DESC:FORM 2

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

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

AN IMPROVED PROCESS FOR THE PREPARATION OF TRIHEPTANOIN

AUROBINDO PHARMA LTD. HAVING CORPORATE OFFICE AT
GALAXY, FLOORS: 22-24,
PLOT No.1, SURVEY No.83/1,
HYDERABAD KNOWLEDGE CITY,
RAIDURG PANMAKTHA,
RANGA REDDY DISTRICT,
HYDERABAD – 500 032,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

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 an improved process for the preparation of Triheptanoin (I).

Formula I
BACKGROUND OF THE INVENTION
Triheptanoin is chemically known as heptanoic acid, 1,1',1''-(1,2,3propanetriyl) ester. Triheptanoin is a medium-chain triglyceride indicated as a source of calories and fatty acids for the treatment of pediatric and adult patients with molecularly confirmed long-chain fatty acid oxidation disorders (LC-FAOD). Triheptanoin is marketed under the brand name DOJOLVI®.
Triheptanoin is a medium chain triglyceride (MCT) containing three odd chain fatty acid heptanoate molecules. As typically in known art, the MCTs are obtained by the reaction of glycerol with medium chain length fatty acids in the presence of an acid and at high temperature (140-260ºC) or with use of an enzyme such as lipase at 70-90ºC. The low purity of the triglyceride obtained by these known techniques necessitates decolourization and chromatographic purification/distillation which makes large scale synthesis difficult. In general, the yield and the purity obtained by these known techniques is very low due to incomplete esterification and loss of product during workup and purification.
International Journal of Food Science and Technology 2007, 42, 1504–1508 describes a process for the preparation of Triheptanoin by reaction of glycerol with heptanoic acid at 160-200ºC for 18 hour or more in the absence of catalyst, followed by alkali refining of the crude product yielded to get a refined fraction that was purified by column chromatography on silica gel. The process is commercially not viable because of high temperature and purification by column chromatography.
European Journal of Lipid Science Technology, vol 114, no. 8, 19 2012 (2012-04-19), page 889-895, describes a process for the synthesis of Triheptanoin by esterification of glycerol with heptanoic acid in toluene in the presence of sulfonated charcoal catalyst, refluxed at 140ºC with Dean stark trap. The workup of the obtained product is done with filtration and extraction with toluene or fractional distillation. However, Sulfonated charcoal preparation is tedious process due to involving high temperature (~260°C).
WO 2013/126990 describes a process for the synthesis of C6-C12 medium-chain monocarboxylic fatty acid triglycerides which consists of the reaction of the free fatty acid and glycerol in the presence of a metal catalyst (such as oxide or chloride of Tungsten, Molybdenum, Calcium, Zinc, Chromium or Magnesium) at temperature 160ºC or more. The process is not viable commercially.
WO2022/008856 describes a process for the preparation of a triglyceride in which glycerin was treated with heptanoic acid, the heptanoic acid being in excess relative to the glycerin at 210°C, a heating step being implemented under vacuum by descent into partial vacuum gradually, typically in stages, and the process being carried out in the absence of catalyst. The process involves high temperature and high vacuum which is not feasible commercially.
Considering the importance of Triheptanoin in the pharmaceutical field, there is always a need for an alternative preparative route, which for example, involves fewer steps, uses reagents that are less expensive and/or easier to handle, consume smaller amounts of reagents, involves less temperature, provides a higher yield of product, have smaller and/or more eco-friendly waste products, and/or provide a product of higher purity. The present invention is related to a process for the preparation of Triheptanoin (I) with high yield and high purity.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a simple and cost effective process for the preparation of Triheptanoin (I) with high purity and good yield on commercial scale.

SUMMARY OF THE INVENTION
In one embodiment, the present invention provides an improved process for the preparation of Triheptanoin of Formula (I):

Formula I
which comprises;
reaction of Glycerol of Formula (II) with heptanoic acid of Formula (III) in the presence of a coupling agent.

Formula II Formula III

In another embodiment, the present invention provides a process for the preparation of Triheptanoin of Compound of Formula (I):

Formula I
which comprises;
reaction of Glycerol of Formula (II) with heptanoic acid of Formula (III) in the presence of a coupling agent and a catalyst.

Formula II Formula III

In another embodiment, the present invention provides a process for the preparation of Triheptanoin of Compound of Formula (I):

Formula I
which comprises;
a) reacting heptanoic acid with a metal halide to obtain metal salt of heptanoic acid;
b) conversion of metal salt of heptanoic acid to heptanoic acid of formula III;
c) reaction of Glycerol of Formula (II) with heptanoic acid of Formula (III) in the presence of a coupling agent optionally in the presence of a catalyst.

Formula II Formula III

In another embodiment, the present invention provides a process for the purification of heptanoic acid;
which comprises;
a) reacting heptanoic acid with a metal halide to obtain metal salt of heptanoic acid;
b) conversion of metal salt of heptanoic acid to heptanoic acid of formula III.

DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides an improved process for the preparation of Triheptanoin of Formula (I):

Formula I
which comprises;
reaction of glycerol of Formula (II) with heptanoic acid of Formula (III) in the presence of a coupling agent.

Formula II Formula III

In another embodiment, the present invention provides a process for the preparation of Triheptanoin of Compound of Formula (I):

Formula I
which comprises;
reaction of glycerol of Formula (II) with heptanoic acid of Formula (III) in the presence of a coupling agent and a catalyst.

Formula II Formula III

In another embodiment, the present invention provides a process for the preparation of Triheptanoin of Compound of Formula (I):

Formula I
which comprises;
reaction of glycerol of Formula (II) with heptanoic acid of Formula (III) in the presence of a coupling agent, catalyst, organic base and organic solvent.

Formula II Formula III

In another embodiment, the present invention provides a process for the preparation of Triheptanoin of Compound of Formula (I):

Formula I
which comprises;
a) reacting heptanoic acid with a metal halide to obtain metal salt of heptanoic acid;
b) conversion of metal salt of heptanoic acid to heptanoic acid of formula III;
c) reaction of Glycerol of Formula (II) with heptanoic acid of Formula (III) in the presence of a coupling agent optionally in the presence of a catalyst.

Formula II Formula III

In another embodiment, the present invention provides a process for the purification of heptanoic acid;
which comprises;
a) reacting heptanoic acid with a metal halide to obtain metal salt of heptanoic acid;
b) conversion of metal salt of heptanoic acid to heptanoic acid of formula III.

The process according to present embodiment is carried at a temperature of 0-100ºC.

The coupling agent(s) used in above reaction comprises N,N’-dicyclehexylcarbodiimide (DCC), N,N'-Carbonyldiimidazole (CDI), N-ethyl-N’-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC) or N,N’-diisopropylcarbodimide (DIC), 2-(1H-benzotriazole-1-yl)-1,1,3,3- tetramethyluronium tetrafluoroborate (TBTU), (1H-7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TATU), 1-[(1-(cyano-2- ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinomethylene)]methanaminium hexafluorophosphate (COMU), 2-methyl-6-nitrobenzoic anhydride and/or ethyl 2-cyano-2-(2-nitrobenzenesulfonyloxyimino)acetate (o-NosylOXY).

The metal halide used in the above reaction comprises calcium chloride, calcium bromide, barium chloride, barium bromide, sodium chloride, sodium bromide, potassium chloride, potassium bromide, magnesium chloride and/or magnesium bromide.

The organic base (s) used in the present invention comprises triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine (DIEA), N-methyl morpholine, piperidine, pyridine; 1,8-Diazabicyclo(5.4.0)undec-7-ene (DBU), 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD) guanidine bases such as 1,1,3,3-Tetramethylguanidine (TMG) and/or mixtures thereof.

The solvent(s) used in the reaction comprises water, alcohols, ketones, nitriles, halogenated hydrocarbons, hydrocarbons, amides, sulfoxides, nitriles, esters, ethers and mixtures thereof. The alcohols comprises C1-6 alcohols selected from methanol, ethanol, butanol, isopropanol; ketones selected from acetone, methyl ethyl ketone, methyl isopropyl ketone; nitrile solvent selected from acetonitrile, propionitrile; halogenated hydrocarbons selected from methylene chloride, ethylene chloride, chloroform; hydrocarbons selected from hexane, cyclohexane, toluene, xylene; amides selected from dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone; sulfoxides selected from but are not limited to dimethyl sulfoxide; esters comprises, ethyl acetate and butyl acetate; ethers selected from diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane, tetrahydrofuran; and/or mixtures thereof.
The suitable catalyst (s) used in the present invention comprises nitrogen-based nucleophilic catalysts selected from 4-dimethylaminopyridine, pyridine, 4-pyrrolidinopyridine and/or 9-azajulolidine.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.
EXAMPLES:
EXAMPLE 1: Purification of heptanoic acid:
n-Heptanoic acid (4 g) and sodium hydroxide (1.2 g) in water (40 ml) were charged into reactor at 20-30°C. Thereafter, the aqueous layer was washed with cyclohexane (8 ml). The aqueous layer was warmed up to 50-60°C and aqueous Barium chloride dihydrate (7.5 g) was added and stirred for 100-150 min. The precipitated salts were filtered and the wet product was suspended in a mixture of cyclohexane (20 ml) and water (20 ml). This mixture was acidified with conc. Hydrochloric acid (2.8 ml) and the organic layer was concentrated to afford pure n-Heptanoic acid (Yield in 3 g), Purity 99.98%).

EXAMPLE 2: Preparation of Triheptanoin:
Glycerol (2 g) was added to N,N-Dimethylformamide (14 ml) under nitrogen atmosphere at 20-30°C and the solution was stirred at this temperature for 15±5 min. Later, heptanoic acid (11.3 g) was added and stirred for 15±5 min. Pyridine (12 g) was slowly added to the above clear solution and 4-Dimethylaminopyridine (0.26 g) was added and stirred for 15±5 min. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (20.82 g) was added in four equal lots at a temperature below 50°C and stirred for 8 h. After completion of reaction, the reaction mass was cooled to 20-30°C and purified water (40 ml) was added followed by cyclohexane (50 ml) and stirred for 15±5 min. The reaction solution was acidified by addition of conc. Hydrochloric acid (12 ml) at 20-30? and the layers were allowed to settle for 15±5 min. The layers were separated. The cyclohexane layer was treated with 1N aqueous Hydrochloric acid (20 ml) twice and the cyclohexane layer was separated. Similarly, the cyclohexane layer was treated with ~10% w/v aqueous Sodium carbonate solution (20ml) twice and the cyclohexane layer was separated. Thereafter, cyclohexane layer was stirred with 10% w/v aqueous Sodium chloride solution and separated through filtration. The filtrate was concentrated at a temperature below 45°C under reduced pressure (200-50 mm Hg) to get residue. The residue was dried at temperature below 50-60? under reduced pressure (~20 mm Hg) for 60-70 min to obtain light yellow color viscous liquid.
Yield: 9 g
Purity: 99% by H1NMR analysis. ,CLAIMS:WE CLAIM:

1. A process for the preparation of Triheptanoin of Compound of Formula (I):

Formula I
which comprises;
reacting glycerol of Formula (II) with heptanoic acid of Formula (III) in the presence of a coupling agent and optionally in the presence of a catalyst.

Formula II Formula III

2. A process for the preparation of Triheptanoin of Compound of Formula (I):

Formula I
which comprises;
a) reacting heptanoic acid with a metal halide to obtain metal salt of heptanoic acid;
b) conversion of the metal salt of heptanoic acid to heptanoic acid of formula III;
c) reacting Glycerol of Formula (II) with heptanoic acid of Formula (III) in the presence of a coupling agent optionally in the presence of a catalyst.

Formula II Formula III

3. The process as claimed in claim 2, wherein, the metal halide used is selected from calcium chloride, calcium bromide, barium chloride, barium bromide, sodium chloride, sodium bromide, potassium chloride, potassium bromide, magnesium chloride and/or magnesium bromide.

4. The process as claimed in claim 1 and claim 2, wherein the coupling agent(s) used is selected from N,N’-dicyclehexylcarbodiimide (DCC), N,N'-Carbonyldiimidazole (CDI), N-ethyl-N’-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDC) or N,N’-diisopropylcarbodimide (DIC), 2-(1H-benzotriazole-1-yl)-1,1,3,3- tetramethyluronium tetrafluoroborate (TBTU), (1H-7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TATU), 1-[(1-(cyano-2- ethoxy-2 oxoethylideneaminooxy)dimethylaminomorpholinomethylene)] methanaminium hexafluorophosphate (COMU), 2-methyl-6-nitrobenzoic anhydride and/or ethyl 2-cyano-2-(2-nitrobenzenesulfonyloxyimino)acetate (o-NosylOXY).

5. The process as claimed in claim 1 and claim 2, wherein the catalyst (s) used is Nitrogen-based nucleophilic catalyst selected from 4-dimethylaminopyridine, pyridine, 4-pyrrolidinopyridine and/or 9-azajulolidine.

6. The process as claimed in claim 1 and claim 2, carried at a temperature of 0-100ºC.

7. The process as claimed in claim 1, is optionally carried in the presence of organic base, wherein the organic base is selected from triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine (DIEA), N-methyl morpholine, piperidine, pyridine; 1,8-Diazabicyclo(5.4.0)undec-7-ene (DBU), 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD) and/or 1,1,3,3-Tetramethylguanidine (TMG).

8. The process as claimed in claim 1, is optionally carried in an organic solvent, wherein the organic solvent is selected from methanol, ethanol, butanol, isopropanol, acetone, methyl ethyl ketone, methyl isopropyl ketone, acetonitrile, propionitrile, methylene chloride, ethylene chloride, chloroform, hexane, cyclohexane, toluene, xylene, dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone, dimethyl sulfoxide, ethyl acetate and butyl acetate, diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane and/or tetrahydrofuran.

9. A process for the purification of heptanoic acid; which comprises;
a) reacting heptanoic acid with barium chloride or its hydrate to obtain barium salt of heptanoic acid;
b) conversion of barium salt of heptanoic acid to heptanoic acid of formula III.

10. A process for the preparation of Triheptanoin of Compound of Formula (I):

Formula I
which comprises;
a) reacting heptanoic acid with barium chloride or its hydrate to obtain barium salt of heptanoic acid;
b) conversion of barium salt of heptanoic acid to heptanoic acid of formula III;
c) reacting Glycerol of Formula (II) with heptanoic acid of Formula (III) in the presence of N-ethyl-N’-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC), optionally in the presence of 4-dimethylaminopyridine.

Formula II Formula III