Improved Process for the Preparation of Ezetimibe and its intermediates

Related Applications:

This application claims the benefit of priority of our Indian patent application number 1648/CHE/2006 filed on September 11, 2006.

Field of the Invention: The present invention relates to an improved process for the preparation of

3-((3R,4S)-l-(4-fluorophenyl)-2-oxo-4-(4-(benzyloxy)pheny l)azetidin-3-yl)propionic acid and its novel organic amine salts which is represented by general formula- 1 as shown below

Formula- 1 wherein R ₁ and R ₂ are independently selected from a hydrogen atom; a straight or branched chain alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms or an aminoalkyl group having 2 to 4 carbon atoms, which are optionally substituted by N-alkyl or N,N-dialkyl group wherein the alkyl group is alkyl having 1 to 4 carbon atoms.

The compound of general formula- 1 is a useful intermediate in the preparation of ezetimibe, chemically known as (3R, 4S)-l-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)- 3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone represented by the following structural formula.

Ezetimibe

Ezetimibe is a class of lipid-lowering compounds that selectively inhibits the intestinal absorption of cholesterol and related phytosterols. It is reported action of ezetimibe differs from other lipid-lowering compound, such as HMG-CoA reductase inhibitors, fibric acid derivatives, and others. Ezetimibe reportedly does not inhibit cholesterol synthesis in the liver or increase bile acid excretion. Instead, it appears that ezetimibe localizes and acts at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver which leads to a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood. Ezetimibe is sold under the brand name Zetia®, which is marketed by Merck/Schering-Plough Pharmaceuticals.

Background of the Invention:

Ezetimibe and process for its preparation was first disclosed in U.S. Patent number US 5,767,115. The disclosed process comprises of reacting (S)-4- phenyl-2- oxazolidinone with methyl-4-(chloroformyl)butyrate to obtain a compound of ester and it is condensed with 4-benzyloxybenzylidine(4-fluoro)aniline in the presence of titanium isopropoxide and titanium tetrachloride to give an amide compound and it is cyclised in the presence of tetrabutyl ammonium fluoride and bis trimethyl silyl acetamide to give protected lactam, it undergoes hydrolysis to give a carboxylic acid and further it reacts with p- fluoro phenyl magnesium bromide and zinc chloride in the presence of tetrakis (triphenyl phosphine) palladium to give an aromatic ketone, it is further reduced selectively in the presence of chiral catalyst to obtain a hydroxy compound and it undergoes debenzylation to give Ezetimibe.

Our earlier patent publication WO 2006/137080 first discloses the isolation of benzylated ezetimibe compound of formula- 10 as a solid. The disclosed process for the preparation of ezetimibe compound involves the usage of 3-((3R,4S)-l-(4-fluorophenyl)- 2-oxo-4-(4-(benzyloxy)phenyl)azetidin-3-yl)propionic acid compound as a crude which leads to the formation of impurities in final compound.

The major draw back of the prior art process is that the intermediate 3-((3R,4S)-l- (4-fluorophenyl)-2-oxo-4-(4-(benzyloxy)phenyl)azetidin-3 -yl) propionicacid compound was isolated as crude which has the maximum purity of 92% and the usage of same for the preparation of ezetimibe leads to carry over of related impurities to the final compound.

Generally any synthetic compounds or for example ezetimibe can contain extraneous compounds or impurities that can be derived from many sources. It is known from the art that impurities in any API may arise from degradation of API itself, which is related to the stability of the API during storage, and the manufacturing process, including the chemical synthesis. Process impurities include unreacted starting materials, chemical derivatives of impurities contained in starting materials, synthetic by-products, and degradation products.

As discussed above the ezetimibe prepared as per the prior art process containing the impurities that has derived by the carry over of impurities formed from the intermediate stage to final compound (i.e., continue with the crude intermediate compound without removing the impurities present in the crude). Impurities in ezetimibe or any active pharmaceutical ingredient are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing that active pharmaceutical ingredient. So it is important to reduce the impurities to meet the quality requirement of pharmaceutical active ingredients.

In order to reduce the impurities it is necessary to carryout a number of purifications at final stage of ezetimibe. Generally purification steps at the final stage of the compound leads to loss of material which increases the economics of production, so which is not recommended for commercial scale-up. When we were working in the laboratory to solve the above problems, we surprisingly found that the conversion of 3-((3R, 4S)-l-(4-fluorophenyl)-2-oxo-4-(4-

(benzyloxy)phenyl)azetidin-3-yl)propionic acid intermediate acid compound into its organic amine salt and converting back into acid compound leads to high pure acid compound. We also identified the major impurity which is formed in the preparation of acid intermediate compound of formula-9 i.e. during hydrolysis. The impurity was identified and characterized by the present inventors and designated as di-acid (DA) impurity having the following structural formula. This impurity has been observed due to the cleavage of the lactam ring during base hydrolysis.

DA-Impurity All the prior art processes for the preparation of 3-((3R, 4S)-l-(4-fluorophenyl)-2- oxo-4-(4-(benzyloxy)phenyl)azetidin-3-yl)propionic acid intermediate leads to the formation of the above said impurity at the level of around 20%. The same DA-impurity level reduced to less than 1% by converting the acid intermediate compound into its organic amine salt. The purity of an acid intermediate compound prepared through the organic amine salt is above 98.5% which also avoids the carryover of related impurities to the further stages in the preparation of ezetimibe and ultimately leads to the highly pure ezetimibe.

When the present inventors were working on debenzylation reaction, we observed the low solubility of solid benzylated ezetimibe in low quantity of alcohols like methanol and isopropyl alcohol. We used 3-4 times of methanol for dissolution of benzylated ezetimibe and found that the compound was not completely soluble and when it was filtered we got more purified benzylated ezetimibe. We optimized the quantity of alcohol in the debenzylation reaction and finalized 10 times of alcohol for the dissolution of benzylated ezetimibe, the same has been disclosed in our earlier application i.e., WO2006/137080 in step h) of example 2. As per the literature it has been known that the traces of sulfur and derivatives of sulfur poisons the metal catalyst used in the reduction

reaction. The purified benzylated ezetimibe from methanol also consumes more palladium carbon for debenzylation reaction. The consumption of larger quantities of palladium carbon for debenzylation reaction in ezetimibe may be due to the poisoning of the catalyst by traces of sulfur derivatives. So the present inventors investigated and found that the debenzylated ezetimibe was contaminated with traces of sulfur derivative compounds which poisons the catalyst. The sulfur derivatives observed due to the usage of borane DMS in the reduction of keto compound. The traces of sulfur derivatives removed by base washings to the organic phase of the benzylated ezetimibe as well as by treatment with the charcoal before debenzylation with palladium carbon. These two changes were served the purpose of removing sulfur derivatives which enhanced the rate of the reaction and the quantity of the palladium carbon needed was reduced to 40-50%.

The present invention resolves all the problems of the prior art by providing high pure acid compound of formula- 1 substantially free of DA-impurity and also provides an improved process for the preparation of 3-((3R, 4S)-l-(4-fluorophenyl)-2-oxo-4-(4- (benzyloxy)phenyl)azetidin-3-yl)propionic acid and its novel organic amine salt useful as an intermediate in the preparation of ezetimibe, which is cost effective, suitable for commercial scale up and having high purity.

Brief description of the Invention Accordingly the first aspect of the present invention is to provide an improved process for the preparation of novel organic amine salts of 3-((3R,4S)-l-(4- fluorophenyl)-2-oxo-4-(4-(benzyloxy)phenyl)azetidin-3-yl)pro pionic acid compound of general formula- 1

which is useful as an intermediate in the preparation of ezetimibe, which comprises of the following steps; a. Reacting glutaric anhydride compound of formula-2 with an aliphatic alcohol or alicyclic alcohol in presence of a suitable base to give compound of formula-3, b. Reacting the compound of formula-3 with pivaloyl chloride in presence of an acid trapping agent like inorganic bases and subsequently reacting with a chiral auxiliary compound of formula-4 to give ester compound of formula-5, c. Condensing ester compound of formula-5 with benzylated imine compound of formula-6 in presence of a lewis acid to give amide compound of formula-7, d. Cyclizing the amide compound of formula-7 with a silylating agent, in presence of a fluoride ion catalyst cyclizing agent and in a suitable solvent to give the compound of formula-8, e. Hydrolysing the ester group compound of formula-8 with a suitable base selected from alkali or alkaline earth metal hydroxides and/or alkali metal carbonates in a suitable solvent to give compound of formula-9, f. Treating the carboxylic acid compound of formula-9 with an organic amine in a suitable solvent to give organic amine salt compound of formula- 1.

The above obtained organic amine salt compound of formula- 1 is converted into highly pure 3-((3R,4S)-l-(4-fluorophenyl)-2-oxo-4-(4-(benzyloxy)phenyl)a zetidin-3-yl) propionic acid compound with less than 1% DA-impurity by treating with suitable acid in a suitable solvent. Thus obtained pure acid compound can be converted into high pure ezetimibe as per the second aspect of the present invention or by the conventional methods. The second aspect of the present invention is to provide an improved process for the preparation of ezetimibe from the organic amine salt compound of general formula- 1, which comprises of the following steps; a) Treating the organic amine salt compound of formula- 1 with suitable acid in a suitable solvent to obtain highly pure 3-((3R,4S)-l-(4-fluorophenyl)-2-oxo-4-(4- (benzyloxy)phenyl) azetidin-3-yl) propionic acid compound of formula-9,

b) Converting the highly pure acid compound of formula-9 into acid chloride with oxalyl chloride and further reacting with para bromo fluoro benzene through organo metallic reaction gives the aromatic ketone compound of formula- 10, c) Reducing the ketone compound of formula- 10 with chiral reducing agent in presence of a chiral catalyst gives alcohol compound of formula- 11 in a pure crystalline form, d) Treating the compound of formula- 11 with carbon followed by debenzylating with palladium on carbon gives highly pure ezetimibe.

Advantages of the Present Invention: • Provides highly pure 3-((3R,4S)-l-(4-fluorophenyl)-2-oxo-4-(4-benzyloxy)phenyl) azetidin-3-yl)propionic acid intermediate free of DA-impurity.

• Provides simple process for the preparation of highly pure (>98.5 %) intermediate compound 3-((3R,4S)-l-(4-fluorophenyl)-2-oxo-4-(4-benzyloxy)phenyl)az etidin-3- yl)propionic acid through its organic amine salts. . • Use of 3-((3R,4S)-l-(4-fluorophenyl)-2-oxo-4-(4-benzyloxy)phenyl)az etidin-3- yl)propionic acid for the preparation of ezetimibe to get high purity of about >99.5 %.

• Enhanced rate of reaction in debenzylation reaction and reduction in Pd/C consumption. • Eco-friendly and commercially viable process.

Detailed Description of the Invention:

Figure-1: Illustrates the powder X-ray diffraction pattern of crystalline tertiary butyl amine salt compound of formula- 1 a. Figure-2: Illustrates the IR spectra of crystalline tertiary butyl amine salt compound of formula- Ia.

Figure-3: Illustrates the DSC thermo gram of crystalline tertiary butyl amine salt compound of formula- Ia.

Figure-4: Illustrates the powder X-ray diffraction pattern of crystalline free acid compound of formula-9.

Figure-5: Illustrates the IR spectra of crystalline free acid compound of formula-9.

Figure-6: Illustrates the DSC thermo gram of crystalline free acid compound of formula-9.

Figure-7: Illustrates the HPLC chromatogram of crude free acid compound of formula-9.

Figure-8: Illustrates the HPLC chromatogram of pure acid compound (after organic amine salt purification) of formula-9

Figure-9: Illustrates the IR spectra of crystalline benzylated ezetimibe compound of formula-11.

Figure-10: Illustrates the powder X-ray diffraction pattern of ezetimibe.

Figure-11: Illustrates the DSC thermo gram of ezetimibe, Figure-12: Illustrates the HPLC chromatogram of Ezetimibe

Figure-13: Illustrates ezetimibe having morphology as seen through microscope.

Detailed Description of the Invention:

The present invention relates to an improved process for the preparation of 3-((3R,4S)-l-(4-fluorophenyl)-2-oxo-4-(4-(benzyloxy)phenyl)a zetidin-3-yl)propionic acid and its organic amine salts which is represented by the general formula- 1 as below

Formula- 1

Wherein R ₁ and R ₂ are independently selected from a hydrogen atom; a straight or branched chain alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms or an aminoalkyl group having 2 to 4 carbon atoms, which are optionally substituted by N-alkyl or N,N-dialkyl group wherein the amino alkyl group is alkyl having 1 to 4 carbon atoms.

It is an useful intermediate in the preparation of highly pure ezetimibe which is chemically known as (3R,4S)-l-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-

hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone represented by the following structure.

Ezetimibe

Accordingly the first aspect of the present invention is to provide an improved process for the preparation of organic amine salt of 3-((3R,4S)-l-(4-fluorophenyl)-2-oxo- 4-(4-(benzyloxy)phenyl)azetidin-3-yl)propionic acid compound of general formula-1 which comprises of the following steps, a) Reacting glutaric anhydride compound of formula-2

Formula-2 with linear or branched chain aliphatic Ci-C ₆ alcohols like methanol, ethanol, propanol, isopropanol etc., preferably methanol in presence of a base like sodium methoxide, sodium hydroxide, potassium hydroxide, preferably sodium methoxide gives alkyl ester compound of formula-3,

Formula-3

Wherein R is CH ₃ , C ₂ H ₅ , etc., b) Reacting the compound of formula-3 with pivaloyl chloride in presence of an acid trapping agent like triethyl amine, diisopropyl ethyl amine, preferably tri ethyl amine and subsequent reaction with chiral auxiliary compound of formula-4

Formula-4

gives ester compound of formula-5,

Formula-5 c) Reacting the ester compound of formula-5 with benzylated imine compound of formula-6

Formula-6 in presence of lewis acid such as titanium tetrachloride, zinc chloride etc., preferably titanium tetrachloride in combination with titanium isopropoxide gives an amide compound of formula-7,

Formula-7 d) Cyclizing the amide compound of formula-7 with a silylating agent like N,O-bis trimethyl silyl acetamide, N,O-bis (trimethylsilyl) trifluoro acetamide, preferably N,O-bis trimethyl silyl acetamide and a fluoride ion catalyst cyclizing agent like tetra butyl ammonium fluoride in a suitable solvent like methylene chloride, toluene, xylene, ethylacetate, preferably in toluene gives the compound of formula-8,

Formula-8 e) Hydrolysing the ester group of compound of formula 8 with a base such as an alkali or alkaline earth metal hydroxides like sodium hydroxide, potassium hydroxide and/or alkali metal carbonates like sodium carbonate, potassium carbonate, preferably sodium hydroxide in the mole ratio of 1.0-1.1 in a suitable solvent such as alcohol solvents like ethanol, isopropyl alcohol, tertiary butanol or ketonic solvents like acetone, methyl isobutyl ketone, preferably ketone solvents, more preferably acetone at a temperature range of 15-30 ⁰ C followed by adjusting the pH of the reaction mixture to 5-7, preferably 6.5 to 7.0 and extracting the carboxylic acid compound of formula-9,

Formula-9

DA-Impurity f) Reacting the compound of formula-9 with an organic amine such as (±)-l,2- dimethylpropylamine, 3-(2-aminoethylamino)-propylamine, n-butylamine, secondary

I l

butylamine, tertiary butylamine, dibutylamine, tertiary amylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, dicyclohexylamine, N-methylcyclohexylamine, N.N'-diisopropylethylenediamine, N,N'-diethylene diamine, N-methyl-1,3- propanediamine, N-methylethylenediamine, N,N,N',N'-tetramethyl-l,2- diaminoethane, N,N,N',N'-tetramethyl-l-,4-diaminobutane, N,N,N',N'-tetramethyl-

1 ,6-diaminohexane, 1 ,2-dipiperidinethane, dipiperidine methane, 2-amino-3,3- dimethylbutane, N,N-dimethylcyclohexyl amine, neopentylamine, adamantylamine, N-methylcyclohexylamine, cyclobutylamine, N-isopropylccyclohexylamine, N-diethylcyclohexcylamine, cyclobutylamine and norborylamine preferably tertiary butyl amine and dicylclohexylamine, most preferably tertiary butyl amine in presence of a suitable ketonic solvents like acetone, methyl isobutyl ketone preferably acetone to give corresponding organic amine compound of general formula- 1 .

Formula- 1 Organic amine salt compound of general formula- 1 is converted into corresponding highly pure acid compound by treating with a suitable acid like hydrochloric acid or an organic acid like acetic acid in presence of a suitable solvent selected from chloro solvents like methylene chloride, chloroform and carbon tetra chloride, preferably dichloromethane.

Thus the obtained highly pure acid compound can be converted into highly pure ezetimibe by the second aspect of the present invention or by the conventional methods.

The second aspect of the present invention is to provide an improved process for the preparation of highly pure ezetimibe from novel organic amine salts compound of general formula- 1, which comprises of the following steps;

a) Treating the organic amine salt compound of general formula- 1 with a suitable acid like hydrochloric acid and/or organic acid like acetic acid in presence of a suitable solvent selected from chloro solvents like methylene chloride, chloroform, carbon tetra chloride, dichloromethane preferably dichloromethane to obtain highly pure acid compound of formula-9,

Formula-9 b) Reacting the highly pure acid compound of formula-9 with an oxalyl chloride in a suitable solvent like methylene chloride, toluene, xylene, ethyl acetate, preferably methylene chloride affords acid chloride compound which in situ reacting with 4-fluorophenyl zinc halide in presence of a transition metal acetate or halide in a suitable solvent like methylene chloride, toluene, xylene, ethyl acetate, tetrahydrofuran or mixtures thereof, preferably toluene gives the aromatic ketone compound of formula-10,

Formula- 10 c) Reducing the aromatic ketone compound of formula-10 in presence of a chiral reducing agent such as β-chloro diisopinocampheyl borane (DIP Chloride) alone or reducing agent like borane THF or borane DMS in combination of a chiral catalyst like (R)-tetrahydro-l-methyl-3,3-diphenyl-lH,3H-pyrrolo(l,2-c)(l, 3 ₅ 2) oxazaborole (R-Methyl CBS) or R- Butyl CBS or R-Phenyl CBS in a suitable solvent like methylene chloride, toluene, xylene, ethyl acetate, preferably

methylene chloride, quenching the reaction mixture with hydrogen peroxide followed by basic washings to the organic layer and isolation of hydroxy compound of formula- 11 as a pure crystalline solid using organic solvents selected from methanol, isopropanol, toluene, hexanes and ethers, preferably ethers, more preferably diisopropyl ether,

Formula- 11 d) Treating the benzylated ezetimibe compound of formula- 11 with charcoal in alcohol solvent followed by debenzylation of the compound of formula- 11 with palladium carbon in a suitable solvent like such as alcoholic solvents like methanol, isopropyl alcohol, tertiary butanol, or chloro solvents like methylene chloride, chloroform, preferably isopropyl alcohol, methanol, more preferably methanol gives high pure ezetimibe.

Ezetimibe

The ezetimibe can also be micronized and milled to get the non platelet shaped morphology.

The present invention and also as per the process disclosed in our earlier publication WO2006/137080, leads to high pure ezetimibe having any impurity less than 0.1% as well as residual solvents well within the limit, and meets the ICH quality.

Analysis of related substances of acid intermediate compound of formula-9 by HPLC method is carried out using liquid chromatograph, which is equipped with variable wavelength UV-detector using Inertsil ODS 3 V column 150 X 4.6 mm, 5μm or

equivalent, at a wavelength of 210 nm with flow rate of 1.0 ml/min, at ambient temperature, load is 5 μl, runtime is 50 minutes, the diluent is a mixture of acetonitrile and water mixture (1 :1 ratio) and using sodium dihydrogen phosphate (2.75 grams of sodium dihydrogen phosphate monohydrate in 1000 ml of water) as a buffer.

Analysis of related substances of ezetimibe by HPLC method is carried out using liquid chromatograph, which is equipped with variable wavelength UV-detector using symmetry C-18 150 x 4.6 mm ID, 3.5 μm particle size, at a wavelength of 230 nm with flow rate of 1.0 ml/min, at ambient temperature, load is 10 μl, runtime is 60 minutes, the mobile phase A is a mixture of buffer and acetonitrile in 80:20 ratio and mobile phase B is a mixture of buffer and acetonitrile in 20:80 ration. 20 mM disodium hydrogen phosphate is used as a buffer (2.72 grams of sodium dihydrogen phosphate monohydrate in 1000 ml of water, adjust the pH to 5 with dilute phosphoric acid). The samples are moulded on alumina stubs using double adhesive tape, coated with gold using HUS-5GB vacumm evaporator and observed in Hitachi S-520 Scanning Electron Microscope at an acculation voltage of 10 KV.

Anhydrous ezetimibe is hygroscopic and absorbs water from the atmosphere and get converts into monohydrate. Special measures were necessary for packing and storing anhydrous ezetimibe to prevent the water absorption. The process for packaging and storage used herein increased the stability of the anhydrous ezetimibe and increased its shelf life.

Ezetimibe is packed in a clear low density polyethylene bag flushed out with nitrogen and tied with a thread, placing the primary bag into a secondary packing of black color polyethylene bag with or without silica gel bags and sealed, optionally sealed by evacuating air i.e., vacuum sealing, placing the secondary packing into a triple laminated bag along with or without silica gel bags and sealed, optionally sealed by evacuating air i.e., vacuum sealing, enclosing the sealed laminated bag into a closed HDPE container. The present invention is schematically represented below

VL

FormuIa-4

Pivaloyl Chloride

XH,Ph Dichloromethane

TiCl ₄

Diisopropylethylamine

Formula-6

The process described in the present invention were demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

EXAMPLES: Example-1: Preparation of compound of formula-3:

1.0 gram of sodium methoxide was added to a solution of 100 grams of glutaric anhydride compound of formula-2 and 250 ml of methanol. Stirred the reaction mixture for 6 hours at 25-35 ⁰ C. Distilled the solvent completely under reduced pressure to get the title compound of formula-3 as a residue, which is used for next stage without any purification. Yield: 125 grams.

Example-2:

Preparation of ester compound of formula-5:

Added 37.8 ml of pivaloyl chloride to a solution of 45 grams of compound of formula-3, 67.5 ml of triethyl amine and 225 ml of dichloromethane at 25-35°C. Stirred the reaction mixture for 2 hours at 25-35 ⁰ C. Added a solution of 28 grams of (S)-4-phenyl-2-oxazolidinone, 2.1 grams of 4-dimethyl amino pyridine and 19 ml of dimethylformamide to the reaction mixture. Heated to reflux and stirred for 7 hours. Quenched the reaction mixture with water and separated the organic and aqueous phases. Distilled the solvent completely under reduced pressure. Isolated the title compound using hexanes as a solvent. Yield: 50 grams.

Example-3:

Preparation of compound of formuIa-7:

16 ml of titanium isopropoxide added to a mixture of 18 ml of titanium tetrachloride and 600 ml of dichloromethane at 0-5 ⁰ C. Added a solution of 50 grams compound of formula-V and 600 ml of dichloromethane at 0-5 ⁰ C. Stirred the reaction

mixture for 15 minutes. 65 ml of diisopropylethylamine was added to the reaction mixture. Stirred the reaction mixture for 45 minutes. Cooled the reaction mixture to -20 to -10°C. Added 92 grams of benzylated imine compound of formula-6 to the reaction mixture. Stirred for 4 hours at -20 to -10 ⁰ C. Quenched the reaction mixture with acetic acid and washed the organic layer with sulfuric acid solution. Distilled the solvent completely under reduced pressure. Isolated the title compound using methanol as a solvent. Yield: 65 grams.

Example-4:

Preparation of compound of formula-8:

17 gram of N,O-bis trimethyl silyl acetamide and 1.1 gram of tetrabutyl ammonium fluoride added to a solution of 25 grams of compound of formula-7 and 100 ml of toluene at 45-50°C. Stirred the reaction mixture for 2 hours at 45-50°C. Quenched the reaction mixture with methanol and extracted the reaction mixture with methylene chloride. Washed the organic phase with hydrochloric acid solution, sodium bicarbonate solution and saturated sodium chloride solution respectively. Distilled the solvent completely under reduced pressure. The residue treated with toluene and filtered to separate the recovered (S)-4-phenyl-2-oxazolidinone compound. The filtrate is concentrated. Isolated the title compound in methanol. The obtained solid is dried at 50- 6O ⁰ C to get the title compound of formula-8. Yield: 13 grams; M.R: 60-65 ⁰ C

Example-5:

Preparation of compound of formula-9:

Aqueous sodium hydroxide solution (2.8 grams in 62.5 ml of water) is added to a solution of 25 grams of compound of formula-8 and 25 ml of acetone. Stirred the reaction mixture for 3 hours at ambient temperature. Quenched the reaction mixture with water. Adjusted the reaction mixture pH to 6.7 with aqueous hydrochloric acid. Extracted the

reaction mixture with ethyl acetate. Distilled the solvent completely under reduced pressure to get the residue compound of formula-9. Yield: 22 grams.

Example-6:

Preparation of Tertiarybutylamine salt of 3-((3R,4S)-l-(4-fluorophenyl)-2-oxo-4-(4- (benzyloxy)phenyl)azetidin-3-yl)propionic acid compound of formula-la:

Aqueous sodium hydroxide solution (2.5 grams in 62.5 ml of water) added to a solution of 25 grams of residue compound of formula-9 and 50 ml of acetone. Stirred the reaction mixture for 5 hours at 20-25°C. Quenched the reaction mixture with sodium chloride solution. Adjusted pH of the reaction mixture to 3.6 with aqueous hydrochloric acid solution. Extracted the reaction mixture with 150. ml of ethyl acetate. Separated the organic and aqueous phases. Extracted the aqueous layer with ethyl acetate. Dried the organic layer over sodium sulfate. Added 6 ml of tertiarybutylamine to the organic layer at 20-25°C. Stirred the reaction mixture for 30-45 minutes at 20-25°C. Distilled the solvent completely under reduced pressure. Added 125 ml of acetone and 12.5 ml of water to the reaction mixture and stirred for 15 minutes. Heated the reaction mixture to 50-55°C and stirred for 30 minutes. Slowly cooled to 20-25°C and stirred for one hour. Filtered the precipitated solid and dried at 25-30°C to get the title compound of formula- Ia

Yield: 22.5 grams. HPLC Purity: 98.94 %

Example-7: Preparation of high pure 3-((3R, 4S)-l-(4-fluorophenyl)-2-oxo-4-(4-(benzyloxy) phenyl) azetidin-3-yl)propionic acid compound of formula-9:

25 grams of tertiarybutylamine salt compound of formula-9a dissolved in 125 ml of dichloromethane. Adjusted the pH of the solution to 1.8 with dilute hydrochloric acid at 25-30°C. Stirred the reaction mixture for an hour at 25-30°C. Separated the organic and aqueous phases. Extract the aqueous layer with dichloromethane. Washed the organic layer with vacuum salt. Distilled the solvent completely under reduced pressure at below

45 ⁰ C. The residue treated with cyclohexane. Heated the reaction mixture to reflux. Stirred the reaction mixture at reflux for one hour. Filtered the precipitated solid and dried to get a highly pure title compound 3-((3R,4S)-l-(4-fluorophenyl)-2-oxo-4-(4- (benzyloxy)phenyl)azetidin-3 -yl)propionic acid. Yield: 22.5 grams; M.R.: 96-100°C HPLC Purity: 98.85 %

Example-8:

Preparation of compound of formula-10 Highly pure acid compound of formula-9 (25 grams) was dissolved in dichloromethane in R.B. Flask, and catalytical amount of dimethyl formamide was added. Oxalyl chloride was slowly added at 25-35°C, stirred the reaction mixture for 3 hours at 25-35 ⁰ C temperature. Distilled off the solvent completely under reduced pressure and toluene was added and distilled off completely under reduced pressure. Toluene was added to the crude and cooled to 10-15 ⁰ C and then the palladium acetate and maintained for 15 minutes. 4-fluorophenyl magnesium bromide is taken in another vessel under nitrogen atmosphere and cooled to 0-5 ⁰ C and added anhydrous zinc chloride and stirred for 1 hr. This complex is added to the acid chloride reaction mass at ambient temperature and maintained for 45 minutes. Filtered the reaction mass through hyflow and washed with toluene and THF solution. Distilled the solvent completely under vacuum, added dichloromethane and silica gel to the crude and distilled the solvent completely under vacuum. Cyclohexane was added to the silicagel mixture and stirred for 30 minutes, filtered and washed with cyclohexane. Silicagel mixture was slurried with ethyl acetate and cyclohexane. Distilled both the filtrates under vacuum to get the residue. Yield: 18 grams

ExampIe-9:

Preparation of hydroxy compound of formula-11

Taken toluene (250 ml) into cleaned R.B. Flask under nitrogen atmosphere and cooled to 0-5°C. Borane DMS complex and (R)-tetrahydro-l-phenyl-3,3-diphenyl-l

H,3H-pyrrol (l,2-c)(l,3,2) oxaza borolidine (R-phenyl CBS) was charged into the

reaction mass at 0°C. 25 gm of keto compound of formula-10 was dissolved in toluene

(50 ml) and added to the reaction mixture at 0-5 ⁰ C. Stirred the reaction mixture for 3 hrs.

Quenched the reaction mixture with methanol and followed by 1 N hydrochloric acid solution. Organic layer separated and washed with 5% hydrogen peroxide solution, 5% sodium sulfite solution followed by sodium bicarbonate solution and then with 10% sodium chloride solution. Distilled the solvent completely under reduced pressure at below 75°C. Product was isolated by using diisopropyl ether and dried the product at

60-70 ⁰ C for 6 hours.

Yield: 15 grams

ExampIe-10:

Preparation of hydroxy compound of formula-11

Taken toluene (250 ml) into cleaned R.B.Flask under nitrogen atmosphere and cooled to 0-5 ⁰ C. Borane DMS complex and (R)-tetrahydro-l-phenyl-3,3-diphenyl-l H,3H-pyrrol (l,2-c)(l,3,2) oxaza borolidine (R-phenyl CBS) was charged into the reaction mass at 0 ⁰ C. 25 gm of keto compound of formula-10 was dissolved in toluene

(50 ml) and added to the reaction mixture at 0-5 ⁰ C. Stirred the reaction mixture for 3 hrs.

Quenched the reaction mixture with methanol and followed by 1 N hydrochloric acid solution. Organic layer separated and washed with 5% hydrogen peroxide solution, 5% sodium sulfite solution followed by ammonia solution and then with 10% sodium chloride solution. Distilled the solvent completely under reduced pressure at below 75°C.

Product was isolated by using diisopropyl ether and dried the product at 60-70 ⁰ C for 6 hours.

Yield: 15 grams

Example-ll:

Preparation of highly pure Ezetimibe:

Compound of formula- 11 (25 grams) was taken in isopropyl alcohol (100 ml) was treated with 1 grams of activated carbon. The reaction mixture was filtered through hyflow. The filtrate taken into a hydrogenation flask, added 5 % palladium carbon (4 grams) at 25°C and maintained at 45-50 ⁰ C for 3 hrs under hydrogen pressure, filtered

through hyflow and washed the palladium carbon with isopropanol (20 ml). Distilled the solvent completely under vacuum at below 70°C, product is recrystallised in dichloromethane Yield: 6 grams HPLC Purity: 99.56%

Particle Size: D(O ₃ I) is 2.560 μm; D(0.5) is 8.131 μm; D(0.9) is 19.571 μm; D(l.OO) is 44.34 μm and D[4,3] is 9.846 μm

Example-12: Preparation of highly pure Ezetimibe: Compound of formula- 11 (25 grams) was taken in isopropyl alcohol (100 ml) was treated with 1 grams of activated carbon. The reaction mixture was filtered through hyflow. The filtrate taken into a hydrogenation flask, added 5 % palladium carbon (2.5 grams) at 25°C and maintained at 45-50°C for 3 hrs under hydrogen pressure, filtered through hyflow and washed the palladium carbon with isopropanol (20 ml). Distilled the solvent completely under vacuum at below 70°C, product is recrystallised in dichloromethane Yield: 6 grams

Particle Size: D(O ₅ I) is 2.507 μm; D(0.5) is 7.919 μm; D(0.9) is 19.114 μm; D(l.OO) is 38.89 μm and D[4,3] is 9.605 μm