FIELD OF INVENTION:
The present invention reports Novel amine salts of Saroglitazar along with Novel processes for their preparation. Various Amine salts of Saroglitazar were prepared which were then converted into Saroglitazar Magnesium. Novel improved processes for the preparation of Amorphous Saroglitazar Magnesium salt was developed using spray drying as well as by other techniques.
BACKGROUD OF INVENTION:
In recent years, dual peroxisome proliferator activated receptor (PPAR) a/y agonists have attracted global attention as promising new treatment options for diabetic dyslipidemia due to a unique mechanism of action in improving lipid and glucose profile simultaneously. PPAR-a agonist action improves lipid profile, whereas PPAR-y agonist action improves glucose profile in patients with diabetic dyslipidemia. Many dual PPAR a/y agonists were developed but failed during preclinical stage or the clinical development stage due to lack of efficacy or safety issues. Saroglitazar, developed by Zydus Cadila, is a novel dual PPAR a/y agonist (predominant PPAR-a and moderate PPAR-y actions), aiming to improve lipid and glucose profiles without significant weight gain and edema (common in PPAR-y agonists such as thiazolidinediones).
Saroglitazar Magnesium Pyrrole derivative of present invention is chemically 2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio)phenyl)-lH-pyrrol-l-yl)ethoxy)phenyl)propanoate, which may be optically active or racemic and its pharmaceutically acceptable salts, hydrates, solvates, polymorphs or intermediates thereof. The INN name for pyrrole derivative is Saroglitazar® which is magnesium salt of pyrrole compound of Formula (I), having below chemical structure.
(i)



SCH3

Mg2+

Formula I

The compound of Formula (I) 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. The compound of Formula (I) 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.
Peroxisome Proliferator Activated Receptor (PPAR) is a member of the steroid/retinoid/thyroid hormone receptor family. PPARoc, PPARy and PPAR5 have been identified as subtypes of PPARs. Extensive reviews regarding PPAR, their role in different diseased conditions are widely published [ Endocrine Reviews, 20(5), 649-688 (1999); J. Medicinal Chemistry, 43(4), 58-550 (2000)]. Cell, 55, 932-943 (1999); Nature, 405, 421-424 (2000); Trends in Pharmacological Sci., 469-473 (2000)]. PPARy activation has been found to play a central role in initiating and regulating adipocyte differentiation [Endocrinology 135, 798-800, (1994)] and energy homeostasis, [Cell, 83, 803-812 (1995); Cell, 99, 239-242 (1999)]. PPARy agonists would stimulate the terminal differentiation of adipocyte precursors and cause morphological and molecular changes characteristic of a more differentiated, less malignant state. During adipocyte differentiation, several highly specialized proteins are induced, which are being involved in lipid storage and metabolism. It is accepted that PPARy activation leads to expression of CAP gene [Cell biology, 95, 14751-14756, (1998)], however, the exact link from PPARy activation to changes in glucose metabolism and decrease in insulin resistance in muscle has not been clear. PPARa is involved in stimulating [3-oxidation of fatty acids [Trends Endocrine. Metabolism, 4, 291-296 (1993)] resulting in plasma circulating free fatty acid reduction [Current Biol, 5, 618-621 (1995)]. Recently, role of PPARy activation in the terminal differentiation of adipocyte precursors has been implicated in the treatment of cancer. [Cell, 79, 1147-1156 (1994); Cell, 377-389 (1996); Molecular Cell, 465-470 )1998); Carcinogenesis, 1949-1953 (1998); Proc. Natl. Acad. Sci., 94, 237-241 (1997); Cancer Research, 58, 3344-3352 (1998)]. Since PPARy is expressed in certain cells consistently, PPARy agonists would lead to nontoxic chemotherapy. There is growing evidence that

PPAR agonists may also influence the cardiovascular system through PPAR receptors as well as directly by modulating vessel wall function [Med. Res. Rev., 20 (5), 350-366 (2000)].
PPAR a agonists have been found useful in the treatment of obesity (WO 97/36579). Dual PPAR a and y agonists have been suggested to be useful for Syndrome X (WO 97/25042). PPAR y agonists and HMG-CoA reductase inhibitors have exhibited synergism and indicated the usefulness of the combination in the treatment of atherosclerosis and xanthoma (EP 0753 298).
U.S. Pat. No. 6,987,123 B2 (the U.S. Pat. No. '123 patent) or IN220639 or IN271942 discloses novel heterocyclic compounds, their preparation, pharmaceutical compositions containing them and their use in medicine. The U.S. Pat. No. T23 patent discloses five reaction pathways for the synthesis of pyrrole derivatives.
In route-1 the compound of Formula (la) and (lb) are reacted under Paal-Knorr conditions to obtain compound (1) as shown below:

H2N—(CH2)„ W — Ar


IJ-5 X
N— (CH2)„ W — Ar^
XR7

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

N— (CH2) — L1
HW—Ar^ S^ "ZR8
T
N—(CH2)„ W —Ar^ y^ ^ZR8
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:


N—(CH2)„—WH
R1
R4 (lc)

R' Y
R6
HW—Ar'
XR7


N—(CH2)„—W—Ar
R3 ^~7 R4
(1)

R5 Y
R6

In route-4 the compound of Formula (If) and (lg) are reacted in presence of rhodium salts such as rhodium (II) acetate in suitable solvents like benzene, toluene, ether, THF, dioxane and the like to obtain the compound (1) as shown below:

R7XH (lg)
R5 Y
^N—(CH2)„ W — Ar^
XR7
In route-5 the compound of Formula (le) and (Id) are reacted under Wittig Homer conditions to obtain the compound (1) as shown below:
N—(CH9)„ W — Ar — CHO +
RO C ZR8
Rl
N—(CH2)„ W — Ar
2011/0275669 Al discloses the process for the preparation of pyrrole derivative of general Formula (1) prepared by the five reaction pathways as described herein above.
U.S. Pat. Nos. 7,041,837 B2, 7,323,491 B2, 8,110,598 B2, 8,212,057 B2 discloses different pyrrole derivative of Formula (1) and their intermediates.
WO 2012/104869 Al provides the use of compound of Formula (I) for the treatment of lipodystrophy.
Cadila's application IN 1910/MUM/2013 A discloses substantially amorphous Saroglitazar magnesium having percentage crystallinity less than 25% and process for its preparation.

In India specifically only where the drug is having regulatory approval, it is governed by the Indian patent application numbers 711/MUM/2001 (patent number: IN220639) & and 2040/MUM/2007 (patent number IN271942), both of which are scheduled to expired in July 2021. The formulation seems to be covered in IN220639 patent application. Indian patent application number 2828/MUM/2013 (patent number: IN345194) titled as "Process for preparation of amorphous form of Saroglitazar Magnesium" discloses to a process for
preparation of an amorphous form of Saroglitazar magnesium of Formula (I), the process comprising: (a) dissolving Saroglitazar magnesium of Formula (I) in one or more organic solvents to obtain a solution, (b) adding the solution in one or more of anti-solvent at temperature from -80°C to 150°C to obtain Saroglitazar magnesium of Formula (I); and (c) obtaining the amorphous Saroglitazar magnesium by the removal of the solvent and the anti-solvent.
Indian patent application number 3901/MUM/2015, is an ordinary application titled as "Pyrrole Compound, Compositions and Process for Preparation Thereof. The invention relates to compositions comprising saroglitazar magnesium wherein the saroglitazar magnesium has a purity of greater than or equal to 99% by weight, and dimer compound of Formula (IV) present in an amount relative to saroglitazar magnesium less than about 0.3% by weight by area percentage of HPLC. The present invention also relates to the process for the preparation thereof and pharmaceutical compositions comprising the same.
Indian patent application number 201727037734, a national phase application of PCT application number PCT/IN2016/000121, titled as "Saroglitazar Magnesium for the treatment of Chylomicronemia Syndrome" filed with the Indian Patent Office on October 25, 2017., relates to the use of Saroglitazar Magnesium of formula (1), for the treatment of, or the prevention, delay of progression, or treatment of a disease or condition which is selected from chylomicronemia syndrome, familial chylomicronemia syndrome and Type V hyperlipoproteinemia. The invention further relates to the use of a pharmaceutical composition comprising Saroglitazar Magnesium for the prevention, delay of progression, or treatment of a disease or condition which is selected from chylomicronemia syndrome, familial chylomicronemia syndrome and Type V
hyperlipoproteinemia.

Indian patent application number 201921010654, an ordinary application titled as "[14C] Labelled Saroghtazar and Process for the preparation thereof, relates to Saroghtazar or its pharmaceutically acceptable salt thereof. More specifically, the salt is magnesium salt of Saroghtazar.
The different physical properties exhibited by polymorphs affect important pharmaceutical parameters selected from storage, stability, compressibility, density and dissolution rates (important in determining bioavailability). Stability differences may result from changes in chemical reactivity (e.g., differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph), mechanical changes (e. g., tablets crumble on storage as a kinetically favored crystalline form converts to thermodynamically more stable crystalline form) or both (e. g., tablets of one polymorph are more susceptible to breakdown at high humidity). Solubility differences between polymorphs may, in extreme situations, result in transitions to crystalline forms that lack potency or are toxic. In addition, the physical properties of the crystalline form to that of an amorphous form may be important in pharmaceutical processing. For example, an amorphous form may provide better bioavailability than the crystalline form. Thus, a present amorphous form may be useful for formulations which can have better stability, solubility, storage, compressibility etc important for formulation and product manufacturing and doesn't degrade to crystalline forms of Saroghtazar. Therefore, it is desirable to have 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 amorphous Saroghtazar having no crystallinity whatsoever. The process disclosed in the prior art provides substantially amorphous having presence of crystallinity.
After careful study of the available literature, keeping in view the Target of developing Novel & improved cost-effective processes for the preparation of Amorphous Saroghtazar Magnesium, novel amine salts of Saroghtazar were prepared disclosed herein. The amine salts thus formed can be easily converted to respective Calcium or magnesium salts. Besides this, an improved method of preparation of Amorphous Saroghtazar Magnesium

by use of Spray drying or Fluid bed drying is disclosed herein. The industrial advantages of the current invention is disclosed in the next section of patent application.
SUMMARY OF INVENTION:
The present invention relates to Novel process for preparation of amine salts of
Saroglitazar which is chemically (aS)-a-ethoxy-4-[2-[2-methyl-5-[4-(methylthio)phenyl]-
lH-pyrrol-1-yl] ethoxy]Benzenepropanoic acid . The amine salts used for salt preparation
are selected from dicyclohexylamine, cycloxeylamine, tert-Butylamine, N,N-
diisopropylamine, triethylamine, benzylamine, phenylhydrazine, a,a-diphenyl-4-
piperidinemethanol, 2-(2-methoxyphenoxy)ethylamine,
tris(hydroxymethyl)aminomethane, dibenzyl amine, phenylethylamine, isopropylamine. The detailed process is described in the next section of patent application. These respective amine salts were converted to Saroglitazar Magnesium salt which is the approved pharmaceutically acceptable salt of the Saroglitazar. The product thus formed is highly pure due to technical effectiveness of the process and is highly capable of reducing all impurities which may be process related or due to degradation. It can be prepared in amorphous form too which no crystallinity at all. Also methods of preparation of Amorphous Saroglitazar Magnesium is disclosed using spray drying or fluid bed drying or lyophilization. Their detailed parameter are disclosed in detailed description of invention & examples of this patent application.
This invention also describes a novel process for preparation of Amorphous Saroglitazar Magnesium using spray drying technique in a suitable solvent.
To Start with, feed stock solution of Saroglitazar Magnesium is conveniently prepared by dissolving Saroglitazar Magnesium in solvent that may include but are not limited to a mixture of one or more of alcohols such as methanol, ethanol, isopropanol, 2-propanol, 1 -butanol, t- butyl alcohol or C1-C3 aliphatic ester selected from ethyl acetate, propyl acetate, butyl acetate or a mixture thereof with halogenated hydrocarbon such as methylene dichloride, chloroform, carbon tetrachloride or mixture thereof.
The second step involves isolation of Amorphous of Saroglitazar Magnesium from the fine filtered feed solution. The isolation may be affected by removing the solvent. Suitable techniques which may be used for the removal of solvent include using a rotational

distillation device such as a Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), and the like or any other suitable technique.
In current invention, there is provided spray drying a solution of Saroglitazar Magnesium that involves the spray drying of feed stock, wherein any crystalline form of Saroglitazar Magnesium may be used. The feedstock is dozed into the spray-drying instrument JISL Mini Spray-drier LSD-48 and spray drying is carried out under the specific parameters which elaborated in further part of the current invention.
In another preferred feature, the spray drying of Saroglitazar Magnesium may be performed on JISL Mini Spray-drier LSD-48 by maintaining following parameter a) maintaining the feed rate of the feed stock preferably 20-25 ml/hr; b) maintaining the inlet temperature in the range of 50°C-70°C; c) maintaining the aspirator rate between 30-60 rpm; d) maintaining the outlet temperature in the range of 25°C to 35° C; e) maintaining air flow at 2-4 Kg/cm, preferably 2 Kg/cm; f) maintaining the vacuum at 60-80 mm of Hg.
Advantages of the process disclosed herein are given below:
1) Novel Amine salts of Saroglitazar of High purity which ultimately results High purity Saroglitazar Magnesium.
2) Novel processes for the preparation of Amorphous Saroglitazar having very less Residual solvents.
DETAILED DESCRIPTION OF THE INVENTION:
According to the first embodiment of the present invention, a Novel process for the preparation of (aS)- a-ethoxy-4-[2-[2-methyl-5-[4-(methylthio)phenyl]-lH-pyrrol-l-yl]ethoxy]Benzene propanoic acid. Amine salt is disclosed which comprises:
1. Dissolving Ethyl (S)-2-methoxy-3-(4-(2-(2-methyl-5-(4-(methylthio)phenyl)-lH-pyrrol-l-yl)ethoxy) phenyl)propanoate in an aliphatic alcohol such as methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol or a mixture thereof.
2. Adding aq. Caustic solution
3. Heating the reaction mass to 30-40°C followed by stirring for 60-90 min

4. Adding water
5. Completely removing the solvent from reaction mass under vacuum.
6. Cooling the reaction mass to 20-30 °C
7. Adding an aliphatic ester selected from Ethyl acetate, propyl acetate or isopropyl acetate or mixture thereof under stirring
8. Adjusting the pH of reaction mass to 6.0-7.0 under stirring by Dil. Hydrochloric acid
9. Extracting the product in solvent of step 7
10. Adding the amine selected from dicyclohexylamine, cycloxeylamine, tert-Butylamine, N,N-diisopropylamine, triethylamine, benzylamine, phenylhydrazine, a,a-diphenyl-4-piperidinemethanol, 2-(2-methoxyphenoxy)ethylamine, tris(hydroxymethyl)amino methane, dibenzyl amine, phenylethylamine, isopropylamine.
11. Stirring reaction mass under cooling 10-20°C.
12. Isolation of material as wet cake by routine filtration and drying at 60-70°C for 10-20 hours under vacuum to get desired novel (aS)- a-ethoxy-4-[2-[2-methyl-5-[4-(methyl thio) phenyl]-lH-pyrrol-l-yl]ethoxy] Benzenepropanoic acid. Amine salts.
According to another aspect current embodiment, a novel amine salt of Saroglitazar,
Chemically (aS)-a-ethoxy-4-[2-[2-methyl-5-[4-(methylthio)phenyl]-lH-pyrrol-l-
yl]ethoxy] Benzene propanoic acid dicylohexylamine salt is disclosed having following structure & specific XRD 2-Theta values as given in table 1 below.


Structure II - Saroglitazar Dicyclohexylamine salt.

2 T\eta Int. I (cps deg)
8.79 111
11.71 153
15.14 576
16.44 118
17.56 385
18.40 630
19.40 218
20.51 152
23.20 326
Table 1
According to the second embodiment of the present invention, a Novel process for the preparation of (aS)- a-ethoxy-4-[2-[2-methyl-5-[4-(methyl thio) phenyl]-lH-pyrrol-l-yl]ethoxy] Benzenepropanoic acid magnesium salt is disclosed which comprises:
1. Dissolving (aS)-a-ethoxy-4-[2-[2-methyl-5-[4-(methylthio) phenyl]-lH-pyrrol-l-yl] ethoxy] Benzenepropanoic acid Amine salt in an aliphatic ester selected from Ethyl acetate, propyl acetate or isopropyl acetate or mixture thereof & water.

2. Adjusting pH 6.0-6.5 by adding acetic acid solution
3. Stirring & layer separation.
4. Charcoaling of organic layer
5. Heating the organic layer & completely removing the solvent from reaction mass to get residue.
6. Adding water to the residue above and adjusting the pH to 7.5-8.5 by caustic solution
7. Stirring
8. Adding aq. Solution Magnesium acetate tetrahydrate
9. Further stirring the reaction mass for 1-2 hours
10. Extracting the product in an halogenated hydrocarbon selected form methylene chloride, chloroform or carbon tetrachloride.
11. Heating the organic layer & completely removing the solvent from reaction mass to get product as solid.
12. Again triturating the solid material with an aliphatic alcohol such as methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & completely removing the solvent from reaction mass to remove traces of halogenated hydrocarbon of step 11, to get final product (aS)- a-ethoxy-4-[2-[2-methyl-5-[4-(methyl thio) phenyl]-lH-pyrrol-l-yl]ethoxy] Benzenepropanoic acid magnesium salt as amorphous solid.
According to the Third embodiment of the present invention, an improved process for preparation of Amorphous Saroglitazar is disclosed which comprises:
i. Dissolving Saroglitazar Magnesium in suitable solvent like aliphatic alcohol such
as methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & di ethylene glycol or C1-C3 aliphatic ester selected from ethyl acetate, propyl acetate, butyl acetate or a mixture thereof with halogenated hydrocarbon such as methylene dichloride, chloroform, carbon tetrachloride or mixture thereof.

ii. stirring the reaction mass to 25-35°C for 30 minutes to ensure complete dissolution
followed by fine filtration and used it as feed stock / solution in spray drier.
iii. the spray drying of Saroglitazar Magnesium is to be performed on JISL Mini Spray-drier LSD-48 by aa) maintaining the feed rate of the feed stock preferably 20-25 ml/hr; b) maintaining the inlet temperature in the range of 50°C-70°C; c) maintaining the aspirator rate between 30-60 rpm; d) maintaining the outlet temperature in the range of 25°C to 35° C; e) maintaining air flow at 2-4 Kg/cm, preferably 2 Kg/cm; f) maintaining the vacuum at 60-80 mm of Hg.
iv. Isolating the pure amorphous Saroglitazar Magnesium from cyclone flask in almost powdered form which is further dried at 45-60°C for 8-12 hours, having XRD as given in figure 2.
According to another aspect of the current invention, solvent system used for dissolution is in ratio 4:10 (here 4 parts are of C1-C4 alcohol or C1-C3 aliphatic ester) & 10 parts are of halogenated hydrocarbon.
According to yet another aspect of this embodiment, the ratio can be 1:1 or6:15 or7:15.
The above-mentioned invention is supported by the following non limiting examples.
Example 1 : Process for the preparation of (aS)- a-ethoxy-4-[2-[2-methyl-5-[4-(methyl thio) phenyl]-lH-pyrrol-l-yl]ethoxy] Benzenepropanoic acid. DCHA salt
To a solution of Ethyl (S)-2-methoxy-3-(4-(2-(2-methyl-5-(4-(methylthio)phenyl)-lH-pyrrol-l-yl)ethoxy) phenyl)propanoate (25 g) in Methanol (60ml), a solution of Sodium hydroxide (2.68 g) in DI-Water (26.8 ml) are added at ambient temperature and the reaction mixture was heated at 30-40°C with stirring for 60-90 minutes. After reaction completion, DI- Water was added with stirring. The solvent was recovered under vacuum. The resulting mixture was then cooled to 20-30°C and Ethyl acetate (80 ml) was added to it with stirring. The aqueous layer was extracted with Ethyl acetate (80 ml) twice. To the aqueous layer, solution of aqueous Hydrochloric Acid in Dl-Water was added to adjust the pH (6.5-7.0). The aqueous layer was extracted with Ethyl acetate (100 ml). The combined organic layer was washed with aqueous Sodium chloride solution (60 ml) and was dried over Na2S04 followed by DCHA (7.2 g) addition with stirring. The resulting mass was

cooled to 10-20°C. The product was filtered, washed with a Ethyl acetate and dried under vacuum at 30-40°C to obtain 17 g of (aS)- a-ethoxy-4-[2-[2-methyl-5-[4-(methyl thio) phenyl]-lH-pyrrol-l-yl]ethoxy] Benzenepropanoic acid. DCHA salt (HPLC purity= 99.36% with other individual impurities 0.05%, 0.32%), having XRD partem as given in Figure 1.
Example 2: Process for the preparation of (aS)- a-ethoxy-4-[2-[2-methyl-5-[4-(methyl thio) phenyl]-lH-pyrrol-l-yl]ethoxy] Benzenepropanoic acid. Dicyclohexylamine salt
To a solution of Ethyl (S)-2-methoxy-3-(4-(2-(2-methyl-5-(4-(methylthio)phenyl)-lH-pyrrol-l-yl)ethoxy) phenyl)propanoate (117g) in Methanol (300 ml), a solution of Sodium hydroxide (13.4 g) in Dl-Water (134 ml) are added slowly at ambient temperature and the reaction mixture was heated at 30-40°C with stirring for 90-120 minutes. After reaction completion, DI- Water (1200 ml) was added with stirring. The solvent was recovered under vacuum. The resulting mixture was then cooled to 20-30°C and Ethyl acetate (400 ml) was added to it with stirring. The aqueous layer was extracted with Ethyl acetate (400 ml) twice. To the aqueous layer, Ethyl acetate (500 ml) was added. To this was added solution of aqueous Hydrochloric Acid in Dl-Water to adjust the pH (6.0-6.5). The aqueous layer was extracted with Ethyl acetate (200 ml). The combined organic layer was washed with aqueous Sodium chloride solution (200 ml) and was dried over Na2S04 followed by addition of Dicyclohexylamine (43.8 g) with stirring at ambient temperature. The product was filtered, washed with a Ethyl acetate and dried under vacuum at 30-40°C to obtain 80 g of (aS)- a-ethoxy-4-[2-[2-methyl-5-[4-(methyl thio) phenyl]-lH-pyrrol-l-yl]ethoxy] Benzenepropanoic acid. DCHA salt (HPLC purity=99.36 %), having XRD partem as given in Figure 1. Example 3: Process for the preparation of Saroglitazar Magnesium
To a solution of (aS)- a-ethoxy-4-[2-[2-methyl-5-[4-(methyl thio) phenyl]-lH-pyrrol-1-yl]ethoxy] Benzenepropanoic acid. DCHA salt (80 g) in Ethyl acetate (400 ml) and DI-Water (240 ml) at ambient temperature, a solution of aqueous Acetic Acid in Dl-Water was added to adjust pH (6.0 to 6.5). The organic layer was washed with Dl-Water (4x400 ml) and dried over Na2S04 followed by addition of Carbon with stirring for 30-40 minutes. The reaction mixture was further filtered over hyflo and washed with Ethyl acetate. The solvent was recovered under vacuum to yield residue followed by addition of Dl-Water (400 ml). To the reaction mass a solution of aqueous Sodium Hydroxide in Dl-Water was

added to adjust the pH (7.5-8.5) with stirring, a solution of aqueous Magnesium acetate tetrahydrate (80.7 g) in Dl-Water (160 ml) was added and the reaction was stirred for 1-2 hrs. Methylene di chloride (400 ml) was added and the mixture was stirred for 10-20 minutes. The aqueous layer was extracted with Methylene dichloride (200 ml). The organic layer was combined and washed with aqueous solution of Sodium Chloride (20 g) in DI-Water (200 ml) and dried over Na2S04. The organic layer is concentrated under vacuum followed by addition of Methanol (100 ml). The reaction mixture is concentrated to remove traces of Methylene dichloride under vacuum followed by concentrated to dryness in vacuum affording 69 g of solid, Saroglitazar Magnesium having HPLC Purity=98.87%.
Example 4:
15g of Saroglitazar Magnesium was dissolved in Ethyl Acetate (40 ml) & Methylene Chloride (100 ml). The reaction mass was stirred for 30 min at 25 to 35°C to get clear solution. After fine filtration, solution was followed by Spray drying under below conditions.

S.No. Parameter Conditions
a) Feed Pump Rate 20rpm
b) Inlet Temperature 60°C
c) Outlet Temperature 26-32°C
d) Aspiration Rate 31-60 rpm
e) Vacuum 60-80 mm of Hg
f) Hot Air Supply 2 Kg/cm2
After completion of feeding, the product was collected from the cyclone and dried for 8-12 hrs at 40-50°C. The obtained solid (9.50 g) was Amorphous Saroglitazar Magnesium as shown by X-Ray Diffraction pattern Fig 2.
Example 5:

15g of Saroghtazar Magnesium was dissolved in Methanol (75 ml) & Methylene Chloride (75 ml). The reaction mass was stirred for 30 min at 25 to 35°C to get clear solution. After fine filtration, solution was followed by Spray drying under below conditions.

S.No. Parameter Conditions
a) Feed Pump Rate 20rpm
b) Inlet Temperature 60°C
c) Outlet Temperature 26-32°C
d) Aspiration Rate 45 rpm
e) Vacuum 60 mm of Hg
f) Hot Air Supply 2 Kg/cm2
ompletic >n of feeding, the product was co lected from the cycle )ne and dried ft
hrs at 40-50°C. The obtained solid (9.00 g) was Amorphous Saroghtazar Magnesium as shown by X-Ray Diffraction pattern Fig 2.
Example 6:
15g of Saroghtazar Magnesium was dissolved in Methanol (30 ml) & Methylene Chloride (75 ml). The reaction mass was stirred for 30 min at 25 to 35°C to get clear solution. After fine filtration, solution was followed by Spray drying under below conditions.

S.No. Parameter Conditions
a) Feed Pump Rate 20 rpm
b) Inlet Temperature 70°C
c) Outlet Temperature 25.3°C
d) Aspiration Rate 39 rpm
e) Vacuum 60 mm of Hg

f)

Hot Air Supply

2 Kg/cm2

After completion of feeding, the product was collected from the cyclone and dried for 8-12 hrs at 40-50°C. The obtained solid (8.50 g) was Amorphous Saroglitazar Magnesium as shown by X-Ray Diffraction pattern Fig 3.
Example 7:
15g of Saroglitazar Magnesium was dissolved in Methanol (35 ml) & Methylene Chloride (75 ml). The reaction mass was stirred for 30 min at 25 to 35°C to get clear solution. After fine filtration, solution was followed by Spray drying under below conditions.

S.No. Parameter Conditions
a) Feed Pump Rate 20rpm
b) Inlet Temperature 55°C
c) Outlet Temperature 25.2°C
d) Aspiration Rate 30 rpm
e) Vacuum 60 mm of Hg
f) Hot Air Supply 2 Kg/cm2
ompletic >n of feeding, the product was co lected from the cycle )ne and dried ft
hrs at 40-50°C. The obtained solid (9.0 g) was Amorphous Saroglitazar Magnesium as shown by X-Ray Diffraction pattern Fig 3.
Example 1-2 are repeated with cycloxeylamine, tert-Butylamine, N,N-diisopropylamine, triethylamine, benzylamine, phenylhydrazine, a,a-diphenyl-4-piperidinemethanol, 2-(2-methoxyphenoxy)ethylamine, tris(hydroxymethyl)aminomethane, dibenzyl amine, phenylethylamine, isopropylamine in place of dicyclohexylamine.

WE CLAIM:

1. A novel process for the preparation of (aS)-a-ethoxy-4-[2-[2-methyl-5-[4-
(methyl thio)phenyl]-lH-pyrrol-l-yl]ethoxy]Benzenepropanoic acid amine
salt or Saroglitazar amine salt of claim 1 comprises:
i. dissolving Ethyl(S)-2-methoxy-3-(4-(2-(2-methyl-5-(4-
(methylthio)phenyl)-lH-pyrrol-l-yl)ethoxy) phenyl) propanoate in an aliphatic alcohol selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol or a mixture thereof;
ii. Adding caustic solution and heating the reaction mass to 30-40°C and stirring;
iii. adding water and completely removing the solvent from reaction mass under vacuum;
iv. Cooling reaction mass to 20-30°C;
v. Adding an aliphatic ester selected from ethyl acetate, propyl acetate or isopropyl acetate;
vi. Adjusting the pH to 6-7 using dilute mineral acid such as hydrochloric acid;
vii. Extracting the product in aliphatic ester;
viii. Adding an organic amine selected of claim 1;
ix. Cooling the reaction mass to 10-20°C and stirring; and
x. Isolating the material as wet cake by routine filtration and drying at 60-70°C for 10-20 hours to get desired (aS)-a-ethoxy-4-[2-[2-methyl-5-[4-(methylthio)phenyl]-lH-pyrrol-l-yl]ethoxy]Benzene propanoic acid amine salt or Saroglitazar amine.
2. An improved process for the preparation of (aS)-a-ethoxy-4-[2-[2-methyl-
5-[4-(methylthio)phenyl]-lH-pyrrol-l-yl]ethoxy]Benzenepropanoic acid
magnesium or Saroglitazar Magnesium salt which comprises:

i dissolving (aS)-a-ethoxy-4-[2-[2-methyl-5-[4-(methylthio) phenyl]-lH-pyrrol-l-yl]ethoxy]benzene propanoic acid amine salt of claim 1, in an aliphatic ester selected from Ethyl acetate, propyl acetate or isopropyl acetate or mixture thereof & water;
ii adjusting pH to 6.0-6.5 using acetic acid;
iii stirring and layer separation and charcoaling the organic layer;
iv removing the solvent from organic layer;
v adding water & adjusting the pH to 7.5-8.5 using caustic solution;
vi stirring and adding aq. magnesium acetate tetrahydrate;
vii stirring the reaction mass for 1-2 hours;
viii Adding methylene chloride or Chloroform to extract the product;
ix performing complete recovery or methylene chloride or chloroform layer of step viii);
x dissolving the residue of step ix) in an aliphatic alcohol selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol; and
xi again performing complete recovery of reaction mass of step x) to get desired material (aS)-a-ethoxy-4-[2-[2-methyl-5-[4-(methylthio)phenyl]-lH-pyrrol-l-yl]ethoxy]Benzenepropanoic acid magnesium or Saroglitazar Magnesium salt as amorphous solid.
3. An improved process for the preparation of (aS)-a-ethoxy-4-[2-[2-methyl-
5-[4-(methylthio)phenyl]-lH-pyrrol-l-yl]ethoxy]Benzenepropanoic acid magnesium or Saroglitazar Magnesium salt as an amorphous material using spray drying technique which comprises:

i. dissolving any crystalline form of (aS)-a-ethoxy-4-[2-[2-methyl-5-[4-
(methylthio)phenyl] - lH-pyrrol-1 -yl] ethoxy]Benzenepropanoic acid
magnesium or Saroglitazar Magnesium salt in solvent mixture of two or more solvents in a specific ratio;
ii. stirring the reaction mass at 25-35°C for 30 minutes and used it as feed stock / solution in JISL Mini Spray-drier LSD-48;
iii. maintaining the feed rate of the feed stock preferably 20-25 ml/hr;
iv. maintaining the inlet temperature in the range of 50-70°C;
v. maintaining the aspirator rate between 30-60 rpm;
vi. maintaining the outlet temperature in the range of 25°C to 35° C;
vii. maintaining air flow at 2-4 Kg/cm, preferably 2 Kg/cm;
viii. maintaining the vacuum at 60-80 mm of Hg;
ix. isolating the pure Amorphous Saroglitazar magnesium from cyclone flask; and
x. further drying the powder at 45-60°C for 8-12 hours to get final amorphous Saroglitazar magnesium having XRD as per Fig 2.
4. A process as claimed in claim 2 wherein solvent mixture consists of two
solvents, first of which is a aliphatic alcohol selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & diethylene glycol & second solvent is a halogenated aliphatic hydrocarbon selected from methylene dichloride, chloroform, carbon tetrachloride in ratio varying from 1:1 or 6:15 or 7:15.

A process as claimed in claim 2 wherein solvent mixture consists of two solvents, first of which is C1-C3 aliphatic ester selected from ethyl acetate, propyl acetate, butyl acetate or a mixture thereof & second solvent is a halogenated aliphatic hydrocarbon selected from methylene dichloride, chloroform, carbon tetrachloride in ratio varying from 1:1 or 6:15 or 7:15.
(aS)-a-ethoxy-4-[2-[2-methyl-5-[4-(methylthio)phenyl]-lH-pyrrol-l-
yl]ethoxy]Benzenepropanoic acid amine salt or Saroglitazar amine salt as
per process as claimed in claim 1 to 5 wherein amine is selected from
dicyclohexylamine, cycloxeylamine, tert-Butylamine, N,N-
diisopropylamine, triethylamine, benzylamine, phenylhydrazine, a,a-
diphenyl-4-piperidinemethanol, 2-(2-methoxyphenoxy)ethylamine,
tris(hydroxymethyl)aminomethane, dibenzyl amine, phenylethylamine, isopropylamine.
(aS)-a-ethoxy-4-[2-[2-methyl-5-[4-(methylthio)phenyl]-lH-pyrrol-l-yl]ethoxy]Benzenepropanoic acid dicyclohexylamine salt or Saroglitazar dicyclohexylamine salt of claim 6 having characteristic XRD peaks at 2-theta 8.79, 11.71, 15.14, 16.44, 17.56, 18.40, 19.40, 20.51 & 23.20 as per Figl.