NZ630279B2 - Process for preparing crystalline sorafenib tosylate - Google Patents
Process for preparing crystalline sorafenib tosylate Download PDFInfo
- Publication number
- NZ630279B2 NZ630279B2 NZ630279A NZ63027912A NZ630279B2 NZ 630279 B2 NZ630279 B2 NZ 630279B2 NZ 630279 A NZ630279 A NZ 630279A NZ 63027912 A NZ63027912 A NZ 63027912A NZ 630279 B2 NZ630279 B2 NZ 630279B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- ssb
- sorafenib
- base
- crystalline
- crystalline sorafenib
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
Abstract
Disclosed is a process for the preparation of crystalline Sorafenib (4-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide)) free base- Form-SSB, characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 2?°peaks selected from the XRPD peak set of 9.9, 11.4, 12.6, 14.6, 15.2, 15.6, 18.1,18.6, 21.8, 22.5, 22.9, 23.6, 24.8, 25.2 ± 0.202?° comprising reacting 4-(4-aminophenoxy)-N-methyl picolinamide (III) with 4-chloro-3-(trifluoromethyl)phenylisocyanate (IV) in a high boiling organic solvent selected from methyl ethyl ketone (MEK) or methyl isobutyl ketone (MIBK) or mixtures thereof, at a temperature ranging between 75-90 °C, to yield crystalline Sorafenib base- Form-SSB. Also disclosed is a pharmaceutical composition comprising crystalline Sorafenib base- Form-SSB, together with one or more pharmaceutically acceptable excipients, wherein crystalline Sorafenib base - Form-SSB is characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 2?°peaks selected from the XRPD peak set of 9.9, 11.4, 12.6, 14.6, 15.2, 15.6, 18.1, 18.6, 21.8, 22.5, 22.9, 23.6, 24.8, 25.2 ± 0.20 2?° and DSC isotherm performed at heating rate of 10°C/min comprising a single endothermic peak having an onset at 205.1°C and a peak melting point of 207.7°C. Further disclosed is a process for the preparation of Sorafenib tosylate Form-I characterized by X-ray powder diffraction pattern comprising characteristic 2?°peaks of 4.4, 13.1. 14.7, 16.6, 17.8, 20.4, 20.7, 21.4, 22.8± 0.20 2?°, using crystalline Sorafenib base- Form-SSB, comprising steps of: a) reacting 4-(4-aminophenoxy)-N-methylpicolinamide (III) with 4-chloro-3-(trifluoromethyl)phenylisocyanate (IV) in a high boiling organic solvent selected from methyl ethyl ketone (MEK) or methyl isobutyl ketone (MIBK) or mixtures thereof; at a temperature ranging between 75-90 °C, to yield crystalline Sorafenib base (II)- Form-SSB; and b) combining crystalline Sorafenib base - Form-SSB with p-toluenesulfonic acid in the presence of methyl ethyl ketone at a temperature below 35°C, to give Sorafenib tosylate (I). ed from the XRPD peak set of 9.9, 11.4, 12.6, 14.6, 15.2, 15.6, 18.1,18.6, 21.8, 22.5, 22.9, 23.6, 24.8, 25.2 ± 0.202?° comprising reacting 4-(4-aminophenoxy)-N-methyl picolinamide (III) with 4-chloro-3-(trifluoromethyl)phenylisocyanate (IV) in a high boiling organic solvent selected from methyl ethyl ketone (MEK) or methyl isobutyl ketone (MIBK) or mixtures thereof, at a temperature ranging between 75-90 °C, to yield crystalline Sorafenib base- Form-SSB. Also disclosed is a pharmaceutical composition comprising crystalline Sorafenib base- Form-SSB, together with one or more pharmaceutically acceptable excipients, wherein crystalline Sorafenib base - Form-SSB is characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 2?°peaks selected from the XRPD peak set of 9.9, 11.4, 12.6, 14.6, 15.2, 15.6, 18.1, 18.6, 21.8, 22.5, 22.9, 23.6, 24.8, 25.2 ± 0.20 2?° and DSC isotherm performed at heating rate of 10°C/min comprising a single endothermic peak having an onset at 205.1°C and a peak melting point of 207.7°C. Further disclosed is a process for the preparation of Sorafenib tosylate Form-I characterized by X-ray powder diffraction pattern comprising characteristic 2?°peaks of 4.4, 13.1. 14.7, 16.6, 17.8, 20.4, 20.7, 21.4, 22.8± 0.20 2?°, using crystalline Sorafenib base- Form-SSB, comprising steps of: a) reacting 4-(4-aminophenoxy)-N-methylpicolinamide (III) with 4-chloro-3-(trifluoromethyl)phenylisocyanate (IV) in a high boiling organic solvent selected from methyl ethyl ketone (MEK) or methyl isobutyl ketone (MIBK) or mixtures thereof; at a temperature ranging between 75-90 °C, to yield crystalline Sorafenib base (II)- Form-SSB; and b) combining crystalline Sorafenib base - Form-SSB with p-toluenesulfonic acid in the presence of methyl ethyl ketone at a temperature below 35°C, to give Sorafenib tosylate (I).
Description
PROCESS FOR PREPARING CRYSTALLINE SORAFENIB TOSYLATE
FIELD OF INVENTION:
The present invention provides an industrially suitable process for the preparation of
substantially pure 4-{4-[({[4-chloro(trifluoromethyl)-phenyl]amino} carbonyl)amino]
phenoxy}-N-methylpyridinecarboxamide or nib and its te salt, with a suitable
impurity profile and without requirement of any additional purification steps. The present
invention also provides Sorafenib base (II) as a stable lline Form-SSB.
The present invention r relates to a process for the preparation of crystalline Sorafenib
tosylate Form-I which is free from contamination of any other polymorphic form of
Sorafenib tosylate, for e.g. Form II or Form III, and does not involve any seeding requirement
for crystallization step.
BACKGROUND OF THE INVENTION:
Sorafenib is chemically also known as ({[4-chloro(trifluoromethyl)-phenyl]amino}
yl)amino]phenoxy}-N-methylpyridinecarboxamide (II).
CF3 O
Cl O CH3
O N
H
N
N N
H H
(II)
Sorafenib blocks the enzyme RAF kinase, a critical component of the RAF/MEK/ERK
signaling pathway that ls cell division and proliferation. In addition, Sorafenib inhibits
the VEGFR-2/PDGFR-beta signaling cascade, thereby blocking tumor angiogenesis. It is a
small molecular inhibitor of RAF kinase, PDGF (platelet-derived growth factor), VEGF
receptor2 and 3 and c Kit, the receptor for stem cell factor.
Sorafenib, marketed as NEXAVAR® by Bayer, is a drug approved for the treatment of
advanced renal cell carcinoma (primary kidney cancer)and advanced hepato cellular
carcinoma (primary liver cancer).NEXAVAR, is the tosylate salt of Sorafenib (I).In the label
of NEXAVAR is chemically mentioned as 4-(4-{3-[4-Chloro(trifluoromethyl)
1
phenyl]ureido}phenoxy)N2methylpyridinecarboxamide 4-methylbenzene sulfonate i.e.
Sorafenib tosylate. Sorafenib tosylate is a white to yellowish or brownish solid which is
practically insoluble in aqueous media and slightly soluble in ethanol.
CF3 O
Cl O CH3
O N
H .
N
N N
H H SO3H
(I)
The compound 4-{4-[({[4-chloro(trifluoromethyl)-phenyl]amino}carbonyl) amino]
phenoxy}-N-methylpyridinecarboxamide or Sorafenib of formula II is described in WO
12.WO 00/42012also reports a process for the preparation of Sorafenib base and its
analogues. Pharmaceutically able salts of Sorafenib, particularly Sorafenib tosylate of
formula I are mentioned in patent application references WO 00/42012, WO 03/068228 and
WO 579.
Bankston et al.in c Process Research & Development,2002,6,777-781 discloses a
process for the ation of Sorafenib tosylate, which es reacting 2-picolinic acid
with thionyl chloride in a t inert towards thionyl chloride without using dimethyl
formamide to form acid chloride salt. This acid salt on further reaction with aqueous solution
of methylamine or s methyl amine gives amide derivative, which on reaction with 4-
aminophenol along with addition of carbonate salt in the presence of base yields 4-(4-
aminophenoxy)-N-methylpicolinamide(4-aminophenoxy)-N-methylpicolinamide which
when reacted with 4-chloro(trifluoromethyl) phenyl isocyanate in a non-chlorinated
c solvent, inert towards isocyanate gives Sorafenib. nib by admixing with ptoluene
sulfonic acid in a polar solvent gives Sorafenib tosylate.
Patent application WO 2006/034796 discloses a process for the ation of Sorafenib
tosylate, which involves reacting 4-(4-aminophenoxy)-N-methylpicolinamide with 4-chloro-
3(trifluoromethyl)phenyl isocyanate in a lorinated organic solvent, giving Sorafenib
base. After admixing the Sorafenib base with p-toluene sulfonic acid in polar solvent, water is
added to the reaction mixture and, if appropriate, a clarifying filtration is conducted and if
required seeding procedure is done to give Sorafenib tosylate.
2
WO 2006/034797 provides a process for the preparation of Polymorph I of Sorafenib
tosylate, which involves the initial preparation of polymorph II of Sorafenib tosylate and its
further conversion to Polymorph I of Sorafenib tosylate.
Patent application WO 2011/036647 discloses a process for the preparation of rph I of
Sorafenib tosylate, which involves the addition of p-toluenesulfonic acid to Sorafenib in the
presence of water.
Though the review of the above mentioned literature discloses many processes for the
preparation of Sorafenib and its tosylate salt, but due to one or more reasons, for e.g.
unfavorable ty profile, multiple steps, use of multiple solvents, low yield and difficult
isolation procedures etc. these processes are not particularly convenient and suitable for
industrial scale tion.
Thus, there is an apparent need to develop improved processes for the preparation of highly
pure Sorafenib and its tosylate salt, which may be cost-effective, industrially le, with
good % of yield and may overcome the drawbacks of various prior disclosed processes. Thus
according to the present invention there is provided a novel industrially applicable process for
the preparation of Sorafenib and its tosylate salt, with suitable impurity profile and without
requirement of any additional cation steps.
For Sorafenib base, uent to s, the concern has remained for the solid form
isolated. Though extensive information is available for polymorphic forms of Sorafenib
tosylate, not much is known regarding polymorphism in actual active moiety of the drug i.e.
Sorafenib base. Patent ations WO2009/106825 and WO 2010/142678 disclose
Sorafenib base amorphous form.
Existence of polymorphism is known to be unique phenomenon in solid materials, wherein
existence of different al forms including shape, size, and arrangement of les in
the al state or polymorphs of same nd are known in the nature. A single
compound, or a salt complex, may give rise to a variety of solids having distinct al
properties, which often results in substantial differences in bioavailability, stability, and other
differences between production lots of formulated pharmaceutical products. Due to this
reason, since polymorphic forms can vary in their chemical and al properties,
3
regulatory ities often require that efforts be made to identify all polymorphic forms,
e.g., hydrate or anhydrate, crystalline or amorphous, solvated or un-solvated forms, base
forms or salt forms etc. of the drug substances. However, the existence, and possible
numbers, of polymorphic forms for a given nd cannot be predicted. In on, there
are no "standard" procedures that can be used to prepare polymorphic forms of a substance.
New polymorphs of pharmaceutically active / useful compounds provide an opportunity to
improve the drug performance characteristics of such product. Further, discovery of
polymorphic forms may help in the identification of the polymorphic content of a batch of an
active pharmaceutical ingredient. ore, inventors of the present application provide new
stable crystalline form of Sorafenib base designated as SB. Crystalline Sorafenib base
Form-SSB is very stable, wherein the physicochemical properties remain substantially the
same (at least up to more than 6 months). This stable form offers various advantages in terms
of storage, shelf life and favorable impurity profile.
SUMMARY OF THE INVENTION:
Particular aspects of the present application relate to the process for the ation of pure 4-
{4-[({[4-chloro(trifluoromethyl)-phenyl]amino}carbonyl)amino]phenoxy}-N-methyl
pyridinecarboxamide or Sorafenib and its te salt.
In one aspect of the present application, the present invention provides a process for the
ation of Sorafenib sing, on of 4-(4-aminophenoxy)-N-methylpicolinamide
(III) with 4-chloro(trifluoromethyl)phenylisocyanate (IV) in a high boiling organic solvent
at a temperature ranging between 75-90 °C, to yield Sorafenib base (II).
O CF3 CF3 O
Cl Cl O CH3
O CH3 O N
N
H + N H
N N N
H2N NCO H H
III IV II
In a further aspect of the present ation, the present invention provides Sorafenib base -
lline Form-SSB characterized by X-ray powder diffraction pattern comprising at least
5 characteristic 2θ°peaks selected from the XRPD peak set of9.9, 11.4, 12.6, 14.6, 15.2,
15.6,18.1,18.6, 21. 8, 22.5, 22.9, 23.6, 24.8, 25.2 ± 0.20 2θ° and DSC isotherm comprising a
single endothermic peak ranging between 202 to 212°C.
4
In another aspect of the present application, the present invention provides a process for the
preparation of Sorafenib tosylate salt, sing steps of:
a) reacting 4-(4-aminophenoxy)-N-methylpicolinamide (III) with 4-chloro
(trifluoromethyl)phenylisocyanate (IV) in a high g organic solvent at a
temperature ranging between 75-90 °C, to yield Sorafenib base (II);
O CF3 CF3 O
Cl Cl O CH3
O CH3 O N
N
N H
H +
N N N
H2N NCO H H
III IV II
b) combining Sorafenib base (II) with p-toluenesulfonic acid in the presence of methyl
ethyl ketone at a temperature below 35 °C, to give crystalline Sorafenib tosylate (I).
CF3 O CF3 O
Cl O CH3
O N Cl O CH3
O N
N H +
N N N H .
H H N N
SO3H H H
SO3H
II I
In another aspect of the present application, the present invention provides aone-pot process
for the preparation of Sorafenib tosylate (I), comprising the steps of:
a) reacting 4-(4-aminophenoxy)-N-methylpicolinamide (III) with 4-chloro
(trifluoromethyl)phenylisocyanate (IV) in a high boiling organic solvent at a
temperature g n 75-90 °C;
O CF3
O CH3 Cl
N
H
N
H2N NCO
III IV
b) adding enesulfonic acid to the reaction mass of step a) in the presence of
methyl ethyl ketone at a temperature below 35 °C;
c) ing the material as Sorafenib tosylate (I).
CF3 O
Cl O CH3
O N
N H .
N N
H H
SO3H
I
5
In a further aspect of the present application, the present invention provides process for the
preparation of nib tosylate, wherein Sorafenib tosylate obtained is substantially pure
crystalline Sorafenib tosylate Form I which is free from contamination of any other
polymorphic form of Sorafenib tosylate, for e.g. Form II or Form III.
Further particular s of the invention are detailed in the description part of the
specification, wherever appropriate.
BRIEF DESCRIPTION OF THE DRAWINGS:
Figure 1: PXRD pattern of crystalline nib base (Form-SSB) ed according to the
procedure given in Example 1.
Figure 2: DSC curve of crystalline Sorafenib base (Form-SSB)obtained according to the
procedure given in Example 1.
Figure 3: TGA thermogram of crystalline Sorafenib base (Form-SSB) obtained according to
the procedure given in e 1.
Figure 4: PXRD pattern of crystalline Sorafenib tosylate obtained according to the procedure
given in Example 2.
Figure 5: DSC curve of crystalline Sorafenib tosylate obtained according to the procedure
given in Example 2.
Figure 6: TGA spectrum of lline Sorafenib tosylate obtained according to the
procedure given in Example 2.
DETAILED DESCRIPTION
As set forth herein embodiments of the present invention provide the process for preparation
of Sorafenib and its tosylate salt, to give substantially pure product with a suitable impurity
profile and without requirement of any additional purification steps.
One embodiment of the present application provides a process for the ation of
Sorafenib, comprising, reaction of minophenoxy)-N-methylpicolinamide (III)with 4-
chloro(trifluoromethyl)phenylisocyanate (IV) in a high boiling c solvent at a
temperature ranging between 75-90 °C, to yield Sorafenib base (II).
6
O CF3 CF3 O
Cl O CH3
O CH3 Cl O N
N
H + N H
N N N
H2N NCO H H
III IV II
High boiling organic solvent used in this reaction may be ed from C4-8 ketones or a
mixture thereof. Non-limiting es of the C4-8 ketones that can be used as high boiling
organic solvent in this reaction e methyl ethyl ketone (MEK) or methyl isobutyl ketone
(MIBK) or a mixture thereof.
Reaction temperature plays a very important role in this reaction with regard to the purity of
the obtained final product. Reaction of 4-(4-aminophenoxy)-N-methylpicolinamide (III) with
4-chloro(trifluoromethyl)phenylisocyanate (IV), is carried out at high temperature ranging
from 75-90 °C, more preferably 80-85 °C but not at temperature lower than 70 °C.
It was observed that at lower temperature for e.g. below 70 °C, a substantial amount of the
starting material 4-(4-aminophenoxy)-N-methylpicolinamide (III) remains ted and is as
such carried till the final API stage as a residual impurity. This impurity 4-(4-
aminophenoxy)-N-methylpicolinamide (III) has been found to be mutagenic and is very
difficult to remove by purification of the final API.
High temperature conditions employed in this reaction of the present invention provide the
advantage that the amount of ted 4-(4-aminophenoxy)-N-methylpicolinamide found in
the final API is very well below the stipulated regulatory requirement of not more than 0.1%.
The quantity of the high g t used in this reaction is also pivotal in the reaction
course. The quantity of high boiling solvent ranges between 2 to 5 times (in volume) with
respect to the weight of4-(4-aminophenoxy)-N-methylpicolinamide. In one particular
embodiment, for 20 g of 4-(4-aminophenoxy)-N-methylpicolinamide, 60 ml of the high
boiling solvent methyl ethyl ketone was used.
The reaction of 4-(4-aminophenoxy)-N-methylpicolinamide (III) with 4-chloro
uoromethyl)phenylisocyanate (IV) is done by stirring the reaction mass at the raised
7
temperatures mentioned, for time ranging between 2-8 hrs ding on the actual reaction
conditions employed).
Optionally, the Sorafenib base as obtained in the present reaction may also be given washings
with toluene or a high boiling c solvent used initially, at temperature ranging between
20-70 °C. After drying of the reaction mass at temperature g n45-60 °C,
isolation of the product is done by conventional methods which include but are not limited to
cooling the on mass, filtering (with or without vacuum) and neutralizing wherever
required.
In another embodiment of the t application, the present invention provides Sorafenib
base as Crystalline Form-SSB, which is characterized by X-ray powder diffraction pattern
comprising at least 5 characteristic ks ed from the XRPD peak set of 9.9, 11.4,
12.6, 14.6, 15.2, 15.6,18.1,18.6, 21.8, 22.5, 22.9, 23.6, 24.8, 25.2 ± 0.20 2θ° and DSC
isotherm comprising a single endothermic peak ranging between 202 to 212°C.
Sorafenib base crystalline Form-SSB, according to the present invention is characterized by
X-ray powder diffraction pattern substantially according to Fig-1, DSC isothermal n
substantially according to Fig-2 and TGA thermogram substantially according to Fig-3.The
characteristic peaks and their d spacing values of the new crystalline Form-SSB are tabulated
in the Table-1.
S.No. Angle (2θ°)±0.20 d Spacing Value (A°)
1. 9.90 8.917
2. 11.42 7.738
3. 12.58 7.029
4. 14.60 6.603
5. 15.20 5.844
6. 15.65 5.657
7. 18.11 4.896
8. 18.65 4.755
9. 21.78 4.078
10. 22.49 3.950
11. 22.94 3.873
8
12. 23.59 3.769
13. 24.78 3.590
14. 25.21 3.530
Table-1: Characteristic XRPD Peaks of Sorafenib base Crystalline SB
Minor ions in the observed 2θ° angles values may be expected based on the analyst
person, the specific XRPD diffractometer employed and the sample preparation technique.
r possible variations may also be expected for the relative peak intensities, which may
be largely affected by the non-uniformity of the particle size of the sample. Hence,
identification of the exact crystalline form of a compound should be based primarily on
observed 2 theta angles with lesser importance attributed to relative peak intensities. The 2
theta diffraction angles and corresponding d-spacing values account for positions of various
peaks in the X-ray powder diffraction pattern. D-spacing values are calculated with observed
2 theta angles and copper K α wavelength using the Bragg equation well known to those of
having skill in the art of XRPD diffractometry e.
In view of ility of marginal error in the assigning 2 theta angles and d-spacings, the
preferred method of comparing X-ray powder diffraction patterns in order to identify a
particular crystalline form is to overlay the X-ray powder diffraction pattern of the n
form over the X-ray powder diffraction pattern of a known form. For example, one skilled in
the art can overlay an X-ray powder diffraction pattern of an unidentified crystalline form of
Sorafenib base over FIG. 1 and readily determine whether the X-ray diffraction pattern of the
unidentified form is substantially the same as the X-ray powder diffraction pattern of the
crystalline form of this invention. If the X-ray powder ction pattern is substantially the
same as FIG. 1, the usly unknown crystalline form of Sorafenib base can be readily and
accurately identified as the crystalline SB of this invention.
The nib base crystalline Form-SSB appears to be an anhydrate, which may be evident
from the Fig-3 showing the TGA thermogram. A sample of the crystalline Form-SSB
prepared by the ors had moisture content up to about 0.3%w/w by KF method, which
also confirmed the anhydrate nature of the compound. While the invention is not limited to
any specific , it should be understood however that the crystalline form SSB of
9
Sorafenib base may contain additional residual or unbound moisture without losing its
anhydrate character and/or its anhydrate crystalline form-SSB teristics.
Another embodiment of the present application es a process for the preparation of
Sorafenib tosylate salt, comprising steps of:
a) reacting 4-(4-aminophenoxy)-N-methylpicolinamide with 4-chloro(trifluoro
methyl) phenylisocyanate in a high boiling organic solvent at a temperature ranging
between 75-90 °C, to yield Sorafenib base;
b) combining Sorafenib base with p-toluenesulfonic acid in the presence of methyl ethyl
ketone at a temperature below 35 °C, to give Sorafenib tosylate.
The individual steps of the s according to the present invention for preparing Sorafenib
tosylate salt are detailed tely herein below.
Step a) comprises reacting 4-(4-aminophenoxy)-N-methylpicolinamide (III) with 4-chloro
uoromethyl)phenylisocyanate (IV) in a high boiling c t at a temperature
ranging from 75-90 °C, to yield nib base (II).
O CF3 CF3 O
Cl CH3
O CH3 Cl O
O N
N
+ N H
H
N N N
H2N NCO H H
III IV II
High boiling organic solvent, quantities of different reagents, reaction temperature used, and
other relevant s of this step, are similar to the ones described in the previous
embodiment related to the preparation of Sorafenib base (II).
Step b) comprises combining Sorafenib base (II) with p-toluenesulfonic acid in the presence
of methyl ethyl ketone at a temperature below 35 °C, to give Sorafenib tosylate (I).
CF3 O CF3 O
Cl O CH3
O N Cl O CH3
O N
N H + N H .
N N
H H N N
SO3H H H
SO3H
II I
The process for the preparation of Sorafenib tosylate, by reaction of Sorafenib base (II) with
p-toluenesulfonic acid in this step, is carried out at an ambient temperature below 35 °C,
10
preferably ranging between 20-35 °C, but not above 40 °C. In view of prior known processes,
present ion process in this step, offers significant age of preparing Sorafenib
tosylate at easily maintainable temperature range which is commercially and industrially
viable.
The quantity of the MEK solvent used in this reaction, ranges n 5 to 12 times (in
volume) with respect to the weight of Sorafenib material (crude/purified material as obtained
from step a) or from any other method known in prior art). In one particular ment, for
10 g of nib, 80 ml of the t methyl ethyl ketone was used.
Reaction duration for the present reaction ranges between 2-8 hrs (depending on the actual
reaction conditions employed and the progress of the reaction, which is intermittently
checked by HPLC).The final product is dried and isolated by tional methods. The
tional methods for isolating the product may include but are not limited to filtering
(with or without vacuum), optionally washing with suitable solvent and drying.
Advantageously, according to the process of the present invention, substantially pure end
product is ed and there is no requirement of any additional purification of final API to
remove the impurities so as to bring the final API in compliance with the stipulated
regulatory requirements.
In another embodiment of the present application, the present invention provides ot
process for the preparation of Sorafenib tosylate (I), comprising the steps of:
a) reacting 4-(4-aminophenoxy)-N-methylpicolinamide (III) with 4-chloro
(trifluoromethyl)phenylisocyanate (IV) in a high boiling organic solvent at a
temperature ranging between 75-90 °C;
O CF3
O CH3 Cl
N
H
N
H2N NCO
III IV
b) adding p-toluenesulfonic acid to the reaction mass of step a) in the presence of
methyl ethyl ketone at a temperature below 35 °C;
c) isolating the material as Sorafenib tosylate (I).
11
CF3 O
Cl O CH3
O N
N H .
N N
H H
SO3H
I
The high boiling organic solvent used for this reaction in step a) may beselected from methyl
ethyl ketone (MEK), methyl isobutyl ketone (MIBK) or a mixture thereof.
The compound of formula-I may be isolated by conventional methods and optionally may be
dried suitably. The tional methods for isolating the product may include but are not
limited to cooling the reaction mass, wherever required neutralizing , maintaining , filtering
(with or without vacuum), optionally washing with suitable solvent and drying.
In an embodiment of the t invention, for the processes mentioned herein, Sorafenib
tosylate ed is characterized by PXRD pattern similar to Fig. 4, DSC curve similar to
Fig. 5 and TGA spectrum similar to Fig. 6. This analytical data orates that Sorafenib
tosylate obtained by the invention of present application, is rphic Form I of Sorafenib
tosylate.
In a r embodiment of the present application, it provides industrially applicable process
for direct preparation of crystalline Sorafenib tosylate polymorphic Form I, without any
seeding requirement and without isolation of the polymorphic Form II, which are some of the
limiting factors for prior disclosed processes. Pure Sorafenib tosylate rphic Form I
obtained by the processes mentioned herein is ntially free of any other known form of
Sorafenib tosylate, for e.g. Form II or Form III etc.
The Sorafenib base crystalline SB and Sorafenib tosylate Form-I described herein
may be characterized by X-ray powder diffraction pattern (XRPD) and Thermal techniques
such as differential ng calorimetry (DSC) analysis. The samples of Sorafenib tosylate
Form-I were analyzed by XRPD on a Bruker AXS D8 Advance Diffractometer using X-ray
source - Cu Kα radiation using the wavelength 1.5418 Å and lynx Eye detector. DSC was
done on a Perkin Elmer Pyris 7.0 instrument. rative examples of analytical data for the
Sorafenib base crystalline Form-SSB and Sorafenib te Form-I obtained in the Examples
are set forth in the Figs. 1-6.
12
In a further embodiment according to the specification, Sorafenib base crystalline Form-SSB
may be formulated into a composition, of which at least 95%, by total weight of the Sorafenib
in the composition, is the crystalline Form- SSB. In yet another embodiment of the invention,
the ition may be substantially free of any other known forms of Sorafenib base
whether amorphous or crystalline form.
The Sorafenib base crystalline SB, may be ated as solid compositions for oral
administration in the form of es, tablets, pills, powders or granules. In these
compositions, the active product is mixed with one or more ceutically acceptable
excipients. The drug substance can be formulated as liquid compositions for oral
administration including solutions, suspensions, syrups, elixirs and emulsions, containing
solvents or vehicles such as water, sorbitol, glycerin, propylene glycol or liquid paraffin.
In one embodiment of the present invention, it also includes premix comprising one or more
pharmaceutically acceptable ents in the range of 1 to 50% w/w with nib base
crystalline Form-SSB, while retaining the nature of the premix.
The compositions for parenteral administration can be suspensions, emulsions or s or
non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol,
vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be
employed. These itions can contain adjuvants, especially wetting, emulsifying and
dispersing agents. The sterilization may be carried out in several ways, e.g. using a
bacteriological , by incorporating sterilizing agents in the composition, by irradiation or
by heating. They may be prepared in the form of sterile compositions, which can be
dissolved at the time of use in sterile water or any other e injectable medium.
Pharmaceutically acceptable ents used in the itions sing Sorafenib base
lline SB of the t application include, but are but not limited to diluents
such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose,
dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders
such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants
such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium,
colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc
stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or
wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other
13
ceutically acceptable excipients that are of use include but not limited to film formers,
plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives,
antioxidants and the like.
Pharmaceutically acceptable excipients used in the compositions of Sorafenib base crystalline
Form-SSB of the t application may also se to include the pharmaceutically
acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired
dosage form preparation.
Certain specific aspects and embodiments of the present application will be explained in
more detail with reference to the following examples, which are provided by way of
illustration only and should not be construed as limiting the scope of the invention in any
.
EXAMPLES:
Example 1: Preparation of Sorafenib base crystalline Form-SSB
Charged 60 ml of methyl ethyl ketone at ambient ature(25-30°C) in round bottom
flask. 20 g of 4-(4-aminophenoxy)-N-methylpicolinamide was added to MEK and stirred for
about 15 minutes. Further, 4-chlorotrifluoromethylisocyanate(30g) was added slowly over
a period of 5-10 min. Then reaction temperature was raised to 80-85°C, where stirring of the
on mixture was done for 4-5 h. The reaction mixture was cooled to room ature,
filtered and washed with toluene. The title product was isolated after drying, as a crystalline
material (having XRPD pattern as per Fig-1; DSC rm as per Fig-2 and TGA
thermogram as per Fig-3).
Yield – 75%HPLC purity – 99.5%
Example 2: Preparation of crystalline Sorafenib tosylate
Charged 80 ml of methyl ethyl ketone at room temperature in round bottom flask. Added
10gm of Sorafenib and stirred for about 15-20 minutes. Slowly added p-toluenesulfonic
acid(5.32 g) ved in 50 ml MEK. Stirred the reaction mass at C for 4-5 h. Filtered
the product and washed with 40 ml of MEK. The title product(having XRPD diffractogram as
shown in Fig-4, DSC curve as shown in Fig-5 and TGA spectrum as shown in Fig-6)was
isolated after drying.
Yield – 95%HPLC purity – 99.9%
14
Example 3: One pot preparation of lline nib tosylate
Charged 60 ml of methyl ethyl ketone at ambient temperature in round bottom flask. Added
20 g of minophenoxy)-N-methylpicolinamide and stirred for about 15 minutes. Further,
4-chlorotrifluoromethylisocyanate (30g) was added slowly over a period of 5-10 min and
the reaction temperature was raised to 80-85°C. Stirred the reaction mixture at this
ature for 4-5 h. Then, the reaction temperature was cooled to room temperature and 80
ml of methyl ethyl ketone was added. Then slowly, p-toluenesulfonic acid (20g) dissolved in
50 ml MEK was added to the on mass which was stirred for 4-5 h. Filtered the product
and washed with 120 ml of MEK. The title product was isolated and dried under vacuum at
50-55 °C for 15-17h.
Yield – 88%HPLC purity – 99.6%
While the foregoing provides a detailed description of the preferred embodiments of the
invention, it is to be understood that the descriptions are illustrative only of the principles of
the invention and not limiting. Furthermore, as many s can be made to the invention
without departing from the scope of the invention, it is intended that all material contained
herein be interpreted as illustrative of the invention and not in a limiting sense.
Claims (2)
1) A process for the preparation of crystalline Sorafenib base- Form-SSB, characterized by X-ray powder diffraction pattern comprising at least 5 characteristic ks selected from the XRPD peak set of 9.9, 11.4, 12.6, 14.6, 15.2, 15.6,18.1,18.6, 21.8, 22.5, 22.9, 23.6, 24.8, 25.2 ± 0.20 2θ° comprising reacting 4-(4-aminophenoxy)-N-methyl picolinamide (III) with 4-chloro(trifluoromethyl)phenylisocyanate (IV) in a high g organic solvent selected from methyl ethyl ketone (MEK) or methyl isobutyl ketone (MIBK) or mixtures thereof, at a temperature ranging between 75-90 °C, to yield crystalline Sorafenib base- Form-SSB. O CF3 CF3 O Cl Cl O CH3 O CH3 O N N H + N H N N N H2N NCO H H III IV II
2) A process for the preparation of crystalline Sorafenib base- Form-SSB according to claim 1, wherein crystalline Sorafenib base - Form-SSB obtained is characterized by X-ray powder diffraction pattern at 9.9, 11.4, 12.6, 14.6, 15.2, 15.6,18.1,18.6, 21.8, 22.5, 22.9, 23.6, 24.8, 25.2 ± 0.20 2θ°, substantially according to
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN2059/CHE/2012 | 2012-05-23 | ||
IN2059CH2012 | 2012-05-23 | ||
PCT/IN2012/000866 WO2013175483A1 (en) | 2012-05-23 | 2012-12-31 | Process for preparing crystalline sorafenib tosylate |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ630279A NZ630279A (en) | 2016-07-29 |
NZ630279B2 true NZ630279B2 (en) | 2016-11-01 |
Family
ID=
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