FIELD OF THE INVENTION

The present invention is related to a process for preparation of 5-hydroxy-5-aryl-pyrrol-2- ones and their arylated furanones. The present invention also relates to a two-stage process for preparation of 5-hydroxy-5-aryl-pyrrol-2-ones, particularly 4-chloro-5- hydroxy-l-substituted-5-arylated-lH-pyrrol-2(5H)-ones. In the first stage, the arylated furanone intermediates are prepared by a Lewis acid catalysed Friedel Crafts reaction. In the second stage, the final compound, the active pharmaceutical ingredient (API) is obtained by a lactonisation reaction from the intermediate.

BACKGROUND OF THE INVENTION

The 5-hydroxy-5-aryl-pyrrol-2-ones class of compounds have been reported to act as Cholecystokinin (CCK) receptor ligand.

The Indian patent application 1994/CHE/2011 describes compounds having a 5-hydroxy- 5-arylpyrrol-2-one core structure that are disclosed therein as having CCK binding activity. Further, it discloses a method for preparation of 5-hydroxy-5-aryl-pyrrol-2-ones, 15 compounds and their binding with the receptor.

The preparation method disclosed in 1994/CHE/2011 is associated with certain drawbacks. The scale on which the disclosed method can be practiced is limited to a small scale only. Due to the exothermic nature of the reaction the same is not safe to be performed on a larger scale for it may result in an explosion of reactor or formation of class particles resulting from an overheated reactor. Therefore, the disclosed process is neither safe nor is it industrially or economically viable.

The addition of the Lewis acid is fine on a small scale, but on a large scale, it is very dangerous and additionally the HCL gas formation is uncontrollable which can have disastrous effects such as the tragic events of the Bhopal gas disaster. Furthermore, excessive usage of cancerogenic solvents such as benzene, which are used as reagent and solvent are also not advisable in terms of health and the environment. The solvent use of expensive fluorinated reagents in stage 1 to obtain the intermediate is not commercially viable. Similarly, the use of expensive amines at the final stage, in order to bind HCL gas, liberated during the lactonisation process, is also not commercially viable

In conclusion, there is a need in the prior art to obtain highly pure 5-hydroxy-5-aryl- pyrrol-2-ones using a safe, industrially viable and economically viable process for the preparing the intermediates and then leading up to the final compound stages.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide an improved process for the preparation 5-hydroxy5-aryl-pyrrol-2-ones of formula (I), which is safe for industrial application, and is industrially and economically viable.

It is also an object of the present invention to provide an improved process for the preparation of arylated furanone intermediates, particularly 2(5H)-furanones by an improved Lewis acid catalysed Friedel Crafts reaction.

It is also an object of the present invention to provide an improved process for the preparation of 5-hydroxy5-aryl-pyrrol-2-ones of formula (I) from he arylated furanone intermediates by an improved lactonisation reaction.

The arylated furanone intermediates and the final compounds obtained according to of the present invention are obtained in high yield and purity, produce less number of undesirable by-products being formed in the synthesis.

SUMMARY OF THE INVENTION

An embodiment of the present invention provides a process for preparation of 5- hydroxy5-aryl-pyrrol-2-ones of formula (I) Wherein, X is selected from hydrogen, a hydroxyl group, a halogen which is selected from fluorine, chlorine, bromine and iodine; preferably chlorine and most preferred fluorine and R is selected from isobutyl, benzyl and phenyl-ethyl; the process comprising; a) reacting of a mucohalic acid with benzene or substituted benzene in the presence of a Lewis acid in a haloalkane solvent to obtain the compound of formula (II) b) reacting the compound of formula (II) with a combination of a suitable amine and a trialkyl amine in an organic solvent to obtain the compound of formula (I),

An embodiment of the present invention provides a process for preparation of a compound of formula (II) comprising: reacting a mucohalic acid with benzene or a substituted benzene in the presence of a Lewis acid in a haloalkane solvent to obtain a compound of formula (II) wherein, X is selected from hydrogen, a hydroxyl group or a halogen.

Another embodiment of the present invention relates to a process for the preparation of 5- hydroxy5-aryl-pyrrol-2-ones of formula (I) from a compound of formula (II) comprising: treating a compound of formula (II) with a combination of primary amine and a tertiary amine in an organic solvent to obtain a compound of formula (I) wherein, X is selected from hydrogen, a hydroxyl group or a halogen; and R is selected from isobutyl, benzyl, phenyl or alkylated phenyl.

As used herein, mucohalic acid refers to the group of halogenated furanones, particularly 2,3-dihalogenomalealdehydeic acids, including mucochloric acid (2,3- Dichloromalealdehydic acid) and mucobromic acid (2,3-Dibromomalealdehydic acid).

In a preferred embodiment, the mucohalic acid is mucochloric acid, X is fluorine and R is isobutyl or an alkylated phenyl such as benzyl or phenylethyl. Another embodiment of the present invention provides a process for preparation of 5- hydroxy-1 -substituted -5-aryl-lH-pyrrol-2(5H)-one comprising; a) Reacting mucochloric acid with benzene in the presence of aluminum chloride in a halohydrocarbon solvent to obtain the compound of formula (III), b) treating the compound of formula (III) or formula (IV) with primary amines c) Formation and purification of 5-hydroxy-l-substituted-5-aryl-lH-pyrrol-2(5H)-ones in presence of a tertiary amine such as triethyl amine.

DETAILED DESCRIPTION OF THE INVENTION

One embodiment of the present invention provides a process for preparation of the compound of formula (I): wherein X is selected from hydrogen, a hydroxyl group, a halogen which is selected from fluorine, chlorine, bromine and iodine; preferably chlorine and fluorine; and R is selected from isobutyl, benzyl and phenyl -ethyl.

An embodiment of the present invention provides a process for preparation of a compound of formula (II) comprising: reacting a mucohalic acid with benzene or a substituted benzene in the presence of a Lewis acid in a haloalkane solvent to obtain a compound of formula (II) wherein, X is selected from hydrogen, a hydroxyl group or a halogen.

Another embodiment of the present invention relates to a process for the preparation of 5- hydroxy5-aryl-pyrrol-2-ones of formula (I) from a compound of formula (II) comprising: treating a compound of formula (II) with a combination of primary amine and a tertiary amine in an organic solvent to obtain a compound of formula (I)

wherein, X is selected from hydrogen, a hydroxyl group or a halogen; R is selected from isobutyl, benzyl, phenyl or alkylated phenyl. In an embodiment, the process according to the present invention comprises: a) reacting a mucohalic acid with benzene or substituted benzene in the presence of a Lewis acid in a halohydrocarbon solvent to obtain the compound of formula (II) b) reacting the compound of formula (II) with a combination of primary and tertiary amine in an organic solvent to obtain the compound of formula (I).

In an embodiment the process according to the present invention may optionally further comprise purifying the compound of formula (I) and/or isolating.

In an embodiment the process of the present invention comprises a process of purification of the compound of formula (I), said process comprising the steps of: a) dissolving the compound of formula (I) in a halo-hydrocarbon solvent to obtain a solution, b) distillation of the solution under vacuum at a temperature in the range of 30-50°C to obtain a solid, c) drying the solid, and d) recrystallising the compound of formula (I) from the solid.

The halo-hydrocarbon solvent used in this purification of compound of formula (I) may be is selected from trichloromethane, dichloromethane, 1,2 -dichloroethane or combinations thereof. The recrystallising of the compound of formula I may be carried out using toluene or using ethanol/water mixture

In an embodiment, X is a halogen selected from fluorine, chlorine, bromine and iodine, preferably chlorine and fluorine, most preferably fluorine.

In an embodiment, R is isobutyl, phenyl, ethyl and alkylated phenyl, such as benzyl and phenylethyl groups.

In a preferred embodiment, X is fluorine and R isobutyl and alkylated phenyl, such as benzyl and phenylethyl groups.

In another preferred embodiment, X is fluorine and R isobutyl and alkylated phenyl, such as benzyl and phenylethyl.

In an embodiment, the mucohalic acid selected from mucochloric acid or mucobromic acid, preferably mucochloric acid.

In a preferred embodiment the LA (Lewis acid) is Aluminium chloride and most preferred solvent dichloromethane (DCM).

In an embodiment of the present invention, the reaction of mucohalic acid with benzene or substituted benzene is carried out in the presence of a Lewis acid, which is selected from aluminum chloride, ferric chloride and zinc chloride and the like; preferably aluminum chloride. Anhydrous aluminium chloride is the most preferred (LA) Lewis acid.

The haloalkane solvent is a chloroalkane solvent selected from chloromethane, dichloromethane, trichloromethane, dichloroethane and the like; preferably dichloromethane. Presence of ethers such as tetrahydrofuran(THF), Methyl tert-butyl (MTB) ether and diethylether resulted in lower yields due to increased formation of byproducts.

The use of a co-solvent selected from a range of haloaklanes particularly chlorinated chloroalkane solvents surprisingly suppressed the formation of the bisarylated by products in the intermediate preparation step. In the final step resulting in the preparation of the active compound the presence of equimolar ratio of an auxiliary amine and the suppression of the 4- substituted by-products. This allowed the process to become cleaner and economically more viable.

In another embodiment the present invention relates to a novel process towards the furanone intermediate (II) from mucohalic acids using chlorinated co-solvents to control the formation of intermediate (II) over bis-arylated acids by products. The most preferred chlorinated alkane is (DCM) dichloromethane.

In another embodiment, the present invention relates to a novel process to convert the intermediate furanones of formula (II) with primary amines into 5 -hydroxy- IH-pyrrol- 2(5H)-ones (I) in presence of tertiary amines, most preferred (TEA) trimethylamine, comprising; a) reacting mucochloric acid with arenes or substituted benzenes in the presence of Lewis acid in haloalkane solvent to obtain the compound of formula (II) b) Reaction of compound of formula (II) with a suitable amine/ trialkyl amine combination in an organic solvent to obtain the compound of formula (I) c) Formation of 5-hydroxy-l-substituted-5-aryl-lH-pyrrol-2(5H)-ones of formula (1) in presence of a tertiary amine such as triethyl amine / trisopropylamine, most preferred TEA and purification therof.

In yet another embodiment the present invention relates to the synthesis of compounds of formula (I) in the presence of an equimolar ratio of an auxiliary amine and the suppression of the 4- substituted by-products. In another embodiment of the present invention, the reaction intermediates for formula (II) may be isolated or converted further in situ into the compounds of formula (I).

In another embodiment of the present invention, recrystallisation of API compounds of formula (I) from toluene provided amorphous material with improved bioavailability. Recrystallisation of API compounds of formula (I) from aqueous alcohol mixtures provided crystalline material ideal for purification of API (I) towards pharmaceutical grade purity.

In another embodiment of the present invention, the intermediate compound of formula (II) is further purified. The purification is carried out using a solvent such as dimethylether, diethylether, tetra hydro furan (THF) or hexane.

In embodiment of the present invention, the process step of treating the intermediate compound of formula (II) with an amine/trialkylamine combination in an organic solvent is carried out at a temperature in the range of -10 to 50°C. The primary amine is selected from benzylamine, fluorobenzylamine, isopropylamine and phenylethylamine. The tertiary amine is a triaklyl amine is selected from triethyl amine and triisopropylamine. The primary amine is in the range of 1.1 to 3 molar equivalents by molecular weight to the tertiary amine; preferably about 1.2 equivalents. In a preferred embodiment, the tertiary amine is in the range of 1.1 -1.5 equivalents by molecular weight to the primary amine. In another preferred embodiment, the primary amine and tertiary amine are used in equimolar ratios.

In yet another embodiment of the present invention, the process as claimed in claim 2, wherein the organic solvent is selected from ether and halo-hydrocarbon or combinations thereof. In a preferred embodiment, the organic solvent is an ether, preferably methyltertiarybutyl ether.

In yet another embodiment of the present invention compound of formula (I) is further isolated using any conventional method such as precipitation or solvent evaporation.

Another embodiment of the present invention provides a process for preparation of 5- hydroxy-1 -substituted -5-aryl-lH-pyrrol-2(5H)-one comprising; a) Reacting mucochloric acid with benzene in the presence of aluminum chloride in a halohydrocarbon solvent to obtain the compound of formula (III),

or (IV) b) treating the compound of formula (III) with primary amines c) Formation and purification of 5-hydroxy-l-substituted-5-aryl-lH-pyrrol-2(5H)-ones of formula (I) in presence of a tertiary amine such as triethyl amine.

The reaction of mucochloric acid with benzene in the presence of aluminum chloride is conducted at -10 to 40°C; preferably 0-10°C in dichloromethane solvent. Use of dichloromethane solvent was advantageous in terms of reducing the quantity of benzene as a solvent in this reaction stage. Further, solubility of these reactant in benzene solvent is lesser compared to use of dichloromethane. Therefore, use of dichloromethane resulted in complete solubility of the reactants and provides a better yield and a much improved purity of compounds of formula (III) and (IV). 2-phenylethylamine with adjunct amine was reacted with the compound of formula (III) to form final API compound 5-hydroxy- l-phenethyl-5-phenyl-lH-pyrrol-2(5H)-one (API-1). The reaction step of treating the compound of formula III with a primary amine is carried out in an organic solvent such as ether, esters, hydrocarbon; preferably methyl-tertiary-butyl ether.

Control of rate of reaction allowed scale up and provided for the first time an industrially feasible and safe save process for the formation of the intermediates III and IV from mucochloric acid. Also, chlorinated derivatives may be produced by the same process and they may be useful in other product applications.

Surprisingly, it was found that about 2 equivalents of amine compound, one equivalent of primary amine and 1 eq. of a tertiary amine by molecular weight is sufficient to obtain the final compound in higher yield and purity.

A preferred embodiment of the present invention is depicted in the following Scheme I.

Scheme I. From mucochloric acid via arylated furanone intermediate towards hydroxy-pyrrolone API

The methods of the present invention are described in further detail in the by way of the examples.

EXAMPLE 1: INTERMEDIATE SYNTHESIS METHODS

In the first stage, the synthesis of the intermediate of formula (II) was carried out in the temperature range between -10°C and 40°C; Higher temperatures were avoided as the chlorinated solvent becomes reagent and by-products are formed, yield and purity is then decreased. For activated arenes, such as benzene the temperature range from 4-10°C were most preferred. For halogenated arenes, such as flurobenzene, the temperature was kept higher in the range from 15-20 C. Monitoring was maintained to avoid the formation of bisarylated arylic acids.

The introduction of a halogenated solvent, most preferably DCM was paramount in the commercial synthesis of the intermediates of formula (II). The addition of a catalyst to the mixture of mucochloric acid and benzene was damaging the reactor and plant and represents a critical danger to the plant, and the infrastructure and human life.

The addition of mucochloric acid as a solid to the mixture of benzene and lewis acid gave a higher percentage of the bisarylated impurity and a lower overall yield.

A large range of solvents and co-solvents were tested. When the arene was added we were able to control safely the exothermic process; a brown mass in particular with ethers was obtained.

The process described here in detail is giving high yields, excellent purity, thus converting the intermediate in situ. The crude material may be used directly and cheaply to prepare the final active compounds.

By adding arene in the end the bis-arylated by-products are minimised and the rate of the reactions were carefully monitored/controlled. DCM is the most preferred solvent. Other co-sol vents, such as MTB ether were not beneficial in the intermediate technical synthesis.

The process was further optimised as shown in Table 1 with respect to order of reagents, solvents and Lewis acid.

TABLE 1: Method optimisation Intermediate stage (II)

Process is applicable to muco-halogen acids and their cognate preparations

3.4-dichloro-5-phenylfuran-2(5H)-one, 3,4-dichloro-5-p-fluoro-phenylfuran-2(5H) one;

3.4-dichloro-5-p-chlorophenylfuran-2(5H)-one was preferred by method 3 or 4 and most preferred by method 4.2.1. Tetrachloromethane formed by-products and could not be used at low temperatures. The dichloro-ethylen may replace dichloromethane. Using sulphuric acid or performing the reaction at high temperatures resulted in higher production of the bis-arylated acids.

Scheme II. Intermediate formation of 2(5H)-furanones and bisarylated by-products. The intermediate compound of formula (II) is optionally purified using ether solvent selected from dimethylether, diethylether, THF and the like.

The intermediate compounds of formula (II) may be further isolated. No chromatography is applied and furane intermediates (II) are most preferred isolated by crystallisation from hexane and toluene, not the usually reported alcohols as isopropanol and ethanol.

Recrystallization with solvent hexane yielded preferable results, which was surprising, as the intermediate as lipophilic molecule should be recrystallized best from isopropanol in theory. Recrystallisation or co-distillation with alcohols was not found to be suitable as esters are formed as by-products by these purification attempts. If hexane is replaced by toluene the intermediate (II) may be in situ converted into pyrrolone (I) using the same reactor.

EXAMPLE 2: API SYNTHESIS METHOD - LACTONISATION

API formation and synthesis of hydroxypyrrolones (I) from arylated furanone intermediates (II) was carried out. The reaction in this stage was conducted at -10°C-50°; preferably in steps below room temperature and then completion of conversion from lactone to lactame is achieved at 10-40°C.

Suitable amine was in the range of 1.1 to 3 equivalent by molecular weight; preferably about 1.2 equivalents was used in this reaction step to obtain higher yield in presence of 1.1-1.5 equivalent by molecular weight of tertiary amine.

The addition of tertiary amines appeared as a key factor to save 1 eq of expensive amines as fluoro-benzyl amine. This also unexpectedly improved the yield and purity in the preparation of the API (I) from the intermediates (II). Inorganic bases, such as hydrogen carbonate led to complex mixtures.

All tertiary amines, such as trietylamine and tri-isopropyl amine accelerated the rate of lactonisation, thus allowing a reduction of the reaction temperature, which also led to cleaner API formation. Organic solvent

Scheme 3. Sites for nucleophilic attacks, role of adjunct amine, ring-opening ringclosure lactonisation The adjunct tertiary amine is controlling the selectivity of the nucleophilic attack of the primary amine. In addition, by reducing reactant amine for costly amines, such as fluorinated amines and expensive amines the production costs are reduced further.

The furanone system has various sites for attacks, such as the IPSO substitution in the 4- position and the lactonisation (5 position). Secondary amines react at the 4 and 5 position. The combination of a primary with a tertiary amine resulted in increasing yield, provided API (I) in high purity and saved costs as amine in excess was only applied in equimolar range (1.1-1.2 eq).

Table 2 describes how the method for lactonisation was further optimised in a stepwise manner, leading to most preferred aprotic conditions and equimolar use of amine with tertiary amine adjunct and low reaction temperatures Table 2: Optimisation of methods, API stage (I)

The adjunct amines, tri-isopropyl amine and triethyl amine were found chemically equivalent. They appear to be acting at various stages of the mechanism, a ring opening ring closure reaction, possibly via SN2‘ reaction. Here, the carboxylic acid may be activated by the adjunct amine, allowing the primary amine to form initially the amide and then via the shown tautomeric form of the allyl chloride structure, forming the lactone in high yield and very high purity.

The organic solvent selected from ether, halo-hydrocarbon etc was used in this step; preferably methyltertiarybutylether is used. Polar solvents favour the reaction in the 4- position and secondary amine and gave a mixture of products.

Most preferred is the reaction of primary amine (benzylamine, fluorobenzylamine, isopropylamine and phenylethylamine) in the presence of a tertiary amine (triethyl amine, triisopropylamine), present in equimolar ratios to be added as a mixture of amines.

Further isolation of compound of formula (I) can be done by a conventional isolation method such as precipitation, solvent evaporation etc. Using toluene, the process can be performed in situ.

The compounds of formula (I) are further isolated by recrystallization from a solvent preferably toluene and excessive washing with water removing by products and reactants. No chromatography is applied to this process also. The clean process under fully optimised reaction conditions makes sophisticated purification stages redundant. EXAMPLE 3: SYNTHESIS OF 2(5H)- FURANONE INTERMEDIATES 1-1, 1-2 AND 1-3

Furanone intermediates of Formula (II) viz., 3,4-dichloro-5-phenylfuran-2(5H)-one (1-1), 3,4-dichloro-5-p-fluoro-phenylfuran-2(5H) one(I-2); 3,4-dichloro-5-p-chlorophenylfuran- 2(5H)-one (1-3) were synthesised, preferably by the optimised method 4 and most preferred by method 4.2.1 as mentioned in Table 1 above.

Synthesis of Intermediate 1-1: 3,4-dichloro-5-phenylfuran-2(5H)-one (1-1)

Aluminium chloride (296.4 gram) was added to the reactor to form a suspension in dichloromethane (2500ml). Mucochloric acid (250 gm) was added into a reaction flask. Subsequently at 0-5°C benzene (275 ml) was added and stirred for 150 minutes at 0- 10°C. The reaction mass was quenched with concentrated 25 HC1 (0.75 litre) and stirred for 30 minutes. The layers were separated and the organic layer was washed with water followed by the organic layers were combined and distilled out under vacuum at 35-50°C.

To the residue, petroleum ether (2500 ml) was added and stirred for 60-120 minutes at 5- 10°C followed by the precipitation was filtered and washed with petroleum ether (500 mL) and dried. Yield: 160 grams.

Synthesis of Intermediate 1-2: 3,4-dichloro-5-p-fluoro-phenylfuran-2(5H) one(I-2)

Aluminium chloride (296.4 gram) was added to form a suspension in dichloromethane (2500ml)

Mucochloric acid (250 gm) was added into a reaction flask. Subsequently at 5-10°C fluoro-benzene (270 ml) was added and stirred for 150 minutes at RT. The reaction mass was quenched with concentrated 25 HC1 (0.75 litre) and stirred for 30 minutes. The layers were separated and the organic layer was washed with water followed by the organic layers were combined and distilled out under vacuum at 35-50°C.

To the residue, petroleum ether (2500 ml) was added and stirred for 60-120 minutes at 5- 10°C followed by the precipitation was filtered and washed with petroleum ether (500 mL) and dried. Yield: 120 grams. Synthesis of Intermediate 1-3: 3,4-dichloro-5-p-chlorophenylfuran-2(5H)-one

Aluminium chloride (296.4 gram) was added to a round bottom flask to form a suspension in dichloromethane (2500ml). Mucochloric acid (250 gm) was added into a reaction flask. Subsequently at 5-10°C fluorobenzene (275 ml) was added and stirred for 150 minutes at RT. The reaction mass was quenched with concentrated 25 HC1 (0.75 litre) and stirred for 30 minutes. The layers were separated and the organic layer was washed with water followed by the organic layers were combined and distilled out under vacuum at 35-50°C.

To the residue, petroleum ether (2500 ml) was added and stirred for 60-120 minutes at 5- 10°C followed by the precipitation was filtered and washed with petroleum ether (500 mL) and dried. Yield: 130 grams.

EXAMPLE 4: SYNTHESIS OF 5-HYDROXY5-ARYL-PYRROL-2-ONES OF FORMULA (I) [API-1 to API-7]

Synthesis of API-1:

The intermediate compound 1-1 was added to a reaction flask containing methyltertiary butylether (1150 mL) at 10°C followed by 2-phenylethylamine (56 gram) and triethyl amine (58g) was added under stirring for 60 minutes at 0-10°C. Temperature was raised to 40°C and stirred for 2 hours. Water (1000 ml) was added to the reaction mass and the layers were separated. The organic layer was washed with water and then filtered. The filtrate containing the organic layer was distilled under vacuum at 50°C. Yield: 180 grams of 5-hydroxy-l-phenethyl-5-phenyl-lH-pyrrol-2(5H)-one (API-1).

Purification 5-hydroxy-l-phenethyl-5-phenyl-lH-pyrrol-2(5H)-one:

The crude API-1 5-hydroxy-l-phenethyl-5-phenyl-lH-pyrrol-2(5H)-one (150 gram) obtained above was dissolved in dichloromethane (2300 ml) and washed with hyflo bed with dichloromethane (100 ml) followed by filtered through hyflo bed and top wash with dichloromethane (100 ml). The filtrate was distilled under vacuum at 45-50°C to obtain a solid. Water (900 mL) was added to the solid and stirred for 30 minutes, filtered and washed with water (100 mL). The wet solid was dried to obtain pure 5 -hydroxy- 1- phenethyl-5-phenyl-lH-pyrrol-2(5H)-one. Yield: 76 grams. Purity: 100% (by HPLC); Moisture content: 0.08%. Alternatively, the crude products may be recrystallized from toluene.

Synthesis of API-2:

The intermediate 1-2 was added to a reaction flask containing methyl-tertiary butylether (1150 mL) at 10°C followed by fluoro-benzylamine (56 gram) and triethyl amine (58g) was added under stirring for 60 minutes at 0-10°C. Temperature was raised to 40°C and stirred for 2 hours. Water (1000 ml) was added to the reaction mass and the layers were separated. The organic layer was washed with water and then filtered. The filtrate containing the organic layer was distilled under vacuum at 50°C. Yield: 160 grams of 4- Chloro-5-(4-fluoro-phenyl)-5-hydroxy-l-p-fhiorobenzyl-l,5-di hydro-pyrrol-2-one (API- 2). Tri-isopropylamine was used alternatively to triethylamine and yields and purity are not significantly different.

Purification:

10g of 4-Chloro-5 -(4-fluoro-phenyl)-5 -hydroxy- 1 -p-fluorobenzyl- 1 ,5 -dihydro-pyrrol-2- one was dissolved in a mixture of 60% water and 40% ethanol under reflux. Cooling overnight provided a crystalline material in very high purity (>99.7%). Alternatively, the crude material is heated in pure ethanol and 50% hot water was added to give an increasingly clouding mixture, from which crystals formed over night at RT. This crystalline material, re -crystallised from hot toluene, provided an amorphous powder.

The following final API molecules were also prepared through cognate method :

The 5-hydroxy-l-phenethyl-5-phenyl-lH-pyrrol-2(5H)-one (API-1) and the other APIs were further purified by a method comprising; a) Dissolution of the API in halo- hydrocarbon solvent, preferably selected from trichloromethane, dichloromethane, 1,2- dichloroe thane and the like; b) Distillation of the solution obtained in step (a) under vacuum at 30-50°C, c) Drying the solid obtained in step (b); and d) re -crystallization of the API from toluene and washing with excess water.

The process according to the present invention provides 5-hydroxy-l-phenethyl-5- phenyllH-pyrrol-2(5H)-one, 4-Chloro-5-(phenyl)-5-hydroxy-l-isobuyl-l,5-dihydro- pyrrol-2-one; 4-Chloro-5-(4-fluoro-phenyl)-5-hydroxy-l-isobutyl-l,5-dihydr o-pyrrol-2- one ; 4-Chloro-5 -(4-fluoro-phenyl) -5 -hydroxy- 1 -benzyl- 1 ,5 -dihydro-pyrrol-2 -one ; 4- Chloro-5-(4-fluoro-phenyl)-5-hydroxy-l-p-fluorobenzyl-l,5-di hydro-pyrrol-2-one; 4- Chloro-5-(4-phenyl)-5-hydroxy-l -phenethyl-1 ,5-dihydro-pyrrol-2-one; 4-Chloro-5-(4- chloro-phenyl)-5-hydroxy-l-phenethyl-l,5-dihydro-pyrrol-2-on e; 4-Chloro-5-(4-Fluoro- phenyl) -5 -hydroxy- 1 -phenethyl-1, 5-dihydro-pyrrol -2 -one having purity >99%; preferably>99.7%; more preferably >99% (by HPLC).

The present invention also covers a polymorph or amorphous form of 5 -hydroxy- 1- phenethyl-5-phenyl-lH-pyrrol-2(5H)-one and other APIs obtained according to the process disclosed herein. Recrystallisation from ethanol water mixtures provided highly crystalline material and the crystallisation from toluene provided us with amorphous powders. This applied to the series of API (I). Bioavailability is increased for the microcrystalline material and this is useful for the arylated examples, occurring a lower bioavailability in general compared to the alkylated examples.