An improved process for the synthesis of nintedanib esylate

Article abstract of DOI:10.1080/00397911.2017.1297459

Nintedanib esylate is synthesized via novel intermediates of (Z)-methyl 3-(acetoxy-phenyl)methylene)-1-acetyl-2-oxoindoline-6-carboxylate and N-(4-aminophenyl)-2-chloro-N-methylacetamide in good yields.

Full text of DOI:10.1080/00397911.2017.1297459

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
An Improved Process for the Synthesis of
Nintedanib Esylate
Veerareddy. Arava & Surendrareddy. Gogireddy
To cite this article: Veerareddy. Arava & Surendrareddy. Gogireddy (2017): An Improved
Process for the Synthesis of Nintedanib Esylate, Synthetic Communications, DOI:
10.1080/00397911.2017.1297459
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Date: 24 February 2017, At: 01:03

An Improved Process for the Synthesis of Nintedanib Esylate
Veerareddy. Arava1, Surendrareddy. Gogireddy1
1R&D Centre, Suven Life Sciences Ltd, Jeedimetla, Hyderabad, India.
Coresponding author: Veerareddy. Arava E-mail: reddyvenis@rediffmail.com
Abstract
Nintedanib Esylate is synthesized via novel intermediates of (Z)-methyl 3-(acetoxy-
phenyl)methylene)-1-acetyl-2-oxoindoline-6-carboxylate and
N-(4-aminophenyl)-2-
chloro-N-methylacetamide in good yields.
Graphical Abstract
KEYWORDS: Nintedanib Esylate; Benzoyl chloride; (Z)-methyl 3-(acetoxyphenyl)
methylene)-1-acetyl-2-oxoindoline-6-carboxylate; N-(4-aminophenyl)-2-chloro-N-
methylacetamide.
INTRODUCTION
Indolinones are promising scaffolds as kinase inhibitors,[1] which represent an important
class of heterocyclic compounds endowed on interesting pharmacological[2-3] and
biological activities[4-7]. In addition, the last decade’s 2-indolinone derivatives have
become lead compounds in the research of kinase inhibitors. Substituted indolin-2-ones
1

(C-3, C-5 & C-6) have been identified as a versatile scaffold for the development of
protein kinase inhibitors which exhibit selectivity toward different tyrosine kinases by
altering the various substituents. The exploration for synthetic inhibitors of protein
kinases as anti cancer drugs has been revived by successful approval of a number of
molecules that target tyrosine kinase.
Nintedanib Esylate 1 (Fig.1) fall into the indolin-2-one class, which is a small molecule
inhibitor of multiple receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases
(nRTKs)[8]. It was first approved in 2014 by US FDA and was first developed and
marketed by Boehringer Ingelheim (BI) under the brand names of Ofev & Vargatef. It is
used for the treatment of Idiopathic Pulmonary fibrosis (IPF)[9,10], approved by FDA,
EMA & PMDA and for non-small cell lung cancer (NSCLC) approved by EMA.
Roth G J et al.[8,11] and Heckel et al. [12] reported the synthesis of Nintedanib from two
key building blocks, one is the indolinone based key building block (Z)-methyl 1-acetyl-
3-(methoxyphenyl)methylene)-2-oxoindoline-6-carboxylate 4, which is prepared from
methyl1-acetyl-2-oxoindoline-6-carboxylate 2 by reacting with trimethylorthobenzoate 3.
The enol ether 4 was coupled with second key building block N-(4-aminophenyl)-N-
methyl-2-(4-methylpiperazin-1-yl)acetamide 5 to furnish Nintedanib base 6 as shown in
Scheme 1.
Merten et al. [13, 14] prepared the Nintedanib base by condensation of 7 with 3 and
subsequent condensation with 5 as shown in Scheme 2.
2

Nong X et al.[15] reported the synthesis of 6 by condensation of 9 with 3 and subsequent
condensation with 5 as shown in Scheme 3.
Cheng G [16] reported the synthesis of 6 via the intermediate of 11 (Fig. 2) and Yong Li et
al.[17] reported via the intermediate of 12 (Fig .3).
According to literature i.e. the indolinone based key materials 4 & 8 were prepared by
reacting indolinone (2 & 7) with 3 at elevated temperature in one pot synthesis. This
reaction is critical and yields are highly unpredictable. Considering the importance of
Nintedanib, we developed an alternate and improved process. The present process is
simple, convenient and cost effective for large scale production.
RESULTS AND DISCUSSIONS
Initially, we were unsuccessful to synthesize 14 by condensation of 2 with
DMF:dimethylbezamide complex 13 by in situ generation. Our next efforts of coupling
of commercially available 15 with 2 and DMAP furnished the desired (Z)-methyl 1-
acetyl-3-(hydroxy(phenyl)methylene)-2-oxoindoline-6-carboxylate 16 but in 15% yield
only. The O-alkylation with various bases and methylating agents to get 4 was
unsuccessful and the C –alkylated product 17 was isolated in 15% yield as shown in
scheme 4.
3

The best condensation conditions for 18 with 15 were studied with different bases and
solvents and finally found that isopropyl-alcohol and sodium methoxide powder works
better (see Table 1) as shown in Scheme 5.
In our attempts to have better leaving group than -OMe, we found that acetyl group
works better. Acetylation with pyridine and acetic anhydride on 19 gave methyl 3-
(acetoxyphenyl)methylene)-1-acetyl-2-oxoindoline-6-carboxylate 20 in good yield and
quality. The condensation of 20 with 5 gave only 50% of product 21 as shown in Scheme
6.
To improve the yields, compound 20 was condensed with 21 (instead of 5) under neutral
conditions to give 22. This 22 was further elaborated to Nintedanib Esylate 1 as shown
in scheme 7.
In conclusion we have developed a simple and novel method of the preparation
of Nintedanib Esylate 1 via novel intermediates of (Z)-methyl 3-
(acetoxy(phenyl)methylene)-1-acetyl-2-oxoindoline-6-carboxylate 20 and N-(4-
aminophenyl)-2-chloro-N-methylacetamide 21. The final product 1 is completely in
agreement with the reported one[13] by all spectral means.
EXPERIMENTAL
All the reagents were obtained commercially, were of the highest commercial quality,
and were used without further purification. Solvents were freshly distilled and used.
4

Melting points were determined in open capillaries and are uncorrected. Thin layer
chromatography (TLC) or high-performance liquid chromatography (HPLC) was
routinely used to check the purity of all compounds. Infrared (IR) spectra were recorded
on Perkin- Elmer model 2000 instrument in KBr phase. 1H-NMR (400MHz) and 13C-
NMR (100MHz) spectra were recorded in CDCl3 or Dimethyl sulfoxide (DMSO) using a
Bruker instrument and mass spectra were recorded on a Perkin-Elmer mass spectrometer
operating a 70 ev.
Preparation Of Methyl-3-(Hydroxy(Phenyl)Methylene)-2-Oxoindoline-6-
Carboxylate (19)
To the suspension of methyl 2-oxoindoline-6-carboxylate 18[16,17] (50 g, 0.261 mol) in
IPA (350 ml) was added slowly sodium methoxide-powder (33.8 g, 0.626 mol) and
stirred for about 15 min. Benzoyl chloride (44 gm, 0.313 mol) was added and stirred at (-
)5 to (-)10ºC for about 5h. After completion of the reaction, the reaction mixture was
quenched into ice-water (700 ml) and acidified with Conc.HCl up to pH 2.0-2.5. Filtered
the reaction mixture, washed with water (2X100 ml) and dried the precipitate to obtain
crude product, which was recrystallized from acetonitrile (28 ml) to obtain methyl-3-
(hydroxy(phenyl)methylene)-2-oxoindoline-6-carboxylate pure crystalline solid (32 g)
(61%) (HPLC purity >97%). The filtrate was evaporated in vacuum to get the unreacted
methyl 2-oxoindoline-6-carboxylate.
m.p.: 216-223ºC; IR (KBr, cm-1): 3178, 1711, 1651; 1H-NMR (400 MHz, DMSO): δ 3.80
(s, 3H), 7.17 (s, 1H), 7.28-7.31 (m, 2H), 7.46-7.50 (m, 3H), 7.72 (d, 2H, J = 6.0 Hz), 9.52
5

(s, 1H), 11.53 (s, 1H); 13C-NMR (100 MHz, DMSO): δ 22.12, 52.41, 101.13, 111.13,
119.23, 123.06, 126.65, 127.06, 128.65, 129.21, 132.26, 134.47, 136.99, 166.58, 172.52
and 175.80; HRMS(ESI): m/z calcd. For C17H13NO4: 295.0845. Found: 296.0921 [M]+1.
Preparation Of Methyl-3-(Acetoxy(Phenyl)Methylene)-1-Acetyl-2-Oxoindoline-6-
Carboxylate (20)
To the suspension of methyl-3-(hydroxy(phenyl)methylene)-2-oxoindoline-6-carboxylate
19 (45 g, 0.1512 mol) in acetic anhydride (300 ml) was added pyridine (4.5 g) slowly
(drop-wise) and stirred the reaction at 0-5ºC for about 30 min. After completion of the
reaction, the temperature of the reaction mass was raised to 75-80ºC and stirred for about
1h. The reaction mass was cooled and stirred for about 30 min at 25-28ºC, filtered and
washed with hexane (100 ml) and dried to obtain methyl-3-(acetoxy(phenyl)methylene)-
1-acetyl-2-oxoindoline-6-carboxylate.
m.p.: 226-229ºC; IR (KBr, cm-1): 3413, 1771, 1743, 1717, 1640; 1H-NMR (400 MHz,
CDCl3): δ 2.38 (s, 3H), 2.62 (s, 3H), 3.92 (s, 3H), 7.44 (m, 3H), 7.62 (d, 2H, J = 7.004
Hz), 7.68 (d, 1H, J = 8.12 Hz), 7.91 (d, 1H, J = 8.0 Hz), 8.90 (s, 1H); 13C-NMR (100
MHz, CDCl3): δ 21.08, 21.38, 26.96, 52.25, 52.34, 115.17, 117.18, 121.33, 122.77,
125.82, 126.19, 126.56, 128.15, 128.87, 129.27, 129.34, 130.81, 130.90, 131.47, 131.82,
132.80, 138.55, 160.85, 165.95, 166.38, 166.42, 167.01, 170.67 and 170.76; HRMS(ESI):
m/z calcd. For C21H17NO6: 379.1056. Found: 380.1184 [M]+1.
6

Preparation of methyl-1-acetyl-3-(((4-(2-chloro-N-methylacetamido)phenyl)amino)
Phenyl)Methylene)-2-Oxoindoline-6-Carboxylate (22)
Suspension of methyl-3-(acetoxy(phenyl)methylene)-1-acetyl-2-oxoindoline-6-
carboxylate 20 (49 g, 0.129 mol) and N-(4-aminophenyl)-2-chloro-N-methylacetamide
(25.66 g, 0.129 mol) in a mixture of methanol (350 ml) and DMF (88 ml) was heated and
stirred for about 12h at 60-65°C. After completion of the reaction, cooled the reaction
mass and stirred for about 30min at RT. The reaction mixture was filtered and washed
with methanol (2X50ml) and dried the precipitate to obtain methyl-1-acetyl-3-(((4-(2-
chloro-N-ethylacetamido)phenyl)amino(phenyl)methylene)-2-oxoindoline-6-carboxylate.
m.p.: 247-250ºC; IR (KBr, cm-1): 3432, 1712, 1675, 1591; 1H-NMR (400 MHz, DMSO):
δ 2.74 (s, 3H), 3.11 (s, 3H), 3.78(s, 3H), 3.87 (s, 2H), 5.75 (d, 1H, J = 8.08 Hz), 7.01 (d,
2H, J = 7.96 Hz), 7.22 (d, 2H, J = 6.08Hz), 7.36 (d, 1H, J = 8.48 Hz), 7.46 (d, 2H, J =
7.24 Hz), 7.54-7.64 (m, 3H), 8.74 (s, 1H), 11.92 (s, 1H); 13C-NMR (100MHz, DMSO): δ
27.17, 37.76, 42.48, 52.40, 96.38, 116.17, 117.59, 124.80, 125.33, 125.68, 128.09,
129.00, 130.10, 131.35, 131.97, 134.05, 160.93, 165.63, 166.68, 168.49 and 171.28;
HRMS(ESI): m/z calcd. For C28H24ClN3O5:: 517.1404. Found: 518.1404 [M]+1.
ACKNOWLEDGMENT
The authors are grateful to Suven Life Sciences management for allowing them to
publish these results.
SUPPORTING INFORMATION
7

Experimental detail, 1H, 13C- NMR spectra and HPLC chromatograms. This material can
be found via the “Supplementary Content” section of this article’s webpage.
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9

Table 1: Screening of solvent and base conditions for synthesis of 19.
S.NO
Solvent
Benzoyl chloride Base
mole ratio
Conversion Remarks
by HPLC
IPA
1.2
SMO-Solution 1-2%
Not Isolated
1.
2.
3.
Methanol 1.2
SMO-Powder
SMO-Powder
0.5-1%
15-20%
Not Isolated
Ethanol
1.2
>75% Ethyl ester derivati-
ve i.e Ester Exchanged
Very low isolated yield
Not Isolated
DMF
DMF
IPA
1.2
1.2
1.2
DMAP
75%
30%
4.
5.
6.
t-BuOK
SMO-Powder 70-75%
Freely Isolated
10

Scheme 1: Synthesis of 6 from 2 & 3.
11

Scheme 2: Synthesis of 6 from 7 & 3.
12

Scheme 3: Synthesis of 6 from 9 & 3.
13

Scheme 4:
14

Scheme 5: Synthesis of 19 from 18 & 15.
15

Scheme 6: Synthesis of 21 from 19.
16

Scheme 7: Synthesis of 1.
17

Figure 1.
18

Figure 2.
19

Figure 3.
20