DESC:FIELD OF THE INVENTION
The present invention relates to process for the preparation of Ripretinib and
intermediates thereof. The present invention also relates to solid state forms of
Ripretinib and process for the preparation thereof.
BACKGROUND OF THE INVENTION
Ripretinib is the adopted name for a drug chemically described as 1-(4-bromo-
5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl)-
3-phenylurea and is represented by structural Formula I.
Formula I
Ripretinib is a kinase inhibitor and is marketed in USA under the brand name
as QINLOCK ® tablets in 50 mg strength for the treatment of adult patients with
advanced gastrointestinal stromal tumor (GIST) who have received prior treatment
with 3 or more kinase inhibitors, including imatinib.
U.S. patent no. 8,461,179 discloses general procedure for the preparation of
Ripretinib.
PCT publication no. WO2020185812A1 discloses solid state forms of
Ripretinib, processes for preparation thereof.
Polymorphism is an important aspect of pharmaceutical drug in terms of its
solubility and bioavailability. One of the most important physical properties of
pharmaceutical compounds is their solubility in aqueous solution, particularly their
solubility in the gastric juices of a patient. Different crystalline forms of polymorphs
of the same pharmaceutical compounds can and reportedly do have different aqueous
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solubility. The different solubility of the drug compound affects the bioavailability of
drug at target site.
The prior art process for the preparation of Ripretinib have major drawbacks
such as difficulties with respect to removal of process related impurities; poor
commercial viability due to use of hazardous reactants; use of column chromatography
and/ or low yields and purity of intermediates and final product. Therefore, there
remains a need to develop such a process, which overcomes one or more of the above
drawbacks associates with prior art process for preparation of Ripretinib.
The reported solid forms of Ripretinib are not viable at industrial scale and there
remains a need for alternate solid forms of Ripretinib and their preparative processes.
The inventors of present invention have found out an improved process for the
preparation of Ripretinib and intermediates thereof and solid state forms thereof.
Although methods and materials similar or equivalent to those described herein
can be used in the practice or testing of the present invention, suitable methods, and
materials are described below. All publications, patent applications, patents, and other
references mentioned herein are incorporated by reference in their entirety. In addition,
the materials, methods, and examples are illustrative only and not intended to be
limiting.
SUMMARY OF THE INVENTION
In one embodiment, the present invention provides a process for the preparation
of Ripretinib of Formula I,
Formula I
comprising:
a) reacting a compound of Formula II’,
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Formula II’
with a compound of formula III’
Formula III’
in presence of a base to obtain compound of formula IV’
Formula IV’
b) reacting a compound of Formula IV’ with a compound of formula V
Formula V
in presence of a base of obtain compound of formula VI
Formula VI
c) converting compound of formula VI to Ripretinib of formula I;
wherein P1 and P2 are each independently selected from group consisting of hydrogen
or a suitable protecting group and X1 and X2 are each independently selected from
group consisting of: halogen, C1-C6 alkoxy, C6-C10 aryloxy or a 5-membered heteroaryl
containing at least one nitrogen directly bonded to the C-O of the compound of
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formula III’, each optionally substituted with one or more substituents independently
selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, halogen, CN, OH,
C1-C6 alkoxy, or NR1R2, wherein R1 and R2 are each independently selected from
hydrogen or C1-C6 alkyl.
In another embodiment, the present invention provides a process for the
preparation of Ripretinib of Formula I,
Formula I
comprising converting compound of formula IV'
Formula IV’
to Ripretinib of formula I; wherein X1 is as defined above.
In another embodiment, the present invention provides a process for the
preparation of Ripretinib intermediate of Formula V,
Formula V
comprising:
treating a compound of Formula VII
Formula VII
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with an oxidizing agent to obtain Ripretinib intermediate of Formula V.
In another embodiment, the present invention provides a process for the
preparation of Ripretinib intermediate of Formula VII,
Formula VII
comprising:
treating a compound of Formula VIII
Formula VIII
with a reducing agent to obtain Ripretinib intermediate of Formula VII.
In one embodiment, the present invention provides a crystalline form R3 of
Ripretinib characterized by X-ray diffraction pattern having characteristic peaks at
about 7.6°, 10.9°, 11.3°, 14.1°, 19.5°, 22.0° and 27.5° ± 0.2° 2?.
In another embodiment, the present invention provides a crystalline form R3 of
Ripretinib characterized by X-ray diffraction pattern as depicted in Figure 1.
In another embodiment, the present invention provides a process for the
preparation of crystalline form R3 of Ripretinib, comprising steps of:
i) providing Ripretinib in one or more suitable organic solvents;
ii) optionally, adding one or more suitable anti-solvents;
iii) isolating crystalline form R3 of Ripretinib.
In another aspect, the present invention provides a pharmaceutical
composition comprising crystalline form R3 of Ripretinib and atleast one
pharmaceutically acceptable excipient.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an illustration of a PXRD pattern of crystalline form R3 of Ripretinib
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DETAILED DESCRIPTION OF THE INVENTION
While the specification concludes with the claims particularly pointing and
distinctly claiming the invention, it is believed that the present invention will be better
understood from the following description. All percentages and ratios used herein are
by weight of the total composition and all measurements made are at 25oC and normal
pressure unless otherwise designated. All temperatures are in Degrees Celsius unless
specified otherwise. The present invention can comprise (open ended) of the
components of the present invention as well as other ingredients or elements described
herein.
As used herein, "comprising" means the elements recited, or their equivalent in
structure or function, plus any other element or elements which are not recited. The
terms "having" and "including" are also to be construed as open ended unless the
context suggests otherwise.
All ranges recited herein include the endpoints, including those that recite a
range "between" two values.
Terms such as "about," "generally," "substantially," and the like are to be
construed as modifying a term or value such that it is not an absolute, but does not read
on the prior art. Such terms will be defined by the circumstances and the terms that
they modify as those terms are understood by those of skill in the art. This includes, at
very least, the degree of expected experimental error, technique error and instrument
error for a given technique used to measure a value.
The starting materials used in this aspect may be obtained according to any
method known in the art or may be procured from the commercially available
sources.
In one embodiment, the present invention provides a process for the preparation
of Ripretinib of Formula I,
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Formula I
comprising:
a) reacting a compound of Formula II’,
Formula II’
with a compound of formula III’
Formula III’
in presence of a base to obtain compound of formula IV’
Formula IV’
b) reacting a compound of Formula IV’ with a compound of formula V
Formula V
in presence of a base of obtain compound of formula VI
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Formula VI
c) converting compound of formula VI to Ripretinib of formula I;
wherein P1 and P2 are each independently selected from group consisting of hydrogen
or a suitable protecting group and X1 and X2 are each independently selected from
group consisting of: halogen, C1-C6 alkoxy, C6-C10 aryloxy or a 5-membered heteroaryl
containing at least one nitrogen directly bonded to the C-O of the compound of
formula III’, each optionally substituted with one or more substituents independently
selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, halogen, CN, OH,
C1-C6 alkoxy, or NR1R2, wherein R1 and R2 are each independently selected from
hydrogen or C1-C6 alkyl.
The suitable protecting group may be selected from the group consisting of acyl
groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, phenylacetyl,
phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-
bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as
phenylsulfonyl, benzenesulfonyl, 4-nitrobenzenesulfonyl, p-toluenesulfonyl and
the like; carbamate forming groups such as benzyloxycarbonyl, pchlorobenzyloxycarbonyl,
p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,
2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-
dimethoxybenzyloxycarbonyl, 3,5-dimethoxy-benzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl,
4-methoxybenzyl-oxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl,
3,4,5-trimethoxybenzyl-oxycarbonyl, 1-(p-biphenylyl)-1-
methylethoxycarbonyl, a,a-dimethyl-3,5-di-methoxybenzyloxycarbonyl, benzhydryloxycarbonyl,
t-butyloxycarbonyl, di-isopropylmethoxycarbonyl, isopropyloxycarbonyl,
ethoxycarbonyl, methoxy-carbonyl, allyloxycarbonyl, 2,2,2,-
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trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-
methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyl -
oxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl,
triphenylmethyl (trityl), p-methoxyphenyl-diphenylmethyl, benzyloxymethyl and
the like; and silyl groups such as trimethylsilyl or the like. Protecting groups are
known to those skilled in the art and can be added or removed using well -known
procedures such as those set forth in Protective Groups in Organic Synthesis,
Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York, N.Y., (3rd Edition,
1999).
In one embodiment, the present invention provides a process for the preparation
of Ripretinib of Formula I,
Formula I
comprising:
a) reacting a compound of Formula II,
Formula II
with a compound of formula III
Formula III
in presence of a base to obtain compound of formula IV
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Formula IV
b) reacting a compound of Formula IV with a compound of formula V
Formula V
in presence of a base of obtain compound of formula VI
Formula VI
c) converting compound of formula VI to Ripretinib of formula I.
In another embodiment, the present invention provides a process for the
preparation of Ripretinib of Formula I,
Formula I
comprising converting compound of formula IV'
Formula IV’
to Ripretinib of formula I; wherein X1 is as defined above.
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The reaction of step-a) may be carried out in the presence of a suitable base.
In a preferred embodiment the reaction is carried out in the presence of 1-
methylpyrrolidine. The reaction of step-a) may be carried out in the presence of
suitable organic solvent. In a preferred embodiment the reaction is carried out in
the presence of tetrahydrofuran.
The compound of formula III can be prepared by reaction of aniline with phenyl
chloroformate in presence of a base and an organic solvent. In a preferred embodiment
the compound of formula III can be prepared by reaction of aniline with phenyl
chloroformate in presence of potassium carbonate and tetrahydrofuran.
The reaction of step-b) may be carried out in the presence of a suitable base.
In a preferred embodiment the reaction is carried out in the presence of Lithium
hydroxide monohydrate (LiOH.H2O). The reaction of step-b) may be carried out in
the presence of suitable organic solvent. In a preferred embodiment the reaction is
carried out in the presence of N,N-Dimethylacetamide (DMAc).
In another embodiment, the present invention provides a process for the
preparation of Ripretinib intermediate of Formula V,
Formula V
comprising:
treating a compound of Formula VII
Formula VII
with an oxidizing agent to obtain Ripretinib intermediate of Formula V.
The reaction may be carried out in the presence of a suitable oxidizing agent.
The oxidizing agents may be selected from the group consisting of general oxidizing
agents such as hydrogen peroxide, urea hydrogen peroxide, percarbonates, benzoyl
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peroxide, peracetic acid, di-t-butyl peroxide, persulfate, sodium peroxide, periodic
acid, periodate, perboric acid, perborates, permanganic acid, permanganates, iodic
acid, iodates, molecular iodine, cerium ammonium nitrate, ferric nitrate, 2,2,6,6-
Tetramethylpiperidine 1-oxyl (TEMPO) or the like, or mixtures thereof. In a
preferred embodiment the reaction is carried out in the presence of mixture of
2,2,6,6-Tetramethylpiperidine 1-oxyl (TEMPO) and molecular iodine.
In another embodiment, the present invention relates to use of Ripretinib
intermediate of Formula V prepared according to the methods disclosed herein in the
preparation of Ripretinib.
In another embodiment, the present invention provides a process for the
preparation of Ripretinib intermediate of Formula VII,
Formula VII
comprising:
treating a compound of Formula VIII
Formula VIII
with a reducing agent to obtain Ripretinib intermediate of Formula VII.
The reaction may be carried out in the presence of a suitable reducing agent.
The reducing agents may be selected from the group consisting of that can
potentially be employed for this transformation are: lithium aluminium hydride
(LiAlH4), lithium tri-tert-butoxyaluminum hydride (LiAlH(Ot-Bu)3)
diisobutylaluminium hydride (DIBAL-H), Lithium borohydride (LiBH4); Lithium
triethylborohydride (LiBHEt3); Magnesium borohydride [Mg(BH4)2]; Aluminum
borohydride [Al(BH4)3]; Calcium borohydride [Ca(BH4)2]; Sodium borohydride
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(NaBH4), Sodium in ethanol (Bouveault–Blanc reduction); Sodium bis(2-
methoxyethoxy)aluminium hydride (Red-Al); Lithium tri-tert-butoxyaluminum
hydride (LiAlH[OC(CH3)3]3); calcium alkoxyaluminium hydride (CALH) or the
like. In a preferred embodiment the reaction is carried out in the presence of sodium
borohydride (NaBH4).
In another embodiment, the present invention relates to use of Ripretinib
intermediate of Formula VII prepared according to the methods disclosed herein in the
preparation of Ripretinib.
In another aspect the present invention provides Ripretinib, obtained according
the processes of above aspects.
In another aspect the present invention provides a pharmaceutical composition
comprising Ripretinib, obtained according the processes of above aspects and at least
one pharmaceutically acceptable excipient.
In one embodiment, the present invention provides a crystalline form R3 of
Ripretinib characterized by X-ray diffraction pattern having characteristic peaks at
about 7.6°, 10.9°, 11.3°, 14.1°, 19.5°, 22.0° and 27.5° ± 0.2° 2?.
In another embodiment, the crystalline form R3 of Ripretinib may be further
characterized by X-ray diffraction pattern having characteristic peaks at about 5.7°,
7.6°, 10.9°, 11.3°, 12.7°, 13.6°, 14.1°, 15.09°, 17.6°, 19.5°, 20.05°, 21.5°, 22.06°,
23.09°, 24.6°, 26.4°, 27.5°, 30.3°, 30.6°, 32.2°, 35.2° and 39.0° ± 0.2° 2?.
In another embodiment, the present invention provides a crystalline form R3 of
Ripretinib characterized by X-ray diffraction pattern as depicted in Figure 1.
In another embodiment, the present invention provides a process for the
preparation of crystalline form R3 of Ripretinib, comprising steps of:
i) providing Ripretinib in one or more suitable organic solvents;
ii) optionally, adding one or more suitable anti-solvents;
iii) isolating crystalline form R3 of Ripretinib.
In a preferred embodiment the suitable organic solvent or anti -solvent may
be selected from the group consisting of ethyl acetate and hexane.
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In another aspect, the present invention provides a pharmaceutical
composition comprising crystalline form R3 of Ripretinib and at least one
pharmaceutically acceptable excipient.
In another embodiment, the crystalline form R3 of Ripretinib of the present
invention is stable under thermal, humid and stress conditions. Further, the
crystalline form R3 of Ripretinib of the present invention exhibits superior solubility
in solvents such as water, as compared to reported crystalline forms of Ripretinib.
In another embodiment, Ripretinib, obtained according the processes of
present invention and the crystalline form R3 of Ripretinib of the present invention or
the pharmaceutical compositions thereof, comprises Ripretinib with a chemical
purity of at least 99% by HPLC or at least 99.5% by HPLC or at least 99.9% by
HPLC.
The suitable ‘organic solvent’ or "solvent" or “anti-solvent” at any stage of
the process of the present invention may be selected from the group consisting of
alcohols, such as methanol, ethanol, 2-propanol, n- propanol, n-butanol, isoamyl
alcohol, octanol, 1,2-propanediol, S-(+)-1,2-propanediol and ethylene glycol;
ethers, such as diisopropyl ether, dibutyl ether, cyclopentyl methyl ether, methyl
tert-butyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran (THF), methyl THF, and
diglyme; esters, such as methyl acetate, ethyl acetate, isopropyl acetate, n-propyl
acetate and t-butyl acetate; ketones, such as acetone, methyl ethyl ketone,
cyclohexanone and methyl isobutyl ketone; halogenated hydrocarbons, such as
dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like;
nitriles, such as acetonitrile; hydrocarbons include but not limited to such as
benzene, toluene, xylene, pentane, hexane, heptane, cyclohexane and tetraline;
polar aprotic solvents, such as N,N-dimethylformamide, N,N-dimethylacetamide,
N-methyl 2-pyrrolidone, dimethylsulfoxide, pyridine, phenol, DMA, carbon
disulphide, acetic acid and the like; water; or mixtures thereof.
The suitable base at any stage of the process of the present invention may be
selected from alkali metal carbonates, such as, for example, sodium carbonate,
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potassium carbonate, lithium carbonate, cesium carbonate, or the like; alkali metal
bicarbonates, such as, for example, sodium bicarbonate, potassium bicarbonate, or
the like; alkali metal fluorides, such as, for example, sodium fluoride, potassium
fluoride, cesium fluoride or the like; metal alkoxides, such as, for example, sodium
tert-butoxide, lithium tert-butoxide, potassium tert-butoxide, sodium methoxide,
sodium ethoxide or the like; organometallic base, such as lithium diisopropylamide,
butyl lithium, lithium bis(trimethylsilyl)amide, lithium tetramethylpiperidide
(LTMP) or the like; metal hydroxides such as lithium hydroxide, lithium hydroxide
on alumina, sodium hydroxide, calcium hydroxide, barium hydroxide or the like;
other organic base such as triethylamine, 1-methylpyrrolidine, N,Ndiisopropylethylamine,
or the like.
Suitable temperatures for the reaction at any stage of the process of the present
invention may be less than about 150°C, less than about 100°C, less than about
80°C, less than about 60°C, or any other suitable temperatures.
Suitable times for the hydrogenation step at any stage of the process of the
present invention may be from about 30 minutes to about 10 hours, or longer.
The removal of solvent at any stage of the process of the present invention
may be carried out by methods known in the art or any procedure disclosed in the
present application. In preferred embodiments, removal of solvent may include, but not
limited to: solvent evaporation or sublimation under atmospheric pressure or reduced
pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, spray
drying, freeze drying (Lyophilization), agitated thin film drying and the like.
The compounds at any stage of the process of the present invention may be
isolated using conventional techniques known in the art. For example, useful
techniques include but are not limited to, decantation, centrifugation, gravity filtration,
suction filtration, concentrating, cooling, stirring, shaking, combining with an antisolvent,
adding seed crystals, evaporation, flash evaporation, simple evaporation,
rotational drying, spray drying, thin-film drying, freeze-drying, or the like. The
isolation may be optionally carried out at atmospheric pressure or under reduced
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pressure. The solid that is obtained may carry a small proportion of occluded mother
liquor containing a higher percentage of impurities and, if desired, the solid may be
washed with a solvent to wash out the mother liquor.
The compounds at any stage of the process of the present invention may be
recovered from a suspension/solution using any of techniques such as decantation,
filtration by gravity or by suction, centrifugation, slow evaporation, or the like, or any
other suitable techniques. The reaction can be efficiently completed at room
temperature or ambient temperature or if required reaction mass can be heated to
elevated temperatures or up to about the reflux temperatures, and maintained for about
10 minutes to about 5 hours or longer.
The resulting solid may be optionally further dried. Drying may be suitably
carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed
dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced
pressure. Drying may be carried out at temperatures less than about 100°C, less than
about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric
pressure or under reduced pressure, and in the presence or absence of an inert
atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out
for any desired time periods to achieve a desired purity of the product, such as, for
example, about 1 to about 15 hours, or longer.
In an embodiment, Ripretinib of present invention has average particle size of
particles between 1 to 100 µm, less than 90 µm, less than 80 µm, less than 60 µm, less
than 50 µm, less than 40 µm, less than 30 µm, less than 20 µm, less than 10 µm, less
than 5 µm or any other suitable particle sizes. In another embodiment, Ripretinib of
present invention may have particle size distribution: D10 of particles smaller than 20
µm, smaller than 15 µm, smaller than 10 µm, or smaller than 5 µm; D50 of particles
smaller than 100 µm, smaller than 90 µm, smaller than 80 µm, smaller than 70 µm,
smaller than 60 µm, smaller than 50 µm, smaller than 40 µm, smaller than 30 µm,
smaller than 20 µm, smaller than 10 µm; D90 of particles smaller than 200 µm, smaller
than 175 µm, smaller than 150 µm, smaller than 140 µm, smaller than 130 µm, smaller
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than 120 µm, smaller than 110 µm, smaller than 100 µm, smaller than 90 µm, smaller
than 80 µm, smaller than 70 µm, smaller than 60 µm, smaller than 50 µm, smaller than
40 µm, smaller than 30 µm, smaller than 20 µm, smaller than 10 µm.
Particle size distributions of Ripretinib particles may be measured using any
techniques known in the art. For example, particle size distributions of Ripretinib
particles may be measured using microscopy or light scattering equipment, such as, for
example, a Malvern Master Size 2000 from Malvern Instruments Limited, Malvern,
Worcestershire, United Kingdom. As referred herein, the term “D10” in the context of
the present invention is 10% of the particles by volume are smaller than the D10 value
and 90% particles by volume are larger than the D10 value. “D50” in the context of the
present invention is 50% of the particles by volume are smaller than the D50 value and
50% particles by volume are larger than the D50 value. “D90” in the context of the
present invention is 90% of the particles by volume are smaller than the D90 value and
10% particles by volume are larger than the D90 value.
In an embodiment, Ripretinib of present invention can be micronized or milled
using conventional techniques to get the desired particle size to achieve desired
solubility profile to suit to pharmaceutical composition requirements. Techniques that
may be used for particle size reduction include, but not limited to ball milling, roller
milling and hammer milling. Milling or micronization may be performed before drying,
or after the completion of drying of the product.
In another embodiment, the present invention provides pharmaceutical
compositions comprising Ripretinib prepared according to method disclosed herein
alone or in combination with other drugs. Further the present invention provides a
process of preparing a pharmaceutical composition comprising alone or in combination
with other drugs. Conveniently various pharmaceutically acceptable excipients can be
employed in a process according to the present invention.
In another embodiment, at least one pharmaceutically acceptable excipient of
this aspect may be selected from the group consisting of polyvinyl pyrrolidone,
povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate,
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co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate
phthalate, polysorbate 80, polyoxyethylene–polyoxypropylene copolymers
(Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl
ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose,
methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hydroxypropylmethyl
cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose
phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS),
hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL),
hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L),
hydroxyethyl cellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetatepolyethylene
glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl
cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate
phthalate, carboxymethylethylcelluloseand the like; cyclodextrins, gelatins,
hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble
sugar excipients, preferably having low hygroscopicity, which include, but are not
limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates,
dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives,
polyvinyl alcohols, propylene glycol derivatives and the like; organic amines such as
alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines,
cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its
derivatives, and guanidine or its derivatives, or any other excipient at any aspect of
present invention. A thorough discussion of pharmaceutically acceptable excipients is
presented in Remington's Pharmaceutical Sciences (17th ed., Mack Publishing
Company) and Remington: The Science and Practice of Pharmacy (21st ed., Lippincott
Williams & Wilkins), which are hereby incorporated by reference.
The use of mixtures of more than one of the pharmaceutical excipients to
provide desired release profiles or for the enhancement of stability is within the scope
of this invention. Also, all viscosity grades, molecular weights, commercially available
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products, their copolymers, and mixtures are all within the scope of this invention
without limitation.
The compound of this application is best characterized by the X-ray powder
diffraction pattern determined in accordance with procedures that are known in the art.
X-ray diffraction was measured using Rigaku Desktop X-ray diffractometer, Model:
MiniFlex600. System description: CuK-Alpha 1 wavelength= 1.54060, voltage 40 kV,
current 15 mA, divergence slit = 1.25°; Sample stage=Reflection. Scan type:
Continuous; Detector – Scintillator NaI (T1); Measurement parameters: Start Position
[°2Th.]: 3; End Position [°2Th.]: 40; Step Size [°2Th.]: 0.02; Scan Speed [°/min]: 1
Generally, a diffraction angle (2?) in powder X-ray diffractometry may have an
error in the range of ± 0.2o. Therefore, the aforementioned diffraction angle values
should be understood as including values in the range of about ± 0.2o. Accordingly,
the present application includes not only crystals whose peak diffraction angles in
powder X-ray diffractometry completely coincide with each other, but also crystals
whose peak diffraction angles coincide with each other with an error of about ± 0.2o.
Therefore, in the present specification, the phrase "having a diffraction peak at a
diffraction angle (2? ± 0.2o) of 7.9o" means "having a diffraction peak at a diffraction
angle (2?) of 7.7o to 8.1o”. Although the intensities of peaks in the x-ray powder
diffraction patterns of different batches of a compound may vary slightly, the peaks
and the peak locations are characteristic for a specific polymorphic form.
Alternatively, the term "about" means within an acceptable standard error of the mean,
when considered by one of ordinary skill in the art. The relative intensities of the
PXRD peaks can vary depending on the sample preparation technique, crystal size
distribution, various filters used, the sample mounting procedure, and the particular
instrument employed. Moreover, instrument variation and other factors can affect the
2-theta values. Therefore, the term "substantially" in the context of PXRD is meant to
encompass that peak assignments can vary by plus or minus about 0.2 degree.
Moreover, new peaks may be observed or existing peaks may disappear, depending on
the type of the machine or the settings (for example, whether a Ni filter is used or not).
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Certain specific aspects and embodiments of the present application will be
explained in greater detail with reference to the following examples, which are
provided only for purposes of illustration and should not be construed as limiting the
scope of the application in any manner.
Examples
Example 1: Preparation of compound of Formula VII
Formula VII
Methanol (30 mL) and TEA (4.4 g) were charged under N2 atmosphere to a mixture of
compound of formula VIII (10 g) in THF (150 mL) at 25-35 °C. Sodium borohydride
(4.1 g) was charged portion wise in to the reaction mixture at 25-35 °C and the reaction
mixture was heated for 12 h at 60-65 °C. After completion of reaction, the reaction
mixture was cooled to 25-35 °C. Water (100 mL) and DCM (100 mL) were charged in
to the reaction mixture at 30 °C. Layers were separated and the aqueous layer was
extracted with DCM (70 mL). The combined DCM layer was washed with 10%
aqueous ammonium chloride solution (100 mL), followed by brine (100 mL). The
DCM layer was dried over sodium sulfate and concentrated under vacuum below 50
°C to obtain a solid. Hexane (60 mL) was charged into the solid thus obtained at RT.
The suspension was stirred for 30 min at RT. The solid was filtered and washed with
hexane (50 mL). The solid was dried in a hot air oven at 40 °C for 2 h to obtain to
obtain the title compound of Formula VII (6.2 g).
Example 2: Preparation of compound of Formula V:
Formula V
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To a mixture of compound of Formula VII (500 mg) and toluene (6.75 mL) maintained
at 20-25 °C was added aqueous sodium bicarbonate solution (prepared by dissolving
675 mg NaHCO3 in 6.75 mL water). Iodine (1.3 g) was charged to the above reaction
mixture and the reaction mass was stirred for 5 min at 20-25 °C. TEMPO (41.8 mg)
was charged in to the reaction mixture at 20-25 °C. The reaction mixture was stirred at
20-25° C for 16 h. After the completion of reaction, the reaction mixture was diluted
with EtOAc (10 mL). Water (10 mL) was charged in to the reaction mixture which was
then stirred for 10 min at 25-35 °C. Layers were separated. The aqueous layer was
extracted with EtOAc (10 mL). The organic layers were combined and washed with
10% aqueous sodium thiosulphate (20 mL), followed by brine. The organic layer was
dried over anhydrous sodium sulfate and concentrated under reduced pressure at 40-
45° C to obtain the crude product. Hexane (2.5 mL) was charged into the stirred crude
product at RT. The mixture was cooled to 0-5° C and stirred at the same temperature
for 30 min. The solid was filtered and washed with ice cold hexane (2 mL) to obtain
title compound of Formula V (310 mg).
Example 3: Preparation of compound of Formula III:
Formula III
Aniline (10 g), tetrahydrofuran (150 mL) were charged into reactor at room
temperature. Potassium carbonate (29.6 g) followed by water (500 mL) was charged
into the reaction mixture and the reaction mixture was cooled to 15-25°C. Phenyl
chloroformate (20.1 g) was gradually added into the reaction mixture at 15-25 °C and
the reaction mixture was stirred for 1-2 h for 25-35° C. After completion of the reaction,
water (70 mL) was charged into the reaction mixture at room temperature. Layers were
separated and the aqueous layer was extracted with ethyl acetate (2 X 50 mL). The
layers were separated and the combined organic layer was washed with water (70 mL)
followed by brine (70 mL). The organic layer was dried over sodium sulfate and
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concentrated under reduced pressure at 40-45° C to obtain residue. Hexane (50 mL)
was charged into the residue and the reaction mixture was stirred for 30-40 min at 25-
35°C. The solid was dried in a hot air oven at 40° C for 4-5 h to obtain the title
compound of Formula III.
Example 4: Preparation of compound of Formula IV:
Formula IV
To a mixture of ethyl 2-(5-amino-2-bromo-4-fluorophenyl)acetate (compound of
formula II, 3.0 g) and THF (75 mL) at 25-35 °C was added under nitrogen atmosphere
compound of formula III (11.6 g) and 1-methylpyrrolidine (4.6 g). The reaction mixture
was heated to 60-65 °C for 16 h. After completion of reaction, the reaction mass was
concentrated under reduced pressure below 50 °C. DCM (30 mL) was charged into the
above residue at 25-35 °C. The reaction mixture was stirred for 20-30 min at 25-35 °C.
The solid obtained was filtered and washed obtained with DCM (10 mL). The filtrate
and washings were concentrated under vacuum below 50 °C to obtain the crude
product. The crude product was purified by column chromatography using 100-200
mesh silica gel and 18- 20% EtOAc-hexane as eluent. The fractions containing the pure
product were combined and concentrated under reduced pressure below 50 °C to obtain
the title compound of Formula IV (2.3 g) as an off white solid.
Example 5: Preparation of compound of Formula VI
Formula VI
6-chloro-4-(ethylamino)nicotinaldehyde (compound of formula V, 0.9 g) was charged
under nitrogen atmosphere to a solution of compound of Formula IV (2.1 g) in N,NDocuSign
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dimethylacetamide (21 mL) at 25-35 °C. Lithium hydroxide monohydrate (0.33 g) was
charged into the reaction mixture at 25-35 °C. The reaction mixture was stirred at RT
for 4-5 h. After completion of reaction, water (61 mL) was charged into the reaction
mixture at 25-35 °C. The suspension obtained was stirred for 1 h at 25-35 °C. The solid
was filtered under suction and washed with water (21 mL). The wet solid was unloaded
and suspended in methanol (21 mL). The suspension was stirred for 10 min at 25-35
°C. The solid was filtered under suction and washed with methanol (5.5 mL). The solid
was dried in a hot air oven at 45 °C for 8 h to obtain the title compound of Formula VI
(2.01 g) as a pale yellow colored solid.
Example 6: Preparation of Ripretinib (Formula I):
Formula I
A mixture of compound of Formula VI (0.5 g), DMSO (15 mL) and 40% aqueous
methylamine solution (7.5 mL) was heated at 70-75 °C for 24 h. After completion of
the reaction, the reaction mixture was cooled to 25-35° C. Water (25 mL) was charged
into the reaction mixture at RT. The mixture was stirred for 30 min at 25-35° C. The
solid was filtered and washed with water (15 mL). The wet solid was unloaded and
dried in a hot air oven at 40 °C for 5 h to obtain the crude product as a pale brown solid.
The crude product was purified by column chromatography using 60-120 mesh silica
gel and 70-80% ethyl acetate in hexane as eluent to obtain Ripretinib of compound of
formula I (0.2 g).
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Example 7: Preparation of crystalline form R3 of Ripretinib (Formula I):
Formula I
Ripretinib (1 g) was provided in 70-80% ethyl acetate in hexane (10 mL). The reaction
mass was stirred at RT for about 3-4 hours. The reaction mass was filtered under
vacuum and dried in VTD at 80°C about 4-5 hours to obtain crystalline form R3 of
Ripretinib of compound of formula I. ,CLAIMS:WE CLAIM:
1) A process for the preparation of Ripretinib of Formula I, comprising:
a) reacting a compound of Formula II’ with a compound of formula III’ in presence
of a base to obtain compound of formula IV’
b) reacting a compound of Formula IV’ with a compound of formula V in presence
of a base of obtain compound of formula VI.
c) converting compound of formula VI to Ripretinib of formula I;
wherein P1 and P2 are each independently selected from group consisting of hydrogen
or a suitable protecting group and X1 and X2 are each independently selected from
group consisting of: halogen, C1-C6 alkoxy, C6-C10 aryloxy or a 5-membered heteroaryl
containing at least one nitrogen directly bonded to the C-O of the compound of
formula III’, each optionally substituted with one or more substituents independently
selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, halogen, CN, OH,
C1-C6 alkoxy, or NR1R2, wherein R1 and R2 are each independently selected from
hydrogen or C1-C6 alkyl.
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2) The process of claim 1, wherein both P1 and P2 are each independently hydrogen.
3) A process for the preparation of Ripretinib intermediate of Formula V, comprising
treating a compound of Formula VII with an oxidizing agent to obtain Ripretinib
intermediate of Formula V.
4) A process for the preparation of Ripretinib intermediate of Formula VII, comprising
treating a compound of Formula VIII with a reducing agent to obtain Ripretinib
intermediate of Formula VII.
5) The process as claimed in claim 4, wherein reducing agent is selected from the group
consisting of lithium aluminium hydride (LiAlH4), lithium tri-tert-butoxyaluminum
hydride (LiAlH(Ot-Bu)3) diisobutylaluminium hydride (DIBAL-H), Lithium
borohydride (LiBH4), Lithium triethylborohydride (LiBHEt3), Magnesium
borohydride [Mg(BH4)2], Aluminum borohydride [Al(BH4)3], Calcium
borohydride [Ca(BH4)2], Sodium borohydride (NaBH4), Sodium bis(2-
methoxyethoxy)aluminium hydride (Red-Al), Lithium tri-tert-butoxyaluminum
hydride (LiAlH[OC(CH3)3]3), calcium alkoxyaluminium hydride (CALH).
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6) A crystalline form R3 of Ripretinib, characterized by X-ray diffraction pattern having characteristic peaks at about 7.6°, 10.9°, 11.3°, 14.1°, 19.5°, 22.0° and 27.5° ± 0.2° 2?.
7) The crystalline form of claim 6, further characterized by X-ray diffraction pattern having characteristic peaks at about 5.7°, 7.6°, 10.9°, 11.3°, 12.7°, 13.6°, 14.1°, 15.09°, 17.6°, 19.5°, 20.05°, 21.5°, 22.06°, 23.09°, 24.6°, 26.4°, 27.5°, 30.3°, 30.6°, 32.2°, 35.2° and 39.0° ± 0.2° 2?.
8) A process for the preparation of crystalline form R3 of Ripretinib, as claimed in claim 6, comprising steps of:
i) providing Ripretinib in one or more suitable organic solvents;
ii) optionally, adding one or more suitable anti-solvents;
iii) isolating crystalline form R3 of Ripretinib.
9) The process of claim 8, wherein the suitable organic solvent is selected from the group consisting of ethyl acetate and hexane.
10) The process of claim 8, wherein the suitable anti-solvent is selected from the group consisting of ethyl acetate and hexane.