An efficient synthesis of nilotinib (AMN107)

Article abstract of DOI:10.1055/s-2007-983754

A concise synthesis of AMN107, a compound currently undergoing several phase II/III clinical trials for chronic myelogenous leukemia is described. The new procedure reduces the number of synthetic steps from eight to four, with an overall yield of 65%. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983754

PAPER
2121
An Efficient Synthesis of Nilotinib (AMN107)
S
W
ynthesis of
N
ilotinib (A
e
MN107) i-Sheng Huang,* William C. Shakespeare
ARIAD Pharmaceuticals, 26 Landsdowne Street, Cambridge, MA 02139, USA
Fax +1(617)4948144; E-mail: wei-sheng.huang@ariad.com
Received 18 January 2007; revised 17 May 2007
methylmidazole followed by functional group manipula-
tions to yield advanced intermediate 2, and c) coupling of
Abstract: A concise synthesis of AMN107, a compound currently
undergoing several phase II/III clinical trials for chronic myeloge-
nous leukemia is described. The new procedure reduces the number
of synthetic steps from eight to four, with an overall yield of 65%.
1
and 2 to furnish the target compound. The S Ar reaction
N
yielded two regioisomers resulting from N-arylation at
both N-1 and N-3 of 4-methylimidazole; the regioisomers
were separated but their ratio was not reported.
Key words: AMN107, Abl kinase inhibitor, Cu-catalyzed N-aryla-
tion, Pd-catalyzed N-arylation, atom economy
Recently, copper-catalyzed N-arylation of p-excessive ni-5
trogen heterocycles has been reported by several groups.
Imatinib (also called Gleevec, STI571), a Bcr-Abl ty- Many functional groups including free amines are tolerat-
rosine kinase inhibitor developed by Novartis, has been ed in this reaction. Additionally, palladium-catalyzed am-
the first-line treatment for patients with chronic myeloge- ination of aryl halides have demonstrated wide
nous leukemia (CML) since 2001. Most newly diagnosed applicability in the synthesis of substituted aryl amines.6
CML patients with chronic phase disease treated with By employing both of these recently developed synthetic
Imatinib achieve durable response; however, relapses methodologies we have completed an efficient synthesis
have been observed in most patients with more advanced of AMN107 which is depicted in Scheme 2.
1
disease. Mutations in the Bcr-Abl gene are the most com-
mon cause of acquired Imatinib resistance. Nilotinib
Aryl bromides are generally poor substrates in copper-cat-
alyzed N-arylation of azoles. Indeed, when we tried sev-
5
(
AMN107), a rationally designed, second-generation in-
eral CuI–diamine catalyst systems including N,N¢-
dimethylethylenediamine, (±)- trans-cyclohexanedi-
amine, and 1,10-phenanthroline, all of which enjoy much
success in the N-arylation with aryl iodides as the sub-
hibitor, is at least 20-fold more potent than Imatinib and
effectively inhibits all Imatinib-resistant Bcr-Abl mutants
2
a
with the exception of T315I. A recently published phase
I clinical trial involving AMN107 and patients with either
Philadelphia chromosome-positive (Ph+) CML who are
resistant or intolerant to Gleevec or patients with relapsed
or refractory Ph+ acute lymphoblastic leukemia (ALL) in-
dicated AMN107 has a relatively favorable safety profile
5
strate, each gave low conversion and poor regioselectiv-
ity in the reactions of 3-bromo-5-trifluoromethylaniline
and 4-methylimidazole. Gratifyingly, the use of CuI/8-hy-
droxyquinoline, a protocol discovered by researchers at
7
DuPont Pharmaceuticals, was found to catalyze this reac-
2
and is active in Imatinib-resistant CML. AMN107 has
tion very efficiently. Essentially complete conversion of
bromide to product was observed with a regioselectivity
now entered a phase II clinical trial for patients with
Ph+CML, Ph+ALL, systemic mastocytosis or hypereosi-
nophilic syndrome/chronic eosinophilic leukemia. Fur-
thermore, a very recent study suggests AMN107 could be
important in the treatment of Imatinib-resistant gas-
trointestinal stromal tumor (GIST) patients in whom resis-
tance has developed as a result of changes in cellular
transport mechanisms for which AMN107 is not a sub-
1
19
of 85:15 (determined by HPLC, H and F NMR). Purifi-
cation by silica gel column chromatography and recrystal-
lization gave the major regioisomer in 75–80% isolated
yield. Structural identification of the desired imidazole,
compound 3, was based on the following data: 1) the pro-
ton–proton coupling constant J2,5 (1.29 Hz) for the imida-
zole ring is greater than J2,4 (0.68 Hz) observed for the
2
h
strate. During the course of our investigations into dual
alternative regioisomer which is consistent with the liter-
3
Src/Abl inhibitors we needed ready access to AMN107
8
ature report that J2,5 is always greater than J , and 2) the
2,4
as a reference compound. Herein we report an efficient
synthesis of this pharmaceutically important compound.
melting point (126–129 °C) agreed with Novartis’ data
4
(
127–131 °C). Furthermore, the observation that 1,4-dis-
To the best of our knowledge, Novartis’ preparation of ubstitution predominated is consistent with previous re-
AMN107 has only been disclosed in a patent application.4 sults involving copper-catalyzed N-arylation of 4-
Their eight-step synthesis is illustrated in Scheme 1 and methylimidazole.5
b,e
outlined as follows: a) construction of the phenylamine-
For the amide bond formation in step two, we initially
pyrimidine core to form compound 1, b) an S Ar reaction
N
tried coupling aniline 3 with 3-iodo-4-methylbenzoic acid
by using the standard EDCI/HOBt methodology, howev-
er, no conversion of 3 was observed at room temperature
and the intermediate active ester was isolated. Upon heat-
ing, about 60% conversion of 3 to 4 was observed, how-
ever, aniline 3 was ultimately coupled with readily
between 3-fluoro-5-trifluoromethylbenzonitrile and 4-
SYNTHESIS 2007, No. 14, pp 2121–2124
x
x.
x
x
.
2
0
0
7
Advanced online publication: 03.07.2007
DOI: 10.1055/s-2007-983754; Art ID: M00507SS
Georg Thieme Verlag Stuttgart · New York
©

2
122
W.-S. Huang, W. C. Shakespeare
PAPER
N
N
NH
NH2
HN
NH2
a
b
OEt
O
N
NH
OEt
O
OEt
O
1
N
N
N
F
c
d
e
N
N
N
O
F3C
CN
OH
F3C
CN
F3C
F3C
N
O
H
O
2
N
N
N
f
1
N
NH
N
OH
h
N
NH
O
N
H
N
N
N
O
g
N
2
CF3
AMN107
F3C
NH2
Scheme 1 Reagents and conditions: (a) H NCN, concd HCl, 90 °C, 15 h; (b) 3-(dimethylamino)-1-(3-pyridinyl)prop-2-en-1-one (A), NaOH,
2
EtOH, reflux, 68 h; (c) 4-methylimidazole, DMF, 145 °C, 19 h; (d) 1 M aq NaOH, dioxane, 95 °C, 18 h; (e) diphenylphosphorylazide, Et N, t-
3
BuOH, 80 °C, 16 h; (f) 2 M aq NaOH, EtOH, 45 °C, 2.5 h; (g) 4 M HCl in i-PrOH, 60 °C, 15 h; (h) diethyl cyanophosphate, Et N, DMF, 60 °C,
3
12 h.
available 3-iodo-4-methylbenzoyl chloride to furnish 4 in the amination of aryl iodides in Buchwald’s lab,11 we
9
8% yield.
were able to couple 4 and 5 efficiently. Both starting ma-
terials were consumed within five hours and no side-
product was detected. The isolated yield was 89%.
In the final step, iodide 4 was coupled to the weakly nu-
cleophilic amine 5. Amine 5 is commercially available but
can also be readily prepared from the reaction of guani- In summary, we have developed a four-step synthesis of
9
12
dine and compound A, an intermediate used in Novartis’ AMN107. Our procedure is atom-economical since it
procedure (Scheme 1). Use of a common coupling proto- essentially assembles four chemicals, 3-bromo-(5-trifluo-
col which includes Pd(OAc) /BINAP as the catalyst and romethyl)aniline, 4-methylimidazole, 3-iodo-4-methyl-
2
6
,10
Cs CO or t-BuONa as base
was inefficient, giving benzoyl chloride, and 4-(pyridin-3-yl)pyrimidin-2-
2
3
3
0% conversion after heating in toluene at 90 °C for 20 ylamine (5) into AMN107 while yielding three equiva-
hours; moreover, some reduction of aryl iodide to arene lents of HX as the only by-products. It is amenable to a
was observed. Alternatively, by using Pd (dba) /Xant- large scale production because of its simple operation and
2
3
phos as catalyst system, a protocol developed recently for high yield. Furthermore, it should facilitate AMN107 an-
Synthesis 2007, No. 14, 2121–2124 © Thieme Stuttgart · New York

PAPER
Synthesis of Nilotinib (AMN107)
2123
I
N
N
H2N
Br
H2N
N
H
a
b
N
N
O
CF3
CF3
CF3
4
3
N
N
c
d
AMN107
N
N
O
N
NH2
A
5
commercially available
Scheme 2 Reagents and conditions: (a) 4-methylimidazole, 15 mol% 8-hydroxyquinoline, 15 mol% CuI, 110 mol% K CO , DMSO, 120 °C,
2
3
1
5 h; (b) 3-iodo-4-methylbenzoyl chloride, (i-Pr) NEt, THF, r.t., 2 h; (c) guanidine hydrochloride, NaOEt, EtOH, reflux, 8 h; (d) compound 4,
2
Cs CO , 5 mol% Pd (dba) , 10 mol% Xantphos, 1,4-dioxane, t-BuOH, 100 °C, 7 h.
2
3
2
3
alogue synthesis since a large number of structurally di- 19F NMR (DMSO-d
verse aryl amines, halobenzoic acids and haloanilines are MS: m/z = 242 (M + H)+.
): d = –62.5.
6
1
3
commercially available.
Anal. Calcd for C H F N : C, 54.77; H, 4.18; N, 17.42. Found: C,
1
1
10
3
3
5
4.83; H, 3.95; N, 17.47.
All reagents and solvents were purchased from Sigma-Aldrich or
1
13
3-Iodo-4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluo-
romethyl)phenyl]benzamide (4)
Chempacific and used as received. H NMR (300.1 MHz),
NMR (74.5 MHz), and F NMR (282.4 MHz) spectra were record-
C
1
9
3
-Iodo-4-methylbenzoic acid (2.62 g, 10 mmol) was refluxed in
ed on a Bruker spectrometer, using TMS, DMSO-d as internal stan-
6
SOCl (10 mL) for 1 h. The volatile components were removed on
dard, and CFCl as external standard, respectively. MS spectra were
2
3
a rotavap and the residue was dissolved in benzene (10 mL), con-
centrated to dryness on a rotavap, and further dried under vacuum.
The resulting acyl chloride was added to a solution of 3-(4-methyl-
recorded on a Waters Micromass ZQ spectrometer. Elemental anal-
yses were performed by Robertson Microlit Laboratories in Madi-
son, New Jersey. HPLC was performed on an Agilent 1100 HPLC
system.
1
1
H-imidazol-1-yl)-5-(trifluoromethyl)benzeneamine (3; 2.46 g,
0.2 mmol), DIPEA (1.56 g, 12 mmol), and a catalytic amount of
DMAP in THF (20 mL). After stirring at r.t. for 2 h, the reaction was
3
-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzene-
quenched with H O. EtOAc was then added and the layers separat-
amine (3)
2
ed. The combined organic layers were concentrated to dryness and
then purified on a silica gel column (5% MeOH–CH Cl ) to give the
A suspension of 3-bromo-5-(trifluoromethyl)aniline (4.80 g, 20
mmol), 4-methylimidazole (1.97 g, 24 mmol), K CO (3.04 g, 22
mmol), CuI (0.57 g, 3 mmol), and 8-hydroxyquinoline(0.44 g, 3
mmol,) in anhyd DMSO (20 mL) in a pressure tube or a round-bot-
tom flask was degassed by bubbling N into the suspension for 10
min while stirring. The tube/flask was then sealed tightly. The mix-
ture was heated at 120 °C (oil bath temperature) for 15 h. The mix-
ture was cooled down to 45–50 °C and 14% aq NH OH (20 mL)
was added. The mixture was maintained at this temperature for 1 h.
After cooling to r.t., H O and EtOAc were added. The aqueous layer
was extracted with EtOAc and the combined organic layers were
passed through a short silica gel column to remove most of green/
2
2
2
3
desired product in 95% yield (4.60 g); white solid; mp 235–237 °C.
1
H NMR (DMSO-d ): d = 10.66 (s, 1 H), 8.46 (d, J = 1.3 Hz, 1 H),
6
2
8.27 (s, 1 H), 8.21 (d, J = 1.2 Hz, 1 H), 8.13 (s, 1 H), 7.94 (dd,
J = 1.3, 7.9 Hz, 1 H), 7.73 (s, 1 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.50
(s, 1 H), 2.46 (s, 3 H), 2.18 (s, 3 H).
4
13
C NMR (DMSO-d ): d = 164.1, 145.3, 141.1, 138.9, 137.9, 137.4,
6
1
34.9, 133.1, 130.8 (q, J = 32.5 Hz), 129.8, 127.8, 123.6 (q, J = 272
2
Hz, CF ), 114.9, 114.2, 114.1, 111.7, 101.0, 27.9, 13.9.
3
1
9
F NMR (DMSO-d ): d = –61.2.
6
blue Cu salts. The filtrate was dried (Na SO ) and concentrated on
MS: m/z = 486 (M + H)+.
2
4
a rotavap. The crude product was recrystallized from EtOAc–hex-
anes or purified on silica gel column (5% MeOH–CH Cl ), giving
Anal. Calcd for C H F IN O: C, 47.03; H, 3.12; N, 8.66. Found:
1
9
15
3
3
2
2
C, 47.01; H, 3.13; N, 8.61.
pure pale yellow needles. The mother liquor was concentrated and
the residue was purified on silica gel column (5% MeOH–CH Cl ),
2
2
4
-Methyl-3-{[4-(3-pyridinyl)-2-pyrimidinyl]amino}-N-[5-(4-
yielding a second crop. The total yield was 75% (3.66 g); pale yel-
low needles; mp 126–129 °C.
methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benz-
amide (AMN107)
4-(Pyridin-3-yl)pyrimidin-2-amine (5; 165 mg, 0.96 mmol), 3-iodo-
1
H NMR (DMSO-d ): d = 8.41 (d, J = 1.3 Hz, 1 H), 7.77 (s, 1 H),
6
7
.38 (s, 1 H), 7.30 (s, 1 H), 7.17 (s, 1 H), 6.20 (s, 2 H), 2.51 (s, 3 H).
4
-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluorometh-
1
3
yl)phenyl]benzamide (4; 513 mg, 1.06 mmol), Cs CO (0.44 g, 1.35
C NMR (DMSO-d ): d = 151.2, 138.8, 135.1, 131.6 (q, J = 31.7
2
3
6
mmol), Pd (dba) (44 mg, 0.048 mmol), and Xantphos (55.7 mg,
Hz), 120.8 (q, J = 272 Hz, CF ), 114.5, 108.2, 108.1, 103.6, 103.5,
2
3
3
1
3.9.
0.096 mmol) were placed in a round-bottom flask capped with a
Synthesis 2007, No. 14, 2121–2124 © Thieme Stuttgart · New York

2
124
W.-S. Huang, W. C. Shakespeare
PAPER
rubber septum. After the solid mixture underwent 3 cycles of vacu-
Sundaramoorthi, R.; Bohacek, R.; Weigele, M.; Sawyer, T.
Chem. Biol. Drug Design 2006, 67, 46. (c) Brunton, V. G.;
Avizienyte, E.; Fincham, V. J.; Serrels, B.; Metcalf, C. A.
III; Sawyer, T. K.; Frame, M. C. Cancer Res. 2005, 65,
1335. (d) O’Hare, T.; Walters, D. K.; Stoffregen, E. P.;
Sherbenou, D. W.; Heinrich, M. C.; Deininger, M. W. N.;
Druker, B. J. Clin. Cancer Res. 2005, 11, 6987. (e) Corbin,
A. S.; Demehri, S.; Griswold, I. J.; Wang, Y.; Metcalf, C. A.
III; Sundaramoorthi, R.; Shakespeare, W. C.; Snodgrass, J.;
Wardwell, S.; Dalgarno, D.; Iuliucci, J.; Sawyer, T. K.;
Heinrich, M. C.; Druker, B. J.; Deininger, M. W. N. Blood
um–N refilling, anhyd 1,4-dioxane (7.2 mL) and t-BuOH (3.6 mL)
2
were added via syringe. The resulting suspension was heated at
1
00 °C for 7 h. Upon cooling, the volatile components were re-
moved on a rotavap and the residue was partitioned between EtOAc
and H O. The combined organic layers from extractions were con-
2
centrated to dryness and then purified on a silica gel column (10%
MeOH–CH Cl ) to give the desired product in 89% yield (452 mg);
2
2
white solid; mp 231–233 °C.
1
H NMR (DMSO-d ): d = 10.77 (s, 1 H), 9.51 (s, 1 H), 9.29 (d,
6
J = 1.6 Hz, 1 H), 9.17 (s, 1 H), 8.69 (dd, J = 1.5, 4.8 Hz, 1 H), 8.59
2
005, 106, 227. (f) O’Hare, T.; Pollock, R.; Stoffregen, E.
(
8
s, 1 H), 8.56 (d, J = 5.2 Hz, 1 H), 8.47 (dd, J = 2.0, 6.2 Hz, 1 H),
.33 (s, 1 H), 8.23 (s, 1 H), 8.00 (s, 1 H), 7.90 (s, 1 H), 7.79 (dd,
P.; Keats, J. A.; Abdullah, O. M.; Moseson, E. M.; Rivera,
V. M.; Tang, H.; Metcalf, C. A. III; Bohacek, R. S.; Wang,
Y.; Sundaramoorthi, R.; Shakespeare, W. C.; Dalgarno, D.;
Clackson, T.; Sawyer, T. K.; Deininger, M. W.; Druker, B.
J. Blood 2004, 104, 2532.
J = 1.7, 7.9 Hz, 1 H), 7.54 (dd, J = 4.9, 8.0 Hz, 1 H), 7.49 (d, J = 5.1
Hz, 1 H), 7.47 (d, J = 7.4 Hz, 1 H), 2.37 (s, 3 H), 2.35 (s, 3 H).
1
3
C NMR (DMSO-d ): d = 165.6, 161.6, 161.0, 159.5, 151.4, 148.1,
6
1
41.3, 138.9, 138.2, 137.9, 136.8, 134.9, 134.2, 132.1, 131.8, 130.8
(
(
4) Breitenstein, W.; Furet, P.; Jacob, S.; Manley, P. W. WO
2004005281, 2004; Chem. Abstr. 2004, 140, 77161.
5) (a) Altman, R. A.; Buchwald, S. L. Org. Lett. 2006, 8, 2779.
(b) Antilla, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S.
L. J. Org. Chem. 2004, 69, 5578. (c) Zhang, H.; Cai, Q.;
Ma, D. J. Org. Chem. 2005, 70, 5164. (d) Cristau, H.-J.;
Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem. Eur. J.
2004, 10, 5607. (e) Kiyomori, A.; Marcoux, J.-F.;
(
q, J = 32.5 Hz), 130.4, 124.2, 123.7, 123.6 (q, J = 272 Hz, CF3),
1
23.5, 114.9, 114.3, 114.2, 111.5, 107.9, 18.2, 13.5.
1
9
F NMR (DMSO-d ): d = –62.2.
6
MS: m/z = 530 (M + H)+.
Anal. Calcd for C H F N O: C, 63.51; H, 4.19; N, 18.52. Found:
2
8
22
3
7
C, 63.28; H, 4.09; N, 18.36.
Buchwald, S. L. Tetrahedron Lett. 1999, 40, 2657.
6) (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002,
(
Acknowledgment
2
19, 131. (b) Hartwig, J. F. Handbook of Organopalladium
Chemistry for Organic Synthesis, Vol. 1; Wiley: Hoboken,
002, 1051–1096.
The authors thank Dr. David C. Dalgarno and Dr. R. Mathew Tho-
mas for helpful discussions.
2
(
7) (a) Zhou, J. C.; Confalone, P. N.; Li, H.-Y.; Oh, L. M.;
Rossano, L. T.; Clark, C. G.; Teleha, C. A. WO 200208199,
2
002; Chem. Abstr. 2002, 136, 134674. (b) Liu, L.; Frohn,
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Synthesis 2007, No. 14, 2121–2124 © Thieme Stuttgart · New York