Description:FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Saroglitazar. In particular, the invention relates to an improved process for the preparation of Saroglitazar comprising condensation of 2-[2-methyl-5-(4-methylsulfanyl-phenyl)-pyrrol-1-yl] derivate compound of formula II and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester compound of formula III. The invention also relates to an novel compound 1-(2-haloethyl)-2-methyl-5-[4-(methylsulfanyl)phenyl]-1H-pyrrole of formula IIa.

BACKGROUND OF THE INVENTION

The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.

Saroglitazar is chemically 2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-1-yl)ethoxy)phenyl)propanoate, which may be optically active or racemic and its pharmaceutically acceptable salts. The Saroglitazar which is marketed as its magnesium salt, having below chemical structure.

Saroglitazar lower or modulate triglyceride levels and/or cholesterol levels and/or lower density lipoproteins (LDL) and raise HDL plasma levels and hence are useful in combating different medical conditions, where such lowering (and raising) is beneficial. Thus, it could be used in the treatment and/or prophylaxis of obesity, hyperlipidemia, hypercholesteremia, hypertension, atherosclerotic disease events, vascular restenosis, diabetes and many other related conditions. Saroglitazar are useful to prevent or reduce the risk of developing atherosclerosis, which leads to diseases and conditions selected from arteriosclerotic cardiovascular diseases, stroke, coronary heart diseases, cerebrovascular diseases, peripheral vessel diseases and related disorders.

U.S. Patent No. 6,987,123 B2 (the US 123 Patent) discloses novel heterocyclic compounds, their preparation, pharmaceutical compositions containing them and their use in medicine. The US 123 patent discloses reaction pathways for the synthesis of pyrrole derivatives.

In route- 1 the compound of Formula (la) and (lb) are reacted under Paal-Knoor conditions to obtain compound (1) as shown below:

In route-2 the compound of Formula (lc) and (1d) are reacted in presence in suitable organic solvent to obtain the compound (I) as shown below:

In route-3 the compound of Formula (le) and (Id) are reacted in presence of coupling agents like DCC, EDC etc. to obtain the compound (1) as shown below:

International (PCT) Publication No. WO 2015/033357 discloses an improved process for the preparation of saroglitazar magnesium by reacting a hydroxy compound (A) with a mesylate compound (Al) to obtain alkoxy ester compound of Formula (II);

Therefore, it may be desirable to have an amorphous form of drugs with high purity to meet the regulatory requirements and also highly reproducible processes for their preparation.

In view of the above, it is therefore, desirable to provide an efficient, more economical, less hazardous and eco-friendly process for the preparation of saroglitazar having high purity. However, the present invention provides a process for the preparation of saroglitazar thereof suitable for development of finished formulations having high purity.

In view of the above, the present invention aims to provide improved methods for synthesizing saroglitazar, so that the method of the present invention significantly reduces the impurity and improves the purity of saroglitazar on the premise of ensuring the total yield of the saroglitazar.

SUMMARY OF THE INVENTION

The one aspect of the present invention is to provide a process for the preparation of saroglitazar compound of formula I comprising condensation of 2-[2-methyl-5-(4-methylsulfanyl-phenyl)-pyrrol-1-yl] derivate compound of formula II and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester compound of formula III:

Wherein R1 is hydroxyl or halogen atom such as chlorine, bromine or iodine.

In another aspect, there is provided an novel compound 1-(2-haloethyl)-2-methyl-5-[4-(methylsulfanyl)phenyl]-1H-pyrrole of formula IIa

Wherein X is halogen atom such as chlorine, bromine or iodine.

In another aspect, there is provided an provide a process for the preparation of saroglitazar comprising condensation of 1-(2-haloethyl)-2-methyl-5-[4-(methylsulfanyl)phenyl]-1H-pyrrole of formula IIa and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester compound of formula III

Wherein X is halogen atom such as chlorine, bromine or iodine.

In another aspect, there is provided an provide a process for the preparation of saroglitazar comprising condensation of 1(2-ethanol)-2-methyl-5-[4-(methylsulfanyl)phenyl]-1H-pyrrole of formula IIb and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester compound of formula III

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.

For the purposes of the present invention, the following terms are defined below.

The singular forms "a," "an," and "the" may refer to plural articles unless specifically stated otherwise.

The term "about," as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term "about" should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures.

As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are suitable for pharmaceutical use, preferably for use in the tissues of humans and lower animals without undue irritation, allergic response and the like. Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds, are well known in the art. For example, S. M. Berge, et al., describe pharmaceutically acceptable salts in detail in J Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting a free base or free acid function with a suitable reagent, as described generally below. For example, a free base function can be reacted with a suitable acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may, include metal salts such as alkali metal salts, e. g. sodium or potassium salts; and alkaline earth metal salts, e. g. calcium or magnesium salts. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed by direct reaction with the drug carboxylic acid or by using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, sulfonate and aryl sulfonate.

The term "purified" refers to a compound that has been processed to remove impurities. Impurities can include solvents, reagents used to prepare the compound, starting materials, and byproducts of a reaction giving rise to the compound. In some embodiments, a purified compound is substantially free of other species.

The term "crude compound" refers to a mixture containing a desired compound (such as a compound of Formula I as described herein) and at least one other species selected from a solvent, a reagent such as a base, a starting material, and a byproduct of a reaction giving rise to the desired compound.

"Anti-solvent" is a solvent which when added to an existing solution of a substance reduced the solubility of the substance.

When referring to a chemical reaction, the terms "treating", "contacting" and "reacting" are used interchangeably herein and refer to adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or desired product. It should be appreciated that the reaction which produces the indicated and/or desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or desired product.

In the first embodiment of the present invention provides process for preparation of saroglitazar compound of formula I comprising: condensation of 2-[2-methyl-5-(4-methylsulfanyl-phenyl)-pyrrol-1-yl] derivate compound of formula II and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester compound of formula III
Reaction scheme:

Wherein R1 is hydroxyl or halogen atom such as chlorine, bromine or iodine.

In certain embodiments, said condensing agent is selected from the group consisting of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) / N-Hydroxybenzotriazole (HOBt) / Diisopropylethylamine(DIPEA), triphenylphosphine, azodicarboxylate such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD).

In certain embodiments, product Saroglitazar may be further purified or washed with the solvent multiple times to produce Saroglitazar essentially free of impurites.

In various embodiments, the solvent is selected from but not limited to solvents are one or more of esters selected from hydrocarbons selected from pentane, hexane, heptane and cyclohexane, ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; hydrocarbons selected from toluene, xylene, ethyl benzene, heptane, hexane, and cyclohexane; and chlorinated solvents selected from methylene dichloride, ethylene dichloride, chlorobenzene, chloroform, and carbontetrachloride, N-Methyl-2-pyrrolidone (NMP), Dichloromethane (DCM), Tetrahydrofuran (THF), Ethyl acetate (EtOAc), Acetone, Dimethylformamide (DMF), Acetonitrile (MeCN), Dimethyl sulfoxide (DMSO), Dimethylacetamide; N,N-Diisopropyl ethylamine, dioxane, tetrahydrofuran, acetone, hexane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, n-butanol, isopropanol, n-propanol, ethanol, methanol, water, water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, sulfolane methanol, ethanol, propanol, butanol, methylene chloride, monochlorobenzene, and EDC and ethylene chloride, toluene, xylene, heptane, cyclohexane and hexane, and combinations thereof.

In various embodiments, the base is selected from but not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride, potassium tert-butoxide, and sodium pentoxide.

In various embodiments, the phase transfer catalyst is selected from but not limited to tetrabutyl ammonium bromide (TBAB), tetrabutyl ammonium iodide (TBAI), benzyl triethyl ammonium chloride (TEBAC), polyethylene Glycol (PEG- 200, 400, 600, 800, 1000), crown ethers selected from 12-crown-4, 15-crown-5, 18- crown-6, dibenzo- 18-crown-6, and diaza- 18-crown-6.

In another embodiment, there is provided an provide a process for the preparation of saroglitazar comprising condensation of 1-(2-haloethyl)-2-methyl-5-[4-(methylsulfanyl)phenyl]-1H-pyrrole of formula IIa and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester compound of formula III

Wherein X is halogen atom such as chlorine, bromine or iodine.

In various embodiments, reaction may be carried out in the presence of solvents, such as acetone, tetrahydrofuran, dimethylsulfoxide, dioxane, acetonitrile, dimethyl formamide, DME, benzene, toluene, pet. ether, heptane, hexane, 2-butanone, xylene, alcohols such as methanol, ethanol, propanol, butanol, iso-butanol, tert-butanol, pentanol and the like or a mixture thereof.

In general, the base comprises of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, strontium hydroxide, zinc hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride, potassium tert-butoxide, and sodium pentoxide.

In another embodiment,, there is provided an provide a process for the preparation of saroglitazar comprising condensation of 1(2-ethanol)-2-methyl-5-[4-(methylsulfanyl)phenyl]-1H-pyrrole of formula IIb and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester compound of formula III in presence of condensing agent

In above embodiments, said condensing agent is selected from the group triphenylphosphine, azodicarboxylate such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD).

In various embodiments, the solvent is selected from but not limited to solvents chlorinated. hydrocarbons selected from methylene dichloride, ethylene dichloride and chlorobenzene; aromatic hydrocarbons selected from toluene, xylene, and ethylbenzene. The anti-solvent comprises one or more of aliphatic hydrocarbons selected from pentane, hexane, heptane and cyclohexane; ethers selected from tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, and methyl tertbutyl ether. In particular, the anti-solvent may be n-heptane. Optionally, the anti-solvent may be diluted with one or more of another solvent comprises of esters selected from ethyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate and isobutyl acetate. In particular, n-butyl acetate may be used.

In certain embodiments, product Saroglitazar may be further purified or washed with the solvent multiple times to produce Saroglitazar essentially free of impurites.

Preparation of compound of Formula I

Reference example-1:
In a 1 L RBF charged a solution of 2-(2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-1-yl)ethan-1-ol (Formula IIb) (52.0 g; 0.21 mol) in 250 ml of 1,4-dioxan followed by solution of ethyl (S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate (Formula III) (50.0 g; 0.21 mol) in 250 ml 1,4-dioxan. The mixture was stirred for 5 minutes. Triphenylphosphine (66 g; 0.251 mol) was added to the reaction mixture. Diisopropyl azodicarboxylate (51 g; 0.25 mol) was added slowly. Reaction was stirred for 2 hrs and completion of reaction is ensured by TLC. The reaction mixture was distilled under vacuum to remove solvent completely. The viscous semisolid was triturated with diisopropylether. TPPO was filtered as unwanted solid. The filtrate obtained was distilled under vacuum to give viscous mass. This was again triturated with diisopropyl ether to remove traces of TPPO. The filtrate was distilled under vacuum to give viscous residue. The residue was loaded on to silica column and purified to give 94 g of ethyl (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio) phenyl)-1H-pyrrol-1-yl)ethoxy) phenyl) propanoate (Formula I) in 95% yield. HPLC purity was 88%. This material was subjected to ester hydrolysis in suitable solvent and base to get Saroglitazar with quality suitable for pharmaceutical applications.

Reference example-2:
In a 1 L RBF charged a solution of 2-(2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-1-yl)ethan-1-ol (Formula IIb) (52.0 g; 0.21 mol) in 250 ml of tetrahydrofuran followed by solution of ethyl (S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate (Formula III) (50.0 g; 0.21 mol) in 250 ml tetrahydrofuran. The mixture was stirred for 5 minutes. Triphenylphosphine (66 g; 0.251 mol) was added to the reaction mixture. Diisopropyl azodicarboxylate (51 g; 0.25 mol) was added slowly. Reaction was stirred for 4 hrs and completion of reaction is ensured by TLC. The reaction mixture was distilled under vacuum to remove solvent completely. The viscous semisolid was triturated with diisopropylether. TPPO was filtered as unwanted solid. The filtrate obtained was distilled under vacuum to give viscous mass. This was again triturated with diisopropyl ether to remove traces of TPPO. The filtrate was distilled under vacuum to give viscous residue. The residue was loaded on to silica column and purified to give 95 g of ethyl (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-1-yl)ethoxy)phenyl)propanoate (Formula I) in 96% yield.

Reference example-3:
In a 1 L RBF charged a solution of 1-(2-chloroethyl)-2-methyl-5-[4-(methylsulfanyl)phenyl]-1H-pyrrole (Formula IIa) (52.0 g; 0.21 mol) in 250 ml of tetrahydrofuran followed by solution of ethyl (S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate (Formula III) (50.0 g; 0.21 mol) in 250 ml tetrahydrofuran. The mixture was stirred for 5 minutes. Triphenylphosphine (66 g; 0.251 mol) was added to the reaction mixture. Diisopropyl azodicarboxylate (51 g; 0.25 mol) was added slowly. Reaction was stirred for 4 hrs and completion of reaction is ensured by TLC. The reaction mixture was distilled under vacuum to remove solvent completely. The viscous semisolid was triturated with diisopropylether. TPPO was filtered as unwanted solid. The filtrate obtained was distilled under vacuum to give viscous mass. This was again triturated with diisopropyl ether to remove traces of TPPO. The filtrate was distilled under vacuum to give viscous residue. The residue was loaded on to silica column and purified to give 92 g of ethyl (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-1-yl)ethoxy)phenyl)propanoate (Formula I) in 94% yield.

The present invention process for the preparation of saroglitazar process is shorter wherein process avoids mesylation of Formula-IIb. Further present invention avoids hazardous reagent Mesyl chloride. Present invention also avoids mesyl intermediate which is a genotoxic impurity (PGI) as a process impurity in final API. Further Coupling of Formula IIb and Formula I occurs at ambient and mild conditions, where as prior-art process involves reaction of Mesyl derivative of Formula II with Formula I in the presence of base, PTC and at elevated temperature of about 80deg.
, Claims:CLAIMS:
We Claim,
1) A process for the preparation of saroglitazar compound of formula I comprising
condensation of 2-[2-methyl-5-(4-methylsulfanyl-phenyl)-pyrrol-1-yl] derivate compound of formula II and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester compound of formula III in presences of condensing agent and solvent:

Wherein R1 is hydroxyl (OH) or halogen atom such as chlorine, bromine or iodine.

2) The process for the preparation of saroglitazar compound of formula I as claimed in claim 1 wherein condensing agent is selected from the group triphenylphosphine, azodicarboxylate such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD).

3) The process for the preparation of saroglitazar compound of formula I as claimed in claim 2 wherein condensing agent is triphenylphosphine, diisopropyl azodicarboxylate (DIAD).

4) The process for the preparation of saroglitazar compound of formula I as claimed in claim 1 wherein solvent is selected from but not limited to solvents chlorinated. hydrocarbons selected from methylene dichloride, ethylene dichloride and chlorobenzene; aromatic hydrocarbons selected from toluene, xylene, and ethylbenzene. The anti-solvent comprises one or more of aliphatic hydrocarbons selected from pentane, hexane, heptane and cyclohexane; ethers selected from tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, and methyl tertbutyl ether. In particular, the anti-solvent may be n-heptane. Optionally, the anti-solvent may be diluted with one or more of another solvent comprises of esters selected from ethyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate and isobutyl acetate.

5) The process for the preparation of saroglitazar compound of formula I as claimed in claim 4 wherein solvent is ethers selected from tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, and methyl tertbutyl ether.

6) An novel compound 1-(2-haloethyl)-2-methyl-5-[4-(methylsulfanyl)phenyl]-1H-pyrrole of formula IIa

Wherein X is halogen atom such as chlorine, bromine or iodine.

7) The process for the preparation of saroglitazar compound of formula I as claimed in claim 1 wherein compound of formula II is 1-(2-haloethyl)-2-methyl-5-[4-(methylsulfanyl)phenyl]-1H-pyrrole of formula IIa

Wherein X is halogen atom such as chlorine, bromine or iodine.

8) The process for the preparation of saroglitazar compound of formula I as claimed in claim 1 wherein compound of formula II is 1(2-ethanol)-2-methyl-5-[4-(methylsulfanyl)phenyl]-1H-pyrrole of formula IIb


Dated this 09th Day of June 2022.