DESC:FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Saroglitazar calcium salt. In particular, the invention relates to an improved process for the preparation of Saroglitazar calcium comprising condensation of 2-(2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-1-yl)ethyl methanesulfonate compound of formula II and ethyl (S)-2-ethoxy-3-(4-hydroxyphenyl) propanoate compound of formula III to obtain ethyl (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio) phenyl)-1H-pyrrol-1-yl)ethoxy)phenyl)propanoate (Saroglitazar ethyl ester) compound of formula IV; Reacting ethyl (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio) phenyl)-1H-pyrrol-1-yl)ethoxy)phenyl)propanoate (Saroglitazar ethyl ester) compound of formula IV with S-Methylbenzylamine; Reacting Saroglitazar SMBA salt compound of formula V with S-Methylbenzylamine in presences of Process water, Acetic acid, Sodium hydroxide, Calcium acetate, Dichloromethane, n-Heptane.

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 calcium salt compound of formula I comprising
a) condensation of 2-(2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-1-yl)ethyl methanesulfonate (SRG-B) compound of formula II and ethyl (S)-2-ethoxy-3-(4-hydroxyphenyl) propanoate (SRG-A) compound of formula III to obtain ethyl (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio) phenyl)-1H-pyrrol-1-yl)ethoxy)phenyl)propanoate (Saroglitazar ethyl ester) compound of formula IV in presences of Toluene, Tetrabutylammoniumbromide, Potassium carbonate, Cesium carbonate and Ethyl acetate, n-Hexane, Silica gel

b) Reacting ethyl (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio) phenyl)-1H-pyrrol-1-yl)ethoxy)phenyl)propanoate (Saroglitazar ethyl ester) compound of formula IV with S-Methylbenzylamine in presences of Isopropyl alcohol, Sodium hydroxide, Ethyl acetate, Acetic acid, tert-Butylmethylether to obtain Saroglitazar SMBA salt compound of formula V;

c) Reacting Saroglitazar SMBA salt compound of formula V with S-Methylbenzylamine in presences of Process water, Acetic acid, Sodium hydroxide, Calcium acetate, Dichloromethane, n-Heptane;

In another aspect, there is provided an improved process for preparation of ethyl (S)-2-ethoxy-3-(4-hydroxyphenyl) propanoate (SRG-A) compound of formula III

Comprising steps of:
a) Reacting L-Tyrosinecompound of formula VI with Benzyl chloride in presences of Sodium hydroxide, Copper sulfate pentahydrate, EDTA disodium, Methanol to obtain (S)-2-amino-3-(4-(benzyloxy)phenyl)propanoic acid compound of formula VII;

b) Reaction (S)-2-amino-3-(4-(benzyloxy)phenyl)propanoic acid compound of formula VII in presences of Sodium nitrite, Conc. Sulfuric acid, 1,4-dioxan to obtain (S)-3-(4-(benzyloxy)phenyl)-2-hydroxypropanoic acid compound of formula VIII

c) Reaction of (S)-3-(4-(benzyloxy)phenyl)-2-hydroxypropanoic acid compound of formula VIII in presences of Potassium hydroxide, Toluene, Diethyl sulfate, TBAB, Celite, Process water, Conc Hydrochloric acid, Sodium bicarbonate, Isopropyl alcohol, Diisopropyl ether, Sodium chloride to obtain compound of formula IX;

d) Reduction of compound of formula IX in presences of Isopropyl alcohol 10% Pd/C (50% wet), Triethylamine, Hydrogen gas, Hexane to obtain of ethyl (S)-2-ethoxy-3-(4-hydroxyphenyl) propanoate (SRG-A) compound of formula III.

In another aspect, there is provided an improved process for preparation of 2-(2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-1-yl)ethyl methanesulfonate (SRG-B) compound of formula II
Comprising steps of:
a) Reacting Thioanisole compound of formula X with Acetyl chloride in presences of Aluminium chloride, Dichloromethane, Conc. Hydrochloric acid, Sodium bicarbonate to obtain 1-[4-(methylsulfanyl)phenyl]ethan-1-one compound of formula XI;

b) Bromination of 1-[4-(methylsulfanyl)phenyl]ethan-1-one compound of formula XI in presences of Bromine and Isopropyl alcohol to obtain 2-bromo-1-(4-(methylthio)phenyl)ethan-1-one compound of formula XII;

c) Reacting 2-bromo-1-(4-(methylthio)phenyl)ethan-1-one compound of formula XII with Methyl acetoacetate in presences of Sodium methoxide powder, Ammonium chloride and solvent Toluene to obtain intermediated compound of formula XIII, which is further reacted with Methanol and Sodium hydroxide inpresences of Sodium chloride and diisopropyl ether to obtain 1-[4-(methylsulfanyl)phenyl]pentane-1,4-dione compound of formula IXX;

a) Cyclization of 1-[4-(methylsulfanyl)phenyl]pentane-1,4-dione compound of formula IXX inpresences of Ethanolamine and Pivalic acid and solvent Toluene to obtain poly(2-{2-methyl-5-[4-(methylsulfanyl)phenyl]-1H-pyrrol-1-yl}ethan-1-ol) compound of formula XX;
b) poly(2-{2-methyl-5-[4-(methylsulfanyl)phenyl]-1H-pyrrol-1-yl}ethan-1-ol) compound of formula XX is reacted with Methanesulfonyl chloride inpresenes of Triethylamine and solvent Toluene to obtain 2-(2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-1-yl)ethyl methanesulfonate (SRG-B) compound of formula II.

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 calcium salt compound of formula I comprising:
a) condensation of 2-(2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-1-yl)ethyl methanesulfonate (SRG-B) compound of formula II and ethyl (S)-2-ethoxy-3-(4-hydroxyphenyl) propanoate (SRG-A) compound of formula III to obtain ethyl (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio) phenyl)-1H-pyrrol-1-yl)ethoxy)phenyl)propanoate (Saroglitazar ethyl ester) compound of formula IV in presences of Toluene, Tetrabutylammoniumbromide, Potassium carbonate, Cesium carbonate and Ethyl acetate, n-Hexane, Silica gel

b) Reacting ethyl (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio) phenyl)-1H-pyrrol-1-yl)ethoxy)phenyl)propanoate (Saroglitazar ethyl ester) compound of formula IV with S-Methylbenzylamine in presences of Isopropyl alcohol, Sodium hydroxide, Ethyl acetate, Acetic acid, tert-Butylmethylether to obtain Saroglitazar SMBA salt compound of formula V;

c) Reacting Saroglitazar SMBA salt compound of formula V with S-Methylbenzylamine in presences of Process water, Acetic acid, Sodium hydroxide, Calcium acetate, Dichloromethane, n-Heptane;

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 Calcium may be further purified or washed with the solvent multiple times to produce Saroglitazar Calcium 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 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 process for preparation of ethyl (S)-2-ethoxy-3-(4-hydroxyphenyl) propanoate (SRG-A) compound of formula III

Comprising steps of:
a) Reacting L-Tyrosinecompound of formula VI with Benzyl chloride in presences of Sodium hydroxide, Copper sulfate pentahydrate, EDTA disodium, Methanol to obtain (S)-2-amino-3-(4-(benzyloxy)phenyl)propanoic acid compound of formula VII;

b) Reaction (S)-2-amino-3-(4-(benzyloxy)phenyl)propanoic acid compound of formula VII in presences of Sodium nitrite, Conc. Sulfuric acid, 1,4-dioxan to obtain (S)-3-(4-(benzyloxy)phenyl)-2-hydroxypropanoic acid compound of formula VIII;

c) Reaction of (S)-3-(4-(benzyloxy)phenyl)-2-hydroxypropanoic acid compound of formula VIII in presences of Potassium hydroxide, Toluene, Diethyl sulfate, TBAB, Celite, Process water, Conc Hydrochloric acid, Sodium bicarbonate, Isopropyl alcohol, Diisopropyl ether, Sodium chloride to obtain compound of formula IX;

d) Reduction of compound of formula IX in presences of Isopropyl alcohol 10% Pd/C (50% wet), Triethylamine, Hydrogen gas, Hexane to obtain of ethyl (S)-2-ethoxy-3-(4-hydroxyphenyl) propanoate (SRG-A) compound of formula III.

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. Base such as alkali metal carbonate such as K2CO3, Na2CO3, CsCO3, and the like; or alkali metal hydroxide such as NaOH, KOH and the like, may be used during this reaction.

In various embodiment copper sulfate salt selected from anhydrous copper sulfate, copper (II) sulfate monohydrate, copper (II) sulfate pentahydrate and copper (II) sulfate heptahydrate.

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 a process for the preparation of process for preparation of 2-(2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-1-yl)ethyl methanesulfonate (SRG-B) compound of formula II
Comprising steps of:
d) Reacting Thioanisole compound of formula X with Acetyl chloride in presences of Aluminium chloride, Dichloromethane, Conc. Hydrochloric acid, Sodium bicarbonate to obtain 1-[4-(methylsulfanyl)phenyl]ethan-1-one compound of formula XI;

e) Bromination of 1-[4-(methylsulfanyl)phenyl]ethan-1-one compound of formula XI in presences of Bromine and Isopropyl alcohol to obtain 2-bromo-1-(4-(methylthio)phenyl)ethan-1-one compound of formula XII;

f) Reacting 2-bromo-1-(4-(methylthio)phenyl)ethan-1-one compound of formula XII with Methyl acetoacetate in presences of Sodium methoxide powder, Ammonium chloride and solvent Toluene to obtain intermediated compound of formula XIII, which is further reacted with Methanol and Sodium hydroxide inpresences of Sodium chloride and diisopropyl ether to obtain 1-[4-(methylsulfanyl)phenyl]pentane-1,4-dione compound of formula IXX;

c) Cyclization of 1-[4-(methylsulfanyl)phenyl]pentane-1,4-dione compound of formula IXX inpresences of Ethanolamine and Pivalic acid and solvent Toluene to obtain poly(2-{2-methyl-5-[4-(methylsulfanyl)phenyl]-1H-pyrrol-1-yl}ethan-1-ol) compound of formula XX;
d) poly(2-{2-methyl-5-[4-(methylsulfanyl)phenyl]-1H-pyrrol-1-yl}ethan-1-ol) compound of formula XX is reacted with Methanesulfonyl chloride inpresenes of Triethylamine and solvent Toluene to obtain 2-(2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-1-yl)ethyl methanesulfonate (SRG-B) compound of formula II.

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 various embodiment sodium salts are selected from sodium chloride, sodium bromide, sodium iodide, sodium fluoride, sodium sulfate

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

Experiment 1: Process for preparation of (S)-ethyl 2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio) phenyl)-1H-pyrrol-1-yl) ethoxy) phenyl) propanoate (Formula IV):
(S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl) propanoate (A) (100.0 g, 420 mmol) and toluene (750.0 ml) were charged and stirred for 15 min. Potassium carbonate (87.0 g, 629 mmol), cesium carbonate (27.3 g, 84 mmol) and tetra butyl ammonium bromide (27.1 g, 84 mmol) were charged, heated to 50° to 60°C and stirred for 2 hours. 2-(2-methyl-5-(4-(methylthio) phenyl)-1H-pyrrol-1-yl) ethyl methane sulfonate (B) (122.9 g, 378 mmol) and toluene (250.0 ml) were charged, heated at 85°C±5°C and stirred for 20 hours. The progress of reaction was monitored by HPLC (Limit of unreacted (A) and (B) by HPLC not more than 5.0%)

After completion of reaction, the reaction mixture was cooled at room temperature, filtered and washed with toluene (400.0 ml). The filtrate was washed with water (1000.0 ml). The separated organic layer was distilled to remove toluene and the residue was collected (Residue-1A).

Purification of saroglitazar ethyl ester (Residue-1A)
Residue-1A was characoalized with (40.0 g) charcoal in cyclohexane (4000.0 ml), stirred for 30 min, filtered and washed with cyclohexane (1000.0 ml). The filtrate was distilled to remove cyclohexane to yield the title compound (I) [(S)-ethyl 2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio) phenyl)-1H-pyrrol-1-yl) ethoxy) phenyl) propanoate] (140.0 g). Chromatographic purity of compound (I) was monitored by HPLC. Yield: 71%, Chromatographic Purity: 70%
The resulting compound (I) was used directly into the next step without further purification or purified by column chromatography over silica gel (100-200 mesh) using 20% ethyl acetate in hexane as an eluent to get highly pure compound (IV).
MS: m/z 468.5 (M+1)
1HNMR (CDCl3, 400 MHz): ? 7.337-7.266 (m, 4H), 7.100-7.078 (d, 2H), 6.629-6.608 (d, 2H), 6.097-6.088 (d, 1H), 5.967-5.956 (dd, 1H), 4.288-4.255 (t, 2H), 4.189-4.136 (q, 2H), 3.957-3.911 (m, 3H), 3.607-3.567 (m, 1H), 3.352-3.312 (m, 1H), 2.929-2.910 (m, 2H), 2.516 (s, 3H), 2.372 (s, 3H), 1.245-1.210 (t, 3H), 1.174-1.139 (t, 3H)

Experiment 2: Process for Preparation of (S)-1-phenylethanaminium (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio) phenyl)-1H-pyrrol-1-yl) ethoxy) phenyl) propanoate (Formula V):

(S)-ethyl 2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio) phenyl)-1H-pyrrol-1-yl) ethoxy) phenyl) propanoate (I) (100 g, 214 mmol) and isopropyl alcohol (500.0 ml) were charged and stirred for 15 min. Sodium hydroxide (19.2 g, 481 mmol) solution in water (250.0 ml) was added and the reaction mixture was stirred for 3 hours. The progress of reaction was monitored by HPLC (Limit of unreacted (I) by HPLC not more than 5.0%). After completion of reaction, the reaction mixture was distilled to remove isopropyl alcohol and the residue was collected (Residue-2A).

Residue-2A was diluted with water (1000.0 ml), stirred for 15 min, washed with ethyl acetate (2 × 1000.0 ml). The separated aqueous layer was acidified at pH 4 to 5 with acetic acid (50.0 ml) and product was extracted with MTBE (2 × 500.0 ml). The organic layer was treated with (S)-(-)-methylbenzyl amine (31.1 g, 257 mmol) and stirred for 5 hours. The reaction mixture was then filtered and again washed with MTBE (2 × 100.0 ml). The wet-cake was dried to obtain Compound (II) [(S)-1-phenylethanaminium (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio) phenyl)-1H-pyrrol-1-yl) ethoxy) phenyl) propanoate] (85.0 g). Chromatographic purity of compound (II) was monitored by HPLC.
Yield: 71%, Chromatographic purity: 99%.

MS: m/z 440.4 (M = Free acid MW) (M+1)
1HNMR (CDCl3, 400 MHz): ? 7.401-7.383 (m, 3H), 7.326-7.305 (m, 4H), 7.283-7.252 (m, 2H), 7.015-6.993 (d, 2H), 6.588-6.566 (d, 2H), 6.089-6.080 (d, 1H), 5.958-5.948 (dd, 1H), 5.182 (bs, 3H), 4.271-4.238 (t, 3H), 4.209-4.159 (q, 1H), 3.910-3.878 (t, 2H), 3.659-3.628 (dd, 1H), 3.410-3.370 (m, 1H), 3.078-3.037 (m, 1H), 2.802-2.759 (m, 1H), 2.650-2.592 (m, 1H), 2.498 (s, 3H), 2.357 (s, 3H), 1.525-1.508 (d, 3H), 1.011-0.976 (t, 3H)
Experiment 3: Calcium(S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio) phenyl)-1H-pyrrol-1-yl) ethoxy) phenyl) propanoate (Formula I):
(S)-1-phenylethanaminium (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio) phenyl)-1H-pyrrol-1-yl) ethoxy) phenyl) propanoate (II) (100.0 g, 178 mmol) and water (1000.0 ml) were charged and stirred for 15 min. The reaction mixture was acidified at pH 4-5 with acetic acid (10.0 ml) and product was extracted with ethyl acetate (1000.0 ml). The separated organic layer was treated with aqueous solution of sodium hydroxide (10.7 g, 268 mmol) (1000.0 ml) and stirred for 5 minutes. The separated aqueous layer was treated with Calcium acetate monohydrate (58.1 g, 330 mmol) and stirred for 30 min. The Product was extracted with methylene dichloride (1000.0 ml). The separated organic layer was washed with water (1000.0 ml). The resulting organic layer was distilled to remove methylene dichloride and the residue was collected (Residue-3A).

Residue-3A was dissolved in methylene dichloride (500.0 ml), added in n-heptane (500.0 ml) and stirred for 30 min. The reaction mixture was distilled to remove solvent and residue was collected (Residue-3B).

To the Residue-3B, n-heptane (500.0 ml) was added and stirred for 1 hour. The product was filtered, washed with n-heptane (2 × 100.0 ml) and dried in vacuum tray dryer at 50°C±5°C for 12 hours to obtain Compound (III) [Calcium(S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio) phenyl)-1H-pyrrol-1-yl) ethoxy) phenyl) propanoate] (55.0 g). Chromatographic purity of compound (III) was monitored by HPLC.
Yield: 67%, Chromatographic purity: 99%

MS: m/z 440.4 (M = Free acid MW) (M+1)
1HNMR (DMSO-d6, 400 MHz): ? 7.359-7.338 (d, 2H), 7.283-7.262 (d, 2H), 7.081-7.059 (d, 2H), 6.622-6.601 (d, 2H), 5.969-5.961 (d, 1H), 5.850-5.840 (dd, 1H), 4.241-4.212 (t, 2H), 3.936-3.907 (t, 2H), 3.608-3.549 (m, 2H), 3.127-3.087 (m, 1H), 2.902-2.872 (m, 1H), 2.634-2.575 (m, 1H), 2.477 (s, 3H), 2.292 (s, 3H), 0.958-0.923 (t, 3H).

OPTIMIZATION STUDY:
1. OPTIMIZATION FOR SYNTHESIS OF FORMULA (IV) (Ethyl Ester) (Residue-1A):

A. Selection of Base:

The following table summarizes the results of experiments conducted using various bases while keeping all other parameters constant. The yield and purity of each experiment are presented for comparison.
Table-1: Effect of different base on yield/quality of Residue-1A

Sr. No. Base Condition Observation % Yield
1 K2CO3 SRG-A/B, TBAB, Toluene Reaction incomplete hence final chromatographic purity not checked 79
2 CS2CO3 SRG-A/B, TBAB, Toluene Reaction completed, Chromatographic purity: 69.52% 98
3 NaOH SRG-A/B, TBAB, Toluene Reaction does not proceed NA
4 K2CO3/CS2CO3 SRG-A/B, TBAB, Toluene Reaction completed, Chromatographic purity: 68.63% 100

Conclusion: Based on the tabular summary and considering the high cost of cesium carbonate, a mixture of K2CO3 and Cs2CO3 was selected for subsequent experiments. This choice balances cost-effectiveness with the desired chemical reactivity, ensuring both economic feasibility and optimal performance in the reaction. Further investigations using this mixture will help assess its efficiency and potential for scaling up.

B. Optimization of Tetra butyl ammonium bromide (TBAB) equivalents:

The required equivalents of tetra-n-butylammonium bromide (TBAB) for the reaction were optimized by testing different amounts of TBAB, while keeping all other parameters constant. The corresponding yield and quality data from these experiments are summarized in the table below.

Table-2: Effect of tetra butyl ammonium bromide equivalent on yield/quality of Residue-1A

Sr. No. Mole equivalents of TBAB Condition Observation % Yield
2 0.4 SRG-A/B, Toluene, Cs2CO3, K2CO3 Chromatographic purity: 50.15% 92
3 0.3 SRG-A/B, Toluene, Cs2CO3, K2CO3 Chromatographic purity:54.78% 92
4 0.2 SRG-A/B, Toluene, Cs2CO3, K2CO3. Chromatographic purity: 67.94% 100

Conclusion: Based on the tabular summary, 0.2 mole equivalent of tetra-n-butylammonium bromide (TBAB) was identified as the most suitable for further experiments. This concentration demonstrated optimal performance in terms of yield and purity, making it the preferred choice for subsequent trials. Further studies will focus on evaluating the scalability and consistency of the results achieved with this specific mole equivalent of TBAB.

C. Optimization of Temperature:

Multiple reactions were conducted at varying temperatures, with all other parameters held constant. The corresponding yield and quality data from these experiments are summarized in the table below.

Table-3: Effect of temperature on yield/quality of Residue-1A

Sr. No. Reaction temperature Condition Observation % Yield of Residue-1A
1 50°C SRG-A/B, Toluene, Cs2CO3, K2CO3, TBAB SRG-A/B not consumed by TLC, Low product formation 55
2 60°C SRG-A/B, Toluene, Cs2CO3, K2CO3, TBAB SRG-A/B not consumed by TLC, Low product formation 62
3 70°C SRG-A/B, Toluene, Cs2CO3, K2CO3, TBAB SRG-A/B not consumed by TLC, Low product formation 75
4 80°C SRG-A/B, Toluene, Cs2CO3, K2CO3, TBAB Reaction completed, Chromatographic purity: 67.25% 100

Conclusion: In the experiments conducted at Sr. Nos. 1, 2, and 3, the product yield was suboptimal, and therefore, chromatographic purity was not evaluated. However, in the experiment at Sr. No. 4, the yield was 100%, and the chromatographic purity met the specified requirement (not less than 50%). Based on these results, 80°C was determined to be the optimal temperature for achieving both improved yield and quality in Stage-01 of the process.

2. OPTIMIZATION FOR PURIFICATION OF FORMULA (V) (Ethyl Ester) (I):

A. Purification by Column chromatography:
Table-4: Effect of Column chromatography on yield/quality

Sr. No. Column Gradient Conditions Observations % Yield
1 Ethyl acetate/Hexane Silica gel (60:120) Chromatographic purity: 99.38% 49

B. Purification by Binding and Slurry by Organic Solvents:
Table-5: Effect of Binding on yield/quality

Sr. No. Binding Slurry by Organic Solvents Observations % Yield
1 Silica gel (60:120) Cyclohexane Primary TLC data were showing in-sufficient purification hence Chromatographic purity was not checked. 20
2 Silica gel (60:120) 5% Ethyl acetate/Cyclohexane 45
3 Silica gel (60:120) 10% Ethyl acetate/Cyclohexane 60

C. Purification by Charcoal:
Table-6: Effect of Charcoal on yield/quality

Sr. No. Binding Conditions Observations % Yield
1 Charcoal Cyclohexane Chromatographic purity: 73.74% 75

Conclusion: Based on the above tabular summary, charcoalization in cyclohexane was determined to be the optimal condition for Stage-01, as it provided the best yield and product quality.

3. OPTIMIZATION FOR SYNTHESIS OF FORMULA(I) (SMBA Salt) (II):

Table-7: Effect of Solvents on yield/quality

Sr. No. Solvents Observation % Yield
1 THF/Methanol/Water Chromatographic purity: 84.30% 92
2 Dioxane/Water TLC monitoring showing incomplete consumption of SRG-Ethyl ester hence Chromatographic purity was not checked. NA
3 IPA/Water Chromatographic purity: 99.22% 74

Conclusion: From the above tabular summary, IPA/Water solvent mixture was selected for better yield and quality of Stage-02.

4. OPTIMIZATION FOR SYNTHESIS OF FORMULA( I) (Ca Salt) (III):
Table-8: Effect of Solvents on yield/quality
Sr. No. Solvents Conditions Observation % Yield
1 Water/Ethyl acetate/ MDC/n-Heptane 1.2 Eq. NaOH, 1.5 Eq. Calcium acetate Chromatographic purity: 98.58 68
2 Water/Ethyl acetate/ MDC/n-Heptane 1.7 Eq. NaOH, 2 Eq. Calcium acetate, Chromatographic purity: 98.00 70
3 Water/Ethyl acetate/ MDC/heptane 1.5 Eq. NaOH, 1.85 Eq. Calcium acetate Chromatographic purity: 99.41% 73

Conclusion:
Based on the above tabular summary, 1.5 equivalents of NaOH and 1.85 equivalents of calcium acetate were identified as the optimal quantities for achieving the desired yield and quality in Stage-03 of the process.
,CLAIMS:Claims,

I/We claim
1. An improved process for the preparation of saroglitazar calcium salt compound of formula I thereof:

Formula I
comprising the steps of:

a. condensation of 2-(2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-1-yl)ethyl methanesulfonate compound of formula II and ethyl (S)-2-ethoxy-3-(4-hydroxyphenyl) propanoate compound of formula III to obtain ethyl (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio) phenyl)-1H-pyrrol-1-yl)ethoxy)phenyl)propanoate compound of formula IV in presences of phase transfer catalyst, mixture of base and organic solvent.

b. Reacting ethyl (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio) phenyl)-1H-pyrrol-1-yl)ethoxy)phenyl)propanoate (Saroglitazar ethyl ester) compound of formula IV with S-Methylbenzylamine in presences of base, organic acid and organic solvent to obtain Saroglitazar SMBA salt compound of formula V;

c. Reacting Saroglitazar SMBA salt compound of formula V with S-Methylbenzylamine in presences of Process base, organic acid, and combination of organic solvent.;

2. A process for preparation of ethyl (S)-2-ethoxy-3-(4-hydroxyphenyl) propanoate compound of formula (III)

Formula III
Comprising steps of:
a) reacting L-Tyrosinecompound of formula VI with Benzyl chloride in presences of base, Copper sulfate salt, EDTA disodium, organic solvent to obtain (S)-2-amino-3-(4-(benzyloxy)phenyl) propanoic acid compound of formula VII;

b) reaction (S)-2-amino-3-(4-(benzyloxy)phenyl)propanoic acid compound of formula VII in presences of Sodium nitrite, organic acid and organic solvent to obtain (S)-3-(4-(benzyloxy)phenyl)-2-hydroxypropanoic acid compound of formula VIII;

c) reaction of (S)-3-(4-(benzyloxy)phenyl)-2-hydroxypropanoic acid compound of formula VIII in presences of base, phase transfer catalyst and combination of organic solvent to obtain compound of formula IX;

d) reduction of compound of formula IX in presences of 10% Pd/C (50% wet), base, Hydrogen gas and organic solvent to obtain of ethyl (S)-2-ethoxy-3-(4-hydroxyphenyl) propanoate (SRG-A) compound of formula III.

3. A process for preparation of 2-(2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-1-yl) ethyl methanesulfonate (SRG-B) compound of formula II

Formula III
Comprising steps of:
a) reacting Thioanisole compound of formula X with Acetyl chloride in presences of Aluminium chloride, base, organic solvent and organic acid to obtain 1-[4-(methylsulfanyl)phenyl]ethan-1-one compound of formula XI;

b) bromination of 1-[4-(methylsulfanyl) phenyl] ethan-1-one compound of formula XI in presences of Bromine and Isopropyl alcohol to obtain 2-bromo-1-(4-(methylthio) phenyl) ethan-1-one compound of formula XII;

c) reacting 2-bromo-1-(4-(methylthio) phenyl) ethan-1-one compound of formula XII with Methyl acetoacetate in presences of Sodium methoxide powder, Ammonium chloride and solvent Toluene to obtain intermediated compound of formula XIII, which is further reacted with organic solvent and base in presences of Sodium chloride and diisopropyl ether to obtain 1-[4-(methylsulfanyl) phenyl] pentane-1, 4-dione compound of formula IXX;

e) cyclization of 1-[4-(methylsulfanyl) phenyl] pentane-1,4-dione compound of formula IXX in presences of Ethanolamine and Pivalic acid and solvent Toluene to obtain poly(2-{2-methyl-5-[4-(methylsulfanyl)phenyl]-1H-pyrrol-1-yl}ethan-1-ol) compound of formula XX;
f) poly(2-{2-methyl-5-[4-(methylsulfanyl)phenyl]-1H-pyrrol-1-yl}ethan-1-ol) compound of formula XX is reacted with Methanesulfonyl chloride in presences of Triethylamine and solvent Toluene to obtain 2-(2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-1-yl)ethyl methanesulfonate (SRG-B) compound of formula II.

4. The process for preparation of formula I, claimed in claim 1, , wherein organic solvent are selected from 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.

5. The process for preparation of formula I, claimed in claim 1, wherein base is selected from alkali metal carbonate such as K2CO3, Na2CO3, CsCO3, and the like; or alkali metal hydroxide such as NaOH, KOH and sodium hydride, potassium hydride, potassium tert-butoxide, and sodium pentoxide.

6. The process for preparation of formula I claimed in claim 1, wherein organic acid is selected from acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, pivalic acid, succinic acid or malonic acid.

7. The process for preparation of formula II, claimed in claim 2 , wherein organic solvent are selected from 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.

8. The process for preparation of formula II, claimed in claim 2, wherein base is selected from alkali metal carbonate such as K2CO3, Na2CO3, CsCO3, and the like; or alkali metal hydroxide such as NaOH, KOH and sodium hydride, potassium hydride, potassium tert-butoxide, and sodium pentoxide.

9. The process for preparation of formula II claimed in claim 2, wherein copper sulfate salt selected from anhydrous copper sulfate, copper (II) sulfate monohydrate, copper (II) sulfate pentahydrate and copper (II) sulfate heptahydrate.

10. The process for preparation of formula III, claimed in claim 3 , wherein organic solvent are selected from 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.

11. The process for preparation of formula III, claimed in claim 3, wherein base is selected from alkali metal carbonate such as K2CO3, Na2CO3, CsCO3, and the like; or alkali metal hydroxide such as NaOH, KOH and sodium hydride, potassium hydride, potassium tert-butoxide, and sodium pentoxide.

12. The process for preparation of formula III claimed in claim 3, wherein organic acid is selected from acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, pivalic acid, succinic acid or malonic acid.

13. The process for preparation of formula III claimed in claim 3, wherein sodium salt are selected from sodium chloride, sodium bromide, sodium iodide, sodium fluoride, sodium sulfate.
Dated this 30th Day of November 2024