DESC:FORM 2

THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION

IMPROVED PROCESS FOR THE PREPARATION OF BETINE ANHYDROUS

Nuray Chemicals Private Limited
Plot No. 111, SIDCO Industrial Estate,
Kakkalur, Thiruvallur District,
Tamil Nadu, India 602003

The following specification describes the nature of the invention and manner in which it has performed.

Field of the Invention

The present invention relates to an improved process for the preparation of anhydrous betaine of Formula-I.

Background of the Invention

Betaine anhydrous is chemically known as trimethylgylcine. It is approved under brand name of CYSTADANE for the treatment of homocystinuria. Homocystinuria is a serious life-long disease and is associated with a high morbidity and mortality. Homocystinuria is an inherited disorder of the metabolism of the amino acid methionine leading to accumulation of homocysteine in the blood and urine. This is due to a dysfunction in one of the metabolic pathways responsible for transulfuration and remethylation of homocysteine. It is considered the second most common inborn error of amino acid metabolism after phenylketonuria. The major clinical manifestations include mental retardation, dislocation of the optic lentis (ectopia lentis), skeletal abnormalities and a tendency to thromboembolic episodes. The estimated incidence of homocystinuria due to Cystathionine beta-synthase (CBS) deficiency is 1 in 335 000 births worldwide, with marked regional variations. Treatment aims to reduce homocysteine accumulation and to restore the transmethylation capacity by normalising the concentrations of S-adenosylmethionine (SAH) and S-adenosylhomocysteine (SAM).
Betaine anhydrous powder contains no ingredients other than anhydrous betaine and it is a white, granular, hygroscopic powder, which is diluted with water and consumed immediately

Betaine technical grade is extracted from sugar beet molasses as a result of a purification process. Betaine occurs with an average abundance of 0.2 % - 0.3 % in the common variety of sugar beets (beta vulgaris L) and is a natural key-intermediate of the amino acid and methyl metabolism in all vertebrates. Efforts of the sugar industry to increase sugar yields have led to the development of chromatographic processes for large scale desugarization of molasses. Ion exclusion is used to separate sugar and non-sugar fractions of molasses.

The technical grade material is manufactured by ion exclusion chromatography, concentration of betaine fraction and centrifugation. The technical grade material is purified by dissolving in water, distillation, carbon treatment and crystallization. The above process is tedious and need special type and dedicated utilities. This process yields large amount of wastages and handling this wastage is cumbersome.

There are many available other reported chemical methods for the preparation of Betaine anhydrous.

US patent 3480,665 described a process for the preparation of betaine anhydrous by reaction of trimethylamine with a monochloroacetate salt in aqueous medium. The metallic ions present in the aqueous medium with betaine are removed by treating with ion exchange resin.

US patent 7,005,543 described a process for the preparation of betaine by following steps (a) mixing sodium carbonate with chloroacetic acid to form a solution A; (b) dropping liquid trimethylamine into said solution A to form a solution B at a temperature and pH value within a range between 7 and 8; (c) decompressing said solution B until a betaine compound crystal is formed; and (d) centrifugalizing and drying said betaine compound crystal to form said betaine compound. This patent also treating final betaine compound with ion exchange resin to remove unwanted metallic ions.

The disadvantage of the above process is the starting material monochloroacetic acid itself genotoxic and it contains small amount of dichloroacetic acid. The other raw material trimethylamine also contains small amount of mono and dimethylamine compounds which will form corresponding amine compounds during the reaction. All these impurities are genotoxic and need to be controlled in lower than toxic levels in final drug substance. The removal of these impurities involves multiple purification including some process steps which lower the yield of the product, increase the overall cost and it makes this process is not commercially viable.

CN107556268 described a process for the preparation of betaine anhydrous of formula (I) by methylating glycine with formaldehyde and sodium cyanoborohydride followed by treating with methyl iodide. This process is hazardous and it is not cost effective.

Hence there is a need of simple and commercially viable process for the preparation of Betaine anhydrous. The present inventors surprisingly found simple workout methods in the process for the preparation of Betaine anhydrous of formula (I) which is enhance the yield and cost effective.

Objectives of the Invention

The main objective of the present invention is to provide a simple and cost effective process for the preparation process the preparation of betaine anhydrous of Formula (I).

Another objective of the present invention is to provide commercially viable process for the preparation of betaine anhydrous of Formula (I).

Summary of the Invention

The present invention relates to an improved process for the preparation of betaine anhydrous of formula (I) which comprises:
reacting glycine compound of formula (II) with methylating agent in presence of suitable base and solvent.
The present invention is illustrated by following scheme

Detailed Description of the Invention

In an embodiment of the present invention, the glycine compound is selected from glycine, monomethyl glycine or dimethyl glycine.
In an embodiment of the present invention, the methylating agent is selected from group consisting of methyl iodide, dimethylsulfate, monomethyl sulfate, dimethyl carbonate, · dimethyl dicarbonate, trimethylsilyldiazomethane or combination thereof.

In an embodiment of the present invention the methylating agent comprises dimethylsulfate.

In one more embodiment of the present invention, the base is base is selected from group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, lithium bicarbonate, cesium bicarbonate, and a combination thereof.

In another embodiment of the present invention, the solvent selected from water, alcohols such as methanol, ethanol, propanol, and butanol. Isopropanol ethylene glycol, propylene glycol, diethylene glycol, triethylene glycol, ketone solvent selected from acetone, methylethyl ketone, methyl isobutyl ketone, etc., ethers such as diisopropyl ether, dibutyl ether, ethylene glycol dimethyl ether, diglyme, triglyme, etc.; aprotic polar solvents such as dimethylformamide, dimethylacetamide, acetonitrile, dimethylsulfoxide, etc.; and saturated hydrocarbons such as hexane, heptane, cyclopentane, cyclohexane, etc., and a combination thereof.

In another embodiment of the present invention, the reaction mass is heated to about 40 °C to about 70 °C.

In another embodiment of the present invention, the crude betaine anhydrous treated with resin to remove metal ions present the betaine material.

In another embodiment of the present invention, the technical grade betaine anhydrous is purified by dissolving technical grade betaine anhydrous in solvent selected from methanol, ethanol, isopropanol, butanol and isobutanol and a combination thereof followed by precipitating solid by adding anti-solvent such as acetone or ethyl acetate.

Example 1:
To an aqueous sodium hydroxide solution 50 g in 200 mL, 100 of N, N-dimethyl glycine was added lot wise at temperature in 20±5 °C and stirred. The reaction mass temperature was slowly raised to 25±5 °C and stirred. To the reaction mass 150 g methanol was added, cooled to 20±5 °C, 160 g of dimethylsulfate was added to the reaction mass and stirred at 25±5 °C. The reaction mass was heated to 50±5 °C and stirred for 90-150 minutes. After completion of the reaction, the reaction mass was cooled to 25±5 °C and unloaded from the reactor.

Purification:
The glass column filled with DIAION SK1BH resin, eluted with purified water. The reaction solution obtained in above process was added to the column. The column was eluted with 25 % aqueous solution and the product fraction as collected. The product fractions were combined, heated to 70±20°C and water was distilled completely. To the residue, 80 g methanol was added heated to 70±20°C and distilled. The reaction mass was cooled to room temperature and methanol was added to get the clear solution. The solution was treated with carbon for 2 hrs and filtered; the bed was washed with methanol. The combined filtrates are combined and distilled at 40±10 °C. To the reaction mass, methanol was added at 42±3 and stirred for 1 hour. To the reaction mass acetone was added, stirred, the obtained solid was filtered and suck dried.

To the crude material of methanol was added, slowly heated the reaction mass to 50-70 °C stirred for 1 hr and cooled to 40-45 °C. To the reaction mass acetone was added, stirred for 1 hr, the obtained solid was filtered and suck dried then dried under vacuum to obtain pure white solid.

Dated this 21st day of May 2022
for Nuray Chemicals Private Limited

Dr. K. Ravi
Technical Director and Plant Head
,CLAIMS:We Claim,
1. An improved process for the preparation of betaine anhydrous of formula (I) which comprises:

reacting glycine compound of formula (II)

wherein R1 and R2 each independently selected from hydrogen or methyl
with methylating agent in presence of suitable base and solvent.
2. The process according to the claim-1, wherein the methylating agent is selected from group consisting of methyl iodide, dimethylsulfate, monomethyl sulfate, dimethyl carbonate, · dimethyl dicarbonate, trimethylsilyldiazomethane or combination thereof.

3. The process according to the claim-1, wherein the methylating agent is dimethyl sulfate or methyl iodide.

4. The process according to the claim-1, wherein the solvent used for the reaction is selected from water, alcohols such as methanol, ethanol, propanol, and butanol, isopropanol, ethylene glycol, propylene glycol, diethylene glycol, triethylene glycol, ketone solvent selected from acetone, methylethyl ketone, methyl isobutyl ketone, etc., ethers such as diisopropyl ether, dibutyl ether, ethylene glycol dimethyl ether, diglyme, triglyme, etc.; aprotic polar solvents such as dimethylformamide, dimethylacetamide, acetonitrile, dimethylsulfoxide, etc.; and saturated hydrocarbons such as hexane, heptane, cyclopentane, cyclohexane, etc., and a combination thereof.

5. The process according to the claim-1, wherein the reaction is carried out at about 40 °C to about 70 °C.

6. The process for purification of betaine anhydrous comprising steps of:
a) providing crude betaine anhydrous
b) dissolving crude betaine anhydrous in a solvent
c) adding anti-solvent to the reaction mass
d) isolating pure betaine anhydrous

7. The process according to the claim 5, wherein the crude betaine anhydrous dissolved in water, methanol, ethanol, isopropanol, methanol, ethanol, propanol, and butanol, isopropanol, ethylene glycol, propylene glycol, diethylene glycol, triethylene glycol, aprotic dimethylformamide, dimethylacetamide, acetonitrile, dimethylsulfoxide, heptane, cyclopentane or cyclohexane and a combination thereof.

8. The process according to the claim 5, wherein the anti-solvent used in the reaction of step c) is selected from group consisting of acetone, methylethyl ketone, methyl isobutyl ketone, diisopropyl ether, dibutyl ether, ethylene glycol dimethyl ether, diglyme, triglyme and combination thereof.

9. The process according to the claim 6, wherein the betaine anhydrous is dissolved under heating.

10. The process according to the claim 6, wherein the betaine anhydrous is cooled to about 0-30 °C.

Dated this 21st day of May 2022
for Nuray Chemicals Private Limited

Dr. K. Ravi
Technical Director and Plant Head