Published Patent

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See sections 10 & rule 13)
1. TITLE OF THE INVENTION
METHOD FOR PREPARING 4-OXIME-5`-(2-METHYLPROPIONYL) URIDINE,

INTERMEDIATES THEREOF AND PROCESS FOR PREPARING THE SAME
2. APPLICANT (S)
NAME NATIONALITY ADDRESS
Plot No. 68 & 69, Fifth Floor,

Jubilee Heights, Survey No. 66 &
Vijayasri Organics Private
IN 67, Jubilee Enclave, Madhapur,
Limited
Near Shilparamam, Hyderabad
- 500081, Telangana, India.
3. PREAMBLE TO THE DESCRIPTION
COMPLETE SPECIFICATION
The following specification particularly describes the invention and the manner in which it
is to be performed.
1
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`-
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-
10 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
15 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,
20 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.
25 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.
30 [0005] One of the synthetic routes as suggested in the patent application
WO2019113462, the process uses uridine as the starting material. This approach
2
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.
5 [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.
10 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
15 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
20 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
25 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
30 purifications to provide an industrially scalable and commercially and ecologically
viable synthesis process. There also remains an unmet need of intermediate
3
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
5 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.
10 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
15 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)-
20 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-
25 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-
30 oxopyrimidin-4-yl)-N,N-dimethylformamidine and process for preparing the same
carried out in absence of base and solvent; and an intermediate compound
4
((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-
5 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:
10 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
15 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.
20 [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:
25 i) providing an indeterminate compound of Formula (Ia) or (Ib) comprising
DMA) in equivalence of 1 to 6
5
(Me)2NHC N
N
N O
HO O
O O
H N(Me)2
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
5 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);
10
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
15 hydrochloride, or hydroxylamine sulphate.
[00019] In another aspect, the present disclosure provides a compound of
Formula (Ia) or (Ib):
(Me)2NHC N
N
N O
HO O
O O
H N(Me)2
Formula (Ia) (Ib);
6
[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-
5 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).
10 [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).
15 [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
20 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
25 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
7
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
5 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.
10
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.
15 [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
20 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).
25 [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
30 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
8
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
5 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
10 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
15 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.
20 [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
25 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
30 the broad scope of some embodiments of the invention are approximations, the
9
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
5 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
10 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
15 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.
20 [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
25 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-
30 oxime-5`-(2-methylpropionyl) uridine.
10
[00046] In one embodiment, the present disclosure provides a method for
preparing 4-oxime-5`-(2-methylpropionyl) uridine compound of Formula (III):
Formula (III)
5 in which, the method comprises:
i) providing an indeterminate compound of Formula (Ia) or (Ib) comprising
DMA) in equivalence of 1 to 6
(Me)2NHC N
N
N O
HO O
O O
H N(Me)2
10 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
15 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
11
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.
5 [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
10 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
15 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
20 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
25 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
30 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
12
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,
5 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.
10 [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`-
15 (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
20 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),
25 so that the method of this disclosure may be worked in a facile way and as a
commercial process of producing the molnupiravir.
13
NH2 (Me)2NHC N
N N
O
DMF-DMA TEA
N O N O +
HO O HO O DCM
Cl DMAP
Methanol
Oxalic acid
HO OH HO OH
Cytidine 1
Formula (Ia)
OH
NH2 HN
N N
N O O Hydroxylamine N O
O O OH O O
HO IPA/H2O
O O
O
HO OH HO OH
2 II 3
Formula Formula III .
[00058] In one embodiment, the present disclosure provides a compound of
Formula (Ia) or (Ib):
(Me)2NHC N
N
N O
HO O
O O
H N(Me)2
5 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)
10 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
15 a compound of Formula (Ia) or (Ib).
14
[00061] In one embodiment, the present disclosure provides a compound of
Formula (II):
Formula (II).
5 [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;
10 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
free base; and
c) optionally converting the compound of Formula (II) free base into a salt by
15 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
20 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
25 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
15
for preparing the compound of Formula II avoids or minimises the formation of
diacetyl impurity having structural formula as:
O
HN
N
N O
O O
O
HO OH
Diacetyl impurity
5 [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.
10 [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:
OH
HN
N
N O
HO O
HO OH
Hydroxy Impurity
15 [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
20 process and the process can be carried out in less ecological hazardous manner.
16
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
5 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
10 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-
15 (hydroxymethyl) furan-2-yl)-2-oxopyrimidin-4-yl)-N,N-dimethylformamidine
of Formula (Ia):
NH2 (Me)2NHC N
N N
DMF-DMA
N O N O
HO O HO O
HO OH HO OH
Cytidine Formula (Ia)
[00071] DMF-DMA mixture (58.8gm, 0.493mol) was charged into a clean dried
20 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
25 up to disappearance of the starting material. When TLC showed that cytidine was
disappeared. The reaction mixture was evaporated under reduced pressure to give
17
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.
5 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):
NH2 (Me)2NHC N
N N
DMF-DMA
N O N O
HO O HO O
HO OH O O
H N(Me)2
10 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
15 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
20 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
25
18
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):
5 [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):
NH2
(Me)2NHC N
N
N
O TEA N O O
N O + O O OH
HO O DCM HO
Cl DMAP O O
Methanol
Oxalic acid OH
HO
10 HO OH
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-
15 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
20 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
25 afford as compound of Formula (II) (126.0gm, 93.0%).
19
[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).
5 Example 2(b):
NH2
(Me)2NHC N
N
N O
O TEA N O O
N O + O O OH
HO O DCM HO
O DMAP O
Methanol O
Oxalic acid OH
HO
HO OH
Formula (Ia) isobutyric anhydride Formula (II)

10 nitrogen atmosphere then triethyl amine (68.0gm, 0.67mol) and 4-
Dimethylaminopyridine (DMAP) (50mg) were added and then the compound of
reaction mixture was cooled up to (-)5 to 0°C and slowly isobutyric anhydride
15 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
for 15-20 mins then oxalic acid (60.0gm,0.67mol) was added. The reaction mixture
20 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.
25 [00083] MS (ESI) calculated for C13H19N3O6:313.1[M+H] observed at :313.9 as
can be seen from Mass Spectra in FIG. 1B.
20
Example 2(c):
NH2
(Me)2NHC N
N
N O
N TEA N O O
N O + O O O OH
HO O DCM HO
DMAP O O
Methanol
Oxalic acid OH
HO
HO OH
Formula (Ia) acetone oxime O-isobutyryl ester Formula (II)

5 [00084] Into the reaction flask dichloromethane (100.0ml) was charged under
reaction mixture was cooled up to (-)5 to 0°C and slowly acetone oxime O-
10 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
15 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):
(Me)2NHC N NH2
N N
O
N O O TEA N O O
HO O O O OH
+
DCM HO
O DMAP O
Methanol O
O O Oxalic acid
HO OH
20 H N(Me)2
Formula (Ib) isobutyric anhydride Formula (II)
21
Formula (Ib) (0.35mol) into the reaction flask as per the mentioned order. The
5 reaction mixture was cooled up to (-)5 to 0°C and slowly isobutyric anhydride
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
10 for 15-20 mins then oxalic acid (60.0gm,0.67mol) was added. 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),
15 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).
Example 3
Preparation of ((2R,3S,4R,5R)-3,4-dihydro-5-(4-(hydroxyamino)-2-
20 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
25 hydrochloride, and hydroxylamine sulphate separately as follows:
30
22
Example 3(a):
OH
NH2 HN
N N
N O O Hydroxylamine hydrochloride N O
O O OH O O
HO IPA/H2O
O O
O
HO OH HO OH
Formula (II) Formula (III)

5
[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
10 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,
15 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,
20 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.
25
23
Example 3(b):
OH
NH2 HN
N N
N O O Hydroxylamine N O
O O OH O O
HO IPA/H2O
O O
O
HO OH HO OH
Formula (II) Formula (III)

5
[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
10 disappearance of the starting material, the reaction mixture was cooled to room
and stirred for about 30mins. When the mixture was cooled to room temperature,
15 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).
4.28 (d, 2H), 4.13 (t, 1H), 4.09 – 4.05 (m, 2H), 2.63 (multi 1H), 1.17 (dd,
20 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.
25
24
Example 3(c):
OH
NH2 HN
N N
N O O Hydroxylamine sulphate N O
O O OH O O
HO IPA/H2O
O O
O
HO OH HO OH
5 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
10 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
15 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).
20 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
25 330.37 as can be seen from Mass spectra in FIG. 2B.
25
[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.
5 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.
10 4-oxime-5`-(2-methylpropionyl) uridine compound molnupiravir which can be
carried out in commercially scalable and ecologically less hazardous manner.
4-oxime-5`-(2-methylpropionyl) uridine compound molnupiravir which provides
final end product in higher yields with high purity.
15
26
We Claim:
1. A method for preparing 4-oxime-5`-(2-methylpropionyl) uridine compound

of Formula (III)
5
Formula (III)
the process comprises:
i) providing an indeterminate compound of Formula (Ia) or (Ib) comprising
10 DMA) in equivalence of 1 to 6
(Me)2NHC N
N
N O
HO O
O O
H N(Me)2
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
15 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);
27
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
5 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
10 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
15 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
20 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).
25 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
28
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.
5 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).
10 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
15 (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
20 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):
(Me)2NHC N
N
N O
HO O
O O
(or) H N(Me)2
Formula (Ia) (Ib);

25 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
29
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,
5 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).
10 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):
15
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
20 solvent and cooling the mixture to about 0°C to about (-) 5°C;
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
25 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
30
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
5 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.
10 For Vijayasri Organics Private Limited
Tarun Khurana
Regd. Patent Agent [IN/PA-1325]
Dated: 07th September, 2021
15
31
ABSTRACT
METHOD FOR PREPARING 4-OXIME-5`-(2-METHYLPROPIONYL)
URIDINE, INTERMEDIATES THEREOF AND PROCESS FOR
PREPARING THE SAME
5
The present disclosure relates to an efficient 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-
10 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.
15
For Vijayasri Organics Private Limited
Tarun Khurana
Regd. Patent Agent [IN/PA-1325]
20 Dated: 07th September, 2021
32

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FORM 2

THE PATENTS ACT, 1970

The Patent Rules, 2003

(See sections 10 & rule 13)

1. TITLE OF THE INVENTION

METHOD FOR PREPARING 4-OXIME-5`-(2-METHYLPROPIONYL) URIDINE,

NAME NATIONALITY ADDRESS

Plot No. 68 & 69, Fifth Floor,

BACKGROUND OF THE INVENTION

10 OBJECTS OF THE INVENTION

Formula (Ia) (Ib);

Formula (Ia) (Ib);

DETAILED DESCRIPTION OF THE INVENTION

10 Formula (Ia) (Ib);

Formula (II); and

5 Formula (Ia) (Ib);

Formula (Ia) isobutyryl chloride Formula (II)

Formula (Ia) isobutyric anhydride Formula (II)

Formula (Ia) acetone oxime O-isobutyryl ester Formula (II)

Formula (Ib) isobutyric anhydride Formula (II)

Formula (II) Formula (III)

Formula (II) Formula (III)

5 Formula (II) Formula (III)

[00095] Hydroxylamine sulphate (81.4gm,0.49mol) solution was added to the

5 ADVANTAGES OF THE INVENTION

1. A method for preparing 4-oxime-5`-(2-methylpropionyl) uridine compound

Formula (Ia) or (Ib);

Formula (Ia) (Ib);

10 For Vijayasri Organics Private Limited

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