DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Glycerol phenylbutyrate of formula (I)

(I)
The present invention also relates to novel intermediate of compound of formula (II) as depicted below:

(II)
BACKGROUND OF THE INVENTION
“Glycerol phenylbutyrate” is marketed under brand name of Ravicti for treatment of certain inborn urea cycle disorders; the medication works by preventing harmful buildup of ammonia in the body. It is chemically known as 1, 2, 3-propanetriyl tris(4-phenylbutanoate) and is represented by following general formula (I)

(I)
Glycerol phenylbutyrate is disclosed in US5968979 and this patent states that the compound of invention can be produced by standard esterification processes.
Preparation of Glycerol phenylbutyrate as disclosed in IT1317073 includes reaction of 4-phenylbutyric acid with 5 fold excess of thionyl chloride to give 4-phenylbutyryl chloride, followed by removal of excess thionyl chloride and treatment of 4-phenylbutyryl chloride with glycerol.
Kasumov et al (Drug metabolism and disposition, volume 32, issue 1, pages 10-19, 2004 discloses preparation of Glycerol phenylbutyrate by reacting glycerol with excess 4-phenylbutyryl chloride in the presence of pyridine and catalytic amount of N,N-dimethylaminopyridine. The product was purified by flash chromatography on silica.
Chang et al (Journal of Biotechnology, Volume: 127, Issue: 4, pages 694-702, 2007) discloses preparation of Glycerol phenylbutyrate from glycerol and 4-phenylbutyric acid by lipase catalyzed esterification in a solvent free system.
EP2607366 A1 discloses preparation of 4-phenyl-butyric acid 2-hydroxy-3-(4-phenyl-butyryloxy)-propyl ester by reacting glycerol with 4-phenylbutyryl chloride. In this preparation Glycerol phenylbutyrate is obtained as side product in 1.7% yield.
WO2015/063659 discloses preparation of Glycerol phenylbutyrate by reacting 4-phenylbutyryl chloride with glycerol in presence of organic base and chlorinated hydrocarbon solvent, followed by purification by chromatographic technique.
WO2020/070760 discloses a process, wherein glycerol is reacted with 4-phenyl butyric acid in presence of coupling agent, base and solvent. This also discloses further purification of Glycerol phenylbutyrate of formula (I).
Present invention provides a process for the preparation of Glycerol phenylbutyrate which is not only efficient but also economical and can be performed on large scale.
OBJECTS OF THE INVENTION
The main object of the present invention is to provide an efficient and economical process for the preparation of Glycerol phenylbutyrate.
Another object of the invention is to provide a process for preparation of glycerol phenylbutyrate of formula (I); wherein intermediate of formula (II) is converted to Glycerol phenylbutyrate (I):

Yet another object of the present invention is to provide a process for preparation of Glycerol phenylbutyrate, wherein intermediate of formula (II) is prepared by reacting compound of formula (III) with 4-phenylbutyric acid of formula (IV):

Another object of the invention is to provide an intermediate of formula (II)

Yet another object of the invention is to provide use of intermediate of formula (II) for the preparation of Glycerol phenylbutyrate.
Primarily, the object of present invention is to provide an economically viable process for the preparation of Glycerol phenylbutyrate involving novel intermediate of formula (II) and their conversion to Glycerol phenylbutyrate by simple and efficient process.
SUMMARY OF THE INVENTION
In an aspect the present invention provides a process for preparation of Glycerol phenylbutyrate of formula (I):

(I)
comprising step of converting intermediate of formula (II)

to Glycerol phenylbutyrate of formula (I).
In another aspect the present invention provides a process for preparation of Glycerol phenylbutyrate wherein intermediate of formula (II) is prepared by reacting compound of formula (III) with 4-phenyl butyric acid of formula (IV) as depicted below:

In another aspect, the present invention provides a process to prepare Glycerol phenylbutyrate comprising steps of:
i) converting a compound of formula (III) to an intermediate of formula (II) by reacting with phenyl butyric acid of formula (IV);

ii) hydrolyzing intermediate of formula (II) to obtain intermediate compound of formula (V);

(iii) reacting intermediate of formula (V) with phenyl butyric acid of formula (IV) to provide Glycerol phenylbutyrate of Formula (I); and
(iv) optionally, purifying compound of formula (I) obtained in step (iii).
In yet, another aspect the present invention provides intermediate of formula (II)

In yet another aspect the present invention provides use of intermediate of formula (II) for preparation of Glycerol phenylbutyrate.
DETAILED DESCRIPTION OF THE INVENTION
The main embodiment of present invention is to provide process for preparation of Glycerol phenylbutyrate of formula (I); the complete process of present invention can be represented by following scheme.
Scheme I

In an embodiment the process of present invention comprises reacting compound (2,2-dimethyl-1,3-dioxolan-4-yl)-methanol of formula (III) with 4-phenyl butyric acid (IV) as represented by step I in the presence of coupling reagent, optionally using solvent and base.
In another embodiment the present invention provides a process for hydrolysis of intermediate of formula (II) to provide compound of formula (V) as represented in step II of the scheme I
Hydrolysis can be carried in the presence of an acid. The acid can be selected from phosphoric acid, sulfuric acid and the like or any other suitable acid.
In yet another embodiment the present invention involves reacting an intermediate compound of formula (V) with 4-phenyl butyric acid of formula (IV) in the presence of coupling agent, optionally using solvent and base.
The coupling agent for step I and step III can be selected from group comprising of N, N’- dicyclohexyl carbodiimide (DCC). carbonyldiimidazole (CDI), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, chloroformates such as alkyl or aryl chloroformates, oxalyl chloride, thionyl chloride, pivalyl chloride, methanesulfonyl chloride, para toluene sulfonyl chloride and the like: or any other suitable coupling reagent. .
Solvent used can be selected from hydrocarbon, alcohol, chlorinated solvents, ether, nitriles, ester, polar solvents, polar aprotic solvents, water or the like; and mixture thereof.
The base used for step I and III can be selected inorganic or organic bases such as “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; “alkali metal amides” such as sodium amide, potassium amide, lithium amide and the like; and organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, tertiary butyl amine, benzyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6- lutidine, lithium diisopropylamide; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) or mixtures thereof.
The intermediates compounds formed in the process and the final product Glycerol phenylbutyrate can be isolated from the reaction mixture by conventional techniques such as filtration, layer separation, distillation of solvents or any other suitable technique known in the art.
Glycerol phenylbutyrate obtained in step III of the process (Scheme I) can be purified by any suitable purification method such as chromatography, or by adsorption of material on silica gel and elution with solvent, or by using a solvent or mixture selected from alcohol, hydrocarbon, halogenated solvents, nitriles, ethers, esters, aromatic hydrocarbon, polar protic solvent, polar aprotic solvent, water or mixture thereof. The purification can also be carried out by using solvent- antisolvent method or acid base treatment.
In yet another embodiment Glycerol phenylbutyrate can be purified by recrystallization from solvent like cyclohexane, methyl-cyclohexane, ethyl acetate, isopropyl acetate, isopropanol, methanol, ethanol, tertiary butanol ,n-butanol, tertiary butyl methyl ether and the like or mixture thereof. The product can also be purified by chromatographic methods.
EXAMPLES:
Example1: Preparation of (2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl-4-phenyl butanoate (II):
To the mixture of cyclohexane (1000 ml), 4-phenylbutyric acid (149 g) and (2,2-dimethyl-1,3-dioxolan-4-yl) methanol (100 g ), 4-dimethylaminopyridine (46 g ) was added. The reaction mixture was cooled to 10 to 15 °C. To this, the solution of N, N’ dicyclohexyl carbodimide (DCC) (172 g) in cyclohexane (500 ml) was added and stirred at the same temperature for 2 to 3 hours. After completion of the reaction, aqueous sodium bicarbonate solution (15 mg sodium bicarbonate in 500 ml water) was added to the reaction mixture and the layers were separated. The organic layer was distilled off to obtain the title intermediate compound of formula (II). (Yield 200 g)
Example 2: Preparation of 2, 3-dihyroxypropyl -4-phenylbutanoate (V)
To the mixture of intermediate compound of formula (II) (100 g) in water (1000 ml) was added phosphoric acid (10 g). The reaction mixture was heated to 40 to 50 °C and stirred for 4 to 5 hours. The progress of the reaction was monitored by HPLC. After completion of the reaction, reaction mass was cooled to 25 to 30° C and dichloromethane (500 ml) was added, layers were separated, the organic layer was washed with aqueous sodium bicarbonate solution, followed by distillation of solvent to obtain title intermediate compound of formula (V). (Yield 70 g)
Example 3:
Preparation of Glycerol phenylbutyrate (I)
To the mixture of 4-phenyl butyric acid (151 g), 2, 3-dihydroxypropyl-4-phenylbutanoate (100 g) in dichloromethane (1000 ml), 4-dimethylaminopyridine (25 g) was added. The reaction mixture was cooled to 10 to 15 °C, stirred, and the solution of N, N’-dicyclohexyl carbodimide (DCC) (171 g) in dichloromethane (500 ml) was added. The reaction mixture was stirred for 2 to 3 hours, the progress of the reaction was monitored by HPLC. After completion, the reaction mixture was filtered, the filtrate was distilled off completely and to this cyclohexane (1000 ml) was added. Filtered, the reaction mixture and the filtrate was washed with aqueous sodium bicarbonate solution, followed by water wash. The organic layer was distilled off to remove the solvent to obtain the title compound of formula (I). (Yield 300 g) ,CLAIMS:We Claim:
1. A process to prepare glycerol phenylbutyrate of formula (I) comprising steps of
a) reacting (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (III) with 4-phenyl butyric acid (IV)
b) converting 2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-phenylbutanoate (II) obtained in step a) to 2,3-dihydroxypropyl-4-phenylbutnoate (V)
c) reacting 2,3-dihydroxypropyl-4-phenylbutanoate (V) obtained in step b) with 4-phenylbutyric acid to obtain glycerol phenyl butyrate of formula (I)
2. Process as claimed in claim (1) step a) wherein reaction of compound of formula III with 4-phenylbutyric acid

is carried out in presence of a coupling agent and base.
3. Process as claimed in claim 2, wherein coupling agent is selected from dicyclohexyl carbodimide, chloroformate, 1-ethyl-3(3-dimethylaminopropyl) carbodimide, BOP, PyBOP, HATU, HBTU, TBTU, oxalyl chloride and pivalyl chloride
4. Process as claimed in claim 2 wherein base is selected from inorganic and organic base.
5. A process as claimed in claim 1, wherein process of step b)

is carried out in presence of acid.
6. A process as claimed in claim 5, wherein acid can be selected from hydrochloric acid, phosphoric acid, carbonic acid and sulfuric acid.
7. A process as claimed in claim 1, wherein process of step c)
is carried out in presence of coupling agent and base.
8. A process as claimed in claim 3 and 7, wherein coupling agent can be selected from dicyclohexyl carbodimide, chloroformate, 1-ethyl-3(3-dimethylaminopropyl) carbodimide, BOP, PyBOP, HATU, HBTU, TBTU, oxalyl chloride and pivalyl chloride.
9. A process as claimed in claim 4 and 7, wherein base is selected from alkali metal carbonate, alkali metal hydroxide, alkali metal bicarbonate, alkali metal hydroxide, alkali metal oxide, dimethyl amine, triethylamine, pyridine, piperidine, 4-dimethylaminopyridine, N-methyl morpholine.
10. Compound of formula II