FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of
compound of formula I,
Formula I
wherein, R1 and R2 are each independently hydroxy, alkoxy, aryloxy, or
aralkoxy; or R1 and R2 together form a moiety derived from an alphahydroxy
carboxylic acid compound or a beta..,hydroxy carboxylic acid
compound, wherein the atom attached to boron in each case is an oxygen
atom; or R1 and R2 together form the boronate esters ofboronic acid
More particularly, the present process relates to preparation of lxazomib citrate of
compound of formula Ia,
Formula Ia
the process comprises the use of diimidazole or ditriazole based coupling reagent
for amide and peptide bond formation. The present process is more economical
and less time consuming than processes described in the literature due to easier
isolation of intermediates and Ixazomib of compound of formula,
2
Ixazomib
The present invention also relates to preparation and isolation of an amorphous
form of Ixazomib citrate of formula Ia.
BACKGROUND OF THE INVENTION
Ixazomib citrate is boronic ester compound and marketed as Ninlaro®, it
structurally known as compound of formula Ia,
Formula Ia
The Ixazomib citrate is an antineoplastic agent and works as pro drug. After oral
administration it rapidly hydrolyzes to its biologically active form, Ixazomib of
formula,
Ixazomib
The ixazomib citrate is R-stereoisomer and chemically known as 1,3,2-
dioxaborolane-4,4-diacetic acid, 2-[(lR)-1-[[2-
[(2,5dichlorobenzoyl)amino ]acetyl]amino ]-3-methylbutyl]-5-oxo. It is indicated
3
in combination with lenalidomide and dexamethasone for the treatment of patients
having multiple myeloma and who have received at least one prior therapy.
The boronic ester compounds particularly the Ixazomib citrate as represented by
formula Ia is disclosed in W02009/154737A1 (hereinafter referred as W0'737).
The synthetic scheme described in W02009/154 73 7 A 1 is depicted below as
scheme -1:
~CI THF
.; CH3
H ~ CH3
~~~ ..
Cl 0 0 . Cl 0
~ NH~ y iBuB(OH)2, I ~ NH~ ~ 3
I .--:;::. 0 y cH3 Strirred overnight .--:;::. 0 y CHa
Cl ~H, I CH3
3 Boroxine Derivative
Citric Acid, EtOAc •
Scheme -1
In first step, the amide bond is formed by reacting 2,5-dichlorobenzoyl chloride
with glycine under basic environment at 0±1 °C. The preparation of 2,5-
dichlorobenzoyl chloride is not disclosed in W0'737 however commonly known
reagents like thionyl chloride or oxalyl choride are extensively used in industry
for the formation of acid chloride from their acid precursors. The reagents like
4
thionyl chloride or oxalyl choride are hazardous and not advisable at large scale
production.
In second step, the peptide bond IS formed by reacting 2,5-
[(dichlorobenzoyl)amino]acetic acid with trifluoroacetic acid salt of (lR)-3-
methyl-1-[(3aS,4S,6S, 7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1 ,3,2-
benodioxaborol-2-yl]butan-1-amine in presence of coupling reagent 0-
(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) and
diisopropylethylamine (DIPEA) base in dimethylformamide. After completion of
the reaction the mixture is diluted with ethyl acetate then washed multiple times,
with sodium chloride, potassium carbonate and phosphoric acid.
The resulting organic layer is concentrated to a thick oil, diluted with heptane and
evaporated to yield 2,5-dichloro-N -[2-( { (1 R)-3-methyl-1-[ (3aS,4S,6S, 7 aR)-
3a,5,5- trimethylhexahydro-4,6-methano-1 ,3,2-benzodioxaborol-2-
yl]butyl}amino)-2-oxoethyl]benzamide. The obtained benzamide compound is
further dissolved in methanol/hexane mixture and stirred overnight in presence of
(2-methylpropyl)boronic acid ((iBuB(OH)z) to form Ixazomib (a free boronic acid
derivative) or its boroxine derivative. The isolation of these derivatives requires
long acid-base processing of the reaction mixture, which is tedious and time
consuming.
The isolated Ixazomib or its boroxine derivative is further reacted with citric acid
in ethyl acetate (EtOAc) to form Ixazomib citrate, which is isolated in two
different crystalline forms I and II by controlling the process of cooling of the
reaction mixture.
Th~ process disclosed in W0'737 suffers from following disadvantages;
1) The 2,5-dichlorobenzoyl chloride is liquid above 30°C, which is difficult to
handle at large scale production.
2) The reaction of 2,5-dichlorobenzoyl chloride with glycine is performed at
0± 1 °C, which is tedious to maintain at large scale production.
5
3) The u'se of coupling reagent such as 0-(Benzotriazol-1-yl)-N,N,N',N'tetramethyluronium
tetrafluoroborate (TBTU) during the peptide bond
formation is not advisable, the TBTU and its by-products such as
hydroxybenzotriazole (HOBt) are not water soluble. Hence removal of these
from the reaction mixture requires very long and tedious processing steps
like multiple washings with sodium chloride, potassium carbonate and
phosphoric acid, which is time consuming and equally not economical.
4) The use of costly reagents such as (2-methylpropyl)boronic acid
((iBuB(OH)2) for the hydrolysis to form Ixazomib is also not advisable. The
use of (2-methylpropyl)boronic acid requires long acid-base treatment of the
reaction mixture before the isolation of Ixazomib.
W02016/165677Al (hereinafter referred as W0'677) discloses an amorphous
form of Ixazomib citrate characterized by an X-ray pattern and glass transition
temperature Tg=104.1 °C. The W0'677 further discloses the process of
preparation of amorphous form of Ixazomib citrate by lyophilisation of a freezedried
solution.
The process disclosed m W0'677 involves the use of special instrument for
lyophilisation of the freeze-dried solution, which is difficult to use and not viable
at industrial scale production.
As evident from the above discussion the disclosed processes of W0'737 and
W0'677 suffer from many disadvantages hence there is a need to develop an
improved process for the preparation of boronic ester compound such as Ixazomib
citrate and its amorphous form.
The inventors of the present application have developed a process which involves
a diimidazole or ditriazole based coupling reagent for the formation of amide and
peptide bonds to prepare Ixazomib citrate of compound of formula Ia. The use of
6
a diimidazole or ditriazole based coupling reagent is advantageous, which devoid
the use of hazardous reagent, use of low temperature condition and reduces the
long processing time of the reaction mixture for the isolation of intermediates and
Ixazomib.
Further, the process of present invention is cleaner, more economical, less time
consuming and does not require any special instrument as compared to processes
described in the literature.
SUMMARY OF THE INVENTION
In a first aspect, the present invention relates to an improved process for the
preparation of compound of formula I,
Cl 0 R
1
~NHnNHYJ"R2 y o ycH3
Cl CH3
Formula I
wherein, R1 and R2 are each independently hydroxy, alkoxy, aryloxy, or
aralkoxy; orR 1 and R2 together form a moiety derived from an alpha-hydroxy
carboxylic acid compound or a beta-hydroxy carboxylic acid compound,
wherein the atom attached to boron in each case is an oxygen atom; or R 1 and
R2 together form the boronate esters ofboronic acid
comprising the steps of:
a) reacting a compound of formula Ila,
Cl 0
~ Cl
Formula Ila
wherein, X is imidazole or triazole
with glycine in suitable solvent to obtain a compound of formula III,
7
Cl 0
¢[('("
Cl
Formula III
b) optionally, converting the compound of formula III to a compound of
formula Ilia,
Formula Ilia
wherein, X is imidazole or triazole
c) reacting the compound of formula III or formula Ilia with a compound of
formula IV or its salt in suitable solvent,
Formula IV
wherein, R 1 and R 2 are same as defined for the compound of formula I
to obtain the compound of formula I.
Another aspect of the present invention relates to an improved process for the
preparation of compound of formula I,
Cl 0 R1
~NHnNHyJ'"R2 y 0 YCH3
Cl CH3
Formula I
8
wherein, R1 and R2 are each independently hydroxy, alkoxy, aryloxy, or
aralkoxy; or R1 and R2 together form a moiety derived from an alpha-hydroxy
carboxylic acid compound or a beta-hydroxy carboxylic acid compound,
wherein the atom attached to boron in each case is an oxygen atom; or R 1 and
R2 together form the boronate esters ofboronic acid
comprising the reaction of a compound of formula Ilia,
YCI 0 NH'j(
0
I
Formula Ilia
wherein, X is imidazole or triazole
with a compound of formula IV or its salt in suitable solvent,
Formula IV
wherein, R1 and R2 are same as defined for the compound of formula I
to obtain the compound of formula I.
Another aspect of the present invention relates to an improved process for the
preparation of a compound of formula IIa,
wherein, X is imidazole or triazole
My
Cl
Formula Ila
by reacting a compound of formula II,
9
~OH
Cl
Formula II
with diimidazole or ditriazole based coupling reagent in suitable solvent.
Another aspect of the present invention relates to an improved process for the
preparation of a compound of formula Ilia,
yM N~ 0
Cl
Formula Ilia
wherein, X is imidazole or triazole
by reacting a compound of formula III,
Formula III
with diimidazole or ditriazole based coupling reagent in suitable solvent.
Another aspect of the present invention relates to use of compound of formula Ila
and/or lila,
Cl 0 r Cl
Formula Ila Formula Ilia
wherein, X is imidazole or triazole
10
for the preparation of the compound of formula I.
Yet another aspect of the present invention relates to an amorphous form of
Ixazomib citrate of a compound of formula Ia,
Formula Ia
Still yet another aspect of the present invention relates to preparation of an
amorphous form of compound of formula Ia,
CIO 0~ 0
I O OH
~NH~B......_0 OH
NH II .
o ycH3 o
Cl CH3
Formula Ia
comprising the steps of:
a) dissolving a compound of formula Ia in suitable solvent,
b) removing the solvent to isolate the amorphous form of compound of
formula Ia.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an illustration of an X-ray powder diffraction (PXRD) pattern of an
amorphous form of compound of formula Ia
FIG. 2 is an illustration of a Differential Scanning Calorimetry (DSC) of an
amorphous form of compound of formula Ia
FIG. 3 is an illustration of a Thermogravimetric analysis (TGA) of an amorphous
form of compound of formula Ia
11
FIG. 4 is a schematic representation of the process of preparation of a compound
of formula I and Ia
DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS
The following definitions are used in connection with the present invention unless
the context indicates otherwise.
The term "Amorphous" as used herein, refers to a solid state form of a compound
of formula Ia wherein the three dimensional structure positions of the molecules
relative to one another are essentially random, [for example, see Hancock et al.
"Characteristics and significance of the amorphous state in pharmaceutical
systems" J. Pharm. Sci. Vol. 86, pp. 1-12 ( 1997)]. As a result, amorphous material
will have only liquid-like short range order, and, when examined by X-ray
diffraction (XRPD), will generally produce broad, diffuse scattering will result in
peak intensity sometimes centered on one or more amorphous halos. Thus, XRPD
analysis of amorphous material will provide a 2-theta pattern with one or more
broad bands with no distinctive peaks.
The "Amorphous" compound of formula Ia may sometimes be characterized by
its glass transition temperature (Tg), which defines a pseudo second order phase
transition in which a super cooled melt of formula Ia yields, on cooling, a glassy
structure with properties similar to those of crystalline compound of formula Ia.
However, since Tg is a kinetic parameter, its value will be dependent on the melt
cooling rate and the measurement conditions used for its determination (e.g., the
slower the melt cooling rate, the lower Tg will be).
The glass transition temperature (Tg) for a sample of amorphous form of
compound of formula Ia may be obtained by differential scanning calorimetry
(DSC).
12
The terms "amide bond and peptide bond" are distinguish in the context that
amide bond results in amide derivative, which is any derivative of oxoacid in
which the hydroxyl group has been replaced with an amino or substituted amino
group while peptide bond results in a derivative of at least two amino acids in
which the amine of one is reacted with the carboxylic acid of the next to form a
peptide bond.
The term "alpha-hydroxy carboxylic acid compound" refers to a compound which
contains a carboxylic acid functional group and hydroxy functional group
separated by one carbon atom.
The term "beta-hydroxy carboxylic acid compound" refers to a compound which
contains a carboxylic acid functional group and hydroxy functional group
separated by two carbon atoms.
The terms "alpha-hydroxy carboxylic acid compound" and "beta-hydroxy
carboxylic acid compound" are not intended to be limited to compounds having
only one hydroxyl group and one carboxylic acid group.
The term "moiety derived from an alpha-hydroxy carboxylic acid compound"
refers to a moiety formed by condensation of carboxylic acid and hydroxyl group
of an alpha-hydroxy carboxylic acid compound, wherein hydroxyl group of an
alpha-hydroxy carboxylic acid compound is present in an alpha position relative
to the carboxylic acid group.
The term "moiety derived from a beta-hydroxy carboxylic acid compound" refers
to a moiety formed by condensation of carboxylic acid and hydroxyl group of a
beta-hydroxy carboxylic acid compound, wherein hydroxyl group of a betahydroxy
carboxylic acid compound is present in a beta position relative to the
carboxylic acid group.
13
The terms "about, general, generally" and the like are to be construed as
modifying a term or value such that it is not an absolute. Such terms will be
defined by the circumstances and the terms that they modify, as those terms are
understood by those skilled 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.
As used herein, the terms "comprising" and "comprises" mean the elements
recited, or their equivalents 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. All
ranges recited herein include the endpoints, including those that recite a range
between two values. Whether so indicated or not, all values recited herein are
approximate as defined by the circumstances, including the degree of expected
experimental error, technique error, and instrument error for a given technique
used to measure a value.
The term "optional" or "optionally" is taken to mean that the event or
circumstance described in the specification may or may not occur, and that the
description includes instances where the event occurs and instances where it does
not.
The first aspect of the present invention relates to an improved process for organic
synthesis, more particularly for the synthesis of amide and peptide bonds, and new
intermediates of compound of formula I,
14
Formula I
wherein, R1 and R2 are each independently hydroxy, alkoxy, aryloxy, or
aralkoxy; or R1 and R2 together form a moiety derived from an alphahydroxy
carboxylic acid compound or derived from a beta-hydroxy
carboxylic acid compound, wherein the atom attached to boron in each
case is an oxygen atom; or R 1 and R 2 together form the boronate esters of
boronic acid,
the boronate esters of boronic acid of formula I contains a derivative
which may be formed by reacting the acid groups of the boronic acid with
a hydroxy compound. Preferred hydroxy compounds are dihydroxy
compounds, especially pinacol, perfluoropinacol, pinanediol, ethylene
glycol, diethylene glycol, 1 ,2-cyclohexanediol, 1 ,3-propanediol, 2,3-
butanediol, glycerol or diethanolamine,
The present invention involves efficient methods for formation of amide and
peptide bonds to prepare compound of formula I. •
In first stage, the amide bond is formed by reacting a compound of formula IIa,
Cl 0 cY Cl
Formula Ila
wherein, X is imidazole or triazole
with glycine to form a compound of formula III;
In second stage, the peptide bond is formed by reacting a compound of formula
Ilia,
15
•
Cl 0 cY""Y Cl
Formula Ilia
wherein, X is imidazole or triazole
with compound of formula IV or its salt to obtain a compound of formula I.
The compound of formula Ila and lila are activated carboxylic acid derivatives,
these derivatives are formed by reacting their corresponding acid compound of
formula II and III,
My OH
Cl
Formula II
M OH y ~g
Cl
Formula III
with diimidazole or ditriazole based coupling reagent in suitable solvent.
The activation of carboxylic acid group of compound of formula II or compound
of formula III with a suitable diimidazole or ditriazole based coupling reagent
forms following derivatives,
CTN~N
Cl
N
Cl o r ~ Y N__.f
NH~
0
I
Formula Ila1 Formula 11Ia1
16
y~ v·~ '=N
Cl
Formula Ila 11
M 7~-'" y ·"1("-J
Cl
Formula Illa11
These derivatives may be isolated before subjecting to formation of amide or
peptide bond and also a part of preferred aspect of the present invention.
The present process resides in a novel and greatly improved method of producing
activated carboxylic acid group with diimidazole or ditriazole based coupling
reagent. The diimidazole or ditriazole based coupling reagent may be selected
from the group comprising of 1,1'-carbonyldiimidazole (CDI), 1,1'-carbonyldi(
1,2,4-triazole), 1,1 '-thiocarbonyldiimidazole and 1,1 '-oxalyldiimidazole.
The other coupling reagents may also be utilized for producing the activated
carboxylic acid group of the compounds of present invention, these coupling
reagent may be selected from the group comprising of carbodiimide such as N,N'dicyclohexylcarbodiimide
(DCC), N,N'-diisopropylcarbodiimide (DIC), 1-ethyl-
3-(3-dimethylaminopropyl)carbodiimide (EDC) and the like.
The compounds II or III of the present invention react readily with diimidazole or
ditriazole based coupling reagent to form carbon dioxide and imidazole or triazole
as by-products. The carbon dioxide is gaseous by-product, which is easily
removed from the reaction mixture wherein imidazole or triazole is soluble in
water hence does not require any cumbersome methods such as multiple washings
with sodium chloride, p'otassium carbonate and phosphoric acid to remove them
from the reaction mixture.
The use of diimidazole or ditriazole based coupling reagent for the preparation of
activated carboxylic acid compound of formula IIa also devoid the use of
hazardous chlorinating reagent such as thionyl chloride or oxalyl chloride for the
17
preparation of acid chloride derivative, 2,5-dichlorobenzoyl chloride. The problem
of handling liquid 2,5-dichlorobenzoyl chloride and maintaining reaction
temperature at 0±1 oc during its reaction with glycine are also solved by the
'
process of the present invention.
The activation of carboxylic acid group of formula II is performed by reacting it
with diimidazole or ditriazole based coupling reagent at suitable temperature in
suitable solvent, optionally isolating the compound of formula Ila, then reacting it
with glycine for 30 minutes to 5 hours at 0°C to 20°C, preferably for 1 to 2 hours
at 0°C to 1 0°C. It is advantageous to use aqueous alkaline solution of glycine,
preferably aqueous sodium hydroxide solution of glycine. After completion of the
reaction compound of formula III is isolated by any known methods of the art.
The compound of formula III can be converted to compound of formula I as per
the disclosed method ofW0'737.
Preferably, the carboxylic acid group of compound of formula III, My (yO H
Cl
Formula III
is further activated by reacting it with diimidazole or ditriazole based coupling
reagent at suitable temperature in suitable solvent, optionally isolating the
compound of formula Ilia, then reacting it with compound of formula IV or its
salt such as hydrochloric acid, hydrobromic acid, p-toluene sulfonic acid,
phosphoric acid or trifluoroacetic acid and the like,
Formula LV
18
wherein, R1 and R2 are each independently hydroxy, alkoxy, aryloxy, or
aralkoxy; or R1 and R2 together form a moiety derived from an alphahydroxy
carboxylic acid compound or a beta-hydroxy carboxylic acid
compound, wherein the atom attached to boron in each case is an oxygen
atom; orR 1 and R2 together form the boronate esters ofboronic acid,
the boronate esters of boronic acid of formula IV may be formed by
I
reacting the acid groups of the boronic acid with a hydroxy compound.
Preferred hydroxy compounds are dihydroxy compounds, especially
pinacol, perfluoropinacol, pinanediol, ethylene glycol, diethylene glycol,
1 ,2-cyclohexanediol, 1 ,3-propanediol, 2,3-butanediol, glycerol or
diethanolamine,
Preferably, the salt of compound of formula IV is trifluoroacetic acid salt
of pinanediol derivative of boroleucine of compound of formula IVa,
y
Formula IVa
The reaction mixture of compound of formula Ilia and IV or IVa is stirred for 30
minutes to 5 hours at ooc to 20°C, preferably for 1 to 2 hours at 0°C to 1 0°C.
After completion of the reaction, the compound of formula I is isolated by any
known methods of the art.
Preferably, the isolation of resulting compound I, compound of formula Ila and
Ilia may be achieved by filtration of precipitated solid by gravity or by suction,
distillation, centrifugation, cooling, crystallization, anti-solvent addition, removal
of solvent by evaporation or the like.
19
During the preparation of compound of formula I,
Cl 0 R
1
~NHI(NH~B./......_R2 y o yCH3
Cl CH3
Formula I
wherein, R 1 and R 2 are other than hydroxyl group or compound of formula I is not
a compound of formula Ia, the resulting compound ·of formula I is further
hydrolysed with suitable reagent based on the nature ofR1 and R2
•
Preferably, the resulting compound of formula I is pinanediol boronate ester of
compound of formula lb,
Formula Ib
which is hydrolysed by acid in suitable solvent to obtain Ixazomib or its boroxine
derivative,
Boroxine derivative
The suitable acid for the hydrolysis may be selected from the group comprising of
hydrochloric acid, boric acid, isobutyl boronic acid, paratoluenesulphonic acid
(PTSA), phosphoric acid; and mixtures thereof. The strength and concentration of
the acids may be varied as per the hydrolysis condition to achieve the desired
result.
20
The Ixazomib or its boroxine derivative is further reacted with citric acid in
suitable solvent to obtain Ixazomib citrate of formula Ia.
As discussed above, the suitable solvent may be selected from the group
comprising of acetone, methyl ethyl ketone, isobutyl methyl ketone; dimethyl
ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane; methanol,
ethanol, propanol, isopropyl alcohol, n-butanol; ethyl acetate; acetonitrile,
propionitrile; dimethylformamide, dimethylacetamide, dimethyl sulfoxide or
mixtures thereof.
Preferably, the solvent is acetonitrile during the activation of the carboxylic acid
group of compound of formula II or III, the hydrolysis of pinanediol boronate
ester of formula lb is preferably carried out in acetonitrile or diisopropyl ether or
mixture thereof. The formation of citrate salt of Ixazomib is preferably carried out
in acetone.
The second aspect of the present invention relates to an amorphous form of
Ixazomib citrate of formula Ia and process of preparation thereof.
The amorphous form of Ixazomib citrate of formula Ia is characterized by the Xray
powder diffraction (PXRD) pattern as shown in Fig.l and/or characterized by
the Differential scanning calorimetry (DSC) as shown in Fig.2 and/or
characterized by the Thermogravimetric analysis (TGA) as shown in Fig.3.
The amorphous form of Ixazomib citrate of formula Ia is further characterized by
glass transition temperature Tg = 112.06°C.
The preparation of an amorphous form of Ixazomib citrate of formula Ia
comprising steps of:
a) dissolving a compound of formula Ia in suitable solvent,
21
b) removmg the solvent to isolate the amorphous form of compound of
formula Ia.
The suitable solvent for the preparation of amorphous form of a compound of
formula Ia may be selected from the group comprising of methanol, ethanol,
propanol, isopropyl alcohol, n-butanol; acetone, methyl ethyl ketone, methyl iso
butyl ketone (MIBK); ethyl acetate; dichloromethane, chloroform; dimethyl ether,
diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane; acetonitrile,
propionitrile or mixtures thereof.
Preferably, the solvent is methanol or its mixture with dichloromethane or acetone
or ethyl acetate.
In step a), optionally undissolved particles, if any, may be removed suitably by
filtration, centrifugation, decantation, and any other known techniques. The
solution can be filtered by passing through paper, glass fiber, or other membrane
material, or a clarifying agent such as celite. Depending upon the equipment used
and the concentration and temperature of the solution, the filtration apparatus may
need to be preheated to avoid premature isolation.
In step b), the removal of the solvent from solution is performed by suitable
techniques which may be selected from the group comprising of evaporation,
evaporation under vacuum, flash evaporation, simple evaporation, rotational
drying, agitated nutsche filter drying, pressure nutsche filter drying or any other
technique known in the art.
The resulting amorphous compound may be optionally further dried. Drying can
be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary
vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The
drying can be carried out at temperatures of less than about 70°C, or any other
suitable temperatures; at atmospheric pressure or under a reduced pressure; as
long as the amorphous Ixazomib citrate is not degraded in its quality. The drying
can be carried out for any desired times until the required product quality is
achieved.
22
The X-ray Powder Diffraction (XRPD): XRPD analysis of amorphous Ixazomib
citrate of formula Ia is conducted on a Panalytical, Model-Empyrean X-Ray
powder diffractometer. The instrumental parameters are mentioned below, and
graph XRPD graph is shown in Fig. 1:
Start position [o2Theta]
End position [o2Theta]
Step size [o2Theta]
Scan step time ( s)
Anode material
Generator setting
Spinning
Goniometer
Sample stage
Sample mode
Sample specimen preparation
3.0
40.0
0.013
39.27
Cu
40mA,45 KV
Yes
theta: theta
Reflection-transmission spinner
Reflection
Sample back loading technique
The thermal analysis of amorphous Ixazomib citrate of formula Ia is conducted by
differential scanning calorimetry (DSC) (TA Instruments- DSC Q-2000) equipped
with refrigerated cooling system (RCS90). Analysis is performed by taking 2 to 3
mg of sample encapsulated into aluminum sample pan with crimped lid. The
thermogram is recorded from 25°C to 250°C under nitrogen atmosphere of 50
mL/min by using following methodology,
a) Equilibrate at 25°C
b) Modulate ( ±) 1 °C every 60 seconds
c) Isothermal for 5 minutes
d) Ramp 5°C/minutes to 250°C
23
The glass transition temperature (Tg) is observed at 112.06°C. The corresponding
thermogram is shown in Fig.2.
The thermal gravimetric analysis (TGA Q-500) of amorphous Ixazomib citrate of
formula Ia is conducted on TA Instruments model Q-500. The sample (about 10-
30 mg) is placed in a platinum pan previously tared. The weight loss of the sample
is determined by heating the sample from room temperature to 300°C at a heating
rate of 1 0°C/minutes under nitrogen atmosphere of 60 mL/min. The weight loss of
Ixazomib citrate of formula Ia from RT to ~ 150°C is found to be 2.52 % w/w and
the corresponding thermogram is shown in Fig.3.
EXPERIMENTAL
Detailed experimental parameters according to the present invention are provided
by the following examples, which are intended to be illustrative and not limiting
of all possible aspects of the invention.
EXAMPLES
PREPARATION OF IXAZOMIB CITRATE
Example 1: Synthesis for N-(2,5-dichlorobenzoyl)glycine (Formula III)
1,1'-Carbonyldiimidazole (CDI) (127.3 g) was added to a mixture of 2,5-
dichlorobenzoic acid (100 g) in acetonitrile (500 mL) under nitrogen atmosphere
at ambient temperature. The reaction mixture was stirred for 1 hour at the same
temperature to obtain compound of formula Ila 1
• After stirring, the reaction mass
was added to a mixture of water (1500 mL), sodium hydroxide (NaOH; 31.4 g)
and glycine (58.9 g) at 0-10°C. The obtained reaction mass was stirred for 1 hour
at 0-1 0°C. After completion of the reaction, the reaction mixture was maintained
at pH 2-3 with hydrochloric acid solution to obtain a solid residue. The solid
residue was filtered to obtain N-(2,5-dichlorobenzoyl)glycine. (Yield: 97.7 %)
24
Example 2: Synthesis of 2,5-dichloro-N-[2-({(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-
3a,5,5-trimethylhexa- hydro-2H-4,6-methano-1 ,3,2-benzodioxaborol-2-
yl]butyl}amino)-2-oxoethyl]benzamide (Formula Ib)
1,1 '-Carbonyldiimidazole (CDI) (15.7 g) was added to a mixture of N-(2,5-
dichlorobenzoyl)glycine (20 g) in acetonitrile (100 mL) at 20-30°C to obtain
compound of formula Ilia 1
• The reaction mixture was cooled to 0-1 0°C then
added trifluoroacetic acid salt of pinanediol derivative of boroleucine of formula
IVa (29.0 g). The reaction mixture was stirred for 1 hour at the same temperature.
After completion of the reaction, methanol (100 mL) and demineralised water
(300 mL) was added to the reaction mass and stirred for 3 hours at 20-30°C. The
solid was collected by filtration to obtain the title compound. (Yield: 93.7 %)
Example 3: Synthesis of Ixazomib
The pinanediol boronate ester (5 g) of compound of formula Ib was mixed with a
mixture of concentrated hydrochloric acid (5 mL) and boric acid (1.9 g) in
diisopropyl ether (100 mL) at ambient temperature. The reaction mixture was
stirred for 5 hours and solid was filtered and washed with diisopropyl ether (25
mL). The isolated solid was dried under vacuum to obtain Ixazomib. (Yield: 86.5
%)
Example 4: Synthesis of Ixazomib citrate of formula Ia
The Ixazomib (5 g) was added in a solution of citric acid (2.93 g) in acetone (100
mL) at ambient temperature. The reaction mixture was stirred for 30 minutes and
filtered. The filtrate was stirred for 4-5 hours. The solid was collected by filtration
and dried to give Ixazomib citrate. (Yield- 95 %)
Example 5: Preparation of amorphous form of Ixazomib citrate
The Ixazomib citrate (2 g) was dissolved in methanol (30 mL) at ambient
temperature. The solvent was removed under vacuum at 50-55°C and further
degassed for 2-3 hours at the same temperature to obtain amorphous form of
Ixazomib citrate.
25
Example 6: Preparation of amorphous form of Ixazomib citrate
The Ixazomib citrate (2 g) was dissolved in methanol (15 mL) and
dichloromethane (55 mL) at ambient temperature. The solvent was removed under
vacuum at 40-50°C and further degassed for 2-3 hours at the same temperature to
obtain amorphous form of Ixazomib citrate.
Example 7: Preparation of amorphous form of Ixazomib citrate
The Ixazomib citrate (2 g) was dissolved in methanol (4 mL) and acetone (40 mL)
at ambient temperature. The solvent was removed under vacuum at 50-55°C and
further degassed for 2-3 hours at the same temperature to obtain amorphous form
of Ixazomib citrate.

We Claim:
1. A process for preparation of a compound of formula I,
Cl 0 R
1
Ay l-".ry"y t., o y cH3
Cl tH3
Formula I
wherein, R1 and R2 are each independently hydroxy, alkoxy, aryloxy, or aralkoxy;
or R 1 and R2 together form a moiety derived from an alpha-hydroxy carboxylic
acid compound or a beta-hydroxy carboxylic acid compound, wherein the atom
attached to boron in each case is an oxygen atom; or R1 and R2 together form the
boronate esters of boronic acid
comprising the steps of,
a) reacting a compound of formula Ila,
Formula Ila
wherein, X is imidazole or triazole
with glycine in suitable solvent to obtain a compound of formula III,
Cl 0
cY~nOH
Cl
Formula III
b) optionally, converting the compound of formula III to a compound of
formula Ilia,
My N~ 0
Cl
Formula Ilia
wherein, X is imidazole or triazole
27
c) reacting the compound of formula III or formula Ilia with a compound of
formula IV or its salt in suitable solvent,
Formula IV
wherein, R1 and R2 are same as defined for the compound of formula I
to obtain the compound of formula I.
2. A process for the preparation of a compound of formula Ila,
Formula Ila
wherein, X is imidazole or triazole
comprising the reaction of a compound of formula II,
~OH
Cl
Formula II
with diimidazole or ditriazole based coupling reagent in suitable solvent to obtain
the compound of formula IIa.
3. The process for the preparation of the compound of formula I, according
to claim 1, wherein the conversion of step b) comprising the steps of, reacting a
compound of formula III,
28
Formula III
with diimidazole or ditriazole based coupling reagent in suitable solvent to obtain
a compound of formula lila,
Formula Ilia
wherein, X is imidazole or triazole
4. A process for the preparation of a compound of formula I,
Formula I
wherein, R 1 and R2 are each independently hydroxy, alkoxy, aryloxy, or aralkoxy;
or R1 and R2 together form a moiety derived from an alpha-hydroxy carboxylic
acid compound or a beta-hydroxy carboxylic acid compound, wherein the atom
attached to boron in each case is an oxygen atom; or R1 and R2 together form the
boronate esters ofboronic acid
comprising the steps of:
reacting a compound of formula lila,
Formula Ilia
29
wherein, X is imidazole or triazole
with a compound of formula IV or its salt in suitable solvent,
Formula IV
wherein, R 1 and R2 are same as defined for the compound of formula I
to obtain the compound of formula I.
5. A process for the preparation of a compound of formula I,
Cl 0 R
1
y~" "i("yL•' o ycH3
Cl CH3
Formula I
wherein, R1 and R2 are each independently hydroxy, alkoxy, aryloxy, or aralkoxy;
or R1 and R2 together form a moiety derived from an alpha-hydroxy carboxylic
acid compound or a beta-hydroxy carboxylic acid compound, wherein the atom
attached to boron in each case is an oxygen atom; or R1 and R2 together form the
boronate esters of boronic acid
comprising the steps of:
a) reacting a compound of formula II,
sYOH
Formula II
with diimidazole or ditriazole based coupling reagent in suitable solvent to obtain
a compound of formula Ila,
30
wherein, X is imidazole or triazole
M y
Cl
Formula Ila
b) reacting the compound of formula Ila with glycine in suitable solvent to
obtain a compound of formula III,
Cl 0
cY~~OH
Cl
Formula III
c) reacting the compound of formula III with diimidazole or ditriazole based
coupling reagent in suitable solvent to obtain a compound of formula Ilia,
Formula Ilia
wherein, X is imidazole or triazole
d) reacting the compound of formula Ilia with a compound of formula IV or
its salt in suitable solvent,
Formula IV
wherein, R1 and R2 are same as defined for the compound of formula I
to obtain the compound of formula I.
31
6. The process according to any of claims 1 to 5, wherein the diimidazole or
ditriazole based coupling reagent is selected from the group comprising of
1,1 '-carbonyldiimidazole (CDI), 1,1 '-carbonyldi-( 1 ,2,4-triazole ), 1,1 '-
thiocarbonyldiimidazole
carbonyldiimidazole (CDI).
and 1,1 '-oxalyldiimidazole, preferably
7. The process according to any of claims 1 to 5, wherein the suitable solvent
is selected from the group comprising of acetone, methyl ethyl ketone,
isobutyl methyl ketone; dimethyl ether, diisopropyl ether, tetrahydrofuran,
dioxane, dimethoxyethane; methanol, ethanol, propanol, isopropyl alcohol,
n-butanol; ethyl acetate; acetonitrile, propionitrile; dimethylformamide,
dimethylacetamide, dimethyl sulfoxide or mixtures thereof.
8. The process according to any of claims 1 to 5, wherein the compound of
formula I is a compound of formula Ib,
Formula lb
9. The process according to any of claims 1 to 5, wherein the compound of
formula I is a compound of formula Ia,
Formula Ia
10. A process for the preparation of a compound of formula Ib,
32
Formula lb
comprising the steps of:
a) reacting a compound of formula II,
~OH
Formula II
with 1,1 '-carbonyldiimidazole (CDI) in acetonitrile to obtain a compound of
formula 1Ia1
,
Py .~. '=/
Ct
Formula IIa 1
b) reacting the compound of formula IIa 1 with glycine to obtain a compound
of formula III,
Cl 0
cr~gOH
Cl
Formula III
c) reacting the compound of formula III with 1,1 '-carbonyldiimidazole (CDI)
in acetonitrile to obtain a compound of formula Ilia 1
,
33
Formula Illa1
d) reacting the compound of formula Ilia 1 with trifluoroacetic acid salt of
compound of formula IV a,
Formula IVa
to obtain the compound of formula lb.
11. The process according to claim 10, further comprising converting the
compound of formula 1 b to a compound of formula 1 a,
a) hydrolysing the compound of formula lb with boric acid and hydrochloric
acid in diisopropyl ether to obtain Ixazomib of a compound of formula,
b) treating the Ixazomib with citric acid in acetone to obtain a compound of
formula Ia,
Formula Ia
34
12. A compound of formula Ila,
Formula Ila
wherein, X is imidazole or triazole
13. A compound of formula Ilia,
X NHY
0
Formula Ilia
wherein, X is imidazole or triazole
14. An amorphous form of compound of formula Ia, which is characterized by
the X-ray pattern as shown in Fig. 1.
15. An amorphous form of compound of formula Ia with the glass transition
temperature Tg = 112.06°C.
16. A process for preparation of amorphous form of a compound of formula
I a,
Formula Ia
comprising the steps of:
a) dissolving the compound of formula Ia in suitable solvent,
35
b) removmg the solvent to isolate amorphous form of the compound of
formula Ia.
17. The process according to claim 16, wherein the suitable solvent is selected.
from the group comprising of methanol, ethanol, propanol, isopropyl
alcohol, n-butanol; acetone, methyl ethyl ketone, methyl iso butyl ketone
(MIBK); ethyl acetate; dichloromethane, chloroform; dimethyl ether,
diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane; acetonitrile,
propionitrile.
18. The process according to claim 16, wherein the removal of solvent is
selected from the group comprising of evaporation, evaporation under
vacuum, flash evaporation, simple evaporation, rotational drying, agitated
nutsche filter drying, pressure nutsche filter drying.
19. The process according to claim 16, wherein preparation of amorphous
form of a compound of formula Ia,
Formula Ia
comprising the steps of:
a) dissolving the compound of formula Ia in methanol or its mixture with
dichloromethane or acetone or ethyl acetate,
b) evaporating the solvent to isolate amorphous form of the compound of
formula Ia.