DESC:Field of the Invention:
The present application relates to an improved process for the preparation of
Penciclovir, and intermediates thereof; which is represented by the following structural
formula-I.
5
Formula-I
Background 10 of the Invention:
Penciclovir, has a chemical name 2-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)
butyl]-6H-purin-6-one. Penciclovir is a guanosine analogue antiviral drug used for the
treatment of various herpesvirus infections. It is a nucleoside analogue which exhibits low
toxicity and good selectivity. Because penciclovir is absorbed poorly when given orally (by
15 mouth) it is more often used as a topical treatment. Famciclovir is a prodrug of penciclovir
with improved oral bioavailability. Penciclovir was approved in USA as 1 % topical cream
for the treatment of various herpesvirus infections.
The US patent No. US5075445 (herein after designated as US’445) first reported penciclovir
as product and process for preparation thereof. The process for preparation of Penciclovir
20 was represented in scheme-1.
The US patent No. US4798833 covers a process for preparation of penciclovir and
intermediates thereof.
The US patent No. US5175288A covers a process for preparation of penciclovir and
intermediates thereof.
3
Scheme-I: The process reported in US’445.
Scheme-II: The process reported in US’445.
5
There are various processes reported for the preparation of penciclovir and
intermediates thereof, using different solvents and reagents.
4
Based on draw back of the prior art processes, there is a need for providing an
improved process for the preparation of penciclovir and salts thereof, which involves simple
experimental procedures, well suited to industrial production, which avoids the use of
column chromatography purification, and which affords high pure penciclovir and salts
5 thereof.
The present invention provides an improved process for preparation of penciclovir
and salts thereof, which is efficient, industrially viable and cost effective.
Brief Description :
10 The first aspect of the present invention is to provide an improved process for the
preparation of the compound of formula-I.
The second aspect of the present invention provides an improved process for the
preparation of compound of formula-2.
The third aspect of the present invention provides an improved process for the
15 preparation of compound of formula-7.
Brief description of the drawings:
Figure 1: Illustrates the PXRD pattern of crystalline Form-M of Penciclovir compound of
formula-I.
20 Figure 2: Illustrates the IR spectrum of crystalline Form-M of of Penciclovir compound of
formula-I.
Figure 3: Illustrates the PXRD pattern of crystalline Form-M of Penciclovir compound of
formula-I according to example-5
25 Detailed Description:
As used herein the term “suitable solvent” used in the present invention refers to
“hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petether, toluene, pentane,
cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as
dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene
30 glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether,
5
diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl
ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl
acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as
dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), Nmethylpyrrolidone
(NMP) and the like; “chloro solvents” such 5 as dichloromethane,
dichloroethane, chloroform, carbontetra chloride and the like; “ketone solvents” such as
acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as
acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol,
ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-
10 fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-ethoxyethanol,
diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol
monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar
solvents” such as water or mixtures thereof.
As used herein the present invention the term “suitable base” refers to inorganic or
15 organic base. Inorganic base refers to “alkali metal carbonates” such as sodium carbonate,
potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as
sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as
sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal
alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium
20 ethoxide, sodium tert.butoxide, potassium tert-butoxide, lithium tert-butoxide and the like;
alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the
like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like;
and organic bases such as like dimethylamine, diethylamine, diisopropyl amine, diisopropyl
ethylamine, diisobutylamine, triethylamine, pyridine, piperidine, 4-dimethyl amino pyridine
25 (DMAP), N-methyl morpholine (NMM), or mixtures thereof.
The term “reducing” agent used in the present invention refers suitable reducing reagents are
selected from Lithium aluminium hydride, sodium borohydride, BF3 etherate solution, Pd/C,
Ray-nickel;
The term “protecting” agent / group (PG) used in the present invention refers to a suitable
30 protecting reagents that are selected selected from di-tert-butyl dicarbonate, chlorobenzyl
6
formate, benzoylchloride, benzylbromide, benzylchloride, acetylchloride, fluorenyl
methyloxy carbonyl chloride; The term “phase transfer catalyst (PTC)” used in the present
invention refers are selected from triethylbenzyl ammonium chloride, tetrabutyl ammonium
bromide, tetrabutyl ammonium chloride, tetrabutyl ammonium acetate, methyl tributyl
ammonium chloride, tetrabutyl ammonium hydroxide, tributylbenzylammonium 5 chloride;
The first aspect of the present invention provides an improved process for the
preparation of compound of formula-I
10 Formula-I
comprising of:
a) Reacting the compound of formula-1
Formula-1
15 with ethylchloroformate, suitable reagent, suitable solvent to provide compound of formula-
1a, further reacting with potassium tert-butoxide to provide potassium salt of compound of
formula-1a, further reacting with dibromo ethane to get compound of formula-2,
Formula-2
20
b) reacting the compound of formula-2 with compound of formula-3
7
Formula-3
with suitable reagent, solvent to provide compound of formula-4, optionally purifying in
suitable solvent to get pure 5 compound of formula-4,
Formula-4
c) reacting the compound obtained in step-b) with sodium methoxide, suitable solvent to
provide compound of formula-5, further reducing with sodium borohydride in suitable
10 solvent to provide of compound of formula-6, further protecting with acetic anhydride in
presence of organic base to provide compound of formula-7,
15 Formula-5 Formula-6 Formula-7
d) reacting the compound obtained in step-c) with suitable reagents to provide compound of
formula-I ,
8
Formula-I
e) optionally purifying the compound obtained in step-d) using a suitable solvent to provide
the title compound.
5
wherein in step-a) the suitable solvent is selected from chloro solvents, ether, protic polar,
aprotic polar, polar, dimethylformamide, dimethylsulfoxide, NMP, toluene, alcohol or any
mixture thereof; suitable reagents are magnesium, iodine, 1,2-dibromoethane, 1,2-dichloro
ethane, 1-chloro-2-bromo ethane and mixture thereof; base is selected from organic base,
inorganic base; suitable temperature 10 : 0-100°C; pH range 0-4;
wherein in step-b) the suitable solvent is selected from non polar solvent, chloro solvents,
ketone solvents, ester solvents, polar solvents, alcohol solvents, polar aprotic solvents, polar
protic solvents, toluene, water or any mixture thereof; suitable base inorganic base,
potassium carbonate, sodium carbonate and organic base mixture thereof; suitable
15 temperature : 0-100°C.
wherein in step-c) the suitable solvent is selected from alcohol solvent, chloro solvents, ether
solvents, ketone solvents, ester solvents, polar solvents, polar aprotic solvents, polar protic
solvents or water any mixture thereof; organic base such as triethylamine, diisopropyl ethyl
amine, diisopropylamine, inorganic base and mixture thereof. The pH range 0-4;
20 wherein in step-d) the suitable reagent is hydrochloric acid, sodium hydroxide, lithium
hydroxide, potassium hydroxide and mixture thereof; the suitable solvent is selected from
alcohol solvent, chloro solvents, ether solvents, ketone solvents, toluene, ester solvents, polar
solvents, polar aprotic solvents, polar protic solvents or water any mixture thereof. The pH
range 0-12 ; wherein in step-e) the suitable solvent is selected from chloro solvents, ether
25 solvents, ketone solvents, toluene, ester solvents, polar solvents, alcohol solvents, polar
aprotic solvents, polar protic solvents or water any mixture thereof;
9
The preferred embodiment of the present invention provides an improved process for the
preparation of compound of formula-I
Formula-I
5 comprising of:
a)Reacting the compound of formula-1
Formula-1
with ethylchloroformate, magnesium, 1,2-dibromoethane in ethanol to produces compound
10 of formula-1a,
b)reacting the compound obtained in step-a) with potassium tert-butoxide in ethanol to
provide compound of formula-1b,
15 Formula-1b
c) reacting the compound obtained in step-b) with 1,2-dibromoethane in presence of
potassium carbonate in DMF to get compound of formula-2,
10
Formula-2
d)reacting the compound of formula-2 with compound of formula-3,
5 Formula-3
in presence of potassium carbonate in NMP to provide compound of formula-4,
Formula-4
e)reacting the compound obtained in step-d) with sodium methoxide in methanol to get the
10 compound of formula-5,
Formula-5
f)reducing the compound obtained in step-e) with sodium borohydride in dichloromethane,
methanol to provide compound of formula-6,
11
Formula-6
g) protecting the compound obtained in step-f) with acetic anhydride in presence triethyl
amine, dimethyl aminopyridine in dichloromethane to provide compound of formula-7,
5
Formula-7
h)reacting the compound obtained in step-g) with hydrochloric acid followed by sodium
hydroxide to provide compound of formula-I,
10 Formula-I
i) purifying the compound obtained in step-h) in water to provide the title compound-I.
The second aspect of the present invention provides an improved process for the
preparation of compound of formula-2,
15
Formula-2
12
comprising of:
a)Reacting the compound of formula-1
Formula-1
with ethyl chloroformate, magnesium, 1,2-dibromoethane in ethanol 5 to produce compound
of formula-1a,
Formula-[1a]
b)reacting the compound obtained in step-a) with potassium tert-butoxide in ethanol to
10 provide compound of formula-1b,
Formula-1b
c) reacting the compound obtained in step-b) with dibromoethane in presence of potassium
carbonate in DMF to get compound of formula-2,
15
Formula-2
Other embodiment of the present invention is preparing various salts of compound of
formula-1b, to remove the impurities. Without purification of formula-1b there is a
possibility to form various impurities in the subsequent reactions. The formed impurity
20 compounds removal is needed various purification's, time taking process and impact on
time and yields.
13
Other embodiment of the present invention is a compound of formula-A
formula-A
Wherein M is potassium, sodium, Lithium, caesium, calcium, 5 Magnesium, strontium
and barium.
The third aspect of the present invention provides an improved process for the
preparation of compound of formula-7,
10 Formula-7
comprising of
a) reacting the compound of formula-4,
15 Formula-4
with sodiummethoxide in methanol to get the compound of formula-5,
14
Formula-5
b)reducing the compound obtained in step-a) with sodium borohydride in dichloromethane,
methanol to provide compound of formula-6,
5
Formula-6
c) protecting the compound obtained in step-b) with acetic anhydride in presence triethyl
amine, dimethyl aminopyridine in dichloromethane to provide compound of formula-7,
10
Formula-7
The other aspect of the present invention is a purification process for the preparation
of compound of formula-I, comprising of;
a ) Stirring penciclovir in presence of base 15 in suitable solvent,
b) isolating the penciclovir salt,
c) acidifying the compound obtained in step-b) using the suitable acid,
15
d) stirring the compound obtained in step-c) in a suitable solvent,
e) isolating the compound obtained is step-d) and dried to get the title compound.
Wherein the suitable solvents are selected form alcohol solvents, chloro solvents, ether
solvents, ketone solvents, toluene, ester solvents, polar solvents, polar aprotic 5 solvents, polar
protic solvents or water any mixture thereof. wherein the suitable acids and bases are
hydrochloric acid, hydrobromic acid, sodium hydroxide, lithium hydroxide, potassium
hydroxide and mixture thereof; the suitable temperature is 10-100°C.
10 The preferred embodiment of the present invention a purification process for the
preparation of compound of formula-I, comprising of;
a )Stirring penciclovir in presence of potassium hydroxide in acetone and water,
b) filtering the penciclovir potassium salt,
c)acidifying the compound obtained in step-b) using Conc.HCl,
15 d)stirring the compound obtained in step-c) in water,
e) filtering the compound obtained is step-d) and dried to get the title compound.
The preferred embodiment of the present invention a process for the preparation of
crystalline form-M of Penciclovir,
comprising of:
20 a) Stirring penciclovir in presence of potassium hydroxide solution in acetone,
b) filtering the penciclovir potassium salt,
c)acidifying the compound obtained in step-b) using Conc.HCl,
d) stirring the compound obtained in step-c) in water,
e) filtering the compound obtained is step-d) and drying to get the title compound.
25
The process for the preparation of compound of formula-I developed by the present
inventors produces highly pure compound of formula-I with good yield. All the related
substances and residual solvents are controlled well within the limits as suggested by ICH
guidelines and most of the related substances are controlled in non-detectable levels.
16
The compound of formula-I produced by the process of the present invention is
having purity of greater than 99.5%, preferably greater than 99.7%, more preferably greater
than 99.9% by HPLC.
The present invention described as follows in a schematic 5 representation :
10 The patent US5075445 first reported penciclovir as product and processes thereof.
The US’445 reported a purification process for penciclovir, recrystallized from water to give
pure 9-(4-hydroxy-3-hydroxy methylbut-1-yl)guanine compound of formula-I as a white
crystalline solid, with Melting range (MR) as 275°-277°C.
17
The present invention also repeated the same process reported in US’445, Penciclovir was
purified, i.e.recrystallized from water and dried to get a white crystalline solid and designated
as crystalline form- M of Penciclovir, complies the MR with the reported value.
The crystalline Form-M of penciclovir is characterized by its powder X-Ray
diffraction pattern having peaks at about 7.5, 11.03, 14.7, 15.10, 17.16, 5 17.92, 19.15, 20.00,
20.34, 21.25, 21.96, 22.90, 23.18, 24.29, 24.69, 25.69, 26.14, 27.91, 30.58, 31.68, 33.85,
34.84 & 39.56 ± 0.2° 2è. The said crystalline Form-M is further characterized by its powder
X-Ray diffraction pattern substantially in accordance with figure-1, by its IR spectrum shown
in figure-2 .
10 The process described in the present invention was demonstrated in examples
illustrated below. These examples are provided as illustration only and therefore should not
be construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of compound of formula-2.
15 A round bottom flask was charged with ethanol (150 mL), magnesium (15.17 g) and
1,2-dibromo ethane (11.7 g), heated to 55-65°C and stirred for 45 min. A solution of
compound of formula-1(100 g) in ethanol (100 mL) was added slowly to the reaction
mixture and stirred for 4 hr at 55-65°C. The reaction mixture was cooled to 25-35°C,
added a solution of ethylchloro formate (101.62 g) in THF (100 mL) and heated to 55-
20 65°C stirred for 1 hr. Cooled the reaction mixture to 25°C, stirred for 12 hr and charged
with water (200 mL) adjusted the pH to 2.5 with Con. HCl. The reaction mixture was
charged with ethyl acetate (600 mL), separated the layers. The aqueous layer was
extracted with ethyl acetate (2 x 200 mL). The combined organic layer was washed
with brine solution (100 mL) and evaporated the solvent. The obtained crude
25 compound was charged to a solution of potassium tertiary butoxide (63.05 g) in ethanol
(260 mL) stirred for 2 hr at 25-35°C. Filtered the obtained solid and washed with
ethanol (25 mL). The obtained compound was charged to a solution of potassium
carbonate (28.40 g) in DMF (360 mL), heated to 55-65°C stirred for 45 min and
charged with 1,2-dibromoethane (117.25 g) and stirred for 4 h. Cooled the reaction
30 mixture to 25-35°C, charged with chilled water (600 mL), toluene (400 mL) and stirred
18
for 15 min and separated the layers. The combined organic layers were washed with
water and evaporated to get the title compound.
Yield:116 g ; Purity by GC: 93.92%; HIUI:1.51%.
Example-2: Preparation of compound of formula-4.
A round bottom flask was charged with compound of formula-5 3 (100 g), compound of
formula-2 (219.75 g) and potassium carbonate (122 g) in N-Methyl-2-pyrrolidone (500
mL) the resulting mixture was heated to 45-50 °C, stirred for 26 hr. Cooled the reaction
mass to 25-35°C, charged with water (1L) stirred for 2 hr. Filtered the obtained solid
and washed with water (100 mL). The wet compound slurried in water (1 L) and n10
heptane (500 mL) and isolated the title compound.
Yield:175 g
Example-3: Preparation of compound of formula-7.
A round bottom flask was charged with compound of formula-4 (50 g) in methanol
(300 mL:), followed by a solution of sodium methoxide (25 g) in methanol (50 mL) at
15 5-15°C and stirred for 3 hr. Cooled the reaction mass to 5-10°C, filtered the
precipitated solid and washed with methanol (25 mL) to get the wet compound of
formula-5. The obtained compound was charged with dichloromethane (120 mL),
sodium borohydride (9.66 g), slowly added methanol (50 mL) at 5-10°C and the
reaction mass stirred at 25-35°C for 2 hr. Cooled the reaction mass to 0-10°C, adjusted
20 the pH to 6.5 with HCl stirred for 3 hr. Filtered the obtained compound and washed
with water (15 mL) to get compound of formula-6. The obtained wet compound was
charged with dichloromethane (175 mL), dimethyl amino pyridine (0.81 g), triethyl
amine (26.8 g) followed by acetic anhydride (26.8 g) at 25-35°C. The reaction mass
was heated to 35-45°C and stirred for 3 hr. Cooled the reaction mass to 25-35°C added
25 NaHCO3 solution (5 g in 50 mL of water). The both layers were separated, organic
layer was washed with water (50 mL). The organic layer was dried, distilled
completely, co-distilled with methanol (15 mL). The crude material was stirred in a
mixture of methanol (56 mL) and water (18 mL), heated to 55-65°C stirred for 45 min.
Cooled the reaction mixture, filtered the obtained solid and washed with methanol (13
30 mL) and water (5 mL), dried to get the title compound.
19
Yield: 20 g
Example-4: Preparation of compound of formula-I.
A compound of formula-7 (50 g) was charged to a round bottom flask containing a premixed
solution of Con.HCl (60 mL), water (450 mL) and heated to 90-100°C for 40 hr. The
reaction mixture was cooled to 0-5°C, adjusted the pH to 11.5 with aq. 5 sodium hydroxide (50
g in 125 mL of water), stirred at 25-35°C for 2 hr. The reaction mixture was cooled to 0-5°C
and adjusted the pH to 6.5 with Con. HCl (12 mL) and stirred for 2 hr. Filtered the obtained
solid and recrystallized from water (100 mL) to get the title compound.
Yield: 20 gr . The obtained PXRD depicted in figure-1.
10 Purity by HPLC: 99.5 %. M.R: 275°-277°C
Example-5: Purification of compound of formula-I.
A round bottom flask charged with Penciclovir (100 g), water (150 mL) and potassium
hydroxide (44.3 g in 100 mL water) stirred for 10 mints. The reaction mixture was added to a
mixture of acetone (800 mL) and methanol (200 mL) at 25-35°C, heated to 40-50°C and
15 stirred for 1 hr. The reaction mixture was cooled to 25-35°C, stirred for 1 hr, the precipitated
solid was filtered, and washed with atetone (80 mL), methanol (20 mL).
The wet compound was charged with water (1450 mL), carbon (2 g) and stirred for 15 min at
25-35°C. Filtered the reaction mixture through hyflo, washed with water (30 mL) and
adjusted the filtrate solution pH to 6.5 with Conc.HCl (70 mL), the precipitated solid was
20 heated to 90-100°C, stirred for 45 min. The solution was cooled to 25-35°C, stirred for 1.5 hr.
Filtered the obtained solid, washed with water (100 mL) and dried to get the title compound.
Yield: 70.5 g; M.R: 275°-277°C
The obtained PXRD is similar to the figure-3.
Example-6: Purification of compound of formula-I.
25 A round bottom flask charged with Penciclovir (25 gr), water (250 ml) was heated to 90-
100°C and stirred for 1 hr. The reaction mixture was cooled to 0-5°C, the precipitated solid
was filtered, and dried to get the title compound.
Yield: 17.5 gr . The obtained PXRD is similar to the figure-1.
M.R: 275°-277°C ,CLAIMS:We Claim:
1. An improved process for the preparation of compound of formula-2,
5 Formula-2
Comprising of :
a)Reacting the compound of formula-1
Formula-1
10 with ethyl chloroformate, magnesium, 1,2-dibromoethane in ethanol to produce compound
of formula-1a,
Formula-[1a]
b) reacting the compound obtained in step-a) with potassium tert-butoxide in ethanol to
15 provide compound of formula-1b,
Formula-1b
c) reacting the compound obtained in step-b) with dibromoethane in presence of potassium
carbonate in DMF to get compound of formula-2.
20
21
2. A process for the preparation of compound of formula-I
Formula-I
comprising of:
a) Reacting the 5 compound of formula-1
Formula-1
with ethylchloroformate, magnesium, 1,2-dibromoethane in ethanol to produces compound
of formula-1a,
10
b) reacting the compound obtained in step-a) with potassium tert-butoxide in ethanol to
provide compound of formula-1b,
Formula-1b
15 c) reacting the compound obtained in step-b) with 1,2-dibromoethane in presence of
potassium carbonate in DMF to get compound of formula-2,
22
Formula-2
d) reacting the compound of formula-2 with compound of formula-3,
5 Formula-3
in presence of potassium carbonate in NMP to provide compound of formula-4,
Formula-4
e) reacting the compound obtained in step-d) with sodium methoxide in methanol to get the
10 compound of formula-5,
Formula-5
f) reducing the compound obtained in step-e) with sodium borohydride in dichloromethane,
methanol to provide compound of formula-6,
23
Formula-6
g) protecting the compound obtained in step-f) with acetic anhydride in presence triethyl
amine, dimethyl aminopyridine in dichloromethane to provide compound of formula-7,
5
Formula-7
h) reacting the compound obtained in step-g) with hydrochloric acid followed by sodium
hydroxide to provide compound of formula-I,
10 Formula-I
i) purifying the compound obtained in step-h) in water to provide the title compound-I.
3. A purification process for the preparation of compound of formula-I,
Comprising of;
15 a ) Stirring penciclovir in presence of base in suitable solvent,
b) isolating the penciclovir salt,
c) acidifying the compound obtained in step-b) using the suitable acid,
d) stirring the compound obtained in step-c) in a suitable solvent,
e) isolating the compound obtained is step-d) and drying to get the title compound.
24
4. The process as claimed in claim 3 wherein the suitable solvents is selected form alcohol
solvent, chloro solvents, ether solvents, ketone solvents, toluene, ester solvents, polar
solvents, polar aprotic solvents, polar protic solvents or water any mixture thereof. wherein
the suitable acids and bases are hydrochloric acid, sodium hydroxide, 5 lithium hydroxide,
potassium hydroxide and mixture thereof; the suitable temperature is 10-100°C.
5. A purification process for the preparation of compound of formula-I,
Comprising of;
10 a ) Stirring penciclovir in presence of potassium hydroxide in acetone and water,
b) filtering the penciclovir potassium salt,
c) acidifying the compound obtained in step-b) using Conc.HCl,
d) stirring the compound obtained in step-c) in water,
e) filtering the compound obtained is step-d) and drying to get the title compound.
15
6. A process for the preparation of crystalline form-M of Penciclovir,
Comprising of:
a) Stirring penciclovir in presence of potassium hydroxide solution in acetone,
b) filtering the penciclovir potassium salt,
20 c)acidifying the compound obtained in step-b) using Conc.HCl,
d) stirring the compound obtained in step-c) in water,
e) filtering the compound obtained is step-d) and drying to get the title compound.
Dated this day: 06- April-2021.
25
Authorized Signatory
(Chakilam Nagaraju)
Maithri Drugs Private Limited