FIELD OF THE INVENTION
The present invention relates to an imdroved, cost effective, commercially viable
and industrially advantageous process for preparation of Seratrodast of Formula I,
which involves condensation of compound of Formula I1 with compound of
Formula I11 in presence of methanesulfonic acid.
BACKGROUND OF THE INVENTION
Seratrodast chemically known as 7-phenyl-7-(2,4,5-trimethyl-3,6-
dioxocyclohexa- l,4-dien- 1 -yl)heptanoic acid as represented in Formula I.
Seratrodast and other related compounds were invented by Takeda Chemical
Industries, Ltd., Japan and disclosed in US patent 5,180,742 ("US 742").
Seratrodast,was received first marketing approval in Japan in 1997 and marketed
under the trade name of "Bronica". Seratrodast is currently marketed in Japan,
China and India as an add-on controller therapy in the management of asthma. "US
742" also discloses an analogous process for preparation of Seratrodast in
examples 2 and 10. According to Table-1 of "US 742" with reference to compound
50 (Seratrodast) as mentioned therein, the analogous preparation of Seratrodast
given in example 2 can be extrapolated as represented herein below in scheme 1.
Scheme 1:
Formula I1
Oxidizing agent
Condensation
Y /
/
Formula 111 I
Formula IV
According to "US 742", compounds of Formula I1 and Formula I11 undergoes
condensation reaction in presence of an acid catalyst especially boron trifluoride
ethyl etherate for 4 days at room temperature followed by oxidation to obtain crude
Seratrodast, which is purified over silica gel column chromatography to get pure
Seratrodast. In "US 742", aluminium chloride, stannic chloride, p-toluenesulfonic
acid, D-camphorsulfonic acid are further suggested as acid catalysts for the above
condensation reaction.
Seratrodast was prepared by the present inventors according to example-2 of "US
742" by condensing compounds of Formula I1 and Formula 111 in presence of boron
trifluoride ethyl etherate as an acid catalyst. The crude product thus obtained was
in moderate yield and purity. During synthesis it was found that column
chromatography is essential for purification and isolation of crude Seratrodast
because obtained material was charring in nature and impossible to crystallize
using adequate solvents.
Further, present inventors had performed the same condensation reaction using
different acid catalysts as mentioned in "US 742" but in any case no satisfactory
yield and purity was achieved in final product. In case of these acid catalysts, viz.
, D-camphor sulfonic acid, aluminiurrl chloride, p-toluene sulfonic acid and
stannous chloride, even reaction did not proceed at room.temperature.
Hence, from the above, the process disclosed in "US 742" for manufacturing
Seratrodast using several acid catalysts is not satisfactory in terms of long reaction
time taken in condensation, low yield and low purity. Further, use of
chromatographic purification makes this process uneconomical, difficult to handle
and non-reproducible at. large scale.
~ c c o r d i nt~o Chinese publication 104744244, Seratrodast is prepared by
condensing compounds of Formula I1 and Formula 111 in presence of D-camphor-
10-sulfonic acid in toluene at 70°C for 20 hours followed by oxidation. Seratrodast
thus obtained is further purified by chromatography.
However, use of costly D-camphor-1 0-sulfonic acid, long reaction time taken in
condensation step, high reaction temperature, low yield and low purity, further use
of chromatography in purification makes this process uneconomical, difficult to
handle and non-reproducible at large scale.
According to another Chinese publication 100999452, Seratrodast is prepared by
condensing compounds of Formula I1 and Formula 111 using boron trifluoride
etherate as an acid catalyst in presence of tetrahydrofuran (THF) as a solvent at
reflux condition for 5 hours followed by oxidation. The product thus obtained is
decolorized with charcoal and further recrystallize from methanol to get pure
Seratrodast with 58-78 % yield.
The above process avoids use of column chromatography for purification of
Seratrodast that is an improvement over prior art. However, use of methanol in
recrystallization may produce ester impurity and the final product thus obtained is
not essentially pure. Further, use of costly and hazardous tetrahydrofuran (THF) as
solvent, use of charcoal for decolorization, high reaction temperature and low
purity makes this process un-economical as well as not environmentally safe at
large scale production.
According to European Patent 0537954, Seratrodast is prepared by condensing
compounds of Formula VII and Formula I1 in presence of methanesulfonic acid as
an acid catalyst.
Scheme 2:
Formula I1
Condensation
1 "b Formuln V
Formula VII Formuln I
As per European Patent 0537954 ("EP 9543 the intermediate compound of
Formula VII is prepared by reacting compound of Formula-V with benzaldehyde
(Formula VI). Starting material, (3-carboxypropy1)-triphenylphosphonium
bromide of Formula V used in the preparation of intermediate compound of
Formula VII is very costly, hazardous and also not easily commercially available.
Further, compound of Formula VII and Seratrodast thus obtained are purified using
silica gel column chromatography. Hence, the process disclosed in "EP 954" is
uneconomical, not environmentally safe, difficult to handle and non-reproducible
at large scale.
Therefore, there is a need to develop an improved process for preparation of
Seratrodast using easily and commercially available starting materials, reagents
and solvents which would be economical, less time consuming, environmental
friendly and easy to handle at large scale production.
OBJECTS OF THE INVENTION
An object of the present invention is to provide an improved process for
preparation of Seratrodast in high yield and purity which would be economical,
environmental friendly, easy to handle and reproducible at large scale production.
Another object of the present invention is to provide a process for preparation of
Seratrodast in high yield and purity at ambient temperature in convenient reaction
time.
Further object of the present invention is to provide a process for preparation of
pure crystalline Seratrodast without using column chromatography for purification
of intermediate and final Seratrodast.
From the various methods reported in above mentioned prior arts utilized for
preparation of Seratrodast, it is quite evident that almost all methods invariably
utilize column chromatography for purification of Seratrodast and /or its
intermediates. The time taken in condensation reaction of Formula I1 and Formula
111 is quite high for example according to "US 742", almost 4 days are required to
complete the condensation reaction and in "CN 244" almost 20 hours are required
for condensation and also the reaction is carried out at high temperature.
Further, from practicing prior art methods, inventors of the present invention have
found while.utilizing aluminium chloride, stannic chloride, p-toluenesulfonic acid,
D-camphorsulfonic acid as acid catalysts suggested in "US 742", even, reaction
does not proceed and no product is produced.
The inventors of present invention have found that compounds of Formula I1 and .
111 can be condensed completely using methansulfonic acid as an acid catalyst,
which apart from being free of the shortcomings associated in general with use of
all reported acid catalysts in prior art.
In particular, the inventors of present invention have found that compound of
formula I1 can be condensed with compound of Formula 111 during preparation of
Seratrodast using methane sulfonic acid and the invented process has following
advantages:
The condensation can be carried out at ambient temperature, which makes the
process easy to handle at plant scale production;
Purification of crude Seratrodast can be easily done by crystallizing it in suitable
solvents without using chromatographic purification that makes the process
economical and reproducible at large scale production ;
The time taken in condensation is very less in comparison to the prior art methods
that makes the process economical and easy to handle; and
Use of already known and easily available starting material makes the process very
economical at large scale production.
SUMMARY OF' T) INVENTION
In the first aspect, present invention relates to a process for preparation of
Seratrodast of Formula I
comprising the steps of:
a) condensing the compound of Formula I1
OH
Formula I1
with compound of ~oimulaI1 1
Formula 111 roH 0
in a solvent and in presence of methane
Formula IV
sulfonic acid to obtain compound
b) oxidising compound of Formula IV to obtain compound of Formula-I.
In second aspect, the present invention relates to a process for preparation of pure
crystalline Seratrodast comprises the steps of
a) dissolving crude Seratrodast obtained from step b) in acetonitrile by heating
from room temperature to 70°C; .
b) adding demineralized water in the solution;
c) cooling the reaction mixture to room temperature; and
c) isolating pure crystalline Seratrodast.
In a further aspect, the present invention relates to a pure crystalline form of
Seratrodast characterized by at least one of the following:
a) an X-Ray Powder Diffraction (XRPD) spectrum that comprises peaks at twotheta
angle of 5.90, 11.06, 11.38,. 11.88, 12.0, 13.52, 14.47, 14.97, 17.82, 18.38,
19.64, 22.02, 22.35, 22.73, 23.73, 24.13, 25.00, 25.59, 26.92, 27.12, 28.10, 29.47,
30.31, 30.56, 31.27, 32.24, 33.11, 33.78, 34.60, 34.90, 35.71, 36.17, 37.37, 38.61,
38.88, 39.61 and 39.78 & 0.2 degree and
b) Differential Scanning Calorimetry (DSC) comprises a single endothermic peak
at 130.44"C.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure-1 is an x - R ~Di~ffr actogram of pure crystalline Seratrodast.
Figure3 is an Differential Scanning Calorimetry thermogram of pure crystalline
Seratrodast.
DETAILED DESCRIPTION OF THE INVENTION
In the present invention as used herein, the term "HPLC" or "High Performance
Liquid Chromatography" refers to liquid chromatography in which the degree of
separation is increased by forcing the mobile phase under pressure through a
stationary phase, typically a densely packed column. I
In the present invention, as used herein, the term "crude Seratrodast" refers to
Seratrodast having purity 5 99% peak area by HPLC.
In the present invention as used herein, the term "pure crystalline Seratrodast"
refers to Seratrodast having purity > 99% peak area by HPLC. .
In the present invention as used herein, the term "XRPD or "X-Ray Powder
Diffraction" refers to any method for determining the nature of a sample by
calculating its diffraction pattern in either scattered or back-scattered techniques.
In the present invention as used herein, the term "DSC" or "Differential Scanning
Calorimetry" refers as a thermoanalytical technique in which the difference in the
amount of heat is required to increase the temperature of a sample and reference is
measured as a function of temperature.
In the present invention as used herein, the term "in situ" means within the reaction
wherein, the compounds formed in the reaction are taken to the next step as such,
without isolation from the reaction mass.
In the, present invention as used herein, "Ambient-temperature" refers to
temperature under circumstances without any special heating and cooling and is,
for example, about 20°C to 25' C.
In the present invention as used herein, the term "Charring" defines a degraded
reaction by-product which inhibit to crystallize desired product by .simple
crystallization.
According to the invention, there is provided a process for the preparation of
Seratrodast of Formula I
comprising the steps of:
a) reacting the compound of Formula I1
OH
Formula I1
with compound of Formula I11
in a solvent and in presence of methane sulfonic acid to obtain compound of
Formula IV
b) oxidising.compound of Formula IV to obtain Seratrodast of Formula I.
The process according to present invention wherein, in step a), the methane
sulfonic acid may be employed in mole ratio of 0.7 : 1 to 2.0 : 1 relative to the
compound of Formula 11. Preferably, the methane sulfonic acid is employed in
mole ratio of 1.1 1 : 1 relative to the compound of Formula 11.
The process according to present invention wherein, in step a), the methane
sulfonic acid may be employed in mole ratio of 0.6 : 1 to 1.8 : 1 relative to the
'compound of Formula 111. Preferably, the methane sulfonic acid is employed in
mole ratio of 1: 1 relative to the compound of Formula 111.
The process according to the present invention, wherein in step a), 2 to 6 hours of
'stirring can be required to complete the condensation reaction, preferably 2 to 3
hours of stirring is required to complete the reaction.
The condensation reaction of step a) can be carried out at a temperature ranging
10°C to 40°C, preferably the reaction is,carri&d out at a temperature ranging 20°C
to 25OC.
The solvent used in step a) can be selected from a group consisting of methylene
dichloride, 'toluene, tetrahydrofuran, ethylene dichloride and mixture thereof.
Preferably, the solvent used in step a) is methylene dichloride.
The oxidizing agent used in step b) can be selected from a group consisting of ferric
chloride, ferric sulfate, hydrogen peroxide and m-chloroperbenzoic acid.
Preferably, the oxidizing agent used in step b) is ferric chloride,
The oxidation can be carried out in a solvent selected from a group consisting of
acetonitrile, dioxane, tetrahydrofuran and mixture thereof. Preferably, the
oxidation is carried out in acetonitrile.
In one embodiment, the process for preparation of Seratrodast comprises isolating
the Compound of Formula IV from mother liquor and then subjected to oxidation.
In another embodiment, the compound of Formula IV may not be isolated and the
reaction mass comprising condensation product (Compound of Formula IV) can
be subjected to oxidation.
In further aspect, the invention relates to a process for preparation of pure
crystalline Seratrodast comprising the following steps:
a) dissolving crude Seratrodast obtained from the above process in acetonitrile by
heating from room temperature to 70°C;
b) adding demineralized water in the solution;
c) cooling the reaction mixture to room temperature; and
d) isolating pure crystall'ine Seratrodast.
Isolation of Seratrodast may be carried out using any known method, viz. filtration,
distillation and extraction or any other suitable means.
Seratrodast characterized. by at least one of the following:
a) an X-Ray Powder Diffraction (XRPD) spectrum that comprises peaks at twotheta
angle of 5.90, 11.06, 11.38, 11.88, 12.0, 13.52, 14.47, 14.97, 17.82, 18.38,
19.64, 22.02, 22.35, 22.73, 23.73, 24.13, 25.00, 25.59, 26.92, 27.12, 28.10, 29.47,
I 30.31, 30.56, 31.27, 32.24, 33.11, 33.78, 34.60, 34.90, 35.71, 36.17, 37.37, 38.61,
38.88, 39.61 and 39.78 * 0.2 degree and
b) Differential Scanning Calorimetry (DSC) comprises a single endothermic peak
at 130.44OC.
In one embodiment, the pure crystalline Seratrodast.obtained from the process of
present invention has HPLC purity of greater than 99%, preferably has 99.50 %
HPLC purity.
Compound of Formula I1 is commercially available and can be purchased from any
available sources.
Compound of Formula 111 can be prepared from a method describe herein below
in Scheme 3.
Scheme 3: 6 + ci c y c l o h e ~ pMiBDeCn,z 2o)0y-l2 cSh°lCo r, i2d-e3, ThoEuArs & I OO°C, 10- 12 hours /N<) conc. HCI. DM water,
N NaHCO, 2-3 hours /
H I I Formula IX
k' Formilla Vlll
OH
Formula X
Cyclohexanone is reacted with morpholine in the presence of cyclohexane yielded
compound of Formula VIII. To obtain compound of Formula IX, compound of
Formula VIII is reacted with benzoyl chloride in the presence of triethyl amine
(TEA) in methylene dichloride (MDC) followed by acid hydrolysis in presence of
concentrated HCI. Cleavage of cyclization of compound of Formula IX in the
presence of sodium methoxide in methanol and followed by hydrolysis provides
compound of Formula X. On the reduction of keto group of compound of Formula
X with the help of NaBH4 in methanol gives compound of Formula I11 which is
transformed in to compound of Formula I according to present invention.
The above and other, objects of the present invention are further attained and
supported by the following embodiments described herein. However, the described
embodiments are in accordance with the best mode of practice and the scope of the
invention is not restricted to the described embodiments herein after.
Analytical methods:
The XRPD of the pure crystalline Seratrodast was measured on PANalytical-X'
Pert-3 powder X-ray Diffractometer using a Cu K alpha-1 radiation source.
Sample of pure crystalline Seratrodast was analysed for thermal properties (DSC)
on ~ e r k i n ' ~ l m e r - ~ ~ ~i-n8st0ru0m0en t.
HPLC purity of related compounds were evaluated on Waters HPLC e2695
separation module using UVIVIS detector as per methods given in Indian
Pharmacopoeia.
# ~eversPeh ase
# Column: Cosmosil SC18 - MS-11, 250 8 4.6 mm, make-Nacalai Tesque Inc.
Example 1: Process for the Preparation of Compound of Formula IV.
Trimethyl hydroquinone of Formula I1 (48.688, 0.3198 mol) and hydroxyl
compound of Formula 111 (79.0g, 0.3554 mol) were dissolved in 395 ml methylene
dichloride in Round Bottom Flask. Methanesulfonic acid (34.12g , 0.3554 mol)
was added to the reaction mass and stirred at 20-25OC for 2-3 hours. After
completion of reaction demineralized water was added to the reaction mass and
stirred for 2-3 hours at 20-25OC.The reaction mass was filtered and dried under
reduced pressure at 50°C to 60°C to yield compound of Formula IV.
Yield: 108.00g (94.72%)
Purity (HPLC): 87.41 %
Example 2: Process for the Preparation of Compound of Formula I.
Compound of Formula IV (108g, 0.302 mol) was dissolved in 756 ml acetonitrile
in Round Bottom Flask at room temperature. Aqueous Ferric chloride (122.80g in
324 ml water) was added to the reaction mass and stirred at 20-25OC. The reaction
mass was stirred for 1 hour at 70°C. After completion of reaction, the reaction mass
was cooled to 20-25OC and stirred for 3-4 hours. The reaction mass was filtered
and the wet weight, DM water (500 ml) and methylene dichloride were charged
in RBF and was stirred for 15 minutes. The layers were separated and organic layer
was distilled out to obtain crude Seratrodast.
Yield: 88.7g (82.59%)
Purity (HPLC): 98.93%
Example 3: Process for the Preparation of pure crystalline Seratrodast of
Formula I,
Crude Seratrodast obtained from example 2 was charged in 540 ml acetonitrile in
round bottom flask. The reaction mixture was heated - upto 65OC-75OC. -c
Demineralize water was added in the solution and cooled to room temperature and
stirred for 4-5 hours. The reaction mass was filtered, washed with water and dried
under vacuum at 50°C to 60°C to obtain pure crystalline Seratrodast.
I
Yield: 75.0g (70.09%)
Purity (HPLC): 99.50%
Comparative Examples:
.A detailed study on acid catalyst mentioned in prior art for condensation of
comuounds of Formula I1 and 111 during preparation of Seratrodast is carried out
and the experiments are summarized hereinbelow in Table 1 :
Table 1:
Examples
Comparative
Example No. 1
Comparative
Example No. 2
Comparative
Example No. 3
Results
Column
chromatography .is
essential for
purification.
No reaction
No reaction
Reaction conditions
Acid Catalyst
boron trifluoride
ethyl etherate
D-camphor
sulfonic acid
D-camphor
sulfonic acid,
Solvent
Toluene
Toluene
Toluene
Temperature
20°C-30°C
20°C-30°C
2 0 " ~ - 3 0 " ~ ~
Hence, from the above it is clearly evident that in comparative examples 2 to 7 .
either reaction did not proceed or the reaction percentage was very less. Further,
following comparative examples 1 and 8, it was found that'the final product was
sticky or charred in nature and column chromatography was essential for
purification..

WE CLAIMS:
1. A process for preparation of Seratrodast of Formula I
comprising the steps of:
a) condensing the compound of Formula I1
OH
Formula I1
with compound of Formula I11
HO
OH
in a solvent and in presence of methane sulfonic acid to obtain compound of
Formula IV .
I
Formula IV \ -. .
b) oxidising compound of Formula IV to obtain compound of Formula I.
2. The process according to claim 1 wherein in step a), the methane sulfonic acid
is employed in mole ratio of 0.7 : 1 to 2.0 : 1 relative to the compound of Formula
11, preferably the methane sulfonic acid is employed in mole ratio of 1.1 1 : 1
relative to the compound of Formula 11.
3. The process according to claim 1 wherein in step a), the methane sulfonic acid
is employed in mole ratio of 0.6 : 1 to 1.5 : 1 relative to the compound of Formula
111, preferably the methane sulfonic acid is employed in mole ratio, of 1 : 1 relative
to the compound of Formula 111.
4. The process according to claim 1 wherein in step a), stirring of 2 to 6 hours is
required to complete the condensation reaction, preferably stirring of 2 to 3 hours
is required to complete the reaction.
5. The process according to claim 1 wherein in step a), reaction is carried out at a
temperature ranging 10°C to 409C, preferably, the reaction is carried out at a
temperature ranging 20°C to 25°C.
I
6. The process according to claim 1, wherein in step a), the solvent is selected from
a group consisting of methylene dichloride, toluene, tetrah-ydro furan, ethylene
dichloride and mixture thereof, preferably the solvent is methylene dichloride.
7. The process according to claim 1, wherein in step b), the oxidizing agent is
selected from a group consisting of ferric chloride, ferric sulfate, hydrogen
peroxide and m-chloroperbenzoic acid, preferably ferric chloride and the solvent
is selected from a group consisting of acetonitrile, dioxane, tetrahydrofuran and
mixture thereof, preferably acetonitrile.
8. The process according to claim 1, further comprises the steps of,
a) dissolving crude Seratrodast.obtained from step b),of claim 1 in acetonitrile by
heating from room temperature to 65OC to 75OC;
b) adding demineralized water in the solution;
c) cooling the reaction mixture to room temperature; and
c) isolating pure crystalline Seratrodast.
9. The process according to claim 8, wherein the pure crystalline Seratrodast is
characterized by an.X-Ray Powder Diffraction Pattern comprising peaks at twotheta
angle of 5.90, 11.06, 11.38, 11.88, 12.0, 13.52, 14.47, 14.97, 17.82, 18.38,
38.89, 39.62 , a.n d 39.78 f 0.2 or a Differential Scanning Calorimetry Thermogram
comprises an endothermic peak at 130.44OC.
10. The process according to claim 9, wherein the pure crystalline Seratrodast has
anHPLC purity greater than 99.0 %, preferably has,an HPLC purity of 99.50 %.