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Title:
PROCESS FOR THE PREPARATION OF DERIVATIVES OF 5-FLUORO PYRIMIDINES USED AS ANTI CANCER AGENTS
Document Type and Number:
WIPO Patent Application WO/2022/049462
Kind Code:
A1
Abstract:
The present invention relates to an improved process for the preparation of (2R, 3R, 4R, 5R)-2-(5-fluoro-2-oxo-4-(2-propylpentanamido)pyrimidin-1-(2H)-yl)-5-methyl tetrahydrofuran-3,4-diyl diacetate also disclosed is its purification method by suspending or dissolving the crude in an appropriate solvent, removing the insoluble matter by filtration, and condensing the filtrate. The process is useful for producing (2R, 3R, 4R, 5R)-2-(5-fluoro-2-oxo-4-(2-propylpentanamido)pyrimidin-1-(2H)-yl)-5-methyl tetrahydrofuran-3,4-diyl diacetate with high yield and purity % through a simple procedure.

Inventors:
KANDULA MAHESH (IN)
Application Number:
PCT/IB2021/057813
Publication Date:
March 10, 2022
Filing Date:
August 26, 2021
Export Citation:
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Assignee:
CELLIX BIO PRIVATE LTD (IN)
International Classes:
C07D487/04
Domestic Patent References:
WO2020026054A12020-02-06
WO2018002739A12018-01-04
Foreign References:
EP0602478B11996-07-31
Attorney, Agent or Firm:
THOMAS, Santhamma (IN)
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Claims:
CLAIMS I Claim: 1. A process for producing compound of formula I, comprising: Formula I a) preparing of 2-propylpentanoyl chloride; b) condensation of 2’,3’-Di-O-Acetyl-5’-deoxy-5-fluorocytidine with propylpentanoyl chloride from step a) to obtain compound of formula I; and c) compound of formula I obtained from step b) is subjected to purification of the compound of formula I in presence of the suitable organic solvents. 2. The process according to claim 1, wherein the 2-propylpentanoyl chloride of step a) is prepared by reacting the ice cold stirred solution of 2-propylpentanoic acid in organic solvent with oxalyl chloride. 3. The process according to claim 1, wherein the condensation reaction of step b) comprises adding 2-propylpentanoyl chloride to a reaction mixture comprising 2’,3’-Di-O-Acetyl-5’- deoxy-5-fluorocytidine suspended in an organic solvent with a suitable base and in presence of an N- acylation catalyst to form compound of formula I, further the compound of formula I is extracted in step wise manner. 4. The process according to claim 3, wherein the compound of formula I is extracted from the condensation reaction mixture by first charging with water resulting in formation of a upper aqueous and a bottom organic layer. 5. The process according to claim 3 wherein the organic layer is separated, from the aqueous layer and sequentially washed with water, HCl, and saturated aqueous sodium bicarbonate solution and brine and further dried, filtered and distilled to extract compound of formula I.

6. The process according to claim 5 wherein the extract compound of formula I is dissolved in heptane and filtered and washed again with heptane further dried under vacuum to obtain purified form of compound of formula I. 7. The process according to claim 1, catalyst used for the condensation reaction is N-acylation catalyst wherein the N-acylation catalyst is selected from 4-dimethylaminopyridine, diisopropylamine, 1-hydroxybenzotriazole, 2-pyridone, 1,4-diazabicyclo[2.2.2]octane, 1,8- diazabicylco [5.4.0]undec-7-ene, and 2,6-lutidine, 4-pyrrolidinopyridine, 2-hydroxypyridine, tributylphosphine, 1-methylimidazole, Aluminum chloride, Iron chloride, Galium trichloride, Antimony pentachloride, Zinc Chloride, Stannous chloride, Aluminum Bromide, Iron Bromide, Stannic chloride, Gallium tribromide, Hydrogen Flouride, Boron trifluoride, trimethylsilyl trifluoromethane sulfonate, platinum, palladium, or rhodium in concentrated sulfuric acid, or a mixture thereof. 8. The process according to claim 3, wherein the bases is selected from organic bases such as Organolithiums, Grignard reagents, Amines, trimethylamine (TEA), N-heterocyclic compounds, Tetra alkylammonium compounds and phosphonium hydroxides, Metal alkoxides and amides and metal silanoates such as n-butyllithium, sec-butyllithium, tert- butyllithium, hexyllithium, isopropyllithium, butylmagnesium chloride, isopropylmagnesium chloride, propylmagnesium chloride, sec-butylmagnesium chloride solution, tert- butylmagnesium chloride, 2-tert-butyl-1,1,3,3-tetramethylguanidine, ethylmagnesium bromide, ethylmagnesium chloride, hexylmagnesiumchloride, isobutylmagnesiumchloride, 2,2,6,6-Tetramethylpiperidine, 4-(dimethylamino)pyridine, N,N diisopropylmethylamine, diethylamine, Morpholine, Piperidine, (Piperidinomethyl)polystyrene,4- (Dimethylamino)pyridin, N-Ethyldiisopropylamine, Lithium tert-butoxide , Barium tert- butoxide , Magnesium di-tert-butoxide, Magnesiumethoxide, Potassiumethoxide, Sodium tert-butoxide, Tetrabutylammonium hydroxide, Tetramethylammonium hydroxide solution, Trimethylphenylammonium hydroxide, Tetrapropylammoniumhydroxide ,Tetrahexylammonium hydroxide solution , Sodium tert-pentoxide, Sodium ethoxide, Sodium tert-butoxide, Potassium tert-butoxide,Lithiumisopropoxide Lithiumethoxide,Lithium tert- butoxide, Barium tert-butoxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium methoxide and similar lithium, potassium, calcium, magnesium, barium compounds, diisopropyl ethylamine or mixtures thereof.

9. The process according to claim 3, wherein the organic solvent is selected from polar aprotic solvents, dimethyl formamide, dimethyl sulfoxide, N-methylpyrrolidinone, ethereal solvents, tetrahydrofuran, 2-methyl tetrahydrofuran, methyl t-butyl ether, dimethyl ether, diisopopyl ether, methyl tert butyl ether 1,4-dioxne and diethoxymethane, hydrocarbons, benzene, toluene, hexanes, xylene, heptane, halogenated solvents, dichloromethane, chloroform, carbon tetrachloride, trichloroethane, 1,2-dichloroethane, benzotrifluoride, acetates, ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile, methyl vinyl ketone, N,N- dimethylacetamide, t-butyl methyl ether, petroleum ether, diethyl ether; water-soluble alcohols, butanol, methanol, ethanol, isopropanol, biphasic solvent systems or mixtures thereof. 10. The process according to any of the proceeding claims, wherein the compound of formula I obtained is substantially free of all impurities. 11. Compound of formula I prepared by the process according to the preceding claims can be used in preparation of medicament for treating or preventing cancers.

Description:
PROCESS FOR THE PREPARATION OF DERIVATIVES OF 5-FLUORO PYRIMIDINES USED AS ANTI CANCER AGENTS PRIORITY [0001] The present application claims the benefit of Indian Provisional Patent Application No. 202041038383 filed on 5 September 2020 the entire disclosure of which is relied on for all purposes and is incorporated into this application by reference. FIELD OF INVENTION [0002] The aspects of the present invention relates to the process for the preparation of novel anti- tumor agents, specifically discloses the preparation method of (2R, 3R, 4R, 5R)-2-(5-fluoro-2-oxo-4- (2-propylpentanamido) pyrimidin-1(2H)-yl)-5-methyltetrahydrofuran-3, 4-diyl diacetate). BACKGROUND OF THE INVENTION [0003] Cancer is an important disease that threatens human health, and has surpassed cardiovascular disease as the leading killer of human death. Cancer cells have faulty DNA synthesis and replication, so when DNA synthesis is blocked, they can effectively inhibit the growth of cancer cells, and then achieve the purpose of anti-tumor. [0004] The prime focus of research is to explore new drugs that could be easily available, with lesser side effects and cost-effective. Fluoro pyrimidines are one such class of chemical compounds with the anti-cancer activity. Specifically capecitabine, carmofur, doxifluridine, fluorouracil, tegafur etc are few such drugs that belong to this class of fluoro pyrimidines with anti-cancer activity. [0005] These drugs are widely used in the treatment of breast cancer, colorectal cancer, gastric cancer, gall bladder cancer, lung cancer, colorectal cancer, head and neck cancer, liver cancer, pancreatic cancer etc. [0006] But these drugs also possess side effects like myelosuppression, central neurotoxicity and gastrointestinal toxicity (especially diarrhea), appetite loss, vomiting, nausea, stomatitis, abdominal pain, fatigue, weakness, hand foot syndrome, fever, pain, head ache etc. Hence there is always a quest for new anti-cancer drugs with minimum side effects. [0007] International Application Publication No. WO 2020/026054 A1 discloses compounds or its pharmaceutically acceptable compositions, polymorphs, solvates, enantiomers, stereoisomers, hydrates that function as nucleic acid synthesis inhibitors and disclosed are the methods for the treatment of cancers. (2R, 3R, 4R, 5R)-2-(5-fluoro-2-oxo-4-(2-propylpentanamido) pyrimidin-1(2H)- yl)-5-methyltetrahydrofuran-3, 4-diyl diacetate) is one of the novel anti-cancer compound disclosed as Formula-(1-1) in WO 2020/026054 A1. The patent application discloses the synthesis of (2R, 3R, 4R, 5R)-2-(5-fluoro-2-oxo-4-(2-propylpentanamido) pyrimidin-1(2H)-yl)-5- methyltetrahydrofuran-3, 4-diyl diacetate) in small scale. [0008] The present invention discloses an industrially applicable process of manufacture of the compound of formula I using economical reagents and chemicals for better quality and yield. SUMMARY OF THE INVENTION [0009] The present invention relates to processes for the preparation of compound of formula-I. IUPAC Name: (2R, 3R, 4R, 5R)-2-(5-fluoro-2-oxo-4-(2-propylpentanamido) pyrimidin-1(2H)-yl)-5- methyltetrahydrofuran-3, 4-diyl diacetate). Internal reference code: CLX-SYN-G155A-C03. [0010] In one aspect, the present invention describes a process for the preparation of formula-I (CLX- SYN-G155A-C03) by the condensation of the 2’,3’-Di-O-Acetyl-5’-deoxy-5-fluoro cytidine (formula-II) with 2-propyl pentanoyl chloride (formula-III) as below:

[0011] The other aspect of the present invention is to provide pure compound of formula-I (CLX- SYN-G155A-C03). [0012] Another aspect of the present invention is to provide a process for the purification of the compound of formula-I (CLX-SYN-G155A-C03) by eliminating the impurities. [0013] Another aspect of the present invention is to provide a process for the preparation of the compound of formula-I (CLX-SYN-G155A-C03) which improves the overall yield. DETAILED DESCRIPTION OF THE INVENTION [0014] Definitions [0015] As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art. [0016] The term as used herein “substantially pure” means a chemical purity equal to or greater than 99.8 %, and/or a total content of impurities less than or equal to 0.2%, and /or each individual impurity being present in an amount less than or equal to 0.1%, as determined using high performance liquid chromatography (HPLC). [0017] The term as used herein “substantially removing” the solvent refers to at least 80%, specifically greater than about 85%, more specifically greater than about 90%, still more specifically greater than about 99%, and most specifically essentially complete (100%), removal of the solvent from the solution or suspension. [0018] The term as used herein “Condensation catalyst or N-acylation catalyst”, may refer to the catalyst that increases the rate of the condensation or N-acylation reaction involved. [0019] The term as used herein “Choice of catalyst”, may influence whether or not a particular product is formed selectively (where the possibility of more than one product exists) and thus the catalyst may be selected according to the product or products desired from the reaction. It is envisaged that, where appropriate, combination of two or more suitable catalysts could be used. However, the use of a single catalyst is preferred. Alternatively, or additionally, selectivity may be controlled by independently varying one or more of the temperature, pressure, flow rate (in the case of a continuous process) and concentrations of the reactants. [0020] The term as used herein “anti-solvent” refers to a solvent which when added to an existing solution of a substance reduces the solubility of the substance. [0021] The term as used herein purity is based on the "organic" purity of the compound. Purity does not include a measure of any amount of water, solvent, metal, inorganic salt, etc. In one aspect, the purity of desired compound is compared to the purity of the reference standard by comparing the area under the peak. [0022] International Application Publication No. WO 2020/026054 A1 is incorporated by reference entirely. [0023] The present invention includes processes for preparing substantially pure form of compound of formula-I (CLX-SYN-G155A-C03). [0024] The detailed process in the preparation of the compound of formula I of the present invention comprises of: Stage-A (Condensation): [0025] Condensation of 2’,3’-Di-O-Acetyl-5’-deoxy-5-fluorocytidine( formula II) with that of the 2- propyl pentanoyl chloride (formula III), to give compound of formula-I (2R, 3R, 4R, 5R)-2-(5-fluoro- 2-oxo-4-(2-propyl pentanamido) pyrimidin-1(2H)-yl)-5-methyltetrahydrofuran-3,4-diyl diacetate) (CLX-SYN-G155A-C03) in presence of suitable solvent , base and a catalyst.

Stage-B (Purification) [0026] Purification of the compound of formula I (CLX-SYN-G155A-C03) obtained from stage A in presence of the suitable organic solvents. [0027] In another embodiment the condensation catalysts or N-acylation catalyst used for the reaction include, without limitation DMAP(4-dimethylaminopyridine), diisopropylamine (DIPEA), 1- hydroxybenzotriazole, 2-pyridone, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicylco [5.4.0]undec-7-ene (DBU), and 2,6-lutidine, 4-pyrrolidinopyridine, 2-hydroxypyridine, tributylphosphine, 1-methylimidazole, Aluminum chloride (AlCl3), Iron chloride(FeCl3), Galium trichloride (GaCl3), Antimony pentachloride (SbCl5), Zinc Chloride (ZnCl2), Stannous chloride (SnCl2), Aluminum Bromide (AlBr3), Iron Bromide (FeBr3),Stannic chloride (SnCl4), Gallium tribromide (GaBr3) , Hydrogen Flouride (HF), Boron trifluoride (BF3), trimethylsilyl trifluoromethane sulfonate, platinum, palladium, or rhodium in concentrated sulfuric acid, and the like preferably DMAP. In still another embodiment suitable bases include, but are not limited to: organic bases such as Organolithiums, Grignard reagents, Amines, trimethylamine (TEA), N- heterocyclic compounds, Tetra alkylammonium compounds and phosphonium hydroxides, Metal alkoxides and amides and metal silanoates such as n-butyllithium, sec-butyllithium, tert-butyllithium, hexyllithium, isopropyllithium, butylmagnesium chloride, isopropylmagnesium chloride, propylmagnesium chloride, sec-butylmagnesium chloride solution, tert-butylmagnesium chloride, 2- tert-butyl-1,1,3,3-tetramethylguanidine, ethylmagnesium bromide, ethylmagnesium chloride, hexylmagnesiumchloride, isobutylmagnesiumchloride, 2,2,6,6-Tetramethylpiperidine, 4- (dimethylamino)pyridine, N,N diisopropylmethylamine, diethylamine, Morpholine, Piperidine, (Piperidinomethyl)polystyrene,4-(Dimethylamino)pyridin, N-Ethyldiisopropylamine, Lithium tert- butoxide , Barium tert-butoxide , Magnesium di-tert-butoxide, Magnesiumethoxide, Potassiumethoxide, Sodium tert-butoxide, Tetrabutylammonium hydroxide, Tetramethylammonium hydroxide solution, Trimethylphenylammonium hydroxide, Tetrapropylammoniumhydroxide ,Tetrahexylammonium hydroxide solution , Sodium tert-pentoxide, Sodium ethoxide, Sodium tert- butoxide, Potassium tert-butoxide,Lithiumisopropoxide Lithiumethoxide,Lithium tert-butoxide, Barium tert-butoxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium methoxide and similar lithium, potassium, calcium, magnesium and barium compounds preferably Diisopropyl ethylamine. In an embodiment the amounts of the catalysts used in the reaction is about 0.2 to 2 molar equivalents, per molar equivalent of the compound of Formula-II. [0028] In one embodiment the condensation reaction or N-acylation reaction is carried out in the presence of an organic solvent. Organic solvents useful for the condensation reaction include but are not limited to, polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, and N- methylpyrrolidinone; ethereal solvents such tetrahydrofuran, 2-methyl tetrahydrofuran, methyl t- butyl ether, dimethyl ether, diisopopyl ether, methyl tert butyl ether 1,4-dioxne and diethoxymethane; hydrocarbons such as benzene, toluene, hexanes, xylene and heptane; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; acetates such as ethyl acetate, isopropyl acetate, and butyl acetate, and other solvents such as acetonitrile, methyl vinyl ketone, N,N-dimethylacetamide; and mixtures thereof preferably dichloromethane. In another embodiment the condensation reaction may be performed at temperatures −50° C. to about 150° C., preferably in the range of from −25° C. to about 100° C., and more preferably in the range of from 0° C. to 50° C. [0029] In another embodiment the condensation reaction may be carried out for any desired time periods to achieve the desired product yield and purity, with time periods from about 1 to 10 hours, or longer, as required for the reaction completion. [0030] In another embodiment the formed wet cake from the condensation reaction of the compound of formula II is charged with water resulting in two layers and is extracted. The upper aqueous layer and the bottom organic layer are separated. [0031] The pH of the extraction solvent may be from about pH 2.0 to about 7.0, namely, for example, from about pH 2.0 to about pH 5.0, from about pH 2.0 to about pH 4.0, or from about pH 2.0 to about pH 3.0. [0032] In a specific embodiment, the extraction solvent is aqueous, for example, is water and optionally an acid and / or base, in an amount providing a pH of from about pH 2.0 to about 7.0, namely, from about pH 2.0 to about pH 5.0, from about pH 2.0 to about pH 4.0, or from about pH 2.0 to about pH 3.0. To achieve the desired pH of the extraction solvent, any suitable acid or base may be used, namely, for example, HCl, NaOH, citric acid and the like. [0033] The extraction can be carried out at a temperature of from about 25 ° C to about 90 ° C, namely, for example, from about 30 ° C to about 80 ° C, from about 35 ° C to about 75 ° C, from about 40 ° C to about 70 ° C, from about 45 ° C to about 65 ° C, or from about 50 ° C to about 60 °C. [0034] In embodiments where the extraction method is a stepwise extraction method, the duration of the extraction can vary from about 0.5 hours to about 24 hours, namely, for example, from about 1 hour to about 12 hours, from about 1 hour to about 8 hours or from about 1 hour to about 6 hours. [0035] In embodiments where the extraction method is a continuous process, the duration of the extraction can vary from about 1 hour to about 5 hours, namely, for example, from about 2.5 hours to about 3 hours. [0036] The upper aqueous layer is extracted using organic solvents such as, dichloromethane, 1,2- dichloromethane, 1,2-dichloroethane chloroform, carbon tetrachloride, toluene, xylene, n-heptane, hexane and the like, ethers such as , for example, diethyl ether, dimethyl ether, diisopropyl ether, methyl tert butyl ether, tetrahydrofuran, 1,4-dioxane, and the like; and any mixtures thereof preferably dichloromethane. [0037] In another embodiment the bottom organic layer is washed with acids without limitation mineral acids, acetic acid, acidic amino acids, citric acid, fumaric acid and other α-hydroxy acids, hydrochloric acid, ascorbic acid, phosphoric acid, sulfuric acid, tartaric acid, nitric acid, and others known to those of ordinary skill in the art and the desired compound is extracted, preferably by the addition of dilute hydrochloric acid [0038] In yet another embodiment the desired compound is extracted from the organic layer using halides, hydroxides, carbonates, and alkoxides of alkali metals or alkaline earth metals, e.g., sodium chloride, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium methoxide, and similar lithium, potassium, calcium, magnesium and barium salts preferably sodium bicarbonate followed by sodium chloride. [0039] Removal of solvent is accomplished, for example, by substantially complete evaporation of the solvent, concentrating the solution or distillation of solvent, under inert atmosphere to obtain solid state form of the desired compound. [0040] In one embodiment, the solvent is removed by distillation under vacuum. The distillation process can be performed at atmospheric pressure or reduced pressure. Specifically, the solvent is removed at a pressure of about 760 mm Hg or less, more specifically at about 400 mm Hg or less, still more specifically at about 80 mm Hg or less, and most specifically from about 30 to about 80 mm Hg at temperatures such as 35oC to about 80o C. [0041] In another embodiment the extracted compound of formula I is dissolved in organic solvents. Non-limiting examples of organic solvents includes ethers such as t-butyl methyl ether, petroleum ether, diethyl ether; Halogenated solvents such as chloroform, Dichloromethane, benzotrifluoride, dichloroethane, Carbon tetrachloride, trichloroethane; Water-soluble alcohols such as butanol, methanol, ethanol, isopropanol; Water-soluble esters such as ethyl acetate, isopropyl acetate; Acetonitrile and toluene. Suitable biphasic solvent systems can be prepared from these abovementioned solvents, preferably those such as, in particular at least containing: n-heptane and / or acetonitrile, n-heptane / acetonitrile n-heptane / ethyl acetate / acetonitrile; n-heptane / ethyl acetate / t-butyl methyl ether / acetonitrile; n-heptane / ethyl acetate / methanol / water; n-heptane / ethanol / water more preferably ethyl acetate. In another embodiment, ethyl acetate is added in an amount of 100 to 750% by weight, preferably 150 to 500% by weight, based on the amount of crude product of the desired compound used. In another embodiment, the isolation of pure solid state form of the compound of formula I, is achieved through crystallization, substantial removal of the solvent from the solution or suspension, or a combination thereof. Crystallization may be initiated by a method usually known in the art such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution or a combination thereof. [0042] In the stage B anti-solvents are used for purification. The non-limiting examples of anti- solvents include, but are not limited to, a hydrocarbon, an ether, and mixtures thereof. Specifically, the anti-solvent is selected from the group consisting of n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, monoglyme, diglyme, and mixtures thereof; and most specifically diethyl ether, diisopropyl ether, and mixtures thereof. In another embodiment, the suitable anti-solvent used is n-heptane by charging into the reactor at a temperature of 45±5oC.In one embodiment, the crystallization is carried out by cooling the solution while stirring at a temperature of below 30° C for at least 10 minutes, specifically at about 0° C to about 35° C for about 30 minutes to about 20 hours. [0043] In an embodiment, the final solution comprising the pharmaceutically acceptable product of the compound of formula I is filtered. After filtration, a pharmaceutically acceptable solvent, preferably the same solvent as described above, is added. [0044] In another embodiment, the pharmaceutically acceptable solvent added to the final compound of formula I obtained after filtration is preferably n-heptane. [0045] In one embodiment the drying is carried out at atmospheric pressure or reduced pressures, such as below about 200 mm Hg, or below about 50 mm Hg, at temperatures such as 35° C. to about 80° C. The drying can be carried out for any desired time period that achieves the desired result, such as about 1 to 20 hours. Drying may also be carried out for shorter or longer periods of time depending on the product specifications. Temperature and pressure are chosen based on the volatility of the solvent being used and the foregoing should be considered as only a general guidance. Dying can be suitably carried out in a tray dryer, a vacuum oven, an air oven, or using a fluidized bed drier, a spin flash dyer, a flash dryer or suck drying, vacuum dryer and the like. Drying equipment selection is well within the ordinary skill in the art. [0046] In another embodiment the drying of the final desired compound is carried out at a temperature range of 25±35oC. [0047] In one embodiment the reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g.1H or13C), infrared spectroscopy, spectrophotometry (e.g., UV- visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC). Compounds can be purified by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) [0048] In one embodiment, the present invention relates to the desired final compound of formula-I (CLX-SYN-G155A-C03) having a purity greater than about 98%. In one embodiment, the purity is determined by HPLC. In one embodiment, the purity is greater than about 98.5%. In one embodiment, the purity is greater than about 99.0%. In one embodiment, the purity is greater than about 99.5. [0049] The above described improved process for the preparation of compound of Formula-I (CLX- SYN-G155A-C03) is resulting in cost-effective and reproducible process on industrial scale. The process of present invention provides higher overall yield and purity. [0050] Certain specific aspects and embodiments of the invention will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the invention in any manner. METHODS OF MAKING [0051] Examples of synthetic pathways useful for making compound of Formula-I are set forth in the examples below. Example 1: [0052] Preparation of 2-propylpentanoyl chloride(KSM-I): [0053] To an ice cold stirred solution of 2-propylpentanoic acid (1.40g, 0.277 mol) in dicloromethane (400 mL) was added oxalyl chloride (70.41 g, 0.555 mol) followed by the addition of DMF(7.0 mL,0.083 mmol). The resulting reaction mixture was stirred at room temperature for next 4 h. After completion of the reaction, solvent was evaporated under reduced pressure under nitrogen atmosphere to get the desired compound 2- propylpentanoyl chloride as light yellow liquid. The crude is used directly for the next condensation step. (Yield: 40.0g, 89%) Example 2: [0054] Preparation of (2R, 3R, 4R, 5R)-2-(5-fluoro-2-oxo-4-(2-propylpentanamido)pyrimidin-1-(2H )- yl)-5-methyltetrahydro furan-3,4-diyl diacetate (Stage-A): [0055] To a stirred solution of 2’, 3’-Di-O-Acetyl-5’-deoxy-5-fluorocytidine of (50.0 gms, 0.15 mol) is suspended in Dichloromethane (10.0 vol.) was added DMAP (0.25 eq.) followed by diisopropylethylamine (3.0 eq.) at 0 to 5oC and stirred for 15 min. 2-propylpentanoyl chloride (1.3 eq.) was added to the reaction mixture between 0 to 5oC.Then the reaction mixture was allowed to room temperature and stirred for 3-4 h. After the completion of the starting material, the reaction mixture was quenched by adding water (5 vol.) and stirred for 20-30 minutes. Organic layer is separated, and the aqueous layer was re-extracted with dichloromethane (DCM) (5 vol.).Organic layers were combined and sequentially washed with water (5.0.), 0.5 N HCl (5 vol.), water (5 vol.).Sat.Aq.Sodium bicarbonate solution (2*5 vol.) and finally with brine (5 vol.). Organic layer was dried Na2SO4, filtered and distilled the solvent under reduced pressure. (Yield% = 87%). Example 3: [0056] Purification of the (2R, 3R, 4R, 5R)-2-(5-fluoro-2-oxo-4-(2-propylpentanamido)pyrimidin-1- (2H)-yl)-5-methyl tetrahydro furan-3,4-diyl diacetate (Stage-B): [0057] Dissolve the (2R, 3R, 4R, 5R)-2-(5-fluoro-2-oxo-4-(2-propylpentanamido)pyrimidin-1-(2H )-yl)-5- methyl tetrahydro furan-3,4-diyl diacetate is added with heptane (10 vol.) at room temperature and stirred for 4-5 hr. Filter the reaction mixture and wash with heptane (2 vol.). Material is dried under vacuum for 2-3 h to obtain (CLX-SYN-G155A-C03) as white solid. (Purity % = 99.85%). EQUIVALENTS The present disclosure provides among other things the industrial scale processes for the preparation of (2R, 3R, 4R, 5R)-2-(5-fluoro-2-oxo-4-(2-propylpentanamido) pyrimidin-1-(2H)-yl)-5-methyl tetrahydrofuran-3,4-diyl diacetate (CLX-SYN-G155A-C03)with better yield and purity %. While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the systems and methods herein will become apparent to those skilled in the art upon review of this specification. The full scope of the claimed processes and methods should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations. INCORPORATION BY REFERENCE All publications and patents mentioned herein, including those items listed above, are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.