DESC: FORM 2

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

COMPLETE SPECIFICATION
(SECTION 10 AND RULE 13)

AN IMPROVED PROCESS FOR SYNTHESIS OF “4-FLUORO-7-(METHYLSULFONYL)-
2,3-DIHYDRO-1H-INDEN-1-ONE” AND IT’S PURIFICATION THEREOF

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 SYNTHESIS OF “4-FLUORO-7-(METHYLSULFONYL)-
2,3-DIHYDRO-1H-INDEN-1-ONE” AND ITS PURIFICATION THEREOF

FIELD OF THE INVENTION:
The present invention relates to an improved process for synthesis of 4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one of Formula (I). The invention further relates to purification of 4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one of Formula (I).

Formula (I)

BACKGROUND OF THE INVENTION:

4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one of Formula (I) is an important intermediate used in the preparation method of an anti-cancer medication Belzutifan and a HIF-2 alpha inhibitor PT2385.

WO2015035223 discloses a process for synthesis of 4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one of Formula (I) by taking para-fluorophenol (Formula A) as a raw material (Scheme I).

SCHEME-I
This route is so long (7 steps) and not suitable for commercial production as it includes higher temperature conditions for preparation of intermediate C (~180°C) and E (~220°C) respectively. The yields for the conversion of compound C to compound F are low and required harsh conditions which increases the production cost and is also not suitable for larger scale synthesis. Our impugned invention overcomes the problem by a short (3 steps), mild and high yield process starting from 1,4-difluorobenzene (Scheme II).

SCHEME-II
CN113651735 discloses a process for 4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one of Formula (I) starting from 1,4-difluorobenzene (Formula IV) but is silent on purities of the intermediates of Formula II and III. The intermediate compounds were further carried over to next steps without any purification. As a result, this method produces multiple impurities with a lower yield and required multiple purifications of final desired product which increases the production cost and is not suitable for industrial production. Our impugned invention avoids the same by a simple and easily practicable purification technique at each individual step and provides a viable and commercially scalable process.

CN113651735 Present Invention Comments
Step 1 Reaction conditions:
3-chloropropionylchloride/
AlCl3/ 120°c/ 12 hr

Purification:
No purification

Yield: 94.7%
Purity: Not mentioned Reaction conditions:
3-bromopropionylchloride (or)
3-bromopropionylbromide/ sodium chloride/
AlCl3/ 160°c/ 4 hr

Purification:
Using Ethylacetate and hexane mixture

Yield: ~96%
Purity: > 99.8% The change in the reagent and usage of sodium chloride not only drastically decreases the time cycle of the reaction and also reduces formation of impurities because of prolonged high temperature conditions and thus avoids the time consuming process and also lowers the cost of the project.

Purification with Ethylacetate and Hexane mixture yields highly pure Step-1 product.

Thus, Step-1 of the present invention is not only new but also involves economic significance in comparison with prior art process.
Step 2 Reaction conditions:
Aqueous solution of sodium methyl mercaptide/ DMF/ room temperature/ 8 hr

Purification:
No purification

Yield: 93.9%
Purity: Not mentioned Reaction conditions:
Sodium thiomethoxide/
THF/ room temperature / 3 hr

Purification:
Using MTBE solvent

Yield: ~93.8%
Purity: > 99.8% The usage of sodium thio methoxide instead of aqueous sodium methyl mercaptide reduces the time period of the reaction cycle from 8 hours to 3 hours. Also, purification of crude product results high pure stage-II product in higher yields.
Step 3 Reaction conditions:
m-CPBA/ MDC/ room temperature/ 18 hr

Purification:
Using Ethylacetate : Hexane (1: 4) mixture

Yield: 87.7%
Purity: Not mentioned Reaction conditions:
70% m-CPBA/ MDC/ 0 to 5°C then m-CPBA/ MDC/ room temperature/ 2 hour

Purification:
Treatment with NaHCO3

Yield: ~92%
Purity: > 99.8% Conversion of compound of Formula (III) to Formula (I) by present invention using 70% m-CPBA/ MDC was completed in shorter time periods.

Purification of crude product by treating it with NaHCO3 is a new and improved process which yields the product in good yields and purities.

Purification of crude product using NaHCO3 is not only new and also non-obvious to a person in skilled art.
In addition, purification with NaHCO3 also had technical advancement compared to prior art as it includes simple and viable process for large scale production.

Due to the drawbacks associated with the processes known in the literature for the preparation of 4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one of Formula (I), there is a need for the development of industrially advantageous, cost effective, less time- consuming processes which overcome the problem associated with partial oxidation of stage-II product in step-III and formation di-substituted product in Step-II without effecting the yields and purities of the desired products.
Based on the aforementioned drawbacks, the inventors of present invention have developed an improved, commercially viable and environmentally friendly process for preparing 4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one of Formula (I) with higher yields and purities to resolve the problems associated with the processes described in the prior art.

ADVANTAGES OF PRESENT INVENTION OVER PRIOR ART:
1. Synthesis of pure 4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one with high purity and yields in an economically significant way.
2. Lesser steps and mild conditions.
3. Avoided the formation of di-substituted product (In Step-II) and partial oxidation product (In Step III) as impurities by careful optimization of reaction conditions.
4. Avoid of toxic and expensive catalysts.
5. Easily operable, reproducible and non-tedious isolation process for higher yields and purities.
6. New and technically advanced purification process suitable for large scale synthesis.

SUMMARY OF THE INVENTION:
An embodiment of the present invention is to provide a process for synthesis of 4-fluoro-7-(methylsulfonyl)-2,3-dihydr o-1H-inden-1-one of Formula (I), comprising the steps of:

a) conversion of 1,4-difluorobenzene (Formula IV) into 4,7-difluoro-2,3-dihydro-1H-inden-1-one (Formula III),
b) conversion of 4,7-difluoro-2,3-dihydro-1H-inden-1-one (Formula III) obtained in step (a) into 4-fluoro-7-(methylthio)-2,3-dihydro-1H-inden-1-one (Formula II),
c) conversion of 4-fluoro-7-(methylthio)-2,3-dihydro-1H-inden-1-one (Formula II) obtained in step (b) into 4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one (Formula I).
The synthetic route disclosed herein results 4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one at higher levels of purity and yields by reducing the cost, time of product cycle and also by eliminating formation of di-substituted impurity (In Step-II) and partial oxidation impurity (In Step III).

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 a preferred embodiment, the present invention provides a process for synthesis of 4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one of Formula (I), comprising the steps of:

a) reaction of 1,4-difluorobenzene (Formula IV) with aluminium trichloride (AlCl3) in presence of sodium chloride at suitable temperature followed by purification with suitable solvent or solvent mixture to form 4,7-difluoro-2,3-dihydro-1H-inden-1-one (Formula III),

b) reaction of 4,7-difluoro-2,3-dihydro-1H-inden-1-one (Formula III) obtained in step (a) with sodiumthiomethoxide (NaSMe) in presence of a suitable solvent at suitable temperature followed by purification with suitable solvent or solvent mixture to form 4-fluoro-7-(methylthio)-2,3-dihydro-1H-inden-1-one (Formula II),

c) reaction of 4-fluoro-7-(methylthio)-2,3-dihydro-1H-inden-1-one (Formula II) obtained in step (b) with m-CPBA (meta-Chloroperoxybenzoic acid) in presence of a suitable solvent at suitable temperature followed by purification using suitable reagent in suitable solvent to form 4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one (Formula I).

In aspects, conversion of 1,4-difluorobenzene (Formula IV) into 4,7-difluoro-2,3-dihydro-1H-inden-1-one (Formula III) (Step-I) may carried out using 3-halopropionylhalides in presence of aluminium trichloride (AlCl3) and sodium chloride at a suitable temperature followed by purification with suitable solvent. 3-halopropionylhalides used include but not limited to 3-chloropropionylchloride and 3-bromopropionylbromide. Specifically, may be 3-bromopropionylchloride. The suitable temperature for the conversion is in range of 120 to 180°C. Preferably, in between 160 - 170°C. Solvents used for purification include but not limited to methanol, ethanol, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, dichloromethane, chloroform, diethyl ether, methyltertiarybutyl ether (MTBE), isopropyl ether, ethyl acetate, isopropyl acetate, acetonitrile, acetone, THF, DMF, DMAc, hexane, heptane, pentane, water and like or a mixture thereof. Specifically, the solvent may be mixture of Ethylacetate and hexane.

In aspects, conversion of 4,7-difluoro-2,3-dihydro-1H-inden-1-one (Formula III) into 4-fluoro-7-(methylthio)-2,3-dihydro-1H-inden-1-one (Formula II) (Step-II) may carried using sodiumthiomethoxide (NaSMe) in presence of a suitable solvent at suitable temperature followed by purification with suitable solvent. Solvents used for reaction include but not limited to methanol, ethanol, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, dichloromethane, chloroform, diethyl ether, methyltertiarybutyl ether (MTBE), isopropyl ether, ethyl acetate, isopropyl acetate, acetonitrile, acetone, THF, DMF, DMSO, DMAc, hexane, heptane, pentane, water and like or a mixture thereof. Specifically, the solvent may be THF. The suitable temperature for the conversion is in range of 0°C to 40°C. Preferably, in between 25-35°C. Solvents used for purification include but not limited to methanol, ethanol, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, dichloromethane, chloroform, diethyl ether, methyltertiarybutyl ether (MTBE), isopropyl ether, ethyl acetate, isopropyl acetate, acetonitrile, acetone, THF, DMF, DMAc, hexane, heptane, pentane, water and like or a mixture thereof. Specifically, the solvent may be methyltertiarybutyl ether (MTBE).

In aspects, conversion of 4-fluoro-7-(methylthio)-2,3-dihydro-1H-inden-1-one (Formula II) into 4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one (Formula I) (Step-III) may carried using m-CPBA (meta-Chloroperoxybenzoic acid) in presence of a suitable solvent at suitable temperature followed by purification using suitable reagent in suitable solvent. Solvents used for reaction include but not limited to methanol, ethanol, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, dichloromethane, chloroform, diethyl ether, methyltertiarybutyl ether (MTBE), isopropyl ether, ethyl acetate, isopropyl acetate, acetonitrile, acetone, THF, DMF, DMSO, DMAc, hexane, heptane, pentane, water and like or a mixture thereof. Specifically, the solvent may be dichloromethane. The suitable temperature for the conversion is in range of 0°C to 40°C. Preferably, in between 25-35°C. Suitable reagent used for purification is a base includes but not limited to alkali metal carbonates and alkali metal bicarbonates. Preferably, alkali metal bicarbonates. More preferably, sodium bicarbonate. Solvents used for purification include but not limited to methanol, ethanol, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, dichloromethane, chloroform, diethyl ether, methyltertiarybutyl ether (MTBE), isopropyl ether, ethyl acetate, isopropyl acetate, acetonitrile, acetone, THF, DMF, DMAc, hexane, heptane, pentane, water and like or a mixture thereof. Specifically, the solvent may be dichloromethane.

The invention is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art.
The present invention is further explained in the form of following examples. However, it is to be understood that the following examples are merely illustrative and are not to be taken as limitations upon the scope of the invention.

Brief Manufacturing process:
Example 1:
Conversion of 1,4-difluorobenzene into 4,7-difluoro-2,3-dihydro-1H-inden-1-one (using 3-bromopropionylchloride): (Step-I):

Added 3-bromopropionylchloride (1.05 eq.) slowly drop wise to a mixture of p-difluorobenzene (10.0 g, 1.0 eq.), aluminum trichloride (3.71eq), and sodium chloride (1.85eq) at room temperature and then heated to 50 to 55°C for 3 hours. Further heated the reaction mass to 160-165°C and stirred for 5 hours. On completion, cooled the reaction mass to 80-90°c and diluted with toluene (70.0 mL). Poured the reaction mixture slowly drop wise into a mixture of 200g ice water containing 40ml hydrochloric acid. Reaction mass was passed through celite bed. The resulting layers were separated. The organic layer was evaporated and recrystallized using Ethylacetate-Hexane mixture to obtain 14.2 g of the product (Yield: 96.5%, Purity: 99.84%). 1HNMR (400MHz, CDCl3) d 7.32–7.19 (m, 1H), 7.03–6.96(m, 1H), 3.22–3.11(m, 2H), 2.83–2.72 (m, 2H).

Example 2:
Conversion of 1,4-difluorobenzene into 4,7-difluoro-2,3-dihydro-1H-inden-1-one (using 3-bromopropionylbromide): (Step-I):

Added 3-bromopropionylbromide (1.05 eq.) slowly drop wise to a mixture of p-difluorobenzene (10.0 g, 1.0 eq.), aluminum trichloride (3.71eq), and sodium chloride (1.85eq) at room temperature and then heated to 50 to 55°C for 3 hours. Further heated the reaction mass to 160-165°C and stirred for 5 hours. On completion, cooled the reaction mass to 80-90°c and diluted with toluene (70.0 mL). Poured the reaction mixture slowly drop wise into a mixture of 200g ice water containing 40ml hydrochloric acid. Reaction mass was passed through celite bed. The resulting layers were separated. The organic layer was evaporated and recrystallized using Ethylacetate-Hexane mixture to obtain 14.1 g of the product (Yield: 95.9%, Purity: 99.85%).

Example 3:
Conversion of 4,7-difluoro-2,3-dihydro-1H-inden-1-one into 4-fluoro-7-(methylthio)-2,3-dihydro-1H-inden-1-one: (Step-II):

To a stirred solution of 4,7-difluoro-2,3-dihydro-1H-inden-1-one (3.2 g, 1.0 eq.) in THF (16 mL) was added sodium thiomethoxide (1.12 eq.) slowly at 0 to 5°C in lots over a period of 30 minutes. Raised the reaction mixture temperature to room temperature and stirred for 3 hours. On completion, the reaction mass was treated with water (60mL) and ethyl acetate (60 mL). Stirred well and separated the organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuo to obtain crude product which was triturated with methyl-tert-butyl ether (MTBE) and filtered to obtain 3.5 g of desired product (Yield: 93.8%, Purity: 99.87%).
1HNMR (400MHz, CDCl3) d7.24 (t, 1H), 7.07 (dd, 1H), 3.19–3.12 (m, 2H), 2.78– 2.71 (m, 2H), 2.51(s, 3H).

Example 4:
Conversion of 4-fluoro-7-(methylthio)-2,3-dihydro-1H-inden-1-one into 4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one: (Step-III):

To a stirred solution of 4-fluoro-7-(methylthio)-2,3-dihydro-1H-inden-1-one (1.5g, 1.0 eq.) in dichloromethane (35 mL) was added 70% 3-chloroperoxybenzoic acid (m-CPBA) (2.0 eq.) at 0-5°C over a period of 30min. Raised the reaction mass temperature to room temperature and stirred for 1-2hrs. Cooled the reaction mass to 0-5°C and quenched with 5% aqueous sodium bisulfite solution. Warmed resulting reaction mixture to room temperature and separated the organic layer. Organic layer washed with brine solution (20ml) twice. Organic layers were dried over sodium sulfate and evaporated to obtain crude 4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one (1.9 g).

Example 5:
Purification of 4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one:

Crude 4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one (1.9g) was dissolved in MDC (10 mL) and treated with NaHCO3 (4 g) at room temperature for 30 to 60 minutes. Reaction mass was filtered and washed with MDC (10 mL). Filtrates were evaporated under reduced pressure below 45°C to obtain 1.6 g of desired product (Yield: 91.9 %, Purity: 99.87%).
1HNMR (400MHz, CDCl3) d 8.16 (dd, 1H), 7.41 (t, 1H), 3.42 (s, 3H), 3.24-3.21 (m, 2H), 2.88-2.85 (m, 2H)

Dated this Nov, 20th 2024

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

I/ We Claim:
1. A process for preparation of 4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one of Formula (I),

Formula (I)
Comprising;
a) reaction of 1,4-difluorobenzene (Formula IV) with 3-halopropionylhalide (Formula V) using aluminium trichloride in presence of sodium chloride to form 4,7-difluoro-2,3-dihydro-1H-inden-1-one (Formula III),

b) reaction of 4,7-difluoro-2,3-dihydro-1H-inden-1-one (Formula III) obtained in step (a) with sodiumthiomethoxide (NaSMe) in presence of a suitable solvent to form 4-fluoro-7-(methylthio)-2,3-dihydro-1H-inden-1-one (Formula II),

c) reaction of 4-fluoro-7-(methylthio)-2,3-dihydro-1H-inden-1-one (Formula II) obtained in step (b) with m-CPBA (meta-Chloroperoxybenzoic acid) in presence of a suitable solvent to form crude 4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one; and optionally purifying crude product to afford pure 4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one (Formula I) with a purity greater than 99.5%.

2. The process as claimed in claim 1, wherein the 3-halopropionylhalide used in step (a) is either 3-chloropropionylchloride, 3-bromopropionylchloride or 3-bromopropionylbromide.

3. The process as claimed in claim 1, wherein the suitable solvent used in step (b) and step (c) is selected from a group consisting of water, alcohol, ether, ester, nitrile, amide, hydrocarbons, THF, DMF, chlorinated solvents and like or mixtures thereof.

Dated this Nov, 20th 2024

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

TITLE: AN IMPROVED PROCESS FOR SYNTHESIS OF “4-FLUORO-7-(METHYLSULFONYL)-2,3-DIHYDRO-1H-INDEN-1-ONE” AND IT’S PURIFICATION THEREOF

ABSTRACT
The present invention relates to an improved process for synthesis and purification of 4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one of Formula (I).

Formula (I)

Dated this Nov, 20th 2024

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

,CLAIMS:I/ We Claim:
1. A process for preparation of 4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one of Formula (I),

Formula (I)
Comprising;
a) reaction of 1,4-difluorobenzene (Formula IV) with 3-halopropionylhalide (Formula V) using aluminium trichloride in presence of sodium chloride to form 4,7-difluoro-2,3-dihydro-1H-inden-1-one (Formula III),

b) reaction of 4,7-difluoro-2,3-dihydro-1H-inden-1-one (Formula III) obtained in step (a) with sodiumthiomethoxide (NaSMe) in presence of a suitable solvent to form 4-fluoro-7-(methylthio)-2,3-dihydro-1H-inden-1-one (Formula II),

c) reaction of 4-fluoro-7-(methylthio)-2,3-dihydro-1H-inden-1-one (Formula II) obtained in step (b) with m-CPBA (meta-Chloroperoxybenzoic acid) in presence of a suitable solvent to form crude 4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one; and optionally purifying crude product to afford pure 4-fluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one (Formula I) with a purity greater than 99.5%.

2. The process as claimed in claim 1, wherein the 3-halopropionylhalide used in step (a) is either 3-chloropropionylchloride, 3-bromopropionylchloride or 3-bromopropionylbromide.

3. The process as claimed in claim 1, wherein the suitable solvent used in step (b) and step (c) is selected from a group consisting of water, alcohol, ether, ester, nitrile, amide, hydrocarbons, THF, DMF, chlorinated solvents and like or mixtures thereof.

Dated this Nov, 20th 2024

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