Note: Descriptions are shown in the official language in which they were submitted.
CA 02987708 2017-11-29
WO 2017/039425 PCT/LV2015/000009
A METHOD FOR PREPARATION OF IBRUTINIB PRECURSOR
TECHNICAL FIELD
The present invention relates to a method for the preparation of
pharmaceutically active
compounds.
More specifically, the present invention relates to a method for the
preparation of precursor of
anti-cancer drug ibrutinib.
BACKGROUND ART
Ibrutinib is the compound of formula (I) [1.] ¨ anti-cancer drug used to treat
malignant
B-lymphoproliferative disorders.
ONH-11\ C H2
I I N 2 r N 2
4 4
NH, NH,
(I) OPh (11) OPh
Ibrutinib's synthesis scheme involves an intermediate (precursor) of formula
(II), that
contains main fragments of ibrutinib's structure: pyrazolo[3,4-cflpyrimidine
bicyclic system
with 4-phenoxyphenyl group at the position 3, as well as N-unsubstituted
piperidin-3-y1
substituent at the nitrogen atom N-1 of the pyrazolo[3,4-d]pyrimidine
heterocycle.
Conversion of the precursor (II) to ibrutinib (I) is performed by trivial
methods, using
acylation of the piperidine NH group by acrylic acid in the presence of
condensing agents or
by acryloyl chloride. Precursor (II) is obtained from N(1')-protected
intermediate (3) by
removal of the protecting group (Pg) by known methods.
CA 02987708 2017-11-29
WO 2017/039425 PCT/LV2015/000009
OR
cl '13g 0-Pg
,I13 Cp-Pg
RO
0
,...õ.....,N H N, OH (2) N (5)
OPh ..:rr, N
I I N ______ zio r 1 µ1,1 __________ 4, I..
N ,., / Ph3P, DIAD N -., / Pd(PP113),, base N "-
- /
TIE organic solvent, 1120
NII2 NH2 . NH2 Hal
(Mitsunobu (Suzuki reaction) (4)
reaction)
(1) OPh (3) OPh
1
ip
2) 112c ..-1-..x Hal = Br, I
Pg = Boc, Cbz, etc.
I) Deprotection;
Me Me
R = H or R+R = mej¨k¨me
(I) X = CI, imidazol-1-yl, etc.
Ibrutinib
Until recent time most of the published methods for synthesis of the precursor
(II) can be
attributed to one of two general synthetic pathways: 1) Mitsunobu reaction
between (3-aryl-
1H-pyrazolo[3,4-d]pyrimidin-4-yDamine (1) and N-protected 3-hydroxypiperidine
(2) [1, 211;
2) Suzuki reaction between (3-halo-1H-pyrazolo[3,4-d]pyrimidin-4-yDamine (4)
and
arylboronic acid derivative (5) [3, 51.
Both mentioned synthetic pathways involve Mitsunobu reaction that results in
the
inversion of the optical configuration of carbon atom C-3 of the piperidine
cycle. However,
there are reports [11] about partial racemization during Mitsunobu reaction
that may lower the
optical purity of the product.
Another synthetic pathway leading to the intermediate (3), not involving
Mitsunobu
reaction, is described in the recently published patent [4]. The method is
based on the reaction
of compound (6) with (R)-(piperidin-3-yl)hydrazine (7) obtaining pyrazole (8),
which then
reacts with formamide yielding pyrazolo[3,4-d]pyrimidine (3).
/ cN -Pg CN¨Pg 01¨Pg
NC OMe
HN. .
- NH, H2N iq /1\T NI
NC : (7) H2
0 1 N
/ HCON
NC
(6) OPh NH2
Pg = Boc, Cbz, Bn (8) OPh (3) OPh
The starting compound (6) is obtained from 4-phenoxybenzoic acid converting it
into the
corresponding acyl chloride following by condensation with malononitrile and
methylation (e.
g. by dimethyl sulfate). However, synthesis of the optically active (piperidin-
3-yl)hydrazine
(7) in the patent [4] is not disclosed.
2
The known methods of ibrutinib's precursor (II) synthesis are characterized by
complicated
procedures and by use of some reagents that are not convenient for large-scale
synthesis. Thus,
introduction of aromatic fragment into molecule of intermediate (3) is
performed by Suzuki
reaction, that means necessity to use unstable and expensive arylboronic acid,
as well as previous
halogenation step to obtain 3-halopyrazolo[3,4-alpyrimidine (4). Two of the
most popular
ibrutinib's synthetic routes use Mitsunobu reaction to introduce optically
active piperidine
moiety. However, Mitsunobu reaction may cause a partial racemization of the
chiral reagent,
that lowers the optical purity of the product. In another method, involving
condensation of
optically active (pip eri din-3 -yl)hydrazine
with 1. 1 -di cy ano-2-methoxy -2- (4-
phenoxyphenypethylene, it is necessary to use expensive 4-phenoxybenzoic acid
and some toxic
reagents (e. g. SOC12, dimethyl sulfate). Also, in this method it is necessary
to obtain optically
active (piperidin-3-yl)hydrazine, that, obviously, is very complicated
process, for which a
detailed description is not available in the literature.
SUMMARY OF INVENTION
TECHNICAL PROBLEM
Analysis of the background art shows the unsatisfied need of a simple and
technologically
advantageous alternative method for synthesis of ibrutinib's precursor (II).
SOLUTION TO PROBLEM
In accordance with an aspect of at least one embodiment, there is provided a
process for the
preparation of ibrutinib's precursor, compound of formula (II)
OH
/ N
N
NH2
(II) OPh ,comprising arylation of compound (III)
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Date Recue/Date Received 2021-12-30
ON¨Pgi
N
,NH
Pgi (III) ,wherein Pgi and Pg2 are protecting
groups,
Pgi is Boc, Cbz, or Bn; Pg2 is H, Boc, Cbz, or Bn, withl-bromo-4-
phenoxybenzene in the
presence of a palladium catalyst, a nitrogen-containing ligand, and a base in
an organic solvent,
and subsequently isolating a product with formula (IV)
ON¨Pgi
'IN/
N
Pg'
2 NH =
(IV) OPh
, wherein Pgi is Boc, Cbz, or Bn; Pg2 is H,
Boc, Cbz, or Bn, and further comprising deprotecting of compound (IV).
In accordance with at least one embodiment: said catalyst is selected from the
group
consisting of Pd(OAc)2, PdC12, and Pd(CF3C00)2; said ligand is selected from
the group
consisting of 1,10-phenanthroline, and 2,2'-bipyridine; said base is selected
from the group
consisting of Cs2CO3, K2CO3, and K3PO4; and said solvent is selected from the
group consisting
of xylene, N,N-dimethylacetamide, and diglyme.
In accordance with at least one embodiment: the catalyst for said arylation is
Pd(OAc)2, the
ligand is 1,10-phenanthroline, the base is Cs2CO3, and the solvent is xylene
or N,N-
dimethylacetamide.
Direct C-arylation of pyrazolo[3,4-d]pyrimidine at C-3 position was not used
in the synthesis
of ibrutinib's precursor (II) until now. Some works are published [7-10, 12,
131 describing direct
arylation of indazole at C-3 position. However, there are no reports on direct
C-arylation of
amino-substituted indazoles, also direct C-arylation of pyrazolopyrimidines is
not known at all.
Regarding direct C-3 arylation of pyrazolo[3,4-dlpyrimidine, in our case the
situation is
complicated not only by potentially similar reactivity of C-6 atom in the
pirimidine
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Date Recue/Date Received 2021-12-30
cycle, but also by presence of amino group 4-NH2. We unexpectedly found, that
compound with
protected piperidine NH and 4-NH2 groups (III, Pg2 H), as well as compound
with unprotected
4-NH2 group (III, Pg2 = H), reacts withl-bromo-4-phenoxybenzene in the
presence of palladium
catalyst (e. g., Pd(OAc)2-1,10-phenanthroline-Cs2CO3 system) with formation of
compound
(IV). Deprotection of the latter by known methods leads to the ibrutinib's
precursor (II). For
example, 4-(benzyloxy carbonyl)amino-1 - [1-(benzyl oxy carbonyl)piperi din-3 -
yl derivative (III)
(Pgl = Pg2 = Cbz) reacts with 1-bromo-4-phenoxybenzene with high conversion,
selectively
forming compound (IV) (Pgl = Pg2 = Cbz) with good yield (76%). Further
hydrogenation (H2,
Pd/C, Me0H) results in removal of both Cbz protecting groups, thus obtaining
ibrutinib's
precursor (II) with free NH2 group in the pyrimidine cycle and free NH group
in the piperidine
fragment; the obtained compound (II) can be easily acylated to give the final
product ibrutinib
(I).
0"¨Pgi CN¨Pgi CNH
7 7
6 icr/1,.1 6 1\1,1 6
I N 2
3 3 3
4 4 4
,N Alp
Pg2 PgcH NH2
(III)
Pgi = Boc, Cbz, Bn, etc. (IV) OPh (II) OPh
Pg2 = H, Boc, Cbz, Bn, etc.
Continuing our study of direct C-arylation we surprisingly found that compound
(III) with
unprotected 4-NH2 group (Pgi = Boc, Pg2 = H) reacts with 1-bromo-4-
phenoxybenzene in the
presence of palladium catalyst forming compound (IV) (Pgi = Boc, Pg2 = H) with
good yield
(65% or higher). However, arylation of compound (III) with protected 4-NH2
group has certain
preparative advantages, such as higher conversion and yield of the product, as
well as more easy
isolation of the arylated compound (III).
We investigated physico-chemical and NMR spectral characteristics of the
compound (IV)
obtained by the above described direct C-arylation of compound (III) with
unprotected 4-NH2
group. Comparing these characteristics with the corresponding characteristics
of the standard
sample of compound (IV) obtained by other method, we found that these
compounds are
identical. So, despite the presence of the unprotected 4-NH2 group arylation
of the unprotected
compound (III) surprisingly occurs with desired regioselectivity and in the
direct arylation
4a
Date Recue/Date Received 2021-12-30
experiments we obtained exactly C(3)-arylated product (IV) instead of the
possible 4-arylamino-
or 6-aryl-substituted isomers. Compounds (III) with the protected 4-NH2 group
(e.g., Pg2 = Boc
or Cbz) react with 1-bromo-4-phenoxybenzene even faster, the reaction occurs
at lower
temperature and with less amount of impurities than in the case of
unsubstituted compound (III).
After removal of both protecting groups (Pgi and Pg2) by the appropriate
procedure we
obtained compound (II). Acylation of the latter by acryloyl chloride in
standard conditions [1]
leads to ibrutinib (I) which is identical with the standard ibrutinib's sample
by the physico-
chemical and spectral characteristics.
4b
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ADVANTAGEOUS EFFECTS OF INVENTION
The described method allows to obtain the ibrutinib's precursor (II) with good
yields by
direct C-arylation of protected derivatives (III) of known [6] 1-(piperidin-3-
yl)pyrazolo[3,4-
dlpyrimidin-4-amine bearing protecting group at the piperidine nitrogen atom
and, preferably,
also at the 4-NH2 group. Performing synthesis of the ibrutinib's precursor
(II) by the method
described in this invention eliminates work with unstable and expensive
arylboronic acid
derivatives and toxic phosphine ligands. The most preferable ligands for
direct C-arylation are
nitrogen-containing heterocycles, e. g. 1,10-phenanthroline, derivatives of
2,2'-bipyridine,
etc., that are more available, less toxic, stable in air and moisture, and
recoverable (if
necessary). Palladium(II) salts used as the catalysts in the direct C-
arylation reactions are
easily separable from the reaction mixture in the form of amorphous Pd(0).
Performing
ibrutinib's large-scale synthesis, the palladium catalyst also might be
recovered by converting
of the precipitated Pd(0) to the corresponding Pd(II) salt. In the described
direct C(3)-
arylation of pyrazolo[3,4-d]pyrimidine cycle, the chiral centre ¨ C-3 atom of
the piperidine
moiety ¨ is not affected, so the optical purity of the product is not
compromised. The convient
method for aryl group introduction in the final steps of the ibrutinib's (I)
synthesis opens a
possibility to synthesize series of ibrutinib's analogues by varying the aryl
halide used in the
C-arylation.
The described method can be performed in different solvents, e. g. toluene,
xylene,
dimethylacetamide, diglyme, dioxane, 1,2-dimethoxyethane or in a mixture of
solvents.
Different complex-forming compounds can be used as the catalyst, more
preferable ¨
nitrogen-containing heterocycles such as 1,10-phenanthroline, derivatives of
2,2'-bipyridine,
etc. As the base, alkali metal carbonates, phosphates, alkoxides can be used,
e. g. Cs2CO3, t-
BuOK, etc. The reaction temperature, depending on the solvent used, may vary
from 80 to
180 C; the reaction time is from 4 to 48 h. In the following examples, the
process which is the
object of the present patent application is described by way of examples;
these examples are
not intended to limit the scope of protection of the same.
EXAMPLES
Boc-protected compound (III) (Pgi = Boc, Pg2 = H) and its unprotected analogue
(Pgi
= H) are described in the patent [6]. Starting from these compounds, N4,1\11'-
(Boc)2-
protected compound (III) (Pgi = Pg2 = Boc), as well as N4,N1-(Cbz)2-protected
compound
(III) (Pgi = Pg2 = Cbz) were also synthesized by known methods.
Pgi
6 rfrt 1
2
3
4
Pg ,NH (III)
Pgi, Pg2 = H, Boc, Cbz
Example 1
(3R)-3 -14-Amino-3-(4-phenoxypheny1)-1H-pyrazolo13,4-d1py rimidin-l-yll
piperidine-l-
carboxylic acid tert-butyl ester (IV, Pgt = Boc, Pg2 = H)
A mixture of compound (III) (Pgi = Boc, Pg2 = H) (318 mg, 1.00 mmol), Pd(OAc)2
(22 mg,
0.10 mmol), 1,10-phenanthroline (18 mg, 0.10 mmol), Cs2CO3 (358 mg, 1.10
mmol), 1-
bromo-4-phenoxybenzene (274 mg, 1.10 mmol) and xylene (5 ml) was heated in a
sealed tube
under argon atmosphere at 160 C for 24 h with intensive stirring. After
completion of the
reaction the tube was cooled to room temperature, carefully opened, and the
reaction mass was
poured into Et0Ac (20 m1). After intensive stirring for 5 min the obtained
suspension was
filtered through celite and evaporated in vacuum. The product was purified by
column
chromatography (eluent CH2C12-Me0H 20:1, Rf 0.5). Yield 234 mg (48%), viscous
yellowish
oil.
Example 2
(3R)-3-14-Amino-3-(4-phenoxypheny1)-1H-pyrazolo13,4-0 pyrimidin-l-yll
piperidine-1 -
carboxylic acid tert-butyl ester (IV, Pgt = Boc, Pg2 = H)
A mixture of compound (III) (Pgt = Boc, Pg2 = H) (636 mg, 2.00 mmol), Pd(OAc)2
(44 mg,
0.20 mmol), 1,10-phenanthroline (36 mg, 0.20 mmol), K2CO3 (304 mg, 2.20 mmol),
1- bromo-
4-phenoxybenzene (548 mg, 2.20 mmol) and N,N-dimethylacetamide (DMA) (10 ml)
was
heated in a sealed tube under argon atmosphere at 150 C for 16 h with
intensive stirring. The
product (III) was isolated and purified similarly to that described in the
Example 1. Yield 642
mg (66%), viscous yellowish oil. The analytical data of the obtained compound
(III)
correspond to that of the product obtained in the Example 1.
Example 3
(3R)-3-14-Amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-0 pyrimidin-l-yll
piperidine-1 -
carboxylic acid tert-butyl ester (IV, Pgt = Boc, Pg2 = H)
6
Date Recue/Date Received 2021-12-30
A mixture of compound (III) (Pgi = Boc, Pg2 = H) (636 mg, 2.00 mmol), Pd(OAc)2
(44 mg,
0.20 mmol), 4,4'-di(tert-buty1)-2,2'-bipyridine (54 mg, 0.20 mmol), K3PO4 (467
mg, 2.20
mmol), 1-bromo-4-phenoxybenzene (548 mg, 2.20 mmol) and DMA (10 ml) was heated
in a
sealed tube under argon atmosphere at 150 C for 48 h with intensive stirring.
The product (III)
was isolated and purified similarly to that described in the Example 1. Yield
428 mg (44%),
viscous yellowish oil. The analytical data of the obtained compound (III)
correspond to that of
the product obtained in the Example 1.
Example 4
(3R)-3- [4-(B enzyloxy carb onyl amino)-3 -(4-phenoxypheny1)-1H-py razol o
[3,4-dlpyrimi din-1-
yllpiperidine-l-carboxylic acid benzyl ester (IV, Pgi = Pg2 = Cbz)
A mixture of compound (III) (Pgi = Pg2 = Cbz) (973 mg, 2.00 mmol), Pd(OAc)2
(44 mg, 0.20
mmol), 1,10-phenanthroline (36 mg, 0.20 mmol), Cs2CO3 (716 mg, 2.20 mmol), 1-
bromo-4-
phenoxybenzene (548 mg, 2.20 mmol) and xylene (10 ml) was heated in a sealed
tube under
argon atmosphere at 140 C for 16 h with intensive stirring. After completion
of the reaction
the tube was cooled to room temperature, carefully opened, and the reaction
mass was poured
into Et0Ac (40 m1). After intensive stirring for 5 min the obtained suspension
was filtered
through celite and evaporated in vacuum. The product was purified by column
chromatography
(eluent Et0Ac-hexane 1:2, Rf 0.4). Yield 995 mg (76%), white amorphous powder.
Example 5
(3R)-3 - [4-(tert-Butoxy carbonylamino)-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-
d] py rimi din-1-
yllpiperidine-l-carboxylic acid tert-butyl ester (IV, Pgi = Pg2 = Boc)
A mixture of compound (III) (Pgi = Pg2 = Boc) (837 mg, 2.00 mmol), PdC12 (35
mg, 0.20
mmol), 4,4'-di(tert-buty1)-2,2'-bipyridine (54 mg, 0.20 mmol), Cs2CO3 (716 mg,
2.20 mmol),
1-bromo-4-phenoxybenzene (548 mg, 2.20 mmol) and diglyme (10 ml) was heated in
a sealed
tube under argon atmosphere at 110 C for 20 h with intensive stirring. After
completion of the
reaction the tube was cooled to room temperature, carefully opened, and the
reaction mass was
poured into Et0Ac (40 m1). After intensive stirring for 5 min the obtained
suspension was
filtered through celite and evaporated in vacuum. The product was purified by
column
chromatography (eluent Et0Ac-hexane 1:4, Rf 0.3). Yield 727 mg (62%), white
amorphous
powder.
Example 6
3 -(4-Phenoxypheny1)-1 -((3R)-piperidin-3 -y1)-1H-pyrazolo [3,4-d] py rimidin-
4-amine (II)
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Compound (IV) (Pgi = Pg2 = Boc) (2.93 g, 5 mmol) was dissolved in Me0H (15
ml), then
33% HC1 (3 ml) was added, and the reaction mass was heated at 50 C for 4 st
with intensive
stirring (note: a foam is forming during the reaction due to isolation of
gaseous by-products!).
After completion of the reaction the resulting solution was cooled to room
temperature and
evaporated to dryness (note: the vapor contains HCl). Saturated Na2CO3
solution (5 ml) was
added to the dry residue and the mixture was extracted with Et0Ac (3 x 10 ml).
The extract
was dried over Na2SO4 and evaporated in vacuum. Yield 1.89 g (98%), white
amorphous
mass.
From N4,N1.-(Cbz)2-protected compound (IV) (Pgi = Pg2 = Cbz) using standard
hydrogenation conditions in the presence of Pd/C catalyst, compound (II) was
obtained in
99% yield. The analytical data of this product correspond to that of the above
mentioned
product (II) obtained from N4,1\1'-(Boc)2-protected compound (IV) (Pgi = Pg2 =
Boc).
INDUSTRIAL APPLICABILITY
The invented method may be realized in pharmaceutical industry using the
corresponding
equipment and conditions. The method allows to obtain the product, which can
be purified to
pharmaceutical quality (>99%) by routine procedures. The process is
characterized by
utilizable waste and easily separable impurities in the target product.
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CITATION LIST
PATENT LITERATURE
[1] W02008/121742.
[2] U52008/007621.
[3] W02012/158795.
[4] W02014/139970.
[5] W02009/062118.
[6] W02012/058645.
NON PATENT LITERATURE
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Eur. J. Org.
Chem., 7075 (2012).
[8] M. Naas, S. El Kazzouli, E. M. Essassi, M. Bousmina, G. Guillaumet, J.
Org. Chem.,
79, 7286 (2014).
[9] M. Ye, A. J. F. Edmunds, J. A. Morris, D. Sale, Y. Zhang, J.-Q. Yu,
Chem. Sci., 4, 2374
(2013).
[10] A. Unsinn, P. Knochel, Chem. Commun., 48, 2680 (2012).
[11] T. S. Kaufman, Tetrahedron Lett., 37, 5329 (1996).
[12] K. M. Engle, J.-Q. Yu, J. Org. Chem., 78, 8927 (2013).
[13] M. Ye, G.-L. Gao, A. J. F. Edmunds, P. A. Worthington, J. A. Morris, J.-
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