The Wittig-Horner reaction for the synthesis of neratinib

Article abstract of DOI:10.1007/s11164-012-0822-4

The Wittig-Horner reaction is a classic method to get alkenes by reaction phosphonates with carbonyl compounds. In this study, it was used for the synthesis of the anticancer drug neratinib. In this method, ethyl diethoxyphosphinylacetate and dimethylaminoacetaldehyde diethylacetal, replacing (E)-4-(dimethylamino)but-2-enoyl acid hydrochloride and oxalyl chloride, were used to synthesize the 6-position side chain of neratinib.

Full text of DOI:10.1007/s11164-012-0822-4

Res Chem Intermed
DOI 10.1007/s11164-012-0822-4
The Wittig–Horner reaction for the synthesis
of neratinib
•
Ning Gu Jiabin Yang Peng Wang Lushen Li
•
•
•
•
Yang Chen Min Ji
Received: 7 July 2012 / Accepted: 16 September 2012
Ó Springer Science+Business Media Dordrecht 2012
Abstract The Wittig–Horner reaction is a classic method to get alkenes by
reaction phosphonates with carbonyl compounds. In this study, it was used for the
synthesis of the anticancer drug neratinib. In this method, ethyl diethoxypho-
sphinylacetate and dimethylaminoacetaldehyde diethylacetal, replacing (E)-4-
(dimethylamino)but-2-enoyl acid hydrochloride and oxalyl chloride, were used to
synthesize the 6-position side chain of neratinib.
Keywords Neratinib Á Wittig–Horner reaction Á Breast cancer Á Synthesis Á
Phosphonate
Introduction
Neratinib, also known as HKI-272, with the chemical name (E)-N-{4-[3-chloro-4-
(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-
2-butenamide, is a potent, highly selective, irreversible inhibitor of epidermal
growth factor receptor (EGFR) and human epidermal growth factor receptor-2
(HER-2), developed by Wyeth Research. It carries a Michael acceptor at the C-6
position, which covalently bonded to the cysteine residue (cys-773 in EGFR and
cys-805 in HER-2) in the ATP binding pocket of those enzymes [1].
N. Gu Á J. Yang Á P. Wang Á L. Li Á Y. Chen (&)
School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096,
Jiangsu, People’s Republic of China
e-mail: yc@seu.edu.cn
M. Ji (&)
School of Chemistry & Chemical Engineering, Southeast University, Nanjing 210096, Jiangsu,
People’s Republic of China
e-mail: jimin@seu.edu.cn
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J. Yang et al.
In vitro, neratinib can reduce HER-2 and EGFR kinase activity by 50 % (IC50) at
a concentration of 59 and 92 nM, respectively [2]. Promising results were achieved
from phase I/II trials for the treatment of HER-2-positive breast cancer (BC) [3, 4].
Currently, the phase III trial with neratinib in patients with HER-2-positive BC is
being conducted by Pfizer.
To the best of our knowledge, several methods for the synthesis of neratinib have
been reported, which are different at the introduction of the C-4 and C-6 side chains
in different sequences, as shown in Schemes 1 and 2. In Scheme 1, it starts from
4-chloro-3-cyano-7-ethoxy-6-N-acetaminoquinoline. This compound was firstly
coupled with 3-chloro-4-(2-pyridinylmethoxy)-aniline at C-4 position, deacetylased
and alkalified to give the free base (IV), then reacted with (E)-4-(dimethyl-
amino)but-2-enoyl chloride hydrochloride (VII) at the C-6 position to yield
neratinib [5].
The second method for the synthesis of neratinib is described in Scheme 2. It
starts from 4-chloro-6-nitro-3-cyano-7-ethoxy quinoline, and after reduction, where
the 6-crotonamide side chain was firstly attached to the 3-cyano quinoline ring, is
followed by the introduction of aniline at C-4 position [1].
The preparation of VII needs a costly starting material, i.e. (E)-4-(dimethyl-
amino)but-2-enoyl acid hydrochloride (VI) and oxalyl chloride, which is a reagent
with strong corrosivity and high toxicity. And the acid chloride hydrochloride is
unstable [6] (as shown in Scheme 3). These problems result in high cost and
difficulty of purification.
Based on the reported references [7–9], we developed a novel method to obtain
neratinib by the Wittig–Horner reaction. It is a classic method for synthesizing the
trans-olefins from phosphonates and carbonyl compounds (Scheme 4).
O
N
Cl
H
HN
N
Cl
O
CH3SO3H
N
CN
H
N
N
CN
O
+
EtOH, 75 oC, 4h
H2N
Cl
EtO
N
O
EtO
II
I
III
O
N
O
N
HN
Cl
NMP, 0 oC, 16h
1. 2.7 N HCl,
75 oC, 8h
H
HN
N
Cl
N
CN
N
H2N
EtO
CN
O
O
EtO
2. 10% K2CO3,
MeOH, 25 oC, 1h
N
N
Cl
(V)
Neratinib
IV
HCl
VII
(COCl)2, DMF
THF, 30 oC, 2h
O
N
OH
HCl
VI
Scheme 1 Synthesis of neratinib
123

The Wittig–Horner reaction for the synthesis of neratinib
Cl
Cl
N
Cl
H
O2N
EtO
CN
N
CN
H2N
EtO
CN
Fe, HOAc, NaOAc
MeOH, reflux
VII in CH3CN
N
O
N
NMP or DMF, 0 oC
to rt
EtO
N
O
N
HN
Cl
I, pyridine hydrochloride
H
N
CN
N
methoxyethanol or i-PrOH, reflux
O
EtO
N
Neratnib
Scheme 2 Synthesis of neratinib
Further
decomposition
O
O
O
-HCl
N
H
N
Cl
N
OH
HCl
HCl
N
HCl
Cl
O
Scheme 3 Degradation pathway of acid chloride
O
OH
1. K2CO3, KI, DMF, 50-60 oC, 12h
2. Fe, NH4Cl, EtOH, H2O, reflux, 1h
N
HCl
+
HCl
H2N
Cl
I
N
O2N
Cl
O
O
P
EtO
O
N
Cl
EtO
H
N
OEt
I
HN
N
Cl
CN
H2N
EtO
CN
1. CH3SO3H, EtOH, reflux, 2h
2. HCl, H2O, reflux, K2CO3 aq
O
1. KOH, 90%MeOH, reflux, 10 min
2. CDI, THF, rt, 5h
EtO
N
II
IV
O
N
O
N
OEt
OEt
1. 50%HCl, 40 oC, 12h
2.EtONa, LiCl, EtOH, -20 oC, 3h
N
HN
Cl
HN
N
Cl
H
H
O
P
N
CN
N
CN
N
EtO
O
OEt
O
EtO
N
EtO
Neratinib
VIII
Scheme 4 Novel synthesis of neratinib
Experimental
All reagents were obtained from commercial sources and used without further
purification. Melting points were measured in open capillary tubes on a melting
point apparatus and are uncorrected. IR spectra were obtained on a Perkin-Elmer
FT-IR spectrophotometer. 1H NMR and 13C NMR spectra were recorded in DMSO
on a Bruker Avance 500 spectrometer; chemical shifts (d) are reported in parts per
123

J. Yang et al.
million (ppm) relative to the internal standard tetramethylsilane (TMS). Electro-
spray mass spectra were obtained on a Finnigan MAT-95 Spectrometer.
Diethy[4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-
ethoxyquinolin-6-ylamino]-2-oxoethylphosphonate (VIII)
A solution of 50.3 g (0.22 mol) ethyl diethoxyphosphinylacetate in 500 mL
methanol was added dropwise to a stirred solution of 25.0 g (0.45 mol) potassium
hydroxide in 500 mL methanol and 50 mL water. The reaction mixture was refluxed
for 10 min then cooled to room temperature. Concentrated hydrochloric acid was
added to bring the pH of the reaction mixture to 1–2. The solvent was evaporated,
and the residue was extracted with acetone and filtered. Acetone was removed,
giving the diethoxyphosphinylacetic acid as a colorless oil that was used without
additional purification. It was dissolved in 200 mL dry tetrahydrofuran (THF). The
solution thus obtained was designated solution A.
To a mixture of 35.3 g (0.22 mol) 1,1-carbonydiimidazole in 500 mL dry THF, the
solution A was added at 40 °C. After stirring for 30 min, 32.4 g (0.073 mol) of 6-amino-
4-[3-chloro-4-(2-pyridinylmethoxy)-anilino]-3-cyano-7-ethoxyquinoline [10] was added
and stirred at 40 °C for 5 h. Then, it was poured into 2.5 L water. The precipitate was
collected by filtration, washed with water and dried at 45 °C in vacuum to give the title
compound as a light yellow solid (45.1 g, 99.6 % yield); mp 102–104 °C. IR (KBr):
3,245 (NH), 2,210 (CN), 1,674 (C=O), 1,239, 1,044 cm-1 1H-NMR (500 MHz,
.
DMSO-d6) d: 9.62 (s, 1H, NH), 9.46 (s, 1H, NH), 8.60 (d, 1H, J = 4.8 Hz, ArH), 8.48 (s,
1H, ArH), 7.87 (t, 1H, J = 7.7 Hz, ArH), 7.58 (d, 1H, J = 7.7 Hz, ArH), 7.40 (s, 1H,
ArH), 7.36–7.38 (m, 2H, ArH), 7.24 (d, 1H, J = 8.9 Hz, ArH), 7.18 (dd, 1H,
J = 8.1 Hz, J = 2.5 Hz, ArH), 5.28 (s, 2H, –OCH2Py), 4.33 (q, 2H, J = 7.0 Hz,
–OCH2CH3), 4.12–4.05 (m, 4H, –P(O)(CH2CH3)2), 3.36 (d, 2H, J = 21.4 Hz,
–CH2P(O)), 1.47 (t, 3H, J = 7.0 Hz, –OCH2CH3), 1.25 (t, 6H, J = 7.1 Hz, –P(O)
(CH2CH3)2); 13C-NMR (500 MHz, DMSO-d6) d: 163.5, 156.1, 153.2, 151.0, 149.1,
147.6, 142.0, 137.0, 134.0, 127.7, 125.8, 124.0, 123.0, 121.5, 121.4, 117.1, 114.9, 114.3,
113.2, 108.6, 87.3, 71.2, 64.5, 59.7, 45.1, 14.2. MS m/z (ESI): 624.2 [M?1].
Neratinib
Under nitrogen, 10.7 mL (0.055 mol) of dimethylaminoacetaldehyde diethylacetal
was added dropwise to a solution of 13.2 mL of 6 mol L-1 of hydrochloric acid at
0 °C within 20 min. The reaction solution was warmed to 40 °C, stirred for 12 h,
and then cooled to 0 °C. This solution is referred to as solution B.
A mixture of 21.3 g (0.25 mol) of sodium ethylate, 5.2 g (0.125 mol) of lithium
chloride and 31.2 g (0.05 mol) of VIII in 300 mL ethanol was stirred at 0 °C for 30 min.
Then, it was cooled to -20 °C. The solution B was added within 10 min. The reaction
mixture was stirred at -20 °C for 3 h, and 500 mL water and 500 mL ethylacetate were
added. The water layer was extracted with ethylacetate (2 9 300 mL). Combined organic
layers and washed with water (3 9 300 mL) and brine (2 9 100 mL) and dried with
Na2SO4. The ethylacetate was removed and the yellow solid was recrystallised from
CH3CN/THF to give the title compound as a light yellow solid (26.5 g, 95.2 % yield); mp
123

The Wittig–Horner reaction for the synthesis of neratinib
182–184 °C. IR (KBr): 3,279 (NH), 2,211 (CN), 1,720 and 930 (CH=CH), 1676 (C=O),
1,237, 1,037 cm-1.1H NMR(DMSO-d6, 500 MHz)d: 9.60 (s, 1H, NH), 9.48 (s, 1H, NH),
8.96 (s, 1H, ArH), 8.60 (d, 1H, J = 4.8 Hz, ArH), 8.47 (s, 1H, ArH), 7.87 (t, 1H,
J = 7.0 Hz, ArH), 7.58 (d, 1H, J = 7.8 Hz, ArH), 7.39–7.35(m, 3H, ArH), 7.27–7.17(m,
2H, ArH), 6.82–6.73 (m, 1H, –CH=), 6.59 (d, 1H, J = 15.5 Hz, =CH–), 5.28 (s, 2H,
–OCH2Py), 4.31 (q, 2H, J = 7.0 Hz, –OCH2CH3), 3.09 (d, 2H, J = 5.7 Hz, –CH2CH=),
2.18 (s, 6H (CH3)2N–), 1.47 (t, 3H, J = 7.0 Hz, –OCH2CH3); 13C-NMR (500 MHz,
DMSO-d6) d: 163.3, 156.2, 152.4, 152.2, 151.0, 150.5, 149.1, 147.4, 137.0, 134.2, 127.7,
125.7, 123.9, 123.0, 121.5, 121.4, 117.1, 114.3, 113.3, 108.6, 88.8, 71.2, 64.6, 61.8, 35.0,
14.2; MS m/z (ESI): 557.3 [M?1].
Results and discussion
The synthetic pathway utilized to prepare neratinib was initiated by acylated the
6-amino-4-[3-chloro-4-(2-pyridinylmethoxy)-anilino]-3-cyano-7-ethoxyquinoline
(IV) with triethyl phosphonoacetate to afford the key phosphonate intermediate
(VIII), which was coupled with 2,2-diethoxy-N,N-dimethylethylamine in ethanol to
give the final product in satisfactory yield (95.2 %).
The structures of VIII and neratinib were confirmed on the basis of spectroscopic data,
particularly 1H NMR analysis and MS spectra. In VIII 1H NMR, the multiple signals at
4.05–4.12 (4H) ppm and triplet signals at 1.25 (6H, J = 7.1 Hz) ppm were due to
P(O)(CH2CH3)2. The doublet signals at 3.36 (2H, J = 21.4 Hz) were due to –CH2P(O),
which had a large NMR coupling constant because of neighbor coupling. In the ESI–MS
spectrum, the calculated m/z [M?1] of VIII was 623.2, and the m/z found was 623.2.
In neratinib 1H NMR, the multiple signals at 6.73–6.82 (m, 1H) ppm were due to
–CH=C–C=O. The doublet signals at 6.59 (1H, J = 15.5 Hz) ppm were due to
–C=CH–C=O. The stereo of CH=CH was trans, which was identified by the large
coupling constant. The cis-olefin’s coupling constant was in 6.0–12.0, and trans-
was in 12.0–19.0. In addition, the signals in IR at 1,720 and 930 cm-1 also proved
the existence of trans-olefin. In the ESI–MS spectrum, the calculated m/z [M?1] of
neratinib was 557.2, and the m/z found was 557.3.
Conclusions
In conclusion, we developed a facile and high efficiency method for the synthesis of
neratinib via the Wittig–Horner reaction. The synthetic applications of neratinib
derivatives are in progress in our laboratory.
Acknowledgments This work was supported by National Basic Research Program of China
(No. 2011CB933503).
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