Novel process and intermediate for the preparation of xanomeline

Abstract

The present invention relates to a novel process for the preparation of Xanomeline tartrate of Formula (I): using a novel intermediate compound of Formula (III); wherein X comprises methyl sulphate, methyl carbonate, nitrate and sulfonate.

Description

[0001] NOVEL PROCESS AND INTERMEDIATE FOR THE PREPARATION OF XANOMELINE RELATED APPLICATION: This application claims the benefit of Indian provisional application number 202441076586, filed on 09thOctober 2024; the specification of which is hereby Incorporated by reference in its entirety. FIELD OF THE INVENTION The present invention relates to a novel process and intermediate for the preparationof Xanomeline tartrate of Formula (I). The compound of Formula (III) is a key intermediate in the preparation of Xanomeline tartrate of Formula (I); wherein X comprises methyl sulphate, methyl carbonate, nitrate and sulfonate. BACKGROUND OF THE INVENTION Xanomeline tartrate in combination with trospium is a muscarinic antipsychotic for the treatment of schizophrenia and psychosis related to Alzheimer’s disease. Through its novel mechanism of action, it acts as a dual M1 / M4 muscarinic acetylcholine receptor agonist in the central nervous system, which is thought to improve positive, negative, and cognitive symptoms of schizophrenia. Unlike existing treatments, it does not directly block dopamine receptors, representing a potential new approach to treating schizophrenia. The said combination is approved under the brand name Cobenfy®. US 5,043,345 of Novo Nordisk reported first process for preparing Xanomeline free base of Formula (II) by the reaction of 3-(4-hexyloxy-1,2,5-thiadiazol-3-yl)pyridine of Formula (IV) with methyl iodide in acetone to obtain 1-methyl 3-(4-hexyloxy- 1,2,5-thiadiazol-3-yl)- pyridinium iodide (Iodide salt intermediate), which is further reduced using sodium borohydride in ethanol, followed by purified using column chromatography to produce Xanomeline free base of Formula (II). The above process described in the below scheme: Iodide salt intermediate Sodium borohydride, ethanol, ethyl acetate, column chromatography Xanomeline Free base Formula (II) The process has the drawback of utilizing expensive reagents such as methyl iodide in the formation of Iodide salt intermediate (quaternary methylated pyridinium salt) and sodium borohydride in ethanol for reduction. Subsequent purification through column chromatography is required to isolate Xanomeline which is not feasible at industrial level. US 5,834,495 A of Eli Lilly reported a process for the preparation of Xanomeline tartrate which involves the reduction of Iodide salt intermediate by using sodium borohydride in methanol followed by treating with fumaric acid to obtain Xanomeline fumarate, which is further converted to Xanomeline tartrate of Formula (I) using (+) L-tartaric acid in 2-Propanol. The above process described in the below scheme: The disadvantage of the aforementioned process is suffering from the need of multiple operational steps due to the initial isolation of Xanomeline fumarate salt, followed by salt breaking using sodium hydroxide, followed by treating with (L)-tartaric acid to obtain Xanomeline Tartrate. This may lead to the formation of unwanted impurities. Considering the importance of Xanomeline tartrate of Formula (I) and its use in schizophrenia treatment and psychosis related to Alzheimer’s disease, nevertheless, besides the known process of Xanomeline tartrate, there is still need for novel, efficient, and cost-effective process that yields a high-quality product with minimal impurities. Besides the availability of different processes for the preparation of Xanamoline tartrate in state of the art, there is a need for an alternative process for improving the preparation of Xanamoline tartrate and of intermediates thereof, which is cost effective and economically significant. OBJECTIVE OF THE INVENTION The main objective of the present invention is to provide a novel process for the preparation of Xanomeline tartrate of Formula (I). Other objective of the present invention is to provide the compound of Formula (III), which is a key intermediate in the preparation of Xanomeline tartrate of Formula (I); wherein X comprises methyl sulphate, methyl carbonate, nitrate and sulfonate. Another objective of the present invention is to provide a process for the preparation of Formula (III). SUMMARY OF THE INVENTION The main embodiment of the present invention is to provide a novel process for the preparation of Xanomeline tartrate of Formula (I), which comprises: a) reducing compound of Formula (III), wherein, X comprises methyl sulphate, methyl carbonate, nitrate and sulfonate: with a reducing agent to give Xanomeline free base compound of Formula (II); and b) converting Xanomeline free base of Formula (II) to Xanomeline tartrate of Formula (I). And optionally purifying the Xanomeline tartrate with known purification techniques. Another embodiment of the present invention is to provide a novel intermediate of Formula (III); wherein X comprises methyl sulphate, methyl carbonate, nitrate and sulfonate. Yet another embodiment of the present invention is to provide a process for the preparation of novel intermediate of Formula (III). wherein X comprises methyl sulphate, methyl carbonate, nitrate and sulfonate, which comprises: a) condensing a compound of Formula (VII), Formula (VII) with an amine source and a nitrile source to obtain a compound of Formula VI or a salt thereof; Formula (VI) b) cyclizing the compound of Formula (VI) or a salt thereof, by treating with a cyclizing agent to give a compound of Formula (V); which is optionally purified with known purification techniques; Formula (V) c) reacting the compound of Formula (V) with an alkylating agent to obtain a compound of Formula (IV); and d) methylating the compound of Formula (IV) with a methylating agent to obtain the novel intermediate compound of Formula (III). DETAILED DESCRIPTION OF THE INVENTION The present invention is related to a novel process for the preparation of Xanomeline tartrate of Formula (I). The process comprises, reducing a compound of Formula (III): wherein X comprises methyl sulphate, methyl carbonate, nitrate and sulfonate; with a reducing agent to give Xanomeline free base of Formula (II), which is converted to its tartrate salt of Formula (I) by treating with L-tartaric acid. In an embodiment, the X in the compound of Formula (III) comprises methyl sulphate, methyl carbonate, nitrate and sulfonate. Preferably X is methyl sulphate and methyl carbonate. Most preferably X is methyl sulphate. In another embodiment, Xanomeline free base of Formula (II) is optionally isolated, wherein the isolation is carried out by using an acid and / or a base. The reducing agent used in the above process comprises lithium borohydride, sodium borohydride, potassium borohydride, boron hydride, aluminum hydride, an organic magnesium compound and an organic lithium compound and the like or mixtures thereof. The reduction is carried out in the presence or absence of a solvent, wherein the solvent comprises water, alcohol or ketonic solvents comprises methanol, ethanol, propanol, butanol, isopropanol, isobutanol, acetone, diethyl ketone, methyl ethyl ketone, methyl propyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, or ethers such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether or diisopropyl ether and the like or mixtures thereof. In one embodiment, the known purification techniques / methods are such as, crystallization, distillation, sublimation, filtration, chromatography, and extraction. For the purification solvents are selected from water, ketones, ether or alcohols such as methanol, ethanol, propanol, acetone, methyl tert-butyl ketone, methyl ethyl ketone, THF, diethyl ether or its mixture thereof. The acid comprises hydrochloric, sulfuric acid, nitric acid, hydrofluoric acid, phosphoric acid and hydrobromic acid and the like or mixtures thereof. The base comprises NaHCO3, LiOH, NaOH, KOH, KHCO3, LiHCO3, Na2CO3, K2CO3, Li2CO3, CaCO3, MgCO3, potassium tert- butoxide, sodium tert-butoxide, magnesium hydroxide and the like or mixtures thereof. In another embodiment, Xanomeline free base of Formula (II) is converted to its tartrate salt of Formula (I) by treating Xanomeline free base of Formula (II) with L- tartaric acid followed by optionally, seeding to give Xanomeline tartrate salt of Formula (I). The above process is carried out in the presence or absence of a solvent. The solvent comprises water, alcohol or ketonic solvent comprising of methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol, acetone, diethyl ketone, methyl ethyl ketone, methyl propyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone and the like or mixtures thereof, preferably acetone. In other embodiment, Xanomeline tartrate salt of Formula (I) is subjected to purification either by column chromatography or by crystallization by dissolving in a solvent or by adding an anti-solvent. The Xanomeline tartrate salt of Formula (I) is isolated as crystalline or amorphous solid. The solvent or an anti-solvent comprises water or methanol, ethanol, isopropanol, n-propanol, butanol, isobutanol, toluene, benzene, o-xylene, m-xylene, p-xylene, acetone, acetonitrile, ethyl acetate, methylene chloride, chloroform, dioxane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, hexane, cyclohexane, heptanes or mixture thereof. In another embodiment, the compound of Formula (III) is prepared by condensing compound of Formula (VII) with an amine source and a nitrile source to provide a compound of Formula (VI) or its acid salts, wherein the compound of Formula (VI) or its acid salts is further cyclized by treating with cyclizing agent to give a compound of Formula (V), which is optionally purified by known purification techniques, further alkylated using an alkylating agent to give a compound of Formula (IV), wherein the compound of Formula (IV) is methylated using a methylating agent to obtain a novel intermediate compound of Formula (III). In the above process, any of the process steps may be carried out in-situ or isolated or purified prior to proceeding with the next step. The amine source used in the above process comprises ammonium salts, ammonium hydroxide, anhydrous ammonia, amines, ammonia gas. The nitrile source used in the above process comprises sodium cyanide, potassium cyanide, trimethylnitrilosilane (TMSCN), potassium ferricyanate and the like or mixtures thereof. The acid addition salts of the compound of Formula (VI) are preferably comprising hydrochloride, hydrobromide, phosphoric acid and sulfuric acid. The cyclizing agent used in the above process comprises sulfur monochloride (S2Cl2), sulfur dichloride (SCl2) and SOCl2. The alkylating agent used in the above process comprises hexanol or its salts preferably sodium, potassium, lithium, sodium t-amylate and the like or mixtures thereof. The methylating agent used in the above process comprises dimethyl sulphate, dimethyl carbonate, nitromethane and methyl sulfonate. The above process steps may be carried out in the presence or absence of a solvent, wherein the solvent comprises water, methanol, ethanol, isopropanol, n- propanol or butanol; dimethylformamide, dimethylsulfoxide, dimethylacetamide, sulfolane, N-methylpyrrolidone, tetrahydrofuran, 2-methyl tetrahydrofuran, MTBE, dichloro methane, toluene, benzene, o-xylene, m-xylene, p-xylene, acetone, acetonitrile and the like or mixtures thereof. In the above process isolation / purification is carried out in the presence of a solvent or an anti-solvent comprises water or methanol, ethanol, isopropanol MTBE, toluene, benzene, o-xylene, m-xylene, p-xylene, acetone, acetonitrile and the like or mixtures thereof. The process of the present invention is depicted below scheme: Scheme-I

[0002] The following example(s) illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention. EXAMPLES: Example 1: Preparation of compound of Formula V. Purified water (300 mL) was added to the ammonium chloride (75 g) at 20-30°C. Reaction mass was stirred for 10-20 minutes and cooled the reaction mass to 0- 10°C. Aqueous ammonia solution (123 g) was added at 0-10°C. Pyridine-3- carboxaldehyde (100 g) was added and then stirred for 80-100 minutes at 0-10°C. In a separate reactor, sodium cyanide (50 g) was charged to purified water (200 mL) at 20-30oC. The reaction mass was stirred for 20-40 minutes. Sodium cyanide solution was added to the above reaction mixture at 0-10°C for ~40 minutes. Temperature was raised to 15-20°C and stirred for ~4 hours. Sodium carbonate (100 g) was charged, stirred for 10-20 minutes. Sodium sulfate (100 g) was charged, stirred for 10-20 minutes. Methylene chloride (1000 mL) was added and stirred for 25-35 minutes. Organic layer was separated. Methylene chloride (1000 mL) was added and stirred for 25-35 minutes. Organic layer was separated. Filter the combined organic layer, evaporated under reduced pressure to give compound of Formula VI. N,N-Dimethylformamide (200 mL) was charged under nitrogen atmosphere, cooled to -5 to 5oC and stirred for 5-10 minutes. Sulfur monochloride (218 g) was added into the above reaction mass at -5 to 5oC which is stirred for 10-20 minutes at -5 to 5oC. Compound of Formula (VI) in N,N-Dimethylformamide (200 mL) was added to the above reaction mass at -5 to 5oC. The reaction mass was stirred for 30- 40 minutes, temperature was raised to 20-30ºC and stirred for 60-90 minutes. Reaction mass was further cooled to 0-10ºC. Chilled purified water (2000 mL) was added into the reaction mass at 0-10ºC and stirred for ~2 hours. Filtered the reaction mass. Charged the Methyl tert-Butyl ether (1300 mL) to the filtrate and adjusted the pH: 10-12 by using ~36% aqueous Sodium hydroxide solution (300 mL) at 0- 10ºC. Raise the reaction mass temperature to 20-30ºC and stir for 30-40 minutes. Filtered the reaction mass and separated the organic layer. Aqueous layer again extracted with Methyl tert-Butyl ether (1300 mL). Combined organic layer washed with brine solution (200 ml) and followed by carbon treatment. Distil the organic layer and co-distilled with acetone. Charged acetone (300 ml) to the distilled mass and raised the reaction mass temperature to 40-50oC. Slowly added the water (930 ml) at 40-50oC and slowly cooled to 5-15oC. Stirred the reaction mass for ~2 hours and filtered the compound to obtain compound of Formula (V). Yield: 62% Example 2: Preparation of compound of Formula IV. Sodium t-amylate (89.2 g) was charged into toluene (900 mL) under nitrogen atmosphere and stirred for 5-15 minutes at 20-30oC.1-Hexanol (81.68 g) was added to the reaction mass at 20-30oC and stirred for 80-100 minutes. The Compound of Formula V (100 g) was charged under nitrogen atmosphere at 20-35oC and the temperature of the reaction mass was raised to 40-50oC, then stirred for ~9 hours. Cooled the reaction mass to 20-30oC. Purified water was added to the reaction mass at 20-35oC and stirred for 10-15 minutes at 20-35oC. The organic layer (~ 800 mL) was separated and distilled under reduced pressure (below 500 mmHg) below 50 °C. Cooled the reaction mass and charged acetone (400 ml) and rise the temperature to 40-50oC. Water added (700 ml) to the above reaction mass and cooled to 0-10oC. Filtered the reaction mass to give compound of Formula (IV). Yield: 90% Example 3: Preparation of compound of Formula III. Toluene (800 mL) was added to compound of Formula (IV) (100 g) under nitrogen atmosphere and stirred for 10-15 minutes at 20-30oC. Dimethyl sulfate (52.68 g) was added to the above reaction mass and stirred for 10-15 minutes then the temperature was raised to 80-90oC and stirred for 9 hours. Then cooled to 20-30oC. The reaction mass was distilled under reduced pressure (below 500 mmHg) below 50 °C. Methyl tert-Butyl ether (500 ml) added to the reaction mass followed by seed. Stir the reaction mass for 2 hours and filtered to obtain the Compound of Formula (III). Example 4: Preparation of compound of Formula II (Xanomeline free base). Methanol (400 mL) was added to compound of Formula (III) (100 g) under nitrogen atmosphere and stirred for 10-15 minutes at 20-30oC then cooled to -30 to -40oC. Sodium borohydride (18 g) dissolved in ~2% aqueous sodium hydroxide solution (112 ml). Sodium borohydride solution was slowly added for ~3 hours and the reaction mass was stirred for 50-60 minutes. Then the temperature was raised to - 5 to 0oC and pH was adjusted with Conc. HCl to 2-3 at 0 to 10oC. Purified water (1000 mL) was charged to the reaction mass at 0-30oC. MTBE (1600 mL) was added and stirred for 20-30 minutes.10% w / v aqueous sodium hydroxide solution was added to the reaction mass to adjust pH to 8-9 at 20-30oC and the reaction mass stirred for 20-30 minutes at 20-30oC. The Organic layer was separated. Organic layer washed with water (3x600 ml). Organic layer treated with activated Carbon. The Organic layer (~1600 mL) was distilled under reduced pressure (below 500 mmHg) below 45 °C to give Xanomeline free base i.e compound of Formula (II). Example 5: Preparation of compound of Formula I (Xanomeline tartrate). Acetone (240 mL) was added to Xanomeline free base of Formula (II) under nitrogen atmosphere and stirred for 10-15 minutes at 20-30oC. L-Tartaric acid (47.5 g) was charged and stirred for 10-20 minutes. The temperature was raised to 45- 55oC and stirred for 50±10 minutes. The reaction mass was cooled to 20-30oC and Xanomeline Tartrate Seed was added to the reaction mass and stirred for 40±10 minutes at 20-30oC. The reaction mass was cooled to 0-5oC and stirred for 50±10 minutes. Reaction mass was filtered and suck dried. Filter cake was washed with chilled acetone (2 x 100 mL) to give Xanomeline Tartrate crude. Acetone (500 mL) was added to Xanomeline Tartrate crude and stirred for 10-15 minutes. Raised the reaction mass temperature to 40-50oC and cooled the reaction mass temperature to 20-30oC and stirred for 60-90 minutes. The above reaction mass was filtered and suck dried then washed with acetone (100 mL) to give wet Xanomeline tartrate of Formula (I). Charged acetone (900 ml) to wet Xanomeline tartrate and rise the temperature to 45-55oC followed by water (30 ml) addition. Reaction mass treated with carbon and distil the reaction mass to ~150 ml under reduced pressure. Charged acetone (350 ml) to the reaction mass and distil the reaction mass to ~200 ml under reduced pressure. Charged acetone (800 ml) and raised the temperature to 45-55oC, then slowly cool the reaction mass 20-25oC and stir for 2 hours. Filter the compound and wash with acetone to obtain Xanomeline tartrate of Formula (I) which is dried under reduced pressure (~100 mmHg) till LOD content is NMT 0.5% w / w. Yield: ~ 60%

Claims

WE CLAIM:

1. A process for the preparation of Xanomeline tartrate of Formula (I),which comprises: a) reducing compound of Formula (III),wherein, X comprises methyl sulphate, methyl carbonate, nitrate and sulfonate; with a reducing agent to give Xanomeline free base compound of Formula (II); andb) converting Xanomeline free base of Formula (II) to Xanomeline tartrate of Formula (I), which is optionally purified by known purification techniques.

2. A process for the preparation of pure Xanomeline tartrate of Formula (I), which comprises, treating Xanomeline free base of Formula (II) with L-tartaric acid in presence of a solvent to form Xanomeline tartrate and optional seeding the mixture to produce pure Xanomeline tartrate of Formula (I).

3. The process, as claimed in claims 1 and 2, wherein the reducing agent comprises lithium borohydride, sodium borohydride, potassium borohydride, boron hydride, aluminum hydride, an organic magnesium compound and an organic lithium compound and the like or mixtures thereof; wherein the solvent comprises water, alcohol or ketonic solvents comprises methanol, ethanol, propanol, butanol, isopropanol, isobutanol, acetone, diethyl ketone, methyl ethyl ketone, methyl propyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone and the like or mixtures thereof, preferably acetone; or alcohols comprises methanol, ethanol, isopropanol, n-propanol or butanol; tetrahydrofuran, diethyl ether, methyl tert-butyl ether or diisopropyl ether and the like or mixtures thereof.

4. An intermediate compound of Formula (III);wherein X comprises methyl sulphate, methyl carbonate, nitrate and sulfonate.

5. A process for the preparation of novel intermediate of Formula (III);wherein X comprises methyl sulphate, methyl carbonate, nitrate and sulfonate; which comprises: a) condensing a compound of Formula (VII),Formula (VII) with an amine source followed by with a nitrile source to obtain a compound of Formula VI or a salt thereof; Formula (VI)b) cyclizing the compound of Formula (VI) or a salt thereof, by treating with a cyclizing agent to give a compound of Formula (V), which is optionally purified known purification techniques; Formula (V)c) reacting the compound of Formula (V) with an alkylating agent to obtain a compound of Formula (IV); andd) methylating the compound of Formula (IV) with a methylating agent to obtain the novel intermediate compound of Formula (III).

6. The process, as claimed in claim 4, wherein the amine source comprises ammonium salts, ammonium hydroxide, anhydrous ammonia, amines, ammonia gas.

7. The process, as claimed in claim 4, wherein the nitrile source comprises sodium cyanide, potassium cyanide, trimethylnitrilosilane (TMSCN), potassium ferricyanate and the like or mixtures thereof.

8. The process, as claimed in claim 4, wherein the cyclizing agent comprises sulfur monochloride (S2Cl2), sulfur dichloride (SCl2) and SOCl2.

9. The process, as claimed in claim 4, wherein the alkylating agent comprises hexanol or its salts preferably sodium, potassium, lithium, sodium t-amylate and the like or mixtures thereof.

10. The process, as claimed in claim 4, wherein the methylating agent comprises dimethyl sulphate, dimethyl carbonate, nitromethane and methyl sulfonate.

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