The present invention relates to an industrially feasible and improved process for the preparation of Remdesivir of Formula XI and intermediates thereof. The present invention provides acid addition salt of Formula V, which is further used for the preparation of intermediate compound of Formula VI. The intermediate compound of Formula V is further used for the preparation of Remdesivir.

BACKGROUND OF THE INVENTION

Remdesivir is a broad-spectrum antiviral medication developed by the biopharmaceutical company Gilead Sciences. Remdesivir is useful for the treatment of Filoviridae virus infections such as Marburg virus, Ebola virus and Cueva virus infections. Remdesivir is an investigational antiviral compound undergoing clinical trials in a number of countries as a potential treatment for COVID-19. The chemical name for Remdesivir is (2S)-2-{(2R,3S,4R,5R)-[5-(4-aminopyrrolo[2,1-f] [1,2,4] triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydro-furan-2-ylmethoxy]phenoxy-(S)-phosphorylamino}propionic acid 2-ethyl-butyl ester. The CAS Registry Number of Remdesivir is [1809249-37-3] which has the following structure

U.S. Patent No. 9724360 discloses riboside phosphates and prodrugs thereof, which includes Remdesivir and pharmaceutically acceptable salts thereof. Synthetic schemes for the preparation of these riboside derivatives are disclosed in this patent.

PCT Publication WO2009132135A1 discloses the process for the preparation of compound of Formula IV by coupling compound of Formula II with halopyrazole compound of Formula III and finally purifying compound of Formula IV by Column chromatography using (0-50% Ethyl acetate: hexanes).

PCT Publication WO2011035250A1 discloses the process for the preparation of compound of Formula IV by coupling compound of Formula II with halopyrazole compound of Formula III in the presence of tetrahydrofuran as solvent. The purity of thus obtained compound of Formula IV is very low, which is further purified by Column chromatography to provide 1:1 mixture of anomers. Therefore, this route is not commercially viable.

The known processes suffer from problems, such as a cumbersome purification by column chromatography and low yields. Prior art disclosed isolation / purification of compound of Formula IV by column chromatography which is cumbersome and commercially not viable. In view of the preparation methods available for Remdesivir, there is a need for simple, industrially scalable and environmentally-friendly processes for the preparation of Remdesivir that is free from above mentioned drawbacks and achieves high yield and purity.

The prior art process provides an impure reaction mixture having purity of intermediate compound of formula IV as low as 40%, which necessitate the isolation/purification of compound of formula IV by column chromatography which is cumbersome and commercially not viable. The inventors of the present invention have observed that purity of intermediate compound of formula IV is improved by forming acid addition salt without the involvement of column chromatography, which allows a convenient and efficient synthesis of Remdesivir of Formula XI.

OBJECT OF THE INVENTION

It is a principal object of the present invention to improve upon limitations in the prior arts by providing a process for the preparation of Remdesivir.

It is another object of the present invention to provide a simple, commercially viable and environment friendly process for preparing Remdesivir, in high yield and purity.

It is still another object of the present invention to provide an improved and commercially viable process for the preparation of Remdesivir, via compound of Formula V.

It is yet another object of the present invention to provide an acid addition salt of compound of Formula IV i.e. intermediate compound of Formula V.

It is yet another object of the present invention to provide a process for the preparation of an intermediate compound of Formula V.

It is still another object of the present invention to provide highly pure compound of Formula IV, without use of chromatographic methods.

It is yet another object of the present invention to provide compound of Formula V having purity about more than 90%, preferably about more than 95%.

It is still another object of the present invention to provide Remdesivir substantially free of impurities.

SUMMARY OF THE INVENTION

According to one aspect of the present invention there is provided an improved process for the preparation of Remdesivir of Formula XI, as shown in Scheme 1.

According to another aspect of the present invention there is provided an improved process for the preparation of intermediate of Formula V, as shown in Scheme 1.

Scheme 1:

It has been found that Remdesivir is efficiently prepared from intermediate compound of Formula V as shown in Scheme 1. This compound of Formula V is an acid addition salt of compound of Formula IV. This intermediate compound of Formula V is easily isolable with better purity, which finally help in achieving Remdesivir in better yield and purity.

DESCRIPTION OF THE INVENTION

The present invention (Scheme 1) relates to a process for the preparation of Remdesivir of Formula XI comprising the steps of:
(a) Converting lactol of Formula I to compound of Formula II;

(b) coupling compound of Formula II with halopyrazole compound of Formula III to obtain compound of Formula IV with or without its isolation;

wherein Y is halogen selected from the group comprising of Cl, Br or I.

(c) subjecting the said compound of Formula IV or reaction mixture of step (b) with an acid to obtain compound of Formula V;

wherein A is an organic acid selected from the group comprising of oxalic acid, tartaric acid, maleic acid, succinic acid, acetic acid, triflic acid, benzoic acid, trifluoroacetic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, benzenesulfonic acid, ethanesulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine and the like.

(d) converting the compound of Formula V to obtain compound of the Formula VI;

(e) converting the compound of Formula VI to obtain compound of the Formula VII;

(f) converting the compound of Formula VII to obtain compound of the Formula VIII;

(g) coupling the compound of Formula VIII with compound of Formula IX to obtain compound of the Formula X; and

(h) converting the compound of Formula X to obtain Remdesivir of the Formula XI.

In step (a) of Scheme 1, conversion of lactol of Formula I is carried out in an organic solvent with reagent selected from the group comprising of anhydrides such as acetic anhydride, acetic propionic anhydride, acetic butyric anhydride, maleic anhydride, glutaric anhydride and the like or mixtures thereof, preferably acetic anhydride. In step a) an organic solvent is selected from the group comprising of sulfoxides such as dimethyl sulfoxide, dimethyl sulfone; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylformamide, N-methylpyrrolidone and the like or mixtures thereof.

In step (b) of Scheme 1, compound of Formula II is coupled with halopyrazole compound of Formula III with or without isolation of compound of Formula IV. This coupling is carried out with Grignard reagent selected from the group comprising of CH3MgBr, iPrMgCl, tBuMgCl, PhMgCl or iPrMgCl.LiCl or combinations thereof; or trimethylsilyl chloride (TMSCl). This coupling is carried out in presence of an organic solvent selected from the group comprising of ethers such as dimethyl ether, diethyl ether, methyl tert-butyl ether (MTBE), diisopropyl ether, tetrahydrofuran (THF), dioxane and the like or mixtures thereof. Preferably, an organic solvent is tetrahydrofuran (THF).

In step (c) of Scheme 1, compound of Formula IV is converted to compound of Formula V with an acid in an organic solvent. Acid is an organic acid selected from the group comprising of oxalic acid, tartaric acid, maleic acid, succinic acid, acetic acid, triflic acid, benzoic acid, trifluoroacetic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, benzenesulfonic acid, ethanesulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine and the like. Organic acid is preferably oxalic acid. The organic solvent is selected from the group comprising of alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and the like, ketones such as acetone, butanone, methyl ethyl ketone, methyl isobutyl ketone and the like, esters such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and the like, halogenated hydrocarbons such as dichloromethane (DCM), chloroform, dichloroethane, chlorobenzene and the like or mixtures thereof.

HPLC chromatographic conditions for measuring purity of compound of Formula IV and compound of Formula V are as follows:
Mobile Phase-A: 10Mm Ammonium hydrogen phosphate in 1L: ACN (95:5)
Mobile Phase-B: ACN
Column: Inertsil ODS 3V, (250×4.6) mm, 3µm
Column Temperature: 35C
Flow rate: 1.0 mL per minute
Injection Volume: 10mL

In step (d) of Scheme 1, conversion of compound of Formula V to compound of Formula VI is carried out in an organic solvent and reagent. The reagent is selected from the group comprising of trimethylsilyl cyanide (TMSCN), p-Toluenesulfonylmethyl Isocyanide (TosMIC), acetone cyanohydrin, Diethyl Cyanophosphonate and the like; trimethylsilyl)trifluoromethylsulfonate (TMSOTf), trimethylsilyl chloride and the like or combinations thereof. The organic solvent is selected from the group comprising of halogenated hydrocarbons such as dichloromethane (DCM), chloroform, dichloroethane, chlorobenzene and the like, aliphatic hydrocarbons such as alkanes or cycloalkanes such as pentane, hexane, heptane, octane, cyclohexane, cyclopentane and the like; aromatic hydrocarbons such as toluene, xylene and the like or mixture thereof.

In step (e) of Scheme 1, conversion of compound of Formula VI to compound of Formula VII is carried out in an organic solvent selected from the group comprising of halogenated hydrocarbons such as dichloromethane (DCM), chloroform, dichloroethane, chlorobenzene and the like or mixtures thereof; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and the like. Preferably, an organic solvent is dichloromethane.

In step (f) of Scheme 1, conversion of compound of Formula VII to compound of Formula VIII is carried out in an organic solvent selected from the group comprising of acetone, butanone, methyl ethyl ketone, methyl isobutyl ketone, methyl amyl Ketone, di-isobutyl ketone, cyclohexanone methanol, ethanol, n-propanol, isopropanol, n-butanol.

In step (g) of Scheme 1, coupling of compound of Formula VIII with compound of Formula IX to compound of Formula X is carried out in an organic solvent selected from the group comprising of nitriles such as acetonitrile, propionitrile, butyronitrile. This coupling is carried out in presence of base selected from group comprising of methyl amine, ethyl amine, diisopropyl ethyl amine, triethyl amine, tributyl amine, N-methyl morpholine; preferably sodium hydroxide. This coupling is carried out in with reagents such as magnesium chloride, aluminum chloride, ferric chloride, cuprous chloride and the like or mixture thereof.

In step (h) of Scheme 1, compound of Formula X is converted to Remdesivir of Formula XI with reagents such as hydrochloric acid, sulfuric acid and like thereof in an organic solvent. The organic solvent is selected from the group comprising of ethers such as dimethyl ether, diethyl ether, methyl tert-butyl ether (MTBE), diisopropyl ether, tetrahydrofuran (THF), dioxane and the like or mixtures thereof.

Further, compound of Formula VII may be converted to Remdesivir of Formula XI by any methods known in prior art.
Further, when organic acid (A) in step (c) is oxalic acid then compound of formula V’ is as follows-

The present invention also relates to process for the preparation Remdesivir, wherein compound of Formula V is prepared by process comprising the steps of:

(a) Converting lactol of Formula I to compound of Formula II;

(b) coupling compound of Formula II with halopyrazole compound of Formula III to obtain compound of Formula IV with or without its isolation;

wherein Y is halogen selected from the group comprising of Cl, Br or I.
(c) subjecting the said compound of Formula IV or reaction mixture of step (b) with an acid to obtain compound of Formula V; and


wherein A is an organic acid selected from the group comprising of oxalic acid, tartaric acid, maleic acid, succinic acid, acetic acid, triflic acid, benzoic acid, trifluoroacetic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, benzenesulfonic acid, ethanesulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine and the like.
(d) Converting compound of Formula V to Remdesivir.

In step (a) of Scheme 1, conversion of lactol of Formula I is carried out in an organic solvent with reagent selected from the group comprising of anhydrides such as acetic anhydride, acetic propionic anhydride, acetic butyric anhydride, maleic anhydride, glutaric anhydride and the like or mixtures thereof, preferably acetic anhydride. In step a) an organic solvent is selected from the group comprising of sulfoxides such as dimethyl sulfoxide, dimethyl sulfone; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylformamide, N-methylpyrrolidone and the like or mixtures thereof. Preferably, an organic solvent is dimethyl sulfoxide.

In step (b) of Scheme 1, compound of Formula II is coupled with halopyrazole compound of Formula III with or without isolation of compound of Formula IV. This coupling is carried out with Grignard reagent selected from the group comprising of CH3MgBr, iPrMgCl, tBuMgCl, PhMgCl or iPrMgCl.LiCl or combinations thereof; or trimethylsilyl chloride (TMSCl). This coupling is carried out in presence of an organic solvent selected from the group comprising of ethers such as dimethyl ether, diethyl ether, methyl tert-butyl ether (MTBE), diisopropyl ether, tetrahydrofuran (THF), dioxane and the like or mixtures thereof. Preferably, an organic solvent is tetrahydrofuran (THF).

In step (c) of Scheme 1, compound of Formula IV is converted to compound of Formula V with an acid in an organic solvent. Acid is an organic acid selected from the group comprising of oxalic acid, tartaric acid, maleic acid, succinic acid, acetic acid, triflic acid, benzoic acid, trifluoroacetic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, benzenesulfonic acid, ethanesulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine and the like. Organic acid is preferably oxalic acid. The organic solvent is selected from the group comprising of alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and the like, ketones such as acetone, butanone, methyl ethyl ketone, methyl isobutyl ketone and the like, esters such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and the like, halogenated hydrocarbons such as dichloromethane (DCM), chloroform, dichloroethane, chlorobenzene and the like or mixtures thereof. Preferably, an organic solvent is ethyl acetate.

The present invention relates to process for the preparation of Remdesivir of Formula XI via an intermediate compound of Formula V, which is acid addition salt of compound of Formula IV. This intermediate compound of Formula V is easily isolable with better purity, which finally help in achieving Remdesivir in better yield and purity. In the present invention, compound of Formula V is prepared to isolate in salt form from an impure reaction mixture of compound of Formula IV. The present invention relates to process which improve the purity of compound of Formula IV to about more than 90% by HPLC.

A pharmaceutical composition comprising a therapeutically effective amount of a Remdesivir of the Formula XI

The antiviral activity of Remdesivir of the Formula XI as prepared by methods of present invention is measured using standard screening protocols that are known.
The process for the preparation of Remdesivir described in the present invention is demonstrated in the examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
EXAMPLES

Example 1: Preparation of compound of Formula II
The commercially available lactol of Formula I (10 g) was dissolved in anhydrous DMSO (30 mL) under nitrogen. Acetic anhydride (20 mL) was added and the resultant reaction mixture was stirred at RT for about 48 h. The reaction mixture was poured onto ice water (500 mL) and the mixture stirred for 20 min. The mixture was extracted with EtOAc (3x200 mL) and the combined organic extracts were then washed with water (3x200 mL). The organic extract was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure to provide the lactone of Formula II.

Example 2: Preparation of compound of Formula IV
The iodopyrazole of Formula III (75.0 g) was dissolved in THF (1500 ml) and the solution was cooled to about 0°C with stirring under nitrogen. Trimethylsilyl chloride (TMSC1) (62 g) was added and after about 30 min phenyl magnesium chloride (2.0 ? in THF, 280 ml) was slowly added. The reaction mixture was cooled to about -20°C to -15°C and iso-propyl magnesium chloride-lithium chloride complex (1.3 ? in THF, 233 ml) was slowly added. After about 1 h, solution of lactone of Formula II (120 g) in DCM (375 g) was added slowly and the resulting reaction mixture was stirred for about 1.5 h. Then ammonium chloride solution (1100 ml) was added and the mixture was warmed to about 15°C and ethyl acetate (1500 ml) was added and washed the organic layer with 1N hydrochloric acid and then with 5% NaHCO3 solution. Dried the organic layer over sodium sulfate. Finally, the organic layer was evaporated to give the product as an oily mass.
Yield: 120 g

Example 3: Preparation of compound of Formula V (Oxalate salt)
The compound of formula IV (10 g) was heated with MTBE (100 mL) at 60-65°C for 1 h and gradually cooled to 0-5°C and stirred for 10-12 h. Precipitated solid was filtered, washed with MTBE and suck dried. The suck dried material was dissolved in MTBE (80 mL) and treated with oxalic acid (0.81 g) at ambient temperature for 2.5 h. Then the reaction mixture was cooled to 0-5oC and the precipitated solid was filtered. Finally, dried the product under vacuum to yield the desired oxalate salt of formula V.
Yield: 3.8 g
Purity: 97.8%

Example 4: Preparation of compound of Formula V (Oxalate salt)
The compound of formula IV (10 g) was heated with MTBE (100 mL) at 60-65°C for 1 h and gradually cooled to 0-5°C and stirred for 10-12 h. Precipitated solid was filtered, washed with MTBE and suck dried. The suck dried material was dissolved in Ethyl acetate (40 mL) and treated with oxalic acid (0.81 g) at ambient temperature for 2.5 h. Then the reaction mixture was cooled to 0-5oC and the precipitated solid was filtered. Finally, dried the product under vacuum to yield the desired oxalate salt of formula V.
Yield: 3.2 g
Purity: 97.06%

Example 5: Preparation of compound of Formula V (Oxalate salt)
The compound of formula IV (10 g) was heated with MTBE (100 mL) at 60-65°C for 1 h and gradually cooled to 0-5°C and stirred for 10-12 h. Precipitated solid was filtered, washed with MTBE and suck dried. The suck dried material was dissolved in THF (20 mL) : MTBE (20 mL) and treated with oxalic acid (0.81 g) at ambient temperature for 2.5 h. Then the reaction mixture was cooled to 0-5oC and the precipitated solid was filtered. Dried the solid under vacuum to yield the desired oxalate salt.
Yield: 2 g
Purity: 97.9%

Example 6: Preparation of compound of Formula V (Oxalate salt)
The iodopyrazole of Formula III (75.0 g) was dissolved in THF (1500 ml) and the solution was cooled to about 0°C with stirring under nitrogen. Trimethylsilyl chloride (TMSC1) (62 g) was added and after about 30 min phenyl magnesium chloride (2.0 ? in THF, 280 ml) was slowly added. The reaction mixture was cooled to about -20°C to -15°C and iso-propyl magnesium chloride-lithium chloride complex (1.3 ? in THF, 233 ml) was slowly added. After about 1 h, solution of lactone of Formula II (120 g) in DCM (375 g) was slowly added and the resulting reaction mixture was stirred for about 1.5 h. Ammonium chloride solution (1100 ml) was added and the mixture was warmed to about 15°C and then ethyl acetate (1500 ml) was added and washed the organic layer with 1N hydrochloric acid and then with 5% NaHCO3 solution. Dried the organic layer over sodium sulfate and filtered it. Then charged organic layer and Oxalic acid and stirred the reaction mass at 25-30°C for 3-4 h. Filtered the product and washed with ethyl acetate. Dried the product under 25-30°C to get final product.
Yield: 74 g

Example 7: Preparation of compound of Formula VI
Charged the compound of Formula V (Oxalate salt) (10 g) and Dichloromethane (150 mL) at 25-30°C and stirred for 25-30 min. Cooled the solution to -80° to -78°C. Slowly added Trifluoromethane sulfonic acid (5.32 g) at -80° to -78°C drop wise over a period of 25-30 min. Slowly added Trimethylsilyl trifluoromethane sulfonate (20.75 g) at -80° to -78°C drop wise over a period of 25-30 min. Prepared a solution of Trimethylsilyl cyanide (9.26g) in Dichloromethane (500 mL) and added to the above reaction mass at -80 to -78°C. Stirred the reaction mass at -80 to -78°C for 20-30 min. Prepared 20% w/w aqueous potassium hydroxide solution (1200 mL), cooled the solution to -10° to -5°C, and added this aqueous potassium hydroxide solution to the above reaction mass. Gradually raised the temperature of the reaction mass to 25-30°C in 1-2 h. organic layer was separated and washed with 10% sodium chloride solution (500 mL x 3). Filtered the organic layer through Hyflo bed and washed with dichloromethane (100 mL). Concentrated the reaction mass at NMT 40°C under vacuum. Charged IPA (50 mL) and heated the reaction mass to 45-50°C. Gradually cooled the reaction mass to 25-30°C and stirred for 3-4h. Filtered the product and washed with IPA (10 mL) Dried the product under vacuum at 35-40°C for 5-6 h.
Yield: 7.5 g

Example 8: Preparation of compound of Formula VII
Charged the compound of Formula VI (60 g) and Dichloromethane (300 mL) at 25-30°C and stirred for 25-30 min. Cooled the reaction mixture to -30° to -20°C. Slowly added solution of 1M Boron trichloride solution (510g) at -30°C to -20°C in 3h. Slowly methanol (420 mL) was added to it and raised the temperature to 15-20°C and stirred for NLT 12h. Filtered the reaction mass and washed with MeOH (120 mL) and sucked to dryness the wet cake for 30-60 min.(wet cake:35.0g). Charged wet cake & charged premixed 1N HCl (80.4g) & MeOH (120mL) at RT and stirred for 8-10h at 15-20°C (wet cake:30.0g). Charged wet cake at 19-25°C and water (300mL) and adjust the pH (NLT 8.0) with 20% aqueous K2CO3 solution (12g K2CO3 dissolved in 60 mL DM water) at RT. Stirred for 1h at 20-25°C and filtered the solid and washed with DM water (180mL) & MeOH (60mL). Sucked to dryness under vacuum for 45-60 min (wet cake: 25g). Finally, dried the product at NMT 60°C under vacuum for 4-6 hr.
Yield: 24 g;
Purity by HPLC (%): 99.11%

Example 9: Preparation of compound of Formula VIII
Charged the compound of Formula VII (100 g) and acetone (700 mL) at 25-30°C. Charged 2,2-Dimethoxy propane (178 g) and p-TSA (72 g) to reaction mixture. at RT and stirred for 6h. Charged isopropyl acetate (700 mL) and stirred for 2-3h. Filtered the reaction mixture, washed the wet cake with of isopropyl acetate (100 mL). Charged wet cake, ethyl acetate (1000mL), DM water (100mL) and adjusted the pH (NLT 9.0) with 10% w/v aqueous potassium carbonate solution (50g K2CO3 dissolved in 500mL DM water at RT. Separated the layer and washed the organic layer with DM water (2x500mL). Charged organic layer and charcoal (10g) and heated to 35-40°C under stirring for 25-30min. Filtered the reaction mixture through hyflo bed & washed with ethyl acetate (100mL). Charged the filtrate and distilled out under vacuum at temperature NMT 50ºC up to 4-5V residual mass. Gradually cooled the mass to 25-30°C over a period of 2h. Charged n-Heptane (1000mL) over a period of 4h at 25-30°C and cooled it to 10-15°C and stirred for 2h. Filtered the solid at 10-15°C and washed with n-Heptane (200 mL). Sucked to dryness under vacuum for 45-60 min and finally dried the product under vacuum at temperature NMT 50°C for 4-6h
Yield: 93 g;
Purity by HPLC (%): 99.8%

Example 10: Preparation of Remdesivir
Charged the compound of Formula VIII (100 g) and compound of Formula IX (149.5 g) with THF (1000 mL) at RT. Then anhydrous Magnesium chloride (43.10 g) was added to it. DIPEA (96.74 g) was added drop wise at NMT 27°C over a period of 1 hr and stirred it for 2-4 h. The reaction mixture was cooled to 5-10°C and Ethyl acetate (1000 mL) and chilled 10% w/v aqueous citric acid solution (1000 mL) was added Slowly raised the temperature and stirred it for 30-45 min 20-25°C. Layers were separated and organic layer was mixed with 10% w/v aqueous citric acid solution (1000 mL) and again layers were separated. Washed organic layer with 10% w/v aqueous K2CO3 solution (3x 750 mL) and then 10% w/v aqueous NH4Cl solution (1000 mL) was added to the organic layer and stirred it for 15-20 min. Finally, after layer separation, organic layer was concentrated under vacuum until 2.5-3.0 volumes of residual mass. Then, Acetonitrile (1000 mL) was added and distilled under vacuum at NMT 50°C until 2.5-3.0 volumes residual mass. Cooled the reaction mass to RT and acetonitrile (900 mL) was added. Cooled the reaction mass to 0°C and slowly added precooled (0-5°C) Conc. HCl (241.23 g) and stirred for 2 h. Charged Ethyl acetate (1000 mL) and pH was adjusted using 20% w/v aqueous KHCO3 solution (~1300 mL) and layers were separated and the organic layer was concentrated under vacuum at NMT 45°C until 2-2.5 volumes of residual mass. Ethyl acetate (650 mL) was added to reaction mixture and heated to 50-55°C. Then DIPE (900 mL) was added at 50-55°C and gradually cooled it to 25-30°C. Filter the solid under vacuum at 25-30°C and washed with DIPE (200 mL). Suck dried it under vacuum for 15-20 min and finally dried the product under vacuum at NMT 45°C for 4-6 h.

WE CLAIM

1.A process for the preparation of Remdesivir of Formula XI comprising the steps of:
(a) converting lactol of Formula I to compound of Formula II;

(b) coupling compound of Formula II with halopyrazole compound of Formula III to obtain compound of Formula IV with or without its isolation;

wherein Y is halogen selected from the group comprising of Cl, Br or I.

(c) subjecting the compound of Formula IV or reaction mixture of step (b) with acid to obtain compound of Formula V;

wherein A is an organic acid selected from the group comprising of oxalic acid, tartaric acid, maleic acid, succinic acid, acetic acid, triflic acid, benzoic acid, trifluoroacetic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, benzenesulfonic acid, ethanesulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine and leucine.

(d) converting the compound of Formula V to obtain compound of the Formula VI;

(e) converting the compound of Formula VI to obtain compound of the Formula VII;

(f) converting the compound of Formula VII to obtain compound of the Formula VIII;

(g) coupling the compound of Formula VIII with compound of Formula IX to obtain compound of the Formula X; and

(h) converting the compound of Formula X to obtain Remdesivir of the Formula XI.

2. The process as claimed in claim 1, wherein step (a) is carried out with reagent selected from the group comprising of acetic anhydride, acetic propionic anhydride, acetic butyric anhydride, maleic anhydride, glutaric anhydride.

3. The process as claimed in claim 1, wherein step (b) is carried out with Grignard reagent selected from the group comprising of CH3MgBr, iPrMgCl, iPrMgCl.LiCl, tBuMgCl, PhMgCl and combinations thereof.

4. The process as claimed in claim 1, wherein step (c) is carried out with an acid selected from the group comprising of oxalic acid, tartaric acid, maleic acid, succinic acid, acetic acid, triflic acid, benzoic acid, trifluoroacetic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, benzenesulfonic acid, ethanesulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine and leucine.

5. The process as claimed in claim 1, wherein step (d) is carried out with reagent selected from the group comprising of trimethylsilyl cyanide (TMSCN), p-toluenesulfonylmethyl isocyanide (TosMIC), acetone cyanohydrin, diethyl cyanophosphonate, trimethylsilyl)trifluoromethylsulfonate (TMSOTf), trimethylsilyl chloride.

6. The process as claimed in claim 1, wherein step (g) is carried out with reagent selected from the group comprising of magnesium chloride, aluminum chloride, ferric chloride, cuprous chloride or mixture thereof.

7. A process for the preparation Remdesivir, wherein compound of Formula V is prepared by process comprising the steps of:
(a) converting lactol of Formula I to compound of Formula II;

(b) coupling compound of Formula II with halopyrazole compound of Formula III to obtain compound of Formula IV with or without its isolation;

wherein Y is halogen selected from the group comprising of Cl, Br or I.

(c) subjecting the said compound of Formula IV or reaction mixture of step (b) with acid to obtain compound of Formula V; and

wherein A is an organic acid selected from the group comprising of oxalic acid, tartaric acid, maleic acid, succinic acid, acetic acid, triflic acid, benzoic acid, trifluoroacetic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, benzenesulfonic acid, ethanesulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine and leucine.

(d) Converting compound of Formula V to Remdesivir.

8. The compound of Formula V

wherein A is an organic acid selected from the group comprising of oxalic acid, tartaric acid, maleic acid, succinic acid, acetic acid, triflic acid, benzoic acid, trifluoroacetic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, benzenesulfonic acid, ethanesulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine and leucine.

9. The compound of Formula V as claimed in claim 8, wherein organic acid A is oxalic acid.

10. Use of compound of Formula V for the preparation of Remdesivir of Formula XI.