, copper, chromium and zinc.

9. The process as claimed in claim 1, wherein the amino acid is selected from alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamine, glutamic acid, glycine, histidine, hydroxyproline, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, praline, serine, threonine, tryptophan, tyrosine, and valine or combination thereof.

10. The process as claimed in claim 1, wherein the organic acid is selected from
acetic acid, benzoic acid, butyric acid, fumaric acid, lactic acid, levulinic acid, mucic acid, succinic acid, tartaric acid, citric acid and oxalic acid or combination thereof.