Field of the Invention
The present invention relates to an improved, economical and industrially viable process
for the preparation of valacyclovir hydrochloride. More preferably, the present invention
relates to an improved process for the preparation of valacyclovir hydrochloride in
monohydrate form.
Background of Invention
Valacyclovir hydrochloride, also known as.2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-
yl)methoxy]ethyl L-valine ester hydrochloride monohydrate is structurally represented by
Formula A, is an oral antiviral drug,used for the treatment of genital herpes and herpes
' - •
zoster. ' ,
O
HoN
N
H2N N N P
O O
.HC1 .H20
Formula A
Valacyclovir is a prodrug that is derived from acyclovir by.esterifying 3'-hydroxyI group
of acyclovir with L-valine. Acyclovir is an antiviral nucleoside that possesses activity
against human herpes viruses. However, acyclovir is -poorly absorbed -froml the
gastrointestinal tract upon oral administration and this low bioavailability means that
multiple high doses of oral drug are required to be administered, especially for the
treatment of less sensitive viruses or infections in order to achieve and maintain effective
anti-viral levels inthe plasma. The oral administration of valacyclovir hydrochloride is
advantageous than that of .acyclovir because it is rapidly absorbed from" the
gastrointestinal tract after oral administration and is converted to acyclovir and L-valine.
Valacyclovir has been reported to increase the oral bioavailability of acyclovir by 3- to 5-
fold in humans (Antimicrob Agents Chemother: 1995 Dec; 39(12):2759-64).
Valacyclovir hydrochloride is available in the market under the trade names Valtrex® or
Zelitrex®.
2 of 18
1 4 - . - 0 2 . - ^ U - i - v -t-f - .»
( 5
Valacyclovir and its pharmaceutical^. acceptable salts are first disclosed in US
4,957,924. The process involves condensation of acyclovir with CBZ L-valine using
catalytic amount of 4-dimethylaminopyridine (DMAP) and dicyclohexylcarbodiimide
(DCC) in dimethylformamide solvent to obtain N-[(benzyloxy)carbonyl] -L-valine-2-
[(2-amino- 1 ,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester followed by
deprotection of N-[(benzyloxy)carbonyl] -L-valine-2- [(2-amino^ l,6-dihydro-6<)xo-9Hpurinr9-
yl)methoxy]ethyl ester in an autoclave using 5% palladium on carbon, as a
catalyst using methanol (-27 times) and tetrahydrofuran (-27 times) as solvent mixture at
hydrogen pressure of 50 psi for one day. The resulting reaction mixture is then filtered,to
obtain a white solid which was then recrystallized from watef/ethanol to obtain
valacyclovirhydrochloride in 60% yield according to Scheme 1.
o.
"63 OH
O
O x
HN + V rO
OH '
>-o
DCC, DMAP / DMF O
•HN 1
H,N
' o
\\ //
O
CD
Q .
CD
CM
o
CO
o
Pd/Carbon, H2, Aq. HC1
H,N
o • H 2 \ - /
HN^VS O-O
U >~N /—/ O
O
.HCl
Scheme!
The main disadvantage of the process is the use of specialized equipment such as
autoclave, and use of large volume of solvent such as methanol <(~ 27 volume) during the
hydrogenation step. Further, the use of THF as a.solvent at commercial scale not only
decreases the operational suitability but also increases the overall production cost. Also,
the disposal, of such large volume of solvents as effluent at commercial is also
cumbersome. "
US5583225 discloses process for the preparation of acyclovir either by (1) acetylating
guanine using acetic anhydride and acetic acid for 52 hours or (2) acetylating guanine
using acetic anhydride and phosphoric acid for.15 hours to obtain diacetyl guanine which
was then alkylated at the N9 position using l54-diacetoxy-2-oxabutane, acetic anhydride
and phosphoric acid in toluene for 24 hours to obtain diacetyl acyclovir from which
3 of 18
^0-
acyclovir is obtained via alkaline hydrolysis using ammonium hydroxide. The
disadvantage of the process is the use of corrosive and hazardous phosphoric acid at high
temperature for longer period of time (~52 hours) lead to safety concern at the
commercial scale along with the effluent generation, which makes the process unsuitable
for industrial scale production.
US 6849737 discloses alternate process for the preparation of valacyclovir hydrochloride
by replacing the benzyloxycarbonyl group of the valinate moiety by the tertiary
butoxycarbonyl group. The process involves condensation of Boc protected L-valine
ester with acyclovir using dicyclohexylcarbodiimide and 4-Dimethylaminopyridine in
dimethylformamide to obtain Boc-protected valacyclovir, which is subsequently
deprotected using hydrochloric acid-for about 5 hours at room temperature to obtain clear
solution which was further cooled at 0°C, mixed with IPA to obtain precipitate, which
was kept overnight at about 4°C to obtain valacyclovir hydrochloride as depicted in
Scheme 2.
oV oKJ I
A\AN OH + 0
Formula B Formula C
(b) in situ reacting diacetyl guanine of Formula C with l,4-diacetoxy-2-oxabutane in
the absence of catalyst using aromatic hydrocarbon as solvent to obtain diacetyl
acyclovir of Formula D followed by hydrolysis using mild base to obtain
acyclovir of Formula E;
O O
0 ™ v s H•••• ™tV>
H O
Formula D Formula E
(c) reacting acyclovir of Formula E with CBZ L-valine compound of Formula F
using dicyclohexylcarbodiimide as coupling agent and 4-dimethylaminopyridine
as a catalyst in dimethylformamide solvent at temperature between -5 to 10°C to
obtain NT[(benzyloxy)carbonyl]«L-valine-2-[(2-amino-l,6-dihydrp-6-oxo-9Hpurin-
9-yI)methoxy] ethyl ester compound of Formula G;
O
; ; '•'•• • " J j rt
H2NAN^N .OH
9 ••"
Formula E Formula F
Formula G
7 of 18
(d) deprotecting N-[(benzyloxy)carbonyl]^L-vaIine-2-[(2-amino-l36-dihydro-6-oxo-
9H-purin-9-yl)methoxy]ethyl ester compound of Formula G obtained from step
(c) containing alcoholic solvent in presence, of 10% palladium on carbon using.
water and concentrated hydrochloric acid at temperature between 30-40°C to
obtain valacyclovir hydrochloride followed by addition of alcoholic solvent.
Detail description of the Invention
While this specification concludes with claims particularly pointing out and distinctly
claiming that, which is regarded as the invention, it is anticipated that the invention can
be more readily understood through reading the following detailed description of the
invention and study of the included examples.
The present invention overcomes the drawbacks mentioned in the background of the
invention by altering the reagents, reaction conditions, solvents etc. being used at
different stages for the synthesis of key intermediates and the target molecule i.e.
valacyclovir. hydrochloride monohydrate.
According to one aspect of the present invention, there is provided an improved process
for the preparation of valacyclovir hydrochloride monohydrate of Formula A, having
purity greater than 99%;
O . ' O
.HCI .H20
comprising the steps of:
Formula A
(a) reacting guanine with acetic anhydride in presence of organic sulphonic acid to
obtain diacetyl guanine of Formula C;
8of 18
o °
H2N N N H ^Q
Formula B Formula C..
(b) in situ reacting diacetyl guanine of Formula C with l,4-diacetoxy-2-oxabutane in
the absence of catalyst using aromatic hydrocarbon as solvent to obtain diacetyl
acyclovir of Formula D followed by hydrolysis using mild base to obtain
acyclovir of Formula E;
O O
H O
Formula D Formula E
(c) reacting acyclovir of Formula E with CBZ L-valine of Formula F using
dicyclohexylcarbodiimide as coupling agent arid 4-dimethylaminopyridine as a
catalyst in dimethylformamide solvent at temperature between -5 to 10°C to
obtain N-[(benzyloxy)carbonyl]-L-yaline-2-[(2-amino-l,6-dihydro-6-oxo-9Hpurin-
9-yl)methoxy] ethyl ester compound of Formula G;
: H 2 N A N ^ N —OH
\ ^ 0 OH
Formula E Formula F
HNV>
.2H,NN ' N ^O
Formula G
. 9 of 18
«&».
(d) deprotecting N-[(benzyloxy)carbonyl]-L-valine-2-[(2-amino-l,6-dihydro-6-oxo-
9H-purin-9-yI)methoxy]ethyl ester compound of Formula G obtained from step (c)
containing alcoholic solvent in presence of 10% palladium on carbon using water and
concentrated hydrochloric acid at temperature between 30-40°C to obtain
valacyclovir hydrochloride followed by addition of-alcoholic solvent. .
According to the present invention, in step (a) reaction of guanine with acetic anhydride
is carried out in presence of organic sulphonic acid to obtain diacetyl guanine, wherein
organic sulphonic acid is selected from the group comprising of methane sulphonic acid,
p-toluene sulphonic acid and the like. The reaction is carried out at temperature HOMO^
for 10-17 hours.
The resulting diacetyl guanine of Formula C formed in situ\s reacted with 1,4-diacetoxy-
2-oxabutane in step (b) without the use of catalysts using aromatic solvent selected from
toluene or xylene at temperature 100-120°C for 10-17 hours to obtain diacetyl acyclovir
of Formula D.
According to the present invention, preparation of diacetyl acyclovir from diacetyl
guanine is carried out without the use of, catalyst, which not only reduces the reaction
time drastically from 52 hours to 12-15 hours compared to when the same reaction is
carried out in presence of phosphoric acid at high temperature as disclosed in US5583225
patent. Thus, the instant invention offers certain advantages such as reduced reaction time
using specific reaction temperature i.e. 100-120°C, which not only reduces the by-product
formation, but also enhance the purity of the desired product.
The resulting diacetyl acyclovir of Formula D formed undergoes hydrolysis in presence
of mild base to obtain acyclovir of Formula E, wherein the mild base is selected from the
group comprising alkali or alkaline earth metal carbonate, bicarbonate and the "like
wherein alkali or alkaline earth metal is selected from lithium, sodium, potassium,
magnesium, calcium, barium and the like. Preferably the mild base is selected from
sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate,
10 of 18
magnesium carbonate, calcium carbonate or barium carbonate and the like. The reaction
is carried out at temperature between 70-100°C for 2-8 hours.
• ' • i
The advantage of the use of mild base for the hydrolysis not only prevents the formation
of undesirable side product, rather makes the work up step easier compared to strong base
such as metal hydroxide as disclosed in earlier prior art literature.
The resulting acyclovir of Formula E is then reacted "with CBZ L-valine compound of
Formula F using dicyclohexylcarbodiimide as coupling agent and 4-
dimethylaminopyridine as a catalyst in dimethylformamide solvent at temperature
between -5 to 10°C for 10-15 hours to obtain N-[(benzyloxy)carbonyl]-L-valine-2-[(2-
amino-l36-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester compound of Formula G
' from which the pure product is isolated using aqueous alcoholic solvent preferably
isopropanol or ethanol.
The resulting pure N-[(benzyloxy)carbonyl]-L-valine-2-[(2-amino-l,6-dihydro-6-oxo-
9H-purin-9-yl)methoxy]ethyl ester compound of Formula G containing alcoholic solvent
undergoes deproteetion using 10% palladium on carbon using water and concentrated
hydrochloric acid at hydrogen pressure below 2 Kg/cm"2 at temperature 20-50°C for 10-
20 hours. Thus the hydrogenation reaction using concentrated HC1 at specific pH, not
only controls the formation of various impurities, rather makes the work up step simpler
and easier, which result in the formation of valacyclovir hydrochloride having desired
purity.
The resulting purev N-[(benzyloxy)carbonyl]-L-valine-2-[(2-amino-l56-dihydro-6-oxo- v
9H-purin-9-yl)methoxy]ethyl ester compound of Formula G containing alcoholic solvent
where the alcoholic solvent is selected from isopropanol or ethanol.
The resulting valacyclovir hydrochloride monohydrate is directly precipitated from the
solution by mixing with alcohol where the alcohol is selected from isopropanol or
ethanol. The precipitated product is recovered by any technique known to person skilled ' .-
11 of 18 . -
:L.KX. 1 4 - 0 2 - - 2 0 1 ^ . 1 / - 3©
in the art for example by filtration, or centrifugation. The recovered product is then dried
in vacuum.
Another advantage of the process is the use of aqueous alcoholic solvent system for the
preparation of valacyclovir hydrochloride monphydrate starting from N-
[(benzyloxy)carbonyI]-L-valine-2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]
ethyl ester compound of Formula G, which not only makes the process economical and
industrially feasible, but also at the same time provides valacyclovir hydrochloride
monohydrate in high yield and purity, substantially free from the contamination of other
polymorphic forms, preferably anhydrous form.
K • - '
The term substantially free means valacyclovir hydrochloride in anhydrous form is
present in an amount less than about 1% by weight in valacyclovir hydrochloride
monohydrate.
Valacyclovir hydrochloride monohydrate obtained according to the present invention is
having purity of about more than 95% or more, preferably about 98% or more, and more
preferably about 99% or more, as determined using high performance liquid
chromatography.
Valacyclovir hydrochloride obtained according to the present invention contains water
between 4-11 %, preferably 7-10% and more preferably 9-10%. .' "
Valacyclovir hydrochloride obtained according to the present invention is having less
than about 0.5%, preferably less than 0.3%, more preferably less than 0.2% of guanine
and also for acyclovir as determined by HPLC. In another aspect, the present invention
provides valacyclovir hydrochloride having less than about 0.1% of any other impurities.
• . • - . . - )
While the present invention has been described in terms of its specific embodiments,
certain modifications and equivalents will be apparent to those skilled in the art and are
intended to be included within the scope of the present invention.
. ' . V
t /
I
\ ' 12 of 18 .
EXAMPLES
The following examples are provided only to exemplify, but not to limit the scope of the
invention. ' - • •
Example 1
Preparation of Acyclovir:
Acetic anhydride (200g), guanine (50g) and ^-toluene sulphonic acid (3.0g) were added
at room temperature and the reaction mixture was heated to 120-130°C under stirring for
12-15h. After completion of reaction, acetic anhydride was distilled off and the reaction
mass was cooled to 60°C and 1, 4-diacetoxy-2-oxabutane (145g) was added. To the
resulting mass, toluene was added and the reaction mass was heated to 105-115°C for 12-
15h. After completion of the reaction, reaction mass was cooled and was stirred. The
reaction mass was filtered and dried. Sodium bicarbonate solution was added to the
filtered mass and the reaction mass was heated at 85-95°C for 3-6h. Activated charcoal
was added to the resulting reaction mass and was stirred at 85-95°C. The reaction mass
was filtered and acetic acid (18g) was added to the filtrate and stirred for 1 h. The
reaction mass was cooled slowly to 25-30°C and was stirred for 2-3h. The reaction mass"'
was filtered and washed with DM water and dried. DM water was added to crude wet
cake and the reaction mass was heated to 90-95°C. for lh. The reaction mass was filtered
through hyflo bed arid washed with DM water. The filtrate was stirred for an hour to get a
clear solution. The reaction mass was cooled to 25-30°C and was stirred for 2-3h. The
reaction was filtered, washed with DM water and dried at 55-60°C for 8-12h.
Yield (%): 73.8%
HPLC purity: 99.8% '".•';.
Example 2
Preparation of N-[(benzyloxy)carbonyl] -L-valine-2- [(2-amino- l,6-dihydn>6-oxo-
9H-purin-9-yl)methoxy]ethyl ester:
A solution of Cbz protected valine (69.73g) and DMF (500mL) was mixed and cooled to
-5-0°C. To the resulting mixture, N5N-dicyclohexylcarbodiimide solution (59.55g was
mixed with 150 mL DMF) was added and was stirred at temperature below 5°C.
: 13 of 18
iL.H-1. 1 . 4 - 8 2 . - 2 0;19" 17-/- 30? •
Acyclovir (50g) and DMAP (3.79g) were added and the reaction mixture was stirred at 0-
5°C. The reaction mixture was filtered and washed with DMF. The filtrate was
concentrated under vacuum. The reaction mixture was cooled to room temperature and
DM water (750mL) was'added. The resulting mass was heated to 75-80°C under stirring.
The reaction mixture was filtered and the resulting solid was washed with DM water. The
obtained wet cake was treated with ethanol and water and heated at 80-85°C. The
solution was cooled to 25-30°C and stirred for 2h. The filtered solid was washed with the
mixture of ethanol-DM water. The resulting solid was dried under.vacuum for about 10-
12h. • . '
Yield (%): 85.47% ' : "•".-/
HPLC purity: 99.9%
Example 3
Preparation of Valacyclovir hydrochloride monohydrate:
N-[(benzyloxy)carbonyl]-L-valine-2-[(2-amino-l,6-dihydr6-6-oxo-9H-purin-9-
yl)methoxy]ethyl ester (50g) as obtained from Example 2, containing ethanol solvent,
DM water (350mL), HC1 (11.3g) and 10% Pd/C (1.25g) was hydrogenated at 1 Kg/cm2
hydrogen pressure at 30-40°C for 12 hours. The reaction mixture was filtered through
hyflo bed and washed with DM water. pH was adjusted with cone. HC1. DM water was
distilled off and the reaction mass was cooled to 25-30°C. The resulting filtered reaction
mass was stirred for few minutes and water was distilled off. The resulting mass was
cooled, ethanol was added under stirring. The resulting solid was washed with-ethanol
and dried under vacuum at 50-55°C for 8-1 Oh.
Yield (%); 87.4%
HPLC purity: 99.3% *
Water content: 9.0%

Claims:
1. An improved process for the preparation of valacyclovir hydrochloride monohydrate
of Formula A, having purity greater than 99%;
,HC1 -H20
Formula A
comprising the steps of:
(a) reacting guanine with acetic anhydride in presence of organic sulphonic acid to
obtain diacetyl guanine of Formula C;
O
HNVH
H2N N N
Formula B
»
O
O HN V N .
H >o
Formula C
(b) in situ reacting diacetyl guanine of Formula C with l,4-diacetoxy-2-oxabutane in
the absence of catalyst using aromatic hydrocarbon as solvent to obtain diacetyl
acyclovir, of Formula D followed by hydrolysis using^mild base to obtain
acyclovir of Formula E;
O
O HN
H
Formula D
H2 N ^ N ^N
So'
Formula E
OH
(c) reacting acyclovir of Formula E with CBZ L-valine compound of Formula F
using dicyclohexylcarbodiimide as coupling agent and 4-dimethylaminopyridine
15 of 18
esrf1 W1 "
as a catalyst in dimethylformamide solvent at temperature between -5 to 10°C to
obtain N-[(benzyIoxy)carbonyl]-L-valine-2-[(2-amino-l,6-dihydro-6-oxo-9Hpurin-
9-yl)methoxy] ethyl ester compound of Formula G;
O " O
H2NANXN- ,OH °rV
ND OH '
Formula E Formula F
O
™iVS
PfcN" N ^-O
Formula G
(d) deprotecting N-[(benzyloxy)carbonyl]-L-valine-2-[(2-amino-l,6-dihydro-6-oxo-
9H-purin-9-yl)methoxy]ethyl ester compound of Formula G obtained from step
(c) in presence of 10% palladium on carbon using water and concentrated
hydrochloric acid at temperature between 30-40°C to obtain valacyclovir
hydrochloride followed by addition of alcoholic solvent.
2. The process according to claim J, wherein step.(a) wherein organic sulphonic acid is
selected from the group comprising of methane sulphonic acid and p-toluene
sulphonic acid. • , - . . . * ' '
V
3. The process according to claim 1, wherein step (b) arorriatic hydrocarbon is selected
from toluene orxylehe.
4. The process according to claim 1, wherein in step (b) mild base is selected from alkali
or alkaline earth metal carbonate and bicarbonate.
16 of 18
;
5. The process according to claim 4, wherein the alkali and alkaline earth metal is
selected from lithium, sodium, potassium, magnesium, calcium and barium,
preferably the base is selected from sodium carbonate, sodium bicarbonate, potassium
i •
^ carbonate, potassium bicarbonate, magnesium carbonate or calcium carbonate or
- barium carbonate.
6. The process according to claim 1, wherein in step (c) reaction of acyclovir of
Formula E with CBZ L-valine compound of Formula F is carried out for 10-15 hours.
7. The process according to claim 1 wherein in step (d) deprotection of N-
[(benzyloxy)carbonyl] -L-valine-2-[(2-amino-l,6-dihydrq:6-oxo-9H-purin-9-
yl)methoxy]ethylester compound of Formula G using 10% palladium on carbon is
carried out iat hydrogen pressure of below 2 Kg/cm-2.
8. The process according to claim 1 wherein in step (d) N-[(benzyloxy)carbonyl]-Lvaline-
2-[(2-amino-l,6-dihydro-6-oxo-9H-purin«9-yl)methoxy]ethyl ester compound
of Formula G obtained from step (c) contain alcoholic solvent selected from
isopropanol orethanol.
9. The process according to claim T wherein in step (d) deprotection is carried out at
temperature 20-50°C for 10-20 hours.' ^
10. The process according to claim 1 wherein in step (d) valacyclovir hydrochloride is
obtained by the addition of alcoholic solvent wherein the alcoholic solvent is selected
from isopropanol or ethanol.