A PROCESS FOR PURIFICATION OF CARFILZOMIB INTERMEDIATE
FIELD OF THE INVENTION
The present invention relates to a process for purifying an intermediate in the
synthesis of carfilzomib, i.e. the compound of formula II,
Formula II
wherein X may be independently selected from trifluoroacetic acid, hydrochloric
acid, hydrobromic acid, p-toluene sulfonic acid or phosphoric acid, in particular
reducing the level of an impurity of formula III generally formed and/or present
during synthesis of the compound of formula II,
Formula III
wherein X may be independently selected from trifluoroacetic acid, hydrochloric
acid, hydrobrominc acid, p-toluene sulfonic acid or phosphoric acid.
The present invention also relates to the isolation of a compound of formula II as
solid, preferably the compound of formula lla and its use for the preparation of
carfilzomib. The present invention further relates to a crystalline compound of
2
formula Ila having X-ray diffraction peak at 8.39, 15.31, 17.13, 18.83, 20.05 and
20.4 7 ±0.2 degrees two-theta.
Formula Ila
wherein X is trifluoroacetic acid
BACKGROUND OF THE INVENTION
Carfilzomib, (2S)-N-{ (1 S)-1-benzyl-2-[((1 S)-3-methyl-1-{ [(2R)-2-methyloxiran-
2-yl]carbonyl} butyl)amino ]-2-oxoethyl }-4-methyl-2-( { (2S)-2-[(morpholin-4-
ylacetyl)amino ]-4-phenylbutanoyl} amino )pentanamide, is represented by the
formula I:
Formula I
Carfilzomib (CFZ, marketed under the trade name Kyprolis, Onyx
Pharmaceuticals, Inc.) is a tetrapeptide epoxyketone and a selective proteasome
inhibitor. It is an analog of epoxomicin. It was approved by the U.S. Food and
Drug Administration (FDA) for use in combination with dexamethasone or with
lenalidomide plus dexamethasone in patients with relapsed or refractory multiple
myeloma, who have received one to three lines of therapy. It is also indicated as a
3
single agent for the treatment of patients with relapsed or refractory multiple
myeloma, who have received one or more lines of therapy.
Carfilzomib as represented by formula I is disclosed in US Patent No 7,417,042.
The synthetic scheme described in US 7,417,042 is depicted below as scheme -1:
o c~
MeCN, OlEA, HOBT, PyBop ~
0...-B< or Bn CH3 0
NH~ .,..,.ez orBn
N-Boc-l-leucine Phenyl alanine benzoyl or benzyl ester
'""" ~
BocNHLcuPheOBz l ;-w OCM
BocNHl.cuPheOBz(TFA)
t
MeCN HoBT, DIPE, PyBop
Ph
( OH
BocHN-y
0
BocNHhPheC02H
TFNOCM j CJ
TFA NH TI fCHNH'
1
TI Bz or Bn ~"" (2/~:-: ~ NH l :"',:, ~ 0 ~Bz · ~N.rrr or Bn 6 Y'o,... Morpholin acetic acid ~ ~ ~ ~ ~ ° '() OMF OWyBop 6 l)
0 'Do
CARFILZOMIB
Scheme-l
4
wherein, "Boc" means tert-butoxycarbonyl; Bz and Bn means benzoyl and benzyl
groups respectively; MeCN means acetonitrile; TF A means trifluoroacetic acid;
DMF means dimethyl formamide; DCM means Dichloromethane; DIEA means
diisopropyl ethyl amine; HOBT means hydroxyl benzotriazole; PyBop means
benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate.
Further, US patents 7,231,818 and 8,207,297 also describe a similar process for
the synthesis of carfilzomib. The inventors of the present invention found that the
above mentioned scheme results in carfilzomib containing a diol carfilzomib
impurity, represented herein below:
Diol Carfilzomib
A possible reason for impurity formation appears to be opening of the sensitive
epoxide ring.
The removal of diol carfilzomib impurity requires multiple purifications which in
turn reduces overall yield. The multiple purifications may also lead to opening of
the sensitive epoxide ring.
W02005/105827A2 discloses a process for the deprotection of a compound of
formula IV a, represented herein below:
5
Formula IVa
wherein Boc is tert-butoxycarbonyl. The compound of Formula IVa corresponds
to Compound (CC) ofW02005/105827A2.
In W02005/l 05827 A2, the compound of formula IVa is treated with
trifluoroacetic acid in dichloromethane for one hour at room temperature. The
resulting mixture was concentrated and placed under vacuum for two hours.
The inventors of the present invention found that the above mentioned process
results in the formation of an impurity of formula lila, represented herein below:
Formula Ilia
wherein X is trifluoroacetic acid
The above mentioned impurity was measured by High Performance Liquid
Chromatography (HPLC) as 5.33 area% after completion of the process disclosed
in W0200511 05827 A2. It was further found that aforesaid process results in a
product in oily form, which is difficult to isolate or purify.
6
A similar process for the synthesis of compound of formula Ila is disclosed in
W02014/018807Al. In W02014/018807A1, a compound of formula IVa is
treated with trifluoroacetic acid in dichloromethane for four hours at room
temperature. After deprotection, the reaction mixture was concentrated to obtain
the compound of formula Ila. The compounds of Formulae IVa and Ila
correspond to Compounds 1068 and 1069, respectively, of W02014/018807Al.
The authors of W020 14/018807 A 1 disclose that the compound obtained by
following the above process is obtained as brown oil.
The inventors of the present invention found that the compound obtained by
following the process disclosed in W020 14/018807 A 1 contains an impurity of
formula lila 3.06% as measured by HPLC.
Generally, impurities in an active pharmaceutical ingredient (API) may arise from
degradation of the API itself, or may be a process generated impurity. The
inventors of the present invention found that in the present case, the diol
carfilzomib impurity is either formed due to epoxide ring opening of carfilzomib
at the final stage of the preparation of carfilzomib or content of open epoxide ring
present (or forms) in intermediates of carfilzomib may carry forward along with
intermediates to form the diol carfilzomib impurity.
The removal of diol carfilzomib impurity is very difficult and even by usmg
different purification methods including recrystallization, the impurity remains in
the final compound in an undesired amount.
The multiple purifications of carfilzomib are also not desirable due to the presence
of the sensitive epoxide ring, which may open during purification to form the diol
cadilzomib impurity. Hence, there is a need to control the diol impurity of
formula III at the intermediate stage of the preparation of carfilzomib to prepare
carfilzomib free from the diol carfilzomib impurity.
7
The inventors of the present application have found a process of purification of
compound of formula II to prepare a substantially pure compound of formula II.
In particular, the compound of formula II contains less than 0.05 area-% HPLC of
impurity of formula III.
SUMMARY OF THE INVENTION
In a first aspect, the present invention relates to a process for purification of the
compound of formula II,
Formula II
wherein X may be independently selected from trifluoroacetic acid, hydrochloric
acid, hydrobrominc acid, p-toluene sulfonic acid or phosphoric acid,
comprising the steps of:
i) treating the compound of formula II, preferably the compound of formula IIa
with an alkali metal perhalate in a suitable solvent;
ii) adding anti-solvent; and
iii) isolating the substantially pure compound of formula II or IIa.
Another aspect of the present invention relates to a crystalline compound of
formula IIa.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an illustration of a PXRD pattern of a crystalline compound of formula
II a
8
DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS
The following definitions are used in connection with the present application
unless the context indicates otherwise.
The term "amine protecting group" as used herein refers to a group that blocks
(i.e., protects) the amine functionality while reactions are carried out on other
functional groups or parts of the molecule. Those skilled in the art will be familiar
with the selection, attachment, and cleavage of amine protecting groups and will
appreciate that many different protective groups are known in the art, the
suitability of one protective group or another being dependent on the particular
synthetic scheme planned. Treatises on the subject are available for consultation,
such as Greene and Wuts, "Protective Groups in Organic Synthesis," 3rd Ed., pp.
17-245 (J. Wiley & Sons, 1999), the disclosure ofwhich is incorporated herein by
reference.
The term alkali metal refers exclusively to lithium (Li), sodium (Na) and
potassium (K).
Alkali metal perhalate refers to lithium periodate, sodium periodate, potassium
periodate, lithium perbromate, sodium perbromate, potassium perbromate, lithium
perchlorate, sodium perchlorate and potassium perchlorate.
The term "carfilzomib free from the diol carfilzomib impurity" refers to
carfilzomib containing a diol carfilzomib impurity of less than 0.15 area-% as
measured by high performance liquid chromatography (HPLC). More preferably,
carfilzomib, as disclosed herein, contains a diol carfilzomib impurity of less than
0.10 area-% as measured by HPLC and most preferably contains a diol
carfilzomib impurity of less than 0.05 area-% as measured by HPLC.
9
The term "substantially pure compound of formula II" refers to compound of
formula II containing an impurity of formula III of less than 0.15 area % as
measured by HPLC. More preferably, the compound of formula II, as disclosed
herein, contains an impurity of formula III of less than 0.10 area % as measured
by HPLC and most preferably contains an impurity of formula III of less than
0.05 area% as measured by HPLC.
The term 'X' of compound of formula II or compound of formula III relates to
corresponding salts selected from the group comprising of trifluoroacetic acid,
hydrochloric acid, hydrobromic acid, phosphoric acid and para toluenesulphonic
acid. The term 'X' resembles with the choice of deprotecting acids used for
deproctection of PG1 protecting groups of compound of formula IV, represented
herein below:
o )-_ o {-to
PG1 NH~NH~NH~NH~
[ 0 uo
u PG1: tert-butoxycarbonyl (BOC), fluorenylmethyloxycarbonyl (FMOC).
triphenylmethyl (Trityl), methanesulfonyl (Mesyl) or acyl
Formula IV
wherein PG1 may be independently selected from tert-butoxycarbonyl (BOC),
fluorenylmethyloxycarbonyl (FMOC), triphenylmethyl (Trityl), methanesulfonyl
(Mesyl) or acyl
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
10
expected experimental error, technique error and instrument error for a gtven
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 term "anti-solvent" refers to a liquid that, when combined with a solution of
compound of formula II, reduces solubility of the compound of formula II in the
solution, causing crystallization or precipitation in some instances spontaneously,
and in other instances with additional steps, such as seeding, cooling, scratching,
and/or concentrating.
In a first aspect, the application provides a process for purification of a compound
of formula II,
11
Formula II
wherein X may be independently selected from trifluoroacetic acid, hydrochloric
acid, hydrobrominc acid, p-toluene sulfonic acid or phosphoric acid
by treating it with an alkali metal perhalate in a suitable solvent followed by
addition of anti-solvent to isolate a substantially pure compound of formula II
containing an impurity of formula III in an amount of less than 0.10 area-% as
measured by high performance liquid chromatography (HPLC).
The alkali metal perhalate may be selected from the group consisting of lithium
periodate, sodium periodate, potassium periodate, lithium perbromate, sodium
perbromate, potassium perbromate, lithium perchlorate, sodium perchlorate and
potassium perchlorate. Preferably, the alkali metal perhalate is anaqueous solution
of sodium periodate.
The inventors of the present invention found that the use of alkali metal perhalate
reduces the level of the impurity of formula III in the compound of formula II
significantly. In particular, the formula III impurity is reduced to less than 0.05
area% HPLC.
The inventors also found that other oxidizing agents such as perchloric acid
(HC104) may also reduce the formula III impurity effectively.
12
At this stage, the monitoring of formula III impurity is very advantageous as it
reduces the amount of formation of diol carfilzomib. Alternatively, it also avoids
the multiple purifications of carfilzomib to remove the diol carfilzomib.
The compound of formula II is formed due to deprotection of compound of
formula IV, the formation of corresponding salts depend on the use of
corresponding acid used for the deprotection of PG1 of compound of formula IV.
PG1 is a suitable amme protecting group. Suitable amme function protection
groups and protection and deprotection methods are well known in the art (see
notably "Protective groups in organic synthesis", Greene T. W. and Wuts P. G.
M., Wiley-Interscience, 1999). Preferably, the suitable amine protecting groups -
PG 1 can be selected from tert-butyloxycarbonyl (Boc ), 9-
fluorenylmethyloxycarbonyl (FMOC), triphenylmethyl (Trityl), methanesulfonyl
(Mesyl) or acyl.
The amine protected compounds of formula IV are converted to the corresponding
salt of the compounds of formula II by cleaving off the protecting group
PG1 using standard conditions for the deprotection of amines, preferably a suitable
acid such as trifluoroacetic acid, hydrochloric acid, hydrobromic acid, phosphoric
acid and para toluenesulphonic acid can be used in a suitable solvent such as
tetrahydrofuran, ethyl acetate, dichloromethane and acetonitrile for the
deprotection of amines.
The amine deprotection may be carried out using from 1 to 10 equivalents of acid,
more preferably from 1 to 2 equivalents at reduced or elevated temperatures, for
example from -30°C to 40°C, more preferably from -1 ooc to 1 0°C, over a time
period ranging from 1 minute to 10 hours, more preferably from 30 minutes to 5
hours. It is advantageous to perform the deprotection reaction at low temperature
13
preferably below 0°C. The deprotection at low temperature has significantly
reduced the opening of sensitive epoxide ring of compound of formula II which in
turn is useful in reducing the formation of formula III impurity. The low
temperature condition is useful but it does not completely avoid the formation of
formula III impurity.
In a preferred embodiment, the compound of formula II, wherein X is
trifluoroacetic acid is prepared by treating a compound of formula IVa with
trifluoroacetic acid optionally in the presence of a suitable solvent such as
dichloromethane. The reaction mixture is stirred for 1 to 10 hours, more
preferably for 2 to 8 hours at -S°C to 0°C.
The compound of formula II can be isolated as solid or it can be used without
isolation for the next step of purification with an alkali metal perhalate.
Preferably, it is isolated by using a suitable technique known in the art, such as
quenching with an anti-solvent followed by precipitation or by extraction from a
suitable solvent followed by removal of solvent from the reaction mixture by
evaporation, distillation and the like or any other methods can be employed. The
isolation of compound of formula II is preferred as it reduces the content of
dissolved organic and/or inorganic impurities.
The obtained compound of formula II, generally having impurity of formula III
more than 0.2S area-% HPLC, is treated with alkali metal perhalate in suitable
solvent to remove the formula III impurity. The purification process is performed
by stirring the reaction mixture for 2 to 1S hours, more preferably for 4 to 10
hours at a range of temperature from soc to 40°C, more preferably at 20°C to
30°C.
After purification, the isolation of substantially pure compound of formula It is
carried out by addition of suitable anti-solvent. The addition of anti-solvent may
14
be achieved either by adding the reaction mixture to the anti-solvent or by adding
an anti-solvent to the reaction mixture. Addition may be slow or instant. The
substantially pure compound of formula II may optionally be washed with
suitable solvent and dried under suitable drying conditions.
The drying may be suitably carried out using any of an air tray dryer, vacuum tray
dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying
may be carried out at any suitable temperature and under atmospheric pressure or
above, or under reduced pressure.
In a preferred embodiment, the substantially pure compound of formula II is
crystalline.
The suitable solvent for the purification of compound of formula II may be
selected from the group consisting of tetrahydrofuran, dioxane, dimethoxyethane,
methanol, ethanol, propanol, isopropyl alcohol, n-butanol, ethyl acetate,
acetonitrile, propionitrile, dimethylformamide, dimethylacetamide and dimethyl
sulfoxide or mixtures thereof. Preferably, the solvent is tetrahydrofuran.
The suitable anti-solvent may be selected from the group consisting of water,
hydrocarbon such as n-heptane, n-hexane, methyl tert-butyl ether, diisopropyl
ether. Preferably, the anti-solvent is water.
The preferred alkali metal perhalate may be selected from the group consisting of
alkali metal perhalate as discussed above. Most preferably, the alkali metal
perhalate is sodium periodate.
15
The impurity of formula Ilia after purification of compound of formula Ila is
measured by high performance liquid chromatography (HPLC) and the results are
summarized herein below in Table-1.
Table- 1:
Purification of compound of formula Ila
Examples Impurity of formula Illa Impurity of formula Illa Physical
wt% wt% Nature
(After amine deprotection (After purification with
step) an alkali metal perhalate)
Example 1 0.43 0.02 Crystalline
(Step A)
Example 2 0.29 0.04 Crystalline
(Step A)
Reference 5.33 Purification is not reported Oily mass
Example 1
Reference 3.06 Purification is not reported Oily mass
Example 2
An exemplary method for High performance liquid chromatography (HPLC),
analysis of impurity of formula Ilia is using a HPLC system equipped with UV
detector operating at 210 nm and a HPLC Column (YMC Pack Pro C 18 RS (250
x 4.6) mm, 5 f.!m).
The mobile phases are Mobile Phase-A (MP-A) 2.72 g of Potassium dihydrogen
orthophosphate into a 2L bottle. Add 2L of HPLC grade water and 2mL of
16
Triethylamine. Sonicate to dissolve the material completely. Adjust the pH ofthe
solution to 3.2 ± 0.03 with orthophosphoric acid.
(Mobile Phase-B (MP-B) (Acetonitrile), which are pumped through the column at
a flow rate of (1.0 mL/min) column temperature of (25°C) and auto sampler
Temperature of(5°C) The mixture ofMP-A and MP-B was a gradient profile over
the course of the (70 minute run) as follows:
Time (min.) MP-A% MP-B%
Initial 65 35
40 35 65
50 25 75
59 25 75
60 65 35
70 65 35
It is evident from the comparative data of Table 1 that a high content of the diol
impurity of formula Ilia is formed during the amine deprotection step, wherein the
content of the diol impurity is even higher in prior art procedures of reference
examples 1 and 2.
The isolation of compound of formula II is not reported in the prior art procedures
which makes the removal of impurities difficult; however, the purification process
of the present invention involves the use of an alkali metal perhalate followed by
isolation of a substantially pure compound of formula II as crystalline solid,
wherein the content of the diol impurity of formula III is reduced to less than
0.05area-% HPLC.
17
In another embodiment, the substantially pure compound of formula II, preferably
a compound of formula IIa is further utilized for the preparation and isolation of
carfilzomib using methods known in the art such as disclosed in article 'Journal of
Biological Chemistry' Volume 285 No. 51, 40125-40134; 2010. The isolated
carfilzomib preferably is free from the diol carfilzomib impurity, e.g., contains
less than 0.15 area-% as measured by high performance liquid chromatography
(HPLC). More preferably, the isolated carfilzomib contains a diol carfilzomib
impurity of less than 0.10 area-% as measured by HPLC and most preferably
contains a diol carfilzomib impurity of less than 0.05 area-% as measured by
HPLC. The isolated carfilzomib can be crystalline or amorphous.
Another aspect of the present invention provides a novel crystalline compound of
formula IIa and its use for the preparation of carfilzomib.
The crystalline compound of formula Ila shows X-ray diffraction peak at an angle
of refraction 2 theta (8), of 8.39, 15.31, 17.13, 18.83, 20.05 and 20.47 ± 0.2
degrees; preferably it includes five or more peaks at angles of refraction 2 theta
(8) selected from the group consisting of 4.09, 5.98, 8.13, 8.39, 8.72, 9.36, 9.98,
11.00, 11.33, 11.71, 13.02, 13.55, 14.29, 14.61, 15.31, 16.07, 16.65, 16.79, 17.13,
17.53, 17.83, 18.13, 18.83, 19.26, 19.75, 20.05, 20.47, 20.78, 21.02, 21.56, 21.93,
22.54, 22.93, 23.57, 24.02, 24.24, 25.87, 26.44, 27.46, 28.52, 29.42, 29.87, 31.08
and 37.21 ± 0.2 degrees.
X-ray Powder Diffraction (XRPD): XRPD analysis was conducted on a
Panalytical, Model-Empyrean X-Ray powder diffractometer. The instrumental
parameters are mentioned below:
Start position [ o2Theta]
End position [ o2Theta]
Step size [o2Theta]
3.0
40.0
0.013
18
Scan step time ( s)
Anode material
Generator setting
Spinning
Goniometer
Sample stage
Sample mode
Sample specimen preparation
EXPERIMENTAL
39.27
Cu
40mA,45 KV
Yes
theta: theta
Reflection-transmission spinner
Reflection
Sample back loading technique
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 embodiments of the invention.
Examples
To demonstrate the benefits of the present application, examples of the prior art
were worked and indicated as reference examples.
Example-1
Step A: Preparation of crystalline compound of formula Ila
The compound of formula IV a ( 1 70 g) was added in trifluoroacetic acid (720 mL)
followed by dichloromethane (180 mL) was added at -5°C. The reaction was
stirred for 5 hours at the same temperature. After completion of the reaction, the
reaction -mixture was quenched with water (5200 mL). Then reaction was filtered
and washed with water (1800 mL) to obtain a solid residue (having an impurity of
formula Ilia: 0.43 area-% HPLC)
19
The resulting compound was dissolved in tetrahydrofuran (720 mL), then added a
solution of sodium periodate (2.7 g Nal04 in 180 mL water) and stirred for 4
hours at 25-35°C. To the resulting stirred solution watet (5220 mL) was added to
give the title compound (178 g) (having an impurity of formula lila: 0.02 area-%
HPLC).
Example-2
Step A: Preparation of crystalline compound of formula II a
The compound of formula IVa (160 g) was added in trifluoroacetic acid (640 mL)
followed by dichloromethane (640 mL) was added at -5°C. The reaction was
stirred for 5 hours at the same temperature. After completion of the reaction, the
reaction mixture was quenched with water ( 4800 mL). Then reaction was filtered
and washed with water (two times with 800 mL each) to obtain a solid residue
(having an impurity of formula Ilia: 0.29 area-% HPLC)
The resulting compound was dissolved in tetrahydrofuran (640 mL), then added a
solution of sodium periodate (1.6 g Nal04 in 160 mL water) and stirred for 4
hours at 25-35°C. To the resulting mixture water (4800 mL) was added to give the
title compound (157 g) (having an impurity of formula lila: 0.04 area-% HPLC).
Reference examples
Reference example 1 (Example 10 ofW02005/105827A2)
Preparation of compound of formula Ila
The compound of formula IV a (2 g) was added to trifluoroacetic acid :
dichloromethane (8 mL:2 mL) mixture at 20-25°C. The reaction was stirred for 1
hour. After stirring the reaction mixture was reduced under vacuum to give brown
oil (having an impurity of formula Ilia: 5.33 area-% HPLC)
20
Reference example 2 (Preparation of compound 1069 of W02014/018807)
Preparation of compound of formula Ila
The compound of formula IVa (5 g) was added in trifluoroacetic acid (15mL)
followed by dichloromethane (15mL) was added at 20-25°C. The reaction was
stirred for 4 hours at the same temperature. After completion of the reaction, the
reaction mixture was reduced to give brown oil (having an impurity of formula
Ilia: 3.06 area-% HPLC).

We Claim:
1. A process for the purification of a compound of formula II,
Formula II
wherein X may be independently selected from trifluoroacetic acid, hydrochloric
acid, hydrobromic acid, p-toluene sulfonic acid or phosphoric acid
comprising the steps of:
a) treating the compound of formula II with an alkali metal perhalate in solvent;
b) adding anti-solvent; and
c) isolating a substantially pure compound of formula II.
2. The process according to claim 1, wherein the alkali metal perhalate is selected
from the group consisting of lithium periodate, sodium periodate, potassium
periodate, lithium perbromate, sodium perbromate, potassium perbromate, lithium
perchlorate, sodium perchlorate and potassium perchlorate, preferably sodium
periodate.
3. The process according to claim 1, wherein the solvent is selected from the
group consisting of tetrahydrofuran, dioxane, dimethoxyethane, methanol,
ethanol, propanol, isopropyl alcohol, n-butanol, ethyl acetate, acetonitrile,
propionitrile, dimethylformamide, dimethylacetamide and dimethyl sulfoxide,
preferably tetrahydrofuran.
22
4. The process according to claim 1, wherein the anti-solvent is selected from the
group consisting of water, n-heptane, n-hexane, methyl tert-butyl ether and
diisopropyl ether, preferably water.
5. The process according to claim 1, wherein 'X' of compound of formula II is
trifluoroacetic acid.
6. The process according to any of claims 1 to 5, further comprising converting
the substantially pure compound of formula II into carfilzomib of formula I,
Formula I
7. The process according to claim 6, further comprising isolating the carfilzomib.
8. The process according to claim 7, wherein the isolated carfilzomib contains less
than 0.15 area-% of diol carfilzomib impurity as measured by high performance
liquid chromatography (HPLC).
9. A crystalline compound of formula IIa,
Formula Ila
23
wherein X is trifluoroacetic acid
having XRPD peaks at 8.39, 15.31, 17.13, 18.83, 20.05 and 20.47 ± 0.2 degrees
two-theta.
10. A process for the purification of compound of formula Ila,
Formula Ila
wherein X is trifluoroacetic acid
comprising the steps of:
i) treating the compound of formula Ila with sodium periodate in tetrahydrofuran;
ii) adding water; and
iii) isolating substantially pure compound of formula Ila.