WO2022238921A1 - In-situ synthesis of 3-substituted pyridinium compounds - Google Patents

In-situ synthesis of 3-substituted pyridinium compounds Download PDF

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WO2022238921A1
WO2022238921A1 PCT/IB2022/054377 IB2022054377W WO2022238921A1 WO 2022238921 A1 WO2022238921 A1 WO 2022238921A1 IB 2022054377 W IB2022054377 W IB 2022054377W WO 2022238921 A1 WO2022238921 A1 WO 2022238921A1
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compound
methylsulfonyl
ethyl
thiophen
formula
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PCT/IB2022/054377
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French (fr)
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Rameshchandra GUPTA
Sanjay Srivastava
Manish Patel
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Torrent Pharmaceuticals Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/126—Acids containing more than four carbon atoms

Definitions

  • Present invention relates to an in-situ and improved process for the preparation of 3- ⁇ [2- (methylsulfonyl)hydrazinyl]carbonyl ⁇ - l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salts or salt- cocrystal.
  • 3-substituted pyridinium compounds are disclosed in WO 01/25208, EP1243581 and WO 2016/162785.
  • EP1243581A1 discloses 3- ⁇ [2- (methylsulfonyl)hydrazinyl]carbonyl ⁇ - l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salt such as chloride and bromide salts
  • WO 2016/162785 discloses 3- ⁇ [2- (methylsulfonyl)hydrazinyl]carbonyl ⁇ - l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salts or salt- co-crystals such as with decanoic acid or octanoic acid.
  • EP1243581 though disclose general process of preparation of pyndnium compounds, it does not specifically disclose preparation of 3- ⁇ [2- (methylsulfonyl)hydrazinyl]carbonyl ⁇ - l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salts.
  • WO2016/162785 discloses preparation of 3- ⁇ [2-(methylsulfonyl)hydrazinyl] carbonyl ⁇ - l-[2- oxo-2- (thiophen-2-yl)ethyl]pyridinium salt (formula 3) such as chloride salt and such compound is used for preparation of salt-co-crystals of pyridinium compound.
  • compounds such as formula 1(d) is reacted with formula 2(a) in solvent such as DMF as shown in Example 1(e) followed by separation of solid, which is filtered and washed with DMF and ethyl acetate.
  • Compound was purified by refluxing with ethyl acetate and further recrystallization with methanol to give Compound of formula 3.
  • the disclosed process is not desirable as the purification involves lengthy process operation time.
  • WO2016/162785 discloses adding pyridine to the stirred suspension of compound of formula 1(c) such as nicotinic hydrazide in tetrahydrofuran (THF), followed by addition of methane sulfonyl chloride as shown in Example 1(c). Reaction mixture was heated, cooled and filtered. Further filtered solid was recrystallized in water and dried to give compound of formula 1(d) such as N’-(methylsulfonyl)pyridine-3-carbohydrazide as off white solid.
  • compound of formula 1(d) such as N’-(methylsulfonyl)pyridine-3-carbohydrazide as off white solid.
  • WO2016/162785 discloses adding hydrazine hydrate in suspension of niacinamide (Formula 1(b)) in toluene, followed by isolation in THF. Both, pyridine and THF have stringent limit as residual solvents, therefore are not desirable for industrial use.
  • WO2016/162785 also discloses multiple processes for preparation for compound of Formula I from compound of formula 3.
  • compound I is prepared by reacting compound of formula 3 with acid Y in presence of polar solvents and inorganic base.
  • ratio of such acid Y and inorganic base according to WO2016/162785 can vary from 0.5: 1 to 6: 1, exemplified ratio of Y and inorganic base is 1:1, which results in low yield of compound of formula I.
  • Present invention provides an improved process of preparation of compound 3- ⁇ [2- (methylsulfonyl)hydrazinyl] carbonyl ⁇ - l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salt or salt- cocrystal which overcome the problems as identified in prior art.
  • One aspect of present invention is to provide an in situ process for the preparation of 3- ⁇ [2- (methylsulfonyl)hydrazinyl]carbonyl ⁇ - l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridinium salt, the process comprises a. Reacting compound of formula 1 (b)
  • 1(d) HC1 salt c. Neutralizing HC1 salt of formula 1(d) with organic base selected from triethylamine and diisopropylethylamine or alkali metal base selected from sodium hydroxide and potassium hydroxide to obtain compound of formula 1(d); d. Reacting compound of formula 1(d) with compound of formula 2(a), to obtain 3- ⁇ [2- (methylsulfonyl)hydrazinyl] carbonyl ⁇ - l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salt;
  • X is Cl or Br e.
  • Another aspect of the present invention is to provide a process for the preparation of 3- ⁇ [2- (methylsulfonyl)hydrazinyl] carbonyl ⁇ - l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridinium salt, the process comprises
  • Another aspect of present invention is to provide a process for the preparation of 3- ⁇ [2- (methylsulfonyl)hydrazmyl] carbonyl ⁇ - l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridinium salt, the process comprises a. Reacting compound of formula 1 (d) with
  • X is Cl or Br; b. Purifying 3- ⁇ [2-(methylsulfonyl)hydrazinyl] carbonyl ⁇ - l-[2-oxo-2- (thiophen-2- yl)ethyl]pyridinium salt with solvent selected from water, acetone and mixture thereof; c. Optionally further purifying 3- ⁇ [2-(methylsulfonyl)hydrazinyl] carbonyl ⁇ - l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridinium salt with methanol.
  • Another aspect of present invention is to provide process of purifying 3- ⁇ [2- (methylsulfonyl)hydrazinyl] carbonyl ⁇ - l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridinium salt, the process comprises a. Purifying 3- ⁇ [2-(methylsulfonyl)hydrazinyl] carbonyl ⁇ - l-[2-oxo-2- (thiophen-2- yl)ethyl]pyridinium salt with solvent selected from water, acetone and mixture thereof; b.
  • Another aspect of present invention is to provide a process for the preparation of compound of formula 1(d), the process comprises a. Reacting compound of formula 1(c) with methane sulphonyl chloride in presence of solvent selected from water, ethyl acetate and mixture thereof to obtain compound of formula 1 (d) as HC1 salt; b.
  • organic base selected from triethylamine and diisopropylethylamine or alkali metal base selected from sodium hydroxide and potassium hydroxide to obtain compound of formula 1(d).
  • Another aspect of present invention is to provide a process for the preparation of 3- ⁇ [2- (methylsulfonyl)hydrazinyl] carbonyl ⁇ - l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridinium salt, the process comprises a. Converting compound of formula 2 to 2a;
  • Another aspect of present invention is to provide a process for the preparation of 3- ⁇ [2- (methylsulfonyl)hydrazinyl] carbonyl ⁇ - l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridinium salt-co- crystal of compound 1 or 2, the process comprises a.
  • present invention provides in-situ process for the preparation of 3- ⁇ [2- (methylsulfonyl)hydrazmyl] carbonyl ⁇ - l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridinium salt, the process comprises a. Reacting compound of formula 1 (b)
  • 1(d) HC1 salt c. Neutralizing HC1 salt of formula 1(d) with organic base selected from triethylamine and diisopropylethylamine or alkali metal base selected from sodium hydroxide and potassium hydroxide to obtain compound of formula 1(d); d. Reacting compound of formula 1(d) with compound of formula 2(a), to obtain 3- ⁇ [2- (methylsulfonyl)hydrazinyl] carbonyl ⁇ - l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salt;
  • X is Cl or Br e.
  • present invention provides converting 3- ⁇ [2- (methylsulfonyl)hydrazmyl] carbonyl ⁇ - l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridmium salt of step e or f to 3- ⁇ [2-(methylsulfonyl)hydrazinyl] carbonyl ⁇ - l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridimum salt- co- crystal of compound 1 or 2.
  • the step (a) of the process comprises preparation of suspension of compound of formula 1(b) in solvent selected from water, isopropyl alcohol, methanol and mixture thereof; and adding hydrazine hydrate in the suspension, followed by heating at temperature above 40°C, preferably at 60-90°C.
  • the compound of formula 1(b), solvent and hydrazine hydrate are preferably in 1 : 1 : 1 ratio and solvent is preferably methanol
  • solvent is preferably methanol
  • the step (b) comprises adding solvent such as water, ethyl acetate or mixture thereof and methane sulfonyl chloride in the suck dried solid compound of formula 1(c) and heating the reaction mixture at temperature above 50°C, preferably at above 70 °C followed by cooling to room temperature.
  • Step (b) does not involve addition of base such as pyridine in the reaction mixture.
  • the step (c) comprises neutralization of compound obtained in step (b) by basic agent selected from organic base such as triethylamine or N,N-diisopropylethylamine, or suitable alkali metal base such as sodium hydroxide or potassium hydroxide (NaOH or KOH) to obtain compound of formula 1(d).
  • suitable alkali metal base such as sodium hydroxide or potassium hydroxide (NaOH or KOH)
  • neutralization is carried out using organic base such as triethylamine or alkali metal base such as sodium hydroxide.
  • Obtained compound of formula 1 (d) is washed with water or ethyl acetate and suck dried to get wet solid.
  • the step (d) comprises reacting wet solid of compound of formula 1(d) obtained in step (c) with compound of formula 2(a) in presence of suitable solvent such as DMF and heating reaction mixture at temperature above 70°C, preferably at 85-90°C. Obtained solid is filtered and washed with solvents such as DMF or acetone or both.
  • Compound of formula 2(a) used in the reaction is oily material, which is not purified before its reaction with compound of formula 1(d).
  • step (e) compound obtained in step (d) is purified using solvent selected from acetone, water and mixture thereof.
  • Step (e) comprises dissolving solid obtained in step (d) in water and quenching in acetone to provide pure compound 3- ⁇ [2-(methylsulfonyl)hydrazinyl] carbonyl ⁇ - l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salt.
  • step (f) 3- ⁇ [2-(methylsulfonyl)hydrazinyl] carbonyl ⁇ - l-[2-oxo-2- (thiophen-2- yl)ethyl]pyridinium salt of step (e) is stirred in methanol at temperature of more than 50°C, preferably 60-65 °C, cooled and optionally further washed with methanol at room temperature.
  • Compound 3- ⁇ [2-(methylsulfonyl)hydrazinyl] carbonyl ⁇ - l-[2-oxo-2- (thiophen-2- yl)ethyl]pyridinium salt is dried. Steps (e) and (f) of the present invention require lesser operation time as compared to the prior art process.
  • step e and f can be used for purification of 3- ⁇ [2- (methylsulfonyl)hydrazmyl] carbonyl ⁇ - l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridimum salt (compound 3) obtained as per scheme 3 of WO 2016/162785.
  • Compound 3- ⁇ [2-(methylsulfonyl)hydrazmyl] carbonyl ⁇ - l-[2-oxo-2- (thiophen-2- yl)ethyl]pyridinium salt according to present invention is selected from bromide salt or chloride salt.
  • Compound is 3- ⁇ [2-(methylsulfonyl)hydrazinyl] carbonyl ⁇ - l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium chloride.
  • the compound 3- ⁇ [2-(methylsulfonyl)hydrazinyl] carbonyl ⁇ - l-[2-oxo-2- (thiophen-2- yl)ethyl]pyridinium salt obtained according to the process of the invention can be converted to 3- ⁇ [2-(methylsulfonyl)hydrazinyl] carbonyl ⁇ - l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salt-co- crystals such as with decanoic acid or octanoic acid.
  • 3 - ⁇ [2- (methylsulfonyl)hydrazmyl] carbonyl ⁇ - l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridimum chloride is converted to compounds 1 and 2.
  • Another embodiment of the present invention provides a process for the preparation of 3- ⁇ [2- (methylsulfonyl)hydrazmyl] carbonyl ⁇ - l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridinium salt-co- crystal of compound 1 or 2, the process comprises a.
  • Inorganic base according to the process are selected from sodium carbonate, sodium hydroxide, sodium bicarbonate and potassium hydroxide, preferable being sodium hydroxide. Said reaction is preferably carried out at temperature of less than 30°C and obtained solid is filtered, washed with water and dried to provide product with purity of more than 99%.
  • the optimum ratio of decanoic acid or octanoic acid and inorganic base such as sodium hydroxide is 1.5:1 to provide improved yield as compared to the prior art process where ratio of 1: 1 was used.
  • Another embodiment of the present invention provides use of compound of formula 2(a) as oily material for preparation of compound 3- ⁇ [2-(methylsulfonyl)hydrazinyl] carbonyl ⁇ - l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salt, wherein compound of formula 2(a) is not purified before its use, which minimizes hazardous exposure.
  • present invention uses oily compound of formula 2(a) without purifying it which still provides 3- ⁇ [2- (methylsulfonyl)hydrazinyl] carbonyl ⁇ - l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salt, with purity of more than 99%.
  • Another embodiment of present invention provides a process for the preparation of 3- ⁇ [2-(methylsulfonyl)hydrazinyl] carbonyl ⁇ - l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salt, the process comprises a. Converting compound of formula 2 to 2(a);
  • Compound of formula 2 can be converted to 2(a) using sulfuryl chloride in suitable aprotic solvent such as ethylacetate.
  • suitable aprotic solvent such as ethylacetate.
  • Reaction mixture was cooled and solid was filtered, washed with methanol and suck dried.
  • the wet solid (450gm) was charged in ethyl acetate and methane sulfonyl chloride (360ml) was added.
  • Reaction mixture was heated and stirred at 73+3 °C for 4-5hrs.
  • Reaction mixture was cooled and triethylamine (450ml) was added and stirred at 25-30°C. Solid was filtered, washed with ethyl acetate and suck dried to get N'-(methylsulfonyl)pyridine-3-carbohydrazide as a solid material.
  • reaction mixture of wet solid of N'-(methylsulfonyl)pyridine-3-carbohydrazide (972gm) and 2-chloro-l-(thiophen-2-yl)ethanone (625gm) (as obtained in Example 1) was heated and stirred in dimethylformamide at 85-90°C for 15-20hrs.
  • Reaction mixture was cooled to 25-30°C and separated solid was filtered and washed with dimethyl formamide followed by acetone and suck dried.
  • the wet solid was dissolved in hot water and quenched in acetone to afford solid.
  • the separated solid was filtered, suck dried and stirred in methanol at 60-65°C and cooled and stirred further at room temperature.
  • the separated solid was filtered, washed with methanol, suck dried and finally, dried under vacuum to provide title compound as a solid with HPLC purity of more than 99%.
  • reaction mixture was heated and stirred at 60-65°C for 22- 24hrs. Reaction mixture was cooled and solid was filtered, washed with methanol and suck dried. The wet solid (435gm) was charged in ethyl acetate and methane sulfonyl chloride (344ml) was added. Reaction mixture was heated and stirred at 73+3 °C for 4-5hrs. Reaction mixture was filtered and wet solid was charged in water and neutralized by aqueous sodium hydroxide.
  • N'-(methylsulfonyl)pyridine-3-carbohydrazide was filtered, washed with water and suck dried to get N'-(methylsulfonyl)pyridine-3-carbohydrazide as a solid material. Further, reaction mixture of wet solid of N'-(methylsulfonyl)pyridine-3-carbohydrazide (550gm) and 2-chloro-l-(thiophen-2-yl)ethanone (660gm) (as obtained in example 1) was heated and stirred in dimethylformamide at 85-90°C for 15-20hrs. Reaction mixture was cooled to 25-30°C and separated solid was filtered and washed with dimethyl formamide followed by acetone and suck dried.
  • Example 4 The wet solid was dissolved in hot water and quenched in acetone to afford solid. The separated solid was filtered, suck dried and stirred in methanol at 60-65°C, cooled, and stirred further at room temperature. The separated solid was filtered, washed with methanol, suck dried and finally, dried under vacuum to provide title compound as a solid with HPLC purity of more than 99%.
  • Example 4
  • reaction mixture was heated and stirred at 85-87°C for 6-7 hrs. Reaction mixture was cooled to room temperature and was stirred for 30 mins. Water was added to the reaction mixture (100 ml) and was stirred for 15 mins and then cooled to 10-20°C. Methane sulfonyl chloride (240ml) was added to the reaction mixture followed by stirring for 2 hrs at room temperature. Reaction mixture was neutralized by aqueous sodium hydroxide at temperature below 30°C.

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  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

Present invention relates to an in-situ and improved process for the preparation of 3-{[2-(methylsulfonyl)hydrazinyl]carbonyl}- 1-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salts or salt-cocrystal.

Description

IN-SrrU SYNTHESIS OF 3-SUBSTITUTED PYRIDINIUM COMPOUNDS
FIELD OF INVENTION
Present invention relates to an in-situ and improved process for the preparation of 3-{[2- (methylsulfonyl)hydrazinyl]carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salts or salt- cocrystal.
BACKGROUND OF INVENTION:
3-substituted pyridinium compounds are disclosed in WO 01/25208, EP1243581 and WO 2016/162785. Specifically, WO 01/25208, EP1243581A1 discloses 3-{[2- (methylsulfonyl)hydrazinyl]carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salt such as chloride and bromide salts, while WO 2016/162785 discloses 3-{[2- (methylsulfonyl)hydrazinyl]carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salts or salt- co-crystals such as with decanoic acid or octanoic acid.
WO 01/25208, EP1243581 though disclose general process of preparation of pyndnium compounds, it does not specifically disclose preparation of 3-{[2- (methylsulfonyl)hydrazinyl]carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salts.
WO2016/162785 discloses preparation of 3-{[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2- oxo-2- (thiophen-2-yl)ethyl]pyridinium salt (formula 3) such as chloride salt and such compound is used for preparation of salt-co-crystals of pyridinium compound. In the process of preparation of compound of formula 3 (scheme 3) of WO2016/162785, compounds such as formula 1(d) is reacted with formula 2(a) in solvent such as DMF as shown in Example 1(e) followed by separation of solid, which is filtered and washed with DMF and ethyl acetate. Compound was purified by refluxing with ethyl acetate and further recrystallization with methanol to give Compound of formula 3. The disclosed process is not desirable as the purification involves lengthy process operation time.
For preparation of compound of formula 1(d), WO2016/162785 discloses adding pyridine to the stirred suspension of compound of formula 1(c) such as nicotinic hydrazide in tetrahydrofuran (THF), followed by addition of methane sulfonyl chloride as shown in Example 1(c). Reaction mixture was heated, cooled and filtered. Further filtered solid was recrystallized in water and dried to give compound of formula 1(d) such as N’-(methylsulfonyl)pyridine-3-carbohydrazide as off white solid. For preparation of compound of formula 1(c), WO2016/162785 discloses adding hydrazine hydrate in suspension of niacinamide (Formula 1(b)) in toluene, followed by isolation in THF. Both, pyridine and THF have stringent limit as residual solvents, therefore are not desirable for industrial use.
WO2016/162785 also discloses multiple processes for preparation for compound of Formula I from compound of formula 3. In one such process, compound I is prepared by reacting compound of formula 3 with acid Y in presence of polar solvents and inorganic base. Though ratio of such acid Y and inorganic base according to WO2016/162785 can vary from 0.5: 1 to 6: 1, exemplified ratio of Y and inorganic base is 1:1, which results in low yield of compound of formula I.
Apart from problem of low yield and use of hazardous solvents & reagents, other drawbacks identified in WO2016/162785 include purification and drying of every intermediate and purification of compound of formula (2a) such as 2-chloro-l-(thiophen-2-yl)ethanone using isopropyl: cyclohexane, which makes process lengthy and more hazardous. Further, process described in prior art are not economically viable.
Present invention provides an improved process of preparation of compound 3-{[2- (methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salt or salt- cocrystal which overcome the problems as identified in prior art.
SUMMARY OF THE INVENTION
One aspect of present invention is to provide an in situ process for the preparation of 3-{[2- (methylsulfonyl)hydrazinyl]carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridinium salt, the process comprises a. Reacting compound of formula 1 (b)
Figure imgf000004_0001
1(b) with hydrazine hydrate in presence of solvent selected from water, isopropyl alcohol, methanol and mixture thereof to obtain compound of formula 1(c);
Figure imgf000004_0002
1(c) b. Reacting compound of formula 1(c) with methane sulphonyl chloride in presence of solvent selected from water, ethyl acetate and mixture thereof to obtain compound of formula 1 (d) as HC1 salt ;
Figure imgf000004_0003
1(d) HC1 salt c. Neutralizing HC1 salt of formula 1(d) with organic base selected from triethylamine and diisopropylethylamine or alkali metal base selected from sodium hydroxide and potassium hydroxide to obtain compound of formula 1(d); d. Reacting compound of formula 1(d) with compound of formula 2(a), to obtain 3- {[2- (methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salt;
Figure imgf000005_0001
Wherein X is Cl or Br e. Purifying 3-{[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2- yl)ethyl]pyridinium salt with solvent selected from water, acetone and mixture thereof; f. Optionally further purifying 3-{[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salt with methanol.
Another aspect of the present invention is to provide a process for the preparation of 3-{[2- (methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridinium salt, the process comprises
Reacting compound of formula 1 (d) as suck dried material with
Figure imgf000005_0002
compound of formula 2(a) as oily material
Figure imgf000005_0003
Wherein X is Cl or Br, to obtain 3-{[2-(methylsulfonyl)hydrazmyl]carbonyl}- l-[2-oxo-2- (thiophen-2- yl)ethyl]pyridinium salt with purity of more than 99%. Another aspect of present invention is to provide a process for the preparation of 3- { [2- (methylsulfonyl)hydrazmyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridinium salt, the process comprises a. Reacting compound of formula 1 (d) with
Figure imgf000006_0001
Compound of formula 2(a)
Figure imgf000006_0002
2(a)
Wherein X is Cl or Br; b. Purifying 3-{[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2- yl)ethyl]pyridinium salt with solvent selected from water, acetone and mixture thereof; c. Optionally further purifying 3-{[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridinium salt with methanol.
Another aspect of present invention is to provide process of purifying 3- { [2- (methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridinium salt, the process comprises a. Purifying 3-{[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2- yl)ethyl]pyridinium salt with solvent selected from water, acetone and mixture thereof; b. Optionally further purifying 3-{[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridinium salt with methanol. Another aspect of present invention is to provide a process for the preparation of compound of formula 1(d), the process comprises
Figure imgf000007_0001
a. Reacting compound of formula 1(c) with methane sulphonyl chloride in presence of solvent selected from water, ethyl acetate and mixture thereof to obtain compound of formula 1 (d) as HC1 salt;
Figure imgf000007_0002
b. Neutralizing HC1 salt of formula 1(d) with organic base selected from triethylamine and diisopropylethylamine or alkali metal base selected from sodium hydroxide and potassium hydroxide to obtain compound of formula 1(d). Another aspect of present invention is to provide a process for the preparation of 3-{[2- (methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridinium salt, the process comprises a. Converting compound of formula 2 to 2a;
Figure imgf000007_0003
2 b. Reacting compound of formula 2(a) as oily material obtained in step (a) with compound of formula 1(d) to obtain 3-{[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridinium salt; wherein compound of formula 2(a) is not purified before reaction with compound of formula 1(d).
Another aspect of present invention is to provide a process for the preparation of 3-{[2- (methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridinium salt-co- crystal of compound 1 or 2, the process comprises a. Reacting aqueous solution of 3-{[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridinium salt with a aqueous solution of decanoic acid or octanoic acid and inorganic base, wherein ratio of decanoic acid or octanoic acid to inorganic base is 1.5:1; b. Isolating 3-{[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridinium salt- co- crystal of compound 1 or 2. FIGURES
Fig 1: Comparative yield of compound 1 obtained as per prior art WO2016/162785 examples vs examples 6 and 7 of present invention
DETAILED DESCRIPTION OF INVENTION
While selected embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.
The singular form "a", "an" and "the" as used herein includes plural references unless the context clearly dictates otherwise. The term “adding” includes combining, dissolving, slurrying, stirring, or a combination thereof.
The process described herein below for preparation of pyridinium salt is an in-situ process, therefore purification of compounds at each step is not required. The process of invention is fast and robust process, which does not involve use of hazardous reagents.
In an embodiment present invention provides in-situ process for the preparation of 3-{[2- (methylsulfonyl)hydrazmyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridinium salt, the process comprises a. Reacting compound of formula 1 (b)
Figure imgf000009_0001
1(b) with hydrazine hydrate in presence of solvent selected from water, isopropyl alcohol, methanol and mixture thereof to obtain compound of formula 1(c);
Figure imgf000009_0002
b. Reacting compound of formula 1(c) with methane sulphonyl chloride in presence of solvent selected from water, ethyl acetate and mixture thereof to obtain compound of formula 1 (d) as HC1 salt;
Figure imgf000010_0002
1(d) HC1 salt c. Neutralizing HC1 salt of formula 1(d) with organic base selected from triethylamine and diisopropylethylamine or alkali metal base selected from sodium hydroxide and potassium hydroxide to obtain compound of formula 1(d); d. Reacting compound of formula 1(d) with compound of formula 2(a), to obtain 3-{[2- (methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salt;
Figure imgf000010_0001
2(a)
Wherein X is Cl or Br e. Purifying 3-{[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2- yl)ethyl]pyridinium salt with solvent selected from water, acetone and mixture thereof; f Optionally further purifying 3-{[2-(methylsulfonyl)hydrazmyl] carbonyl}- l-[2-oxo-2-
(thiophen-2-yl)ethyl]pyndinium salt with methanol;
In another embodiment, present invention provides converting 3-{[2- (methylsulfonyl)hydrazmyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridmium salt of step e or f to 3-{[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridimum salt- co- crystal of compound 1 or 2. The step (a) of the process comprises preparation of suspension of compound of formula 1(b) in solvent selected from water, isopropyl alcohol, methanol and mixture thereof; and adding hydrazine hydrate in the suspension, followed by heating at temperature above 40°C, preferably at 60-90°C. The compound of formula 1(b), solvent and hydrazine hydrate are preferably in 1 : 1 : 1 ratio and solvent is preferably methanol After cooling, solid is filtered and washed with suitable solvent selected from isopropyl alcohol, water, methanol and mixture thereof, preferably methanol, to obtain compound of formula 1(c). The obtained solid is suck dried and used for next step, without further drying.
The step (b) comprises adding solvent such as water, ethyl acetate or mixture thereof and methane sulfonyl chloride in the suck dried solid compound of formula 1(c) and heating the reaction mixture at temperature above 50°C, preferably at above 70 °C followed by cooling to room temperature. Step (b) does not involve addition of base such as pyridine in the reaction mixture.
The step (c) comprises neutralization of compound obtained in step (b) by basic agent selected from organic base such as triethylamine or N,N-diisopropylethylamine, or suitable alkali metal base such as sodium hydroxide or potassium hydroxide (NaOH or KOH) to obtain compound of formula 1(d). Preferably, neutralization is carried out using organic base such as triethylamine or alkali metal base such as sodium hydroxide. Obtained compound of formula 1 (d) is washed with water or ethyl acetate and suck dried to get wet solid. The step (d) comprises reacting wet solid of compound of formula 1(d) obtained in step (c) with compound of formula 2(a) in presence of suitable solvent such as DMF and heating reaction mixture at temperature above 70°C, preferably at 85-90°C. Obtained solid is filtered and washed with solvents such as DMF or acetone or both. Compound of formula 2(a) used in the reaction is oily material, which is not purified before its reaction with compound of formula 1(d). In step (e) compound obtained in step (d) is purified using solvent selected from acetone, water and mixture thereof. Step (e) comprises dissolving solid obtained in step (d) in water and quenching in acetone to provide pure compound 3-{[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salt.
Optionally, in step (f), 3-{[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2- yl)ethyl]pyridinium salt of step (e) is stirred in methanol at temperature of more than 50°C, preferably 60-65 °C, cooled and optionally further washed with methanol at room temperature. Compound 3-{[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2- yl)ethyl]pyridinium salt is dried. Steps (e) and (f) of the present invention require lesser operation time as compared to the prior art process.
In an alternate embodiment, step e and f can be used for purification of 3-{[2- (methylsulfonyl)hydrazmyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridimum salt (compound 3) obtained as per scheme 3 of WO 2016/162785.
Compound 3-{[2-(methylsulfonyl)hydrazmyl] carbonyl}- l-[2-oxo-2- (thiophen-2- yl)ethyl]pyridinium salt according to present invention is selected from bromide salt or chloride salt. Preferably, Compound is 3-{[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium chloride.
The compound 3-{[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2- yl)ethyl]pyridinium salt obtained according to the process of the invention can be converted to 3- {[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salt-co- crystals such as with decanoic acid or octanoic acid. Specifically, 3 - { [2- (methylsulfonyl)hydrazmyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridimum chloride is converted to compounds 1 and 2.
Figure imgf000012_0001
Another embodiment of the present invention provides a process for the preparation of 3- { [2- (methylsulfonyl)hydrazmyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridinium salt-co- crystal of compound 1 or 2, the process comprises a. Reacting aqueous solution of 3-{[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridinium salt with a aqueous solution of decanoic acid or octanoic acid and inorganic base, wherein ratio of decanoic acid or octanoic acid to inorganic base is 1.5:1; b. Isolating 3-{[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridinium salt- co- crystal of compound 1 or 2.
Inorganic base according to the process are selected from sodium carbonate, sodium hydroxide, sodium bicarbonate and potassium hydroxide, preferable being sodium hydroxide. Said reaction is preferably carried out at temperature of less than 30°C and obtained solid is filtered, washed with water and dried to provide product with purity of more than 99%. The optimum ratio of decanoic acid or octanoic acid and inorganic base such as sodium hydroxide is 1.5:1 to provide improved yield as compared to the prior art process where ratio of 1: 1 was used.
Another embodiment of the present invention provides use of compound of formula 2(a) as oily material for preparation of compound 3-{[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salt, wherein compound of formula 2(a) is not purified before its use, which minimizes hazardous exposure. While prior art necessarily requires purification of compound of formula 2(a) before using it for further reaction, present invention uses oily compound of formula 2(a) without purifying it which still provides 3- { [2- (methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salt, with purity of more than 99%.
Therefore another embodiment of present invention provides a process for the preparation of 3- {[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salt, the process comprises a. Converting compound of formula 2 to 2(a);
Figure imgf000014_0001
2 b. Reacting compound of formula 2a as oily material obtained in step a with compound of formula 1(d) to obtain 3-{[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salt; wherein compound of formula 2a is not purified before reaction with compound of formula 1(d).
Compound of formula 2 can be converted to 2(a) using sulfuryl chloride in suitable aprotic solvent such as ethylacetate. The following examples are presented to illustrate specific embodiments of the present invention and synthetic preparations thereof; and should not be interpreted as limitations upon the scope of the invention.
Example 1
Preparation of 2-chloro-l-(thiophen-2-yl)ethanone: To a stirred cold solution of 2-acetyl thiophene (200gm) in ethyl acetate (1800ml), solution of sulfuryl chloride (160ml) in ethylacetate (200ml) was added and reaction mixture was stirred at room temperature for 45-60 minutes. Cold water was added in reaction mass and organic layer was separated. Organic layer was washed with brine solution. Organic layer was dried over sodium sulphate and ethyl acetate was distilled out under vacuum to get title compound as liquid oil.
Example 2
Preparation of 3-{[2-(methylsulfonyl) hydrazinyl]carbonyl}-l-[2-oxo-2-(thiophen-2- yl)ethyl]pyridinium chloride:
To a stirred suspension of nicotinamide (500gm) in methanol (500ml), hydrazine hydrate (500ml) was charged and reaction mixture was heated and stirred at 60-65°C for 22- 24hrs.
Reaction mixture was cooled and solid was filtered, washed with methanol and suck dried. The wet solid (450gm) was charged in ethyl acetate and methane sulfonyl chloride (360ml) was added. Reaction mixture was heated and stirred at 73+3 °C for 4-5hrs. Reaction mixture was cooled and triethylamine (450ml) was added and stirred at 25-30°C. Solid was filtered, washed with ethyl acetate and suck dried to get N'-(methylsulfonyl)pyridine-3-carbohydrazide as a solid material. Further, reaction mixture of wet solid of N'-(methylsulfonyl)pyridine-3-carbohydrazide (972gm) and 2-chloro-l-(thiophen-2-yl)ethanone (625gm) (as obtained in Example 1) was heated and stirred in dimethylformamide at 85-90°C for 15-20hrs. Reaction mixture was cooled to 25-30°C and separated solid was filtered and washed with dimethyl formamide followed by acetone and suck dried. The wet solid was dissolved in hot water and quenched in acetone to afford solid. The separated solid was filtered, suck dried and stirred in methanol at 60-65°C and cooled and stirred further at room temperature. The separated solid was filtered, washed with methanol, suck dried and finally, dried under vacuum to provide title compound as a solid with HPLC purity of more than 99%.
Example 3
Preparation of 3-{[2-(methylsulfonyl) hydrazinyl]carbonyl}-l-[2-oxo-2-(thiophen-2- yl)ethyl]pyridinium chloride
To a stirred suspension of nicotinamide (500gm) in methanol, hydrazine hydrate (500ml) was charged and reaction mixture was heated and stirred at 60-65°C for 22- 24hrs. Reaction mixture was cooled and solid was filtered, washed with methanol and suck dried. The wet solid (435gm) was charged in ethyl acetate and methane sulfonyl chloride (344ml) was added. Reaction mixture was heated and stirred at 73+3 °C for 4-5hrs. Reaction mixture was filtered and wet solid was charged in water and neutralized by aqueous sodium hydroxide. Solid was filtered, washed with water and suck dried to get N'-(methylsulfonyl)pyridine-3-carbohydrazide as a solid material. Further, reaction mixture of wet solid of N'-(methylsulfonyl)pyridine-3-carbohydrazide (550gm) and 2-chloro-l-(thiophen-2-yl)ethanone (660gm) (as obtained in example 1) was heated and stirred in dimethylformamide at 85-90°C for 15-20hrs. Reaction mixture was cooled to 25-30°C and separated solid was filtered and washed with dimethyl formamide followed by acetone and suck dried. The wet solid was dissolved in hot water and quenched in acetone to afford solid. The separated solid was filtered, suck dried and stirred in methanol at 60-65°C, cooled, and stirred further at room temperature. The separated solid was filtered, washed with methanol, suck dried and finally, dried under vacuum to provide title compound as a solid with HPLC purity of more than 99%. Example 4
Preparation of 3-{[2-(methylsulfonyl) hydrazinyl]carbonyl}-l-[2-oxo-2-(thiophen-2- yl)ethyl]pyridinium chloride
To a stirred suspension of nicotinamide (200gm) in water (200ml), hydrazine hydrate (200ml) was charged and reaction mixture was heated and stirred at 85-87°C for 6-7 hrs. Reaction mixture was cooled to room temperature and was stirred for 30 mins. Water was added to the reaction mixture (100 ml) and was stirred for 15 mins and then cooled to 10-20°C. Methane sulfonyl chloride (240ml) was added to the reaction mixture followed by stirring for 2 hrs at room temperature. Reaction mixture was neutralized by aqueous sodium hydroxide at temperature below 30°C. Solid was stirred for 60-90 mins and filtered, washed with water (200ml) and suck dried to get N'-(methylsulfonyl)pyridine-3-carbohydrazide as a solid material. Further, reaction mixture of wet solid of N'-(methylsulfonyl)pyridine-3-carbohydrazide (290gm) and 2-chloro-l-(thiophen-2-yl)ethanone (362.5gm) (as obtained in example 1), was heated and stirred in dimethylformamide at 85-90°C for 18hrs. Reaction mixture was cooled to 25-30°C and separated solid was filtered and washed with dimethyl formamide followed by acetone and suck dried. Suck dried solid was refluxed in methanol for 30mins, cooled, filtered and washed with methanol and suck dried. Suck dried solid was dissolved in hot water, filtered and quenched in acetone, stirred for 30-40mins, filtered and washed with acetone and suck dried. Finally, material was dried under vacuum to provide title compound as a solid.
Example 5
Preparation of 3-{[2-(methylsulfonyl) hydrazinyl]carbonyl}-l-[2-oxo-2-(thiophen-2- yl)ethyl]pyridinium chloride
Suspension of N'-(methylsulfonyl)pyridine-3-carbohydrazide (125gm) and 2-chloro-l- (thiophen-2-yl)ethanone (112gm), as obtained from the method as in prior art (WO2016/162785), in dimethylformamide was heated and stirred at 85-90°C for 15-17hrs. Reaction mixture was cooled to room temperature, stirred for lhr and separated solid was filtered. Solid was stirred in acetone for 30min, filtered, washed with acetone and suck dried. The wet solid was dissolved in hot water and quenched in acetone to afford solid. The obtained solid was filtered, washed with acetone and suck dried. Wet solid was stirred in methanol at 60- 65 °C, cooled to room temperature and stirred for 15 min. The separated solid was filtered, washed with methanol, suck dried and finally, dried under vacuum to provide title compound as a solid with HPLC purity of more than 99%.
Example: 6
Preparation of compound 1 To a stirred suspension of n- decanoic acid (68.74gm) in water (600ml), was added aqueous solution (400ml) of sodium hydroxide (10.64gm), followed by aqueous solution (2000ml) of 3- {[2-(methylsulfonyl) hydrazinyl]carbonyl}-l-[2-oxo-2-(thiophen-2-yl)ethyl]pyridinium chloride (lOOgm) at 20-25°C and stirred for 1 hour. The separated solid was filtered, washed with water (2000ml) and dried to get title compound (105gm) with HPLC purity more than 99.0 %. Example: 7
Preparation of Compound 1
To a stirred suspension of n- decanoic acid (172.53gm) in water (750ml), was added aqueous solution (500ml) of sodium hydroxide (26.64gm), followed by aqueous solution (2500ml) of 3- {[2-(methylsulfonyl) hydrazmyl]carbonyl}-l-[2-oxo-2-(thiophen-2-yl)ethyl]pyridimum chloride (250gm) at 20-25°C and stirred for 1 hour. The separated solid was filtered, washed with water
(5000ml) and dried to get title compound (281gm) with HPLC purity more than 99.0 %.
Yield of compound 1 obtained according to example 6 and 7 of present invention was compared with prior art WO2016/162785 examples. Figure 1 shows that mole ratio of acid (decanoic acid): base (NaOH) according to present invention provides better yield of compound 1 as compared to prior art process wherein mole ratio of acid: base was 1:1.

Claims

We claim:
1. An in-situ process for the preparation of 3-{[2-(methylsulfonyl)hydrazinyl]carbonyl}- l-[2- oxo-2- (thiophen-2-yl)ethyl] pyridinium salt, comprises a. Reacting compound of formula 1 (b)
1
Figure imgf000018_0001
with hydrazine hydrate in presence of solvent selected from water, isopropyl alcohol, methanol and mixture thereof to obtain compound of formula 1(c);
1
Figure imgf000018_0002
b. Converting compound of formula 1(c) to 3- {[2-(methylsulfonyl)hydrazinyl] carbonyl}- 1- [2-OXO-2- (thiophen-2-yl)ethyl] pyridinium salt
2. The process according to claim 1 , wherein process further comprises reacting compound of formula 1(c) with methane sulphonyl chloride in presence of solvent selected from water, ethyl acetate and mixture thereof to obtain compound of formula 1 (d) as HC1 salt;
Figure imgf000018_0003
1(d) HC1 salt and neutralizing HC1 salt of formula 1(d) with organic base selected from triethylamine and diisopropylethylamine or alkali metal base selected from sodium hydroxide and potassium hydroxide to obtain compound of formula 1(d).
3. The process according to claim 2, wherein process further comprises reacting compound of formula 1(d) with compound of formula 2(a), to obtain 3-{[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salt,
Figure imgf000019_0001
Wherein X is Cl or Br.
4. The process according to any of the preceding claims, wherein process further comprises purifying 3-{[2-(methylsulfonyl)hydrazmyl] carbonyl}- l-[2-oxo-2- (thiophen-2- yl)ethyl]pyridimum salt with solvent selected from water, acetone and mixture thereof.
5. The process according to claim 4, wherein process further comprises purifying 3-{[2- (methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salt with methanol.
6. The process according to claim 3, wherein compound of formula 1(d) is suck dried material and compound of formula 2(a) is oily material.
7. The process according to any of the preceding claims, wherein 3-{[2- (methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium salt is selected from 3-{[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2- yl)ethyl]pyridimum chloride or 3-{[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridinium bromide.
8 The process according to any of the preceding claims, wherein process further comprises converting - { [2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2- yl)ethyl]pyridinium salt to 3-{[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridinium salt-co- crystal of compound 1 or 2.
9. The process according to claim 8, wherein the process comprises a. Reacting aqueous solution of 3-{[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl]pyridmium salt with a aqueous solution of decanoic acid or octanoic acid and inorganic base, wherein ratio of decanoic acid or octanoic acid to inorganic base is 1.5:1; b. Isolating 3-{[2-(methylsulfonyl)hydrazinyl] carbonyl}- l-[2-oxo-2- (thiophen-2-yl)ethyl] pyridinium salt- co- crystal of compound 1 or 2.
10. The process according to claim 9, wherein inorganic base is sodium hydroxide.
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