FIELD OF THE INVENTION
The present application relates to process for the preparation of Anlotinib
dihydrochloride. The present application also relates to the process for the preparation
of Anlotinib intermediates.
BACKGROUND OF THE INVENTION
Anlotinib dihydrochloride is the adopted name for a drug chemically described as 1-
((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-quinolin-7-yloxy)methyl)
cyclopropanamine dihydrochloride and is represented by structural Formula (I).
Formula (I)
Anlotinib dihydrochloride is a novel oral tyrosine kinase inhibitor and is
marketed in China under the brand name as Fukewei capsules in 8 mg, 10 mg and 12
mg strengths for the treatment of locally advanced or metastatic non-small cell lung
cancer patients who have progressed or recurred after receiving at least two systemic
chemotherapy in the past.
U.S. patent no. 8,148,532 B2 discloses the process for the preparation of
Anlotinib and/or its analogues.
CN107771078B, CN108864050B, CN109748902B, CN110357856B,
CN110386892B, CN110376296A1 and CN110845406B describe the processes for the
preparation of Anlotinib dihydrochloride and its intermediates.
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The prior art process for the preparation of Anlotinib dihydrochloride 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 associated with prior art process for preparation
of Anlotinib dihydrochloride.
The inventors of present application have found out a process for the
preparation of Anlotinib dihydrochloride and intermediates thereof. The proposed
process of present invention has cost-improvement process of Anlotinib
dihydrochloride.
Although methods and materials similar or equivalent to those described herein
can be used in the practice or testing of the present application, 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 application provides a process for the
preparation of Anlotinib dihydrochloride of Formula (I), comprising:
Formula (I)
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a) coupling a compound of Formula (II) with a compound of Formula (III) to produce
a compound of Formula (IV).
b) de-protection of a compound of Formula (IV) under the action of HCl to produce a
compound of Formula (I).
DETAILED DESCRIPTION OF THE INVENTION
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
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very least, the degree of expected experimental error, technique error and instrument
error for a given technique used to measure a value.
In one embodiment, the present application provides a process for the
preparation of Anlotinib dihydrochloride of Formula (I), comprising:
Formula (I)
a) coupling a compound of Formula (II) with a compound of Formula (III) to produce
a compound of Formula (IV).
b) de-protection of a compound of Formula (IV) under the action of HCl to produce a
compound of Formula (I).
The above step a) reaction may be carried out in the presence of suitable
reagent and an organic solvent.
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Suitable reagent that may be used in step a) include, but are not limited to
triphenylphosphine, tributylphosphine, triethylphosphine, trimethylphosphine,
diisopropyl azodicarboxylate, diethyl azodicarboxylate, di-tert-butyl azodicarboxylate,
1,1′-(Azodicarbonyl)dipiperidine, 4,7-dimethyl-3,5,7-hexahydro-1,2,4,7-tetrazocin3,8-dione, N,N,N',N'-tetramethylazodicarboxamide or mixtures thereof.
Suitable organic solvent used in step a) include, but are not limited to ether
solvents, such as, for example, diethyl ether, diisopropyl ether, tert-butyl methyl ether,
dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-
ethoxyethanol, anisole, 1, 4-dioxane or the like; ketone solvents, such as acetone, ethyl
methyl ketone, diethyl ketone, methyl isobutyl ketone, C3-C6 ketones or the like;
aromatic hydrocarbon solvents, such as toluene, xylene, chlorobenzene, tetralin or the
like; halogenated hydrocarbons such as dichloromethane, chloroform or the like;
aliphatic hydrocarbon solvents, such as n-pentane, n-hexane, n-heptane or the like;
nitrile solvent, such as acetonitrile, propionitrile, C2-C6 nitriles or the like; ester
solvents, such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl
acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the
like; or mixtures thereof.
The above step b) reaction may be carried out in the presence of HCl and an
organic solvent.
Suitable sources of HCl used in step b) include, but are not limited to
hydrochloric acid, methanolic HCl, ethanolic HCl, isopropanolic HCl, dioxane-HCl or
the like.
Suitable organic solvent used in step b) include, but are not limited to ester
solvents, such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl
acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl
butanoate, or the like; ether solvents, such as, for example, diethyl ether, diisopropyl
ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-
methoxyethanol, 2-ethoxyethanol, anisole, 1,4-dioxane or the like; alcoholic solvents
such as methanol, ethanol, isopropyl alcohol, n-butanol, 1-propanol or the like; ketone
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solvents, such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone,
C3-C6 ketones or the like; aromatic hydrocarbon solvents, such as toluene, xylene,
chlorobenzene, tetralin or the like; halogenated hydrocarbons such as dichloromethane,
chloroform or the like; aliphatic hydrocarbon solvents, such as n-pentane, n-hexane, nheptane or the like; water or mixtures thereof.
The temperature at which the above steps may be carried out in between about
-20 °C and about 200 °C, preferably at about 0 °C and about 150 °C, most preferably
at about 0 °C and about 100 °C, based on the solvent or mixture of solvent used in
particular step.
The advantages of the present invention specifically, in step a) of the ROS
involves a direct etherification between Formula (II) and Formula (III). It bypasses
altogether the need to convert the hydroxy moiety in Formula (III) into a leaving group
(and a potential genotoxic intermediate) before the etherification step. In addition, it
also minimizes the possibility of impurity formation resulting from a competing
alkylation on the indole moiety of Formula (II).
The removal of solvent at any stage of the process of the present application
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 application 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
pressure. The solid that is obtained may carry a small proportion of occluded mother
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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 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.
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.

WE CLAIM:
1) A process for the preparation of Anlotinib dihydrochloride of Formula (I), comprising:
Formula (I)
a) coupling a compound of Formula (II) with a compound of Formula (III) to produce a
compound of Formula (IV).
b) de-protection of a compound of Formula (IV) under the action of HCl to produce a
compound of Formula (I).
2) The process according to claim 1, step a) is carried out in the presence of reagent.
3) The process according to claim 2, reagent is selected from triphenylphosphine,
tributylphosphine, triethylphosphine, trimethylphosphine, diisopropyl azodicarboxylate,
diethyl azodicarboxylate, di-tert-butyl azodicarboxylate, 1,1′-
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(Azodicarbonyl)dipiperidine, 4,7-dimethyl-3,5,7-hexahydro-1,2,4,7-tetrazocin-3,8-
dione, N,N,N',N'-tetramethylazodicarboxamide .
4) The process according to claim 1, step b) is carried out in the presence of hydrochloric
acid.
5) The process according to claim 4, suitable source of hydrochloric acid is selected from
methanolic HCl, ethanolic HCl, isopropanolic HCl, dioxane-HCl.