DESC:FIELD OF THE INVENTION:
The present invention relates to an efficient and industrially advantageous process for the preparation of Pemafibrate intermediates namely 3-[[2-benzoxazolyl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenol of Formula IV, Pemafibrate ethyl ester of Formula VI and their use for the preparation of Pemafibrate of Formula-I or salt thereof.

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, having the structure of Formula-I,

[Formula-I]
Pemafibrate was developed by Kowa company. Pemafibrate was approved by Japanese Pharmaceuticals and Medical Devices Agency (PMDA) on July 03, 2017 under the proprietary name Parmodia®. Pemafibrate is pharmaceutical ingredient indicated for the treatment of hyperlipidaemia (including familial hyperlipidaemia)
US patent number US 7109226 (herein after US’226) first discloses Pemafibrate and its analogous method of preparation by hydrolysis of Pemafibrate ethyl ester.
US’226 does not disclose process for the preparation of Pemafibrate ethyl ester. Further, Pemafibrate prepared by US’226 requires column chromatography.
US patent number 7790903 (herein after US’903) discloses process for the preparation of Pemafibrate by reacting 3-({[3-(4-methoxyphenoxy)propyl]amino}methyl)phenol with 2-chlorobenzoxazole using triethylamine to obtain 3-({benzoxazol-2-yl-[3-(4-methoxyphenoxy)propyl] amino} methyl)phenol which is further reacted with n-butyl-(S)-trifluoromethane sulfonyloxybutyrate to obtain n-butyl ester of Pemafibrate. Resulting ester on de-esterification results into Pemafibrate.
Major drawbacks of US’903 process is, when triethylamine or organic amine is used for the reaction of 3-({[3-(4-methoxyphenoxy)propyl]amino}methyl)phenol with 2-chlorobenzoxazole, it fails to control other side product and hence required multi purification methods of column chromatography and solvent-anti solvent method for the purification of resulting 3-({benzoxazol-2-yl-[3-(4-methoxyphenoxy)propyl] amino} methyl)phenol. Also, US’903 process involves use of n-butyl-(S)-trifluoromethane sulfonyloxybutyrate for the preparation of n-butyl ester of Pemafibrate which is costlier as compared to ethyl (2S)-2-hydroxybutanoate. Therefore, US’903 process is not an attractive option to use for industrial scale.
US patent number 7714141 (herein after US’141) discloses process for the preparation of Pemafibrate by reacting ethyl (R)-2-{3-[N-(benzoxazol-2-yl)-N-(3-(4-methoxyphenoxy) propyl)aminomethyl]phenyloxy}-4-iodobutylate with 10% palladium on carbon and triethylamine to obtain ethyl (R)-2-{3-[N-(benzoxazol-2-yl)-N-(3-(4-methoxyphenoxy) propyl)aminomethyl]phenyloxy}butylate which on de-esterification results into Pemafibrate.
Major drawbacks of US’141 process is, it requires column chromatography. Also this patent is silent about the purity of obtained ethyl (R)-2-{3-[N-(benzoxazol-2-yl)-N-(3-(4-methoxyphenoxy) propyl)aminomethyl]phenyloxy}butylate. The pemafibrate obtained by US’141 process also requires column chromatography. Therefore, US’141 process is not an attractive option to use for industrial scale.
Like any synthetic compound, intermediate compounds can contain extraneous compounds or impurities that can come from many sources which may get carried forward to final API i.e. Pemafibrate or may react to form other by products. These extraneous compounds in the intermediate may be unreacted starting materials, by products of the reaction, products of side reactions, or degradation products or different isomers. Impurities generated due to any reason in any API like Pemafibrate are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API.
The American Food and Drug Administration (FDA) as well as European medicament control offices require, according to the Q7A ICH (International Conference on Harmonization) guidance, that Active Pharmaceutical Ingredient (API) is freed from impurities to the maximum possible extent. The reason is achieving maximum safety of using the drug in the clinical practice. National inspection and control offices usually require that the content of an individual impurity in an API should not exceed the limit of 0.1%. All the substances (generally referred to as impurities) contained in an API over the limit of 0.1% should be isolated and characterized in accordance with the ICH recommendations. Q7A ICH guidance for manufacturers also states that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time and stoichiometric ratio, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
It is always advantageous to use intermediates of high purity which is free from the undesired impurities or such impurities should be present in acceptable amounts. The purity of the chemical compounds can be measured by chromatographic techniques such as high pressure liquid chromatography (HPLC). The control of impurities at intermediate step is always important, since impurities present in the intermediate stage may carried forward and may reacts further with further reagents and which results formation of new impurities along with main product.
All the prior arts discussed above suffer from many disadvantages like tedious work up process, costly reagent or reactant, require column chromatography for purification, which affect the overall yield as well as the purity of the final Pemafibrate product. Therefore, there is an urgent need for an improved process for the preparation of Pemafibrate having high purity which overcomes the drawbacks of the prior arts process.
The present inventors have developed an efficient process for the preparation of Pemafibrate or salt thereof and its intermediates namely 3-[[2-benzoxazolyl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenol, Pemafibrate ethyl ester which offer advantage over the prior art processes in terms of high yield, high purity and less effluents and simple scalable procedure suitable for large scale industrial production of Pemafibrate.
OBJECT OF THE INVENTION:
The main object of the present invention is to provide an efficient and industrially advantageous process for the preparation of Pemafibrate intermediates namely 3-[[2-benzoxazolyl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenol of Formula IV, Pemafibrate ethyl ester of Formula VI and their use for the preparation of Pemafibrate of Formula-I.

SUMMARY OF INVENTION:
First aspect of the present invention is to provide a process for the preparation of Pemafibrate of Formula-I,

[Formula-I]
comprising the steps of:
a) reacting compound of Formula-II,

[Formula-II]
with compound of Formula-III,

[Formula-III]
in presence of alkali metal carbonate and solvent to obtain compound of Formula-IV;

[Formula-IV]
b) reacting compound of Formula-IV with compound of Formula-V,

[Formula-V]
to obtain Pemafibrate ethyl ester of Formula-VI;

[Formula-VI]
c) converting Pemafibrate ethyl ester of Formula-VI to Pemafibrate of Formula I.
Second aspect of the present invention is to provide a process for the preparation of compound of Formula-IV,

[Formula-IV]
comprising reacting compound of Formula-II,

[Formula-II]
with compound of Formula-III,

[Formula-III]
in presence of alkali metal carbonate and solvent to obtain compound of Formula-IV.

Third aspect of the present invention is to provide a process for the preparation of Pemafibrate ethyl ester of Formula-VI,

[Formula-VI]
comprising the steps of reacting compound of Formula-IV,

[Formula-IV]
with compound of Formula-V,

[Formula-V]
to obtain Pemafibrate ethyl ester of Formula-VI.
DEFINITION:
All percentages and ratios used herein are by weight of the total composition and all measurements made are at 25ºC and normal pressure unless otherwise designated.
All temperatures used herein are in degree Celsius unless specified otherwise.
All ranges recited herein include the endpoints, including those that recite a range "between" two values.
As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements that may or may not be recited.
The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise.
The term "about", as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value.

DETAILED DESCRIPTION OF INVENTION:
While the following specification concludes with claims particularly pointing out and distinctly claiming the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description and by studying the included examples.
The best methods and materials of performing the present invention are described here.
The present invention provides a novel, efficient and industrially advantageous process for the preparation of Pemafibrate of Formula-I.
According to first embodiment, the present invention provides a process for the preparation of Pemafibrate of Formula-I,

[Formula-I]
comprising the steps of:
a) reacting compound of Formula-II,

[Formula-II]
with compound of Formula-III,

[Formula-III]
in presence of alkali metal carbonate and solvent to obtain compound of Formula-IV;

[Formula-IV]
b) reacting compound of Formula-IV with compound of Formula-V,

[Formula-V]
to obtain Pemafibrate ethyl ester of Formula-VI; and

[Formula-VI]
c) converting Pemafibrate ethyl ester of Formula-VI to Pemafibrate of Formula I.
In the first embodiment of step a), compound of Formula-II used as a starting material for the preparation of Pemafibrate of Formula-I can be prepared by process known in the prior art.

In the first embodiment of step a), compound of Formula-II can be reacted with compound of Formula-III in presence of alkali metal carbonate and solvent to obtain compound of Formula-IV.

In the first embodiment of step a), alkali metal carbonates can be selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, caesium carbonate or mixture(s) thereof.

In the first embodiment of step a), molar equivalent of alkali metal carbonate with respect to compound of the Formula-II can be 1.1 to 1.5.
In the first embodiment of step a), solvent can be selected from the group consisting of ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof.
In the first embodiment of step a), the reaction of compound of Formula-II with compound of Formula-III in presence of alkali metal carbonate and solvent can be carried out at temperature of about 40°C to about 90°C.
In the first embodiment of step a), the reaction of compound of Formula-II with compound of Formula-III in presence of alkali metal carbonate and solvent can be carried out for 6 hours to 12 hours.
After completion of reaction, water can be added to resulting reaction mixture at temperature of about 25°C to about 30°C and allowed to settle organic and aqueous layer. Resulting layers can be separated and organic layer can be washed with water followed by aqueous sodium chloride. Resulting organic layer can be treated with activated carbon and can be filtered on celite bed to obtained filtrate. Resulting filtrate can be distilled and aliphatic hydrocarbon solvent selected from the group consisting of n-hexane, cyclohexane, n-heptane or mixture(s) thereof can be added to distilled mass. Resulting mixture can be stirred for 1 hour to 2 hours at 25°C to 30°C and can be filtered to obtain a solid. Resulting solid can be dried at temperature of about 55°C to about 65°C to obtain a compound of the Formula IV.
The compound of the Formula IV can have purity greater than 98%, preferably greater than 99.0% by HPLC (High-performance liquid chromatography).
It has been observed that when compound of the Formula II is reacted with compound of the Formula III in presence of organic base as per prior art, Impurity-1 (4% to 6%) is also forming as a by-product.

[Impurity-1]
Thus, to avoid formation of Impurity-1, inventor of the present invention tried several experiments and found, when compound of Formula II is reacted with compound of the Formula III in presence of alkali metal carbonates formation of Impurity-1 is controlled.

In the first embodiment of step b), reaction of compound of Formula-IV with compound of Formula-V can be carried out in presence of azodicarboxylate such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), triphenylphosphine and solvent.

In the first embodiment of step b), solvent can be selected from the group consisting of alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof.
In the first embodiment of step b), reaction of compound of Formula-IV with compound of Formula-V can be carried out at temperature of about 0°C to about 30°C.
In the first embodiment of step b), reaction of compound of Formula-IV with compound of Formula-V can be carried out for 2 hours to 5 hours.
After completion of reaction, water can be added to the resulting reaction mixture at 25°C to 30°C and mixture can be allowed to separate the organic layer and aqueous layer. Resulting organic layer can be washed with water and can be distilled to remove solvent. Ether solvent can be added to resulting distilled mass below 45°C and can be further stirred for 1 hour at 5°C to 10°C. Resulting mixture can be filtered and filtrate can be distilled to obtain a distilled mass. Alcohol solvent can be added to resulting mass and further distilled to obtain a compound of the Formula VI.
Compound of the Formula VI obtain according to present invention can be taken as such for the next step without any purification for the preparation of Pemafibrate of Formula I.
In the first embodiment of step c), Pemafibrate ethyl ester of Formula-VI can be converted to Pemafibrate of Formula I in presence of base and alcohol solvent.
In the first embodiment of step c), base can be selected from sodium hydroxide or potassium hydroxide.
In the first embodiment of step c), solvent can be selected from alcohol such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol or t-butyl alcohol.
In the first embodiment of step c), Pemafibrate ethyl ester of Formula-VI can be converted to Pemafibrate of Formula I at temperature of about 5°C to about 30°C.
In the first embodiment of step c), reaction of Pemafibrate ethyl ester of Formula-VI with base can be carried out for 2 hours to 6 hours.
After completion of reaction, solvent can be removed by distillation and water followed by ether solvent can be added to the reaction mixture at 25°C to about 30°C. Resulting mixture can be allowed to separate the organic and aqueous layers. Resulting aqueous layer can be extracted with ether solvent such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane and pH of the resulting aqueous layer can be adjusted to 3 to 4 at 10°C to about 20°C. Halogenated aliphatic hydrocarbon such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride can be added to resulting mixture at same temperature and mixture can be allowed to separate the organic and aqueous layer. Resulting organic layer can be treated with activated carbon followed by distillation to obtain Pemafibrate of Formula I.
Resulting Pemafibrate of Formula I is obtained in high purity of greater than 99.0% w/w.

In the first embodiment of step c), Pemafibrate of Formula I can be purified using ether solvent such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane and aliphatic hydrocarbon solvent such as n-hexane, cyclohexane, n-heptane or mixture(s) thereof.
In the first embodiment of step c), Pemafibrate of Formula I can be purified by heating mixture of Pemafibrate of Formula I and ether solvent below 60°C. Resulting mixture can be cooled to 15°C to 30°C followed by addition of aliphatic hydrocarbon solvent. Resulting mixture can be stirred at same temperature. Resulting solid can be isolated by filtration or decantation.
Alternatively, Pemafibrate of Formula I can be purified using ethyl acetate and n-heptane.
Resulting Pemafibrate of Formula I is obtained in high purity of greater than 99.5% w/w.

According to second embodiment, the present invention provides a process for the preparation of compound of Formula-IV,

[Formula-IV]
comprising reacting compound of Formula-II,

[Formula-II]
with compound of Formula-III,

[Formula-III]
in presence of alkali metal carbonate and solvent to obtain compound of Formula-IV.
In the second embodiment, compound of Formula-II used as a starting material for the preparation of Pemafibrate of Formula-I can be prepared by process known in the prior art.

In the second embodiment, alkali metal carbonates can be selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or caesium carbonate or mixture(s) thereof.

In the second embodiment, molar equivalent of alkali metal carbonate with respect to compound of the Formula-II can be 1.1 to 1.5.
In the second embodiment, solvent can be selected from the group consisting of ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof.
In the second embodiment, the reaction of compound of Formula-II with compound of Formula-III in presence of alkali metal carbonate and solvent can be carried out at temperature of about 40°C to about 90°C.
In the second embodiment, the reaction of compound of Formula-II with compound of Formula-III in presence of alkali metal carbonate and solvent can be carried out for 6 hours to 12 hours.
After completion of reaction, water can be added to resulting reaction mixture at temperature of about 25°C to about 30°C and allowed to settle organic and aqueous layer. Resulting layers can be separated and organic layer can be washed with water followed by aqueous sodium chloride. Resulting organic layer can be treated with activated carbon and can be filtered on celite bed to obtained filtrate. Resulting filtrate can be distilled and aliphatic hydrocarbon solvent selected from the group consisting of n-hexane, cyclohexane, n-heptane or mixture(s) thereof can be added to distilled mass. Resulting mixture can be stirred for 1 hour to 2 hours at 25°C to 30°C and filtered to obtain a solid. Resulting solid can be dried at temperature of about 55°C to about 65°C to obtain a compound of the Formula IV.
The compound of the Formula IV can have purity greater than 98%, preferably greater than 99.0% by HPLC (High-performance liquid chromatography).
It has been observed that when compound of the Formula II is reacted with compound of the Formula III in presence of organic base as per prior art, Impurity-1 (4% to 6%) is also forming as a by-product, which affect overall yield of the process.

[Impurity-1]
Thus, to avoid formation of Impurity-1, inventor of the present invention tried several experiments and found, when compound of Formula II is reacted with compound of the Formula III in presence of alkali metal carbonates formation of Impurity-1 is controlled.

According to third embodiment, the present invention provides a process for the preparation of Pemafibrate ethyl ester of Formula-VI,

[Formula-VI]
comprising the steps of reacting compound of Formula-IV,

[Formula-IV]
with compound of Formula-V,

[Formula-V]
to obtain Pemafibrate ethyl ester of Formula-VI.
In the third embodiment, reaction of compound of Formula-IV with compound of Formula-V can be carried out in presence of azodicarboxylate such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), triphenylphosphine and solvent.

In the third embodiment, solvent can be selected from the group consisting of alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof.
In the third embodiment, reaction of compound of Formula-IV with compound of Formula-V can be carried out at temperature of about 0°C to about 30°C.
In the third embodiment, reaction of compound of Formula-IV with compound of Formula-V can be carried out for 2 hours to 5 hours.
After completion of reaction, water can be added to the resulting reaction mixture at 25°C to 30°C and mixture can be allowed to separate the organic layer and aqueous layer. Resulting organic layer can be washed with water and can be distilled to remove solvent. Ether solvent can be added to resulting distilled mass below 45°C and can be further stirred for 1 hour at 5°C to 10°C. Resulting mixture can be filtered and filtrate can be distilled to obtain a distilled mass. Alcohol solvent can be added to resulting mass and further distilled to obtain a compound of the Formula VI.
Compound of the Formula VI obtained according to present invention can be as such taken for the next step without any purification for the preparation of Pemafibrate of Formula I.
Compound of the Formula VI obtained according to present invention when converted to Pemafibrate of Formula I it results into pure Pemafibrate of formula I as it controls formation of impurities.
EXAMPLES:
The following examples are illustrative of some of the embodiments of the present invention described herein. These examples should not be considered to limit the spirit or scope of the invention in any way.
Example 01: Preparation of compound of Formula-IV
To a stirred mixture of ethyl acetate (1840 mL), sodium bicarbonate and compound of Formula-II (230 gm), compound of Formula-III (147.5 gm) was added at 25°C to 35°C. Resulting reaction mixture was heated to 75°C to 80°C and stirred for 10 hours. After completion of reaction, water was added to resulting mixture at 25°C to 30°C and allowed to separate the organic and aqueous layer. Resulting layers was separated and organic layer was washed with water followed by aqueous sodium chloride. Resulting organic layer was treated with activated carbon (11.5 g) and filtered on celite bed to obtained filtrate. Resulting filtrate was distilled and ethyl acetate (460 ml) was added to distilled mass. Resulting mixture was heated till clear solution obtained and n-heptane (920 mL) was added at 25-30°C. Resulting mixture was stirred for 1 hour at 25°C to 30°C and filtered to obtain a solid. Resulting solid was dried at 55°C to 65°C to obtain title compound having HPLC purity of 99.3%.
Yield: 88.5%

Example 02: Preparation of Pemafibrate ethyl ester of Formula-VI
To a stirred mixture of dichloromethane (500 mL) and compound of Formula IV (50 g), triphenyl phosphine (71.3 g) and ethyl (2S)-2-hydroxybutanoate of Formula (V) (35.9 g) were added at 25°C to 30°C. Resulting mixture was cooled at 0°C to 5°C and DEAD (47.36 g) was added slowly to mixture at same temperature. After completion of reaction, water (100 mL) was added to the resulting reaction mixture at 25°C to 30°C and mixture was allowed to separate the organic layer and aqueous layer. Resulting organic layer was washed with water (100 mL) and distilled to remove solvent. Methyl tert-butyl ether (250 mL) was added to resulting distilled mass below 45°C and further stirred for 1 hour at 5°C to 10°C. Resulting mixture was filtered and filtrate was distilled to obtain a distilled mass. Methanol (50 mL) was added to resulting mass and further distilled to obtain a title compound.
Purity:> 90%

Example 03: Preparation of Pemafibrate of Formula I
To a stirred mixture of methanol (750 mL) and Pemafibrate ethyl ester of Formula-VI obtained according to example 02, aqueous sodium hydroxide (18.5g in 100 ml water) was added at 5°C to 10°C. Resulting mixture was stirred for 4 hours at 25°C to 30°C. After completion of reaction, solvent was removed by distillation and water (750 mL) followed by methyl tert-butyl ether (750 mL) was added to the reaction mixture at 25°C to about 30°C. Resulting mixture was allowed to separate the organic and aqueous layers. Resulting aqueous layer was extracted with methyl tert-butyl ether (7×250 mL) and pH of the resulting aqueous layer was adjusted to 3.5 using conc. hydrochloric acid (50 g) at 10°C to about 20°C. Dichloromethane (250 ml) was added to resulting mixture at same temperature and mixture was allowed to separate the organic and aqueous layer. Resulting organic layer was treated with activated carbon (2.5 g) followed by filtration to obtain filtrate. Resulting filtrate was distilled and ethyl acetate (100 ml) was added to distilled mass. Resulting mixture was heated to 50°C to 60°C. Resulting mixture was then cooled to 25°C to 30°C and n-heptane (200 mL) was added to mixture at same temperature. Resulting mixture was stirred for 10 hours at 25°C to 30°C and filtered to obtain a solid. Resulting solid was dried at 55°C to 65°C to obtain Pemafibrate of Formula I having purity of 99.6%.
Yield: 79% over two steps of example 02 and example 03

Example 04: Preparation of compound of Formula-IV
To a stirred mixture of ethyl acetate (8.0 L), compound of Formula-II (1.0 Kg) and sodium bicarbonate (0.38 Kg), compound of Formula-III (0.64 Kg) was added at 25°C to 35°C. Resulting reaction mixture was heated to 75°C to 80°C and stirred for 10 hours. After completion of reaction, water (1.0 L) was added to resulting mixture at 25°C to 30°C and allowed to separate the organic and aqueous layer. Resulting layers were separated and organic layer was extracted with water (1.0 L) followed by aqueous sodium chloride. Resulting organic layer was treated with activated carbon (0.05 Kg) and filtered on celite bed to obtained filtrate. Resulting filtrate was distilled and ethyl acetate (1.0 L) was added to distilled mass. Resulting mixture was distilled again to obtain a distilled mass. Ethyl acetate (2.0 L) was added to distilled mass and resulting mixture was heated till clear solution obtained. n-heptane (4.0 L) was added to the resulting solution at 25°C to 30°C. Resulting mixture was stirred for 5 hours at 25°C to 30°C. Resulting solid was filtered, washed with mixture of ethyl acetate and n-heptane to obtain a solid. Resulting solid was dried at 55°C to 65°C to obtain title compound having HPLC purity of 99.44%.
Impurity-1: 0.03% by HPLC
Yield: 89.5%.

Example 05: Preparation of Pemafibrate ethyl ester of Formula-VI
To a stirred mixture of dichloromethane (10.0 L) and compound of Formula IV (1.0 Kg), triphenyl phosphine (0.713 Kg) and ethyl (2S)-2-hydroxybutanoate of Formula (V) (0.360 Kg) were added at 25°C to 30°C under nitrogen. Resulting mixture was cooled at 0°C to 5°C and DEAD (0.473 Kg) was added slowly to mixture at same temperature. Resulting mixture was stirred for 1 hour at 25°C to 30°C. Triphenyl phosphine (0.713 Kg) and ethyl (2S)-2-hydroxybutanoate of Formula (V) (0.360 Kg) were added slowly to resulting mixture at 25°C to 30°C. Resulting mixture was cooled at 0°C to 5°C and DEAD (0.473 Kg) was added slowly to mixture at same temperature. Resulting mixture was stirred for 1 hour at 25°C to 30°C. Triphenyl phosphine (0.356 Kg) and ethyl (2S)-2-hydroxybutanoate of Formula (V) (0.175 Kg) were added slowly to resulting mixture at 25°C to 30°C. Resulting mixture was cooled at 0°C to 5°C and DEAD (0.236 Kg) was added slowly to mixture at same temperature. Resulting mixture was stirred for 1 hour at 25°C to 30°C. After completion of reaction, water (2.0 L) was added to the resulting reaction mixture at 25°C to 30°C and mixture was allowed to separate the organic layer and aqueous layer. Resulting organic layer was washed with water (2.0 L) and distilled to remove solvent. Methyl tert-butyl ether (1.0 L) was added to resulting distilled mass below 45°C and further stirred for 1 hour at 5°C to 10°C. Resulting mixture was filtered and filtrate was distilled to obtain a distilled mass. Methanol (2.0 L) was added to resulting mass and further distilled to obtain a title compound.
Purity:> 90%

Example 06: Preparation of Pemafibrate of Formula I
Methanol (15.0 L) was added to Pemafibrate ethyl ester of Formula-VI obtained in Example 05 at 30°C to 45°C. Resulting mixture was cooled at 5°C to 10°C. Aqueous sodium hydroxide [Sodium Hydroxide (0.37Kg) in water (20.0 L)] was added slowly to resulting mixture at 5°C to 10°C. Resulting mixture was stirred for 4 hours at 25°C to 30°C. After completion of reaction, resulting mixture was distilled to remove methanol completely. Water (15.0 L) was added to distilled mass at 30°C to 40°C. Resulting mixture was cooled at 25°C to 30°C and Methyl tert-butyl ether (15.0 L) was added at same temperature. Resulting mixture was allowed to separate aqueous and organic layers. Resulting aqueous layer was extracted with methyl tert-butyl ether (5 x 5.0 L). Hydrochloric acid was added to resulting aqueous layer to adjust pH between 3.5. Methylene chloride (5.0 L) was added to resulting mixture at 10°C to 15°C. Resulting mixture was allowed to separate aqueous and organic layers. Resulting organic layer was extracted with water. Activated Carbon (0.05 Kg) was added to resulting organic layer at 25°C to 30°C and stirred for 30 minutes at same temperature. Resulting mixture was filtered on celite bed and washed with methylene chloride (2.0 L). Resulting filtrate was distilled to remove methylene chloride. Ethyl acetate (2.0 L) was added to distilled mass below 50°C and stirred for 15 minutes. Resulting mixture was cooled and n-heptane (4.0 L) was added slowly at 25°C to 30°C. Resulting mixture was stirred for 10 hours as same temperature. Resulting solid was filtered, washed with mixture of ethyl acetate and n-heptane followed by drying under vacuum for 8 hours at 50°C to 55°C to obtain a title compound (1.0 Kg).
Purity: 99.85%
Impurity-1: Not detected.

Example 07: Preparation of Pemafibrate of Formula I
To a stirred mixture of dichloromethane (10.0 L) and compound of Formula IV (1.0 Kg), triphenyl phosphine (0.713 Kg) and ethyl (2S)-2-hydroxybutanoate of Formula V (0.360 Kg) were added at 25°C to 30°C under nitrogen. Resulting mixture was cooled at 0°C to 5°C and DEAD (0.473 Kg) was added slowly to mixture at same temperature. Resulting mixture was stirred for 1 hour at 25°C to 30°C. Triphenyl phosphine (0.713 Kg) and ethyl (2S)-2-hydroxybutanoate of Formula V (0.360 Kg) were added slowly to resulting mixture at 25°C to 30°C. Resulting mixture was cooled at 0°C to 5°C and DEAD (0.473 Kg) was added slowly to mixture at same temperature. Resulting mixture was stirred for 1 hour at 25°C to 30°C. Triphenyl phosphine (0.356 Kg) and ethyl (2S)-2-hydroxybutanoate of Formula V (0.175 Kg) were added slowly to resulting mixture at 25°C to 30°C. Resulting mixture was cooled at 0°C to 5°C and DEAD (0.236 Kg) was added slowly to mixture at same temperature. Resulting mixture was stirred for 1 hour at 25°C to 30°C. After completion of reaction, water (2.0 L) was added to the resulting reaction mixture at 25°C to 30°C and mixture was allowed to separate the organic layer and aqueous layer. Resulting organic layer was washed with water (2.0 L) and distilled to remove solvent. Methyl tert-butyl ether (1.0 L) was added to resulting distilled mass below 45°C and further stirred for 1 hour at 5°C to 10°C. Resulting mixture was filtered and filtrate was distilled to obtain a distilled mass. Methanol (15.0 L) was added to resulting mass at 30°C to 45°C. Resulting mixture was cooled at 5°C to 10°C. Aqueous sodium hydroxide [Sodium Hydroxide (0.37Kg) in water (20.0 L)] was added slowly to resulting mixture at 5°C to 10°C. Resulting mixture was stirred for 4 hours at 25°C to 30°C. After completion of reaction, resulting mixture was distilled to remove methanol completely. Water (15.0 L) was added to distilled mass at 30°C to 40°C. Resulting mixture was cooled at 25°C to 30°C and Methyl tert-butyl ether (15.0 L) was added at same temperature. Resulting mixture was allowed to separate aqueous and organic layers. Resulting aqueous layer was extracted with methyl tert-butyl ether (5 x 5.0 L). Hydrochloric acid was added to resulting aqueous layer to adjust pH between 3.5. Methylene chloride (5.0 L) was added to resulting mixture at 10°C to 15°C. Resulting mixture was allowed to separate aqueous and organic layers. Resulting organic layer was extracted with water. Activated Carbon (0.05 Kg) was added to resulting organic layer at 25°C to 30°C and stirred for 30 minutes at same temperature. Resulting mixture was filtered on celite bed and washed with methylene chloride (2.0 L). Resulting filtrate was distilled to remove methylene chloride. Ethyl acetate (2.0 L) was added to distilled mass below 50°C and stirred for 15 minutes. Resulting mixture was cooled and n-heptane (4.0 L) was added slowly at 25°C to 30°C. Resulting mixture was stirred for 10 hours as same temperature. Resulting solid was filtered, washed with mixture of ethyl acetate and n-heptane followed by drying under vacuum for 8 hours at 50°C to 55°C to obtain a title compound (1.0 Kg).
Purity: 99.8%
Impurity-1: Not detected.

Dated this 28th day of March 2024

Mr. Raju Sharma
Sr. Manager- IPR,
Ami Lifesciences Pvt. Ltd.

,CLAIMS:I / We Claim:
1. A process for the preparation of Pemafibrate of Formula-I,

[Formula-I]
comprising the steps of:
a) reacting compound of Formula-II,

[Formula-II]
with compound of Formula-III,

[Formula-III]
in presence of alkali metal carbonate and solvent to obtain compound of Formula-IV;

[Formula-IV]
b) reacting compound of Formula-IV with compound of Formula-V,

[Formula-V]
to obtain Pemafibrate ethyl ester of Formula-VI; and

[Formula-VI]
c) converting Pemafibrate ethyl ester of Formula-VI to Pemafibrate of Formula I.
2. The process according to claim 01, wherein alkali metal carbonate is selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, caesium carbonate or mixture(s) thereof and solvent is selected from the group consisting of ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or Nmethylpyrrolidone; water; or mixture(s) thereof.
3. The process according to claim 01, wherein molar equivalent of alkali metal carbonate with respect to compound of the Formula-II is 1.1 to 1.5.
4. The process according to claim 01, wherein reaction of compound of Formula-II with compound of Formula-III in presence of alkali metal carbonate and solvent is carried out at temperature of 40°C to 90°C.
5. The process according to claim 01, wherein reaction of compound of Formula-IV with compound of Formula-V is carried out in presence of azodicarboxylate such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), triphenylphosphine and solvent selected from the group consisting of alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof at 0°C to 30°C.
6. A process for the preparation of compound of Formula-IV,

[Formula-IV]
comprising reacting compound of Formula-II,

[Formula-II]
with compound of Formula-III,

[Formula-III]
in presence of alkali metal carbonate and solvent to obtain compound of Formula-IV.
7. The process according to claim 06, wherein alkali metal carbonate is selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, caesium carbonate or mixture(s) thereof and solvent is selected from the group consisting of ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or Nmethylpyrrolidone; water; or mixture(s) thereof.
8. The process according to claim 06, wherein molar equivalent of alkali metal carbonate with respect to compound of the Formula-II is 1.1 to 1.5.
9. The process according to claim 06, wherein reaction of compound of Formula-II with compound of Formula-III in presence of alkali metal carbonate and solvent is carried out at temperature of 40°C to 90°C.
10. A process for the preparation of Pemafibrate ethyl ester of Formula-VI,

[Formula-VI]
comprising the steps of reacting compound of Formula-IV,

[Formula-IV]
with compound of Formula-V,

[Formula-V]
to obtain Pemafibrate ethyl ester of Formula-VI.
11. The process according to claim 10, wherein reaction of compound of Formula-IV with compound of Formula-V is carried out in presence of azodicarboxylate such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), triphenylphosphine and solvent selected from the group consisting of alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof.
12. The process according to claim 10, wherein reaction of compound of Formula-IV with compound of Formula-V is carried out at 0°C to 30°C.

Dated this 28th day of March 2024

Mr. Raju Sharma
Sr. Manager- IPR,
Ami Lifesciences Pvt. Ltd.