DESC:Field of Invention
The present invention relates to novel processes for preparing N-(5-Chloro-2-
pyridinyl)-2-{[4-(N,N-dimethylcarbamimidoyl)benzoyl]amino}-5-methoxybenzamide,
i.e., Betrixaban or salts thereof and novel intermediates useful for preparing the same.
The products obtained from the processes of the present invention may be in
crystalline form; amorphous form; solid dispersions/solutions thereof with
pharmaceutically acceptable polymers and complexes thereof with pharmaceutically
acceptable carriers. Also, the products obtained from the present invention may be
used for the preparation of medicaments for the prevention and/or treatment of
diseases and conditions in which Betrixaban is indicated.
Background of the Invention
The present invention is directed to processes for preparing N-(5-Chloro-2-
pyridinyl)-2-{[4-(N,N-dimethylcarbamimidoyl)benzoyl]amino}-5-methoxy benzamide,
i.e. Betrixaban or salts thereof.
Factor Xa, a serine protease, plays an important role in the blood coagulation
pathway. Direct inhibition of factor Xa has been considered to be an efficient
anticoagulant strategy in the treatment of thrombotic diseases. U.S. Patent No.
6,376,515 discloses a class of benzamide based compounds as specific factor Xa
inhibitors and describes the compound Betrixaban, represented by a compound of
Formula 1:
O
NH
O
NH
O
NH
N
N
Cl
Formula 1
U.S. Patent No. 6,844,367 discloses a process to synthesize Betrixaban by
condensation of 2-amino-N-(5-chloropyridin-2-yl)-5-methoxybenzamide with 4-cyano
benzoyl chloride followed by amidine formation and further synthesis of maleate salt
3
form. The process disclosed however involves the use of corrosive chemicals and
harsh conditions and has shown to give a low yield with high number of impurities.
U.S. Patent No. 8394964 B2 discloses a process for the synthesis of
Betrixaban, its maleate salt and the intermediates present in the process by the
condensation of 2-amino-N-(5-chloropyridin-2-yl)-5-methoxybenzamide with 4-
amidinobenzoic acid hydrochloride, followed by amidine formation in the presence of
Lithium hydroxide (LiOH).
U.S. Patent Nos. 8,524,907 B2 and 9,221,758 B2 discloses a process similar
to that of the process disclosed in U.S. Patent '367 wherein Lithium dimethyl amide
(LiN(CH3)2) is used during amidine formation to increase the yield. However, the
methods used in the above US patents '964, '907 and '758 involves the use of n-hexyl
lithium that requires stringent storage conditions due to its explosive and highly
unstable nature, apart from which it is expensive, thus resulting in higher production
costs. Additionally, the method has shown to express difficulty in removal of some
impurities.
A Chinese patent publication CN105732490 A describes a process which
involves the condensation of 6-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione and 5-
chloropyridin-2-amine to yield 2-amino-N-(5-chloropyridin-2-yl)-5-methoxybenzamide,
which further condenses with 4-cyanobenzoyl chloride, followed by amidine formation
in the presence of dimethylamine and n-hexyllithium. Use of n-hexyllithium requires
stringent storage conditions due to its unstable and hazardous nature.
Chinese patent publications CN104693114 A and CN106831553 A disclose the
process of amidine formation by the use of Grignard reagents, however they also
involve the use a large amount of highly corrosive hydrogen chloride gas that involves
the high requirements for corrosion protection devices, and "waste" heavy processing
load. In addition, the final separation and purification by column chromatography is not
conducive to the implementation at industrialization.
U.S. Patent No. 9,555,023 B2 discloses a crystalline polymorphic form of
Betrixaban maleate and its use in a pharmaceutical composition.
A Chinese patent application CN 106995405 A discloses an amorphous form
of Betrixaban maleate and preparation process thereof.
In light of drawbacks of the prior art processes, there exists a need to develop
efficient methods for preparing Betrixaban or salts thereof, which are industrially
feasible and environment-friendly.
4
In the view of prior art, there remains a need to develop stable amorphous/
crystalline polymorphs, complexes, dispersions of Betrixaban or salts thereof that
exhibit higher physical and chemical stability profile when stored at elevated
temperatures and humidity conditions.
The present invention intends to provide for advantageous user-friendly
methods to synthesize Betrixaban or salts thereof that can overcome the use of highly
corrosive, hazardous reagents and achieve an amplified and optimized process to
facilitate production at an industrial scale.
Object of Invention
An object of the invention is to provide an industrially viable, novel process for
the preparation of N-(5-Chloro-2-pyridinyl)-2-{[4-(N,N-dimethylcarbamimidoyl)
benzoyl]amino}-5-methoxybenzamide, i.e. Betrixaban, useful as a Factor Xa inhibitor.
Another object of the invention is to provide an economical process for
preparing Betrixaban or salts thereof, resulting in higher yields.
It is also an object of the invention to provide a process for preparing
Betrixaban, resulting in a stable amorphous compound, stable amorphous solid
dispersions/solutions with pharmaceutically acceptable polymers and stable
amorphous complexes with pharmaceutically acceptable carriers.
Yet another object of the invention is to provide a process for preparing
Betrixaban or alternative salts thereof, resulting in a stable crystalline compound,
stable crystalline solid dispersions with pharmaceutically acceptable polymers, and
stable crystalline complexes with pharmaceutically acceptable carriers.
Also an object of the invention is to provide an industrially viable, cost-effective
process for preparing N-(5-Chloro-2-pyridinyl)-2-{[4-(N,N-dimethyl carbamimidoyl)
benzoyl]amino}-5-methoxybenzamide in stable amorphous or crystalline form as such,
stable solid dispersions, stable complexes and their use in the preparation of
medicaments; useful for the prevention and treatment of diseases and/or conditions
influenced by the inhibition of Factor Xa.
Summary of the Invention
The present invention relates to novel processes for preparing factor Xa
inhibitors, preferably benzamide compounds, useful for the treatment of thrombotic
diseases. More particularly, the present invention relates to novel processes for
5
preparation of N-(5-Chloro-2-pyridinyl)-2-{[4-(N,N-dimethylcarbamimidoyl)benzoyl]
amino}-5-methoxybenzamide (Betrixaban) or pharmaceutically acceptable salts,
polymorphs, hydrates or solvates thereof.
Also the present invention provides novel compounds useful as intermediates
for the synthesis of N-(5-Chloro-2-pyridinyl)-2-{[4-(N, N-dimethylcarbamimidoyl)
benzoyl]amino}-5-methoxybenzamide or pharmaceutically acceptable salts,
polymorphs, hydrates or solvates thereof.
In one embodiment, the present invention provides a novel process for the
preparation of Betrixaban formula (1) or pharmaceutically acceptable salts,
polymorphs, hydrates or solvates thereof, wherein the process comprises of
contacting the compound of formula 1e with compound of formula 1f under suitable
reaction conditions to yield compound of formula 1g and further subjecting the
compound 1g to cleave the amine protecting group to yield the free base, represented
by a compound of formula 1. The free base may be further treated with acids in suitable
solvents to form salts thereof.
In another embodiment, the present invention provides a process for preparing
the compound of formula 1e starting from contacting compound of formula 1b with
compound of formula 1c under suitable reaction conditions to form a compound of
formula 1d and further subjecting the compound of formula 1d to cleave the carboxyl
protecting group to form the compound of formula 1e.
Further in another embodiment, the present invention provides a process for
preparing a compound of formula 1c, wherein the process comprises protecting the
amine group of 4-amidinobenzoic acid under suitable reaction conditions with a
protecting group (PG) to yield the compound of formula 1c, wherein the protecting
group (PG) is an amine protecting group.
In an embodiment, the present invention provides a process for the preparation
of a compound of formula 1b, wherein the process comprises of protection of the
carboxyl group of compound of formula 1a, in the presence of various
inorganic/organic acid halides in suitable solvents to yield a compound of formula 1b
in improved quantities, wherein the protecting group (PG) is an ester function.
In another embodiment, the process of the present invention provides novel
compounds of formula 1d, 1e, and 1g useful as intermediates for the synthesis of
Betrixaban free base or salts thereof.
6
In another embodiment, the present invention provides a novel process for the
preparation of Betrixaban of formula (1) or pharmaceutically acceptable salts,
polymorphs, hydrates or solvates thereof, wherein the process comprises subjecting
the compound of formula 2f to amidine formation under suitable reaction conditions to
yield the free base, represented by a compound of formula 1. The free base may be
further treated with acids in suitable solvents to form salts thereof.
In another embodiment, the present invention provides a process for preparing
a compound of formula 2f, wherein the process comprises amidating compound of
formula 2e under suitable reaction conditions.
Further in another embodiment, the present invention provides a process for
preparing the compound of formula 2e starting from contacting compound of formula
1b with compound of formula 2a under suitable reaction conditions to form a
compound of formula 2b and further subjecting the compound of formula 2b to cleave
the carboxyl protecting group under suitable reaction conditions to form a compound
of formula 2c. Compound of formula 2c is then coupled with a compound of formula 1f
to form a compound of formula 2d, followed by oxidation to obtain a compound of
formula 2e.
In another embodiment, the process of the present invention provides novel
compounds of formula 2b, 2c, 2d, 2e, and 2f useful as intermediates for the synthesis
of Betrixaban free base or salts thereof.
In another embodiment, the intermediates from the processes of the present
invention may be formed as free acid/base or salts thereof.
In another embodiment, the novel processes of the present invention may be
optionally carried out in a single pot, without the isolation of the intermediates or salts
thereof. Alternatively, the intermediates or their salts formed may be isolated and used
in subsequent reactions.
A further embodiment of the present invention provides an improved and
industrially viable process for the preparation of stable crystalline Betrixaban or
alternative salts thereof as such, or by converting the crude compound to a stable
crystalline form by various techniques. The present invention also aims at the
preparation of stable crystalline complexes/solid dispersions with inactive substances
such as pharmaceutically acceptable carriers and pharmaceutically acceptable
polymers, having a suitable polymorphic and chemical stability when stored at higher
temperatures and humidity conditions.
7
The present inventors also provide an improved and industrially viable process
for preparing stable amorphous Betrixaban or amorphous salts thereof as such, or by
converting the crude compound to a stable amorphous form by various techniques.
Also, the present invention is aimed at preparing stable amorphous solid
dispersions/solutions thereof with pharmaceutically acceptable polymers, stable
amorphous complexes thereof with pharmaceutically acceptable carriers, having
suitable physical and chemical stability when stored at higher temperatures and
humidity conditions.
In an embodiment, the products obtained from the processes of the present
invention may be used for the preparation of medicaments useful as an anticoagulant
strategy in the treatment of thrombotic diseases and the prevention and/or treatment
of disease conditions associated with inhibition of Factor Xa.
Detailed Description of the Invention
The present invention is directed to provide industrially viable, novel processes
for the preparation of N-(5-Chloro-2-pyridinyl)-2-{[4-(N,N-dimethyl carbamimidoyl)
benzoyl]amino}-5-methoxybenzamide, i.e. Betrixaban (1), a Factor Xa inhibitor or
pharmaceutically acceptable salts thereof.
Definition of Terms
Unless defined otherwise, all technical and scientific terms used herein have
the same meaning as commonly understood by one of ordinary skill in the art. Although
any methods and materials similar or equivalent to those described herein can be used
in the practice or testing of the present invention, the preferred methods and materials
are described as below:
As used herein, the term "Betrixaban" refers to the chemical compound
represented by Formula 1:
O
NH
O
NH
O
NH
N
N
Cl
Formula 1
8
In some embodiments, Betrixaban is referred to as the "free base" meaning that
compound is able to accept one or more protons or donate one or more pairs of
electrons. In other words, the amine groups are unprotonated.
As used herein, the term "crude product" or "crude material" refers to the
product/material obtained from a process without or before the purification step and
may contain the desired product alone, or together with starting material, reagents,
solvents, byproducts from side reactions, moisture, and/or a variety of other impurities.
This crude material/ product may be wet or dry and obtained as a residue, oil, gummy
solid, solid cake, or used in-situ during the synthetic process.
As used herein, the term "contacting" refers to bringing two or more chemical
molecules to close proximity so that a reaction between the two or more chemical
molecules can occur. Contacting may be done by fully or partially dissolving or
suspending two or more chemicals in one or more solvents, mixing of a chemical in a
solvent with another chemical in solid and/or gas phase or being attached on a solid
support, such as a resin, or mixing two or more chemicals in gas or solid phase and/or
on a solid support, that are generally known to those skilled in the art.
As used herein, the term "reaction conditions" refers to the details under which
a chemical reaction proceeds. Examples of reaction conditions include, but are not
limited to, one or more of the following: reaction temperature, solvent, pH, pressure,
reaction time, mole ratio of reactants, the presence of a base or acid, or catalyst, etc.
Reaction conditions may be named after the particular chemical reaction in which the
conditions are employed, such as, coupling conditions, carboxyl group protecting
conditions, amine group protecting conditions, deprotecting conditions, oxidation
conditions, amidation conditions, amidine formation conditions, salt forming
conditions, etc. Reaction conditions for known reactions are generally known to those
skilled in the art.
As used herein, the term "solvent" refers to a liquid that dissolves a solid, liquid,
or gaseous solute to form a solution. Common solvents are well known in the art and
include but are not limited to, water; saturated aliphatic hydrocarbons, such as
pentanes, hexanes, heptanes, and other light petroleum; aromatic hydrocarbons, such
as benzene, toluene, xylene, etc.; halogenated hydrocarbons, such as
dichloromethane (DCM), chloroform (CHCl3), carbon tetrachloride (CCl4), etc.;
aliphatic alcohols, such as methanol (CH3OH), ethanol (C2H5OH), propanol (C3H7OH),
etc.; ethers, such as diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran (THF),
9
dioxane, etc.; ketones, such as acetone, ethyl methyl ketone, etc.; esters, such as
methyl acetate (MeOAc), ethyl acetate (EtOAc), etc.; nitrogen-containing solvents,
such as dimethylacetamide (DMA), formamide, N,N-dimethylformamide (DMF),
acetonitrile, pyridine, N-methylpyrrolidone (NMP), quinoline, nitrobenzene, etc.; sulfurcontaining
solvents, such as carbon disulfide, dimethyl sulfoxide, sulfolane, etc.;
phosphorus-containing solvents, such as hexamethylphosphoric triamide, etc. The
term solvent includes a combination of two or more solvents unless clearly indicated
otherwise. A particular choice of a suitable solvent will depend on many factors,
including the nature of the solvent and the solute to be dissolved and the intended
purpose, for example, what chemical reactions will occur in the solution, and is
generally known in the art.
As used herein, the term "acid" is intended to refer to a chemical species that
can either donate a proton or accept a pair of electrons from another species.
Examples of acids include organic acids, such as carboxylic acids (e.g., maleic acid,
lactic acid, acetic acid, formic acid, citric acid, oxalic acid, uric acid, etc.);
organofluorines (e.g., Trifluoroacetic acid (TFA), Triflic acid) and sulfonic acids (e.g.,
methanesulfonic acid, p-toluenesulfonic acid); mineral acids (e.g. hydrochloric acid,
nitric acid, phosphoric acid, sulfuric acid, boric acid, hydrofluoric acid, hydrobromic
acid); and Lewis acids. The term "Lewis acid" used herein refers to an electron
deficient species that is capable of accepting a pair of electrons. Examples of Lewis
acids that can be used in the present invention are cations of metals and their
complexes, where such metals include magnesium, calcium, aluminum, zinc, titanium,
chromium, copper, boron, tin, mercury, iron, manganese, cadmium, gallium and
barium.
As used herein, the terms "reagents" or "reactant" generally refers to
substances or compounds that are added to a system in order to bring about a
chemical reaction or are added to see if a reaction occurs. The terms “reactant” and
“reagent” are often used interchangeably—however, a reactant is more specifically a
substance consumed in the course of a chemical reaction, introduced to cause a
desired transformation of an organic substance. Examples include the Collins reagent,
Fenton's reagent, and Grignard reagents. Reagents that may be used in the course of
reaction in the present invention include Thionyl chloride (SOCl2),
Trifluoromethanesulfonic anhydride (Tf2O), Phosphoryl chloride (POCl3), Phosphorus
10
trichloride (PCl3), Phosphorus pentachloride (PCl5), Phosphorus tribromide (PBr3) and
the likes.
As used herein, the term "base" generally refers to chemical compounds that
can accept hydrogen ions. The term "inorganic base" refers to an inorganic compound
that can act as a base. Examples of inorganic base include, but are not limited to,
sodium carbonate (Na2CO3), potassium hydroxide (KOH), barium hydroxide
(Ba(OH)2), cesium hydroxide (CsOH), sodium hydroxide (NaOH), calcium hydroxide
(Ca(OH)2), lithium hydroxide (LiOH), and magnesium hydroxide (Mg(OH)2). The term
"organic base" refers to an organic compound that can act as a base. Examples of
organic base include, but are not limited to, triethylamine, N-methylmorpholine (NMM),
diisopropylethylamine (DIPEA), pyridine and 4-dimethylaminopyridine (DMAP).
As used herein, the terms "oxidizing agent", "oxidizer" or "oxidant" generally
refers to any chemical compound that readily transfers oxygen atoms or a substance
that gains electrons in a redox chemical reaction. Permanganate compounds such as
potassium permanganate (KMnO4); Hexavalent chromium compounds such as
chromic and dichromic acids and chromium trioxide, pyridinium chlorochromate
(PCC), and chromate/dichromate compounds; Silver ion, Ag(I); Osmium tetroxide
(OsO4), etc. Preferably potassium permanganate (KMnO4) is used.
As used herein, the terms "salt formation conditions" or "salt forming conditions"
generally refers to conditions used to form a salt between, for example, a compound
having a basic group, such as Betrixaban with an organic or inorganic acid. Salt
forming conditions may include mixing the molecule having the basic group and the
acid in a solvent or a mixture of solvents for a period of time at a certain temperature,
which would be generally known to a person skilled in the art. Alternatively, the
compound can be passed over an ion exchange resin to form the desired salt or one
salt form of the product can be converted into another using the same general process.
The first salt can then be converted to a second salt such as a maleate salt. Salt
forming conditions may also be conditions where the acid is a by-product of a reaction
forming the compound whose salt is formed.
As used herein, the term "coupling conditions" generally refers to conditions
used in coupling reactions where two chemical entities are connected to form one
chemical entity via a coupling reagent. In some cases, a coupling reaction refers to
the reaction connecting a compound bearing a carboxylic acid group to a compound
bearing an amino group to form a compound having an amide bond, which may be
11
referred to as "amide coupling reaction". Coupling conditions generally include a
coupling reagent, such as an amide coupling reagent in an amide coupling reaction.
Common amide coupling reagents include, but are not limited to, isobutyl
chloroformate, carbonyldiimidazole (CDI), 2-chloro-4,6-dimethoxy-1,2,5-triazine
(CDMT), carbodiimides such as N-N'-dicyclohexylcarbodiimide (DCC), N,N'-diiso
propylcarbodiimide (DIC), and 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide or N-
(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC). The carbodiimides may be used
in conjunction with additives such as dimethylaminopyridine (DMAP) or 1-hydroxy
benzotriazole (HOBt). Amide coupling reagents also include aminium and
phosphonium based reagents, such as N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-
b]pyridine-1-ylmethylene]-N-meth-ylmethanaminium hexafluorophosphate N-oxide
(HATU), N-[(1H-benzotriazol-1-yl) (dimethylamino) methylene] - N-methyl
methanaminium hexafluorophosphate N-oxide (HBTU) and benzotriazol-1-yl-N-oxytris(
pyrrolidino)phosphonium hexafluorophosphate (PyBOP). Amide coupling
conditions may include a solvent such as dimethylformamide (DMF), tetrahydrofuran
(THF), dichloromethane (DCM), dimethylacetamide (DMA), ethyl acetate (EtOAc),
acetonitrile or mixtures thereof, and may also include an organic base such as
pyridine, triethylamine (TEA), diisopropylethylamine (DIEA), dimethylaminopyridine
(DMAP), N-methylmorpholine (NMM) or mixtures thereof. Coupling conditions may
include a temperature of between -10°C to room temperature.
As used herein, the terms “protecting group” or “PG” refers to a compound that
is used to mask a functionality during a process step in which it would otherwise react,
which is undesirable. The protecting group prevents the undesirable reaction at that
step, but may be subsequently removed to expose the original functionality. The
removal or “deprotection” or "deprotecting" occurs after the completion of the reaction
or reactions in which the functionality would interfere. Thus, when a sequence of
reagents is specified, as it is in the processes of the invention, the person of ordinary
skill can readily envision those groups that would be suitable as “protecting groups”.
Suitable groups for that purpose are discussed in standard textbooks in the field of
chemistry [See e.g. Protective Groups in Organic Synthesis by T. W. Greene and P.
G. M. Wuts, 2nd Edition; John Wiley & Sons, New York (1991)]. The carboxyl
protecting group (PG) may be selected from Alcohols, Alkyl esters (wherein the alkyl
may be branched or chain alkyls) such as Methyl esters, tert-Butyl esters; Aryl esters
(wherein the aryls may be unsubstituted or substituted aryls) such as Benzyl esters;
12
Esters of 2,6-disubstituted phenols (e.g. 2,6-dimethylphenol, 2,6-diisopropylphenol,
2,6-di-tert-butylphenol), Silyl esters; Orthoesters; Oxazoline; Pivaloyl esters, and the
like. Preferably the carboxyl protecting groups may be selected form methyl or ethyl
esters. The amine protecting group (PG) may be selected from Carbamates such as
9-Fluorenylmethyl carbamate, t-Butyl carbamate, Benzyl carbamate; Amides such as
Acetamide, Trifluoroacetamide, Tosylamide and the like. Preferably the amino
protecting groups may be selected from the group of tert-Butyl carbamates such as
Di-tert-butyl dicarbonate also known as Boc-anhydride.
As used herein, the term "pharmaceutically acceptable salt" or “salts” refers to
a salt of a compound that is derived from a variety of physiologically acceptable
organic and inorganic counter ions. Such counter ions are well known in the art and
include, by way of example sodium, potassium, calcium, magnesium, aluminum,
lithium and ammonium, for example tetraalkylammonium, and the like, when the
molecule contains an acidic functionality; and when the molecule contains a basic
functionality, salts of organic or inorganic acids, such as hydrochloride, sulfate,
phosphate, diphosphate, nitrate, hydrobromide, tartrate, mesylate, acetate, maleate,
malate, fumarate, tartrate, succinate, citrate, lactate, palmoate, salicylate, stearate,
methanesulfonate, p-toluenesulfonate, and oxalate, and the like. Suitable
pharmaceutically acceptable salts also include those listed in Remington's
Pharmaceutical Sciences, 17th Edition, pg. 1418 (1985) and P. Heinrich Stahl, Camille
G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection, and Use;
2002. Examples of acid addition salts include those formed from acids such as
hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic
acids, such as alginic, ascorbic, anthranilic, benzoic, camphorsulfonic, citric, embonic
(palmoic), ethanesulfonic, formic, fumaric, furoic, galacturonic, gentisic, gluconic,
glucuronic, glutamic, glycolic, isonicotinic, isothionic, lactic, malic, mandelic,
methanesulfonic, mucic, pantothenic, phenylacetic, propionic, saccharic, salicylic,
stearic, succinic, sulfinilic, trifluoroacetic and arylsulfonic for example benzenesulfonic
and p-toluenesulfonic acids. Salts having a non-physiologically acceptable anion or
cation are within the scope of the invention as useful intermediates for the preparation
of physiologically acceptable salts and/or for use in non-therapeutic, for example, in
vitro, situations.
As used herein, the term “alternate salts” unless otherwise specified refers salts
other than maleate salts.
13
As used herein, the term “solid forms” refers to amorphous and/or crystalline
solid dispersions/solutions of Betrixaban with pharmaceutically acceptable polymers,
amorphous and/or crystalline complexes of Betrixaban with pharmaceutically
acceptable carriers.
As used herein, the terms “solid dispersion” or “solid solution” means any solid
composition having at least two components, wherein one component is dispersed
homogeneously throughout the other component or components. For the purpose of
the present invention, the terms “solid dispersion” and “solid solution” are herein used
interchangeably. In certain embodiments, a solid dispersion as disclosed herein
includes Betrixaban dispersed among at least one other component, such as a
pharmaceutically acceptable polymer. The drug substance used may be crystalline or
amorphous in nature.
As used herein, the term “complex” refers to a composition comprising a drug
substance and a pharmaceutically acceptable carrier, the drug substance used maybe
crystalline or amorphous in nature.
As used herein, the term “pharmaceutically acceptable polymers” or
“polymer(s)” refers to the compounds used in methods such as solid dispersion
method to improve the stability/solubility of a drug. Suitable groups for the purpose
include water soluble and water insoluble polymers. Examples of water soluble
polymers include without limitation polyvinyl pyrrolidone (povidone), copovidone,
polyvinyl alcohol, hydroxypropyl methylcellulose (hypromellose), hydroxypropyl
cellulose, polyethylene glycol, polyvinyl caprolactam - polyvinyl acetate - polyethylene
glycol copolymers (Soluplus™), and the like. Examples of water insoluble polymers
include methylcellulose, ethylcellulose, polymethacrylates, hypromellose phthalate,
hypromellose succinate, hypromellose acetate succinate (HPMC AS), cellulose
acetate phthalate, carboxymethyl ethyl cellulose, and the like. In preferred
embodiments of the invention, a water soluble polymer is used for preparing solid
dispersions of Betrixaban.
As used herein, the term “pharmaceutically acceptable carriers” refers to the
compounds used to improve the solubility and stability of a drug. Suitable
pharmaceutically acceptable carriers may include without limitation cyclodextrins or
derivatives thereof such as an a-cyclodextrin, a ß-cyclodextrin, a ?-cyclodextrin or a
modified cyclodextrin such as sulfobutyl ether beta-cyclodextrin; saccharides,
oligosaccharides, polysaccharides; amino acids, fats, waxes, urea etc.
14
As used herein, the term “stable” refers to Betrixaban as an amorphous form or
a crystalline form, as solid dispersions thereof and complexes thereof; that does not
convert to any other solid form when stored at accelerated and long term storage
conditions for a period of at least 3 months or more, having a purity of about 99% or
more.
As used herein, the term "obtainable" means that a composition of matter can
be obtained by a particular method recited or obtained by other method(s) not recited.
As used herein, the term “medicament” refers to a pharmaceutical composition
containing the compounds prepared by the present invention, wherein the
pharmaceutical composition may be used for human or non-human therapy of various
diseases or disorders in a therapeutically effective dose.
According to the present invention, the industrially viable processes yields a
stable amorphous Betrixaban as such or by converting the crude compound
obtainable from the said process to a stable amorphous form by techniques known in
the art.
The present invention also provides stable amorphous solid
dispersions/solutions of Betrixaban with pharmaceutically acceptable polymers, stable
amorphous complexes of Betrixaban with pharmaceutically acceptable carriers,
having a suitable physical and chemical stability profile when stored at higher
temperature and relative humidity conditions.
Alternatively according to the present invention, the process yields a stable
crystalline form of Betrixaban as such or by converting the crude compound obtainable
from the said process to a stable crystalline form by techniques known in the art; the
stable crystalline from may be used to form solid dispersions of Betrixaban with
pharmaceutically acceptable polymers, stable complexes of Betrixaban with
pharmaceutically acceptable carriers to yield a suitable polymorphic and chemical
stability profile when stored at higher temperature and relative humidity conditions.
In one embodiment, the novel process of the present invention is described in
Scheme 1.
In the preferred embodiments of the present invention, novel process for the
preparation of Betrixaban or pharmaceutically acceptable salts, polymorphs, hydrates
or solvates thereof, comprises of condensing a compound of formula 1e with
compound of formula 1f in the presence of a coupling reagent such as DCC, a suitable
base such as DMAP and suitable solvents such as DCM or ethyl acetate, yields a
15
compound of formula 1g and with further deprotection by cleaving of the amine
protecting group to give Betrixaban formula (1) as a free base. Where the free base
may further be treated with an acid in suitable solvent to form a salt thereof.
O
O
OH
NH
O
N
O
O
NH
O R
O
N
N N
Deprotection
1d
1e
Scheme 1
1c
O
HO N
N
Boc
Boc Boc
O
O
NH2
O R
1b
.HCl
R: Me, Et
1f
N
H2N Cl
O
HN
O
NH
O
N
N
N
Cl
Boc
O
HN
O
NH
O
N
NH
N
Cl
1g 1
Deprotection
An embodiment of the present invention provides a novel process for the
preparation of a compound of formula 1e, wherein the process comprises first
synthesizing a novel compound of formula 1d in high yield, by contacting compound
of formula 1b with compound of formula 1c in the presence of a suitable amide
coupling reagent such as DCC, a suitable solvent such as DCM or ethyl acetate and
suitable bases such as NMM and DMAP. Further subjecting the compound 1d to
deprotection by cleaving the carboxyl protecting group in the presence of a suitable
strong base such as KOH and a suitable alcohol such as methanol/ ethanol to yield
compound of formula 1e.
An embodiment of the present invention provides a process for the preparation
of a compound of formula 1c, wherein the process comprises protection of the amine
group of 4-amidino benzoic acid in the presence of an amine protecting group (PG)
such as Boc-anhydride, a solvent such as THF and a suitable base such as anhydrous
pyridine, to yield compound of formula 1c in higher yields.
16
O
HO NH
N
1c
O
HO N
N
Boc
O
HO
N
HN
EtOH.HCl
4-cyanobenzoic acid 4-amidinobenzoic acid
Protection
In another embodiment, the present invention provides a process for the
preparation of a compound of formula 1b, wherein the process comprises of protection
of the carboxyl group of compound of formula 1a by the formation of esters in the
presence of alcohols, a suitable reagent such as SOCl2 and a suitable solvent such
as toluene to yield a compound of formula 1b in improved quantities.
O
OH
NH2
O
O
O
NH2
O R
1a
1b
.HCl
Protection
In an embodiment, the process of the present invention as described in Scheme
1 provides the novel compounds of formula 1d, 1e, and 1g useful as intermediates for
synthesis of Betrixaban or salts thereof. The intermediates in Scheme 1 may be
isolated or used in-situ, as free acid/base or salts thereof.
In another embodiment, the present invention provides an alternative novel
process as described in Scheme 2.
O
O
NH2
O
N
H2N Cl
O
HN
O
NH
O
N
Cl
O
HO
O
O
O
NH
O
R
R
O
O
OH
NH
O
O
HN
O
NH
O
N
Cl
Oxidation
OH
O
1b
2a
2b 2c
2d 2e
Scheme 2
.HCl
1f Amide Formation
Deprotection
.HCl
17
O
HN
O
NH
O
N
Cl
N
O
O
HN
O
NH
O
N
Cl
N
NH
Amidine formation
2f 1
.HCl
In one embodiment, the present invention provides a novel process for the
preparation of Betrixaban or pharmaceutically acceptable salts, polymorphs, hydrates
or solvates thereof, wherein the process comprises subjecting the compound of
formula 2f to amidine formation under reaction conditions that is in the presence of a
base such as pyridine and a reagent such as Tf2O to yield the free base of Betrixaban,
represented by a compound of formula 1. The free base may be further treated with
an acid in suitable solvent to form a salt thereof.
In another embodiment, the present invention provides a process for preparing
a compound of formula 2f, wherein the process comprises formation of amide of
formula 2e, in the presence of dimethylamine, a suitable reagent such as SOCl2 and
suitable solvent such as DCM.
Further in another embodiment, the present invention provides a process for
preparing the compound of formula 2e starting from reacting compound of formula 1b
with compound of formula 2a in presence of suitable base such as DMAP and NMM,
a suitable solvent such as DCM and a coupling reagent such as DCC to form a
compound of formula 2b, wherein the carboxyl protecting group (PG) is an ester and
R denotes alkyl groups such as methyl or ethyl. The carboxyl protecting group is not
limited to alkyl group and can be extended to the branched/chained alkanes and
substituted/ simple aryls. Further the compound of formula 2b was subjected to
deprotection by cleaving the carboxyl protecting group in the presence of a suitable
strong base such as KOH and a suitable alcohol such as methanol/ ethanol to yield a
compound of formula 2c. Compound of formula 2c further undergoes condensation
with compound of formula 1f in the presence of a suitable base such as DMAP, a
suitable solvent DCM and a suitable coupling reagent such as DCC to form a
compound of formula 2d. Finally the compound of formula 2d is subjected to oxidation
in the presence of an oxidizing agent such as KMnO4 to obtain a compound 2e in a
highly pure and improved yield.
18
In an embodiment, the process of the present invention as described in Scheme
2 provides the novel compounds of formula 2b, 2c, 2d, 2e and 2f useful as
intermediates for synthesis of Betrixaban or salts thereof. The intermediates in
Scheme 2 may be isolated or used in-situ, as free acid/base or salts thereof.
In another embodiment, the novel processes of the present invention yield
Betrixaban free base or salts thereof, as crude compound which may be further
purified to yield crystalline or amorphous compounds.
In certain embodiments, the process of the present invention provides stable
crystalline Betrixaban or salts thereof, by dissolving the crude product of Betrixaban
or salts thereof in a solvent or mixture of solvents at increased temperature; or by the
process of recrystallization known in the art.
In one embodiment, the crude compound obtained from the improved process
of the present invention may also be purified by dissolution in one or more solvents,
followed by addition of an anti-solvent to form a precipitate, evaporating the solvent by
techniques known in the art to yield an amorphous compound.
In some embodiments, the process of the present invention provides
amorphous Betrixaban, characterized by a purity of 99% or more, substantially free of
any other crystalline form when stored at accelerated and long term storage conditions
for a period of at least 3 months or more.
In certain embodiments, the present invention provides amorphous solid
dispersions which may be prepared by dissolving Betrixaban or salts thereof and a
pharmaceutically acceptable polymer either individually or together in one or more
organic solvent selected from alcohols, esters, ethers, ketones, nitriles, halogenated
hydrocarbons, aromatic hydrocarbons, aliphatic hydrocarbons, amides, nitroalkanes
and the like to form a solution or suspension and further removal of solvent(s) by
techniques known in the art. The starting material for amorphous solid dispersions
may be a crystalline or amorphous compound. Likewise, the crystalline solid
dispersions of Betrixaban or salts thereof may be prepared.
In one preferred embodiment, the amorphous solid dispersion may be prepared
by dissolving Betrixaban and polymer in suitable solvent, followed by stirring to form a
solution, optionally heating if a suspension is formed to obtain a clear solution;
removing the solvent by distillation under reduced pressure to give a residue, which
may be further dried to yield a stable amorphous dispersion of Betrixaban.
19
In another preferred embodiment, the amorphous solid dispersion may be
prepared by dissolving salt forms of Betrixaban and polymer in suitable solvent,
followed by stirring to form a solution, optionally heating if a suspension is formed to
obtain a clear solution; removing the solvent by distillation under reduced pressure to
give a residue, which may be further dried to yield amorphous dispersions of various
salts of Betrixaban.
Optionally the amorphous solid dispersion comprising Betrixaban or salts
thereof and pharmaceutically acceptable polymer may be prepared by homogenous
mixing of Betrixaban or the individual salts thereof with the latter, following by heating
to form a melt. The melt is subsequently cooled down, which produces an amorphous
solid substance. Methods employed for preparing the melt may be selected from hot
melt extrusion, hot melt granulation, high shear mixer, solvent-free fluid bed
granulation, etc.
In an embodiment, the solvent(s) may be removed by techniques known in the
art such as evaporation, distillation, spray drying, filtration, lyophilization, by using an
agitated thin film drier (ATFD) to yield an amorphous substance.
In another embodiment, the amorphous solid dispersions prepared according
to the present invention are characterized by a purity of about 99% or more; remain
stable for a period of at least 3 months or more when stored at accelerated and long
term storage conditions.
In yet another embodiment, the novel process of the present invention provides
stable amorphous complexes of Betrixaban with pharmaceutically acceptable carriers,
characterized by a purity of about 99% or more, when stored at accelerated and long
term storage conditions for a period of at least 3 months or more.
Further the process for preparing Betrixaban and intermediates thereof
according to the present invention are illustrated in the following examples. The
following specific and non-limiting examples are to be construed as merely illustrative,
and do not limit the present disclosure in any way whatsoever.
Experimental Examples:
Example 1: Preparation of Compound 1b: To a solution of compound of formula 1a
(60 mmol) in methanol (5 mL) was added SOCl2 (180 mmol) at room temperature for
30 min. The temperature was increased to 50°C. The reaction mass was refluxed for
5 h and cooled to room temperature. The volatiles were distilled off under vacuum
20
completely. Toluene (10 mL) was added to dilute the residue and the solvent was
distilled off completely under vacuum to yield the pure compound of formula 1b as an
off white solid.
Example 2: Preparation of Compound 1c: To a solution of 4-cynobenzoic acid (10
mmol) in ethanol (50 mL), a mixture of anhydrous ethanolic hydrochloride (5 mL) was
added and stirred at room temperature overnight. On completion of the reaction the
solvent was evaporated to dryness to yield a residue, which was dissolved in
anhydrous ethanol (50 mL), followed by addition of dimethylamine (12 mmol). The
resulting mixture was refluxed for 1 h, cooled to room temperature and concentrated
under vacuum. The reaction mass was diluted with DCM (50 mL) and washed with
10% NaHCO3 solution. The resulting reaction mixture was dried and concentrated
under vacuum to yield 4-amidino benzoic acid. A solution of 4-amidino benzoic acid
(10 mmol) in THF (50 mL) was taken and a suspension of di-tert-butyl dicarbonate (11
mmol) and anhydrous pyridine (12 mmol) in THF (50 mL) was added, stirred for 4 h at
room temperature and monitored by TLC. The resultant reaction mixture was
concentrated and diluted with DCM (50 mL) washed with brine, dried and evaporated
to give the intermediate compound of formula 1c.
Process according to Scheme 1:
Example 3: Preparation of Betrixaban (1): To a solution of compound of formula 1e
(10 mmol) in DCM (50 mL), a mixture of compound of formula 1f (10 mmol), DCC (11
mmol), DMAP (11 mmol) in DCM (50 mL) was added at 0°C and stirred at room
temperature for a period of 4 h. The resultant product was further diluted with DCM
(100 mL) and the precipitate was filtered off. To the resultant filtrate (compound of
formula 1g) a solution of TFA (30 mmol) in DCM (50mL) was added and stirred at
room temperature for 2 h. The volatiles were distilled off under vacuum and the
resulting product was recrystallized from ethanol to yield the pure compound of
formula 1.
Example 4: Synthesis of Compound 1e: To a solution of compound of formula 1d (10
mmol) in methanol (25 mL), a solution of NaOH (11 mmol) in methanol (25 mL) was
slowly added dropwise to the above system over a period of 10 min, and reacted at
room temperature over a period of 2 h. The reaction was further stirred for 1 h then
quenched by addition of water (50 mL). To the resultant mixture washed with
ethylacetate (30 mL) and the aqueous layer was collected. The aqueous solution pH
was adjusted to 5 with 10% HCl and the product was extracted with DCM (50 mL) as
21
a free acid. The resulting product was dried over anhydrous MgSO4, evaporated and
recrystallized from ethanol to yield the pure compound of formula 1e.
Example 5: Synthesis of Compound 1d: To the solution of compound of formula 1b
(10 mmol) and NMM (11 mmol) in DCM (50 mL), a mixture of compound of formula 1c
(10 mmol), DCC (11 mmol), DMAP (11 mmol) in DCM (50 mL) was added at 0°C and
stirred at room temperature for a period of 4 h. The resultant product was further
diluted in DCM (100 mL) and the precipitate was filtered off. The filtrate was collected
and dried to remove the solvent under pressure by rotary evaporator to yield the
product, compound of formula 1d.
Process according to Scheme 2:
Example 6: Synthesis of Compound 1: To a solution of compound of formula 2f (10
mmol) and pyridine (30 mmol) in anhydrous DCM (50 mL) at -40°C a mixture of Tf2O
(10 mmol) was slowly added. The mixture was allowed to stir at 0°C to room
temperature for 2.5 h. The resultant solution was then cooled to -40°C and a mixture
of methanolic ammonia (50 mmol) was added in one portion. The reaction was then
warmed to room temperature and stirred for 20 h. The completion of the reaction was
monitored by TLC and on completion the mixture was evaporated to dryness under
vacuum and washed with a small volume of water and saturated aqueous NaHCO3.
The organic layer was separated and diluted with DCM and the aqueous layer was
washed with DCM (3*50 mL). The combined organic layers were dried over Na2SO4
and concentrated under reduced pressure to yield a crude product of compound of
formula 1 (Betrixaban) as free base.
Example 7: Synthesis of Compound 2f: To a solution of compound of formula 2e (10
mmol), dimethylamine (30 mmol) and TEA (30 mmol) in DCM (50 mL), a mixture of
SOCl2 (30 mmol) in DCM (50mL) was added dropwise over a period of 10 min and
further stirred for 1 h at room temperature. The reaction mixture was monitored by
TLC. On completion the solvent and traces of unreacted SOCl2 were removed by
evaporation under reduced pressure. The resulting residue was dissolved in DCM and
washed first with 5% aqueous NaHSO4 and then with 1N NaOH. The organic phase
was dried over anhydrous Na2SO4, evaporated on a rotary evaporator and the solvent
is removed to yield compound of formula 2f.
Example 8: Synthesis of Compound 2e: To a solution of compound of formula 2d (10
mmol) in methanol (50 mL), a mixture of KMnO4 (10 mmol), NaOH (75 mmol) in
methanol (50 mL) was added and stirred at room temperature for 12 h. After the
22
completion of the reaction, the reaction mass pH was adjusted to 5-6 with 10% HCl
and resultant product was extracted with DCM (100 mL), dried over anhydrous
Na2SO4, and solvent evaporated under pressure in a rotary evaporator to yield the
compound of formula 2e.
Example 9: Synthesis of Compound 2d: To a solution of compound of formula 2c (10
mmol) in DCM (50 mL), a mixture of compound of formula 1f (10 mmol), DCC (10
mmol), DMAP (10 mmol) in DCM (50 mL) was added at 0°C and stirred at room
temperature for a period of 4 h. The resultant product was further diluted with DCM
(100 mL) and the precipitate was filtered off. The filtrate was collected and dried to
remove the solvent under pressure by rotary evaporator to yield the product,
compound of formula 2d.
Example 10: Synthesis of Compound 2c: To a solution of compound of formula 1b
(10 mmol) and NMM (10 mmol) in DCM (50 mL), a mixture of compound of formula 2a
(10 mmol), DCC (10 mmol), DMAP (10 mmol) in DCM (50 mL) was added at 0°C and
stirred at room temperature for a period of 4 h. The resultant product was further
diluted with DCM (100 mL) and the precipitate was filtered off. The filtrate was
collected and dried to remove the solvent under pressure by rotary evaporator to yield
the product, compound of formula 2b. A solution of compound of formula 2b (10 mmol)
in methanol (25 mL), a solution of NaOH (0.5 g) in methanol (25 mL) was slowly added
dropwise to the above system over a period of 10 min, and reacted at room
temperature over a period of 2 h. The reaction was further stirred for 1 h, then
quenched by addition of water (50 mL). To the resultant mixture, ethylacetate (30 mL)
was added and the aqueous layer was separated. The aqueous solution was acidified
with 10% HCl and the product was extracted with DCM (50 mL) as a free acid. The
resulting product was dried over anhydrous MgSO4, evaporated and recrystallized
from ethanol to yield the pure compound of formula 2c.
Example 11: Preparation of Betrixaban Salt: The wet Betrixaban obtained above was
reacted with an acid (1:1 weight of acid/weight of dry Betrixaban) in solvent and
purified water to form a Betrixaban salt. The solution of the Betrixaban salt was filtered
and concentrated under vacuum. The suspension was cooled to 20°C temperature
and the Betrixaban salt was isolated by filtration, washed with water and dried under
vacuum at a maximum temperature of 40°C.
Although the foregoing invention has been described in some detail by way of
illustration and example for purposes of clarity of understanding, a person skilled in
23
the art will appreciate that certain changes and modifications may be practiced within
the scope of the invention described.
Without being limited by theory, the processes according to the present
invention may be advantageously used to prepare the complex compounds like
Betrixaban. The proposed routes of the drug described in schemes 1 and 2 are such
that it prevents the disadvantages of the prior art. It is envisaged that by providing the
alternative routes of synthesis of compounds or related compounds or intermediates
of the present invention, the shelf life or stability of the product is enhanced and the
impurity content of the product is decreased or rather controlled during the preparation
of intermediates, thereby contributing to the overall efficacy of the product.
The proposed processes according to schemes 1 and 2 of the present invention
are convenient to use by the end users and eliminates impurities shoot out.
Furthermore, the proposed routes of the present invention for the preparation of
Betrixaban reduces the medication cost due to reduction of steps in final preparation
of compound of formula 1, is economic for the end user, reduces drug waste,
minimizes hospital and industrial waste and eliminates risk of toxicity by producing in
higher purity of compounds.
From the foregoing it will be understood that the embodiments of the present
invention described above are well suited to provide the advantages set forth, and
since many possible embodiments may be made of the various features of this
invention, all without departing from the scope of the invention, it is to be understood
that all matter hereinbefore set forth or shown in the description and synthetic schemes
is to be interpreted as illustrative and that in certain instances some of the features
may be used without a corresponding use of other features, all without departing from
the scope of the invention. ,CLAIMS:We Claim,
1. A process for preparing N-(5-Chloro-2-pyridinyl)-2-{[4-(N,N-dimethyl
carbamimidoyl)benzoyl]amino}-5-methoxybenzamide i.e., Betrixaban, salts,
polymorphs, hydrates or solvates thereof, comprising:
(a) Contacting a compound of formula 1b with a compound of formula 1c under
reaction conditions to form compound 1d;
O
O
NH
O R
O
N
N
1d
1c
O
HO N
N
Boc
Boc
O
O
NH2
O R
1b
.HCl
Wherein R is an alkyl group selected from methyl, ethyl,
(b) Subjecting compound 1d to deprotection under reaction conditions to form
compound 1e;
O
O
OH
NH
O
N
O
O
NH
O R
O
N
N N
Deprotection
1d Boc 1e Boc
(c) Condensing compound 1e with a compound of formula 1f under reaction conditions
to form compound 1g;
O
O
OH
NH
O
N
N
1e
Boc
1f
N
H2N Cl
O
HN
O
NH
O
N
N
N
Cl
1g Boc
(d) Deprotecting the compound of formula 1g under reaction conditions to form
Betrixaban (1) or salts thereof.
25
O
HN
O
NH
O
N
N
N
Cl
Boc
O
HN
O
NH
O
N
NH
N
Cl
1g 1
Deprotection
2. A process as claimed in claim 1, wherein the reaction conditions comprise use of
a coupling reagent selected from isobutyl chloroformate, carbonyl diimidazole, 2-
chloro-4,6-dimethoxy-1,2,5-triazine, carbodiimides such as N-N'-dicyclohexyl
carbodiimide, N,N'-diisopropyl carbodiimide, and N-(3-dimethylamino propyl)-N'-
ethylcarbodiimide; an organic base selected from pyridine, triethylamine,
diisopropylethylamine, dimethylaminopyridine, N-methylmorpholine or mixtures
thereof;
deprotection of compound 1d comprises use of a base selected from sodium
carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium
hydroxide and the like; deprotection of compound 1g comprises use of an acid
selected from hydrochloric acid, phosphoric acid, sulfuric acid, trifluoroacetic acid,
sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid; and
solvent selected from dichloromethane, methanol, ethanol, propanol,
tetrahydrofuran, toluene, ethyl acetate, dimethylformamide, dimethylacetamide,
ethyl acetate, acetonitrile or mixtures thereof.
3. A process for preparing N-(5-Chloro-2-pyridinyl)-2-{[4-(N,N-dimethyl
carbamimidoyl)benzoyl]amino}-5-methoxybenzamide i.e., Betrixaban, salts,
polymorphs, hydrates or solvates thereof, comprising:
(a) Treating compound of formula 2e with dimethylamine under reaction conditions to
form compound of formula 2f;
26
O
HN
O
NH
O
N
Cl
OH
2e O
.HCl
O
HN
O
NH
O
N
Cl
N
2f O
.HCl
(b) Subjecting compound 2f to amidine formation under reaction conditions to form
Betrixaban (1) or salts thereof.
O
HN
O
NH
O
N
Cl
N
2f O
.HCl
O
HN
O
NH
O
N
Cl
N
NH
1
4. A process as claimed in claim 3, wherein the reaction conditions comprise use of
an organic base selected from triethylamine, N-methylmorpholine, diisopropyl
ethylamine, pyridine and 4-dimethylaminopyridine; reagent selected from thionyl
chloride, trifluoromethanesulfonic anhydride; and solvent selected from
dichloromethane, methanol, ethanol, propanol, tetrahydrofuran, toluene, ethyl
acetate, dimethylformamide, dimethylacetamide, ethyl acetate, acetonitrile or
mixtures thereof.
5. A process for preparation of a compound of formula 2e comprising:
(a) Reacting compound of formula 1b with a compound 2a under reaction conditions
to form compound 2b;
O
O
NH2
O
O
HO
O
O
O
NH
O
R
R
1b
2a
2b
.HCl
Wherein R is an alkyl group selected from methyl, ethyl,
27
(b) Subjecting compound 2b to deprotection under reaction conditions to form
compound 2c;
O
O
O
NH
O R
2b
O
O
OH
NH
O
2c
Deprotection
(c) Condensing compound 2c with a compound of formula 1f under reaction conditions
to form compound 2d;
O
O
OH
NH
O
2c
N
H2N Cl
O
HN
O
NH
O
N
Cl
2d
1f
(d) Subjecting compound 2e to oxidation to form compound 2e.
O
HN
O
NH
O
N
Cl
2d
O
HN
O
NH
O
N
Cl
Oxidation
OH
O
2e
.HCl
6. A process as claimed in claim 5, wherein the reaction conditions comprise use of
a coupling reagent selected from isobutylchloroformate, carbonyldiimidazole, 2-
chloro-4,6-dimethoxy-1,2,5-triazine, carbodiimides such as N-N'-dicyclohexyl
carbodiimide, N,N'-diisopropyl carbodiimide, and N-(3-dimethylamino propyl)-N'-
ethylcarbodiimide; an organic base selected from pyridine, triethylamine,
diisopropylethylamine, dimethylaminopyridine, N-methylmorpholine or mixtures
thereof;
deprotection of compound 2b comprises use of a base selected from sodium
carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium
hydroxide and the like;
28
oxidation of compound 2d comprises use of an oxidizing agent selected from
permanganate compounds such as potassium permanganate; hexavalent
chromium compounds such as chromic and dichromic acids and chromium
trioxide, pyridinium chlorochromate, and chromate/dichromate compounds; silver
ion, osmium tetroxide; and
solvent selected from dichloromethane, methanol, ethanol, propanol,
tetrahydrofuran, toluene, ethyl acetate, dimethylformamide, dimethylacetamide,
ethyl acetate, acetonitrile or mixtures thereof.
7. Compounds of formulae 1d, 1e, 1g, 2b, 2c, 2d, 2e and 2f useful as intermediates
for preparing Betrixaban, salts, polymorphs, hydrates or solvates thereof,
O
O
OH
NH
O
N
O
O
NH
O R
O
N
N N
1d 1e
Boc Boc
O
HN
O
NH
O
N
N
N
Cl
1g Boc
O
HN
O
NH
O
N
Cl
2d
O
O
O
NH
O R
O
O
OH
NH
O
2b
2c
O
HN
O
NH
O
N
Cl
N
O
2f
.HCl
O
HN
O
NH
O
N
Cl
OH
2e O
.HCl