SUBSTITUTED FLAVONES

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of a key intermediate (as described herein) used in the synthesis of {+)-trans enantiomer of pyrrolidine substituted flavones, represented by the compounds of formula (1 ) or pharmaceutically acceptable salts thereof; which are inhibitors of cyclin dependant kinases (CDKs) and can be used in the treatment of proliferative disorders such as cancer.

BACKGROUND OF THE INVENTION

The cell-division cycle is a process that is regulated by the cyclin dependent kinases (CDKs). Stringent control of this process is essential to ensure that DNA synthesis and subsequent mitotic division are accurately and coordinately executed (Current Opinion in Genetics & Development, 1999, 9, 104-1 1 1 ). A wide variety of diseases are characterized by uncontrolled cell proliferation that results from defects in the regulatory pathways in the cell cycle. The overexpression of cyclin D1 leads to the deregulation of CDK4-D1 kinase activity and thereby contributes to uncontrolled cell proliferation. The CDKs, their regulators, and substrates are the targets of genetic alteration in many human cancers. As a result of this, the CDKs have been targeted for drug discovery and a number of small molecule inhibitors of CDKs have been identified.

CDK inhibitors namely (+)-trans enantiomer of pyrrolidine substituted flavones have been disclosed in US Patent 7,271 ,193. These compounds have been reported to exhibit good selectivity for inhibition of CDK4-D1 , CDK1 -B and CDK9-T1 and potent antiproliferative effects against various human cancer cell lines (Molecular cancer therapeutics, 2007, 6, 3, 918-925). The compounds disclosed in the aforesaid patent have two chiral centers and hence, can exist as four enantiomers i.e. {+)-trans, (-)- trans, (+)-c/ ^' s and (-)-c/ ^' s.

In general, the use of both enantiomers in a racemic formulation of a chiral drug may be unnecessary, and sometimes even introduces extraneous material that may lead to undesired side effects or adverse reactions. Chirality plays an important role in the function of biological processes. The macromolecules in our body, such as proteins and enzymes, are able to discriminate between the two enantiomers, interacting favorably with one isomer while producing potentially adverse effects with the other isomer (Australian Prescriber, 2004, 27, 2, 47-49). The pure single enantiomer provides safer and more effective alternatives to racemates. It is well established that the pharmacological activity is mostly restricted to one of the enantiomers and the individual enantiomers of racemic drugs frequently differ in their biological effects. In many cases, the inactive enantiomer shows unwanted side effects or even toxic effects. For pharmacological studies of such drugs, there is, therefore a need for an effective means of separating and quantifying the enantiomers in biological samples. The chiral switch process (racemate to single enantiomer) has resulted in a number of agents being re-marketed as single enantiomer products. Analytical methods which have been used for enantioseparation include diastereomeric crystallization, biocatalysis, chromatographic techniques (thin layer chromatography, gas chromatography, supercritical and sub-critical fluid chromatography, high-performance liquid chromatography), affinity electrokinetic chromatography and electromigration techniques (capillary electrophoresis and capillary electrochromatography) (International Journal of Pharm. Tech. Research, 2010, 2, 2, 1584-1594).

In the case of the compounds of Formula (1 ), it has been observed that only the (+)-trans enantiomers have CDK inhibitory activity while the (-)-trans enantiomers are inactive. An extensive study by the inventors of the efficacy of the racemic compounds of Formula (1 ) and their separate enantiomers has resulted in the applicant's PCT Publication WO2007148158. The said PCT Publication WO2007148158 describes a synthesis of the (+)-trans enantiomer of pyrrolidine substituted flavones with improved yield and purity by using (-)-dibenzoyl tartaric acid ((-)-DBTA) as a chiral reagent. PCT Publication WO2008007169 describes the enantioselective synthesis of {+)-trans enantiomer of pyrrolidine substituted flavones.

Administration of the active {+)-trans enantiomer of the compounds represented by Formula (1 ), substantially free of its other isomers, would essentially enable a reduction in the dose of drug. Due to the importance of the {+)-trans enantiomers of the compounds represented by Formula (1 ) as inhibitors of cyclin dependant kinases, there exists a need to develop an economical and efficient synthetic process for their production.

The process as described in the PCT publication WO2007148158 involves resolution of an intermediate compound and subsequent conversion of the resolved intermediate compound to the compound represented by Formula (1 ). For instance, (+)- irans-2-(2-chlorophenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1 -methyl-pyrrolidin-3-yl)- chromen-4-one was prepared by resolution of an intermediate, namely (±)-frans-[1 - methyl-3-(2,4,6-trimethoxy-phenyl)-pyrrolidin-2-yl]-methanol , and subsequent conversion of the {-)-trans isomer of the intermediate to (+)-frans-2-(2-chlorophenyl)- 5,7-dihydroxy-8-(2-hydroxymethyl-1 -methyl-pyrrolidin-3-yl)-chromen-4-one. The preparation of the (-)-frans-isomer of the intermediate involves the steps of treating its racemate with a chiral auxiliary to obtain the corresponding (+)- and (-)-trans diastereomeric salts followed by separating the desired diastereomeric salt by crystallization and treating it with a base to yield the desired {-)-trans enantiomer. This resolution method involves significant processing and also the use of resolving agent renders the process costly. Partial recycling of the resolving agent is feasible but such recycling is costly as it requires additional processing and is also associated with waste generation. The undesired enantiomer cannot be recycled and is therefore discarded. The maximum theoretical yield of the key intermediate obtained is just 50 % on a laboratory scale synthesis due to loss of half of the racemate. This yield may be further reduced due to the need for high chiral purity (> 97 % enantiomeric excess).

In fact, the processes for the preparation of the compounds of formula (1 ) reported in the prior art have certain drawbacks, for instance, the processes are lengthy, involve usage of high reaction temperature, use of toxic solvents such as chloroform or carbon tetrachloride, and further, the processes provide the compounds in low yield and less purity. Moreover, the prior art process involving use of excess of resolving agent (-) DBTA renders the process costly.

Thus, there is a need for an improved process for the synthesis of the desired (+)-trans enantiomer of the compounds of formula (1 ), which provides for an efficient large-scale synthesis of the desired compound having high purity. It is also desirable to have a cost-effective synthesis.

Accordingly, the present invention provides a process for the preparation of the compound of formula A which is a key intermediate used in the synthesis of the (+)- trans enantiomer of the compounds of formula (1 ). The present invention also involves synthesis of the compounds of formula (1 ) from the compound of formula (A) in an efficient and cost-effective manner.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to a process for the preparation of an enantiomerically pure {-)-trans enantiomer of a compound, represented by formula A (as presented herein); which is a key intermediate (the chiral precursor) of the compound of formula (1 ) or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a process for the preparation of an enantiomerically pure {+)-trans enantiomer of a compound, represented by formula (1 ) (as presented herein) or a pharmaceutically acceptable salt thereof; from the compound of formula A.

DETAILED DESCRIPTION OF THE INVENTION

For the purpose of the disclosure, listed below are definitions of various terms used to describe the compounds of the present invention. These definitions apply to the terms as they are used throughout the specification. They should not be interpreted in the literal sense. They are not general definitions and are relevant only for this application.

It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, as well as represents a stable compound, which does not readily undergo transformation such as by rearrangement, cyclization, elimination, etc.

The term "racemic" or "racemate" refer to generally equimolar proportions of a (+)-enantiomer and a (-)-enantiomer of a compound in a composition.

The term "enantiomeric excess" (ee) refers to a difference between the amount of one enantiomer and the amount of the other enantiomer that is present in the product mixture (racemate). Thus, for example, enantiomeric excess of 96 % refers to a product mixture having 98 % of one enantiomer and 2 % of the other enantiomer.

The term "enantiomerically pure" refers to a compound or compounds that is or are present in enantiomeric excess of greater than 95 %. Preferably, the enantiomeric excess is greater than 97 %. More preferably, the enantiomeric excess is greater than 99 %.

The term "substantially free" means that the amount of the desired enantiomer predominates in composition relative to the undesired enantiomer. In the present invention, the term "substantially free" means that the amount of the {+)-trans enantiomer predominates the composition relative to the {-)-trans enantiomer of the compound of formula (1 ). More specifically, this means that the amount of the {+)-trans enantiomer relative to the {-)-trans enantiomer by weight is at least about 95 %, more preferably greater than 97 %. The term "pharmaceutically acceptable salt(s)", as used herein, unless otherwise indicated, includes salts of basic or acidic groups of the compound of the invention, which groups are capable of forming salts. In case the compounds according to formula (1 ) contain one or more acidic or basic groups, the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts. Compounds of formula (1 ) which contain one or more basic groups, i.e. groups which can be protonated and can be used according to the invention in the form of their addition salts with non-toxic inorganic or organic acids. Examples of suitable inorganic acids include: boric acid, perchloric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and other inorganic acids known to the person skilled in the art. Examples of suitable organic acids include: acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2- acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, ketoglutaric acid, benzenesulfonic acid, glycerophosphoric acid and other organic acids known to the person skilled in the art. The compounds of formula (1 ) which contain acidic groups can be used according to the invention, for example, as alkali metal salts like lithium (Li), sodium (Na), and potassium (K) salts. The pharmaceutically acceptable salts of the present invention can be synthesized from the subject compound which contains a basic or acidic moiety by conventional chemical methods. Generally the salts are prepared by contacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or dispersant or by anion exchange or cation exchange with other salts. Suitable solvents are, for example, esters, ethers, alcohols, ketonic solvents, or mixtures of these solvents.

The present invention is specifically directed to a process for the preparation of a compound of formula A, which is a key intermediate used in the synthesis of an enantiomerically pure compound of formula (1 ). As mentioned hereinbefore the compounds disclosed in the applicant's US Patent 7,271 ,193 have two chiral centers and hence, can exist as four enantiomers namely {+)-trans, {-)-trans, (+)-c/ ^' s and (-)-c/ ^' s. The efficacy of the racemic compound disclosed in the US Patent 7,271 ,193 and its separate enantiomers have been extensively studied. It has been observed that only the {+)-trans enantiomer is active as a CDK inhibitor. The present invention relates to a process for the preparation of an enantiomerically pure (+)-trans enantiomer pyrrolidines substituted with flavones represented herein by formula (1 );

Formula (1 )

wherein R- _\ is a phenyl group, which is unsubstituted or substituted by one or two identical or different substituents selected from: chloro, nitro and trifluoromethyl; or a pharmaceutically acceptable salt thereof; from the compound of formula A.

The compounds of formula (1 ) are useful in inhibiting CDKs, particularly CDK4/cyclinD1 complexes and find use as anti-proliferative agent in the treatment of diseases characterized by excessive cell growth such as cancers, immunological disorders involving unwanted proliferation of leukocytes and other proliferative smooth muscle disorders.

The process of the present invention primarily involves an improved process for the preparation of a chiral intermediate represented by formula A, which is economical and efficient. The improved process has advantages such as lower reaction temperature and is simple, consistent, cost-effective and avoids use of toxic solvents such as chloroform or carbon tetrachloride. Moreover, the process of the present invention provides the desired (+)-trans enantiomer represented herein by formula (1 ) in higher yield and better purity.

The process of the present invention primarily involves the resolution of a mixture of enantiomers (racemate) to yield a key intermediate represented by formula A using a relatively low amount of a resolving agent.

Formula A

(racemic mixture of enantiomers)

The process of the present invention involves separation of the mixture of enantiomers by coupling of the mixture of enantiomers with a relatively low amount of auxiliary chiral reagent to obtain the corresponding mixture of diastereomeric salts of the (+)- and (-)-enantiomers of formula A, separating the respective diastereomeric salts and converting the diastereomeric salt of the (-)- enantiomer with a base to obtain the free base of the desired (-)-enantiomer of the compound of formula A. The chiral purity of the compound obtained according to the present invention is 97 % ee.

The compound of formula A as {-)-trans enantiomer, a key intermediate in the preparation of the compound of formula (1 ), can be prepared as outlined in following Scheme 1 A.

Compound of Formula A

(-)-trans enantiomer

SCHEME 1 A Therefore, in one aspect of the present invention, there is provided a process for the preparation of enantiomerically pure compound, (-)-frans-(1 -methyl-3-(2,4,6- trimethoxyphenyl)pyrrolidin-2-yl)methanol, represented by the formula A; which process comprises:

(a) treating 1 ,3,5-trimethoxybenzene (compound of formula I I) with N-methyl-4- piperidone (compound of formula III) in the presence of acetic acid and concentrated HCI to obtain a compound of formula IV;

(b) reacting the compound of formula IV with sodium borohydride and boron trifluoride diethyletherate (BF ₃ .Et ₂ 0) in a solvent to obtain a compound of formula V as a mixture of enantiomers of relatively trans configuration;

(c) reacting the compound of formula V with methanesulfonyl chloride and triethylamine to obtain the compound of formula VI, which is further reacted with a base in an alcoholic solvent as a reaction medium to obtain the compound of formula VII as a mixture of enantiomers having relatively trans configuration;

(d) reacting the compound of formula VII (mixture of enantiomers) with sodium hydroxide to obtain a mixture of (-)-frans-[1 -methyl-3-(2,4,6-trimethoxy-phenyl)- pyrrolidin-2-yl]-methanol (VIII) and (+)-frans-[1 -methyl-3-(2,4,6-trimethoxy-phenyl)- pyrrolidin-2-yl]-methanol (IX);

(e) reacting the mixture of compounds as obtained in step (d) with 0.5 to 0.7 eq. of (-)- DBTA ((-)-dibenzoyl tartaric acid monohydrate) as a chiral auxiliary in the presence of 0.3-0.5 equivalent of concentrated HCI in a solvent to yield the crystallized dibenzoyl tartarate salts of (+)- and (-)-frans-[1 -methyl-3-(2,4,6-trimethoxy-phenyl)- pyrrolidin-2-yl]-methanol;

(f) separating the crystallized dibenzoyl tartarate salts of (+)- and (-)- [1 -methyl-3- (2,4,6-trimethoxy-phenyl)-pyrrolidin-2-yl]- methanol obtained in step (e) above and converting the desired (-)-dibenzoyl tartarate salt of compound of formula A to its free base by treatment of the diastereomeric salt with a base in a solvent to obtain the enantiomerically pure {-)-trans enantiomer of compound of formula A.

The reaction steps (a) and (b) involving preparation of the compound of formula (V) starting from the compound of formula (II) are described in US Patent 4,900,727. In the conversion of the compound of formula (V) to that of compound of formula A, the hydroxyl function on the piperidine ring may be converted to a leaving group such as tosyl, mesyl, triflate or halide by treatment with an appropriate reagent such as p- toluenesulfonyl chloride, methanesulfonyl chloride, triflic anhydride or phosphorous pentachloride in the presence of a base selected from triethylamine, pyridine, potassium carbonate or sodium carbonate _, followed by ring contraction in the presence of a base selected from sodium acetate or potassium acetate in an alcoholic solvent selected from isopropanol, ethanol or n-propanol. However, certain improvements have been introduced in the steps (a) and (b) of the process of the present invention in order to have a more efficient and cost-effective process.

In an embodiment, the reaction in step (a) of Scheme 1 A is carried out at a temperature ranging from 25 - 30 °C (room temperature).

The hydroboration reaction of step (b) of Scheme 1 A is carried out with powdered sodium borohydride, improving the diborane generation and increasing purity of the product, compound of formula V from 70 % to 85 %.

The solvent used in step (b) of Scheme 1 A is selected from tetrahydrofuran, 2- methyltetrahydrofuran, dioxane, diethylether or diisopropylether. In one embodiment, the solvent used in step (b) of Scheme 1 A is tetrahydrofuran.

The compound of formula V obtained in step (b) of Scheme 1 A is telescoped to next step without isolation.

In step (c) of Scheme 1 A the compound of formula V is subjected to methylsulfonation followed by ring-contraction reaction with a base selected from sodium acetate or potassium acetate in the presence of an alcoholic solvent selected from methanol, ethanol, 1 -propanol, isopropyl alcohol, n-butanol t-butanol, isobutanol or 2-butanol to obtain the compound of formula VII.

Preferably, the alcoholic solvent used in the ring-contraction reaction is isopropyl alcohol while the base used is sodium acetate.

The compound of formula IX obtained in step (d) of Scheme 1 A by hydrolysis of the compound of formula VII is extracted with an ether selected from diethyl ether, diisopropyl ether or diisobutyl ether to obtain compound of formula IX having an HPLC purity of 95 % a/a. Preferably, the solvent used for extraction of compound of formula IX is diisopropyl ether.

The chiral auxiliary used in the resolution step is (-)-dibenzoyl tartaric acid ((-)- DBTA). Preferably, (-)-DBTA monohydrate is used. The base used in the resolution step may be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium carbonate or potassium carbonate.

In an embodiment, the base used in the resolution step is sodium carbonate or sodium hydroxide.

In an embodiment, the solvent used in step (e) of Scheme 1 A may be selected from methanol, ethanol, n-propanol, 1 -butanol, 2-butanol, amyl alcohol, isopropanol, acetone or acetonitrile, or a mixture of any one or more of the solvents with water.

In an embodiment, the process involving resolution of the intermediate compound of Formula A comprises reacting the racemate of the compound of formula A with 0.5 to 0.7 equivalent of (-)-DBTA ((-)-dibenzoyl tartaric acid) as a chiral auxiliary in the presence of 0.3 to 0.5 equivalent of concentrated HCI and alcohol as a solvent.

In another embodiment, the process involving resolution of the intermediate compound of Formula A comprises reacting the racemate of the compound of formula A with 0.6 equivalent of (-)-DBTA ((-)-dibenzoyl tartaric acid) as a chiral auxiliary in the presence of 0.4 equivalent of concentrated HCI and methanol as the solvent.

In a further embodiment, the solvent used in step (f) of Scheme 1 A is selected from ethyl acetate, isopropyl acetate or methylene dichloride.

In an embodiment, the solvent used in step (f) of Scheme 1 A is isopropyl acetate. In another embodiment, the solvent used in step (f) of Scheme 1 A is ethyl acetate.

The enantiomeric purity of compound of formula A obtained by the process of the present invention was evaluated and compared with that obtained by using the resolution process reported in the aforesaid published US Patent 7,271 , 193 using chiral HPLC. It was established that compound of formula A obtained according to the process of the present invention is a single isomer with a chiral purity of 97 % ee, whereas compound of formula A was obtained in 88.3 % ee when prepared according to the process disclosed in the US Patent 7,271 ,193.

Further, the process according to the present invention is simpler and more cost effective than the known process as it involves a single step reaction to obtain the diastereomeric salt, namely the dibenzoyi tartrate salt. The present process involves a single crystallization. Moreover, use of the chiral auxiliary (-)-DBTA has the advantage in that it is comparatively cheaper than (+)-DBTA, which is used in the process reported in the published US Patent 7,271 ,193. PCT Publication WO2007148158 describes a synthesis of the (+)-trans enantiomer of pyrrolidine substituted flavones with improved yield and purity by using (-)-dibenzoyl tartaric acid ((-)-DBTA) as an auxiliary chiral reagent. The present invention provides the additional advantage that the resolution step was carried out with about 0.6 eq. of (-)-DBTA. Therefore, usage of about 0.4 eq. of the resolving agent (-)-DBTA was avoided, which is desirable as it renders the entire process cost-effective.

In an aspect, the present invention relates to a process for the preparation of the compound of formula (1 ) from the key intermediate i.e. (-)-trans enantiomer of the compound of formula A as outlined in the following Scheme 1 B.

(-)-trans isomer of Formula A XI

Formula (1 ) Formula (1) as HCI salt

SCHEME 1 B

Accordingly, there is provided a process for the preparation of an enantiomerically pure {+)-trans enantiomer of a compound of formula (1 ), or a pharmaceutically acceptable salt thereof, from the enantiomerically pure {-)-trans enantiomer of compound of formula A, which process comprises:

(i) treating the resolved enantiomerically pure {-)-trans enantiomer of the compound of formula A, with acetic anhydride in the presence of a Lewis acid catalyst to obtain the corresponding acetylated compound of formula (X); (ii) reacting the acetylated compound of formula (X) with an acid of formula RiCOOH or an acid chloride of formula R ₁ COCI or an acid anhydride of formula (RiCO) ₂ 0 or an ester of formula R ₁ COOCH ₃ , in the presence of a base and a solvent to obtain a compound of formula (XI);

(iii) treating the compound of formula (XI) with a base in a solvent to obtain the corresponding β-diketone as compound of formula (XIII);

(iv) treating the resolved β-diketone compound of formula (XI II) with an acid such as hydrochloric acid in a solvent to obtain the corresponding cyclized compound of formula (XIV);

(v) subjecting the compound of formula (XIV) to dealkylation by heating it with a dealkylating agent at a temperature ranging from 160-180 °C to obtain the (+)- trans enantiomer of the compound of formula (1 ); and,

(vi) preparing the pharmaceutically acceptable salt of the compound of formula (1 ), by treating the said compound of formula (1 ) with an acid or a base in a solvent.

The Lewis acid catalyst in step (i) of Scheme 1 B is selected from BF ₃ . Et ₂ 0 (boron trifluoride etherate), BF ₃ .CH ₃ COOH (boron trifluoride-acetic acid), BF ₃ .THF (boron trifluoride-tetrahydrofuran), zinc chloride, aluminium chloride or titanium chloride. The preferred Lewis acid catalyst is BF ₃ . Et ₂ 0.

The solvent used for extraction in step (i) is selected from dichloromethane or ethyl acetate. The preferred solvent is dichloromethane.

The base used in the process of step (ii) of Scheme 1 B is selected from triethylamine, pyridine, N-methyl morpholine or a combination of DCC (Ν,Ν'- dicyclohexylcarbodiimide) and DMAP (4-dimethylaminopyridine). The preferred base is triethylamine.

The solvent used in step (ii) is selected from dichloromethane, DMF (N,N- dimethylformamide) or THF (tetrahydrofuran). The preferred solvent is dichloromethane. The base used in step (iii) is selected from lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, sodium hydride, sodium amide or potassium hydride. The preferred base is sodium hydride.

The solvent of step (iii) of Scheme 1 B is selected from DMF, dioxane, NMP (N- methyl-2-pyrrolidone), dichloromethane or THF. The preferred solvent is DMF.

The solvent used for extraction of the compound of formula XIII as obtained in step (iii) is selected from THF or dichloromethane. The preferred solvent is dichloromethane.

It is apparent to those skilled in the art that the rearrangement of the compound of formula (XI) to the corresponding β-diketone compound of formula (XI II) (corresponding to step (iii) of Scheme 1 B) is known as a Baker-Venkataraman rearrangement (J. Chem. Soc, 1381 (1933) and Curr. Sci., 4, 214 (1933)). It is a base- catalyzed rearrangement of o-acyloxyketones to β-diketones, important intermediates in the synthesis of chromones and flavones.

The solvent used in step (iv) is an alcohol selected from methanol, ethanol, isopropanol, n-propanol, n-butanol t-butanol, 2-butanol or isobutanol The preferred solvent is isopropanol.

The purification of compound of formula XIV as obtained in step (v) is carried out with methyl ethyl ketone which yields a compound having an HPLC purity of 90 % a/a.

The dealkylating agent used in step (v) for the dealkylation of the compound of formula (XIV) is selected from pyridine hydrochloride, boron tribromide, boron trifluoride etherate, anhydrous aluminium chloride, iodocyclohexane, aqueous HBr (hydrobromic acid), L-methionine, a mixture of thiourea and anhydrous aluminium chloride or 2- (diethylamino)ethane thiol hydrochloride. The preferred dealkylating agent is pyridine hydrochloride.

The compound of formula (1 ) as obtained in step (v) above is converted to its pharmaceutically acceptable salt such as hydrochloride salt. Thus, the step (vi) involving preparation of hydrochloride salt of the compound of formula (1 ) is carried out using hydrochloride gas dissolved in isopropyl alcohol (IPA.HCI) in the presence of a solvent selected from methanol, ethanol, isopropanol, diethyl ether, diisopropyl ether or a combination thereof. Preferably, the solvent used in step (vi) is a mixture of methanol and diisopropyl ether. The purity of compound of formula (1 ) obtained by this process is 97 % a/a. Representative examples of the compound of formula (1 ) which is prepared from the key intermediate, the compound of formula (A) include: (+)-irans-2-(2- chlorophenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1 -methyl-pyrrolidin-3-yl)-chromen-4- one or its hydrochloride and (+)-frans-2-(2-Chloro-4-trifluoromethyl-phenyl)-5,7- dihydroxy-8-(2-hydroxymethyl-1 -methyl-pyrrolidin-3-yl)-chromen-4-one or its hydrochloride.

The following examples which fully illustrate the practice of the preferred embodiments of the present invention are intended to be for illustrative purpose only and should not be construed in any way to limit the scope of the present invention.

Examples

The following abbreviations/terms are used herein:

a/a : Area/Area

BF ₃ . Et ₂ 0 : Boron trifluoride diethyl etherate

CDK : Cyclin-dependent kinases

cone. : Concentrated

(-)DBTA : (-) Dibenzoyl tartaric acid monohydrate

DCC-DMAP : Λ/,Λ/'-Dicyclohexylcarbodiimide - 4-dimethylaminopyridine

CDCI ₃ : Deuterated chloroform

DMAP : (N,N-dimethylamino)pyridine

DMF : Ν,Ν-Dimethyl formamide

eq. : Equivalent

ee : Enantiomeric excess

g : Gram

GC : Gas Chromatograph

h : Hours

HCI : Hydrochloric acid

HPLC : High Performance liquid chromatogram

Hg : Mercury

IPA : Isopropanol

KBr : Potassium Bromide

Kg : Kilogram

L : Litre

min : Minutes mL Millilitre

mm Millimetre

M.P Melting point

NLT Not less than

THF Tetrahydrofuran

w/w Weight by weight

Example 1 :

1-Methyl-4-(2,4,6-trimethoxyphenyl)-1 ,2,3,6-tetrahydropyridine

To a solution of acetic acid (600 mL) and 1 ,3,5-trimethoxybenzene (500 g), was added 340 g of N-methyl-4-piperidone over a period of 1 - 2 h at 20 - 25 °C. To the resulting mixture, 450 mL of cone. HCI was added over a period of 1 - 2 h at 20 - 25 °C and maintained for 20 - 30 h till 1 ,3,5-trimethoxybenzene was not more than 25 % by HPLC. After completion of reaction, the mixture was quenched in 4850 mL of chilled water (5 - 10 °C). The reaction mixture was washed with 1 L of toluene, aqueous layer was separated and adjusted the pH to 1 1 - 12 using 1 L of 50 % sodium hydroxide solution at 5 - 10 °C to precipitate out the solid. The resulting solid was filtered and dried under vacuum (NLT 650 mm of Hg) at 50 - 60 °C until moisture content was not more than 0.5 %.

Yield: 550 g, 71 %; HPLC purity: 98 % a/a; Melting Point (M.P): 1 12 -1 14 °C; IR(KBr): 3045, 2900, 1600, 1585 cm ^"1 ; ¹ H NMR(CDCI ₃ , 300 MHz): δ 6.15(s, 2H), 5.55(s, 1 H), 3.85(s, 3H), 3.75(s, 6H), 3.10(d, 2H), 2.55(t, 2H), 2.40(s, 3H), 2.35(m, 2H); MS(EI): m/z 263 (M ⁺ ) Example 2:

(±)-frans-1 -Methyl-4-(2,4,6-trimethoxyphenyl)-piperidin-3-ol

To a solution of THF (3850 mL) and compound of example 1 (550 g) under nitrogen atmosphere, was added 99 g of powdered sodium borohydride at 20 - 25 °C. The resulting mixture was cooled to 0 - 5 °C, 605 mL of boron trifluoride diethyl etherate was added to it and slowly heated the reaction mixture to 50 - 55 °C and maintained for 1 h at 50 - 55 °C. After completion of the reaction, the mixture was cooled to 20 - 25 °C, 165 mL cold water and 687.5 mL of concentrated hydrochloric acid was slowly charged under stirring by maintaining the temperature between 20 - 25 °C. The reaction mixture was slowly heated to 50 - 55 °C and maintained at 50 - 55 °C for 1 h. The resulting mixture was gradually cooled to 20 - 25 °C, 687.6 mL of 50 % sodium hydroxide solution (pH should be 9 - 10) and 247.5 mL of 50 % hydrogen peroxide solution were added by maintaining the temperature of the reaction mixture at 20 - 25 °C. The reaction mixture was slowly heated to 50 - 55 °C and maintained at 50 - 55 °C for 1 h. After completion of reaction, 550 mL of cold water (15 - 20 °C) was charged and filtered through celite bed. The main filtrate was collected and the bed was washed with 3 x 550 mL ethyl acetate and stored the filtrate (ethyl acetate) in a separate container. The organic layer was separated from the main filtrate and washed the aqueous layer with the filtrate (ethyl acetate) collected in a separate container. The organic layers were combined and washed with 550 mL of 10 % brine solution. The organic layer was distilled out (THF and ethyl acetate) under vacuum at 40 - 45 °C and chased with 550 mL of ethyl acetate repeatedly till THF content in distillate by GC should be less than 0.5 %. To the resulting viscous liquid at 10 - 15 °C, was added 550 mL of 3.6 % dilute hydrochloric acid (Note: pH should be less than 1 ) at 15 - 20 °C and stirred for 5 -10 min to get a clear solution. The resulting solution was washed with 1 100 mL of isopropyl acetate, aqueous layer was separated and basified the aqueous layer using 192.5 mL of 50 % sodium hydroxide solution to pH 1 1 - 12 at 20 - 25 °C. The reaction mixture was extracted with 3 x 550 mL of ethyl acetate and washed the combined organic layer with 550 mL of brine solution. The aqueous layer was separated and further extracted with ethyl acetate. The combined organic layer was separated and dried over anhydrous sodium sulfate. The organic layer was distilled out completely under vacuum (NLT 650 mm of Hg) at 40 - 45 °C to yield a viscous liquid.

Yield: 440 g, 75 %; HPLC purity: 90 % a/a; IR (KBr): 3582, 3374, 3017 cm ^"1 ;

1 H NMR(CDCI ₃ , 300 MHz): δ 6.15(s, 2H), 4.40(m, 1 H), 3.79(s, 3H), 3.74(s, 6H), 3.20(dd, 1 H), 3.00(m, 1 H), 2.80(m, 1 H), 2.40(m, 1 H), 2.37(s, 3H), 2.00(m, 1 H), 1 .90(t, 1 H), 1 .52(m, 1 H); MS(CI): m/z 282 (M ⁺¹ )

Example 3:

(±)-frans-[1-Methyl-3-(2,4,6-trimethoxyphenyl)-pyrrolidin-2 -yl]-methanol

To a cooled solution of 1760 mL of THF and 440 g of compound of example 2 at 0 - 5 °C, was added 277.2 mL of triethylamine followed by drop-wise addition of 154 mL of methanesulfonyl chloride under nitrogen atmosphere, maintained for 1 h at 0 - 5 °C. After completion of the reaction, the reaction mixture was filtered through celite bed and the bed was washed with 660 mL of THF. The filtrate was collected in a separate container and stored below 5 °C under a nitrogen atmosphere. To another flask containing a solution of 2640 ml. of isopropyl alcohol and 257.4 g of sodium acetate maintained at 80 - 85 °C, was added the above filtrate stored below 5 °C over a period of 3 - 4 h, in such a way that THF was distilled out during the addition of mesylate. The reaction mixture was further maintained at 80 - 85 °C for 1 h. After completion of the reaction, the reaction mixture was cooled to 20 - 25 °C and pH was adjusted to 10 - 1 1 using 880 mL of 10 % sodium hydroxide solution at 25 - 30 °C. The reaction mixture was heated to 50 - 55 °C and maintained for 1 h. After completion of the reaction, the mixture was cooled to 20 - 25 °C and the layers were allowed to settle down. The upper isopropyl alcohol was separated and diluted with thrice the volume of isopropyl alcohol layer using ice cold water. The resulting solution was extracted with thrice the volume of isopropyl alcohol layer using ethyl acetate, organic layer was separated and the extraction of aqueous layer was carried out using the same volume of ethyl acetate as above. The organic layers were combined and washed with thrice the volume of isopropyl alcohol layer using brine solution. The organic layer was separated and dried over sodium sulfate. The organic layer was evaporated under vacuum at 45 - 50 °C to reduce the volume to 20 % (visual) to get a viscous liquid and extracted the viscous liquid with seven times the volume of the viscous liquid using diisopropyl ether at 60 - 65 °C. The extractions were repeated using thrice the volume of the viscous liquid using diisopropyl ether at 60 - 65 °C. The total organic layers were combined, evaporated under vacuum at 45 - 50 °C to reduce the volume to about 10 %, cooled to 5 - 10 °C and the precipitated solid was filtered. The bed was washed with 220 mL hexane, dried under vacuum (NLT 650 mm of Hg) at 35 - 40 °C for 10 - 12 h to yield a pale yellow solid.

Yield: 198 g, 45 %; HPLC purity: 95 % a/a; Melting Point (M.P): 84 - 90 °C; IR (KBr): 3421 , 3009, 1607 cm ^"1 ; ¹ H NMR(CDCI ₃ , 300 MHz): δ 6.13(s, 2H), 4.00(m, 2H), 3.81 (s, 1 H), 3.79(s, 3H), 3.76(s, 6H), 3.20(m, 1 H), 2.75(m, 1 H), 2.69(m, 1 H), 2.47(s, 3H), 2.00(m, 2H), 1 .99(s, 3H); MS(CI): m/z 282 (M ⁺¹ ). Example 4:

(-)-frans-[1 -Methyl-3-(2,4,6-trimethoxyphenyl)-pyrrolidin-2-yl]-methanol

80 g of (-)-DBTA and 150 mL of methanol were stirred for 30 min to get a clear solution (Solution A). In another flask, a solution of 100 g of compound of example 3 in 150 mL of methanol was stirred to get a clear solution (Solution B). The above prepared solution A was transferred into solution B and added 14 mL of cone. HCI at 25 - 30 °C. The reaction mixture was slowly heated to 60 - 65 °C, maintained for 10 min and allowed to cool to 43 - 45 °C over a period of 2 h. The seeding material was added at 43 - 45 °C, gradually cooled the mixture to 38 - 40 °C over a period of 1 h and maintained at 38 - 40 °C for 2 h. The reaction mixture was further cooled to 20 - 25 °C over a period of 1 .0 - 1 .5 h, the precipitated solid was centrifuged and the bed was washed with 15 mL of chilled methanol. The wet cake was unloaded, the salt was dried under vacuum (NLT 650 mm of Hg) at 45 - 50 °C in an air oven, submitted the salt sample for optical rotation and a small sample was converted to free base for chiral purity (SOR is -83° to -86° at c = 0.2 in methanol and chiral purity of 97 % ee).

Free Base: The salt obtained above and 200 mL of ethyl acetate were stirred, 200 mL of 5 % sodium hydroxide solution was added until the pH is 10 - 1 1 . The organic layer was separated and extracted the aqueous layer with 200 mL of ethyl acetate. The organic layers were combined, washed with 2 x 100 mL of brine solution and dried over 10 g of anhydrous sodium sulfate. The organic layer was distilled under vacuum at 45 - 50 °C to reduce the volume of mixture to 5 %, 200 mL of hexane was added and the precipitated solid was filtered. The bed was washed with 10 mL of hexane, the wet cake was dried under vacuum (NLT 650 mm of Hg) at 40 - 45 °C for 12 - 16 h to yield an off white solid.

Yield: 22 g, 44 % (on wanted isomer); HPLC purity: 95 % a/a; Chiral purity: 97 % ee; Melting Point (M.P): 84 - 90 °C; IR (KBr): 3421 , 3009, 1607 cm ^"1 ; ¹ H NMR(CDCI ₃ , 300 MHz): δ 6.15(s, 2H), 3.92(m, 1 H), 3.81 (s, 1 H), 3.80(s, 9H), 3.60(dd, 1 H), 3.45(d, 1 H), 3.20(m, 1 H), 2.78(m, 1 H), 2.50(m, 1 H), 2.42(s, 3H), 2.00(m, 1 H), 1 .92(m, 1 H); MS(ES ⁺ ): m/z 282 (M ⁺¹ ).

Example 5:

2-chlorobenzoyl chloride

To a solution of 150 mL of methylene dichloride, 50 g of 2-chlorobenzoic acid and 0.5 mL of DMF, was added 34 mL of oxalyl chloride drop-wise over a period of 3 - 4 h at 5 - 10 °C and the mixture was slowly allowed to reach 25 - 30 °C over a period of 2 - 3 h. The resulting solution was heated to 35 - 40° C over a period of 1 - 2 h and maintained for 3 - 4 h. After completion of the reaction, dichloromethane was distilled completely under vacuum below 40 °C, chased with 25 mL of diisopropyl ether under vacuum below 40 °C and distilled under vacuum to remove the traces of solvent below 40 °C to yield yellow residue. Yield: 55 g, quantitative.

Example 6:

(-)-frans-Acetic acid-3-(3-acetyl-2-hydroxy-4,6-dimethoxyphenyl)-1 -methyl- pyrrolidin-2-yl methyl ester

50 g of compound of example 4 was added in portions into a flask containing 97 mL of acetic anhydride by maintaining the temperature below 45 °C under nitrogen atmosphere. The resulting solution was cooled to -5 to 0 °C and to this solution, 135 mL of boron trifluoride diethyl etherate was added slowly over a period of 2 - 3 h at -5 to 0 °C. The reaction mixture was allowed to attain 25 - 30 °C over a period of 1 h and maintained for 20 - 24 h. After completion of the reaction, the mixture was cooled to 0 - 5 °C and quenched into 1250 mL of ice-cold water below 5 °C to which 150 mL of 33 % sodium carbonate solution was added over a period of 3 - 4 h by maintaining the temperature between 0 - 5 °C until pH was maintained at 8 to 9. The reaction mixture was extracted with 2 x 200 mL of dicholoromethane, the organic layer was separated and washed with 2 x 165 mL of 10 % sodium chloride solution. The organic layer was dried over 5 g of anhydrous sodium sulfate and distilled under vacuum below 45 °C. The residue was dried under vacuum (NLT 650 mm of Hg) for 2 - 3 h to yield viscous liquid.

Yield: 62.5 g, quantitative; HPLC Purity: 90 % a/a; IR(KBr): 2926, 1739, 1616, 1419 cm ^"1 ; ¹ HNMR(CDCI ₃ , 300 MHz): δ 14.20(s, 1 H), 5.96(s, 1 H), 4.10(d, 2H), 3.90(s, 3H), 3.89(s, 3H), 3.85(m, 1 H), 3.26(m, 1 H), 2.82(m, 1 H), 2.74(m, 1 H), 2.66(s, 3H), 2.52(s, 3H), 2.21 (m, 2H), 2.10(s, 3H); MS(CI): m/z 352 (M ⁺¹ )

Example 7:

(-)-frans-2-(2-(acetoxymethyl)-1-methylpyrrolidin-3-yl)-6-ac etyl-3,5-dimethoxy phenyl-2-chlorobenzoate

To a cooled solution of 62.5 g of compound of example 6 in 149.5 mL of methylene dichloride at -5 to 0 °C under nitrogen, 130 mL of triethylamine was added drop-wise over a period of 1 - 2 h and maintained for 15 min. 48.1 g of 2-chlorobenzoyl chloride of example 5 was dissolved in 49.4 mL of methylene dichloride and added drop-wise into the above reaction mixture over a period of 1 - 2 h at 0 - 5 °C. The reaction mixture was slowly allowed to reach 25 - 30 °C over a period of 1 h and maintained for 14 - 16 h. After completion of the reaction, the reaction mixture was quenched with 249.6 mL of ice-cold water, the organic layer was separated and the aqueous layer was extracted with 49.4 mL of methylene dichloride. The combined organic layer was washed with 124.8 mL of 6 % sodium bicarbonate solution followed by 247 mL of 10 % sodium chloride solution. The organic layer was separated, dried over 13 g of anhydrous sodium sulphate and distilled out the solvent from the organic layer below 40 °C under vacuum completely to yield residue.

Yield: 86 g, quantitative; HPLC Purity: 85 % a/a; IR (KBr): 3462, 2947, 1739, 1605, 1468 cm ^"1 ; ¹ H NMR(CDCI ₃ , 300 MHz): δ 8.09(d, 1 H), 7.49(d, 2H), 7.40(m, 1 H), 6.44(s, 1 H), 4.14(dd, 1 H),3.91 (s, 6H), 3.87(d, 1 H), 3.58(m, 1 H), 3.1 1 (t, 1 H), 2.70(m, 1 H), 2.49(s, 2H), 2.47(m, 1 H), 2.34(s, 3H), 2.15(m, 1 H),1 .91 (m, 1 H), 1.89(s, 2H), 1 .75(s, 3H), 1 .27(s, 1 H); MS(CI): m/z 490 (M ⁺¹ ).

Example 8:

(+)-frans-2-(2-Chlorophenyl)-8-(2-hydroxymethyl-1 -methylpyrrolidin-3-yl)-5,7- dimethoxy-chromen-4-one

To a cooled solution of 182 mL of dimethyl formamide and 21 .84 g of 50 % sodium hydride at -5 - 0 °C under nitrogen atmosphere, a solution of 86 g of the compound of example 7 previously dissolved in 364 mL of dimethyl formamide was added through an addition funnel by maintaining at -5 - 0 °C. After completion of the reaction, the reaction mixture was quenched with 21 .8 mL of methanol at 0 - 5 °C, followed by 455 mL of 20 % ammonium chloride solution and 910 mL of ice water. The reaction mixture was extracted with 2 x 455 mL of methylene dichloride, separated the organic layer and washed the combined organic layer with 2 x 455 mL of 10 % of sodium chloride solution. The organic layer was separated, dried over 200 g of anhydrous sodium sulphate and distilled out the solvent from the organic layer below 40 °C under vacuum to yield a viscous liquid. To which 364 mL of isopropyl alcohol-HCI was added at 10 - 15 °C, slowly allowed to 25 - 30 °C and maintained for 10 - 16 h. After completion of the reaction, distilled out IPA below 45 °C under vacuum and diluted the reaction mixture with 910 mL of ice cold water. The resulting mixture was cooled to 10 - 15 °C and basified to pH 9 -10 using 273 mL saturated sodium carbonate solution. The reaction mixture was extracted with 2 x 455 mL of methylene dichloride and the organic layer was washed with 2 x 455 mL of 10 % sodium chloride solution. The organic layer was separated, dried over 45.5 g of anhydrous sodium sulphate and the solvent was distilled out completely below 40 °C under vacuum to yield a residue.

Yield: 72 g; HPLC Purity: 75 % a/a Purification:

72 g of the compound of example 8 was dissolved in 216 mL of methyl ethyl ketone at 50 - 55 °C and maintained for 15 - 30 min till the reaction mixture was a clear solution. To the resulting solution 7.92 g of charcoal was added at 50 - 55 °C, stirred for 15 min and the reaction mixture was filtered through a celite bed (36 g celite in methyl ethyl ketone) at 50 - 55 °C. The bed was washed with 36 mL of hot methyl ethyl ketone, the filtrate was transferred into another flask, the mixture was cooled to 20 - 25 °C and 7.92 mL of demineralized water was added drop-wise to this reaction mixture. The reaction mixture was further cooled to 0 - 5 °C, filtered and the bed was washed with 36 mL methyl ethyl ketone followed by 90.7 mL hexane to yield a wet cake. The wet compound was dried under vacuum below 50 °C to yield a dry solid.

Yield: 36 g, 48 %; HPLC Purity: 97 % a/a; IR (KBr): 3431 , 1648, 1598, 1571 cm ^"1 ; ¹ H NMR(CDCI ₃ , 300 MHz): δ 7.70(dd, 1 H), 7.52(m, 1 H), 7.45(m, 2H), 6.50(s, 1 H), 6.44(s, 1 H), 4.17(m, 1 H), 4.00(s, 3H), 3.97(s, 3H), 3.64(dd, 1 H), 3.40(d, 1 H), 3.15(m, 1 H), 2.74(d, 1 H), 2.52(m, 1 H), 2.32(s, 3H), 2.00(m, 2H); Melting point (M.P): 91 - 93 °C; [a] D ²⁵ : +5.8 ⁰ (c = 0.7, methanol); MS(ES+): m/z 430 (M ⁺¹ ).

Example 9:

(+)-frans-2-(2-Chlorophenyl)-5,7-dihydroxy-8-(2-hydroxymethy l-1 -methyl- pyrrolidin-3-yl)-chromen-4-one

35 g of compound of example 8 and 38.5 g of pyridine hydrochloride were heated to 135 - 140 °C, maintained for 60 min and pyridine was simultaneously distilled out until temperature of 175 - 180 °C was attained. The reaction mixture was further maintained at 175 - 180 °C over a period of 5 - 8 h. After completion of the reaction, the reaction mixture was cooled to 65 - 70 °C, the reaction mixture was dissolved in 35 mL of methanol and quenched with 15 % sodium carbonate solution (350 mL) at 25 - 30 °C under stirring. The resulting mixture was filtered, and the bed was washed with 60 mL of demineralised water followed by 60 mL of methylene dichloride and 60 mL of hexane. The wet cake was dried under vacuum at 75 - 80 °C for 15 - 18 h to yield dry pale yellow solid. Yield: 28 g; HPLC purity: 94 % a/a. A) Purification of (+)-frans-2-(2-Chlorophenyl)-5,7-dihydroxy-8-(2-hydroxymethy l- 1-methyl-pyrrolidin-3-yl)-chromen-4-one

21 .5 mL of methanol, 28 g of the compound of example 9 and 130 mL of methylene dichloride were suspended in a flask and maintained for 1 h at 40 - 45 °C. The resulting mixture was cooled to 10 - 15 °C and maintained for 60 min. The reaction mixture was filtered and the bed was washed with 56 mL of methylene dichloride followed by 56 mL of hexane. The wet cake was dried under vacuum (NLT 650 mm of Hg) at 70 - 75 °C for 10 - 12 h to yield pale yellow dry solid.

Yield: 22.4 g; HPLC Purity: 97 % a/a.

B) Purification of (+)-frans-2-(2-Chlorophenyl)-5,7-dihydroxy-8-(2-hydroxymethy l- 1-methyl-pyrrolidin-3-yl)-chromen-4-one by water slurry method

1 10 mL of demineralized water and compound of example 9 were maintained at 55 - 60 °C for 2 h. The resulting mixture was cooled to 20 - 25 °C and maintained at this temperature for 60 min. The reaction mixture was then filtered and the bed was washed with 44 mL of demineralized water followed by 44 mL of hexane. The wet cake was dried under vacuum (NLT 650 mm of Hg) at 75 - 80 °C for 45 - 48 h to yield yellow dry solid.

Yield: 20 g, 62 %; HPLC Purity: 97 % a/a; IR (KBr): 3422, 3135, 1664, 1623, 1559 cm ^"1 ; ¹ H NMR(CDCI ₃ , 300 MHz): δ 7.56(d, 1 H), 7.36(m, 3H), 6.36(s, 1 H), 6.20(s, 1 H), 4.02(m, 1 H), 3.70(m, 2H), 3.15(m, 2H), 2.88(m, 1 H), 2.58(s, 3H), 2.35(m, 1 H), 1 .88(m, 1 H), 2.74(d, 1 H), 2.52(m, 1 H), 2.32(s, 3H), 2.00(m, 2H); MS(ES+): m/z 402 (M ⁺¹ ).

Example 10:

(+)-frans-2-(2-Chlorophenyl)-5,7-dihydroxy-8-(2-hydroxyme thyl-1 -methyl- pyrrolidin-3-yl)-chromen-4-one hydrochloride

20 g of the compound of example 9 was suspended in a mixture of 120 mL of methanol and 30 mL of isopropyl alcohol-HCI and maintained at 45 - 50 °C for 30 min. To this solution, 1 g of activated carbon was added and maintained at 45 - 50 °C for 15 min and filtered through 10 g celite bed. The bed was washed with 20 mL of methanol, the filtrate was collected and concentrated below 50 °C under vacuum till 2.5 volumes of reaction mixture was retained in the flask. The reaction mixture was further chased with 2 x 100 mL of diisopropyl ether by maintaining 2.5 volumes of reaction mixture retained in the flask. Finally 20 mL of methanol and 80 mL of diisopropyl ether were charged into the flask and stirred for 30 min at 45 - 50 °C. The reaction mixture was cooled to 25 - 30 °C over a period of 1 - 2 h and an additional volume of 20 mL methanol was added into the flask and stirred for 1 h at 25 - 30 °C. The reaction mixture was filtered and the bed was washed with a mixture of 20 mL of diisopropyl ether and 4 mL of methanol. The wet cake was dried at 75-80 °C under vacuum for 72 h to yield the compound of formula (1) Yield: 14 g, 64%; HPLC Purity: 97% a/a; IR (KBr): 3398, 3058, 1663, 1618, 1583, 1509, 855, 839, 772, 734, 657 cm ^"1 ; ¹ H NMR(CDCI ₃ , 300 MHz): δ 7.80(d, 1H), 7.60(m, 3H), 6.53(s, 1H), 6.37(s, 1H), 4.23(m, 1H), 3.89(m, 2H), 3.63(m, 1H), 3.59(dd, 1H), 3.38(m, 1H), 2.90(s, 3H), 2.45(m, 1H), 2.35(m, 1H); Melting point (M.P): 188-192 °C; [a] D ²⁵ : +21.3 ⁰ (c = 0.2, methanol); MS(ES+): m/z 402 (M ⁺¹ ).