Development of an optimized process for the preparation of 1-benzylazetidin-3-ol: An industrially important intermediate for substituted azetidine

Article abstract of DOI:10.1021/op100247m

A thoroughly optimized and robust process for the synthesis of 1-benzylazetidin-3-ol has been emphasized. 1-Benzylazetidin-3-ol has been utilized as a starting material in the commercial synthesis of azetidin-3-ol hydrochloride. Synthesis of azetidin-3-ol hydrochloride involves the usage of very low cost and commercially available starting material (benzylamine) and with reduced formation of di(3-chloro-2-hydroxypropyl) benzylamine significantly resulting in an economical process that allows the effective production of 1-benzyl azetidin-3-ol as well as azetidin-3-ol hydrochloride.

Full text of DOI:10.1021/op100247m

TECHNICAL NOTE
pubs.acs.org/OPRD
Development of an Optimized Process for the Preparation of
1-Benzylazetidin-3-ol: An Industrially Important Intermediate
for Substituted Azetidine
V. V. R. M. Krishna Reddy,† D. Udaykiran,† U.S. Chintamani,† E. Mahesh Reddy,†
Ch. Kameswararao,§ and G. Madhusudhan*,†
†Research and Development, Inogent Laboratories Private Limited, (A GVK BIO Company), 28A, IDA, Nacharam,
Hyderabad, Andhra Pradesh 500076, India
§Analytical Research and Development, Inogent Laboratories Private Limited, (A GVK BIO Company), 28A, IDA,
Nacharam, Hyderabad, Andhra Pradesh 500076, India
S Supporting Information
b
ABSTRACT: A thoroughly optimized and robust process for the synthesis of 1-benzylazetidin-3-ol has been emphasized.
1-Benzylazetidin-3-ol has been utilized as a starting material in the commercial synthesis of azetidin-3-ol hydrochloride. Synthesis of
azetidin-3-ol hydrochloride involves the usage of very low cost and commercially available starting material (benzylamine) and with
reduced formation of di(3-chloro-2-hydroxypropyl) benzylamine significantly resulting in an economical process that allows the
effective production of 1-benzyl azetidin-3-ol as well as azetidin-3-ol hydrochloride.
Scheme 1. Synthesis of 1-benzhydrylazetidin-3-ol, 1a
1. INTRODUCTION
Drugs comprising azetidine derivatives have been thoroughly
investigated for their pharmacological and biological effects.1
The number of recent research articles provides evidence of the
large use of the azetidine ring system in medicinally important
molecules.1 Among the various derivatives of azetidines, 3-sub-
stituted azetidine is most important constituent in various
potential therapeutic moieties.1 The required synthetic azetidine
compounds are gaining much attention in the pharmaceutical
industry as well as drug discovery for the synthesis of drugs
comprising azetidine derivatives. Several research articles de-
scribe the synthesis of 3-substituted azetidines.1,2 Recently, we
reported an improved, one-pot, and multikilogram-scale synthe-
sis of 1-benzhydrylazetidin-3-ol, 1a (Scheme 1) starting from
benzhydrylamine, 2a and epichlorohydrin 3 via 3-chloro-1-
diphenylmethylamino-2-hydroxypropane, 4a.3 1-Benzhydrylaze-
tidin-3-ol 1a is utilized as a starting material in the commercial
synthesis of an industrially important key structural motif,
azetidin-3-ol hydrochloride 5 (Figure 1).3,4
Although the reported synthesis of 1a is efficient, the total cost
for the preparation of azetidin-3-ol hydrochloride 5 has not
reached our expectation (even though the overall yield in
preparing 5 is about 77% starting from 2a). Upon a raw-material
cost exercise, we evaluated that the contribution of benzhydry-
lamine 2a (starting material for preparation of either 1a or 5) is
more than 55% in total cost of 5, and we simultaneously
evaluated possibilities to replace the benzhydrylamine 2a with
other amines.
yield as low as 15% while preparing compound 5 starting from
benzylamine 2b, the raw-material cost (RMC) of 5 will be similar
to 80% overall yield of 5 starting from benzhydrylamine 2a. This
gave us incentive to develop the process to prepare compound 5
staring from benzylamine via 1-benzylazetidin-3-ol 1b. Another
advantage of using benzylamine 2b instead of benzhydrylamine
2a is the byproduct during hydrogenolysis is toluene (in the case
of benzylamine) that can be very easily removed by simple
atmospheric distillation when compared to diphenylmethane,
the byproduct in the case of benzhydrylamine.
Initially, the compounds 4b and 1b were synthesized as per the
literature-documented process.5 Numerous procedures were
reported for 4b including minor process modifications with
varied yields ranging from 40 to 95%.5 However, we often
observed lower yields and formation of di(3-chloro-2-hydroxy-
propyl)benzylamine 6b (bis impurity) in major proportion
(Figure 2). The reaction of epichlorohydrin 3 with benzylamine
Our interest in replacing 2a to synthesize azetidin-3-ol hydro-
chloride 5 was thus renewed due to the low cost of benzylamine
2b (commercial cost of benzylamine 2b is about 25 times lower
than that of benzhydrylamine 2a). Even if we achieve an overall
Received: September 9, 2010
Published: January 05, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/op100247m Org. Process Res. Dev. 2011, 15, 462–466
|

Organic Process Research & Development
TECHNICAL NOTE
Table 1. Effect of solvent and temperature on reaction prog-
ress and impurity 6b formation
reaction conditions
solventb
content (%)a
Figure 1. Structures of azetidin-3-ol hydrochloride 5 and 1-benzylaze-
tidin-3-ol 1b.
entry no.
temperature (°C)
SM
6b
1
water
0-5
25-30
0-5
1.2
4.9
5.1
2
water
42.7
3
acetonitrile
acetonitrile
acetonitrile
toluene
toluene
toluene
hexane
no reaction
4
15-20
25-30
0-5
35.2
22.5
8.5
5
12.7
Figure 2. Structure of bis impurity 6.
6
no reaction
7
15-20
25-30
0-5
52.0
44.0
7.9
Scheme 2. Synthesis of 1-benzylazetidin-3-ol, 1b
8
10.0
9
no reaction
10
11
hexane
15-20
25-30
7.2
28.0
hexane
7.3
43.8
a Area % by HPLC (216 nm) in the reaction mass. Remaining major
portion in reaction mixture was identified as product, i.e., 3-chloro-1-
phenylmethyl amino-2-hydroxypropane, 4b. Any other major single max-
imum impurity (>1.0%) was not observed. Each reaction was maintained in
its respective conditions for more than 24 h. b Note. No reaction has been
observed at below 0 °C in any of the above-mentioned solvents.
2b was not greatly encouraging even when subjected to the
conditions described for 1a, and the formation of bis impurity 6b
was about 20-22%, whereas 7-9% of 6a in case of benzhy-
drylamine 2a. Probably steric factors could be the reason for
formation of 6b in enriched levels as compared to that of 6a.
Attempts were unsuccessful to recrystallize 1-(benzylamino)-3-
chloropropan-2-ol 4b (step 1 product in preparation of 1-benzy-
lazetidin-3-ol 1b) when associated with bis impurity 6b in larger
portions (20-25%). This conclusively indicated that the reac-
tion conditions previously described (for 1-benzhydrylazetidin-
3-ol, Scheme 1) are not suitable or applicable to 1-benzylazetidin-
3-ol 1b. Therefore, we took on the task of reducing the formation
of 6b in the preparation of 1-(benzylamino)-3-chloropropan-2-ol
4b by optimizing the reaction conditions (critical process param-
eters and robustness testing).
Table 2. Dilution effect on impurity 6b formation
reaction conditions
entry no.
solvent
volumesa (vol)
% of impurity 6bb
1.
2.
3.
4.
water
water
water
water
5
10
15
20
15.1
8.2
7.5
5.1
a Solvent volumes with respect to benzylamine. b Area % in HPLC (216
nm) in the reaction mass. In all the experiments, the absence of
benzylamine was observed by HPLC.
(about 30 min), observed the enrichment of formation of 6b to
about 5-6% but upon increasing, there is not much impact on
formation of 6b.
2. RESULTS AND DISCUSSION
Further, we studied the effect of solvent and reaction tem-
perature on formation of 6b. The solvent isopropanol at reflux
temperature (identified as better solvent as in the case of
preparation of 4a) resulted 20-25% of 6b. Therefore, we studied
the impact of formation of 6b in less polar and more polar
solvents than isopropanol as well as at temperatures ranging from
0 to 30 °C. The results are quite encouraging and tabulated in
Table 1.
From these studies it has been identified that formation of 6b
is in reduced level comparatively at low temperatures in water,
acetonitrile or toluene as solvent while no reaction has been
observed at 0-5 °C in acetonitrile, toluene and hexane. The best
condition among the results tabulated is water as solvent at 0-
5 °C for the reaction of benzylamine with epichlorohydrin with
respect to reaction progress. On the other hand, the dilution
(concentration) of the reaction mixture (solvent volume/
quantity) is also playing a key role in the formation of impurity
6b and therefore the dilution effect has been studied by using
water as a solvent. These results are summarized in Table 2.
Reaction time is one of the most important parameters. If the
step 1 reaction mixture is maintained at reaction conditions even
To develop an efficient and robust process for 1-benzyl
azetidin-3-ol 1b, the synthesis of 1b was studied as a two-step
process i.e., the formation of respective chlorohydrin 4b followed
by intramolecular cyclisaiton to get 1b. First step involves the
opening of oxirane ring in epichlorohydrin using benzylamine to
give 4b. Initially, we studied the impact of mole ratio of both the
starting materials (epichlorohydrin and benzylamine), rate of
addition of epichlorohydrin, effect of solvent, temperature and
reaction time on the formation of bis impurity 6b during
preparation of 4b (Scheme 2).
Equimolar ratio of benzylamine and epichlorohydrin resulted
in incomplete reaction. Increasing epichlorohydrin mole ratio
increases the formation of bis impurity 6b as expected, but the
results are not vice versa. Excess benzylamine did not reduce 6b
formation and also the reaction encountered difficulty in isola-
tion of 4b. Summarizing the study, the optimized molar ratio of
benzylamine and epichlorohydrin is arrived at 1:1.16 respec-
tively. Addition time was studied. Epichlorohydrin is added in to
the stirred solution of isopropanol and benzylamine over a period
of more than 1 h. Upon decreasing the addition time to its half
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TECHNICAL NOTE
Scheme 3. N-Benzyl(oxiran-2-yl)methanamine 7b
Table 3. RT and RRT of compounds 1b, 2b, 4b, and 5
compound
RT
RRT
1b
2b
4b
5
5.81
5.52
6.58
7.53
1.00
0.95
1.13
1.29
Scheme 4. Synthesis of compound 8 and compound 5 from
compound 1b
75% (Scheme 4). This showed a remarkable improvement in the
reduction of RMC for 5. In the similar way prepared O-mesyl
derivative 8 of 1b by following the reported procedure.5d As
explained, the azetidine ring inclusion used to be done by
1-benzhydrylazetidinine-3-ol 1a. Instead of 1-benzhydrylazetidi-
nine-3-ol 1a, 1-benzylazetidine-3-ol 1b can be utilized for such
kinds of purposes which give more atom economy as well as
lower manufacturing cost.
HPLC Method. Nonchiral RP-HPLC method for the analysis
of compounds 1, 2, 4, and 5: A Waters model Alliance 2690-
separation module equipped with a Waters 996-photodiode array
UV detector was used. ZORBAX ECLIPSE XDB C18 4.6 ꢀ 150
mm, 5.0 μ, injection volume 10 μL, Solvent A: 0.05% TFA
(trifluoroacetic acid) in water, Solvent B: 0.05% TFA in aceto-
nitrile, gradient 10-90% B in 25 min, then 10% B for 10 min, at
0.8 mL/min and detection at 216 nm using a ultraviolet visible
detector. Samples were dissolved in acetonitrile. The approx-
imate retention time (RT) and relative retention time (RRT) of
compounds 1b, 2b, 4b, and 5 are given in Table 3. RRT of each
compound was specified relative to that of compound 1b.
The robustness of the optimized process of 1-benzylazetidin-
3-ol 1b has been checked in various scales initially in the lab
by conducting three process consistency batches (200-g scale)
and also demonstrated to pilot plant by executing the process on
>10-kg scale. The results are as expected, and the Hazard and
Operability (HAZOP) studies were also carried out for existing
process and operations in order to evaluate potential hazards and
operability problems before execution of the final process on
>10-kg level. However, we have not identified any possible
deviations from normal operations and also placed appropriate
safeguards to prevent accidents.
after consumption of the benzylamine (12-14 h), the enriched
level of bis impurity is observed as expected. Finally optimized
reaction conditions for the opening of the oxirane ring in epi-
chlorohydrin using benzylamine is water as a solvent (20 times
with respect to benzylamine), at 0-5 °C with 12-14 h.
We also planned to develop a reprocessing method to remove
impurity 6b (from 4b) which could be useful in unanticipated
situations since the formation of impurity 6b is dependent on
many parameters such as solvent volume, temperature, addition
time, and reaction time. The development of the reprocessing
method for the product (even though not necessary) is a general
practice while performing critical reactions in pilot plant or
production. In this case, various solvents and solvent mixtures
were screened, and toluene was identified as a better solvent.
However, this reprocessing method could be useful in cases
where impurity 6b is less than 15% in the crude 4b.
Additionally, the formation of N-benzyl(oxiran-2-yl)methan-
amine 7b has not been observed in step 2 in the case of
benzylamine as the starting material compared to that of
benzhydrylamine. No further conversion of 4b into N-benzyl-
(oxiran-2-yl)methanamine 7b was confirmed by reaction of
3-chloro-1-phenylmethylamino-2-hydroxy propane 4b in step 1
conditions and also at ambient temperature (Scheme 3).
Progress of the later step (cyclization of compound 4b) was
also studied thoroughly using different bases such as Na2CO3,
NaHCO3, K2CO3, KHCO3, N,N-diisopropylethylamine (DIPEA),
or triethylamine (TEA) in different solvents such as methanol,
isopropanol, N,N-dimethylformamide (DMF), or acetonitrile at
reflux temperature. While monitoring of all the described reactions
using HPLC, the identified better condition among all the attempts
was NaHCO3 with acetonitrile as solvent in a period of 5-7 h at
reflux temperature followed by isolation in hexane yielding the
targeted compound 1b with appropriate quality and quantity.
Azetidin-3-ol hydrochloride 5 can be prepared from 1-benz-
hydrylazetidin-3-ol 1a but it was tedious to remove the by
product, diphenylmethane by high vacuum distillation. However,
the byproduct in deprotection of benzyl group of 1-bezhydryla-
zetidin-3-ol 1b is toluene which can be easily removed from the
reaction mixture either by distillation or filtration. Manufacturing
cost of azetidin-3-ol hydrochloride 5 prepared from benzylamine
as starting material via 1-benzylazetidin-3-ol 1b reduced over
’ CONCLUSION
Herein we report an optimized and robust process for the
synthesis of 1-benzylazetidin-3-ol 1b and also demonstrated
the synthesis of azetidine-3-ol hydrochloride 5 which involves the
use of commercially available starting material and benzylamine
and also reduces the formation of di(3-chloro-2-hydroxypro-
pyl)benzylamine significantly. The optimized process is more
economical and allows effective production of 1-benzylazetidin-
3-ol 1b as well as azetidine-3-ol hydrochloride 5.
’ EXPERIMENTAL SECTION
Benzylamine and epichlorohydrin were obtained from com-
mercial sources and used without further purification. All
reagents and solvents employed were of commercial grade and
were used as such, unless otherwise specified. Reaction flasks
were oven-dried at 200 °C, flame-dried, and flushed with dry
nitrogen prior to use. All moisture- and air-sensitive reactions
were carried out under an atmosphere of dry nitrogen. Organic
extracts were dried over anhydrous Na2SO4. Flash chromatog-
raphy was performed using Kieselgel 60 brand silica gel
(230-400 mesh). The melting points were determined in an
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TECHNICAL NOTE
open capillary tube using a B€uchi B-540 melting point instrument
and were uncorrected. The IR spectra were obtained on a Nicolet
380 FT-IR instrument (neat for liquids and as KBr pellets for
solids). NMR spectra were recorded with a Varian 300 MHz
Mercury Plus spectrometer at 300 MHz (1H) and at 75 MHz
(13C). Chemical shifts were given in ppm relative to trimethylsi-
lane (TMS). Mass spectra were recorded on Waters quattro
premier XE triple quadrupole spectrometer using either electron
spray ionisation (ESI) or atmospheric pressure chemical ioniza-
tion (APCI) technique.
3-Chloro-1-phenylmethylamino-2-hydroxypropane (4b). A
250-L glass-lined reactor was charged with demineralized water
(150 L) and benzylamine 2b (10 kg, 93.33 mol). To this stirred
solution was added epichlorohydrin 3 (10 kg, 108.08 mol) over a
period of 1 h, maintaining the batch temperature <5 °C. After the
addition, the mixture was agitated for an additional 10-12 h at 0-
5°C and then sampled for HPLC analysis. HPLC typically indicated
less than 2.0 area % of 2b remaining in the reaction mixture. At this
point the obtained white solids were filtered, and the wet cake was
washed with additional demineralized water (25 L) followed by
n-heptane (50 L). The wet cake was dried under vacuum at <45 °C
(LOD = 0.5%) to give 3-chloro-1-phenylmethylamino-2-hydroxy
propane 4b as a white crystalline solid in 75% yield (14 kg) with an
HPLC purity of 98.2 area %. Mp 72-73 °C; 1H NMR (CDCl3):
δ 2.56-2.7 (m, 2H), 3.5-3.6 (m, 2H), 3.62-3.7 (m, 1H), 3.72-
3.88 (m, 3H), 5.2 (br s, 1H), 7.2-7.4 (m, 5H). 13C NMR (CDCl3):
δ 47.4, 51.5, 53.5, 69.3, 127.2, 128.1, 128.4, 139.1. IR (KBr): 3290,
2900, 1449, 1340, 1254, 1073, 882 cm-1. ESI-MS m/z: 199.8
[Mþ þ 1].
(90 L), followed by water (10 L), and was charged with 5% Pd/C
(0.5 kg) and H2 (50 psi). After 24 h at room temperature, the
reaction was complete. The catalyst was filtered off, and the
filtrate was concentrated to an oily solid. The crude product was
slurried in ethyl acetate (25 L) overnight and then filtered to give
azetidin-3-ol hydrochloride (5) as a white crystalline solid in 90%
yield over two steps, 6.07 kg, with an HPLC purity of 99.3 area %.
Mp 86-88 °C; 1H NMR (DMSO-d6): δ 3.7 (m, 2H), 4.0 (m,
2H), 4.5 (m, 1H), 6.2 (br s, 1H, D2O exchangable), 9.1 (br s, 2H,
D2O exchangable); 13C NMR (100 MHz, CDCl3): δ 55.0, 61.3;
ESI-MS: m/z 74.1 [Mþ þ 1].
1-Benzylazetidin-3-yl Methanesulfonate Hydrochloride
(8). To a solution of 1-benzylazetidne-3-ol 1b (100 g, 0.613
mol) in dichloromethane (1 L) was added triethylamine (86.7 g,
0.858 mol) at <5 °C under nitrogen atmosphere. Methanesulfo-
nyl chloride (82 g, 0.713 mol) was added slowly at <5 °C over a
period of 1 h, and the reaction mixture was maintained another
1 h at the same temperature (<5 °C) and then sampled for HPLC
analysis. HPLC typically indicated less than 2.0 area % of 1b
remaining in the reaction mixture. The temperature of reaction
mixture was raised to room temperature, the inorganic salts were
filtered, and the wet cake was washed with dichloromethane (150
mL). Dry HCl gas was slowly purged from the filtrate at <5 °C
from pH 1.0 up to pH 2.0. The reaction mixture was maintained
for an additional 1 h at the same temperature. The resulted solids
were filtered, and the wet cake was washed with dichloromethane
(200 mL) and dried at <60 °C under vacuum to give 1-benzy-
lazetidin-3-yl methane sulfonate hydrochloride (8) as a white
crystalline solid in 66% yield, 112 g, with an HPLC purity of 98
1
area %. Mp 137-138 °C; H NMR (CD3OD): δ 2.8 (s, 3H),
1-Benzylazetidne-3-ol (1b). A 250-L glass-lined reactor was
purged with nitrogen and charged with acetonitrile (170 L) and
3-chloro-1-phenylmethylamino-2-hydroxy propane 4b (14 kg,
70.11 mol). To this stirred solution was added sodium bicarbonate
(14.7 kg, 175 mol) at <30 °C. The temperature of the reaction
mixture was raised to reflux, stirred for 5-7 h, and then sampled
for HPLC analysis. HPLC indicated less than 2.0 area % of 4b
remaining in the reaction mixture. The temperature of reaction
mixture was cooled to room temperature, the inorganic salts were
filtered, and the wet cake was washed with acetonitrile (30 L).
The majority of the organic volatiles (acetonitrile) from the filtrate
were removed by distillation at <50 °C under reduced pressure
(80-100 Torr), giving crude compound 1b. n-Heptane (2 ꢀ
100 L) was added to the crude 1b and codistilled at <50 °C under
reduced pressure (80-100 Torr). The resulted residue was
triturated with n-heptane (28 L) and stirred for 2 h at 25 °C.
The obtained solids were filtered, the wet cake was washed with
n-heptnae (10 L) and dried under vacuum at <45 °C to give
1-benzylazetidne-3-ol 1b as a white crystalline solid in 88% yield
(10.07 kg) with an HPLC purity of 94.98 area %. Mp 64-65 °C;
1H NMR (CDCl3): δ 3.0 (m, 2H), 3.54-3.60 (m, 2H), 3.62-
6.64 (m, 2H), 3.7-4.0 (br s 1H), 4.4 (m, 1H), 7.23-7.33 (m,
5H). 13C NMR (CDCl3): δ 61.1, 63.1, 63.4, 127.1, 127.6, 128.0,
128.1, 128.3, 136.8. IR (KBr): 3387, 2838, 1493, 1451, 1341, 1176,
1082, 743 cm-1. ESI-MS m/z: 164.1 [Mþ þ 1].
3.54-3.7 (m, 3H), 3.8 (m, 1H), 4.4 (d, 1H), 4.55-4.6 (d, 1H),
4.82 (m, 1H), 7.48 (m, 5H). IR (KBr): 2975, 2676, 2491, 1350,
1172 cm-1. MS m/z: 242 [Mþ þ 1].
Di(3-chloro-2-hydroxypropyl)benzylamine (Bis Impurity,
6b). To a stirred mixture of benzylamine (10 g, 0.09 mol) in
water (50 mL) was added epichlorohydrin (20.0 g, 0.19 mol) at
<5 °C over a period of 1 h, and then the temperature of the
reaction mixture was allowed to reach room temperature. The
reaction mixture was stirred for an additional 24 h at the same
temperature. After completion of the reaction (by TLC), solids
were filtered and purified by column chromatography eluting
with ethyl acetate/hexane (1:9) to give 6b as a white solid in 60%
yield, 9.0 g. Mp 93-95 °C; 1H NMR (CDCl3): δ 2.7-2.9 (m,
4H), 3.3-3.5 (m, 6H), 3.7-3.8 (m, 2H), 3.85-4.0 (m, 2H),
7.2-7.4 (m, 5H); 13C NMR (CDCl3): δ 30.9, 47.3, 57.8, 58.4,
60.1, 60.2, 68.4, 69.1, 127.7, 128.6, 129.0, 129.1, 137.5; IR (KBr):
ν 3261, 2955, 1452, 1090, 746, 703 cm-1; ESI-MS: m/z 292
[Mþ þ 1].
’ ASSOCIATED CONTENT
S
Supporting Information. Characterization data of com-
b
pound 4b, 1b, 5, 6b, 8 and HPLC chromatogram of 4b, 1b, 5, and
8. This material is available free of charge via the Internet at
http://pubs.acs.org.
Azetidin-3-ol Hydrochloride (5). A 250-L glass-lined reactor
was charged with dichloromethane (100 L) and 1-benzylaze-
tidne-3-ol 1b (10 kg, 61.3 mol). From this stirred solution was
purged HCl gas over a period of 30 min. The precipitated solids
were filtered, and the wet cake was washed with excess of dichloro-
methane. The wet solid was dried at <45 °C and gave 11.4 kg of
the hydrochloride salt of 1b. In a 200-L, hydrogenation reactor,
the hydrochloride salt of 1b (11.4 kg) was diluted with ethanol
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: madhusudhan.gutta@inogent.com and alternate e-mail:
madhusudhan.gutta@yahoo.com. Fax: þ91-40 2715 1270. Tele-
phone: þ91-09849559259.
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TECHNICAL NOTE
’ ACKNOWLEDGMENT
We thank Inogent Laboratories Private Limited (A GVK BIO
Company) for the financial support.
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