FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION
"AN EFFICIENT PROCESS FOR THE MANUFACTURE OF FERROUS
OROTATE"
2. APPLICANT (S)
(a) NAME: WANBURY LIMITED
(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1956
(c) ADDRESS: B- Wing, 10th Floor, BSEL Tech Park, Sector 30 A,
Plot no.39/5 & 39/5A, Opp. Vashi Railway Station, Navi Mumbai- 400 703, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of the Invention:
The present invention relates to a salt containing iron and an anion moiety derived from orotic acid. More particularly, the invention relates to a process for preparation of ferrous orotate in high yield and purity, wherein orotic acid is reacted with various iron salts in an aqueous medium with or without organic solvents.
Background of invention:
Orotic acid, a natural substance also known as pyrimidine carboxylic acid is historically known as Vitamin B13.0rotic acid plays number of important functions in the body such as acting as an intermediate in the pyrimidine biosynthesis, which is required for DNA and RNA synthesis, neutralizing excess ribose and ensuring that adequate levels of beta-alanine, carnosine and anserine are present.
Orotates are the mineral salts of orotic acid. It is believed that minerals and vitamins in orotate form act as superior transporters throughout the body. When a mineral is in an orotate form, it can pass through cell membranes easily without breaking apart so it can get to where it's needed most.
Dr.Hans Nieper, a well known innovator of Active Mineral Transport, indicated the use of specific amino acid chelators to deliver minerals to specific sites in the body. He identified aspartate and orotate as active mineral transport chelators, providing unprecedented rates of mineral absorption and yielding unique therapeutic benefits. The theory called "fixed pore mechanism" suggests that a carrier molecule, in this case Orotic Acid (B13), is attached to the compound being transported. This research has lead to the creation of mineral chelates called orotic acid chelates, or orotates which offers a 20 fold increase in utilizing minerals. The essential minerals which can form chelate with orotic acid include calcium, magnesium, chromium, cobalt, copper, iodine, iron, manganese, molybdenum, phosphorus, potassium, selenium, silicon, sodium, sulfur, and zinc. Of these calcium orotate, lithium orotate, magnesium orotate, potassium orotate, and zinc orotate are currently available as nutritional supplements in some countries, including Germany and the United States.

Calcium orotate was used by Nieper to relieve bone loss and pain due to inflammation or osteoporosis, psoriasis, high blood, pressure, angina pectoris, multiple sclerosis, encephalitis, retinitis and hepatitis.
Supplement of magnesium salts of orotic acid have been shown to successfully increase the athletes tolerance to extended periods of physical exertion (Rosenfeldt FL. Metabolic supplementation with orotic acid and magnesium orotate. Cardiovasc Drugs Ther. 1998: 12 ( Suppl 2) : 147 ). The increased tolerance to exercise after the administration of orotic acid has been attributed to the orotic acid's ability to improve the energy status of the cells ( Classen HG, Magnesium orotate-experimerital and clinical evidence.Rom J Inter Med.2004, 42, 491), by stimulating the synthesis of glycogen and adenosine triphosphate (ATP).
On similar lines, ferrous orotate can also be employed as elemental iron transporter, which can exhibit highest and quickest absorption through the intestine and further highest delivery of iron to the bone marrow. This will further lead to highest and quickest hemoglobin absorption into the body .Moreover, the ferrous orotate can also be employed to fortify foods for the effective treatment of iron-deficiency anemia.
Orotic acid derivatives and its processes for the preparation have been described in the following patents.
US 4400508 describe alkyl, allyl, cyclohexyl and benzyl derivatives of orotic acid useful as either an agricultural chemical or an intermediate thereof.
US 2004/0033981 relates to pyrimidine nucleotide precursors including acyl derivatives of cytidine, uridine and orotate. The said patent also discloses pharmaceutically acceptable salts of orotic acid, wherein, the cation is selected from sodium, potassium or a basic amino acid such as arginine or lysine. Alcohol based esters of orotic acid are also disclosed.

GB1263206 relates to complexes and salts of magnesium with orotic acid and amino acid (preferably glycine), wherein, to the aqueous solution of orotic acid and an amino acid is added magnesium in small portions.
There is very little information on the preparation of ferrous salts of orotic acid in the literature. In view of the vital role of ferrous orotate as a nutritional supplement in a wide range of pharmaceutical compositions; there is a need for preparing ferrous salts of orotic acid in high yield and purity using industrially viable reagents and optimum reaction conditions. This forms the object of the present invention.
Summary of the invention:
The present invention relates to a commercially viable process for production of ferrous orotate in high yield and purity.
In an aspect, Ferrous orotate of formula I is prepared by(a) reacting orotic acid of formula II in a solvent system with iron salts and (b) purification of crude ferrous orotate from water at 20-50°C.
The reaction of step (a) is carried out at a temperature in the range of 30-120°C.
The details of one or more embodiments of the inventions are set forth in the description below,
Detailed description of the invention:
The. subject of the present invention relates to salts of iron with orotic acid and to a commercially viable process for the production thereof.
Iron is essential for the synthesis of hemoglobin and the maintenance of oxygen transport as well as for the function and formation of other physiologically important heme and non-heme compounds. Iron deficiency anemia, a blood disorder, is commonly treated with the oral administration of Fe++ salts, such as ferrous sulfate. However, a traditional iron preparation in Fe++ ionic state increases the chances of gastric irritation. The absorption of iron from these conventional salts is passive and uncontrolled, increases the chances of iron overload which can cause toxicity to the body.

In contrast to the use of conventional iron salts, absorption of iron can be enhanced by forming complexes with a carrier molecule which readily enter the epithelial cells lining the gastrointestinal tract. These artificial transporters can be selected from 2-ammoethylphosphonic acid (AEP), aspartic acid, and orotic acid. They are "artificial" only in the sense that in biological organisms they ordinarily play roles other than that of mineral transporters.
Accordingly, the present invention relates to Ferrous orotate of formula I;

Ferrous orotate of formula 1 can be used as safe elemental iron transporter for the effective treatment of iron-deficiency anemia. It can exhibit highest and quickest absorption through the intestine and further highest delivery of iron to the bone marrow. The salt is very slightly soluble in water and almost insoluble in ethanol and methanol.
In a preferred embodiment, the instant invention provides a commercially viable process for the manufacture and purification of Ferrous orotate which comprises of the following steps:
(a) Reacting orotic acid of formula II under agitation with iron salts in a solvent system at a temperature in the range of 30-120° C; and
(b) Isolating and purifying crude Ferrous orotate obtained in step (a) from water at 20-50° C to obtain pure ferrous orotate free of ferrous and ferric ions.
The process of the present invention is disclosed in the scheme below:


Formula II Formula I
According to the preferred embodiment of the above invention, the iron salts are selected from ferrous sulphate, ferrous chloride, ferrous carbonate, ferrous hydroxide, ferrous acetate and any other salts thereof.
The mole ratio of orotic acid of formula II to the iron salts is in the range of 1:6, preferably in the range of 1:3 and most preferably in the range of 1:1.
The solvent system employed in step (a) is selected from water, aliphatic alcohols selected from methanol, ethanol, IPA etc, cyclic aliphatic ethers such as tetrahydrofuran, dioxane etc, aliphatic sulphoxides such as dimethyl sulphoxide, aliphatic ketones like acetone, methyl isobutyl ketone, methyl ethyl ketone etc, N-substituted aliphatic amides like N, N-dimethyl formamide.
The solvent used in step (a) may be used either alone or as a mixture of solvents. The volume of the solvent for the reaction is selected in the range from 1 to 50 times, preferably in the range from 5 to 40 times and most preferably in the range from 10 to 30 times.
The details of the process of the present invention are further illustrated in the following examples. However these examples are mere illustrative and should not construe the scope of the invention. Any variation obvious to the person skilled in the art is being covered in the ambit of the protection.
Example 1
125 grams of orotic acid was added with constant stirring to 3.0 It, water and heated to 50° -60°C. To this reaction mixture, aqueous solution of 400 grams ferrous sulphate was

gradually added over a period of lhr. After complete addition, the reaction mixture was maintained for 12 hrs. Then the reaction mixture was gradually cooled to RT. Precipitated product was filtered and washed with water. Crude ferrous orotate obtained was further purified by treating with 1 litre water at 45°C. Reaction mixture was further cooled to RT. Product precipitated was filtered and washed with sufficient water to yield 123 gm dry ferrous orotate with purity > 99 %.
Example 2
125 grams of orotic acid was added with constant stirring to a mixture of 500 ml methanol and 2.5 lt.water and heated to 50°-60°C.To this reaction mixture, aqueous solution of 262.9 grams ferrous sulphate was gradually added over period of lhr. After complete addition, the reaction mixture was maintained for a period of 10 hr. Then the reaction mixture was gradually cooled to RT. Filtered the product and washed with DM water. Crude ferrous orotate obtained was purified by treating with 1 It. water at 45° C. Reaction was maintained for lhr and cooled to RT. Reaction mixture was filtered and washed with sufficient water to yield 119 gm ferrous orotate with purity > 99 %.
Example 3
125 grams of orotic acid was added with constant stirring to mixture of 500 ml IPA and 2.5 it. water and heated to 50 ° C to 60°C. To this reaction mixture aqueous solution of 262.9 grams ferrous sulphate was added over l hr. After complete addition maintained the reaction mixture for 10 hrs. The reaction mixture was then gradually cooled to RT. Filtered the product and washed with water. Crude ferrous orotate obtained was purified by treating with 1 It. water at 45° C. Reaction was maintained for lhr and further cooled to RT. Reaction mixture was then filtered and washed with sufficient water to yield ferrous orotate 120 gm ferrous orotate with purity > 99 %.
Example 4
125 grams of orotic acid was added with constant stirring to a mixture of 500 ml ethanol and 2.5 If DM water and heated to 50°-60°C.To this reaction mixture aqueous solution of 262.9 grams ferrous sulphate was added over lhr. After complete addition maintained the reaction mixture for 10 hr. Then cooled the reaction mixture gradually to RT. Filtered the product and washed with DM water. Crude ferrous orotate obtained was purified by treating with 1 It. water at 45°C. Reaction was maintained for lhr and cooled to RT.

Reaction mixture was filtered and washed with sufficient water to yield 121 gm ferrous orotate with purity > 99 %.
Example 5
125 grams of orotic acid was added with constant stirring to a mixture of 500 ml acetone and 2.5 It. water and heated to 50°- 60°C.To this reaction mixture aqueous solution of 262.9 grams ferrous sulphate was added over lhr. After complete addition, maintained the reaction mixture for 10 hrs. Then cooled the reaction mixture gradually to RT. Filtered the product and washed with DM water. Crude ferrous orotate obtained was purified by treating with 1 It. water at 45° C. Reaction was maintained for lhr and cooled to RT. Reaction mixture was filtered and washed with sufficient water to yield 121 gm dry ferrous orotate with purity > 99 %.
Example 6
.125 grams of orotic acid was added with constant stirring to a mixture of 100 ml DMF and 3.0 It water and heated to 80°-90°C. To this reaction mixture aqueous solution of 262.9 grams ferrous sulphate was added over lhr. After complete addition, maintained the reaction mixture for 10 hrs. Then cooled the reaction mixture gradually to RT. Filtered the product and washed with DM water. Crude ferrous orotate obtained was purified by treating with 1 It. water at 45° C. Reaction was maintained for lhr and cooled to RT. Reaction mixture was filtered and washed with sufficient water to yield 105gm dry ferrous orotate with purity > 99 %.
Example 7
125 grams of orotic acid was added with constant stirring to a mixture of 100 ml DMSO and 3.0 It. water and heated to 80° -90°C. To this reaction mixture aqueous solution of 262.9 grams ferrous sulphate was added over lhr. After complete addition, maintained the reaction mixture for 10 hrs. Then cooled the reaction mixture gradually to RT. Filtered the product and washed with DM water.Crude ferrous orotate obtained was purified by treating with 1 It. water at 45° C. Reaction was maintained for lhr and cooled to RT. Reaction mixture was filtered and washed with sufficient water. The product was dried to yield 101 grams ferrous orotate with purity > 99 %.

Example 8
125 grams of orotic acid was added with constant stirring to a mixture of 100 ml THF and 2.5 It. water and heated to 80°-90°C. To this reaction mixture aqueous solution of 262.9 grams ferrous sulphate was added over lhr. After complete addition, maintained the reaction mixture for 10 hrs. Then cooled the reaction mixture gradually to RT. Filtered the product and washed with DM water. Crude ferrous orotate obtained was purified by treating with 1 It. water at 45° C. Reaction was maintained for lhr and cooled to RT. Reaction mixture was filtered and washed with sufficient water. The product was dried to yield 105gm ferrous orotate with purity > 99 %.
Example 9
125 grams of orotic acid was added with constant stirring to 2.5 It DM water and heated to 50° - 60°C. To this reaction mixture aqueous solution of 285 grams ferrous chloride was added over lhr. After complete addition, maintained the reaction mixture for 10 hrs. Then cooled the reaction mixture gradually to RT. Filtered the product and washed with DM water. Crude ferrous orotate obtained was purified by treating with 1 It. water at 45° C. Reaction was maintained for lhr and cooled to RT. Reaction mixture was filtered and washed with sufficient water. The product was dried to yield 105 gm dry ferrous orotate with purity > 99 %.
Example 10
125 grams of orotic acid was added with constant stirring to 2.5 It. water and heated to 50°-60°C.To this reaction mixture aqueous solution of 129 gram ferrous hydroxide was added over lhr. After complete addition, maintained the reaction mixture for 10 hr. Then cooled the reaction mixture gradually to RT. Filtered the product and washed with water. Crude ferrous orotate obtained was purified by treating with 1 It. water at 45°C. Reaction was maintained for lhr and cooled to RT. Reaction mixture was filtered and washed with sufficient water. The product was dried to yield 109.2 gram dry ferrous orotate with purity > 99%.

Example 11
125 grams of orotic acid was added with constant stirring to 2.5 It. water and heated to 50°-60°C.To this reaction mixture aqueous solution of 250 gram ferrous acetate was added over lhr. After complete addition, maintained the reaction mixture for 10 hr. Then cooled the reaction mixture gradually to RT. Filtered the product and washed with DM water. Crude ferrous orotate obtained was purified by treating with 1 It. water at 45° C. Reaction was maintained for lhr and cooled to RT. Reaction mixture was filtered and washed with sufficient water. The product was dried to yield 103.5 gm dry ferrous orotate with purity > 99 %.

We claim,
1. An efficient and commercially viable process for the production of Ferrous orotate
which comprises:
(a) Reacting orotic acid of formula II under agitation with iron salts in a solvent system in the temperature range of 30-120° G; and
(b) Isolating and Purifying crude ferrous orotate obtained in step (a) by treating with water at 20-50° C to obtain pure ferrous orotate free of ferrous and ferric ions.

2. The process according to claim 1, wherein the iron salts of step (a) are selected from ferrous chloride, ferrous hydroxide, ferrous sulphate, ferrous carbonate, ferrous acetate and any other salt thereof
3. The process according to claim 1, wherein the ratio of orotic acid of formula- II with iron salts is in the range from 1 : 6, more preferably from 1 : 3, most preferably 1:1
4. The process according to claim 1 wherein the solvent system of step (a) is selected from water, aliphatic alcohols such as methanol, ethanol, IPA etc, cyclic aliphatic ethers such as tetrahydrofuran, dioxane etc, aliphatic sulphoxides such as dimethyl sulphoxide, aliphatic ketones like acetone, methyl isobutyl ketone, methyl ethyl ketone etc, and N-substituted aliphatic amides like N, N-dimethyl formamide.
5. The process according to claim 1,wherein the volume of the solvent for the reaction is in the range from 1 to 50 times, preferably in the range from 5 to 40 times and most preferably in the range from 10 to 30 times.
6. Ferrous orotate salt prepared by a process as claimed in claims 1 -5.