U.S. patent application number 15/574528 was filed with the patent office on 2018-05-31 for method for preparing nilotinib.
The applicant listed for this patent is ASYMCHEM LABORATORIES (FUXIN) CO., LTD, ASYMCHEM LABORATORIES (TIANJIN) CO., LTD, ASYMCHEM LIFE SCIENCE (TIANJIN) CO., LTD, JILIN ASYMCHEM LABORATORIES CO., LTD, TIANJIN ASYMCHEM PHARMACEUTICAL CO., LTD. Invention is credited to Hao HONG, Gaochao HUANG, Gage JAMES, Changfeng LI, Jiuyuan LI.
Application Number | 20180148430 15/574528 |
Document ID | / |
Family ID | 57392369 |
Filed Date | 2018-05-31 |
United States Patent
Application |
20180148430 |
Kind Code |
A1 |
HONG; Hao ; et al. |
May 31, 2018 |
METHOD FOR PREPARING NILOTINIB
Abstract
A method for preparing nilotinib includes the following steps:
performing an aminocarbonylation reaction on a compound A and
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline to
obtain an amination product; and performing deprotection treatment
of an R group on the amination product to obtain the nilotinib,
wherein the compound A has a structure shown in formula I, and in
formula I, an R group is selected from benzyl, --COCF.sub.3, --CHO
or --CO.sub.2R', where an R' group is C.sub.1.about.C.sub.10 alkyl,
C.sub.1.about.C.sub.3 alkoxy ethyl or C.sub.7.about.C.sub.19
aralkyl. ##STR00001##
Inventors: |
HONG; Hao; (TEDA Tianjin,
CN) ; JAMES; Gage; (TEDA Tianjin, CN) ; LI;
Jiuyuan; (TEDA Tianjin, CN) ; LI; Changfeng;
(TEDA Tianjin, CN) ; HUANG; Gaochao; (TEDA
Tianjin, CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ASYMCHEM LABORATORIES (TIANJIN) CO., LTD
ASYMCHEM LIFE SCIENCE (TIANJIN) CO., LTD
TIANJIN ASYMCHEM PHARMACEUTICAL CO., LTD
ASYMCHEM LABORATORIES (FUXIN) CO., LTD
JILIN ASYMCHEM LABORATORIES CO., LTD |
TEDA Tianjin
TEDA Tianjin
TEDA Tianjin
Liaoning
Jilin |
|
CN
CN
CN
CN
CN |
|
|
Family ID: |
57392369 |
Appl. No.: |
15/574528 |
Filed: |
May 26, 2015 |
PCT Filed: |
May 26, 2015 |
PCT NO: |
PCT/CN2015/079854 |
371 Date: |
November 16, 2017 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 401/14
20130101 |
International
Class: |
C07D 401/14 20060101
C07D401/14 |
Claims
1. A method for preparing nilotinib, comprising the following
steps: performing an aminocarbonylation reaction on a compound A
and 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline to
obtain an amination product; and performing deprotection treatment
of an R group on the amination product to obtain the nilotinib,
wherein the compound A has a structure shown in formula I:
##STR00009## in the formula I, the R group is selected from benzyl,
--COCF.sub.3, --CHO or --CO.sub.2R', wherein an R' group is
C.sub.1.about.C.sub.10 alkyl, C.sub.1.about.C.sub.3 alkoxy ethyl or
C.sub.7.about.C.sub.19 aralkyl.
2. The preparation method of claim 1, wherein performing the
aminocarbonylation reaction on the compound A under a condition
which include an organic solvent, a catalyst and a carbon monoxide,
wherein a molar ratio of the
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline to the
compound A is 0.5:1.about.2:1, and the catalyst is 0.1.about.20% of
a mole number of the compound A.
3. The preparation method of claim 2, wherein the catalyst
comprises a first catalyst and a second catalyst, wherein the first
catalyst is selected from one or more in a group formed by
PdCl.sub.2(PPh.sub.3).sub.2, PdCl.sub.2(PhCN).sub.2,
PdCl.sub.2(CH.sub.3CN).sub.2, Pd(PPh.sub.3).sub.4,
Pd.sub.2(dba).sub.3CH.sub.2Cl.sub.2,
PdCl.sub.2(dppf)CH.sub.2Cl.sub.2 and an allylpalladium chloride
dimer; and the second catalyst is selected from one or more in a
group formed by triphenylphosphine, tricyclohexylphosphonium
tetrafluoroborate, tri-tert-butylphosphine,
1,1'-bis(diphenylphosphino)ferrocene,
1,2-bis(diphenylphosphinoyl)ethane,
1,3-bis(diphenylphosphinoyl)propane and
1,3-bis(diisopropylphosphino)propane.
4. The preparation method of claim 2, wherein the organic solvent
is selected from one or more in a group formed by
N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl
pyrrolidinone, N-ethyl pyrrolidinone, dimethyl sulfoxide and
dioxane.
5. The preparation method of claim 1, wherein in the
aminocarbonylation reaction process, adding a nucleophilic promoter
into a reaction system of that, and the nucleophilic promoter is
selected from one or more in a group formed by phenol,
p-chlorophenol, naphthol and 4-methyl-1-naphthol.
6. The preparation method of claim 5, wherein an amount of the
nucleophilic promoter is 0.17.about.300% of the mole number of the
compound A.
7. The preparation method of claim 5, wherein in the
aminocarbonylation reaction process, adding an acid-binding agent
into the reaction system of that, and the acid-binding agent is
selected from one or more in a group formed by triethylamine,
N,N-diisopropylethylamine, N,N-dimethylaniline, DABCO, DBU,
pyridine, potassium carbonate, potassium phosphate, sodium
carbonate and sodium phosphate; preferably a molar number of the
acid-binding agent is 1.about.10 times to that of the compound
A.
8. The preparation method of claim 1, wherein the
C.sub.1.about.C.sub.10 alkyl is selected from methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or
cyclohexyl.
9. The preparation method of claim 1, wherein the
C.sub.1.about.C.sub.3 alkoxy ethyl is selected from methoxyethyl,
propoxyethyl or chloroethoxyethyl.
10. The preparation method of claim 1, wherein the
C.sub.7.about.C.sub.19 aralkyl is selected from benzyl,
p-nitrobenzyl, p-methoxybenzyl, benzhydryl or triphenylmethyl.
11. The preparation method of claim 3, wherein the organic solvent
is selected from one or more in a group formed by
N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl
pyrrolidinone, N-ethyl pyrrolidinone, dimethyl sulfoxide and
dioxane.
12. The preparation method of claim 2, wherein in the
aminocarbonylation reaction process, a nucleophilic promoter is
added into a reaction system of that, and the nucleophilic promoter
is selected from one or more in a group formed by phenol,
p-chlorophenol, naphthol and 4-methyl-1-naphthol.
13. The preparation method of claim 3, wherein in the
aminocarbonylation reaction process, a nucleophilic promoter is
added into a reaction system of that, and the nucleophilic promoter
is selected from one or more in a group formed by phenol,
p-chlorophenol, naphthol and 4-methyl-1-naphthol.
14. The preparation method of claim 4, wherein in the
aminocarbonylation reaction process, a nucleophilic promoter is
added into a reaction system of that, and the nucleophilic promoter
is selected from one or more in a group formed by phenol,
p-chlorophenol, naphthol and 4-methyl-1-naphthol.
15. The preparation method of claim 6, wherein in the
aminocarbonylation reaction process, an acid-binding agent is added
into the reaction system of that, and the acid-binding agent is
selected from one or more in a group formed by triethylamine,
N,N-diisopropylethylamine, N,N-dimethylaniline, DABCO, DBU,
pyridine, potassium carbonate, potassium phosphate, sodium
carbonate and sodium phosphate; preferably a molar number of the
acid-binding agent is 1.about.10 times to that of the compound
A.
16. The preparation method of claim 2, wherein the
C.sub.1.about.C.sub.10 alkyl is selected from methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or
cyclohexyl.
17. The preparation method of claim 3, wherein the
C.sub.1.about.C.sub.10 alkyl is selected from methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or
cyclohexyl.
18. The preparation method of claim 2, wherein the
C.sub.1.about.C.sub.3 alkoxy ethyl is selected from methoxyethyl,
propoxyethyl or chloroethoxyethyl.
19. The preparation method of claim 7, wherein the
C.sub.1.about.C.sub.3 alkoxy ethyl is selected from methoxyethyl,
propoxyethyl or chloroethoxyethyl.
20. The preparation method of claim 7, wherein the
C.sub.7.about.C.sub.19 aralkyl is selected from benzyl,
p-nitrobenzyl, p-methoxybenzyl, benzhydryl or triphenylmethyl.
Description
TECHNICAL FIELD
[0001] The disclosure relates to the field of medicinal chemistry,
and particularly to a method for preparing nilotinib.
BACKGROUND
[0002] Nilotinib is a potent and accurate second-generation
tyrosine-kinase inhibitor, its application range includes an adult
patient with a chronic myelogenous leukemia-chronic phase or
accelerated phase treatment (including imatinib) history, and a
drug-tolerant or intolerant Philadelphia chromosome of the patient
is positive.
[0003] In existing researches, different synthesis methods for
nilotinib are recorded in many patents and documents.
[0004] Route 1: in most of existing patents and documents,
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline is
adopted as a raw material, and is coupled with
4-methyl-3-(4-(pyridine-3-yl) pyrimidine-2-ylamino)benzoic acid or
a derivative thereof to obtain nilotinib.
##STR00002##
[0005] R.sub.1 is H, and R.sub.2 is OH, Cl, alkoxy or aralkyl; or
R.sub.1 is OH, and R.sub.2 is t-butyloxycarboryl.
[0006] Route 2: an arylcarboxylic acid is reacted with
3-bromo-5-(trifluoromethyl)aniline to produce amide, and the amide
is further coupled with imidazole to obtain a target molecule
nilotinib by a metal catalyst, wherein M is halogen or OH.
##STR00003##
[0007] Route 3: 3-(pyridine-3-yl) pyrimidine-1-ylamine and
substituted iodobenzene are coupled in the presence of a metal
catalyst to obtain a target molecule nilotinib.
##STR00004##
[0008] Route 4: amide is constructed by multiple steps, and then is
coupled with a boric acid in the presence of a metal catalyst to
obtain a target molecule nilotinib.
##STR00005##
[0009] Route 5: 3-nitro-4-methylbenzoyl chloride is reacted with
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline, and
substituted aryl guanidine is obtained by multi-step conversion,
and then is coupled and condensed with an unsaturated ketone to
obtain a target molecule nilotinib.
##STR00006##
[0010] However, the above reaction routes also have some
shortcomings: route 1 is excessively high in starting raw material
cost, and each of routes 2 to 5 has lengthy synthetic sequences.
Because an aromatic amine has poor nucleophilicity (compared with
alkyl amines), a high temperature of over 120.degree. C. is usually
required when it is used for a palladium-catalyzed
aminocarbonylation reaction, and consequently, it is necessary to
increase carbon monoxide pressure, which increases a potential
safety hazards. In addition, an application of a
palladium-catalyzed carbonylation esterification/amination reaction
to synthesis of pharmaceutical molecule containing numerous
heteroatoms is limited. Since complexion of a nitrogen atom and a
metal ion reduces a catalytic activity, a larger using amount of
catalyst or a specially structured ligand is usually required to
achieve a high yield in such a reaction, and these measures
increase cost.
[0011] Based on the above problems, it is necessary to develop a
novel route for synthesizing nilotinib, which is lower in cost and
short in synthesis route.
SUMMARY
[0012] The disclosure is mainly intended to provide a method for
preparing nilotinib, so as to solve the problems of high route cost
and long steps of existing synthesis of the nilotinib.
[0013] In order to achieve the purpose, according to an aspect of
the disclosure, a method for preparing nilotinib is provided, which
includes the following steps: performing an aminocarbonylation
reaction on a compound A and
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline to obtain
an amination product; and performing deprotection treatment of an R
group on the amination product to obtain the nilotinib, wherein the
compound A has a structure shown in formula I:
##STR00007##
[0014] the R group is selected from benzyl, --COCF.sub.3, --CHO or
--CO.sub.2R', wherein an R' group is C.sub.1.about.C.sub.10 alkyl,
C.sub.1.about.C.sub.3 alkoxy ethyl or C.sub.7.about.C.sub.19
aralkyl.
[0015] Furthermore, the aminocarbonylation reaction is performed on
the compound A under a condition which include an organic solvent,
a catalyst and a carbon monoxide, wherein a molar ratio of the
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline to the
compound A is 0.5:1.about.2:1, and the catalyst is 0.1.about.20% of
a mole number of the compound A.
[0016] Furthermore, the catalyst includes a first catalyst and a
second catalyst, wherein the first catalyst is selected from one or
more in a group formed by PdCl.sub.2(PPh.sub.3).sub.2,
PdCl.sub.2(PhCN).sub.2, PdCl.sub.2(CH.sub.3CN).sub.2,
Pd(PPh.sub.3).sub.4, Pd.sub.2(dba).sub.3CH.sub.2Cl.sub.2,
PdCl.sub.2(dppf)CH.sub.2Cl.sub.2 and an allylpalladium chloride
dimer; and the second catalyst is selected from one or more in a
group formed by triphenylphosphine, tricyclohexylphosphonium
tetrafluoroborate, tri-tert-butylphosphine,
1,1'-bis(diphenylphosphino)ferrocene,
1,2-bis(diphenylphosphinoyl)ethane,
1,3-bis(diphenylphosphinoyl)propane and
1,3-bis(diisopropylphosphino)propane.
[0017] Furthermore, the organic solvent is selected from one or
more in a group formed by N,N-dimethylformamide,
N,N-dimethylacetamide, N-methyl pyrrolidinone, N-ethyl
pyrrolidinone, dimethyl sulfoxide and dioxane.
[0018] Furthermore, in the aminocarbonylation reaction process, a
nucleophilic promoter is added into a reaction system of that, and
the nucleophilic promoter is selected from one or more in a group
formed by phenol, p-chlorophenol, naphthol and
4-methyl-1-naphthol.
[0019] Furthermore, an amount of the nucleophilic promoter is
0.17.about.300% of the mole number of the compound A.
[0020] Furthermore, in the aminocarbonylation reaction process, an
acid-binding agent is added into the reaction system of that, and
the acid-binding agent is selected from one or more in a group
formed by triethylamine, N,N-diisopropylethylamine,
N,N-dimethylaniline, DABCO, DBU, pyridine, potassium carbonate,
potassium phosphate, sodium carbonate and sodium phosphate;
preferably a molar number of the acid-binding agent is 1.about.10
times to that of the compound A.
[0021] Furthermore, the C.sub.1.about.C.sub.10 alkyl is selected
from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
tert-butyl or cyclohexyl.
[0022] Furthermore, the C.sub.1.about.C.sub.3 alkoxy ethyl is
selected from methoxyethyl, propoxyethyl or chloroethoxyethyl.
[0023] Furthermore, the C.sub.7.about.C.sub.19 aralkyl is selected
from benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl or
triphenylmethyl.
[0024] According to the technical solution of the disclosure, as a
raw material, the compound A with the structure shown in formula I
is reacted with the
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline to
obtain the amination product. Then, the R group contained on the
amination product is removed to obtain a target product nilotinib
by virtue of the deprotection treatment. In the disclosure, the
aminocarbonylation reaction is creatively applied to a route for
synthesizing the nilotinib, and the preparation method is short in
synthesis route and high in efficiency. More particularly, a
nitrogen atom of an amino group of the compound A, adopted in the
preparation method, contains a protective group R. This is
favorable for avoiding a complexation reaction of the nitrogen atom
on the amino group and another atom in the reaction system, thereby
favorably promoting the aminocarbonylation reaction, improving a
yield, simultaneously reducing preparation cost and improving
economy.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] The drawings forming a part of the disclosure are adopted to
provide a further understanding to the disclosure. Schematic
embodiments of the disclosure and descriptions thereof are adopted
to explain the disclosure and not intended to form improper limits
to the disclosure. In the drawings:
[0026] FIG. 1 is a Nuclear Magnetic Resonance (NMR) spectrogram of
nilotinib prepared according to embodiment 1 of the disclosure.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0027] It is important to note that the embodiments in the
disclosure and characteristics in the embodiments may be combined
under the condition of no conflicts. The disclosure will be
described below in detail with reference to the embodiments.
[0028] As mentioned in the background, the problems of long route
and relatively high cost of nilotinib synthesis in an existing
process are required to be solved. For solving the problems, the
disclosure provides a method for preparing nilotinib. The
preparation method comprises the following steps: performing an
aminocarbonylation reaction on a compound A and
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline to obtain
an amination product; and performing R group deprotection treatment
on the amination product to the nilotinib, wherein the compound A
has a structure shown in formula I:
##STR00008##
[0029] the R group includes, but not limited to, benzyl,
--COCF.sub.3, --CHO or --CO.sub.2R', wherein an R' group includes,
but not limited to, C.sub.1.about.C.sub.10 alkyl,
C.sub.1.about.C.sub.3 alkoxy ethyl or C.sub.7.about.C.sub.19
aralkyl.
[0030] In the disclosure, the aminocarbonylation reaction is
creatively applied to a route for synthesizing the nilotinib.
Particularly, as a raw material, the compound A with the structure
shown in formula I is reacted with the
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline to
obtain the amination product. Then, the R group contained on the
amination product is removed to obtain a target product nilotinib
by virtue of the deprotection treatment. The preparation method is
short in synthesis route and high in efficiency. More particularly,
a nitrogen atom of an amino group of the compound A, adopted in the
preparation method, contains a protective group R. This is
favorable for avoiding a complexion reaction of the nitrogen atom
on the amino group and another atom in a reaction system, thereby
favorably promoting the aminocarbonylation reaction, improving a
yield, simultaneously reducing preparation cost and improving
economy.
[0031] In the preparation method, those skilled in the art may
select a specific operating process for the carbonylation
esterification reaction. In a preferred implementation mode, the
carbonylation esterification reaction is performed on the compound
A under a condition of existence of an organic solvent, a catalyst
and a carbon monoxide, wherein a molar ratio of the
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline to the
compound A is 0.5:1.about.2:1, and a using amount of the catalyst
is 0.1.about.20% of a mole number of the compound A.
[0032] In the preparation method, the catalyst may be common
species of the field. In a preferred implementation mode, the
catalyst includes a first catalyst and a second catalyst, wherein
the first catalyst includes, but not limited to, one or more in a
group formed by PdCl.sub.2(PPh.sub.3).sub.2,
PdCl.sub.2(PhCN).sub.2, PdCl.sub.2(CH.sub.3CN).sub.2,
Pd(PPh.sub.3).sub.4, Pd.sub.2(dba).sub.3CH.sub.2Cl.sub.2,
PdCl.sub.2(dppf)CH.sub.2Cl.sub.2 and an allylpalladium chloride
dimer; and the second catalyst includes, but not limited to, one or
more in a group formed by triphenylphosphine,
tricyclohexylphosphonium tetrafluoroborate,
tri-tert-butylphosphine, 1,1'-bis(diphenylphosphino)ferrocene,
1,2-bis(diphenylphosphinoyl)ethane,
1,3-bis(diphenylphosphinoyl)propane and
1,3-bis(diisopropylphosphino)propane. Compared with independent use
of a palladium chloride catalyst, simultaneous use of the first
catalyst and the second catalyst is favorable for enhancing an
electron density of a palladium atom. As a result, a catalytic
activity of the palladium chloride catalyst is further enhanced. In
addition, the catalyst is low in cost and readily available, and
adopting the catalyst is favorable for further reducing process
cost. Preferably, a molar ratio of the first catalyst to the second
catalyst is 1:0.5.about.1:4. Adopting the ratio is favorable for
further improving the catalytic activity of the catalyst.
[0033] In the preparation method, the organic solvent may be a
common species of the field. In a preferred implementation mode,
the organic solvent includes, but not limited to, one or more in a
group formed by N,N-dimethylformamide, N,N-dimethylacetamide,
N-methyl pyrrolidinone, N-ethyl pyrrolidinone, dimethyl sulfoxide
and dioxane. The organic solvent above has high solubility for all
the reactants used in the disclosure, and may provide a stable
reaction environment for the reactants.
[0034] In the preparation method, adopting the abovementioned
process condition and raw material may shorten the reaction route,
improve the yield of the nilotinib and simultaneously reduce the
production cost. In a preferred implementation mode, in the
carbonylation esterification reaction process, a nucleophilic
promoter is added into the reaction system of that, and the
nucleophilic promoter includes, but not limited to, one or more in
a group formed by phenol, p-chlorophenol, naphthol and
4-methyl-1-naphthol. Compared with alkyl amines, an aromatic amine
has relatively poor nucleophilicity. In the preparation method of
the disclosure, the nucleophilic promoter is added in the
carbonylation reaction process, so that the nucleophilicity of the
aromatic amine may be improved, the reaction condition for the
carbonylation esterification reaction is further reduced, and the
reaction is milder and safer in operation. In addition, adopting
the above nucleophilic promoters is favorable for further improving
the nucleophilicity of the aromatic amine.
[0035] In the preparation method, those skilled in the art may
select an amount of the nucleophilic promoter. In a preferred
implementation mode, the amount of the nucleophilic promoter is
0.17.about.300% of the mole number of the compound A. Controlling
the amount of the nucleophilic promoter within the range above is
favorable for further improving the nucleophilicity of the aromatic
amine and making the reaction condition milder.
[0036] In the preparation method, adopting the abovementioned
process condition and raw material may shorten the reaction route,
improve the yield of the nilotinib and simultaneously reduce the
production cost. In a preferred implementation mode, in the
aminocarbonylation reaction process, an acid-binding agent is added
into the reaction system of that, and the acid-binding agent
includes, but not limited to, one or more in a group formed by
triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline,
DABCO, DBU, pyridine, potassium carbonate, potassium phosphate,
sodium carbonate and sodium phosphate. An acidic byproduct may be
formed in the carbonylation process. Adding the acid-binding agent
may remove the acidic byproduct, thereby increasing the reaction
rate. In addition, all reactions involved in the disclosure are
organic reactions. During a practical operation, a desiccant is
preferably added into the reaction system, and the water remover
includes, but not limited to, one or more in a group formed by a 4
A molecular sieve, sodium sulfate, magnesium sulfate and a calcium
oxide.
[0037] In the preparation method, those skilled in the art may
select an amount of the acid-binding agent. In a preferred
implementation mode, the acid-binding agent is 1.about.10 times the
mole number of the compound A. Controlling the amount of the
acid-binding agent within the range is favorable for further
increasing the reaction rate of the carbonylation esterification
reaction.
[0038] In a practical operating process, raw materials are
preferably added into a reaction kettle at one time, then
performing the carbonylation esterification reaction and amination
reaction with a "one-pot method". Preferably, in a process of
preparing the nilotinib in the disclosure, all the reactants, the
solvent and the catalyst are added together into the reaction
kettle, then CO is introduced into the reaction kettle, pressure is
controlled to be 0.2.about.0.4 MPa, and a reaction temperature is
controlled to be 80.about.110.degree. C.
[0039] In the preparation method, those skilled in the art may
select a type of the protective group R in the compound A as long
as it may protect the nitrogen atom and may be removed by a later
deprotection treatment. In a preferred implementation mode, the
C.sub.1.about.C.sub.10 alkyl includes, but not limited to, methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or
cyclohexyl, the C.sub.1.about.C.sub.3 alkoxy ethyl includes, but
not limited to, methoxyethyl, propoxyethyl or chloroethoxyethyl,
and the C.sub.7.about.C.sub.19 aralkyl includes, but not limited
to, benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl or
triphenylmethyl. The abovementioned substituents are stable in
chemical property, have good electron donating effects, and may be
easily removed in a deprotection treatment process. Therefore,
adopting the abovementioned substituents is favorable for improving
stability of the compound A, and simultaneously makes the
deprotection treatment process easy and convenient to operate.
[0040] In the preparation method, when different protective agents
are introduced into the compound A, those skilled in the art may
select a specific operation for the deprotection treatment. In a
preferred implementation mode, when the R group is the benzyl,
hydrogen is introduced into the system containing the amination
product, which can remove the benzyl by hydrogenation. Then, a
reaction solution is taken out, and the water remover is filtered
to obtain a filtrate. Next, aqueous alkali at a mass concentration
of 1% is added into the filtrate, and solids are precipitated by
stirring. Finally, drying treatment is performed on the solids to
obtain the nilotinib.
[0041] In another preferred implementation mode, when the R group
is the --COCF.sub.3 or the --CHO, the system containing the
amination product is diluted with a Methyl Tert-Butyl Ether (MTBE)
at first, and the water remover is filtered to obtain a filtrate.
Then, aqueous alkali at a mass concentration of 10% is added into
the filtrate, and solids are precipitated by stirring. Finally, the
drying treatment is performed on the solids to obtain the
nilotinib.
[0042] In another implementation mode, when the R group is a
t-butyloxycarbonyl (Boc protective agent), the system containing
the amination product is diluted with MTBE at first, and the water
remover is filtered to obtain filtrate. Then, aqueous alkali at a
mass concentration of 1% is added into the filtrate, and solids are
precipitated by stirring. Next, the obtained solids are added into
a trifluoroacetic acid, and the Boc protective agent is removed.
Later on, the superfluous trifluoroacetic acid is removed by
concentration, then ethanol is added, and crystallization is
performed after heating and dissolving, and nilotinib
trifluoroacetate is obtained. Then, the nilotinib trifluoroacetate
is dissolved with the ethanol, a solution of KOH is added to
regulate pH=6.about.9, and then the nilotinib may be dissociated.
Finally, the system is filtered, washed and dried to obtain the
nilotinib. Preferably, the aqueous alkali is an aqueous solution of
K.sub.2CO.sub.3 or an aqueous solution of KOH.
[0043] When the R group is the --CO.sub.2R' and the R' group is the
C.sub.1.about.C.sub.10 alkyl, the R group is removed by the
following specific treatment steps: filtering solids from the
aminocarbonylation reaction system, adding a 10% aqueous solution
of the KOH, performing heating to 90.about.100.degree. C., and
after complete reaction (8 h), adding an excessive amount of water
to precipitate a crude nilotinib product.
[0044] When the R group is the --CO.sub.2R' and the R' group is the
C.sub.1.about.C.sub.3 alkoxy ethyl, the R group is removed by the
following specific treatment steps: filtering solids from the
aminocarbonylation reaction system, adding a 20% hydrochloric acid
for a stirring reaction, and after tracking to complete reaction (3
h), adding a 20% aqueous solution of the KOH to precipitate a crude
nilotinib product.
[0045] When the R group is the --CO.sub.2R' and the R' group is the
C.sub.7.about.C.sub.19 aralkyl, the R group is removed by the
following specific treatment steps: filtering solids from the
aminocarbonylation reaction system, adding a solution of the KOH at
a mass concentration of 10%, and performing stirring for 6 h at
40.about.50.degree. C. to remove the protective group R. In the
reaction solution, purified water (100 mL) is added to precipitate
the solids.
[0046] The disclosure will be further described below in detail
with reference to specific embodiments, and these embodiments may
not be understood to limit the required scope of protection of the
disclosure.
Embodiment 1
[0047] Dimethylformamide (1 L),
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline (aromatic
amine, 0.54 mol),
(5-bromo-2-methylphenyl(4-(pyridine-3-yl)pyrimidine-2-yl)-tert-butyl
carbamate (0.648 mol), a
1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride
dichloromethane complex (0.016 mol), triphenylphosphine (0.032
mol), phenol (2.5 g, 0.027 mol), triethylamine (1.62 mol) and a 4 A
molecular sieve (100 g) are added into an autoclave for uniform
stirring. Nitrogen is introduced to displace air, and then a carbon
monoxide is introduced to displace the nitrogen and the pressure in
the autoclave is increased to 0.8 MPa. A temperature is increased
by heating to 90.about.105.degree. C. for reaction. After 42 h
reaction, a product system containing an amination product is
obtained. The product system is cooled to be below 50.degree. C.,
and the carbon monoxide is evacuated and displaced with the
nitrogen.
[0048] The product system is diluted with an MTBE (1 L), and the
molecular sieve is filtered to obtain a filtrate. An aqueous
solution of K.sub.2CO.sub.3 (10 L) at a mass concentration of 1% is
added into the filtrate, and solids are precipitated by stirring.
The solids are added into a trifluoroacetic acid (500 mL) to remove
a Boc protective group. After the superfluous trifluoroacetic acid
is removed by concentration, ethanol (2 L) is added for heating
dissolving. Then, crystallization is performed to obtain nilotinib
trifluoroacetate. The nilotinib trifluoroacetate is dissolved with
the ethanol, an aqueous solution of KOH is added to regulate
pH=6.about.9, and a nilotinib product (249 g) is obtained by
filtering, washing and drying, a yield being 87% and an NMR
spectrogram of the product being shown in FIG. 1. A High
Performance Liquid Chromatography (HPLC) purity of the product is
measured to be 99%.
Embodiment 2
[0049] Dimethylformamide (10 mL),
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline
(aromatic amine, 4.5 mmol),
(5-bromo-2-methylphenyl(4-(pyridine-3-yl)
pyrimidine-2-yl)-tert-butyl carbamate (5.4 mmol), a
1,1'-bis(diphenylphosphino) ferrocene-palladium(II) dichloride
dichloromethane complex (0.135 mmol), triphenylphosphine (0.27
mmol), phenol (0.225 mmol), triethylamine (13.5 mmol) and a 4 A
molecular sieve (1 g) are added into an autoclave for uniform
stirring. Nitrogen is introduced to displace air, and then a carbon
monoxide is introduced to displace the nitrogen and the pressure in
the autoclave is increased to 0.8 MPa. A temperature is increased
by heating to 90.about.105.degree. C. for reaction. After 72 h
reaction, a product system containing an amination product is
obtained. The product system is cooled to be below 50.degree. C.,
and the carbon monoxide is evacuated and displaced with the
nitrogen.
[0050] The system is diluted with an MTBE (10 mL), and the
molecular sieve is filtered to obtain a filtrate. An aqueous
solution of K.sub.2CO.sub.3 (100 mL) at a mass concentration of 1%
is added into the filtrate, and solids are precipitated by
stirring. A 4 mol/L hydrochloric acid (2 mL) is added to remove a
Boc protective group by 4 h stirring. Ethanol (20 mL) is added into
the reaction solution for heating dissolving. Then, crystallization
is performed to obtain nilotinib trifluoroacetate. The nilotinib
trifluoroacetate is dissolved with the ethanol, an aqueous solution
of KOH is added to regulate pH=6.about.9, and a nilotinib product
(1.7 g) is obtained by filtering, washing and drying, a yield being
72%. An HPLC purity of the product is measured to be 98%.
Embodiment 3
[0051] Dioxane (10 mL),
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline (aromatic
amine, 4.5 mmol), (N-benzyl-N-5-bromo-2-methylpheny
1(4-pyridine-3-yl)pyrimidine-2-amine (5.4 mmol),
trans-dichlorobis(triphenyl-phosphine)palladium (0.135 mmol),
1,1'-bis(diphenylphosphino)ferrocene (0.135 mmol), phenol (0.225
mmol), triethylamine (13.5 mmol) and a 4 A molecular sieve (1 g)
are added into an autoclave for uniform stirring. Nitrogen is
introduced to displace air, and then a carbon monoxide is
introduced to displace the nitrogen and the pressure in the
autoclave is increased to 0.8 MPa. A temperature is increased by
heating to 90.about.105.degree. C. for reaction. After 65 h
reaction, a product system containing an amination product is
obtained. The product system is cooled to be below 50.degree. C.,
and the carbon monoxide is evacuated and displaced with the
nitrogen.
[0052] The
(N-benzyl-N-5-bromo-2-methylphenyl(4-pyridine-3-yl)pyrimidine-2-
-amine (5.4 mmol), the bis(triphenylphosphine) potassium dichloride
(0.162 mmol) and the 1,1'-bis(diphenylphosphino)ferrocene (0.108
mmol) are added, and hydrogen is introduced into the system to 2
MPa for hydrogenation benzyl removal. After 24 h reaction, the
nitrogen is introduced to displace the hydrogen, and after the
reaction solution is taken out, the molecular sieve is filtered. An
aqueous solution of K.sub.2CO.sub.3 (100 mL) at a mass
concentration of 1% is added into a filtrate, and solids are
precipitated by stirring. Then, the solids are dried to obtain a
nilotinib product (1.48 g), a yield being 62%. An HPLC purity of
the product is measured to be 98%.
Embodiment 4
[0053] N-methyl pyrrolidinone (10 mL),
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline
(aromatic amine, 4.5 mmol),
(5-bromo-2-methylphenyl(4-(pyridine-3-yl)
pyrimidine-2-yl)-tert-butyl carbamate (5.4 mmol),
trans-dichlorobis(triphenyl-phosphine)palladium (0.135 mmol), a
phosphorus ligand XantPhos (0.135 mmol), phenol (0.225 mmol),
triethylamine (13.5 mmol) and a 4 A molecular sieve (1 g) are added
into an autoclave for uniform stirring. Nitrogen is introduced to
displace air, and then a carbon monoxide is introduced to displace
the nitrogen and the pressure in the autoclave is increased to 0.8
MPa. A temperature is increased by heating to 90.about.105.degree.
C. for reaction. After 65 h reaction, a product system containing
an amination product is obtained. The product system is cooled to
room temperature, and the carbon monoxide is evacuated and
displaced with the nitrogen.
[0054] The system is diluted with an MTBE (10 mL), and the
molecular sieve is filtered to obtain a filtrate. An aqueous
solution of K.sub.2CO.sub.3 (100 mL) at a mass concentration of 1%
is added into the filtrate, and solids are precipitated by
stirring. A trifluoroacetic acid (4 mL) is added to remove a Boc
protective group by 0.5 h stirring. Ethanol (20 mL) is added into
the reaction solution for heating dissolving. Then, crystallization
is performed to obtain nilotinib trifluoroacetate. The nilotinib
trifluoroacetate is dissolved with the ethanol, an aqueous solution
of KOH is added to regulate pH=6.about.9, and a nilotinib product
(1.9 g) is obtained by filtering, washing and drying, a yield being
80%. An HPLC purity of the product is measured to be 99%.
Embodiment 5
[0055] Dimethylformamide (10 mL),
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline
(aromatic amine, 4.5 mmol),
N-(5-bromo-2-methylphenyl)-2,2,2-trifluoro-N-(4-(pyridine-3-yl)pyrimidine-
-2-yl)acetamide (5.4 mmol), a
1,1'-bis(diphenylphosphino)ferrocene-palladium (II) dichloride
dichloromethane complex (0.135 mmol), triphenylphosphine (0.27
mmol), phenol (0.225 mmol), triethylamine (13.5 mmol) and a 4 A
molecular sieve (1 g) are added into an autoclave for uniform
stirring. Nitrogen is introduced to displace air, and then a carbon
monoxide is introduced to displace the nitrogen to the pressure in
the autoclave is increased to 0.8 MPa. A temperature is increased
by heating to 90.about.105.degree. C. for reaction. After 72 h
reaction, a product system containing an amination product is
obtained. The product system is cooled to be below 50.degree. C.,
and the carbon monoxide is evacuated and displaced with the
nitrogen.
[0056] The molecular sieve is filtered from the system with the
amination product to obtain a filtrate. A solution of KOH (3 mL) at
a mass concentration of 10% is added into the filtrate, and
stirring is performed for 2 h at 40.about.50.degree. C. to remove a
trifluoroacetyl protective group. Purified water (100 mL) is added
into the reaction solution to precipitate solids. The solids are
dried to obtain a nilotinib product (2.0 g), a yield being 84%. An
HPLC purity of the product is measured to be 98%.
Embodiment 6
[0057] Dimethylformamide (10 mL),
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline
(aromatic amine, 4.5 mmol),
(5-bromo-2-methylphenyl(4-(pyridine-3-yl)
pyrimidine-2-yl)-methoxyethyl carbamate (5.4 mmol), a
1,1'-bis(diphenylphosphino) ferrocene-palladium(II) dichloride
dichloromethane complex (0.135 mmol), triphenylphosphine (0.27
mmol), phenol (0.225 mmol), triethylamine (13.5 mmol) and a 4 A
molecular sieve (1 g) are added into an autoclave for uniform
stirring. Nitrogen is introduced to displace air, and then a carbon
monoxide is introduced to displace the nitrogen and the pressure in
the autoclave is increased to 0.8 MPa. A temperature is increased
by heating to 90.about.105.degree. C. for reaction. After 48 h
reaction, a product system containing an amination product is
obtained. The product system is cooled to be below 50.degree. C.,
and the carbon monoxide is evacuated and displaced with the
nitrogen.
[0058] The system is diluted with an MTBE (10 mL), and the
molecular sieve is filtered to obtain a filtrate. An aqueous
solution of K.sub.2CO.sub.3 (100 mL) at a mass concentration of 1%
is added into the filtrate, and solids are precipitated by
stirring. A 4 mo1/L hydrochloric acid (2 mL) is added to remove a
protective group by 4 h stirring. Ethanol (20 mL) is added into the
reaction solution for heating dissolving. Then, crystallization is
performed to obtain nilotinib trifluoroacetate. The nilotinib
trifluoroacetate is dissolved with the ethanol, an aqueous solution
of KOH is added to regulate pH=6.about.9, and a nilotinib product
(1.8 g) is obtained by filtering, washing and drying, a yield being
75%. An HPLC purity of the product is measured to be 98%.
Embodiment 7
[0059] Dimethylformamide (10 mL),
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline
(aromatic amine, 4.5 mmol),
(5-bromo-2-methylphenyl(4-(pyridine-3-yl) pyrimidine-2-yl)-ethyl
carbamate (5.4 mmol), a 1,1'-bis(diphenylphosphino)
ferrocene-palladium(II) dichloride dichloromethane complex (0.135
mmol), triphenylphosphine (0.27 mmol), phenol (0.225 mmol),
triethylamine (13.5 mmol) and a 4 A molecular sieve (1 g) are added
into an autoclave for uniform stirring. Nitrogen is introduced to
displace air, and then a carbon monoxide is introduced to displace
the nitrogen and the pressure in the autoclave is increased to 0.8
MPa. A temperature is increased by heating to 90.about.105.degree.
C. for reaction. After 48 h reaction, a product system containing
an amination product is obtained. The product system is cooled to
be below 50.degree. C., and the carbon monoxide is evacuated and
displaced with the nitrogen.
[0060] The molecular sieve is filtered from the system with the
amination product to obtain a filtrate. A solution of KOH (3 mL) at
a mass concentration of 10% is added into the filtrate, and
stirring is performed for 2 h at 40.about.50.degree. C. to remove a
protective group. Purified water (100 mL) is added into the
reaction solution to precipitate solids. The solids are dried to
obtain a nilotinib product (1.9 g), a yield being 80%. An HPLC
purity of the product is measured to be 98%.
Embodiment 8
[0061] Dimethylformamide (10 mL),
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline
(aromatic amine, 4.5 mmol),
(5-bromo-2-methylphenyl(4-pyridine-3-yl) pyrimidine-2-yl)-benzyl
carbamate (5.4 mmol), a 1,1'-bis(diphenylphosphino)
ferrocene-palladium(II) dichloride dichloromethane complex (0.135
mmol), triphenylphosphine (0.27 mmol), phenol (0.225 mmol),
triethylamine (13.5 mmol) and a 4 A molecular sieve (1 g) are added
into an autoclave for uniform stirring. Nitrogen is introduced to
displace air, and then a carbon monoxide is introduced to displace
the nitrogen and the pressure in the autoclave is increased to 0.8
MPa. A temperature is increased by heating to 90.about.105.degree.
C. for reaction. After 48 h reaction, a product system containing
an amination product is obtained. The product system is cooled to
be below 50.degree. C., and the carbon monoxide is evacuated and
displaced with the nitrogen.
[0062] The molecular sieve is filtered from the system with the
amination product to obtain a filtrate. A solution of KOH (3 mL) at
a mass concentration of 10% is added into the filtrate, and
stirring is performed for 6 h at 40.about.50.degree. C. to remove a
protective group. Purified water (100 mL) is added into the
reaction solution to precipitate solids. The solids are dried to
obtain a nilotinib product (1.8 g), a yield being 77%. An HPLC
purity of the product is measured to be 98%.
Embodiment 9
[0063] Dimethylformamide (10 mL),
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline
(aromatic amine, 4.5 mmol),
(5-bromo-2-methylphenyl(4-pyridine-3-yl)
pyrimidine-2-yl)-tert-butyl carbamate (5.4 mmol), a
1,1'-bis(diphenylphosphino) ferrocene-palladium(II) dichloride
dichloromethane complex (0.135 mmol), triphenylphosphine (0.27
mmol), phenol (0.045 mmol), triethylamine (13.5 mmol) and a 4 A
molecular sieve (1 g) are added into an autoclave for uniform
stirring. Nitrogen is introduced to displace air, and then a carbon
monoxide is introduced to displace the nitrogen and the pressure in
the autoclave is increased to 0.8 MPa. A temperature is increased
by heating to 90.about.105.degree. C. for reaction. After 96 h
reaction, a product system containing an amination product is
obtained. The product system is cooled to be below 50.degree. C.,
and the carbon monoxide is evacuated and displaced with the
nitrogen.
[0064] The product system is diluted with an MTBE (10 mL), and the
molecular sieve is filtered to obtain a filtrate. An aqueous
solution of K.sub.2CO.sub.3 (100 mL) at a mass concentration of 1%
is added into the filtrate, and solids are precipitated by
stirring. The solids are added into a trifluoroacetic acid (5 mL)
to remove a Boc protective group. After the superfluous
trifluoroacetic acid is removed by concentration, ethanol (20 mL)
is added for heating dissolving. Then, crystallization is performed
to obtain nilotinib trifluoroacetate. The nilotinib
trifluoroacetate is dissolved with the ethanol, an aqueous solution
of KOH is added to regulate pH=6.about.9, and a nilotinib product
(1.7 g) is obtained by filtering, washing and drying, a yield being
70%. An HPLC purity of the product is measured to be 99%.
Embodiment 10
[0065] Dimethylformamide (10 mL),
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline
(aromatic amine, 4.5 mmol),
(5-bromo-2-methylphenyl(4-pyridine-3-yl)
pyrimidine-2-yl)-tert-butyl carbonate (5.4 mmol), a
1,1'-bis(diphenylphosphino) ferrocene-palladium(II) dichloride
dichloromethane complex (0.135 mmol), triphenylphosphine (0.27
mmol), phenol (13.5 mmol), triethylamine (13.5 mmol) and a 4 A
molecular sieve (1 g) are added into an autoclave for uniform
stirring. Nitrogen is introduced to displace air, and then a carbon
monoxide is introduced to displace the nitrogen and the pressure in
the autoclave is increased to 0.8 MPa. A temperature is increased
by heating to 90.about.105.degree. C. for reaction. After 36 h
reaction, a product system containing an amination product is
obtained. The product system is cooled to be below 50.degree. C.,
and the carbon monoxide is evacuated and displaced with the
nitrogen.
[0066] The product system is diluted with an MTBE (10 mL), and the
molecular sieve is filtered to obtain a filtrate. An aqueous
solution of K.sub.2CO.sub.3 (100 mL) at a mass concentration of 1%
is added into the filtrate, and solids are precipitated by
stirring. The solids are added into a trifluoroacetic acid (5 mL)
to remove a Boc protective group. After the superfluous
trifluoroacetic acid is removed by concentration, ethanol (20 mL)
is added for heating dissolving. Then, crystallization is performed
to obtain nilotinib trifluoroacetate. The nilotinib
trifluoroacetate is dissolved with the ethanol, an aqueous solution
of KOH is added to regulate pH=6.about.9, and a nilotinib product
(2.0 g) is obtained by filtering, washing and drying, a yield being
85%. An HPLC purity of the product is measured to be 99%.
Embodiment 11
[0067] Dimethylformamide (10 mL),
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline
(aromatic amine, 4.5 mmol),
(5-bromo-2-methylphenyl(4-pyridine-3-yl)
pyrimidine-2-yl)-tert-butyl carbamate (5.4 mmol), a
1,1'-bis(diphenylphosphino) ferrocene-palladium(II) dichloride
dichloromethane complex (0.135 mmol), triphenylphosphine (0.27
mmol), phenol (0.225 mmol), triethylamine (13.5 mmol) and a 4 A
molecular sieve (1 g) are added into an autoclave for uniform
stirring. Nitrogen is introduced to displace air, and then a carbon
monoxide is introduced to displace the nitrogen and the pressure in
the autoclave is increased to 0.2 MPa. A temperature is increased
by heating to 90.about.105.degree. C. for reaction, and the carbon
monoxide is required to be timely supplemented. After 96 h
reaction, a product system containing an amination product is
obtained. The product system is cooled to be below 50.degree. C.,
and the carbon monoxide is evacuated and displaced with the
nitrogen.
[0068] The product system is diluted with an MTBE (10 mL), and the
molecular sieve is filtered to obtain a filtrate. An aqueous
solution of K.sub.2CO.sub.3 (100 mL) at a mass concentration of 1%
is added into the filtrate, and solids are precipitated by
stirring. The solids are added into a trifluoroacetic acid (5 mL)
to remove a Boc protective group. After the superfluous
trifluoroacetic acid is removed by concentration, ethanol (20 mL)
is added for heating dissolving. Then, crystallization is performed
to obtain nilotinib trifluoroacetate. The nilotinib
trifluoroacetate is dissolved with the ethanol, an aqueous solution
of KOH is added to regulate pH=6.about.9, and a nilotinib product
(1.5 g) is obtained by filtering, washing and drying, a yield being
63%. An HPLC purity of the product is measured to be 98%.
Embodiment 12
[0069] Dimethylformamide (10 mL),
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline
(aromatic amine, 4.5 mmol),
(5-bromo-2-methylphenyl(4-pyridine-3-yl)
pyrimidine-2-yl)-tert-butyl carbamate (5.4 mmol), a
1,1'-bis(diphenylphosphino) ferrocene-palladium(II) dichloride
dichloromethane complex (0.135 mmol), triphenylphosphine (0.27
mmol), phenol (0.225 mmol), triethylamine (13.5 mmol) and a 4 A
molecular sieve (1 g) are added into an autoclave for uniform
stirring. Nitrogen is introduced to displace air, and then a carbon
monoxide is introduced to displace the nitrogen and the pressure in
the autoclave is increased to 4.0 MPa. A temperature is increased
by heating to 90.about.105.degree. C. for reaction. After 36 h
reaction, a product system containing an amination product is
obtained. The product system is cooled to be below 50.degree. C.,
and the carbon monoxide is evacuated and displaced with the
nitrogen.
[0070] The product system is diluted with an MTBE (10 mL), and the
molecular sieve is filtered to obtain a filtrate. An aqueous
solution of K.sub.2CO.sub.3 (100 mL) at a mass concentration of 1%
is added into the filtrate, and solids are precipitated by
stirring. The solids are added into a trifluoroacetic acid (5 mL)
to remove a Boc protective group. After the superfluous
trifluoroacetic acid is removed by concentration, ethanol (20 mL)
is added for heating dissolving. Then, crystallization is performed
to obtain nilotinib trifluoroacetate. The nilotinib
trifluoroacetate is dissolved with the ethanol, an aqueous solution
of KOH is added to regulate pH=6.about.9, and a nilotinib product
(2.1 g) is obtained by filtering, washing and drying, a yield being
87%. An HPLC purity of the product is measured to be 99%.
Embodiment 13
[0071] Dimethylformamide (10 mL),
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline
(aromatic amine, 4.5 mmol),
(5-bromo-2-methylphenyl(4-pyridine-3-yl)
pyrimidine-2-yl)-tert-butyl carbamate (5.4 mmol), a
1,1'-bis(diphenylphosphino) ferrocene-palladium(II) dichloride
dichloromethane complex (0.0045 mmol), triphenylphosphine (0.009
mmol), phenol (0.0075 mmol), triethylamine (13.5 mmol) and a 4 A
molecular sieve (1 g) are added into an autoclave for uniform
stirring. Nitrogen is introduced to displace air, and then a carbon
monoxide is introduced to displace the nitrogen and the pressure in
the autoclave is increased to 0.8 MPa. A temperature is increased
by heating to 90.about.105.degree. C. for reaction. After 96 h
reaction, a product system containing an amination product is
obtained. The product system is cooled to be below 50.degree. C.,
and the carbon monoxide is evacuated and displaced with the
nitrogen.
[0072] The product system is diluted with an MTBE (10 mL), and the
molecular sieve is filtered to obtain a filtrate. An aqueous
solution of K.sub.2CO.sub.3 (100 mL) at a mass concentration of 1%
is added into the filtrate, and solids are precipitated by
stirring. The solids are added into a trifluoroacetic acid (5 mL)
to remove a Boc protective group. After the superfluous
trifluoroacetic acid is removed by concentration, ethanol (20 mL)
is added for heating dissolving. Then, crystallization is performed
to obtain nilotinib trifluoroacetate. The nilotinib
trifluoroacetate is dissolved with the ethanol, an aqueous solution
of KOH is added to regulate pH=6.about.9, and a nilotinib product
(1.19 g) is obtained by filtering, washing and drying, a yield
being 50%. An HPLC purity of the product is measured to be 98%.
Embodiment 14
[0073] Dimethylformamide (10 mL),
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline
(aromatic amine, 4.5 mmol),
(5-bromo-2-methylphenyl(4-pyridine-3-yl)
pyrimidine-2-yl)-tert-butyl carbamate (5.4 mmol), a
1,1'-bis(diphenylphosphino) ferrocene-palladium(II) dichloride
dichloromethane complex (0.9 mmol), triphenylphosphine (1.8 mmol),
phenol (1.5 mmol), triethylamine (13.5 mmol) and a 4 A molecular
sieve (1 g) are added into an autoclave for uniform stirring.
Nitrogen is introduced to displace air, and then a carbon monoxide
is introduced to displace the nitrogen and the pressure in the
autoclave is increased to 0.8 MPa. A temperature is increased by
heating to 90.about.105.degree. C. for reaction. After 10 h
reaction, a product system containing an amination product is
obtained. The product system is cooled to be below 50.degree. C.,
and the carbon monoxide is evacuated and displaced with the
nitrogen.
[0074] The product system is diluted with an MTBE (10 mL), and the
molecular sieve is filtered to obtain a filtrate. An aqueous
solution of K.sub.2CO.sub.3 (100 mL) at a mass concentration of 1%
is added into the filtrate, and solids are precipitated by
stirring. The solids are added into a trifluoroacetic acid (5 mL)
to remove a Boc protective group. After the superfluous
trifluoroacetic acid is removed by concentration, ethanol (20 mL)
is added for heating dissolving. Then, crystallization is performed
to obtain nilotinib trifluoroacetate. The nilotinib
trifluoroacetate is dissolved with the ethanol, an aqueous solution
of KOH is added to regulate pH=6.about.9, and a nilotinib product
(2.1 g) is obtained by filtering, washing and drying, a yield being
88%. An HPLC purity of the product is measured to be 99%.
Embodiment 15
[0075] Dimethylformamide (10 mL),
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline
(aromatic amine, 4.5 mmol),
(5-bromo-2-methylphenyl(4-pyridine-3-yl)
pyrimidine-2-yl)-tert-butyl carbamate (5.4 mmol), a
1,1'-bis(diphenylphosphino) ferrocene-palladium(II) dichloride
dichloromethane complex (0.135 mmol), triphenylphosphine (0.27
mmol), phenol (0.225 mmol), triethylamine (4.5 mmol) and a 4 A
molecular sieve (1 g) are added into an autoclave for uniform
stirring. Nitrogen is introduced to displace air, and then a carbon
monoxide is introduced to displace the nitrogen and the pressure in
the autoclave is increased to 0.8 MPa. A temperature is increased
by heating to 90.about.105.degree. C. for reaction. After 48 h
reaction, a product system containing an amination product is
obtained. The product system is cooled to be below 50.degree. C.,
and the carbon monoxide is evacuated and displaced with the
nitrogen.
[0076] The product system is diluted with an MTBE (10 mL), and the
molecular sieve is filtered to obtain a filtrate. An aqueous
solution of K.sub.2CO.sub.3 (100 mL) at a mass concentration of 1%
is added into the filtrate, and solids are precipitated by
stirring. The solids are added into a trifluoroacetic acid (5 mL)
to remove a Boc protective group. After the superfluous
trifluoroacetic acid is removed by concentration, ethanol (20 mL)
is added for heating dissolving. Then, crystallization is performed
to obtain nilotinib trifluoroacetate. The nilotinib
trifluoroacetate is dissolved with the ethanol, an aqueous solution
of KOH is added to regulate pH=6.about.9, and a nilotinib product
(1.6 g) is obtained by filtering, washing and drying, a yield being
68%. An HPLC purity of the product is measured to be 99%.
Embodiment 16
[0077] Dimethylformamide (10 mL),
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline
(aromatic amine, 4.5 mmol),
(5-bromo-2-methylphenyl(4-pyridine-3-yl)
pyrimidine-2-yl)-tert-butyl carbamate (5.4 mmol), a
1,1'-bis(diphenylphosphino) ferrocene-palladium(II) dichloride
dichloromethane complex (0.135 mmol), triphenylphosphine (0.27
mmol), phenol (0.225 mmol), triethylamine (45 mmol) and a 4 A
molecular sieve (1 g) are added into an autoclave for uniform
stirring. Nitrogen is introduced to displace air, and then a carbon
monoxide is introduced to displace the nitrogen and the pressure in
the autoclave is increased to 0.8 MPa. A temperature is increased
by heating to 90.about.105.degree. C. for reaction. After 48 h
reaction, a product system containing an amination product is
obtained. The product system is cooled to be below 50.degree. C.,
and the carbon monoxide is evacuated and displaced with the
nitrogen.
[0078] The product system is diluted with an MTBE (10 mL), and the
molecular sieve is filtered to obtain a filtrate. An aqueous
solution of K.sub.2CO.sub.3 (100 mL) at a mass concentration of 1%
is added into the filtrate, and solids are precipitated by
stirring. The solids are added into a trifluoroacetic acid (5 mL)
to remove a Boc protective group. After the superfluous
trifluoroacetic acid is removed by concentration, ethanol (20 mL)
is added for heating dissolving. Then, crystallization is performed
to obtain nilotinib trifluoroacetate. The nilotinib
trifluoroacetate is dissolved with the ethanol, an aqueous solution
of KOH is added to regulate pH=6.about.9, and a nilotinib product
(2.1 g) is obtained by filtering, washing and drying, a yield being
88%. An HPLC purity of the product is measured to be 99%.
Embodiment 17
[0079] Dimethylformamide (10 mL),
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline
(aromatic amine, 4.5 mmol),
(5-bromo-2-methylphenyl(4-pyridine-3-yl)
pyrimidine-2-yl)-tert-butyl carbamate (5.4 mmol), a
bis(benzonitrile)palladium(II) chloride (0.135 mmol),
1,2-Bis(diphenylphosphine)ethane (DPPE) (0.27 mmol), phenol (0.225
mmol), triethylamine (13.5 mmol) and a 4 A molecular sieve (1 g)
are added into an autoclave for uniform stirring. Nitrogen is
introduced to displace air, and then a carbon monoxide is
introduced to displace the nitrogen and the pressure in the
autoclave is increased to 0.8 MPa. A temperature is increased by
heating to 90.about.105.degree. C. for reaction. After 48 h
reaction, a product system containing an amination product is
obtained. The product system is cooled to be below 50.degree. C.,
and the carbon monoxide is evacuated and displaced with the
nitrogen.
[0080] The product system is diluted with an MTBE (10 mL), and the
molecular sieve is filtered to obtain a filtrate. An aqueous
solution of K.sub.2CO.sub.3 (100 mL) at a mass concentration of 1%
is added into the filtrate, and solids are precipitated by
stirring. The solids are added into a trifluoroacetic acid (5 mL)
to remove a Boc protective group. After the superfluous
trifluoroacetic acid is removed by concentration, ethanol (20 mL)
is added for heating dissolving. Then, crystallization is performed
to obtain nilotinib trifluoroacetate. The nilotinib
trifluoroacetate is dissolved with the ethanol, an aqueous solution
of KOH is added to regulate pH=6.about.9, and a nilotinib product
(2.38 g) is obtained by filtering, washing and drying, a yield
being 100%. An HPLC purity of the product is measured to be
99%.
[0081] The system is diluted with the MTBE (10 mL), and the
molecular sieve is filtered to obtain the filtrate. At first, an
aqueous solution of K.sub.2CO.sub.3 (100 mL) at a mass
concentration of 2% is added into the filtrate, and solids are
precipitated by stirring. Then, acetonitrile (10 mL) is added into
the solids, and beating purification is performed once to twice to
obtain off-white solids. Next, a trifluoroacetic acid (5 mL) is
added to remove a Boc protective group, the superfluous
trifluoroacetic acid is removed by concentration, and ethanol (20
mL) is added for heating dissolving. Finally, crystallization is
performed to obtain nilotinib trifluoroacetate. The nilotinib
trifluoroacetate is dissolved with the ethanol, an aqueous solution
of KOH is added to regulate pH=6.about.9, and a nilotinib product
(1.42 g) is obtained by filtering, washing and drying, a yield
being 60%. An HPLC purity of the product is measured to be 99%.
Embodiment 18
[0082] Dimethylformamide (10 mL),
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline
(aromatic amine, 4.5 mmol),
(5-bromo-2-methylphenyl(4-pyridine-3-yl)
pyrimidine-2-yl)-tert-butyl carbamate (5.4 mmol), allylpalladium
chloride dimer (0.135 mmol), tricyclohexylphosphonium
tetrafluoroborate (0.27 mmol), phenol (0.225 mmol), triethylamine
(13.5 mmol) and a 4 A molecular sieve (1 g) are added into an
autoclave for uniform stirring. Nitrogen is introduced to displace
air, and then a carbon monoxide is introduced to displace the
nitrogen and the pressure in the autoclave is increased to 0.8 MPa.
A temperature is increased by heating to 90.about.105.degree. C.
for reaction. After 48 h reaction, a product system containing an
amination product is obtained. The product system is cooled to be
below 50.degree. C., and the carbon monoxide is evacuated and
displaced with the nitrogen.
[0083] The product system is diluted with an MTBE (10 mL), and the
molecular sieve is filtered to obtain a filtrate. An aqueous
solution of K.sub.2CO.sub.3 (100 mL) at a mass concentration of 1%
is added into the filtrate, and solids are precipitated by
stirring. The solids are added into a trifluoroacetic acid (5 mL)
to remove a Boc protective group. After the superfluous
trifluoroacetic acid is removed by concentration, ethanol (20 mL)
is added for heating dissolving. Then, crystallization is performed
to obtain nilotinib trifluoroacetate. The nilotinib
trifluoroacetate is dissolved with the ethanol, an aqueous solution
of KOH is added to regulate pH=6.about.9, and a nilotinib product
(1.7 g) is obtained by filtering, washing and drying, a yield being
72%. An HPLC purity of the product is measured to be 99%.
Embodiment 19
[0084] Dimethylformamide (10 mL),
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline
(aromatic amine, 4.5 mmol),
(5-bromo-2-methylphenyl(4-pyridine-3-yl)
pyrimidine-2-yl)-tert-butyl carbamate (9.0 mmol),
1,1'-bis(diphenylphosphino) ferrocene-palladium(II) dichloride
dichloromethane complex (0.135 mmol), triphenylphosphine (0.27
mmol), phenol (0.225 mmol), triethylamine (13.5 mmol) and a 4 A
molecular sieve (1 g) are added into an autoclave for uniform
stirring. Nitrogen is introduced to displace air, and then a carbon
monoxide is introduced to displace the nitrogen and the pressure in
the autoclave is increased to 0.8 MPa. A temperature is increased
by heating to 90.about.105.degree. C. for reaction. After 48 h
reaction, a product system containing an amination product is
obtained. The product system is cooled to be below 50.degree. C.,
and the carbon monoxide is evacuated and displaced with the
nitrogen.
[0085] The product system is diluted with an MTBE (10 mL), and the
molecular sieve is filtered to obtain a filtrate. An aqueous
solution of K.sub.2CO.sub.3 (100 mL) at a mass concentration of 1%
is added into the filtrate, and solids are precipitated by
stirring. The solids are added into a trifluoroacetic acid (5 mL)
to remove a Boc protective group. After the superfluous
trifluoroacetic acid is removed by concentration, ethanol (20 mL)
is added for heating dissolving. Then, crystallization is performed
to obtain nilotinib trifluoroacetate. The nilotinib
trifluoroacetate is dissolved with the ethanol, an aqueous solution
of KOH is added to regulate pH=6.about.9, and a nilotinib product
(2.0 g) is obtained by filtering, washing and drying, a yield being
85%. An HPLC purity of the product is measured to be 99%.
Embodiment 20
[0086] Dimethylformamide (10 mL),
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline
(aromatic amine, 9.0 mmol),
(5-bromo-2-methylphenyl(4-pyridine-3-yl)
pyrimidine-2-yl)-tert-butyl carbamate (4.5 mmol),
1,1'-bis(diphenylphosphino) ferrocene-palladium(II) dichloride
dichloromethane complex (0.135 mmol), triphenylphosphine (0.27
mmol), phenol (0.225 mmol), triethylamine (13.5 mmol) and a 4 A
molecular sieve (1 g) are added into an autoclave for uniform
stirring. Nitrogen is introduced to displace air, and then a carbon
monoxide is introduced to displace the nitrogen and the pressure in
the autoclave is increased to 0.8 MPa. A temperature is increased
by heating to 90.about.105.degree. C. for reaction. After 48 h
reaction, a product system containing an amination product is
obtained. The product system is cooled to be below 50.degree. C.,
and the carbon monoxide is evacuated and displaced with the
nitrogen.
[0087] The product system is diluted with an MTBE (10 mL), and the
molecular sieve is filtered to obtain a filtrate. An aqueous
solution of K.sub.2CO.sub.3 (100 mL) at a mass concentration of 1%
is added into the filtrate, and solids are precipitated by
stirring. The solids are added into a trifluoroacetic acid (5 mL)
to remove a Boc protective group. After the superfluous
trifluoroacetic acid is removed by concentration, ethanol (20 mL)
is added for heating dissolving. Then, crystallization is performed
to obtain nilotinib trifluoroacetate. The nilotinib
trifluoroacetate is dissolved with the ethanol, an aqueous solution
of KOH is added to regulate pH=6.about.9, and a nilotinib product
(1.42 g) is obtained by filtering, washing and drying, a yield
being 60%. An HPLC purity of the product is measured to be 95%.
Embodiment 21
[0088] Dimethylformamide (10 mL),
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline
(aromatic amine, 4.5 mmol),
(5-bromo-2-methylphenyl(4-pyridine-3-yl)
pyrimidine-2-yl)-tert-butyl carbamate (5.4 mmol),
1,1'-bis(diphenylphosphino) ferrocene-palladium(II) dichloride
dichloromethane complex (0.135 mmol), triphenylphosphine (0.27
mmol), triethylamine (13.5 mmol) and a 4 A molecular sieve (1 g)
are added into an autoclave for uniform stirring. Nitrogen is
introduced to displace air, and then a carbon monoxide is
introduced to displace the nitrogen and the pressure in the
autoclave is increased to 0.8 MPa. A temperature is increased by
heating to 90.about.105.degree. C. for reaction. After 96 h
reaction, a product system containing an amination product is
obtained. The product system is cooled to be below 50.degree. C.,
and the carbon monoxide is evacuated and displaced with the
nitrogen.
[0089] The product system is diluted with an MTBE (10 mL), and the
molecular sieve is filtered to obtain a filtrate. An aqueous
solution of K.sub.2CO.sub.3 (100 mL) at a mass concentration of 1%
is added into the filtrate, and solids are precipitated by
stirring. The solids are added into a trifluoroacetic acid (5 mL)
to remove a Boc protective group. After the superfluous
trifluoroacetic acid is removed by concentration, ethanol (20 mL)
is added for heating dissolving. Then, crystallization is performed
to obtain nilotinib trifluoroacetate. The nilotinib
trifluoroacetate is dissolved with the ethanol, an aqueous solution
of KOH is added to regulate pH=6.about.9, and a nilotinib product
(1.2 g) is obtained by filtering, washing and drying, a yield being
50%. An HPLC purity of the product is measured to be 98%.
Embodiment 22
[0090] Dimethylformamide (10 mL),
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline
(aromatic amine, 4.5 mmol),
(5-bromo-2-methylphenyl(4-pyridine-3-yl)
pyrimidine-2-yl)-tert-butyl carbamate (5.4 mmol), a
1,1'-bis(diphenylphosphino) ferrocene-palladium(II) dichloride
dichloromethane complex (0.135 mmol), triphenylphosphine (0.27
mmol), phenol (0.225 mmol) and a 4 A molecular sieve (1 g) are
added into an autoclave for uniform stirring. Nitrogen is
introduced to displace air, and then a carbon monoxide is
introduced to displace the nitrogen and the pressure in the
autoclave is increased to 0.8 MPa. A temperature is increased by
heating to 90.about.105.degree. C. for reaction. After 48 h
reaction, a product system containing an amination product is
obtained. The product system is cooled to be below 50.degree. C.,
and the carbon monoxide is evacuated and displaced with the
nitrogen.
[0091] The product system is diluted with an MTBE (10 mL), and the
molecular sieve is filtered to obtain a filtrate. An aqueous
solution of K.sub.2CO.sub.3 (100 mL) at a mass concentration of 1%
is added into the filtrate, and solids are precipitated by
stirring. The solids are added into a trifluoroacetic acid (5 mL)
to remove a Boc protective group. After the superfluous
trifluoroacetic acid is removed by concentration, ethanol (20 mL)
is added for heating dissolving. Then, crystallization is performed
to obtain nilotinib trifluoroacetate. The nilotinib
trifluoroacetate is dissolved with the ethanol, an aqueous solution
of KOH is added to regulate pH=6.about.9, and a nilotinib product
(1.1 g) is obtained by filtering, washing and drying, a yield being
46%. An HPLC purity of the product is measured to be 99%.
Embodiment 23
[0092] Dimethylformamide (10 mL),
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline
(aromatic amine, 4.5 mmol),
(5-bromo-2-methylphenyl(4-pyridine-3-yl)
pyrimidine-2-yl)-tert-butyl carbamate (5.4 mmol), a
1,1'-bis(diphenylphosphino) ferrocene-palladium(II) dichloride
dichloromethane complex (0.135 mmol), triphenylphosphine (0.27
mmol), phenol (0.225 mmol), triethylamine (13.5 mmol) and a 4 A
molecular sieve (1 g) are added into an autoclave for uniform
stirring. Nitrogen is introduced to displace air, and then a carbon
monoxide is introduced to displace the nitrogen and the pressure in
the autoclave is increased to 0.8 MPa. A temperature is increased
by heating to 120.about.140.degree. C. for reaction. After 24 h
reaction, a product system containing an amination product is
obtained. The product system is cooled to be below 50.degree. C.,
and the carbon monoxide is evacuated and displaced with the
nitrogen.
[0093] The product system is diluted with an MTBE (10 mL), and the
molecular sieve is filtered to obtain a filtrate. An aqueous
solution of K.sub.2CO.sub.3 (100 mL) at a mass concentration of 1%
is added into the filtrate, and solids are precipitated by
stirring. The solids are added into a trifluoroacetic acid (5 mL)
to remove a Boc protective group. After the superfluous
trifluoroacetic acid is removed by concentration, ethanol (20 mL)
is added for heating dissolving. Then, crystallization is performed
to obtain nilotinib trifluoroacetate. The nilotinib
trifluoroacetate is dissolved with the ethanol, an aqueous solution
of KOH is added to regulate pH=6.about.9, and a nilotinib product
(2.0 g) is obtained by filtering, washing and drying, a yield being
85%. An HPLC purity of the product is measured to be 99%.
Embodiment 24
[0094] Dimethylformamide (10 mL),
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline
(aromatic amine, 4.5 mmol),
(5-bromo-2-methylphenyl(4-pyridine-3-yl)
pyrimidine-2-yl)-tert-butyl carbamate (5.4 mmol), a
1,1'-bis(diphenylphosphino) ferrocene-palladium(II) dichloride
dichloromethane complex (0.135 mmol), triphenylphosphine (0.27
mmol), phenol (0.225 mmol), triethylamine (13.5 mmol) and a 4 A
molecular sieve (1 g) are added into an autoclave for uniform
stirring. Nitrogen is introduced to displace air, and then a carbon
monoxide is introduced to displace the nitrogen and the pressure in
the autoclave is increased to 0.8 MPa. A temperature is increased
by heating to 80.about.90.degree. C. for reaction. After 96 h
reaction, a product system containing an amination product is
obtained. The product system is cooled to be below 50.degree. C.,
and the carbon monoxide is evacuated and displaced with the
nitrogen.
[0095] The product system is diluted with an MTBE (10 mL), and the
molecular sieve is filtered to obtain a filtrate. An aqueous
solution of K.sub.2CO.sub.3 (100 mL) at a mass concentration of 1%
is added into the filtrate, and solids are precipitated by
stirring. The solids are added into a trifluoroacetic acid (5 mL)
to remove a Boc protective group. After the superfluous
trifluoroacetic acid is removed by concentration, ethanol (20 mL)
is added for heating dissolving. Then, crystallization is performed
to obtain nilotinib trifluoroacetate. The nilotinib
trifluoroacetate is dissolved with the ethanol, an aqueous solution
of KOH is added to regulate pH=6.about.9, and a nilotinib product
(1.7 g) is obtained by filtering, washing and drying, a yield being
71%. An HPLC purity of the product is measured to be 99%.
Embodiment 25
[0096] Dimethylformamide (10 mL),
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline
(aromatic amine, 4.5 mmol),
(5-bromo-2-methylphenyl(4-pyridine-3-yl)
pyrimidine-2-yl)-tert-butyl carbamate (5.4 mmol), a
1,1'-bis(diphenylphosphino) ferrocene-palladium(II) dichloride
dichloromethane complex (0.135 mmol), triphenylphosphine (0.27
mmol), phenol (0.225 mmol), triethylamine (13.5 mmol) and a 4 A
molecular sieve (1 g) are added into an autoclave for uniform
stirring. Nitrogen is introduced to displace air, and then a carbon
monoxide is introduced to displace the nitrogen and the pressure in
the autoclave is increased to 0.8 MPa. A temperature is increased
by heating to 90.about.105.degree. C. for reaction. After 48 h
reaction, a product system containing an amination product is
obtained. The product system is cooled to be below 50.degree. C.,
and the carbon monoxide is evacuated and displaced with the
nitrogen.
[0097] The product system is diluted with an MTBE (10 mL), and the
molecular sieve is filtered to obtain a filtrate. An aqueous
solution of K.sub.2CO.sub.3 (100 mL) at a mass concentration of 1%
is added into the filtrate, and solids are precipitated by
stirring. The solids are added into a trifluoroacetic acid (5 mL)
to remove a Boc protective group. After the superfluous
trifluoroacetic acid is removed by concentration, ethanol (20 mL)
is added for heating dissolving. Then, crystallization is performed
to obtain nilotinib trifluoroacetate. The nilotinib
trifluoroacetate is dissolved with the ethanol, an aqueous solution
of KOH is added to regulate pH=6.about.9, and a nilotinib product
(1.9 g) is obtained by filtering, washing and drying, a yield being
80%. An HPLC purity of the product is measured to be 99%.
Contrasting Example 1
[0098] Dimethyl sulfoxide (10 mL),
3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline
(aromatic amine, 4.5 mmol),
N-5-bromo-2-methylphenyl(4-(pyridine-3-yl) pyrimidine-2-amine (5.4
mmol), 1, 1'-bis(diphenylphosphino)ferrocene-palladium (II)
dichloride dichloromethane complex (0.135 mmol), triphenylphosphine
(0.27 mmol), phenol (0.225 mmol), triethylamine (13.5 mmol) and a 4
A molecular sieve (1 g) are added into an autoclave for uniform
stirring. Nitrogen is introduced to displace air, and then a carbon
monoxide is introduced to displace the nitrogen to and the pressure
in the autoclave is increased to 0.8 MPa. A temperature is
increased by heating to 90.about.105.degree. C. for reaction. After
72 h reaction, a product system containing an amination product is
obtained. The product system is cooled to be below 50.degree. C.,
and the carbon monoxide is evacuated and displaced with the
nitrogen.
[0099] The reaction solution is taken out, the molecular sieve is
filtered, dichloromethane (100 mL.times.2) is added into a filtrate
for beating purification, filtering is performed, and a filter cake
is washed sequentially with a 10% solution of K.sub.2CO.sub.3 (30
mL.times.3) and purified water (50 mL). Drying is performed to
obtain a product (13.8 g), a yield being 58% and an HPLC purity of
the product being 99%.
[0100] From the above, it can be seen that the embodiments of the
disclosure have the following technical effects.
[0101] (1) The protective group R (such as Boc) is introduced onto
the nitrogen atom of the amino group of the raw material compound
A, which avoids the metal palladium catalyst from being deactivated
by the nitrogen atom, thereby reducing the using amount of the
palladium catalyst.
[0102] (2) The nucleophilic promoter (such as the phenol) is added
to increase a catalytic amount into an equivalent, thus a classical
palladium-catalyzed aminocarbonylation reaction mechanism is
changed (the classical mechanism refers to a direct
aminocarbonylation reaction catalysis cycle, and is regulated to be
divided into two catalysis cycles of carbonylation esterification
and ester-amine exchange). So that an amide product may be
generated from the aromatic amine
[3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline] with
poor nucleophilicity under the mild temperature of within
100.degree. C.
[0103] The above is only the preferred embodiment of the disclosure
and not intended to limit the disclosure. For those skilled in the
art, the disclosure may have various modifications and variations.
Any modifications, equivalent replacements, improvements and the
like made within the spirit and principle of the disclosure shall
fall within the scope of protection of the disclosure.
* * * * *