DESC:RELATED PATENT APPLICATION
This application claims the priority to and benefit of Indian Provisional Patent Application No. 202041005093 filed on February 05, 2020; the disclosures of which are incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of Pemafibrate. The invention further provides a process for preparing a novel polymorphic form of Pemafibrate.
BACKGROUND OF THE INVENTION
Pemafibrate is chemically known as (2R)-2-[3-({1,3-Benzoxazol-2-yl[3-(4-methoxyphenoxy) propyl] amino}methyl)phenoxy] butanoic acid. The drug substance exists in either of 2 enantiomeric forms (S and R), the commercial manufacturing process produces only the R-form having the formula-I as mentioned below.

Pemafibrate is used in the treatment of hyperlipidemia and marketed as Parmodia in Japan by Kowa company. Pemafibrate was first disclosed in the US Patent No. 7109226.

The US Patent No. 7790903 discloses the process preparation of Pemafibrate including the steps of: reacting 4-methoxyphenol with acrylonitrile in the presence of Triton B to obtain 3-(4-methoxyphenoxy)propionitrile; reducing 3-(4-methoxyphenoxy)propionitrile in the presence of boron-tetrahydrofuran complex to 3-(4-methoxyphenoxy)propylamine; reacting 3-(4-methoxyphenoxy)propylamine with 3-hydroxybenzaldehyde to form 3-({[3-(4-methoxyphenoxy)propyl]amino}methyl)phenol; reacting 3-({[3-(4-methoxyphenoxy)propyl] amino}methyl)phenol with 2-chlorobenzoxazole to form 3-({benzoxazol-2-yl-[3-(4-methoxyphenoxy)propyl]amino}methyl)phenol; reacting 3-({benzoxazol-2-yl-[3-(4-methoxy phenoxy)propyl]amino}methyl)phenol with n-butyl-(S)-trifluoromethane sulfonyloxy butyrate followed by the de-esterification of the butyl group. The process as disclosed in the US Patent No.7790903 is mentioned below.

The US Patent No. 7538242 discloses the alternative process of Pemafibrate from n-butyl-(R)-2-(3-formylphenoxy)butyrate and 3-(4-methoxyphenoxy)propylamine as disclosed below.

The US Patent No. 7714141 discloses another preparation of Pemafibrate involving the steps of reacting N-(benzoxazol-2-yl)-N-(3-(4-methoxyphenoxy)propyl)-3-hydroxybenzyamine with 2-trifluoro methanesulfonyloxybutyrolactone to an intermediate as mentioned below

The process of preparing Pemafibrate according to US Patent No. 7790903 employs 3-(4-methoxyphenoxy)propylamine prepared from the 4-methoxyphenol. The preparation of 3-(4-methoxyphenoxy)propylamine prepared from the 4-methoxyphenol employs boron-tetrahydrofuran complex, which is pyrophoric reagent.
Hence there needs a novel process for the preparation of Pemafibrate that avoids disadvantages of the prior arts and is efficient in commercial scale.
SUMMARY OF THE INVENTION
An aspect of the present invention is to provide a process of preparing Pemafibrate thereof comprising the steps of:
(i) reacting 3-halopropylamine derivative of formula-VII,

wherein R1 represents amino protecting group, X represents halogen group, preferably bromo or chloro; with 4-methoxyphenol in the presence of base to obtain 3-(4-methoxyphenoxy)propylamine derivative of formula-VI,

wherein R1 has the same meaning as above;
(ii) converting the 3-(4-methoxyphenoxy)propylamine derivative of formula-VI to 3-(4-methoxyphenoxy)propyl-1-amine of formula-V;

(iii) preparing 3({[3-(4-methoxyphenoxy)propyl]amino}methyl)phenol of formula-IV

by reacting 3-(4-methoxyphenoxy)propyl-1-amine of formula-V with 3-hydroxybenzaldehyde;
(iv) reacting 3({[3-(4-methoxyphenoxy)propyl]amino}methyl)phenol of formula-IV with 2-chlorobenzoxazole of formula-VIII in the presence of base to obtain 3-({benzoxazol-2-yl-[3-(4-methoxyphenoxy)propyl]amino} methyl)phenol of formula-III
; and
(v) reacting 3-({benzoxazol-2-yl-[3-(4-methoxyphenoxy)propyl]amino}methyl)phenol of formula-III with n-butyl-(S)-2-trifluoromethanesulfonyloxybutanoate of formula-IX in the presence of base to obtain n-butyl-(R)-2-[3-[4-(benoxazol-2-yl)-N-(3-(4-methoxyphenoxy)propyl)amino-methyl]phenoxy]butyrate of formula-II,

wherein R2 is alkyl or arylalkyl group; and
(vi) de-esterifying n-butyl-(R)-2-[3-[4-(benoxazol-2-yl)-N-(3-(4-methoxyphenoxy)propyl)amino-methyl]phenoxy]butyrate of formula-II to obtain Pemafibrate of formula-I.
Another aspect of the present invention is to provide novel crystalline form-S of Pemafibrate of formula-I characterized by an X-ray diffraction pattern comprising peaks located at 7.6 degree, 8.1 degree, 11.0 degree, 11.5 degree, 17.3 degree, 18.6 degree, 19.2 degree, 20.7 degree and 22.1 degree two theta angles and having DSC peak at 91.85°C.
Yet another aspect of the present invention is to provide a process for the preparation of novel crystalline form-S of Pemafibrate of formula-I characterized by an X-ray diffraction pattern comprising peaks located at 7.6 degree, 8.1 degree, 11.0 degree, 11.5 degree, 17.3 degree, 18.6 degree, 19.2 degree, 20.7 degree and 22.1 degree two theta angles and having DSC peak at 91.85°C, comprising the steps of:
(a) providing a solution of pemafibrate in ester solvent or its mixtures thereof;
(b) adding an aliphatic or an aromatic hydrocarbon solvent as a non-solvent to the solution provided in the step (a); and
(c) isolating novel crystalline form-S of Pemafibrate of formula-I from the mixture obtained in the step (b).
BRIEF DESCRIPTION OF FIGURES
Fig-1: The PXRD pattern of Crystalline Form-S of Pemafibrate of formula-I
Fig-2: The DSC of Crystalline Form-S of Pemafibrate of formula-I
DETAILED DESCRIPTION OF THE INVENTION
An embodiment of the present invention is to provide a process of preparing Pemafibrate thereof comprising the steps of:
(i) reacting 3-halopropylamine derivative of formula-VII,

wherein R1 represents amino protecting group, X represents halogen group, preferably bromo or chloro; with 4-methoxyphenol in a suitable solvent and in the presence of base to obtain 3-(4-methoxyphenoxy)propylamine derivative of formula-VI,

wherein R1 has the same meaning as above;
(ii) converting the 3-(4-methoxyphenoxy)propylamine derivative of formula-VI to 3-(4-methoxyphenoxy)propyl-1-amine of formula-V, in a suitable solvent and in an acidic medium, preferably by adding hydrochloric acid

(iii) preparing 3({[3-(4-methoxyphenoxy)propyl]amino}methyl)phenol of formula-IV

by reacting 3-(4-methoxyphenoxy)propyl-1-amine of formula-V with 3-hydroxybenzaldehyde, in a suitable solvent;
(iv) reacting 3({[3-(4-methoxyphenoxy)propyl]amino}methyl)phenol of formula-IV with 2-chlorobenzoxazole of formula-VIII in a suitable solvent and in the presence of base to obtain 3-({benzoxazol-2-yl-[3-(4-methoxyphenoxy)propyl]amino} methyl)phenol of formula-III
; and
(v) reacting 3-({benzoxazol-2-yl-[3-(4-methoxyphenoxy)propyl]amino}methyl)phenol of formula-III with n-butyl-(S)-2-trifluoromethanesulfonyloxybutanoate of formula-IX in a suitable solvent and in the presence of base to obtain n-butyl-(R)-2-[3-[4-(benoxazol-2-yl)-N-(3-(4-methoxyphenoxy)propyl)amino-methyl]phenoxy]butyrate of formula-II,

wherein R2 is alkyl or arylalkyl group; and
(vi) de-esterifying n-butyl-(R)-2-[3-[4-(benoxazol-2-yl)-N-(3-(4-methoxyphenoxy)propyl)amino-methyl]phenoxy]butyrate of formula-II to obtain Pemafibrate of formula-I.
The reacting 3-halopropylamine derivative of formula-VII with 4-methoxyphenol in the presence of base according to the step (i) is carried out in a suitable solvent. The suitable solvent for the reaction is selected from the group including, but not limited to halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and chlorobenzene; aromatic hydrocarbons such as benzene and toluene; ether such as tetrahydrofuran, diethyl ether and dioxane; ketones such as acetone and methyl ethyl ketone; ethers such as tetrahydrofuran, diethylether and dioxane; or its mixtures thereof.
The base used during the step of reacting 3-halopropylamine derivative of formula-VII with 4-methoxyphenol according to the step (i) is selected from organic and inorganic bases. Preferably trimethylamine is used
The converting the 3-(4-methoxyphenoxy)propylamine derivative of formula-VI to 3-(4-methoxyphenoxy)propyl-1-amine of formula-V according to step (ii) is carried out in acidic medium in a suitable solvent. Preferably acidic medium is done by adding hydrochloric acid. The suitable solvent for carrying out the step (ii) is selected from the group including, but not limited to ketones such as acetone and methyl ethyl ketone; ethers such as tetrahydrofuran, diethylether and dioxane; alcohol such as ethanol, methanol and propanol; or its mixtures thereof.
The preparing 3({[3-(4-methoxyphenoxy)propyl]amino}methyl)phenol of formula-IV from 3-(4-methoxyphenoxy)propyl-1-amine of formula-V and 3-hydroxybenzaldehyde according to step (iii) is carried out by a process comprising the steps of:
(a) reacting the 3-(4-methoxyphenoxy)propyl-1-amine of formula-V with 3-hydroxybenzaldehyde in a suitable solvent to obtain an intermediate; and
(b) reducing the obtained intermediate in step (a) in the presence of sodium borohydride in a suitable solvent.
The reacting the 3-(4-methoxyphenoxy)propyl-1-amine of formula-V with 3-hydroxybenzaldehyde in a suitable solvent to obtain an intermediate as in step (a) and reducing the obtained intermediate in step (a) in the presence of reducing agent in a suitable solvent as in step (b) is performed in a single suitable solvent or its mixtures thereof. The step (a) and step (b) are performed in same solvent or different solvent or solvent mixtures thereof. The solvent for step (iii) is selected from a group including, but not limited to ethers such as tetrahydrofuran, diethylether and dioxane; esters such as ethyl acetate; alcohol such as ethanol, methanol and propanol; aprotic polar solvent such as acetonitrile, N,N-dimethylformamide and dimethylsulfoxide or its mixtures thereof.
The base for reacting 3({[3-(4-methoxyphenoxy)propyl]amino}methyl)phenol of formula-IV with 2-chlorobenzoxazole of formula-VIII to obtain 3-({benzoxazol-2-yl-[3-(4-methoxyphenoxy)propyl]amino} methyl)phenol of formula-III according step (iv) is selected from a group consisting organic and inorganic bases. Preferably triethylamine is used.
The suitable solvent for reacting 3({[3-(4-methoxyphenoxy)propyl]amino}methyl)phenol of formula-IV with 2-chlorobenzoxazole of formula-VIII to obtain 3-({benzoxazol-2-yl-[3-(4-methoxyphenoxy)propyl]amino} methyl)phenol of formula-III according step (iv) is selected from the group including, but not limited to aromatic hydrocarbons such as benzene and toluene; ether such as tetrahydrofuran, diethyl ether and dioxane; ketones such as acetone and methyl ethyl ketone; ethers such as tetrahydrofuran, diethylether and dioxane; aprotic polar solvent such as acetonitrile, N,N-dimethylformamide and dimethylsulfoxide or its mixtures thereof.
The base for reacting 3-({benzoxazol-2-yl-[3-(4-methoxyphenoxy)propyl]amino}methyl)phenol of formula-III with n-butyl-(S)-2-trifluoromethanesulfonyloxybutanoate of formula-IX in the presence of base to obtain n-butyl-(R)-2-[3-[4-(benoxazol-2-yl)-N-(3-(4-methoxyphenoxy)propyl)amino-methyl]phenoxy]butyrate of formula-II according to step (v) is selected from a group consisting organic and inorganic bases. Preferably potassium carbonate is used.
The suitable solvent for reacting 3-({benzoxazol-2-yl-[3-(4-methoxyphenoxy)propyl]amino} methyl)phenol of formula-III with n-butyl-(S)-2-trifluoromethanesulfonyloxybutanoate of formula-IX according to step (v) is selected from the group including, but not limited to halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and chlorobenzene; aromatic hydrocarbons such as benzene and toluene; ether such as tetrahydrofuran, diethyl ether and dioxane; ketones such as acetone and methyl ethyl ketone; ethers such as tetrahydrofuran, diethylether and dioxane; aprotic polar solvent such as acetonitrile, N,N-dimethylformamide and dimethylsulfoxide or its mixtures thereof.
The de-esterifying n-butyl-(R)-2-[3-[4-(benoxazol-2-yl)-N-(3-(4-methoxyphenoxy)propyl) amino-methyl]phenoxy]butyrate of formula-II according to step (vi) is carried out in basic medium in polar solvent. Preferably acidic medium is done by adding sodium hydroxide solution. Preferably the polar solvent is an alcohol, such as methanol or ethanol, or a combination thereof.
The Schematic representation of the novel process of Pemafibrate of the present invention is mentioned below.

The present novel process of the Pemafibrate overcomes the below mentioned problems of the prior arts:
• cumbersome work up procedures after the reactions due to the formation undesired products during the reactions; and
• the use of boron-tetrahydrofuran complex, a pyrophoric reagent.
Another embodiment of the present invention is to provide novel crystalline form-S of Pemafibrate of formula-I characterized by an X-ray diffraction pattern comprising peaks located at 7.6 degree, 8.1 degree, 11.0 degree, 11.5 degree, 17.3 degree, 18.6 degree, 19.2 degree, 20.7 degree and 22.1 degree two theta angles and having DSC peak at 91.85°C.
Yet another embodiment of the present invention is to provide a process for the preparation of novel crystalline form-S of Pemafibrate of formula-I characterized by an X-ray diffraction pattern comprising peaks located at 7.6 degree, 8.1 degree, 11.0 degree, 11.5 degree, 17.3 degree, 18.6 degree, 19.2 degree, 20.7 degree and 22.1 degree two theta angles and having DSC peak at 91.85°C, comprising the steps of:
(a) providing a solution of pemafibrate in ester solvent or its mixtures thereof;
(b) adding a non-solvent selected from a group comprising of an aliphatic and an aromatic hydrocarbon solvent, to the solution provided in the step (a); and
(c) isolating novel crystalline form-S of Pemafibrate of formula-I from the mixture obtained in the step (b).
Preferable ester solvent as in the step (a) of the present invention is ethylacetate.
Preferable aliphatic hydrocarbon solvent as in the step (b) of the present invention is heptane.
Preferable aromatic hydrocarbon solvent as in the step (b) of the present invention is toluene.
The present invention is explained in detail with reference to the following examples described below, which are given for the purpose of illustration only and are not intended to limit the scope of the invention.

Examples
Example-1: Preparation of tert-butyl-(3-bromopropyl)carbamate
To a mixture of 3-bromopropylamine hydrobromide (100 gm), dichloromethane (2000 ml) and di-tert-butyl dicarbonate (99.64 gm), triethylamine (166.32 gm) was added slowly at 30°C and stirred for 12 hours at the same temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, water (1000 ml) was added to the reaction mass and stirred for 20 minutes at 30°C. The stirred mixture was allowed to form a biphasic mixture. The organic layer was separated and concentrated under vacuum to obtain an oily mass. %Yield: 85.5%
Example-2: Preparation of 3-(4-methoxyphenoxy)propyl-1-amine (Formula-V)
Step-A: To a mixture of 4-methoxyphenol (40 gm), potassium carbonate (133.6 gm) and acetone (200 ml), acetone solution of tert-butyl-(3-bromopropyl)carbamate (91.2 gm of tert-butyl-(3-bromopropyl)carbamate in 200 ml of acetone) was added at 25°C and heated to 50-55°C. Then the reaction mixture was stirred for 6 hours at 50-55°C. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was filtered.
Step-B: To the above filtrate obtained in step-A, hydrochloride acid (80 ml) was slowly added at 25°C and stirred for 12 hours at the same temperature. The resultant solid was filtered and washed with acetone (80 ml). Water (200 ml) and dichloromethane (280 ml) were added to the wet solid at 25°C and stirred for 20 minutes. The pH of the biphasic medium was adjusted 13.5 to 14 using 50% sodium hydroxide solution and stirred for 1 hour at 25°C. The organic layer was separated and concentrated under vacuum to obtain a solid mass. % Yield: 67.93%
Example-3: Preparation of 3-({[3-(4-methoxyphenoxy)propyl]amino}methyl)phenol (Formula-IV)
Step-A: To a mixture of 3-(4-methoxyphenoxy)propyl-1-amine (46 gm) and methanol (230 ml), 3-hydroxy-benzaldehyde (34.5 gm) was added at 25°C and stirred for 5 hours at the same temperature. The reaction mixture was cooled.
Step-B: To the cooled reaction mixture obtained in step-A, sodium borohydride solution (9.6 gm of sodium borohydride in 92 ml of water) was added at -5°C and stirred for 1 hour at the same temperature. The temperature of the reaction mixture was raised to 25°C and stirred for 12 hours at the same temperature. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mass was filtered and washed with methanol (92 ml). To the filtered wet solid, methanol (230 ml) was added and stirred for 20 minutes at 25°C. The stirred contents were heated to 60°C and stirred for 1 hour at the same temperature. The contents were then cooled to 25°C and stirred for 1 hour at the same temperature. The resultant solid was filtered, washed with methanol (46 ml) and dried. Yield: 79.6%
Example-4: Preparation of 3-({benzoxazol-2-yl-[3-(4-methoxyphenoxy)propyl]amino} methyl)phenol (Formula-III)
To a mixture of 3-({[3-(4-methoxyphenoxy)propyl]amino}methyl)phenol (30 gm), acetone (300 ml) and di-isopropyl ethylamine (20.24 gm), 2-chlorobenzoxazole (16 gm) was added slowly at 25°C and stirred for 15 minutes at the same temperature. The reaction mixture was heated to 60°C and stirred for 2 hours at the same temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was concentrated under vacuum. To the concentrated residue, ethyl acetate (300 ml) was added and stirred for 20 minutes at 25°C. The ethyl acetate solution was washed with hydrochloric acid solution (30 ml of hydrochloric acid in 270 ml of water) and concentrated under vacuum. To the concentrated residue, tetrahydrofuran (30 ml) was added followed by the slow addition of heptane (300 ml) at 25°C. The contents were then stirred for 12 hours at 25°C. The resultant solid was filtered, washed with heptane (60 ml) and dried under vacuum. % Yield: 75.8%
Example-5: Preparation of Pemafibrate (Formula-I)
Step-A: To a mixture of 3-({benzoxazol-2-yl-[3-(4-methoxyphenoxy)propyl]amino}methyl) -phenol (20 gm), potassium carbonate (13.66 gm) and acetone (100 ml), n-butyl-(S)-2-trifluoromethane sulfonyloxy butanoate (21.6 gm) was added at 25°C and stirred for 5 hours at the same temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was filtered. The filtrate was concentrated under vacuum at 45°C.
Step-B: The concentrated residue obtained in step-A was dissolved in ethyl acetate (200 ml) at 25°C. The organic phase was washed with water (100 ml) and concentrated under vacuum at 45°C. To the concentrated residue, methanol (250 ml) was added at 25°C and stirred for 20 minutes at the same temperature. The stirred reaction mass was cooled to 5°C. To the cooled reaction mass, sodium hydroxide solution (5.5 gm of sodium hydroxide in 72 ml of water) was added at 5°C and stirred for 20 minutes at the same temperature. The temperature of the reaction mass was then increased to 25°C and stirred for 3 to 5 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was concentrated under vacuum. To the concentrated residue, water (125 ml) was added and stirred. The aqueous phase was washed with methyl tertiary butyl ether (125 ml). To the washed aqueous phase, activated carbon (1.25 gm) was added and stirred for 20 minutes at 25°C. The contents were filtered through hyflo bed and filtrate was cooled to 5°C. The pH of the cooled filtrate was adjusted to 2 to 3 by the addition of hydrochloric acid solution (20 ml hydrochloride acid in 20 ml of water) and stirred for 1 hour at 5°C. The contents were then heated to 25°C and stirred for 12 hours at the same temperature. The resultant solid was filtered, washed with water (125 ml) and dried under vacuum at 40°C. % Yield: 93.3%

Example-6: Purification of the Pemafibrate
A mixture of pemafibrate (18 gm) and ethyl acetate (150 ml) was stirred for 20 minutes at 25°C. The contents were then heated to 35°C and stirred for 20 minutes followed by the addition of activated charcoal (1.25 gm) at 35°C. The contents were stirred for 20 minutes at 35°C and filtered through hyflo bed. The filtrate was cooled to 25°C and stirred for 20 minutes at the temperature. To the cooled contents, heptane (400 ml) was added and stirred for 12 hours at 25°C. The resultant solid was filtered, washed with heptane (50 ml) and dried under vacuum at 45°C. % Yield: 66% ,CLAIMS:1. A process of preparing Pemafibrate comprising the steps of:
(i) reacting 3-halopropylamine derivative of formula-VII,

wherein R1 represents amino protecting group, X represents halogen group, preferably bromo or chloro; with 4-methoxyphenol in a suitable solvent and in the presence of base to obtain 3-(4-methoxyphenoxy)propylamine derivative of formula-VI,

wherein R1 has the same meaning as above;
(ii) converting the 3-(4-methoxyphenoxy)propylamine derivative of formula-VI to 3-(4-methoxyphenoxy)propyl-1-amine of formula-V , in a suitable solvent and in an acidic medium, preferably by adding hydrochloric acid;

(iii) preparing 3({[3-(4-methoxyphenoxy)propyl]amino}methyl)phenol of formula-IV

by reacting 3-(4-methoxyphenoxy)propyl-1-amine of formula-V with 3-hydroxybenzaldehyde in a suitable solvent;
(iv) reacting 3({[3-(4-methoxyphenoxy)propyl]amino}methyl)phenol of formula-IV with 2-chlorobenzoxazole of formula-VIII in a suitable solvent and in the presence of base to obtain 3-({benzoxazol-2-yl-[3-(4-methoxyphenoxy)propyl]amino} methyl)phenol of formula-III
; and
(v) reacting 3-({benzoxazol-2-yl-[3-(4-methoxyphenoxy)propyl]amino}methyl)phenol of formula-III with n-butyl-(S)-2-trifluoromethanesulfonyloxybutanoate of formula-IX in a suitable solvent and in the presence of base to obtain n-butyl-(R)-2-[3-[4-(benoxazol-2-yl)-N-(3-(4-methoxyphenoxy)propyl)amino-methyl]phenoxy]butyrate of formula-II,

wherein R2 is alkyl or arylalkyl group; and
(vi) de-esterifying n-butyl-(R)-2-[3-[4-(benoxazol-2-yl)-N-(3-(4-methoxyphenoxy)propyl)amino-methyl]phenoxy]butyrate of formula-II to obtain Pemafibrate of formula-I.

(2) The process as claimed in claim 1 wherein the suitable solvent of step (i) for the reaction is selected from the groups;
(a) halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and chlorobenzene;
(b) aromatic hydrocarbons such as benzene and toluene;
(c) ether such as tetrahydrofuran, diethyl ether and dioxane;
(d) ketones such as acetone and methyl ethyl ketone;
(e) ethers such as tetrahydrofuran, diethylether and dioxane; or its mixtures thereof.

(3) The process as claimed in claim 1 wherein the base of steps (i), (iv) and (v) is selected from organic and inorganic bases.

(4) The process as claimed in claim 1 wherein the base of step (i) is trimethylamine.

(5) The process as claimed in step (ii) of claim 1 wherein the suitable solvent is selected from the groups;
(a) ketones such as acetone and methyl ethyl ketone;
(b) ethers such as tetrahydrofuran, diethylether and dioxane;
(c) alcohol such as ethanol, methanol and propanol;
or its mixtures thereof.

(6) The process as claimed in claim 1 wherein the compound of formula IV of step (iii) is prepared from 3-(4-methoxyphenoxy)propyl-1-amine of formula-V and 3-hydroxybenzaldehyde is carried out by a process comprising the steps of:
(a) reacting the 3-(4-methoxyphenoxy)propyl-1-amine of formula-V with 3-hydroxybenzaldehyde in a suitable solvent to obtain an intermediate; and
(b) reducing the obtained intermediate in step (a) in the presence of sodium borohydride in a suitable solvent; wherein step (a) and step (b) are performed in same solvent or different solvent or solvent mixtures thereof; wherein the solvent is selected from groups;
(a) ethers such as tetrahydrofuran, diethylether and dioxane;
(b) esters such as ethyl acetate;
(c) alcohol such as ethanol, methanol and propanol;
(d) aprotic polar solvent such as acetonitrile, N,N-dimethylformamide and dimethylsulfoxide or its mixtures thereof.

(7) The process as claimed in step(iv) of claim 1 wherein the suitable solvent is selected from the groups:
(a) aromatic hydrocarbons such as benzene and toluene;
(b) ether such as tetrahydrofuran, diethyl ether and dioxane;
(c) ketones such as acetone and methyl ethyl ketone;
(d) ethers such as tetrahydrofuran, diethylether and dioxane;
(e) aprotic polar solvent such as acetonitrile, N,N-dimethylformamide and dimethylsulfoxide
or its mixtures thereof.

(8) The process as claimed in claim 1 wherein the base of step (iv) is trimethylamine

.(9) The process as claimed in step (v) of claim 1 wherein the suitable solvent is selected from the groups
(a) halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and chlorobenzene;
(b) aromatic hydrocarbons such as benzene and toluene;
(c) ether such as tetrahydrofuran, diethyl ether and dioxane;
(d) ketones such as acetone and methyl ethyl ketone;
(e) ethers such as tetrahydrofuran, diethylether and dioxane;
(f) aprotic polar solvent such as acetonitrile, N,N-dimethylformamide and dimethylsulfoxide
or its mixtures thereof.

(10) The process as claimed in claim 1 wherein the base of step (v) is sodium carbonate

(11) The process as claimed in claim 1 wherein step (vi) is carried out in basic medium, preferably by adding sodium hydroxide solution and in the presence of polar solvent wherein the said polar solvent is an alcohol, preferably methanol or ethanol, or a combination thereof.

(12) A crystalline form-S of Pemafibrate of formula-I characterized by an X-ray diffraction pattern comprising peaks located at 7.6 degree, 8.1 degree, 11.0 degree, 11.5 degree, 17.3 degree, 18.6 degree, 19.2 degree, 20.7 degree and 22.1 degree two theta angles and having DSC peak at 91.85°C.

(13) A process for the preparation of novel crystalline form-S of Pemafibrate of formula-I characterized by an X-ray diffraction pattern comprising peaks located at 7.6 degree, 8.1 degree, 11.0 degree, 11.5 degree, 17.3 degree, 18.6 degree, 19.2 degree, 20.7 degree and 22.1 degree two theta angles and having DSC peak at 91.85°C, comprising the steps of:
(a) providing a solution of pemafibrate in ester solvent or its mixtures thereof; preferably ethylacetate;
(b) adding an aliphatic or an aromatic hydrocarbon solvent, preferably heptane or toluene as a non-solvent to the solution provided in the step (a); and
(c) isolating novel crystalline form-S of Pemafibrate of formula-I from the mixture obtained in the step (b).