Claims:1. A method for preparing 4-oxime-5`-(2-methylpropionyl) uridine compound of Formula (III)

Formula (III)
the process comprises:
i) providing an indeterminate compound of Formula (Ia) or (Ib) comprising reacting cytidine with N, N-dimethylformamide dimethyl acetal (DMF-DMA) in equivalence of 1 to 6

Formula (Ia) or (Ib);
ii) providing an indeterminate compound of Formula (II) by reacting the compound of Formula (Ia) or (Ib) in the presence of an organic base and organic solvent(s) with an agent selected from isobutyryl chloride, isobutyric anhydride, or acetone oxime O-isobutyryl ester for carrying out esterification and isolating an intermediate compound as a free base or reacting the compound with oxalic acid to provide an oxalate salt of compound of Formula (II);

Formula (II); and
iii) providing 4-oxime-5`-(2-methylpropionyl) uridine compound of Formula (III) by reacting the free base or the oxalate salt of compound of Formula (II) with a base selected from hydroxyl amine, hydroxylamine hydrochloride, or hydroxylamine sulphate.
2. The method of synthesis as claimed in claim 1, wherein the process of step (i) includes adding cytidine gradually to DMF-DMA at a temperature of 10°C to 35°C and mixing for 15 mins to 30 mins at same temperature to provide the mixture of cytidine and DMF-DMA; and refluxing the mixture at a temperature from 60°C to 90° for duration from 5 hrs to 10 hrs or until the competition of reaction to provide the compound of Formula (Ia) or (Ib).
3. The method of synthesis as claimed in claim 1 or 2, wherein the DMF-DMA is optionally used in combination with a polar or non-polar solvent selected from toluene, tetrahydrofuran (THF), methylene dichloride (MDC), dimethylformamide (DMF), and N-Methyl-2-pyrrolidone (NMP).
4. The method of synthesis as claimed in any one of claims 1 to 3, wherein in step (i) cytidine is reacted with N, N-dimethylformamide dimethyl acetal (DMF-DMA) at a lower equivalence of 1 to 2, more preferably in equivalence of 1.1 to provide a compound of Formula (Ia).
5. The method of synthesis as claimed in any one of claims 1 to 3, wherein in step (i) cytidine is reacted with N, N-dimethylformamide dimethyl acetal (DMF-DMA) at equivalence of 2.01 to 6, more preferably in equivalence of 4 to 6 to provide a compound of Formula (Ib).
6. The method of synthesis as claimed in claim 1, wherein the process of step (ii) for providing free base compound of Formula (II) includes providing the mixture of the compound of Formula (Ia) or (Ib), the organic base and the organic solvent(s); cooling and maintaining the mixture at about 0°C to about (-) 5°C; esterifying the mixture with an agent selected from isobutyryl chloride, isobutyric anhydride, or acetone oxime O-isobutyryl ester at about 25°C to 35°C for about 30 minutes to about 60 minutes to provide a free base compound.
7. The method of synthesis as claimed in claim 1, wherein the process of step (ii) for providing an oxalate salt of compound of Formula (II) includes reacting the free base compound with an acid in the presence of a solvent for a period of 30 minutes to 90 minutes at a temperature of 25°C to 55°C and cooling the reaction mixture to 5°C to 15°C to provide the oxalate salt of compound of Formula (II).
8. The method of synthesis as claimed in claim 6, wherein in the process of step (ii) the solvent is selected from C1-C6 alcohol, dichloromethane, trichloromethane, and chloroform.
9. The method of synthesis as claimed in claim 6, wherein in the process of step (ii) the base is selected from triethyl amine, 4-dimethylaminopyridine (DMAP), tert-butyl amine (TBA), diisopropylethylamine (DIPEA), and pyridine.
10. The method of synthesis as claimed in claim 1, wherein the process of step (iii) for providing an oxalate of compound of Formula (II) includes reacting the free base or the oxalate salt of a compound of Formula (II) with a reagent selected from hydroxyl amine, hydroxylamine hydrochloride, or hydroxylamine sulphate at a temperature of about 60℃ to about 85℃ for about 3 hrs to10 hrs and isolating the compound of Formula (III) in water.
11. A compound of Formula (Ia) or (Ib):
(or)
Formula (Ia) (Ib);
12. A process for preparing a compound of Formula (Ia) or (Ib) comprising mixing cytidine with N, N-dimethylformamide dimethyl acetal (DMF-DMA) at an equivalence of 1 to 6
and then refluxing the mixture at a temperature of 60°C to 90°C for a period of 5 hrs to 10 hrs or until the completion of reaction to provide a compound of Formula (Ia) or (Ib).
13. The process as claimed in claim 12, wherein the cytidine is reacted with N, N-dimethylformamide dimethyl acetal (DMF-DMA) at a lower equivalence of 1 to 2, more preferably in equivalence of 1.1 to provide a compound of Formula (Ia).
14. The process as claimed in claim 12, wherein the cytidine is reacted with N, N-dimethylformamide dimethyl acetal (DMF-DMA) at equivalence of 2.01 to 6, more preferably in equivalence of 4 to 6 to provide a compound of Formula (Ib).
15. The process as claimed in claim 12, wherein the DMF-DMA is optionally used in combination with a polar or non-polar solvent selected from toluene, tetrahydrofuran (THF), methylene dichloride (MDC), dimethylformamide (DMF), and N-Methyl-2-pyrrolidone (NMP).
16. A compound of Formula (II):

Formula (II)
17. A process for preparing the compound of Formula (II) comprising the steps of:
a) providing a mixture of compound of Formula (Ia) or (Ib), a base, an organic solvent and cooling the mixture to about 0°C to about (-) 5°C;
b) adding an agent selected from isobutyryl chloride, isobutyric anhydride, or acetone oxime O-isobutyryl ester and maintaining the reaction mixture at a room temperature for example from about 25°C to 35°C for about 30 minutes to about 60 minutes to provide the compound of Formula (II) as a free base; and
c) converting the compound of Formula (II) free base into a salt by reacting the free base compound of Formula (II) with an acid in the presence of a solvent for a period of about 60 minutes to about 90 minutes at a temperature of about 50°C to about 75°C and cooling the reaction mixture to about 5°C to about 15°C to provide a salt of compound of Formula (II).
18. The process as claimed in claim 17, wherein the solvent is selected from C1-C6 alcohol, dichloromethane, trichloromethane, chloroform, or the like.
19. The process as claimed in claim 17, wherein the base is selected from triethyl amine, 4-dimethylaminopyridine (DMAP), tert-butyl amine (TBA), diisopropylethylamine (DIPEA), and pyridine.
, Description:FIELD OF THE INVENTION
[0001] The present disclosure pertains to a method for preparing 4-oxime-5`-(2- methylpropionyl) uridine compound and intermediates for preparing the same. In particular, the present disclosure provides a method for preparing 4-oxime-5`-(2- methylpropionyl) uridine compound in substantially pure form and high yield suitable for commercial scale; a novel intermediate N'-(1,2-dihydro-1-((2R,3R,4S,5R)-tetrahydro-3,4-dihydroxy-5-(hydroxymethyl)furan-2-yl)-2-oxopyrimidin-4-yl)-N,N-dimethylformamidine and process for preparing the same; and a novel intermediate compound ((2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate oxalate salt or alternately as a free base and process for preparing the same.

BACKGROUND OF THE INVENTION
[0002] The background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
[0003] 4-oxime-5`-(2-methylpropionyl) uridine compound known as molnupiravir (development codes EIDD-2801, MK-4482) is a prodrug of an oral, biologically active ribonucleoside analog β-d-N4-hydroxycytidine (NHC; EIDD-1931). The active drug incorporates into the genome of RNA viruses, leading to an accumulation of mutations known as viral error catastrophe. As per the recent studies, EIDD-2801 is shown to have a broad-spectrum antiviral activity against the pathogens of SARS-CoV-2, MERS-CoV, SARS-CoV and COVID-19. Molnupiravir may prove to be an effective antiviral drug against different infections. Because oral medications are convenient to use, they can be used as preventive medications and are also suitable for inpatients as well outpatients.
[0004] Currently, there are limited synthesis routes are known for preparing the 4-oxime-5`-(2-methylpropionyl) uridine compound.
[0005] One of the synthetic routes as suggested in the patent application WO2019113462, the process uses uridine as the starting material. This approach includes first protecting the dihydroxy group, esterification with isobutyric anhydride, and then reacting with 1,2,4-triazole. In this route, uridine used is costly and it gives lower yields thereby rendering the process inefficient and commercially nonviable at an industrial level.
[0006] Another approach is disclosed in the CN112608357A patent application, which involves use of enzyme. As known in the art, enzymes are highly costly materials requiring much longer reaction cycles and consumption of large quantities of solvents. Thus, such approaches are industrially not feasible.
[0007] One more approach is disclosed in the patent application CN112552288. Such method involving huge consumption of solvents, costly bicyclic amidine catalyst 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) and deprotection with formic acid results in the lower yield and again such method would be uneconomical at commercial scale.
[0008] Additionally, some of the reported routes require multiple steps synthesis, wherein the first stage reaction requires very high concentrations of base like pyridine. Besides, final stage reaction is very lengthy requiring very long duration with formation of an intermediate, removal of which requires additional steps of purification involving column chromatography. Besides, oily nature of such substance adds to difficulty in purification, lowering yield and thus making such process unsuitable for commercial production. The use of costly enzyme in the other approaches and very long duration of such treatment process makes the synthesis unviable at an industrial scale thus posing limitations in scaling up of such processes.
[0009] Accordingly, there remains a need for an improved process for synthesis of 4-oxime-5`-(2-methylpropionyl) uridine compound molnupiravir and intermediates that can help overcome shortcomings of the processes known in the art. It is required to fulfil the need for a process for synthesis of molnupiravir which involves minimum use of solvents, can be carried out in absence of enzyme, with minimum time cycle and high yield without requiring additional steps of purifications to provide an industrially scalable and commercially and ecologically viable synthesis process. There also remains an unmet need of intermediate compounds which can curtail formation of impurities during the process to provide the compounds with high purity.
[00010] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.

OBJECTS OF THE INVENTION
[00011] It is an object of the present disclosure to provide a method for preparing 4-oxime-5`-(2- methylpropionyl) uridine compound in substantially pure form and high yield suitable for commercial scale.
[00012] It is another object of the present disclosure to provide a novel intermediateN'-(1,2-dihydro-1-((2R,3R,4S,5R)-tetrahydro-3,4-dihydroxy-5-(hydroxymethyl) furan-2-yl)-2-oxopyrimidin-4-yl)-N,N-dimethylformamidine and process for preparing the same.
[00013] It is yet another object of the present disclosure to provide a novel intermediate compound ((2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate as an oxalate salt or as a free base and process for preparing the same.

SUMMARY
[00014] The present disclosure pertains to an efficient method for preparing 4-oxime-5`-(2-methylpropionyl) uridine compound molnupiravir.
[00015] In overall aspects the present disclosure provides a method for preparing 4-oxime-5`-(2- methylpropionyl) uridine compound in substantially pure form and high yield suitable for commercial scale; a novel intermediate N'-(1,2-dihydro-1-((2R,3R,4S,5R)-tetrahydro-3,4-dihydroxy-5-(hydroxymethyl) furan-2-yl)-2-oxopyrimidin-4-yl)-N,N-dimethylformamidine and process for preparing the same carried out in absence of base and solvent; and an intermediate compound ((2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate as an oxalate salt or a free base and process for preparing the same with high yield and purity.
[00016] In an aspect the present disclosure provides a process for synthesis of 4-oxime-5`-(2- methylpropionyl) uridine compound from novel intermediate compounds minimizing formation of impurities and improving yield to make the process suitable for commercial scale.
[00017] In an aspect the present disclosure provides a method for preparing 4-oxime-5`-(2-methylpropionyl) uridine compound molnupiravir comprising:
i) providing an intermediate compound I, an amine protected cytidine by reacting cytidine with N, N-dimethylformamide dimethyl acetal (DMF-DMA) in equivalence of 1-6 without the use of solvent and base;
ii) providing an intermediate compound II, a free base or an oxalate salt with high purity and yield minimising formation of diacetyl impurity; and
iii) providing an end product 4-oxime-5`-(2-methylpropionyl) uridine compound by converting the intermediate compound II, into the end product in presence of a base in shorter duration, avoiding use of hazardous solvents during the workup, minimizing impurity and isolating the end product in substantially pure form from water in high yield.
[00018] In one aspect, the present disclosure provides a method for preparing 4-oxime-5`-(2-methylpropionyl) uridine compound of Formula (III):

Formula (III)
in which the method comprises:
i) providing an indeterminate compound of Formula (Ia) or (Ib) comprising reacting cytidine with N, N-dimethylformamide dimethyl acetal (DMF-DMA) in equivalence of 1 to 6

Formula (Ia) (Ib);
ii) providing an indeterminate compound of Formula (II) comprising reacting the compound of Formula (Ia) or (Ib) in the presence of an organic base and organic solvent(s) with an agent selected from isobutyryl chloride, isobutyric anhydride, or acetone oxime O-isobutyryl ester for carrying out esterification and isolating an intermediate compound as a free base or reacting the compound with an acid for example oxalic acid to provide an oxalate salt of compound of Formula (II);

Formula (II); and
iii) providing 4-oxime-5`-(2-methylpropionyl) uridine compound of Formula (III) comprising reacting the free base or the oxalate salt of compound of Formula (II) with a base selected from hydroxyl amine, hydroxylamine hydrochloride, or hydroxylamine sulphate.
[00019] In another aspect, the present disclosure provides a compound of Formula (Ia) or (Ib):

Formula (Ia) (Ib);
[00020] In an aspect, the present disclosure provides a process for preparation of compound of Formula (Ia) or (Ib) comprising reacting cytidine with N, N-dimethylformamide dimethyl acetal (DMF-DMA) in equivalence of 1 to 6.
[00021] In one aspect, the process comprises reacting cytidine with N, N-dimethylformamide dimethyl acetal (DMF-DMA) at lower equivalence of 1 to 2, more preferably in equivalence of 1.1 to provide a compound of Formula (Ia).
[00022] In another aspect, the process comprises reacting cytidine with N, N-dimethylformamide dimethyl acetal (DMF-DMA) at lower equivalence of 2.01 to 6, more preferably in equivalence of 4 to 6 to provide a compound of Formula (Ib).
[00023] In one aspect, the process for preparation of compound of Formula (Ia) or (Ib) comprises mixing cytidine with (DMF-DMA) and refluxing the mixture at a temperature of the about 60°C to about 90°C for at least a period of about 5 hrs to about 10 hrs or until the completion of reaction to provide a compound of Formula (Ia) or (Ib).
[00024] In yet another aspect, the present disclosure provides a compound of Formula (II):

Formula (II)
[00025] In one aspect, the present disclosure provides a process for preparation of compound of Formula (II) comprising the steps of:
a) providing a mixture of compound of Formula (Ia) or (Ib), a base, and an organic solvent and cooling the mixture to about 0°C to about (-) 5°C;
b) adding an agent selected from isobutyryl chloride, isobutyric anhydride, or acetone oxime O-isobutyryl ester and maintaining the reaction mixture at a room temperature for example from about 25°C to 35°C for about 30 minutes to about 60 minutes to provide the compound of Formula (II) as a free base; and
c) converting the compound of Formula (II) free base optionally into a salt by reacting the free base compound of Formula (II) with an acid for example oxalic acid in the presence of a solvent for a period of about 60 minutes to about 90 minutes, at a temperature of about 50°C to about 75°C and cooling the reaction mixture to about 5°C to about 15°C to provide an oxalate salt of compound of Formula (II).
[00026] Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments.

BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
[00027] The following drawings form part of the present specification and are included to further illustrate aspects and specific embodiments of the present disclosure.
[00028] FIG. 1A is a Proton NMR spectrum of compound of Formula (II) as per one of the exemplary embodiments of Examples 2(b).
[00029] FIG. 1B is a Mass spectrum of compound of Formula (II) as per one of the exemplary embodiments of Examples 2(b).
[00030] FIG. 2A is a Proton NMR spectrum of compound of Formula (III) as per one of the exemplary embodiments of Examples 3(c).
[00031] FIG. 2B is a Mass spectrum of compound of Formula (III) as per one of the exemplary embodiments of Examples 3(c).
[00032] FIG. 2C is X-Ray Diffraction (XRD) spectrum of crystalline polymorph formed during the Example 3(c).
[00033] FIG. 2D is Differential scanning calorimetry (DSC) graph of the crystalline polymorph formed during Example 3(c).

DETAILED DESCRIPTION OF THE INVENTION
[00034] The following is a detailed description of embodiments of the present disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
[00035] Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
[00036] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
[00037] As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise.
[00038] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about”. Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. The term “about” can refer to + 5 of the figure, preceding the term “about”. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.
[00039] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.
[00040] All methods described herein can be performed in suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[00041] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[00042] Various terms are used herein. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[00043] The present disclosure pertains to a method for synthesis of 4-oxime-5`-(2-methylpropionyl) uridine compound molnupiravir, its intermediates and process for preparing the same.
[00044] The present disclosure provides an efficient method for preparing 4-oxime-5`-(2-methylpropionyl) uridine compound molnupiravir carried out in shorter duration, ecologically less hazardous manner, providing the end product in substantially pure form with high yield making the method commercially scalable.
[00045] The present invention provides novel intermediates and process for preparing the same. The intermediates in accordance with the present disclosure minimizes formation of impurities and improve yield of the final end product 4-oxime-5`-(2-methylpropionyl) uridine.
[00046] In one embodiment, the present disclosure provides a method for preparing 4-oxime-5`-(2-methylpropionyl) uridine compound of Formula (III):

Formula (III)
in which, the method comprises:
i) providing an indeterminate compound of Formula (Ia) or (Ib) comprising reacting cytidine with N, N-dimethylformamide dimethyl acetal (DMF-DMA) in equivalence of 1 to 6

Formula (Ia) (Ib);
ii) providing an indeterminate compound of Formula (II) comprising reacting the compound of Formula (Ia) or (Ib) in the presence of an organic base and organic solvent(s) with an agent selected from isobutyryl chloride, isobutyric anhydride, or acetone oxime O-isobutyryl ester for carrying out esterification and isolating an intermediate compound as a free base or reacting the compound with an acid for example oxalic acid to provide an oxalate salt of compound of Formula (II);

Formula (II); and
iii) providing 4-oxime-5`-(2-methylpropionyl) uridine compound of Formula (III) comprising reacting the free base or the oxalate salt of compound of Formula (II) with a base selected from hydroxyl amine, hydroxylamine hydrochloride, or hydroxylamine sulphate.
[00047] In one embodiment, in the process step (i) cytidine is reacted with N, N-dimethylformamide dimethyl acetal (DMF-DMA) at a lower equivalence of 1 to 2, more preferably in equivalence of 1.1 to provide a compound of Formula (Ia).
[00048] In another embodiment, in the process step (i) cytidine is reacted with N, N-dimethylformamide dimethyl acetal (DMF-DMA) at equivalence of 2.01 to 6, more preferably in equivalence of 4 to 6 to provide a compound of Formula (Ib).
[00049] In one embodiment, the process of step (i) includes adding cytidine gradually to DMF-DMA at a temperature of about 10 °C to 35°C and mixing for about 15 mins to about 30 mins at same temperature to provide the mixture of cytidine and DMF-DMA; and refluxing the mixture at a temperature from about 60°C to about 90° for duration from about 5 hrs to about 10 hrs or until the competition of reaction to provide the compound of Formula I.
[00050] In certain embodiment the N, N-dimethylformamide dimethyl acetal (DMF-DMA) can be optionally used in combination with a polar or nonpolar solvent selected from but not limiting to toluene, tetrahydrofuran (THF), methylene dichloride (MDC), dimethylformamide (DMF), N-Methyl-2-pyrrolidone (NMP) or the like solvents or mixture thereof.
[00051] In an embodiment, in step (ii) the process of providing free base compound includes providing the mixture of the compound of Formula (Ia) or (b), the organic base and the organic solvent(s); cooling and maintaining the mixture at about 0°C to about (-) 5°C; esterifying the mixture with an agent selected from isobutyryl chloride, isobutyric anhydride, or acetone oxime O-isobutyryl ester at about 25°C to 35°C for about 30 minutes to about 60 minutes to provide a free base compound.
[00052] In an embodiment, in step (ii) the process of providing an oxalate of compound of Formula (II) includes reacting the free base compound with an acid in the presence of a solvent for a period of about 30 minutes to about 90 minutes at a temperature of 25°C to 55°C and cooling the reaction mixture to 5°C to 15°C to provide the oxalate salt of compound of Formula (II).
[00053] In one embodiment the solvent employed in the process step (ii) can be selected from but not limiting to C1-C6 alcohol, dichloromethane, trichloromethane, chloroform, or the like.
[00054] In one embodiment, the base employed in the process step (ii) can be selected from but not limiting to triethyl amine, 4-dimethylaminopyridine (DMAP), tert-butyl amine (TBA), diisopropylethylamine (DIPEA), pyridine, or the like or the mixture thereof.
[00055] In certain embodiments, in the process step (ii), in place of oxalic acid, any suitable acid can be used to provide a desired salt of compound of Formula (II). The suitable acid that can be employed can be for example tartaric acid to provide tartrate compound.
[00056] In an embodiment, in step (iii) the process of providing the 4-oxime-5`-(2-methylpropionyl) uridine compound of Formula (III) includes reacting the free base or the oxalate salt of a compound of Formula (II) with a base selected from hydroxyl amine, hydroxylamine hydrochloride, or hydroxylamine sulphate at a temperature of about 40℃ to about 85℃, preferably at the temperature from about 60℃ to about 85℃; for about 3 hrs to about 10 hrs, preferably for about 3 hrs and isolating the compound of Formula (III) in water.
[00057] In some embodiments, all the reaction steps of the method for producing the final product 4--oxime-5`-(2-methylpropionyl) uridine compound of Formula (III) from the starting material cytidine may be conducted in one and the same reaction vessel without isolation of the intermediates of formula (Ia) or (Ib) and (II), so that the method of this disclosure may be worked in a facile way and as a commercial process of producing the molnupiravir.
.
[00058] In one embodiment, the present disclosure provides a compound of Formula (Ia) or (Ib):

Formula (Ia) (Ib);
[00059] In one embodiment, the present disclosure provides a process for preparation of compound of Formula (Ia) or (Ib) comprising reacting cytidine with N, N-dimethylformamide dimethyl acetal (DMF-DMA) in equivalence of 1to6, under specified condition(s) and durations to provide a compound of Formula (Ia) or (Ib).
[00060] In one embodiment, the process for preparing the compound of Formula (Ia) or (Ib) includes mixing cytidine with DMF-DMA in equivalence of 1 to 6 and refluxing the mixture at a temperature of the about 60°C to about 90°C for at least a period of about 5 hrs to about 10 hrs or until the completion of reaction to provide a compound of Formula (Ia) or (Ib).
[00061] In one embodiment, the present disclosure provides a compound of Formula (II):

Formula (II).
[00062] In an embodiment, the present disclosure provides a process for preparation of compound of Formula (II) comprising the steps of:
a) providing a mixture of compound of Formula (Ia) or (Ib), a base, an organic solvent and cooling the mixture to about 0°C to about (-) 5°C;
b) adding an agent selected from isobutyryl chloride, isobutyric anhydride, or acetone oxime O-isobutyryl ester and maintaining the reaction mixture at a room temperature for example from about 25°C to 35°C for about 30 minutes to about 60 minutes to provide the compound of Formula (II) as a free base; and
c) optionally converting the compound of Formula (II) free base into a salt by reacting the free base compound of Formula (II) with an acid in the presence of a solvent for a period of about 60 minutes to about 90 minutes at a temperature of about 50°C to about 75°C and cooling the reaction mixture to about 5°C to about 15°C to provide a salt of compound of Formula (II).
[00063] In one embodiment the solvent employed in the process for preparing the compound of Formula (II) can be selected from but not limiting to C1-C6 alcohol, dichloromethane, trichloromethane, chloroform, or the like.
[00064] In one embodiment, the base employed in the process for preparing the compound of Formula (II) can be selected from but not limiting to triethyl amine, tert-butyl amine (TBA), diisopropylethylamine (DIPEA), pyridine, or the like or the mixture thereof.
[00065] As per the present disclosure the intermediate compound that is an amine protected cytidine compound of Formula (Ia) or (Ib) in subsequent reactions for preparing the compound of Formula II avoids or minimises the formation of diacetyl impurity having structural formula as:

Diacetyl impurity
[00066] The inventors of the present invention surprisingly found that the intermediate compound the oxalate salt of Formula (II) when employed for preparing the compound of Formula (III), the use of hazardous solvents such as 2-methyl tetrahydrofuran (THF) and isopropyl acetate used in the conventional processes can be avoided thereby rendering the process safe and eco-friendly.
[00067] It was also unexpectedly found that the intermediate compound the oxalate salt of Formula (II) provides the compound of Formula (III) with as low as NMT 0.10 Hydroxy impurity:

Hydroxy Impurity
[00068] Due to such low level of impurity the compound of Formula (III) can be isolated from water without further purification.
[00069] The present disclosure provides an efficient method for synthesis of 4-oxime-5`-(2-methylpropionyl) uridine compound molnupiravir which can be carried out without the use of a base and a solvent at least in the first stage of the process and the process can be carried out in less ecological hazardous manner. Besides, owing to the simpler reaction scheme with lesser steps and the short duration, in particular in the later steps(s) makes the process more efficient as well as amenable to scale up at commercial level in economical manner that can make the process suitable to meet the demand of molnupiravir, for example to help curb corona virus pandemic.
[00070] While the foregoing description discloses various embodiments of the disclosure, other and further embodiments of the invention may be devised on the basis of the disclosure. The invention is not limited to the described embodiments, versions or examples, which are included are to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art.
EXAMPLES
Example 1(a)
Preparation of N'-(1,2-dihydro-1-((2R,3R,4S,5R)-tetrahydro-3,4-dihydroxy-5-(hydroxymethyl) furan-2-yl)-2-oxopyrimidin-4-yl)-N,N-dimethylformamidine of Formula (Ia):

Cytidine Formula (Ia)
[00071] DMF-DMA mixture (58.8gm, 0.493mol) was charged into a clean dried round bottom flask (RBF) to this slowly as batch wise cytidine (100.0g, 0.4311 mol) was added over a period of time at 10-35°C and stirred for 15-30 mins at same temperature. The reaction mixture temperature was raised up to reflux temperature of 60-90°C with chilled cooling condenser. The reaction mixture was maintained for 5-10 hrs at the same temperature and reaction progress was monitored by TLC up to disappearance of the starting material. When TLC showed that cytidine was disappeared. The reaction mixture was evaporated under reduced pressure to give the titled compound of Formula (Ia) (120.0gm,97.87% and HPLC purity 95%).
[00072] 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.83 (d, 1H), 5.95 (d, 1H),5.70(d,1H),3.54(s,2H)3.16(s,3H),3.03(s,3H)2.89(s,1H),2.73(s,1H).
[00073] MS (ESI) calculated for C12H18N4O5:298.3[M+H] observed at :299.3.
Example 1(b)
Preparation of N'-(1-((3aR,4R,6R,6aR)-2-(dimethylamino)-tetrahydro-4-(hydroxymethyl)furo[3,4-d][1,3]dioxol-6-yl)-1,2-dihydro-2-oxopyrimidin-4-yl)-N,N-dimethylformamidine(Formula-Ib):
Cytidine Formula (Ib)
[00074] DMF-DMA mixture (293.96gm, 2.46mol) was charged into a clean dried round bottom flask (RBF) to this slowly as batch wise cytidine (100.0g, 0.4311 mol) was added over a period of time at 10-35°C and stirred for 15-30 mins at same temperature. The reaction mixture temperature was raised up to reflux temperature of 60-90°C with chilled cooling condenser. The reaction mixture was maintained for 5-10 hrs at the same temperature and reaction progress was monitored by TLC up to disappearance of the starting material. When TLC showed that cytidine was disappeared. The reaction mixture was evaporated under reduced pressure to give the titled compound of Formula (Ib) (125.0gm, 97.0% and HPLC purity 92%).
[00075] 1H NMR (500 MHz, DMSO-d6) 3.166 (s,6H), 3.037 (s,6H), 5.956-5.94(d,1H), 8.096-8.083(d,1H), 7.849-7.833(d,1H), 8.624(s,1H), 7.160-7.086(d,2H), 5.795 – 5.756 (dd,2H), 5.708 – 5.694 (d,1H), 3.95-3.92(d,1H)
[00076] MS (ESI) calculated for C15H23N5O5:353.37[M+H] observed at :354.5

Example 2
Preparation of ((2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate oxalate salt of Formula (II):
[00077] The compound ((2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate oxalate salt of Formula (II) was prepared by using either of the isobutyryl chloride, isobutyric anhydride, and acetone oxime O-isobutyryl ester separately as follows:
Example 2(a):

Formula (Ia) isobutyryl chloride Formula (II)
[00078] Into the reaction flask dichloromethane (100.0ml) was charged under nitrogen atmosphere then triethyl amine (68.0gm, 0.67mol) and 4-Dimethylaminopyridine (DMAP) (50mg) were added and then the compound of Formula (Ia) (0.35mol) into the reaction flask as per the mentioned order. The reaction mixture was cooled up to (-)5 to 0°C and slowly isobutyryl chloride (35.8gm,0.33mol) was added to the reaction mixture and maintained for about 1 hr at room temperature under N2 atmosphere. The TLC was carried out, when the TLC indicated the reaction was finished, the solvent was distilled under vacuum below 40°C and methanol was charged into the residue. The reaction mixture was stirred for 15-20mins then oxalic acid (60.0gm,0.67mol) was added. The reaction mixture was continued to be stirred for about 1hr at 60-65°C and finally the reaction mixture was cooled to 5-10°C and the final product was separated by filtration and dried to afford as compound of Formula (II) (126.0gm, 93.0%).
[00079] 1H NMR (500 MHz, D2O) 7.96(d,2H),6.239(d,1H),5.865(d,1H),4.38(d,2H), 4.36(m,2H), 4.23(m,1H), 3.21-(t,1H), 2.72 (S,6H), 1.309(t,1H) ,1.17(d,6H).
[00080] MS (ESI) calculated for C13H19N3O6:313.1[M+H] observed at :313.9.
Example 2(b):

Formula (Ia) isobutyric anhydride Formula (II)
[00081] Into the reaction flask dichloromethane (100.0ml) was charged under nitrogen atmosphere then triethyl amine (68.0gm, 0.67mol) and 4-Dimethylaminopyridine (DMAP) (50mg) were added and then the compound of Formula (Ia) (0.35mol) into the reaction flask as per the mentioned order. The reaction mixture was cooled up to (-)5 to 0°C and slowly isobutyric anhydride (53.0gm,0.33mol) was added to the reaction mixture and maintained for about 1 hr at room temperature under N2 atmosphere. The TLC was carried out, when the TLC indicated the reaction was finished, the solvent was distilled under vacuum below 40°C and methanol was charged into the residue. The reaction mixture was stirred for 15-20 mins then oxalic acid (60.0gm,0.67mol) was added. The reaction mixture was continued to be stirred for about 1hr at 60-65°C and finally the reaction mixture was cooled to 5-10°C and the final product was separated by filtration and dried to afford as compound of Formula (II) (120.0gm, 89.0%).
[00082] 1HNMR (500 MHz, D2O) 7.96(d,2H), 6.239(d,1H), 5.865(d,1H), 4.38(d,2H), 4.36(m,2H), 4.23(m,1H), 3.21(t,1H), 2.72(S,6H), 1.309(t,1H), 1.17(d,6H) as can be seen from NMR spectra in Fig. 1A.
[00083] MS (ESI) calculated for C13H19N3O6:313.1[M+H] observed at :313.9 as can be seen from Mass Spectra in FIG. 1B.

Example 2(c):

Formula (Ia) acetone oxime O-isobutyryl ester Formula (II)
[00084] Into the reaction flask dichloromethane (100.0ml) was charged under nitrogen atmosphere then triethyl amine (68.0gm, 0.67mol) and 4-Dimethylaminopyridine (DMAP) (50mg) were added and then the compound of Formula (Ia) (0.35mol) into the reaction flask as per the mentioned order. The reaction mixture was cooled up to (-)5 to 0°C and slowly acetone oxime O-isobutyryl ester (72.0gm, 0.50 mol) was added to the reaction mixture and maintained for about 1 hr at room temperature under N2 atmosphere. The TLC was carried out, when the TLC indicated the reaction was finished, the solvent was distilled under vacuum below 40°C and methanol was charged into the residue. The reaction mixture was stirred for 15-20 mins then oxalic acid (60.0gm,0.67mol) was added. The reaction mixture was continued to be stirred for about 1hr at 60-65°C and finally the reaction mixture was cooled to 5-10°C and the final product was separated by filtration and dried to afford as compound of Formula (II) (128.0gm, 94.0%).
Example-2(d):

Formula (Ib) isobutyric anhydride Formula (II)

[00085] Into the reaction flask dichloromethane (100.0ml) was charged under nitrogen atmosphere then triethyl amine (75.0gm, 0.67mol) and 4-Dimethylaminopyridine (DMAP) (50mg) were added and then the compound of Formula (Ib) (0.35mol) into the reaction flask as per the mentioned order. The reaction mixture was cooled up to (-)5 to 0°C and slowly isobutyric anhydride (60.0gm,0.5mol) was added to the reaction mixture and maintained for about 1 hr at room temperature under N2 atmosphere. The TLC was carried out, when the TLC indicated the reaction was finished, the solvent was distilled under vacuum below 40°C and methanol was charged into the residue. The reaction mixture was stirred for 15-20 mins then oxalic acid (60.0gm,0.67mol) was added. The reaction mixture was continued to be stirred for about 1hr at 60-65°C and finally the reaction mixture was cooled to 5-10°C and the final product was separated by filtration and dried to afford as compound of Formula (II) (120.0gm, 89.0%).
[00086] 1HNMR (500MHz,D2O), 7.96(d,2H), 6.239(d,1H), 5.865(d,1H), 4.38(d,2H), 4.36(m,2H), 4.23(m,1H), 3.21-(t,1H), 2.72 (S,6H), 1.309(t,1H), 1.17(d,6H).
[00087] MS (ESI) calculated for C13H19N3O6:313.1[M+H] observed at :313.9.
Example 3
Preparation of ((2R,3S,4R,5R)-3,4-dihydro-5-(4-(hydroxyamino)-2-oxopyrimidine-1(2H)-yl) tetrahydrofuran-2 -Base) methyl isobutyl ester of Formula (III):
[00088] The compound ((2R,3S,4R,5R)-3,4-dihydro-5-(4-(hydroxyamino)-2-oxopyrimidine-1(2H)-yl) tetrahydrofuran-2 -Base) methyl isobutyl ester of Formula (III) was prepared by using either of the hydroxylamine, hydroxylamine hydrochloride, and hydroxylamine sulphate separately as follows:

Example 3(a):

Formula (II) Formula (III)

[00089] Hydroxylamine hydrochloride (34.5gm,0.49mol) was added to the solution of oxalate salt compound of Formula (II) (100.0gm, 0.247mol) in 20% aqueous solution (200.0ml). The reaction mixture was stirred at 80℃ for about 3 hrs and the reaction progress was monitored by TLC. When the TLC indicated the disappearance of the starting material, the reaction mixture was cooled to room temperature and separated into two layers. The aqueous layer was extract with isopropyl alcohol (IPA) (200 ml). The IPA layer was concentrated to give the crude product. The crude product was dissolved in DM water and heated to about 50℃ and stirred for about 30mins. When the mixture was cooled to room temperature, the white solid was obtained by filtration, and dried to afford tittle compound of Formula (III) as white solid material (75.0gm, 91.8%, HPLC: 99.8%, Unknown :0.03%purity).
[00090] 1H NMR (500 MHz, CD3OD) δ 6.90(d, 1H), 5.81 (d, 1H), 5.61 (d,1H), 4.28 (d, 2H), 4.13 (t, 1H), 4.09 – 4.05 (m, 2H), 2.63 (multi 1H), 1.17 (dd, 6H).13CNMR (500MHz, CD3OD) δ 176.05, 149.5, 143.39, 129.9, 98.84, 87.82, 80.78, 72.05, 70.01, 63.94, 33.26, 18.85, 18.82.
[00091] MS (ESI) calculated forC13H20N3O7 330.12 [M +H]+ was found 330.37.

Example 3(b):

Formula (II) Formula (III)

[00092] Hydroxylamine (16.37gm,0.49mol) solution was added to the solution of oxalate salt compound of Formula (II) (100.0gm, 0.247mol) in 20% aqueous solution (200.0ml). The reaction mixture was stirred at 80℃ for about 3 hrs and the reaction progress was monitored by TLC. When the TLC indicated the disappearance of the starting material, the reaction mixture was cooled to room temperature and separated into two layers. The aqueous layer was extract with isopropyl alcohol (IPA) (200 ml). The IPA layer was concentrated to give the crude product. The crude product was dissolved in DM water and heated to about 50℃ and stirred for about 30mins. When the mixture was cooled to room temperature, the white solid was obtained by filtration, and dried to afford tittle compound of Formula (III) as white solid material (70.0gm, 85.7%, HPLC: 99.68%, Unknown :0.05% purity).
[00093] 1H NMR (500 MHz, CD3OD) δ 6.90(d, 1H), 5.81 (d, 1H), 5.61 (d,1H), 4.28 (d, 2H), 4.13 (t, 1H), 4.09 – 4.05 (m, 2H), 2.63 (multi 1H), 1.17 (dd, 6H).13CNMR (500MHz, CD3OD) δ 176.05, 149.5, 143.39, 129.9, 98.84, 87.82, 80.78, 72.05, 70.01, 63.94, 33.26, 18.85, 18.82.
[00094] MS (ESI) calculated for C13H20N3O7 330.12 [M +H]+ was found 330.37.

Example 3(c):

Formula (II) Formula (III)

[00095] Hydroxylamine sulphate (81.4gm,0.49mol) solution was added to the solution of oxalate salt compound of Formula (II) (100.0gm, 0.247mol) in 20% aqueous solution (200.0ml). The reaction mixture was stirred at 80℃ for about 3 hrs and the reaction progress was monitored by TLC. When the TLC indicated the disappearance of the starting material, the reaction mixture was cooled to room temperature and separated into two layers. The aqueous layer was extract with isopropyl alcohol (IPA) (200 ml). The IPA layer was concentrated to give the crude product. The crude product was dissolved in DM water and heated to about 50℃ and stirred for about 30mins. When the mixture was cooled to room temperature, the white solid was obtained by filtration, and dried to afford tittle compound of Formula (III) as white solid material (77.0gm, 94.3%, HPLC: 99.7%, Unknown:0.03% purity).
[00096] 1H NMR (500 MHz, CD3OD) δ 6.90(d, 1H), 5.81 (d, 1H), 5.61 (d,1H), 4.28 (d, 2H), 4.13 (t, 1H), 4.09 – 4.05 (m, 2H), 2.63 (multi 1H), 1.17 (dd, 6H).13CNMR (500MHz, CD3OD) δ 176.05, 149.5, 143.39, 129.9, 98.84, 87.82, 80.78, 72.05, 70.01, 63.94, 33.26, 18.85, 18.82 as can be seen from proton NMR spectra in FIG. 2A.
[00097] MS (ESI) calculated forC13H20N3O7 330.12 [M +H]+ was found 330.37 as can be seen from Mass spectra in FIG. 2B.
[00098] Further, XPRD spectrum as can be seen from FIG. 2C and Differential scanning calorimetry (DSC) graph seen from FIG. 2D shows that the polymorph formed is of crystalline nature.

ADVANTAGES OF THE INVENTION
[00099] The present disclosure pertains to an improved process for synthesis of 4-oxime-5`-(2-methylpropionyl) uridine compound molnupiravir which can be carried out involving minimum use of solvents and with minimum time cycle.
[000100] The present disclosure pertains to an improved process for synthesis of 4-oxime-5`-(2-methylpropionyl) uridine compound molnupiravir which can be carried out in commercially scalable and ecologically less hazardous manner.
[000101] The present disclosure pertains to an improved process for synthesis of 4-oxime-5`-(2-methylpropionyl) uridine compound molnupiravir which provides final end product in higher yields with high purity.