r"
4 < -/
h..
b=d 1
(, ::
P- .;
a:
0
I
I FIELD OF INVENTION
This invention relates to a novel process for the synthesis of prednisolone compounds. More
particularly it is related to a novel process for the synthesis of Isoflupredone acetate.
BACKGROUND OF THE INVENTION
Isoflupredone acetate is an anti-inflammatory drug and is found usefkl in alleviating pain and
other symptoms of arthritis. It is also used as a pharmaceutical raw material and intermediate
in the process of synthesizing several other prednisolone compounds and other related
compounds. Isoflupredone also exhibits properties similar to other corticosteroid and its
derivatives. Isoflupredone is said to be about 14 times potent to hydrocortisone as an antiinflammatory
steroid as measured by the cotton pellet implantation assay. Topically applied
isoflupredone is used for treating ulcerations of the ear flaps, irritated lesions of the skin, and
otitis externa, wounds of the concha other related disorders. Isoflupredone can also be used in
ketosis, musculoskeletal disorders, rheumatism, lameness, anorexia, depression, allergic
reactions, infection, toxicity and shock.
There are no suitable processes existing in prior art for the synthesis of Isoflupredone. Certain
prior art processes, meant for the synthesis of other corticosteroids may be adapted for
isoflupredone, but such processes are not commercially viable and have their own associated
problems.
Hence there is a need for a process for the synthesis of isoflupredone.
OBJECT OF THE INVENTION
An object of the invention is to provide a novel process for the synthesis of isoflupredone
acetate.
SUMMARY
The present invention provides a novel process for the preparation of prednisolone derivative
of formula (I),
Formula I
comprising the steps of
I. Preparing compound of formula (11);
11. hydroxy-halogenation of compound of formula (11)
Formula I1
to obtain compound of formula (111);
0
Formula I11
converting compound of formula (111) to epoxide of formula
0
0
Formula IV
IV. hydro-halogenating the epoxide obtained from step (111) to obtain compound
of formula (I).
V. Optionally converting compound of formula (11) to compound of formula (IV)
r) by epoxidation in the presence of peroxy acids.
I
The compound of formula I1 is prepared by a process comprising the steps of:
a) esterification of 8S,9S, 1 OR, 1 1 S,13S, 14S,17R)- 1 1,17-dihydroxy-17-(2-
hydroxyacetyl)-l0,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-
3H-cyclopenta[a]phenanthren-3-one (prednisolone) to obtain an ester of
formula (V);
0
0
-.I Formula V &Icp* = cu =t b) dehydrating compound of formula (V) to obtain compound of formula (11).
t, :
I.. .q
&' : In another embodiment, the compound of formula (11) may also be prepared by hydroxylating
compound of formula (VI) to obtain compound of formula (11).
0
0
Formula 6
In a further embodiment, the compound of Formula (11) may also be prepared from
compound VII by a process comprising the steps of:
0 3 OEC 2013 ' 3 0
Formula VII
I DEL 1 2 A
a) Esterification of prednisone (compound VII) to obtain an ester (compound of
formula (VIII);
Formula VIII
b) Converting the ester of Formula VIII to compound of formula V.
c) dehydrating compound of formula (V) to obtain compound of formula (11).
The said process has commercially viable yield and is amenable to large scale synthesis and
is environmental friendly.
DETAILED DESCRIPTION OF THE INVENTION:
Accordingly, the present invention provides a novel process for the preparation of
prednisolone compound of formula (I),
Formula I
comprising the steps of:
0 3 DEC 2013 t I
t 7 DEL 1 a
I. Preparing compound of formula (11);
b 11. hydroxy-halogenation of compound of formula (11)
0
Formula I1
to obtain compound of formula (111);
Formula I11
111. converting compound of formula (111) to epoxide of formula (IV);
0
Formula IV
IV. hydrohalogenating the epoxide obtained from step (111) to obtain compound of
formula (I).
V. Optionally converting compound of formula (11) to compound of formula (IV)
by epoxidation in the presence of peroxy acids.
The compound of formula I1 can be prepared as follows:
Step I: The compound of formula I1 may be prepared from prednisolone by a process
comprising the steps of:
a) esterification of 8S,9S,lOR,11 S,13S,14S,17R)-11,17-dihydroxy-l7-(2-
hydroxyacety1)-1 0,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro4
0 3 DEC 2013 4
B
t
3H-cyclopenta[a]phenanthren-3-one (prednisolone) to obtain an ester of
formula (V);
Formula V
b) dehydrating compound of formula (V) to obtain compound of formula (11).
Alternatively, the compound of formula (11) may also be prepared by hydroxylating
compound of formula (6) to obtain compound of formula (11).
0
Formula VI
Further, the compound of formula (11) may also be prepared from compound VII by a process
comprising the steps of:
Formula VII
a) Esterification of prednisone (compound VII) to obtain an ester (compound of formula
(VIII);
0 3 OEC 2013
I
Formula VIII
b) Converting the ester of Formula VIII to the compound of formula V;
c) subjecting the product of step (b) to dehydration reaction to obtain compound of
formula I1 ;
The present invention provides a novel process for the synthesis of Isoflupredone acetate of
Formula I
hb
Formula I
Isoflupredone acetate may be prepared from the following starting reactants as presented by
following schemes:
1. Scheme I: Preparation of Isoflupredone acetate from Prednisolone
2. Scheme 11: Preparation of Isoflupredone acetate from 3TR
3. Scheme 111: Preparation of Isoflupredone acetate from Prednisone
SCHEME I: PREPARATION OF ISOFLUPREDONE ACETATE FROM
PREDNISOLONE
0 3 OEC 2013 '
I
Isoflupredone acetate may be prepared fjo
Comprising the steps of:
I. Preparing compound of formula I1 by a process comprising the steps of:
a) Esterification of prednisolone to obtain an ester (compound of formula (V);
b) subjecting the product of step (a) to dehydration reaction to obtain compound of
formula 11;
11. hydroxy-halogenation of compound of formula I1 to obtain compound of formula 111;
111. epoxidation of the compound of formula I11 to obtain compound of formula IV;
A
q.31
7: IV. hydrohalogenation of the product of step (11) to obtain the product of the present
[; reaction (compound of formula I i.e isoflupredone acetate).
st4 e;.d
0 V . Optionally converting compound of formula (11) to compound of formula (IV) by
epoxidation in the presence of peroxy acids.
SCHEME 11: PREPARATION OF ISOFLUPREDONE ACETATE FROM
Isoflupredone acetate may also be prepared from (8S,10SY13 S,14S)-7,8,12,13,14,15-
hexahydro- 17-(2-hydroxyacety1)- 10,13-dimethyl-6H- cyclopenta[a]phenanthren-
3 (1 OH)-one(Formu1a VI).
Formula VI
comprising the steps of:
0 3 DEC 2013 ;
I. hydroxylating compound of formula (VI) to obtain compound of formula (11);
) 11. hydroxy-halogenation of compound of formula I1 to obtain compound of formula 111;
111. epoxidation of the compound of formula I11 to obtain compound of formula IV;
IV. hydrohalogenation of the product of step (111) to obtain the product of the present
reaction (compound of formula I i.e isoflupredone acetate). I
V. Optionally converting compound of formula (11) to compound of formula (IV) by
epoxidation in the presence of peroxy acids.
d
q' z FORMULA VII
k+
I .- 9. . SCHEME 111: PREPARATION OF ISOFLUPREDONE ACETATE FROM PREDNISONE
g- : u- Isoflupredone acetate may also be prepared from compound of formula VII by a process
comprising the steps of:
I. Preparing compound of formula I1 by a process comprising the steps of:
a) Esterification of prednisone (compound VII) to obtain an ester (compound of formula
(VIII);
b) Converting the ester of Formula VIII to compound of formula V;
c) subjecting the product of step (b) to dehydration reaction to obtain compound of
formula I1 ;
11. hydroxy-halogenation of compound of formula I1 to obtain compound of formula
111;
111. epoxidation of the compound of formula I11 to obtain compound of formula IV;
IV. hydrohalogenation of the product of step (111) to obtain the product of the present
reaction ( compound of formula I i.e isoflupredone acetate).
0 3 DEC 2013 ' 3 rn R-
1
4 2
1
V. Optionally converting compound of formula (11) to compound of formula (IV) by
epoxidation in the presence of peroxy acids.
SCHEME 1: PREPARATION OF ISOFLUPREDONE ACETATE FROM
PREDNISOLONE
An exemplification of the process of the present invention may be represented here below at
scheme 1.
&i F
"-,,
: - ', - A HF 7P# i( EMF. NU. Acebc ac~d H
0
H
0 0
!i(IOS.13S.I#.17Rb9.flumII.17d1h!drm!-lO.I3d1md!I-3-0\~
6.7.8.9.10.11 12.13.14.lj.16.17-dodslh~d~3Hs)clepm~a]phcnmLren~I7.~1~2d~~th~I Epoxlde 2i(U.9R.IOS.13S,14S.17Rb9-bmel I.l7d1h!drox!-
acetate 10.IM1mdyIJdd.7.8.9.IO.lI.IZ.13.14.15.16.l7~~dm
.3H~~lapnb[~]phnmh~-I7~yIba2cedtadtey l
FOR\Il LI I FORIIL W R' FORMULA 111
&mcmbHOb k . ", 0 . 0
R.nhne. S@pd~.b mnantine
/ H /
ld H H H
q: H / H
a,
r;,CC'
/
2i(@.9.9S.IOR.IIS.1u.1a.17RbII.I7dlh1dmv10.13-m2~!~l-( 8 ~ . 1 ~ , 1 ~ , 1 4 ~ , 1 7 ~ b 1 ~ ~ d ~ ~ . l 0 , 1 3 d ~ ~ d ! l - ~ ~
( ~ . l ~ l l ~ l ~ , l ~ , l 7 R ~ l l . l 7 d 1 h ~ d q . 1 7 { 2 - ~ ~ o ~ s e3~-0dl ~.7.l8O.9.1.0I.~11 .12.13.14.I5.l6.l7.dadeflh~dm
[ .".. L~M.7.8.9.10.11.1213.14.15.16.17dodsrhyd~3B 3~~lopen~a]phcnmLrsl-l7~xyebI~k 2~~~1~ 6.7.8.IO.I213.14.15.16.17
1. +' ' gclepmta[o]phmmthrsl.3.me
hh!dm
i,. . ... -3H~clapnta[a] c: FORIlLLI V phenmthm.l7.pl>2.oxcelhyl acetate
Scheme 1: An exemplification of the process of the preparation of isoflupredone acetate
PREDSISOME FOR\ll W II
from prednisolone.
THF, perehlonc acddlbmmabne
4 -- A - 4 90 _ _ 5 2~ ~
The process of preparation of isoflupred6ne at&fiO_r&%kc&blone as &e d, in
) scheme I, comprising the steps of:
Step I(a): Esterification of (8S,9S,lOR, 1 1 S,13S,14S, 17R)-11,17-dihydroxy- 17-(2-
hydroxyacetyl)-lO,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3Hcyclopenta[
a]phenanthren-3-one (prednisolone) to obtain 2-((8S,9S, 1 OR, 1 1 S, 13 S, 14S, 17R)-
cyclopenta[a]phenanthren- 17-y1)-2-oxoethyl acetate (compound of Formula V);
The synthesis of isoflupredone of the present invention, involves prednisolone,
((8S,9S, 1 OR, 1 1 S, 13S, 14S, 17R)- 1 1,17-dihydroxy- 17-(2-hydroxyacety1)- 10,13-dimethyl-
6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[pah]e nanthren-3-one) as one of
the starting material.
Prednisolone
The starting material (prednisolone) may be selectively esterified at the hydroxyl group in the
side chain. Esterification of prednisolone is carried out in the presence of a base, a solvent
and a reagent selected from the group consisting of an acid, an acid chloride and an anhydride
at a temperature in the range of - 10°C to 40°C.
The esterification may be carried out by reacting the hydroxyl group of prednisolone with a
suitable esterifying agent such as an acid or an acid chloride or an anhydride at a temperature
in the range of -10°C to 40°C. The molar ratio of esterifying agent to the starting material is
in the range of 1 : 1.16 to 1 :3. The esterification may also be carried out by Fries
rearrangement or by Williamson's synthesis. Preferably the esterification may be carried out
by orgaqic acids. A suitable acid for carrying out the esterification is acetic acid. The reaction
may be carried out in the presence of a suitable solvent or in the presence of a base. The
O 3 DEC 2013 I
solvent may be selected from the group combri
to 03 volume), Acetone (02 to 03 volume), Methylene dichloride (02 to 03 volume) and its
mixture. The base may be selected from the group comprising Pyridine, Triethyl amine or
Acid catalyst-p-TSA. When the reaction is carried out with acetic acid, it is suggested that
pyridine may be used in the reaction both as a solvent and a base. The acetic acid is taken in
the ratio of 1 :3 with respect to the starting reactant. The temperature of the reaction is kept in
the range of 2"C+3"C. When the reaction is carried out with acetic anhydride, acetic
anhydride is taken in the range of 1 :1.16 to 1 :1.59 with respect to the starting reactant and
with Acetyl chloride, the ratio is 1 :2.29.
Step I(b): Subjecting 2-((8S,9S,lOR,l lS,13S,14S,17R)-11,17-dihydroxy-lO,l3-dimethyl-3-
oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren1-7 -y1)-2-
oxoethyl acetate(Formu1a V) to dehydration reaction to obtain 2-((8S, 1 OS, 13 S, 14S, 17R)- 17-
hydroxy- 10,13-dimethy1-3-oxo-6,7,8,10,12,13,14,15,16,17-decahydro-3H- cyclopenta[a]
phenanthren - 17-yl) -2-oxoethyl acetate (Formula 11);
Further to step (a), the ester of prednisolone (Formula V) may be subjected to dehydration to
obtain compound of formula 11. The dehydration reaction may be acid catalysed. The acid
may be added to the reaction or generated, in situ. The dehydration reaction of the present
invention may be carried out by reacting with Sulphur di- oxide gas and oxidizing agent such
as dibromantine in a solvent. The solvent can be selected from the group consisting of
pyridine, tetrahydrofuran(THF), triethyl amine(TEA) and diethyamine(DEA). The molar
ratio of oxidizing agent is in the range of 1:0.42 to 1:0.76 with respect to the reactant. The
dehydration reaction may be carried out at room temperatures or at temperatures below the
room temperature. Preferably the reaction may be carried out at a temperature range of 0 to
~o'c, most preferably at 0 to S ' C . T ~d~eh ydration reaction may be carried out along with the
oxidation. The reaction is then quenched by treating the reaction mass with mixture of HC1
and water at 18'~. The reaction mass is treated with chloroform (molar ratio 1 :O. 12) at room
temperature for 8 hr to yield STAGE I1 product i.e compound of Formula 11. Post treatment
with chloroform the reaction mass is washed with water and dried. The dried mass is reacted
with methanol at higher temperature such as 40+5'~ for 1 hr. Finally the reaction mass is
washed with methanol and dried in tray.
.-
Step 11: Subjecting 2-((8S, 1 OS, 13S, 14S, 17R)- 17-hydroxy-l0,13-dimethyl-3-0x0-
6,7,8,10,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren1-7 -y1)-2-oxoethyl
acetate (Formula 11) to hydroxyhalogenation to obtain compound of Formula 111;
I The compound of formula I1 obtained is then subjected to hydroxyl-halogenation by addition
of halogenating agent such as hypobromous acid (HOBr) or n-bromosuccinimide or
hydrohalogen. The halogenating agent may be used in the molar ratio in the range of 1 :0.27
to 1 :0.66 with respect to the reactant.
I Hydroxy-halogenation is carried out in the presence of a halogenating agent, oxidizing agent
and a solvent. The halogenating agent is selected from the group comprising hypobromous
acid (HOBr) or n-bromosuccinimide or hydrohalogen. The halogenating agent may be used
in the molar ratio in the range of 1 :0.27 to 1 :0.66w.r.t to the reactant. The oxidising agent is
selected from the group comprising perchloric acid, dibromantine, sodium metabisulfite and
d
e: lli r
Potassium acetate.
oJ*
Gr
('2
tnn 'i
In this process, the product of step I i.e compound of Formula I1 is reacted with a solvent
g.<<
0
such as terahydrofuran at room temperature to obtain the reaction mass. The ratio of solvent
is in the range of 6: 1 to 15: 1 wN with respect to compound of Formula 11. The reaction mass
is cooled to 15+2'C. To the cooled reaction mass, mixture of perchloric acid and water is
added at temperature below 20'~. The molar ratio of perchloric acid is in the range of 1:l to
1:3 and the ratio of water is in the range of 1:4 to 1:7 w.r.t to the reactant. Post reaction, the
reaction mixture is cooled to 15+2'~ and is reacted with Dibromantine in the molar ratio of
1:0.27 to 1:0.66 w.r.t to the reactant for 60 min. The resultant reaction mass is then reacted
with the mixture of sodium metabisulfite, Potassium acetate and purified water in the molar
ratios in the ranges of 1 :O. 1 1 to 1 :O. 15, 1 : 1.72 to 1 :2.0 and 1 :3.6 to 1 :4.0 respectively w.r.t to
the reactant for 30 min at temperature 5OC to 2 5 ' ~to yield stage I11 product. The reaction is
quenched with purified water with continuous stirring for -30 min and is allowed to settle for
2 hr. Finally, the reaction mass is filtered, washed with purified water and dried in tray drier.
S t e ~ 111: Converting 2-((8S,1 OS, 13S,14S, 17R)-17-hydroxy-l0,13-dimethyl-3-oxo-
6,7,8,10,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl
'\ acetate (Formula 111) to its epoxide(Formu1a IV);
0 3 OEC 2013 3-
I d C;do -2:
The end product of step (11) may be subjected to epoxidation reaction. One of the methods to
make the epoxide of the present invention is by reacting the end product of step (11) with
DMF, DBU and acetic acid to obtain the epoxide. The epoxidation reaction is preferably
carried out at a temperature in the range of -10°C to 40°C. The ratio of DBU is taken in the
range of 1: 1 to 1 : 1.5, solvents are DMF (4 to 5.20 volume) and Acetone (5.20 volume). Post
reaction, the temperature is raised to 15 to 2 0 ' ~ and maintained for about half an hour. The
pH of the solution is made neutral with acetic acid to obtain compound of Formula IV. The
reaction is finally quenched and washed with ice cold water and dried. Alternatively, the
epoxides may be prepared by the reaction of the compound of formula I1 with peroxy acids to
obtain compound of formula IV. The peroxides may be taken in the ratios in the range of
15.0 to 1 :6.36 with respect to the compound of Formula 11.
Step IV: Hydrohalogenation of "epoxide" of Formula IV to obtain 2-((1 OS, 13S, 14S, 17R)-9-
fluoro-1 1 ,17-dihydroxy-l0,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-
3H-cyclopenta[a]phenanthren- 17-y1)-2-oxoethyl acetate (Formula I).
The epoxide may be subjected to ring opening to provide the desired end product i.e.
hydrohalogenation. The hydrohalogenation reaction may be conducted by reacting with an
acid containing a nuclueophile. Suitable acids for the reaction include haloacids. When the
haloacid is HF, the reaction will yield, isoflupredone acetate, the product of the present
invention. Preferably, the 70% of HF is utilized for the reaction. The reaction is preferably
carried out at a temperature of -28°C to -32°C for a time period in the range of 3hours+30
min to obtain crude isoflupredone acetate. 70% HF is commercially available as HF.urea
(molar ratio 1 : 17.52), HF.pyridine ( molar ratio1 : 16.6) and HF.DMF (ratio 1 : 17.68). The
molar ratio of HF:reactant is 153 to 1:95. The reaction is quenched wiih ice and the pH of
the reaction mix is adjusted to 6.0 to 6.5 with 10% sodium bicarbonate solution. The resultant
reaction mass is then washed with water and dried. The dried mass is treated with methanol at
higher temperature 7 0 i 2 ' ~ for 1 hr. Post treatment with methanol, the reaction mass is then
washed with methanol and dried to obtain crude isoflupredone acetate.
Step V: Synthesis of Isoflupredone Acetate final.
The Isoflupredone Acetate Crude is reacted with polar aprotic solvent such as acetone at
room temperature with continuous stirring for 20 to 30 minutes till a clear reaction mass is
0 3 OEC 2013 5: 9
-4 t
obtained. To the clear reaction mass carbon -1:0.25 w.r.t. isofluperidone acetate crude is
added and the mix is stirred for 30 minutes. The resultant reaction mass is filtered and
washed with acetone. Finally, the reaction is quenched and the reaction mass is washed with
purified water, followed by drying the mass of Isoflupredone acetate final.
SCHEME 11: PREPARATION OF ISOFLUPREDONE FROM 3TR (Compound of
Formula VI)
An exemplification of the process of the present invention may be represented here below at
Scheme 2.
Epox~de I FORMULA IV
2-((US, IOS.13.T,14S.17R)-l7-hydr0~y-10,13-d1m~thyI-3-o~0-
6.7,8.10.12,13,14,15.16.17
-dcoahydro
-3H-cyolopentn[a]
phenunthren-l7-yl)-2-ox~~hyelo etute
FORMULA I1
#
DMF. DBIJ.A ~ I Wa~ ld Br.
H
2-((8S.9R.l W13S.14S.I 7R)-9-homo- 1 1,17-dhydroxy-lO,13-d1methyl-3-oxh
6.7.8.9.10.11.12.13.14,15.16.17-d4r~uhydrdrdr-3f~ & < - l n t ] p h e n a n t h r m - l 7 - y l ~ - 2 - o x ~ t h yacle tate
/
li FORMULA 111
0 /
FORMULA I
0 ,p=9
0 3 OEC 2013
d
DEL 1 Zi' I
C
Scheme 2: An exemplification of the process of the weparation of isoflupredone acetate
from compound VI (3TR)
Step I: Hydroxylation of (8S,10S,13S,14S)-7,8,12,13,14,15-hexahydro-l7-(2-
hydroxyacety1)- 10,13-dimethyl-6H-cyclopenta[a]phenanthren-3(1 OH)-one (Formula VI) to
obtain 2-((8S,10S,13S,14S,17R)-17-hydroxy-l0,13-dimethyl-3-oxo-
6,7,8,10,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl
acetate (Formula 11).
Mixture of toluene and 3TR -(10:01wN) is charged in glass assembly at room temperature
to yield a reaction mass. The reaction mass is stirred for 20 to 30 minute and checked for
clarity. Post to this, the reaction mass is cooled to 5' to O'C. To the cooled reaction mass, Per
acetic acid (30%)in the range of (1:1.5 to 1:5.5moles/moles w.r.t to the reactyant) is added
and the reaction is continued at temperature 25' to 2 0 ' ~fo r 60 minute to yield STAGE I1
(compound of Formula 11) product. Gradually the reaction temperature is raised to 5025'~
and maintained for 60 minute. The reaction is quenched with ice cold water at 3' to 2 ' ~wit h
continuous stirring. Finally, the reaction is allowed to settle for about 120 minute and the
reaction mass is separated. The organic layer is washed thoroughly with water and distilled
under vacuum to thick oily mass and stage I1 is isolated in methanol and dried in tray drier at
temperature 60'~+5'~.
The preparation of isoflupredone acetate from compound I1 is same as provided in scheme I.
SCHEME 3: PREPARATION OF ISOFLUPRIDONE ACETATE FROM
PREDNISONE
In a preferred embodiment, the process of preparation of isoflupredone acetate from
compound VII as represented in scheme 3, comprising the steps of:
Step I (a): Synthesis of formula VIII
Esterification of (8S,9S, 1 OR, 13S, 14S, 17R)- 17-hydroxy- 17-(2-hydroxyacety1)-10,
13-dimethyl-6,7,8,9,12,14,15,16-octahydrocyclopenta[a]phenanthrene-3,1-d1 ione
(prednisone, compound VII) to obtain an ester of Formula VIII;
10 3 DEC tOl3 I
I t
I
L
Mixture of Pyridine and Prednisone - (5:l 'to 10:l)wN is charged in glass assembly at room r temperature to yield a reaction mass. The reaction mass is stirred for 20 to 30 minute and
checked for clarity. Post to this, the reaction mass is cooled to 3' to 2 ' ~ . To the cooled
reaction mass Acetic Anhydride - (1 : 1.16 to 1 : 1.59)mol/mol is added and the reaction is
continued at lower temperature 3' to 2 ' ~for 60 minute to yield STAGE I product. Gradually
the reaction temperature is raised to 20+5'~ and maintained for 60 minute. The reaction is
then quenched with ice cold water at 3' to 2 ' ~wi th continuous stirring. Finally, the reaction
is allowed to settle for 120 minute and the reaction mass is filtered. The filtered reaction mass
is washed thoroughly with water and dried in tray drier at temperature of 60'~+5'~.
Step I(b): Subjecting the ester of Formula VIII to (please explain the step) to obtain
compound of formula V;
The preparation of compound of Formula V from ester of Formula VIII is a three step
reaction, step-1 -formation of ketal, ~ t e ~ --2re"d~uc tion and step-3rd hydrolysis.
In the first step, mixture of ethylene glycol and formula VIII -(10:01) is charged in glass
assembly at room temperature to yield a reaction mass. The reaction mass is cooled to 20' to
25'~. To the cooled reaction mass tri ethyl ortho formate in the molar ratio of -(l:l) w.r.t to
the reactant is added and the reaction is continued at lower temperature 20' to 2 5 ' ~fo r 60
minute to yield intermediate product. Gradually the reaction temperature is decreased to
O~C+~'aCn d maintained for 60 minutes. The reaction product is filtered and wet cake is
taken in methanol (10:l) and is treated with potassium borohydride in the molar ratio -
1:0.20 to 1: 5 w.r.t to the reactant as a reducing agent, and then quenched with acidic ice cold
water at 3' to 2 ' ~wi th continuous stirring. Finally, the reaction is allowed to settle for 120
minute and the reaction mass is filtered. The filtered reaction mass is washed thoroughly with
water and dried in tray drier at temperature of 6 0 ' ~ + 5 ' ~to form compound of Formula V.
Step I (c): dehydrating compound of formula V to obtain compound of formula 11;
The preparation of isoflupredone acetate from compound I1 is same as provided in scheme I.
An exemplification of the process of the present invention may be represented here below at
scheme 3.
s 1 --,
i ' 4
0 3 DEC 2013
Y H,
\- H
H
H
/ '1 - H
0 H 0
/
0 2<(w9S IOR I IS313S 14s I7Rkl I,17dh~0\?-10 13dnneh!l- ~.((~,IOS,J~S,J~S~~R)13-d~m~e-th~\l\-3~~~\0U-- IO
3~x04789 10 11 12,13 14,I5,16,17dLdKA)dm- 678101213 14151617
3Hq clopenta[a]phenathren- 17-1 I)-2~xdI! l axtale decabdro
FORIIL L4 \ 1I phenanth-3rmH-qIc7l-o\ple)n-ta2[~a\]o el tache\ta te
FOR\IL L4 \ I11
FORIIL L4 I1
" * 0 qr-j 3 -4 3 i , - - &
a,/ J$~.? I$.-* L3.d
0 0
-3~qcl&nta[a]
phenanthrm-I7-!l)-2~\oethl !a cetate
II V111
FORIIL'L4 I THF. perchloric aclddibromatne
0 - C---
HF 70% (H DMF. DBU. Acetic acid H
H
n 0
2~(1OS.l3S.IG.l7Rt%flwlo.-ll7 dihydro~~-lO.l3d~I-3~~0-
6.7.8.9.10.1 1.1113.14.15.16.17~h!dro-3Hqclopentn-l7-
I)-2~xce.oetal?c.elt ate
FORIIIZA K
FOR\ITL.4 I FORMULA Ill
Scheme 3: An exemplification of the process of the preparation of isoflupredone acetate
from prednisone
ADVANTAGES:
The process of the present invention demonstrates several advantages. A non-limiting set of
advantages of the present invention are listed below:
1. The present invention provides a novel process for the synthesis and purification of
Isoflupredone acetate which is very safe, simple and provides good purity as per ICH
guidelines and good yield.
2. The novel process of the present invention includes use of solvents which can be
recycled and reused, thereby promoting green chemistry and ensuring a cleaner
19
*
0 3 OEC 20q - 2' surrounding by putting lesser load on environment. This makes the process mofe r economical and industrially and commercially viable.
3. The process of the present invention is easily operable and avoids the number of
operations as present in prior art, thus resulting in shortening of reaction time,
requirement of less substance, and lowering of labor.
4. The process of the present invention does not involve chromatographic purification
steps for the purification of the final product and hence reduces the cytostatic and
chemical waste and lower down the environmental pollution.
While the invention has been described and exemplified in sufficient detail for those skilled
in this art to make and use it, various alternatives, modifications, and improvements should
be apparent without departing from the spirit and scope of the invention. The examples
provided herein are representative of preferred embodiments, are exemplary, and are not
intended as limitations on the scope of the invention. Modifications therein and other uses
--I
cx will occur to those skilled in the art. These modifications are encompassed within the spirit of
== -
d: the invention and are defined by the scope of the claims.
k:%
3- .;
d: : It will be readily apparent to a person skilled in the art that varying substitutions and C,>
modifications may be made to the invention disclosed herein without departing from the
scope and spirit of the invention.
The following specific examples illustrate the process of present invention, but they are not
intended to limit the scope of the invention.
PREPARATION OF ISOFLUPREDONE ACETATE FROM PREDNISOLONE
Example 1: Synthesis of STAGE I product (compound of Formula V).
Mixture of Pyridine and Prednisolone 3: 1 is charged in glass assembly at room temperature to
yield a reaction mass. The reaction mass was stirred for 20 to 30 minute and checked for
clarity. Post to this, the reaction mass was cooled to 3' to 2 ' ~ . To the cooled reaction mass
Acetic Anhydride 1 : 1.59 was added and the reaction was continued at lower temperature 3'
to 2 ' ~fo r 60 minute to yield STAGE I product, compound of formula V. Gradually the
20
reaction temperature was raised to 2025'~ and maintained for 60 minute. The reaction was
quenched with ice cold water at 3' to 2 ' ~wi th continuous stirring. Finally, the reaction was
allowed to settle for 120 minute and the reaction mass was filtered. The filtered reaction mass
was washed thoroughly with water and dried in tray drier at temperature 60'~+5'~.
Yield 11 0%; Purity not less than 98%; Single Impurity not less than 1.0%; Total Impurity not
more than 2.0%
Example 2: Synthesis of STAGE I1 product (Formula 11)
Mixture of Pyridine (10:l wN w.r.t to the reactant) and Dibromantine (molar ratio w.r.t to
the reactant is 1: 0.76) was prepared at temperature 15"~+2'~T.o the reaction mix, STAGE I
product was added with continuous stirring at temperature 1 5 ° ~ + 2 0P~o.s t mixing the
reaction was cooled to a lower temperature such as 3' to 2 ' ~to obtain the reaction mass. The
reaction mass was purged with sulfur di oxide gas at 1 8 ' ~fo llowed by cooling the resultant
reaction mass to 3' to 2 ' ~ . The reaction was Quenched by treating the reaction mass by
mixture of HCl and water at 18 'c. The reaction mass was treated with chloroform (1 :O. 12) at
room temperature for 8 hr to yield STAGE I1 product. Post treatment with chloroform the
reaction mass was washed with water and dried. The dried mass was reacted with methanol at
higher temperature such as 40+5'~ for 1 hr. Finally the reaction mass was washed with
methanol and dried in tray.
Yield 82%; Purity not less than 96%; Single Impurity not less than 2.0%; Total Impurity not
more than 4.0%
Example 3: Synthesis of Stage I11 product (compound of formula 111).
The STAGE I1 product was reacted with terahydrofuran 1 1 : 1 with respect to compound of
Formula I1 at room temperature to obtain the reaction mass. The reaction mass was cooled to
15+/-2'~. To the cooled reaction mass mixture of perchloric acid and water 1 : 1.15 and 1 5.7
was added at temperature below 20'~. Post reaction, the reaction mixture was cooled to
1522'~ and was reacted with Dibromomantine in the molar ratios of 1 :0.27 for 60 min. The
resultant reaction mass was reacted with the mixture of sodium metabisulfite, Potassium
acetate and purified water in the molar ratios 1 :O.l lto 1 :0.15, 1: 1.72 to 1:2.0 and 1 :3.6 to
1 :4.0 respectively w.r.t to the reactant for 30 min at temperature 5OC to 2 5 ' ~to yield stage I11
21
,O 3 DEC 2014(
w
t Y d - - IlEL 1 2 :
product. The reaction was quenched with purified water with continuous stirring for 30 min
and was allowed to settle or 2 hr. Finally, the reaction mass was filtered, washed with
purified water and dried in tray drier.
Yield 11 1%; Purity not less than 96%; Single Impurity not less than 2.0%; Total Impurity not
more than 4.0%
Example 4: Synthesis of Stage IV product (epoxide of Formula IV).
The STAGE I11 product was reacted with dimethyl formarnide 5.20:l wN w.r.t to the
reactant at room temperature to obtain a reaction mass. The reaction mass was cooled to 2 ' ~
and was reacted with precooled DBU in the ratio of 1 : 1.5 w.r.t to the reactant (compound of
formula 3) with proper stirring for 30 minutes. Post reaction the temperature was raised to 18
OC and was maintained for 30 minutes. The pH of the reaction mix was adjusted to neutral
with acetic acid to obtain the Stage IV product. Finally the reaction was quenched and
washed with ice cold water and dried.
Yield 80%; Purity not less than 96%; Single Impurity not less than 2.0%; Total Impurity not
C q ' -:.;
e:. more than 4.0%
i".
b. Example 5: Synthesis of Isoflupredone Acetate Crude.
P' ' c,
The epoxide, Stage IV product was reacted with hydrofluoric acid 1:95 wN at -30'~ with
continuous stirring for 3hrk 30 min to yield Isoflupredone Acetate Crude. The reaction was
quenched with ice and the pH of the reaction mix was adjusted to 6.0 to 6.5 with 10% sodium
bicarbonate solution. The resultant reaction mass was washed with water and dried. The dried
mass was treated with methanol at higher temperature 70+2OC for 1 hr. Post treatment with
methanol the reaction mass was washed with methanol and dried.
Yield 90%; Purity not less than 95%; Single Impurity not less than 2.0%; Total Impurity not
more than 5.0%.
Example 6: Synthesis of Isoflupredone Acetate final.
The Isoflupredone Acetate Crude was reacted with acetone in a ratio 1:42 wN at room
temperature with continuous stirring for 20 to 30 minutes till a clear reaction mass was
2 2
o 3 DEC 2013
0
obtained. To the clear reaction mass carbon
) added and the mix was stirred for 30 minutes. The resultant reaction mass was filtered and
washed with acetone. Finally, the reaction was quenched and the reaction mass was washed
with purified water, followed by drying the mass of Isoflupredone acetate final.
Yield 92%; Purity not less than 98%; Single Impurity not less than 1.0%; Total Impurity not
more than 2.0%.
PREPARATION OF ISOFLUPREDONE ACETATE FROM 3TR
Example 6: Synthesis of compound of formula I1
Mixture of toluene and 3TR (10:Ol) is charged in glass assembly at room temperature to
yield a reaction mass. The reaction mass was stirred for 30 minute and checked for clarity.
Post to this, the reaction mass was cooled to 5' to O'C. To the cooled reaction mass, Per
acetic acid 30% (1:4.82) was added and the reaction was continued at temperature 25' to
2 0 ' ~fo r 60 minute to yield STAGE I1 product. Gradually the reaction temperature was raised
to 50+/-5OC and maintained for 60 minute. The reaction was quenched with ice cold water at
4 3' to 2 ' ~wi th continuous stirring. Finally, the reaction was allowed to settle for 120 minute
T n4 65 and the reaction mass was separated. The organic layer was washed thoroughly with water
b.,:
k> and distilled under vacuum to thick oily mass and stage 11 is isolated in methanol and dried in
p
P '
a.S >, tray drier at temperature 6 0 ' ~ + / - 5 ~ ~ .
%J
Yield 100%; TLC- single spot (HPLC not match)
Example 7: Synthesis of compound of formula I11
The formula I1 product was reacted with terahydrofuran in a ratio of 11:l wN w.r.t to the
reactant at room temperature to obtain the reaction mass. The reaction mass was cooled to
15+/-2'~. To the cooled reaction mass mixture of perchloric acid and water 1 : 1.15 and 1 5.7
was added at temperature below 20'~. Post reaction, the reaction mixture was cooled to
15+2'~ and was reacted with Dibromomantine in the ratios of 1 :0.3 for 60 min. The resultant
reaction mass was reacted with the mixture of sodium metabisulfite, Potassium acetate and
purified water in the ratios 1 :O. 1 1, 1 : 1.72 and 1 :3.6 respectively w.r.t to the reactant for 30
min at temperature below 2 5 ' ~to yield stage I11 product The reaction was quenched with
2 3
4
0 3 DEC 20fi
purified water with continuous stirring for 30 min and was allowed to settle for 2 hr. Finally, r the reaction mass was filtered, washed with purified water and dried in tray drier.
Yield 100%; Purity not less than 80%; Single Impurity not less than 10.0%; Total Impurity
not more than 20.0%
Example 8: Synthesis of compound of formula IV
The formula I11 was reacted with dimethyl formamide 1:5.20 wN at room temperature to
obtain a reaction mass. The reaction mass was cooled to 2 ' ~and was reacted with precooled
DBU in the molar ratio of 1:1.5 with proper stirring for 30 minutes. Post reaction the
temperature was raised to 1 8 ' ~an d was maintained. for 30 minutes. The pH of the reaction
mix was adjusted to neutral with acetic acid to obtain the Stage IV product. Finally the
reaction was quenched and washed with ice cold water and dried.
Yield 70%; Purity not less than 80%; Single Impurity not less than 10.0%; Total Impurity not
more than 20.0%
4 Example 9: Synthesis of Isoflupredone Acetate Crude.
T
'-&2 .
f.9
&3 The epoxide, formula IV product was reacted with hydrofluoric acid in the ratio of 1 :95 at -
s-4 &xd 3 0 ' ~ with continuous stirring for 3h.e 30 min to yield Isoflupredone Acetate Crude. The .- .
'4 reaction was quenched with ice and the pH of the reaction mix was adjusted to 6.0 to 6.5 with
10% sodium bicarbonate solution. The resultant reaction mass was washed with water and
dried. The dried mass was treated with methanol at higher temperature 7022'~ for 1 hr. Post
treatment with methanol the reaction mass was washed with methanol and dried.
Yield 80%; Purity not less than 85%; Single Impurity not less than 5.0%; Total Impurity not
more than 15.0%.
Example 10: Synthesis of Isoflupredone Acetate final.
The Isoflupredone Acetate Crude was reacted with acetone at room temperature with
continuous stirring for 20 to 30 minutes till a clear reaction mass was obtained. To the clear
reaction mass carbon was added and the mix was stirred for 30 minutes. The resultant
reaction mass was filtered and washed with acetone. Finally, the reaction was quenched and
24
--
the reaction mass was washed with purified water, followed by drying the mass of
Isoflupredone acetat
Yield 92%; Purity not less than 98%; Single Impurity not less than 1.0%; Total Impurity not
more than 2.0%.
PREPARATION OF ISOFLUPREDONE ACETATE FROM PREDNISONE
Example 11: Synthesis of compound of formula VIII
Mixture of Pyridine and Prednisone (6: 1) was charged in glass assembly at room temperature
to yield a reaction mass. The reaction mass was stirred for 30 minute and checked for clarity.
Post to this, the reaction mass was cooled to 3' to 2 ' ~ . To the cooled reaction mass Acetic
Anhydride in the molar ratio of 1 : 1.52 was added and the reaction was continued at lower
temperature 3' to 2 ' ~fo r 60 minutes to yield STAGE I product. Gradually the reaction
temperature was raised to 20+5'~ and maintained for 60 minute. The reaction was then
quenched with ice cold water at 3' to 2 ' ~wi th continuous stirring. Finally, the reaction was
allowed to settle for 120 minute and the reaction mass was filtered. The filtered reaction mass
Q: was washed thoroughly with water and dried in tray drier at temperature of 60'~+5'~. z b- ?
Q2 ..I. A,
Yield 100%; Purity not less than 98%; Single Impurity not less than 1.0%; Total Impurity not s more than 2.0%
Example 12: Synthesis of compound of formula V
Mixture of ethylene glycol and formula VIII (10:Ol) was charged in glass assembly at room
temperature to yield a reaction mass. The reaction mass was cooled to 20'. To the cooled
reaction mass tri ethyl ortho formate(1: 1) was added and the reaction was continued at lower
temperature 20' to 2 5 ' ~fo r 60 minute to yield intermediate product. Gradually the reaction
temperature is decrease to O~C+~'aCnd maintained for 60 minutes. The reaction was filtered
and wet cake was taken in methanol (1:10) and treated with potassium borohydride (1:3.72)
then quenched with acidic ice cold water at 3' to 2 ' ~wi th continuous stirring. Finally, the
reaction was allowed to settle for 120 minute and the reaction mass was filtered. The filtered
reaction mass was washed thoroughly with water and dried in tray drier at temperature of
60°c+5'c.
I
I 1 Yield 70%; Purity not less than 80%; Single
more than 20.0%
Example 13: Synthesis of compound of formula I1
Mixture of Pyridine (1O:lwN) and Dibromantine (molar ratio of 1 :0.76) was prepared at
temperature 1 ~ O C + ~ ' C . To the reaction mix, formula V was added with continuous stirring at
temperature 15°~+/-20P~o.s t mixing the reaction was cooled to a lower temperature such as
3' to 2 ' ~to obtain the reaction mass. The reaction mass was purged with sulfur di oxide gas
at 1 8 ' ~ followed by cooling the resultant reaction mass to 3' to 2 ' ~ . The reaction was
Quenched by treating the reaction mass by mixture of HC1 and water at 18 'c. The reaction
mass was treated with chloroform at room temperature for 8 hr to yield STAGE I1 product.
Post treatment with chloroform the reaction mass was washed with water and dried. The
dried mass was reacted with methanol at higher temperature such as 4025'~ for 1 hr. Finally
the reaction mass was washed with methanol and dried in tray.
Yield 72%; Purity not less than 80%; Single Impurity not less than 10.0%; Total Impurity not
4 more than 20.0%
2<:
- 1 Example 14: Synthesis of compound of formula I11
P%
€"' The formula I1 product was reacted with terahydrofuran1:ll at room temperature to obtain d the reaction mass. The reaction mass was cooled to 15+/-2'~. To the cooled reaction mass
mixture of perchloric acid and water, molar ratios 1 : 1.15 and 1 5.7 respectively was added at
temperature below 20'~. Post reaction, the reaction mixture was cooled to 1522'~ and was
reacted with Dibromomantine in the ratios of 1 :0.27 for 60 min. The resultant reaction mass
was reacted with the mixture of sodium metabisulfite, Potassium acetate and purified water in
the molar ratios 1 :0.11, 1: 1.72 and 1 :3.6 respectively w.r.t to the reactant for 30 min at
temperature below 2 5 ' ~ to yield stage I11 product The reaction was quenched with purified
water with continuous stirring for 30 min and was allowed to settle or 2 hr. Finally, the
reaction mass was filtered, washed with purified water and dried in tray drier.
Yield 100%; Purity not less than 80%; Single Impurity not less than 10.0%; Total Impurity
not more than 20.0%
1 Example 15: Synthesis of compound of ' formula IV The formula I11 was reacted with dimethyl formamide 5.20:l wN w.r.t to the reactant at
room temperature to obtain a reaction mass. The reaction mass was cooled to 2 ' ~an d was
reacted with precooled DBU in the molar ratio of 1:1.5 with proper stirring for 30 minutes.
Post reaction the temperature was raised to 1 8 ' ~an d was maintained for 30 minutes. The pH
of the reaction mix was adjusted to neutral with acetic acid to obtain the Stage IV product.
Finally the reaction was quenched and washed with ice cold water and dried.
Yield 70%; Purity not less than 80%; Single Impurity not less than 10.0%; Total Impurity not
more than 20.0%
Example 16: Synthesis of Isoflupredone Acetate Crude.
The epoxide, formula IV product was reacted with hydrofluoric acid in a ratio of 1 :95 wN at
-30'~ with continuous stirring for 3& 30 min to yield Isoflupredone Acetate Crude. The
reaction was quenched with ice and the pH of the reaction mix was adjusted to 6.0 to 6.5 with
10% sodium bicarbonate solution. The resultant reaction mass was washed with water and
4 dried. The dried mass was treated with methanol at higher temperature 7022'~ for 1 hr. Post
2T treatment with methanol the reaction mass was washed with methanol and dried. 3 t&y4 Yield 80%; Purity not less than 85%; Single Impurity not less than 5.0%; Total Impurity not
6 more than 15.0%.
Example 17: Synthesis of Isoflupredone Acetate final.
The Isoflupredone Acetate Crude was reacted with acetone at room temperature with
continuous stirring for 20 to 30 minutes till a clear reaction mass was obtained. To the clear
reaction mass carbon was added and the mix was stirred for 30 minutes. The resultant
reaction mass was filtered and washed with acetone. Finally, the reaction was quenched and
the reaction mass was washed with purified water, followed by drying the mass of
Isoflupredone acetate final.
Yield 82%; Purity not less than 90%; Single Impurity not less than 5.0%; Total Impurity not
more than 10.0%.

We Claim:
A process for the
e -.
, -27 I
0 3 DEC 2013 f
tl-i nEL
LJ 1
-
preparation of prednisolone compound of formula (I),
0
0
Formula I
comprising the steps of:
I. Preparing compound of formula I1
11. hydroxy-halogenation of compound of formula (11)
To obtain
Formula I1
compound of formula (111);
0
Formula I11
111. converting compound of formula (111) to epoxide of formula (IV);
1
0 3 OEC 2013 I
Formula IV
IV. hydrohalogenating the epoxide obtained from step (111) to obtain crude
compound of formula (I);
V. purifying the product of step IV to obtain pure isoflupredone acetate.
VI. Optionally converting compound of formula (11) to compound of formula (IV)
by epoxidation in the presence of peroxy acids.
2. The process as claimed in claim 1, wherein the compound of formula I1 is prepared by
a process comprising the steps of :
esterification of 8S,9S,1 OR, 1 1 S, 13S, 14S, 17R)-11,17-dihydroxy-17-(2-
hydroxyacety1)-1 0,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-
3H-cyclopenta[a]phenanthren-3-one (prednisolone) to obtain an ester of
formula formula (V);
0
Formula V
b) dehydrating compound of formula (V) to obtain compound of formula (11).
3. The process as claimed in claim 1, wherein the compound of formula (11) is prepared
by hydroxylating compound of formula (VI):
Formula VI
4. The process as claimed in claim 1, wherein the compound of formula I1 is prepared by
process comprising the steps of :
a). Esterification of prednisolone(compound VII) to obtain an ester (compound of
formula (VIII);
b). Converting the ester of Formula VIII to compound of formula V;
c). subjecting the product of step (b) to dehydration reaction to obtain compound
of formula 11;
Formula VIII
5. The process as claimed in step I1 of claim 1, wherein the hydroxy-halogenation is
carried out in the presence of a halogenating agent, oxidizing agent and a solvent.
6. The process as claimed in claims 1 or 4, wherein the halogenating agent is selected
from the group consisting of hypobromous acid(HOBr), n- bromosuccinimide,
dibromantine and hydrohalogen.
The process as claimed in claim 4, wherein the oxidizing agent is selected from the
group of, potassium acetate, sodium metabisulfite and perchloroacetic acid and the
solvent is selected from the group of pyridine, and tetrahydrohran.
The process as claimed in any of the preceding claims wherein the molar ratio of the
halogenating agent is in the range of 1 :0.27 to 1 :0.66.
The process as claimed in claim 1, wherein the epoxidation reaction of step 111 is
carried out in the presence of a base selected from the group consisting of dimethyl
formarnide (DMF) or 1,8-Diazabicyclo[5.4.0] undec-7-ene (DBU) and acetic acid.
The process as claimed in claim 9, wherein the molar ratio of dimethyl formarnide
(DMF) is in the range of 1 : 1 to 1 : 1.5 and the ratio of DMF is in the range of 4 to 5.20
wN.
The process as claimed in step IV of claim 1, wherein the hydrohalogenation reaction
is carried out in the presence of a haloacid preferably hydrogen flouride at a pH in the
range of 6.0 to 6.5.
The process as claimed in claim 11, wherein the ratio of reactant : HF is in the range
of 1:53 to 1:95.
The process as claimed in any of the preceding claims, wherein the esterification of
prednisolone is carried out in the presence of a base, a solvent and a reagent selected
from the group consisting of an acid, an acid chloride and an anhydride at a
temperature in the range of -10°C to 40°C .
The process as claimed in claim 8, wherein the base is selected from a group
consisting of pyridine, triethyl amine or acid catalyst-p-TSA.
The process as claimed in claim 8, wherein the solvent selected from a group
consisting of pyridine, Acetic acid, Acetone, Methylene dichloride and its mixture.
The process as claimed in claim 8, wherein the reagent is selected from acetic acid,
acetic anhydride and acetyl chloride.
3 1
? 17. The process as claimed in step (b) of claim 2, wherein the dehydration is carried out in
the presence of sulfur dioxide gas and an oxidizing agent in a suitable solvent at a
temperature in the range of 0 to 20°C.
18. The process as claimed in claim 17, wherein the oxidizing agent is selected from the
group consisting of dibromantine and the solvent is selected from the group consisting
of pyridine, tetrahydrofuran(THF), triethyl arnine(TEA) and diethyamine(DEA),HCl,
chloroform and methanol.
19. The process as claimed in claim 17, wherein the molar ratio of oxidizing agent is
1 :0.42 to 1 :0.76 with respect to compound of Formula V.
20. The process as claimed in claim 3, wherein the hydroxylation is carried out in the
presence of 30% Peracetic acid and a solvent preferably toulene.
21. The process as claimed in step (b) claim 4, wherein the compound of Formula V is
prepared by a process comprising the , steps of:
&,f
%?-# 1. reacting compound of Formula VIII with ethylene glycol and tri ethyl ortho
formate at a temperature in the range of 10 to 40°C to obtain a ketal;
ii.. . .
c 'A+ 11. reacting the ketal formed in step (i) with a reducing agent preferably
0 potassium borohydride in a solvent preferably methanol;
...
111. hydrolyzing the product of step (ii) with acidic water at a temperature in the
range of 0 to 5 "C to obtain compound of formula V.
22. A compound of Formula I prepared by the process of claim 1

23. A compound of Formula I11 prepared by the process of claim 1