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

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

BACKGROUND OF THE INVENTION
“Glycerol phenylbutyrate” is marketed under brand name of Ravicti for treatment of certain inborn urea cycle disorder; 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; Journal of Molecular catalysis B; Enzymatic volume 61, issues 3-4, December 2009, Pages 117-122 describes preparation of glycerol phenyl butyrate 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-butyrloxy)-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.

Another object of the present invention is to provide a process for preparation of glycerol phenylbutyrate, wherein intermediate of formula II is prepared by firstly, converting compound of formula III to compound of formula IV or commercially procuring compound of formula IV and then reacting with phenyl butyric acid of formula (V) to get compound of formula (II)

or salts thereof; and further conversion of intermediate of formula II to glycerol phenylbutyrate.
Primarily, the object of present invention is to provide simple, efficient and economically viable process for the preparation of glycerol phenylbutyrate, involving use of novel intermediate of formula (II).
SUMMARY OF THE INVENTION
In an aspect the present invention provides a process for preparation of glycerol phenylbutyrate of formula (I)

(I)
comprising the 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 comprising:
i) converting intermediate of formula II to compound of formula (VI);

ii) reacting compound of formula (VI) with phenyl butyric acid of formula (V) to obtain glycerol phenylbutyrate.

In another aspect, the present invention provides a process for preparing glycerol phenylbutyrate, wherein intermediate of formula (II) is prepared from compound of formula (IV) as depicted in below scheme:

In another aspect, the present invention provides a process to prepare glycerol phenylbutyrate comprising steps of:
i) reacting compound of formula (IV) with phenyl butyric acid of formula (V)

to obtain an intermediate of formula (II);

(iii) converting intermediate of formula (II) to compound of formula (VI); and

(iv) reacting compound of formula (VI) with phenyl butyric acid of formula (V) to give glycerol phenylbutyrate (I).

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 the preparation of glycerol phenylbutyrate.

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

For the process of present invention 2,5-bis (hydroxyl methyl)-1,4 dioxane-2,5-diol compound of formula (III) can be converted to compound of formula (IV) as represented by step I in presence of a suitable solvent and base. Otherwise compound of formula IV i.e. 1,3-dihyroxypropane-2-one can be can be procured commercially. For the purpose of present invention compound of formula IV is commercially procured.
In another embodiment, the present invention provides a process for reacting compound of formula IV with phenyl butyric acid of formula (V) this is represented by step II in scheme I. The reaction can be performed using suitable coupling agent, optionally in presence of solvent and base.
The coupling agent used in process of step II can be selected from any suitable reagent such as N’N’- dicyclohexyl carbodimide (DCC). Carbonylimidazole (CDI), 1-ethyl-3-(3-dimethylaminopropyl) carbodimide 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 agent.
The solvent used for the process of step II can be selected from group comprising of hydrocarbon, alcohol, chlorinated solvents, ether, nitriles, ester, polar solvents, polar aprotic solvents, water and the like or mixture thereof.
The base can be selected from 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) and the like or mixtures thereof, or any other base suitable for the process of step II.
Another embodiment of the present invention provides a process for reduction of intermediate of formula II to obtain a compound of formula VI this is represented by step III in scheme I. The reduction of intermediate II can be carried in the presence of any suitable reducing/hydrogenating agent, optionally in presence of solvent and catalyst. The reducing agent can be selected form sodium borohydrate, Lithium aluminum hydride, diisobutyl aluminum hydride (DIBAL-H), or with hydrogen in presence of catalysts such as Raney Ni, platinum, palladium or any other suitable reducing/hydrogenating agent.
In another embodiment, the present invention provides a process wherein intermediate of formula VI is reacted with phenyl butyric acid of formula (V) to obtain glycerol phenylbutyrate of formula (I) this is represented by step IV in scheme I. Process of step IV is an esterification reaction which can be carried out using any suitable esterification/coupling reagents such as dicyclohexyl carbodiimide, or reagents such as thionyl chloride, oxalyl chloride, para toluene sulfonic acid, methanesulfonyl chloride, para toluene sulfonyl chloride, or any suitable chloroformate. Esterification can be carried out in presence of solvent such as chlorinated, solvents, hydrocarbon, ether, ester, nitrile or any other suitable solvent as described with process of step II. Any suitable base like pyridine, 4-diemthylaminopyridine or acid such as sulfuric acid can also be used in esterification reaction.
The intermediates as well as 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 phenyl butyrate obtained in step IV of the process (Scheme I) can be purified by any suitable purification method such as chromatography, or by adsorption 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 from recrystallization from solvent like cyclohexane, methyl-cyclohexane, ethyl acetate, isopropyl acetate, isopropanol, ethanol, tertiary butanol, tertiary butyl methyl ether and the like or mixture thereof. The product can also be purified by chromatographic methods.
Example 1 Preparation of 2-oxopropane 1,3-diyl bis (4-phenylbutanoate) of formula II
In a 200 ml round bottom flask 600ml of methylene dichloride, 20 g of 1,3-dihydroxypropane-2-one and 80 g of 4-phenyl butyric acid, 13 g 4-dimethylaminopyridine , 600 ml toluene and solution of 100 g N,N dicyclohexyl carbodimide in 100 ml toluene were added. Reaction mixture was stirred at 25-30°C for 4-5 hrs. Once the reaction is complete reaction mixture is filtered and to the filtrate solution of sodium bicarbonate is added. Layers are separated, solvent from organic layer is distilled of to obtain the solid product of formula II in a yield of 67%
Example 2: Preparation of 2-oxopropane 1,3-diyl bis (4-phenylbutanoate) of formula III
In one liter round bottom flask 20 g of, 1g of sodium borohydrate, 100ml methanol, 400 ml of Methylene dichloride, 100 ml of purified water were added. The reaction was cooled to 5-10°C and stirred at the same for 4-5 hours. After completion of reaction 100 ml of water was added to reaction flask and the mixture was extracted to separate the layers. Organic layer was distilled off and the solid product was dried to give title product in a yield of 80%
Example 3: Preparation of glycerol phenylbutyrate
In a 500 ml round bottom flask 10 g of 2-hydrocypropane-1,3-diyl , 4.7 g of phenyl butyric acid , 5.9 g DCC, 1.6 g 4-dimethylaminopyridine, 220 ml dichloromethane were added. Reaction mixture was cooled to 15-20°C and stirred for 3-4 hours at the same temperature. Once the reaction is complete sodium carbonate solution is added to reaction mixture and layers are separated, organic layer extracted and solvent is distilled off to obtain product as oil in yield of 92.8%. ,CLAIMS:We claim
1. A process to prepare glycerol phenyl butyrate of formula I comprising steps of :
(I)
a) reacting compound of formula IV

with phenyl butyric acid to obtain an intermediate of formula (II)

b) reducing intermediate of formula II to obtain intermediate of formula (VI)

c) reacting intermediate of formula VI with phenyl butyric acid.
2. The process as claimed in claim 1 wherein reaction of compound of formula (IV) with phenybutyric acid is carried out in presence of a coupling agent.
3. A process as claimed in claim 2 wherein coupling agent is selected from dicyclohexyl carbodimide, carbonyl diimidazole, EDC and chloroformates.
4. A process as claimed in claim 1 which is carried out in presence of a coupling agent and a base.
5. A process as claimed in claim 4wherein base can be selected from organic or inorganic base.
6. A process as claimed in claim wherein compound of formula II is subjected to reduction in presence of a reducing agent and solvent.
7. A process as claimed in claim 5, wherein reducing agent is selected from sodium borohydride, lithium aluminium hydride, DIBAL, Raney Ni, Pd/C and ruthenium
8. A compound of formula (II)

9. A process as claimed in claim 1 wherein compound of formula VI is reacted with phenyl butyric acid in presence of solvent and base.
10. A process as claimed in any of the preceding claim wherein solvent can be selected from organic and