476 JOURNAL OF CHEMICAL RESEARCH 2015
Boc
N
O
O N
2
H N
O
2
O N
2
4
O
N
CHCl
3
S
HN
N
H N
2
S
O
N
Cl
N
5
Cl
O
Cl
CH
3
CN
9
5%
2
6
9
4%
O
O
HN
N
N
Boc
Pd/C
HN
N
N Boc
N
O
N
O
S
HN
S
HN
O
O
H
2
8
O N
2
7
H N
2
O
Sandmeyer
reaction
HN
N
NH
N
O
6
7%
S
HN
O
LDK378
Scheme 3
Cl
intermediate 8. The 5-amino group of 8 would derive from the
-nitro group of 7 by reduction. Finally, the tetracyclic 5-nitro
compound 7 can be broken into three fragments, 1,3-dichloro-
-nitropyridine 5, 2-(propane-2-sulfonyl)-phenylamine 2 and
2- Chloro- 4- [2- (propane-2-sulfonyl) -phenylamino] -5-
nitropyrimidine (6): 2-(Propane-2-sulfonyl)-phenylamine 2 (0.95
equiv.) was added to a solution of 2,4-dichloro-5-nitro-pyrimidine
9
5
(
5.0 g) in CHCl (100 mL) at room temperature. The resulting reaction
4
3
o
solution was heated to 60 C and stirred for 6 h. After completion of
the reaction, the reaction mixture was concentrated under reduced
the Boc-protected compound 4, the latter two compounds are the
9
starting materials for the Novartis synthesis. We saw the nitro
o
pressure and cooled to 0 C. Then methyl t-butyl ether (MTBE) was
group as an activator providing an enhanced intrinsic reactivity
difference between the two chlorine atoms in compound 5 to
sequentially introduce the two variously substituted aniline 2
added. The mixture was filtered and the solid cake was washed with
MTBE. The crude product was purified by recrystallisation to give 6
o
1
as a brown solid, m.p. 186–188 C (CHCl /MTBE); H NMR δ 11.56
and 4 to the central pyrimidine ring via intermolecular SN
3
Ar
2
4
(s, 1H), 9.26 (s, 1H), 8.26 (d, J=8.4, 1H), 8.03 (d, J=8.0 Hz, 1H),
reactions. This procedure employed mild reaction conditions
and avoided the use of expensive reagents (e.g. Xantphos ligand)
compared to the original synthetic route reported by the Novartis
7
1
1
.77(t, J=8.0, 16.0 Hz, 1H), 7.48(t, J=7.6, 15.2 Hz, 1H), 1.34 (s, 3H),
13
.33 (s, 3H); C NMR δ 163.9, 157.9, 153.3, 135.2, 134.6, 131.6, 128.0
+
27.6, 126.4, 125.6, 55.8, 15.3; HRMS (m/z) [M + Na] calcd for
9
group.
C H ClN O S Na 379.0244, found 379.0237.
13
13
4
4
The total synthesis of LDK378 commenced with commercially
available 1,3-dichloro-4-nitropyridine 5 as outlined in Scheme
(
7): Intermediate 6 (1.0 equiv.) was added to a solution of
9
trisubstituted aniline 4 (5.0 g) in 100 mL CH CN at room temperature.
The resulting reaction mixture was heated to 80 C and stirred for
3
3. Initially displacement of the 3-chloro group of 5 by the amino
o
group of compound 2 in chloroform provided 6 in 95% yield.
Then, displacement of the 1-chloro group of 6 by the amino group
of 4 in acetonitrile at a higher temperature yielded 7 in 94%
yield. Catalytic reduction of 7 with hydrogen over Pd/C gave a
quantitative yield of the corresponding amine 8. Introduction of the
8
h. After completion of the reaction, the reaction mixture was
o
concentrated under reduced pressure. The mixture was stirred at 0 C
for 2 h and filtered. The crude product 7 was used in the next step
without further purification. A small sample of 7 was recrystallised to
o
1
give a brown solid, m.p. 220–221 C(CH CN/MTBE); H NMR δ 11.3
3
5-chloro group of LDK378 was achieved from 5-amino derivative
(s, 1H), 9.21 (s, 1H), 8.01 (m, 3H), 7.87 (m, 1H), 7.65 (m, 1H), 7.45 (m,
8
through a Sandmeyer reaction under optimal reactions in 67%
1
H), 6.73 (s, 1H), 4,59 (m, 1H), 4.28 (m, 2H), 3.27 (m, 1H), 2,79 (m,
yield. To further evaluate the synthetic potential of this procedure,
gram-scale reactions were performed under the optimised reaction
conditions. Gratifyingly, the reactions proceeded smoothly to give
3H), 2.07 (s, 1H), 1.93 (m, 2H). 1.41–1.75(m, 25H); 13C NMR δ 154.9,
136.5, 134.2, 131.4, 125.8, 79.6, 71.7, 55.0, 38.4, 32.5, 28.5, 22.2, 18.8,
15.4; HRMS (m/z) [M+Na] calcd for C H N O SNa 691.2890, found
691.2885.
+
33
44
6
7
1
the desired product in 63% yield. Finally, comparison of the H
NMR spectra at 400 MHz of LDK378 in CDCl proved to fully
align with previously reported spectral data.
(8): Pd/C (0.5%) was added to a solution of intermediate 7 (5.0 g)
in methanol (100 mL) under 1 atm hydrogen at room temperature.
The resulting mixture was stirred for 8 h. The progress of the reaction
was monitored by thin-layer chromatography. After completion of
the reaction, the reaction mixture was filtered through celite and the
solid cake was washed with methanol. The combined organics were
concentrated under reduced pressure. The crude product 8 was used
in the next step without further purification. A small sample of 8
3
9
Experimental
All reagents including analytical-grade solvents were purchased from
Sigma-Aldrich (USA), Aladdin (China), or Sinopharm Chemical
Reagent (China) and used without further purification. Melting points
are uncorrected. NMR spectra were obtained on a Bruker 400 MHz
1
13
o
spectrometer ( H NMR at 400 Hz, C NMR at 100 Hz) in CDCl using
was recrystallised to give a brown solid; m.p. 105–106 C (methanol/
3
1
TMS as internal standard. Chemical shifts (δ) are given in ppm and
coupling constants (J) in Hz. Mass spectra (MS) were obtained from
Finnigan (USA) MAT-95 Spectrometry Services. Silica gel (200–300
µm) for flash chromatography was purchased from Qingdao Haiyang
Chemical (China).
MTBE). H NMR δ 9.50 (s, 1H), 8.71 (d, 1H), 8.13 (s, 1H), 7.91 (m,
2H), 7.64 (m, 1H), 7.41 (s, 1H), 7.29 (s, 1H), 7.19 (m, 1H), 6.72 (s, 1H),
4.56 (m, 1H), 4.28 (m, 2H), 3.28 (m, 1H), 2,83 (m, 5H), 1.33–1.52(m,
13
27H); C NMR (100 MHz) δ 155.2, 154.9, 153.9, 147.5, 144.3, 139.6,
136.0, 134.8, 131.2, 128.8, 126.9, 123.4, 122.6, 122.0, 120.0, 118.0,
Liu, Haidong
