DESC:FORM 2

THE PATENTS ACT,
(39 OF 1970)
THE PATENT RULES, 2003.

COMPLETE SPECIFICATION
(SECTION 10 AND RULE 13)

AN IMPROVED PROCESS FOR PREPARATION OF
“2-[1-(SULFANYLMETHYL)CYCLOPROPYL]ACETIC ACID”

Suraj Laboratories Pvt Ltd
Raja Praasadamu, Plot No.6/A, 6/B,
Masjid Banda, Kondapur,
Hyderabad, Telangana, INDIA-500084.

The following specification particularly describes the invention and the manner in which it is to be performed

AN IMPROVED PROCESS FOR PREPARATION OF
“2-[1-(SULFANYLMETHYL)CYCLOPROPYL]ACETIC ACID”

FIELD OF THE INVENTION
The present invention relates to an improved process for preparation of 2-[1-(sulfanylmethyl)cyclopropyl]acetic acid of Formula-I. The invention further relates to synthesis of (R-(E))-1-(((1-(3-(2-(7-Chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl) phenyl)propyl)thio)methyl)cyclopropaneacetic acid of Formula II and its pharmaceutically acceptable salts using 2-[1-(sulfanylmethyl)cyclopropyl]acetic acid of Formula-I.

Formula I

BACKGROUND OF THE INVENTION:
(R-(E))-1-(((1-(3-(2-(7-Chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl) phenyl)propyl)thio)methyl)cyclopropaneacetic acid is a leukotriene antagonist, and is thus useful as an anti-asthmatic, anti-allergic, anti-inflammatory and cytoprotective agent. Its sodium is currently indicated for the treatment of asthma and allergic rhinitis.
CN114702416A discloses a process for preparation of 2-[1-(sulfanylmethyl) cyclopropyl]acetic acid of Formula-I starting from 1,1-cyclopropyldicarboxylic acid. The process involves the usage of expensive Ru-based catalysts and also involves the usage of toxic and pyrophoric chemicals such as zinc chloride and aluminum trichloride. Usage of these chemicals leads to increase the cost of the project and also harm to both human and environment and not suitable for large scale synthesis. Our impugned invention relates to an improved process devoid of the mentioned chemicals.
US5523477A discloses a process for preparation of 2-[1-(sulfanylmethyl) cyclopropyl]acetic acid of Formula-I starting from 1,1-cyclopropanedimethanol. The process is cumbersome and suffers of lower yields and difficult separation and extraction methods. These steps involve the disadvantages of high cost and difficult industrialization. Present invention avoids such tedious and time consuming separation methods and achieves high purity levels by a simple and improved process.
CN114591140A discloses a process for preparation of 2-[1-(sulfanylmethyl) cyclopropyl]acetic acid of Formula-I starting from 1,1-cyclopropanedimethanol. The process involves the conversion of 1,1-bis(chloromethyl)cyclopropane to 2-(1-(chloromethyl) cyclopropyl)acetonitrile. The reaction suffers with repetition of reaction and lower yields. Our impugned invention avoids the drawbacks of the scheme with an improved and simple operable process.
In view of above prior arts, the inventors of the present invention have developed a remarkable worthy process for the preparation of compound of Formula I at high purity level and are easily reproducible, more economical, and highly scalable at commercial levels.
The present invention also provides process for the preparation of compound of Formula I in the favorable conditions as an essential requirement to reduce the cost of raw materials for the preparation of (R-(E))-1-(((1-(3-(2-(7-Chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid and its pharmaceutically acceptable salts with good yield and high purity with reduced time duration.
SUMMARY OF THE INVENTION:
An embodiment of the present invention provides an improved process for the preparation of 2-[1-(sulfanylmethyl) cyclopropyl]acetic acid of Formula (I),

Formula I
Which comprises,
Step-a) Conversion of Pentaerythritol to 2,2-bis(bromomethyl)propane-1,3-diol,
Step-b) Conversion of 2,2-bis(bromomethyl)propane-1,3-diol to 2-(1-(hydroxylmethyl) cyclopropyl)acetonitrile,
Step-c) Conversion of 2-(1-(hydroxylmethyl)cyclopropyl)acetonitrile to (1-(cyanomethyl) cyclopropyl)methylcarbamimidothioate or its hydrochloride salt,
Step-d) Conversion of (1-(cyanomethyl)cyclopropyl)methylcarbamimidothioate or its corresponding hydrochloride to 2-[1-(sulfanylmethyl)cyclopropyl]acetic acid.

In another embodiment, the present invention also provides a method for the synthesis of (R-(E))-1-(((1-(3-(2-(7-Chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl) phenyl)propyl)thio)methyl)cyclopropaneacetic acid of Formula-II or its corresponding pharmaceutically acceptable salt from 2-[1-(sulfanylmethyl) cyclopropyl]acetic acid.

Formula II
Which comprises,
Step-e) Conversion of (S,E)-1-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxy propan-2-yl)phenyl)propyl methanesulfonate (Formula III) to DCHA salt of (R-(E))-1-(((1-(3-(2-(7-Chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl) phenyl)propyl)thio)methyl)cyclopropaneacetic acid (Formula IV),
Step-f) Conversion of compound of Formula IV to sodium salt of (R-(E))-1-(((1-(3-(2-(7-Chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl) phenyl)propyl)thio)methyl)cyclopropaneacetic acid of Formula II.
Compared to prior art, the preparation methods according to the present invention has the advantage of using low-cost raw materials for large scale industrial production of 2-[1-(sulfanylmethyl)cyclopropyl]acetic acid of Formula-I having high purity and low impurity content and has considerable economic and practical value and wide application prospects.
ABBREVIATIONS:
DCHA: Dicyclohexylamine
DMF: N,N-dimethylformamide
HBr: Hydrobromicacid
DMSO: Dimethyl sulfoxide
DCM: Dichloromethane (also known as MDC)
NaI: Sodium iodide
PBr3: Phosphorus tribromide
TBAB: Tetrabutylammoniumbromide
DETAILED DESCRIPTION OF THE INVENTION:
The present invention will be further described below in conjunction with specific embodiments. The examples are only preferred embodiments of the present invention and are not intended to limit the present invention.
In one embodiment, the below process illustrates a method for the preparation of 2-[1-(sulfanylmethyl) cyclopropyl]acetic acid of Formula (I) by Scheme-I.
Schematic representation of Scheme-I is depicted below:

Scheme-I
In aspects, conversion of Pentaerythritol to 2,2-bis(bromomethyl)propane-1,3-diol may be performed using suitable brominating reagent in presence of suitable solvent. Brominating reagents used include but not limited to aqueous HBr, bromine, N-Bromosuccinimide, PBr3 and the like or mixtures thereof. Preferably, aqueous HBr. The solvents used include but not limited to glacial aceticacid, toluene, xylene, sulfuric acid, hydrochloric acid, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, dichloromethane, chloroform, isopropyl ether, ethyl acetate, isopropyl acetate, acetonitrile, DMF, water and like or a mixture thereof. Specifically, the solvent may be glacial aceticacid.
In aspects, conversion of 2,2-bis(bromomethyl)propane-1,3-diol to cyclopropane-1,1-diyldimethanol may be performed using suitable reductant in presence of suitable solvent. Reductants used include but not limited to Zinc, Iron, Nickel powders and like or mixtures thereof. Preferably, Zinc. The solvents used include but not limited to toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, dichloromethane, chloroform, isopropyl ether, ethyl acetate, isopropyl acetate, acetonitrile, DMF, ethanol, methanol, water and like or a mixture thereof. Specifically, the solvent may be ethanol.
In aspects, conversion of cyclopropane-1,1-diyldimethanol to 5,7-dioxa-6-thiaspiro[2.5]octane 6-oxide may be performed using suitable reagent in presence of suitable base and solvent. Suitable reagents used include but not limited to Thionyl chloride, Bis(1-methylethyl)sulfite and like or mixtures thereof. Preferably, Thionyl chloride. Bases used include but not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine, pyridine, 2,6-Lutidine and the like or mixtures thereof. Preferably, triethylamine. The solvents used include but not limited to toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, dichloromethane, chloroform, isopropyl ether, ethyl acetate, isopropyl acetate, acetonitrile, DMF, ethanol, methanol, water and like or a mixture thereof. Specifically, the solvent may be dichloromethane.
In aspects, conversion of 5,7-dioxa-6-thiaspiro[2.5]octane 6-oxide to 2-(1-(hydroxymethyl)cyclopropyl)acetonitrile may be performed using suitable reagent in presence of suitable catalysts and solvent. Suitable reagents used include but not limited to Sodium cyanide, potassium cyanide and like or mixtures thereof. Preferably, Sodium cyanide. Suitable reagents used include but not limited to sodium iodide, potassium iodide, Tetrabutylammoniumbromide, Benzyltriethylammoniumchloride, methyltributylammoniumchloride, methyltricaprylammonium chloride and the like or mixtures thereof. Preferably, Tetrabutylammoniumbromide and sodium iodide mixture. The solvents used include but not limited to toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, dichloromethane, chloroform, isopropyl ether, ethyl acetate, isopropyl acetate, acetonitrile, DMF, DMSO, ethanol, methanol, water and like or a mixture thereof. Specifically, the solvent may be DMF.
In aspects, conversion of 2-(1-(hydroxymethyl)cyclopropyl)acetonitrile to 2-(1-(halomethyl)cyclopropyl)acetonitrile may be performed using suitable reagent in presence of suitable solvent. Suitable reagents used include but not limited to Thionyl chloride, hydrochloric acid, phosphorous oxychloride, ammonium chloride, chlorosucinimide, chlorine, zinc chloride, lithium chloride, sodium chloride, magnesium chloride, sulfuryl chloride, phosphorus pentachloride, cyanuric chloride, chlorotrimethyl silane, oxalyl chloride, bromine, PBr3, tetrabutylammonium bromide (TBAF), hydrogen bromide, N-Bromosuccinimide, carbon tetrabromide (CBr4), iodine, sodium iodide and like or mixtures thereof. Preferably, Thionyl chloride. The solvents used include but not limited to toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, dichloromethane, chloroform, isopropyl ether, ethyl acetate, isopropyl acetate, acetonitrile, DMF, DMSO, ethanol, methanol, water and like or a mixture thereof. Specifically, the solvent may be DMF.
In aspects, conversion of 2-(1-(halomethyl)cyclopropyl)acetonitrile to (1-(cyanomethyl) cyclopropyl)methylcarbamimidothioate or its hydrochloride may be performed using Thiourea in presence of suitable solvent. The solvents used include but not limited to toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, dichloromethane, chloroform, isopropyl ether, ethyl acetate, isopropyl acetate, acetonitrile, DMF, DMSO, ethanol, methanol, water and like or a mixture thereof. Specifically, the solvent may be acetonitrile.
In aspects, conversion of (1-(cyanomethyl) cyclopropyl)methylcarbamimidothioate or its hydrochloride to 2-(1-(sulfanylmethyl)cyclopropyl)acetic acid (Formula I) may be performed using suitable reagent in presence of suitable solvent. Suitable reagents used include but not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide and the like or mixtures thereof. Preferably, sodium hydroxide. The solvents used include but not limited to toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, dichloromethane, chloroform, isopropyl ether, ethyl acetate, isopropyl acetate, acetonitrile, DMF, ethanol, methanol, water and like or a mixture thereof. Specifically, the solvent may be ethyl acetate.
In another embodiment, the below process illustrates a method for the preparation of (R-(E))-1-(((1-(3-(2-(7-Chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl) propyl)thio)methyl)cyclopropaneacetic acid (Formula II) or its corresponding pharmaceutically acceptable salt by Scheme-II.
Schematic representation of Scheme-II is depicted below:

Scheme-II
In aspects, conversion of (S) Benzenepropanol a-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-2-(1-hydroxy-1-methyl ethyl)-a-methane sulfonate compound of Formula (III) to (R-(E))-1-(((1-(3-(2-(7-Chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid DCHA salt of Formula (IV) may be performed by the reaction of compound of Formula III with 2-(1-(sulfanylmethyl)cyclopropyl)acetic acid compound of Formula I using suitable base in presence of suitable solvent. Suitable base used include but not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium tert-butoxide, n-Butyl lithium, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like or mixtures thereof. Preferably, sodium methoxide. The solvents used include but not limited to toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, dichloromethane, chloroform, isopropyl ether, ethyl acetate, isopropyl acetate, acetonitrile, DMF, DMSO, ethanol, methanol, water and like or a mixture thereof. Specifically, the solvent may be DMF.
In aspects, conversion of (R-(E))-1-(((1-(3-(2-(7-Chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid DCHA salt of Formula (IV) to (R-(E))-1-(((1-(3-(2-(7-Chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid Sodium (Formula II) may be performed using suitable reagent in presence of suitable solvent. Suitable reagent used include but not limited to sodium hydroxide, sodium methoxide, sodium tert-butoxide, sodium carbonate, sodium bicarbonate and the like or mixtures thereof. Preferably, Sodium methoxide. The solvents used include but not limited to heptane, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, dichloromethane, chloroform, isopropyl ether, ethyl acetate, isopropyl acetate, acetonitrile, DMF, ethanol, methanol, water and like or a mixture thereof. Specifically, the solvent may be Toluene and heptane.
Advantages of the present invention over prior art:
• The reagents employed in the present invention are low-cost, easily available, non-hazardous and has considerable good storage stability. It avoids the usage of expensive Ru-based catalysts and toxic chemicals such as aluminum trichloride.
• The present invention overcome the problems (reproducibility, impurities formation, isolation procedures and lower yields) in the preparation of 2-(1-(chloromethyl)cyclopropyl)acetonitrile from cyclopropane-1,1-diyldimethanol by its new and improved process by preparing 2-(1-(chloromethyl)cyclopropyl)acetonitrile from 2-(1-(hydroxymethyl)cyclopropyl)acetonitrile.
• Applicant of present invention tried multiple permutations and combination reactions for the preparation of 2-(1-(chloromethyl)cyclopropyl)acetonitrile from cyclopropane-1,1-diyldimethanol and ended with lower yielding and difficult isolation procedures because of multiple impurity formations. Finally, applicant succeeded in designing a new and worthy process for the conversion of cyclopropane-1,1-diyldimethanol to 2-(1-(chloromethyl)cyclopropyl) acetonitrile via 2-(1-(hydroxymethyl)cyclopropyl) acetonitrile, which avoids the difficulties occurred in the prior art.
• Present invention avoids tedious and time consuming separation methods and achieves high purity levels by a simple and improved process.
• The process is not only new and improved but also has technical advancement and economical significance compared to prior arts.
The details of the invention are given in the examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention.
Examples:
Preparation of 2-[1-(SULFANYLMETHYL)CYCLOPROPYL]ACETIC ACID (Formula-I) by Scheme-I:

Example 1:
Preparation of 2,2-bis(bromomethyl)propane-1,3-diol:
To a stirred solution of Pentaerythritol (100 g) in glacial acetic Acid was added 47% aqueous HBr at ambient temperature. Raised the temperature to 110-115°C and stirred for 2 hours. Cooled the reaction mass to 40-60°C and added Toluene (200 mL). Reaction mass was further cooled to 5-10°C and added purified water (100 mL). Stirred the reaction mass at same temperature for 2-3 hours. Filtered the reaction mass and washed with Toluene (50.0 mL). Dried the material at 50-60°C to get the desired product.
Example 2:
Preparation of cyclopropane-1,1-diyldimethanol:
To a stirred solution of 2,2-bis(bromomethyl)propane-1,3-diol (120 g) in ethanol (360 mL) was added Zinc dust (36 g) at 25-35°C. Raised the temperature to 75-80° C and stirred for completion of reaction. Cooled the reaction mass to 60-65°C and filtered the Zinc over hyflo bed. Cooled the filtrates further to 0-5°C and purged ammonia gas for precipitation of Zinc ammonium bromide salts. Filtered the resulting solids and washed with chilled ethanol (120 mL). Distilled the resulting filtrates under vacuum at temperature below 50°C to obtain the desired product.
Example 3:
Preparation of 5,7-dioxa-6-thiaspiro[2.5]octane 6-oxide: (Cyclic sulphite preparation)
To a stirred solution of cyclopropane-1,1-diyldimethanol (120 g) in MDC (300 mL) was added Triethylamine (89.2 g) at 25-35°C. Cooled the reaction mass to -5 to 0°C. Thionyl chloride (52.4 g) was added slowly and maintained the reaction mass at same temperature for 1 to 2 hours. Quenched the reaction mass with chilled water and separated the layers. Organic layers were distilled under vacuum below 30°C to get the desired product as a brown colored semi solid.
Example 4:
Preparation of 2-(1-(hydroxymethyl)cyclopropyl)acetonitrile:
To a stirred solution of 5,7-dioxa-6-thiaspiro[2.5]octane 6-oxide (obtained in example 3) in DMF (180 mL) was added NaI (6.9 g) and TBAB (7.4 g) at 25-35°C. Added Sodium cyanide (33.6 g) at 25-35°C and raised the reaction temperature to 90-95°C. After completion of reaction, cooled the reaction mass to 70-75°C and added Toluene. Filter the reaction mass at 70-75°C and evaporated the resulting filtrates under vacuum to obtain desired product as a viscous liquid. Yield: 89%.
Example 5:
Preparation of 2-(1-(chloromethyl)cyclopropyl)acetonitrile:
To a stirred solution of 2-(1-(hydroxymethyl)cyclopropyl)acetonitrile (obtained in example 4) in MDC (140 mL) was added DMF (22.1 g) at 25-35°C. Cooled the reaction mass to -5 to 0°C and added Thionyl chloride slowly. Raised the reaction mass temperature to 10-20°C and stirred for completion of reaction. On completion of reaction by TLC, cooled the reaction mass to 0-5°C and added chilled water (140 mL) slowly. Extracted the product with MDC twice and evaporated under reduced pressure at temperature below 40°C to get the desired product as a dark brown liquid. The product was characterized by 1H-NMR (Fig. 1).
1H-NMR (CDCl3, 400 MHz): 3.54 (2H, s), 2.62 (2H, s), 0.84 – 0.75 (4H, m).
Example 6:
Preparation of (1-(cyanomethyl) cyclopropyl)methylcarbamimidothioate hydrochloride:
To a stirred solution of 2-(1-(chloromethyl)cyclopropyl)acetonitrile (obtained in example 5) in acetonitrile (112 mL) was added Thiourea (23 g) at 25-35°C. Raised the reaction mass temperature to 80-85°C and stirred for 12 hours. Cooled the reaction mass to 25-35°C and stirred for 30 minutes. Cooled the reaction mass further to 0-5°C and stirred for 1 to 2 hours. Filtered the resulting precipitate and washed with acetone. Dried the material in hot air oven at 50-55°C to get the desired product. Yield: 91%.
Example 7:
Preparation of 2-(1-(sulfanylmethyl)cyclopropyl)acetic acid (Formula I):
Charged 40 g of (1-(cyanomethyl) cyclopropyl)methylcarbamimidothioate hydrochloride obtained in example 6 to sodium hydroxide solution (prepared by dissolving 46.7 g of NaOH in 96 mL of water) at 25-35°C. Raised the reaction mass temperature to 95-100°C and stirred for 14 hours. On completion of reaction, cooled the reaction mass to 0-5°C and diluted with Ethylacetate (400 mL). Adjust the pH in between 3.0 to 4.0 using conc. hydrochloricacid. Separated both the layers and extracted the product with Ethylacetate twice. Evaporate the combined organic layers under vacuum at temperature below 40°C to get the desired product. Yield: 83%.
Preparation of (R-(E))-1-(((1-(3-(2-(7-Chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid (Formula II) and its pharmaceutically acceptable salts by Scheme-II:
Example 8:
Preparation of (R-(E))-1-(((1-(3-(2-(7-Chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid DCHA salt (Formula IV):
To a stirred solution of DMSO (400 mL) and sodium methoxide in methanol solution (200 mL) was added 2-(1-(sulfanylmethyl)cyclopropyl)acetic acid (Formula I) (35 g) at -5 to 0°C and stirred for 1 hour. Added (S) Benzenepropanol a-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-2-(1-hydroxy-1-methyl ethyl)-a-methane sulfonate compound of Formula (III) (100 g) to the reaction mixture at -5 to 0° C. Stirred the reaction mixture at -5 to 5° C. for 10 hours. On completion of reaction, added chilled water (3 lit) to the reaction mixture and stirred at 10-20° C. for 30 minutes. Slowly added sodium hydroxide solution at 10-20° C and washed the reaction mixture with toluene and removed the toluene layer. Cooled the aqueous layer to 10-20° C and slowly added 50% acetic acid solution. Extracted the reaction mixture with Ethylacetate and washed the total organic layer with water. Combined organics were evaporated at below 55°C under reduced pressure. Added 500 ml of Ethylacetate to the above obtained crude at 25-35°C and stirred for 45 minutes under nitrogen atmosphere. Added dicyclohexylamine at 25-35°C and stirred the reaction mixture for 10 hours. Filtered the solid and washed with Ethylacetate under nitrogen atmosphere. Wet material taken into a mixture of toluene (500 mL) and hexane (500 mL) and heated to 55-65°C for 60 minutes. Cooled the mass to 25-35° C and stirred for 8 hours. Separated the solid by filtration and dried at 40-60°C to get title compound.
Example 9:
Preparation of (R-(E))-1-(((1-(3-(2-(7-Chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid sodium (Formula II):
To a stirred solution sodium methoxide (23 g) in methanol (210 mL) was added DCHA salt of (R-(E))-1-(((1-(3-(2-(7-Chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid (Formula IV) (100 g) at 25-35°C and stirred for 1-2 hour. Filtered the resulting reaction mass and washed with hexane. Filtrates were distilled completely under reduced pressure at below 55°C. To the resulting crude was added toluene followed by heptane at 25-35° C under nitrogen atmosphere and stirred for 45 minutes. Separated the solid by filtration and washed with heptane. Dried the compound at 60-70°C under reduced pressure to get desired compound.

Dated this Dec, 13th 2023

Signature:
VINOD SAGAR TIRUMALARAJU
Patent Agent Reg. No.: IN/PA-5328
,CLAIMS:We claim:

1. An improved process for preparation of 2-[1-(sulfanylmethyl)cyclopropyl] acetic acid of Formula-I, which comprising,
a) conversion of Pentaerythritol to 2,2-bis(bromomethyl)propane-1,3-diol in presence of suitable reagent and suitable solvent;
b) reaction of 2,2-bis(bromomethyl)propane-1,3-diol obtained in step a) with a suitable reductant in presence suitable solvent to obtain cyclopropane-1,1-diyldimethanol, which further converted optionally without isolation into 5,7-dioxa-6-thiaspiro[2.5]octane 6-oxide by the reaction with a suitable reagent and base in presence of suitable solvent, which further converted optionally without isolation into 2-(1-(hydroxymethyl) cyclopropyl)acetonitrile by reaction with a suitable reagent in presence of suitable solvent;
c) reaction of 2-(1-(hydroxymethyl) cyclopropyl)acetonitrile obtained in step b) with a suitable reagent in presence of suitable solvent to obtain 2-(1-(halomethyl)cyclopropyl)acetonitrile, which further converted optionally without isolation into (1-(cyanomethyl) cyclopropyl)methylcarbamimidothioate or its corresponding salt by reaction with Thiourea in presence of suitable solvent;
d) reaction of (1-(cyanomethyl) cyclopropyl)methylcarbamimidothioate or its corresponding salt obtained in step c) with a suitable reagent in presence of suitable solvent to obtain 2-(1-(sulfanylmethyl)cyclopropyl)acetic acid (Formula I);
2. The process as claimed in claim 1, wherein the suitable reagent used in step a) is selected from aqueous HBr, bromine, N-Bromosuccinimide, PBr3 and like or mixtures thereof.
3. The process as claimed in claim 1, wherein the suitable reductant used in step b) is selected from Zinc dust, Iron, Nickel powders and like or mixtures thereof.
4. The process as claimed in claim 1, wherein the suitable reagent used in step b) for conversion of cyclopropane-1,1-diyldimethanol to 5,7-dioxa-6-thiaspiro[2.5]octane 6-oxide is selected from Thionyl chloride, Bis(1-methylethyl)sulfite and like or mixtures thereof.
5. The process as claimed in claim 1, wherein the suitable reagent used in step b) for conversion of 5,7-dioxa-6-thiaspiro[2.5]octane 6-oxide to 2-(1-(hydroxymethyl)cyclopropyl)acetonitrile is selected from Sodium cyanide, potassium cyanide and like or mixtures thereof.
6. The process as claimed in claim 1, wherein the suitable reagent used in step c) for conversion of 2-(1-(hydroxymethyl)cyclopropyl)acetonitrile to 2-(1-(halomethyl)cyclopropyl) acetonitrile is selected from thionyl chloride, hydrochloric acid, phosphorous oxychloride, ammonium chloride, chlorosucinimide, chlorine, zinc chloride, lithium chloride, sodium chloride, magnesium chloride, sulfuryl chloride, phosphorus pentachloride, cyanuric chloride, chlorotrimethyl silane, oxalyl chloride, bromine, PBr3, tetrabutylammonium bromide (TBAF), hydrogen bromide, N-Bromosuccinimide, carbon tetrabromide (CBr4), iodine, sodium iodide and like or mixtures thereof.
7. The process as claimed in claim 1, wherein the suitable reagent used in step d) is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide and the like or mixtures thereof.
8. The process as claimed in claim 1, wherein the suitable base used in step b) is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and the like or mixtures thereof.
9. The process as claimed in claim 1, wherein the suitable solvents used in step a), step b), step c) and step d) are selected from glacial aceticacid, toluene, xylene, sulfuric acid, hydrochloric acid, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, dichloromethane, chloroform, methanol, ethanol, isopropyl ether, ethyl acetate, isopropyl acetate, acetone, acetonitrile, DMF, DMSO, water and like or a mixture thereof.
10. A process for preparing (R-(E))-1-(((1-(3-(2-(7-Chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl) phenyl)propyl)thio)methyl)cyclopropaneacetic acid of Formula –II and its pharmaceutically acceptable salts thereof from 2-(1-(sulfanylmethyl)cyclopropyl)acetic acid of Formula – I substantially as herein before described with reference to preferred aspects, embodiments and features of the invention and illustrated with reference to examples.

Dated this Dec, 13th 2023

Signature:
VINOD SAGAR TIRUMALARAJU
Patent Agent Reg. No.: IN/PA-5328