USOO9428468B2

(12) United States Patent (10) Patent No.: US 9.428,468 B2

Baratella et al. (45) Date of Patent: Aug. 30, 2016
(54) PROCESS FOR THE PREPARATION OF IN WO 2010/109443 * 9/2010
ERLOTINIB WO 96.3O347 10, 1996
WO 2007138612 A2 12/2007
WO 2007138613 A2 12/2007
(71) Applicant: CERBIOS-PHARMASA, WO 2010.109443 A1 9, 2010
Barbengo/Lugano (CH)
OTHER PUBLICATIONS
(72) Inventors: Marco Baratella, Cerano (IT):
Giuseppe Pallanza, Robbio (IT): Chandregowda (Organic Chemistry: An Indian Journal (2009), 5.
Mauro Gaboardi, Novara (IT): (4), 397-400.*
Graziano Castaldi, Briona (IT) Chandregowda et al., "Convergent Approach for Commercial Syn
thesis of Gefitinib and Erlotinib'. Organic Process Research &
(73) Assignee: CERBIOS-PHARMASA, Development, 2007, vol. 11, pp. 813-816.
Barbengo/Lugano (CH) European search report based on IT MI2014 1845.
(*) Notice: Subject to any disclaimer, the term of this * cited by examiner
patent is extended or adjusted under 35
U.S.C. 154(b) by 0 days. Primary Examiner — Valerie Rodriguez-Garcia
(21) Appl. No.: 14/923,875 (74) Attorney, Agent, or Firm — Lucas & Mercanti, LLP
(22) Filed: Oct. 27, 2015 (57) ABSTRACT
A process for the preparation of Erlotinib is disclosed in
(65) Prior Publication Data which the compound of formula (II)
US 2016/O115137 A1 Apr. 28, 2016
(30) Foreign Application Priority Data (II)
No.1n-1O CN

Oct. 28, 2014 (IT) .............................. MI2O14A1845

O
(51) Int. Cl. 1. N-1\o NH2
C07D 239/94 (2006.01)
A 6LX 3/57 (2006.01) Is reacted with the compound of formula (III) in the
(52) U.S. Cl. presence of trifluoroacetic acid and formamidine
CPC ........... C07D 239/94 (2013.01); A61K3I/517 acetate, in an aprotic solvent,
(2013.01)
(58) Field of Classification Search
CPC ........................... A61K 31/517; C07D 239/94 (III)
See application file for complete search history.
(56) References Cited
U.S. PATENT DOCUMENTS
2^ NH, HCI
7,960,545 B2 6/2011 Jyothi Prasad et al. and the reaction product is Subsequently treated with a
FOREIGN PATENT DOCUMENTS source of hydrochloric acid in a suitable solvent to give
Erlotinib hydrochloride.
EP 1044969 10, 2000
EP 2433934 3, 2012 10 Claims, No Drawings
 US 9,428,468 B2
1. 2
PROCESS FOR THE PREPARATION OF miming the ATP structure, but being more stable than that,
ERLOTNB they bind to the receptor and inhibit it. Therefore the
CROSS-REFERENCE TO RELATED
activation of the cell reactions is not allowed, so blocking
APPLICATIONS s the cell expansion.
Erlotinib is a compound of formula (I)
This application claims the benefit of priority from Italian
Patent Application Serial No. MI2014AO01845, filed Oct.
28, 2014, the contents of which are incorporated herein by
reference. 10
(I)
FIELD OF THE INVENTION O N
No1 N-1 n
The present invention relates to a process for the synthesis O N
of Erlotinib and intermediates useful for its preparation. 15 1. N-1No 2
BACKGROUND OF THE INVENTION HN 2

Erlotinib is a drug used in the treatment of cancer dis

eases, in particular for lung and pancreatic cancer. Erlotinib 20
is an inhibitor of the tyrosine kinase receptor, acting in
particular by inhibiting the EGF receptor, the epidermal
growth factor receptor, in cancer there is the over-expression
of growth factor receptors and related ligands. These are, in
fact, some of the factors involved in processes of cancer 25 chemically known as N-3-(ethynyl-phenyl)-6,7-bis-(2-
etiopathogenesis. The stimulation of the growth factors methoxyethoxy)-4-quinazolin amine, described in WO
leads to an increase of the cell proliferation with the con- 96/30347 and marketed with the trademark Tarceva R.
sequent starting of the disease. The receptors, once bound
the ligand, self-phosphorylate so generating a cascade of WO 96/30347 describes a process for the synthesis of
intracellular reactions that lead to the activation of transcrip- Erlotinib reported in the following scheme 1:
Scheme 1
O O O

HO O
of CH3O(CH2)2B,
K2CO3/TBAI
No1 N1 or HNO3, No1 N1 O OEt
O O
HO 1 N-1No 1. n-1No NO
H 45 psi
PtO2·H2O

C (COCl) O HCOONH O

No-1-9 C'C's PMF no-nu-o N - O - Yo1)- OEt

1'N-1- n! 1'N1so s! 1.On-1\o NH2
NH2

iPrCH, py

Šs
ERLOTINIB

65
tion factors involved in the cell proliferation. Erlotinib binds EP 1 044 969 describes a process for the synthesis of
itself to the intracellular catalytic portion of the receptor Erlotinib reported in the following scheme 2:
 US 9,428,468 B2
3 4
Scheme 2

NH2
C CHCN
A HN
No1-9 N + Her O Šs
Ša No1N1 nN
1'N1so s! N O
2a OH
OH 1. n-1No N

Not
ERLOTINIB

TBAF
THF

O Si
No 1N1 nN /\
1. ON-1No 2
4.

iPrCH,

C NH2

No1 N-1O /
h | -Si-E
O
1. N-1\o s
H230 psi
Pt/Al2O3

Br NO

E-S- -- He
EtN
Cul, Pd(II) -Si-E
NO

U.S. Pat. No. 7,960,545 discloses a process for the

synthesis of Erlotinib reported in the following scheme 3:

Scheme 3
O O O
Ac2O
19 HBr 48% HO py AcO
NH -> NH --> NH

No N 2 HO N 2 AcO N 2
(COCl)
DMF
 US 9,428,468 B2
5
-continued
NH2

C
NH3 aq
HN Šs MeOH HN Šs NH
HO sN AcO as N
AcO
HO e AcO e

ERLOTINIB

EP 2 433 934 describes a process for the synthesis of

Erlotinib reported in the following scheme 4:

Scheme 4

X = I, Br, C1, OTs, OMs

NH2

O Acido
forte HN
-as
X
us + HOOC F -> HOOC o Pd(II)/Fosfina
OH XPhOS

OH

OH

ERLOTINIB
 US 9,428,468 B2
7 8
All these processes foresee numerous steps for the prepa necessarily require the formation and the isolation of the
ration of the key intermediate, 4-chloro-6,7-bis(2-methoxy intermediate obtained by the reaction with N,N-dimethyl
ethoxy)guinazoline, that is then reacted with 3-ethynylani formamide dimethylacetal.
line or a derivative thereof. We have now found that it is possible to further reduce the
WO 2007/138612 and WO 2007/138613 describe a pro number of synthetic steps, the use of expensive reagents and
cess for the synthesis of Erlotinib reported in the following the isolation of intermediates so obtaining Erlotinib through
scheme 5: a simpler and cheaper process.

Scheme 5

HO CHO N O CHO
CH3O(CH2)2Br
-e-
1N1 NH2OHHCI
Hs
K2CO3/DMF O py, MeOH
HO 1. N-1\o

OH
M O CN
FN AcO No1 N-1 HNO
-e-

1'N-1s

N-1- CN Fol N-1- CN

O O
1. N-1No NO 1. N-1N NH2
--
N1
ors.
N(Me)2
21
O CN
No.1n-1
NR
-N Šs N1
N

AcOH s NH2

Šs
Šs ERLOTINIB

The processes described in WO 07/138612 and WO SUMMARY OF THE INVENTION

07/138613 have the advantage to reduce the number of steps 65
avoiding the formation and the isolation of the intermediate It is therefore object of the present invention a process for
4-chloro-6,7-bis(2-methoxyethoxy)guinazoline but they the synthesis of Erlotinib comprising:
 US 9,428,468 B2
9 10
a) the reaction of the compound of formula (II)
(II)
No1 N-1
O CN
O ous to the skilled in the art are included in the present
1. N-1\o NH2
with the compound of formula (III)
(III)
NH2 o HCI
2 Example 1
b) the subsequent treatment with a source of hydrochloric
acid in a suitable solvent to give Erlotinib hydrochloride.
DETAILED DESCRIPTION OF THE
INVENTION
The compounds (II) and (III) are both known and com
mercially available or prepared according to methods
described in literature (for example in WO 2007/138612).
The reaction between the compound of formula (II) and the
compound of formula (III) of the process object of the
present invention is preferably carried out in the presence of
trifluoroacetic acid and formamidine acetate in an aprotic
polar solvent selected among acetonitrile, isopropanol, N.N-
dimethylformamide, N,N-dimethylacetamide and tetrahy
drofuran, preferably acetonitrile.
The reaction between the compound (II) and the com
pound (III) represents the most characteristic feature of the
process object of the present invention since it allows to
carry out one-pot the formation of the quinazoline ring and
its functionalization with the 3-ethynylphenylamino group
without requiring the isolation of any intermediate and
directly obtaining Erlotinib.
In particular, the use of formamidine acetate makes the
process of the invention different from all the known meth
ods, in particular also from the methods described in WO
07/138612 and in WO 07/138613, which foresee different
intermediates and mechanisms of action.
In the Subsequent step of the process object of the present
invention a treatment with a source of hydrochloric acid is
carried out to obtain Erlotinib hydrochloride.
Preferably, the source of hydrochloric acid can be a
solution of hydrochloric acid or an amine hydrochloride salt,
preferably selected among benzylamine hydrochloride,
trymethylamine hydrochloride, triethylamine hydrochloride.
An aqueous solution of concentrated hydrochloric acid is
more preferably used.
The treatment with a source of hydrochloric acid is
carried out in a Suitable solvent preferably selected among
isopropanol, methanol, butanol, ethyl acetate and tetrahy
drofuran. Isopropanol and ethyl acetate are the most pre
ferred solvents.
In a preferred embodiment of the process object of the
present invention the reaction between the compounds of
formula (II) and (III) is carried out in the presence of
formamidine acetate and trifluoroacetic acid in acetonitrile
at a warm temperature, above room temperature and, as
shown in the examples, at the reflux temperature of the
Solvent, and the Subsequent treatment with concentrated
hydrochloric acid is carried out in ethyl acetate as solvent,
at room or slightly lower temperature. Erlotinib hydrochlo
ride is so obtained with high yield and high degree of purity.
Although the present invention has been described in its
characterizing features, equivalents and modifications obvi
invention.
The present invention will be now illustrated through
10 Some examples without limiting the scope of the invention.
All the terms used in the present invention, unless other
wise indicated, are to be understood in their common
meaning as known in the art. Other more specific definitions
for certain terms, as used in the present description, are
15
highlighted herein after and constantly applied in the whole
description and claims, unless a different definition provides
specifically a broader meaning.
In a reaction flask, 2-amino-4,5-bis(2-methoxyethoxy)-
benzonitrile (37.01 g, 0.139 mol) and acetonitrile (185 ml)
were charged; 3-ethynylaniline hydrochloride (30.00 g,
0.195 mol), trifluoroacetic acid (17.43 g, 0.152 mol) and
formamidine acetate (15.19 g, 0.145 mol) were added to the
25 resultant mixture. The reaction mixture was brought to the
reflux temperature of the solvent and maintained under such
conditions for about fifteen hours. At the end of the reaction,
the temperature was brought to about 25°C., the solvent was
removed by distillation under vacuum and methylethylke
30 tone (430 ml) was added. The organic phase was washed
with a saturated sodium bicarbonate solution (2x100 ml) and
with water (2x100 ml). The collected organic phases were
concentrated to residue by distillation under vacuum.
The resultant raw product was Suspended in ethyl acetate
35
(450 ml) and a solution of hydrochloric acid at 37% (14.38
g, 0.145 mol) was added, maintaining the temperature at 15°
C. for about thirty minutes. The resultant solid was filtered,
washed and dried in oven under vacuum at 45° C. to give
36.02 g of Erlotinib HC1.
40
Example 2
In a reaction flask, 2-amino-4,5-bis(2-methoxyethoxy)-
benzonitrile (37.01 g, 0.139 mol) and acetonitrile (185 ml)
45 were charged; 3-ethynylaniline hydrochloride (30.00 g,
0.195 mol), trifluoroacetic acid (17.43 g, 0.152 mol) and
formamidine acetate (15.19 g, 0.145 mol) were added to the
resultant mixture. The reaction mixture was brought to the
reflux temperature of the solvent and maintained under such
50 conditions for about fifteen hours. At the end of the reaction,
the temperature was brought to about 25°C., the solvent was
removed by distillation under vacuum and methylethylke
tone (430 ml) was added. The organic phase was washed
with a saturated sodium bicarbonate solution (2x100 ml) and
55 with water (2x100 ml). The collected organic phases were
concentrated to residue by distillation under vacuum.
The resultant raw product was Suspended in ethyl acetate
(450 ml) and benzylamine hydrochloride (20.82 g, 0.145
mol) was added, maintaining the temperature at 15° C. for
60 about thirty minutes. The resultant solid was filtered, washed
and dried in oven under vacuum at 45° C. to give 34.31 g of
Erlotinib HC1.
Example 3
65
In a reaction flask, 2-amino-4,5-bis(2-methoxyethoxy)-
benzonitrile (37.01 g, 0.139 mol) and acetonitrile (185 ml)
 US 9,428,468 B2
11
were charged; 3-ethynylaniline hydrochloride (30.00 g,
0.195 mol), trifluoroacetic acid (17.43 g, 0.152 mol) and
formamidine acetate (15.19 g, 0.145 mol) were added to the
resultant mixture. The reaction mixture was brought to the
reflux temperature of the solvent and maintained under such
conditions for about fifteen hours. At the end of the reaction,
the temperature was brought to about 25°C., the solvent was
removed by distillation under vacuum and methylethylke
tone (430 ml) was added. The organic phase was washed
with a saturated sodium bicarbonate solution (2x100 ml) and
with water (2x100 ml). The collected organic phases were
concentrated to residue by distillation under vacuum.
The resultant raw product was suspended in ethyl acetate
(450 ml) and trimethylamine hydrochloride was added,
maintaining the temperature at 15° C. for about thirty
minutes. The resultant solid was filtered, washed and dried
in oven under vacuum at 45° C. to give 35.01 g of Erlotinib
HC1.
The invention claimed is:
1. A process for the synthesis of Erlotinib hydrochloride,
comprising:
a) reacting the compound of formula (II)
(II)
No1 N-1
O CN
1'N-1-
with the compound of formula (III)
(III)
2 presence of formamidine acetate and trifluoroacetic acid in
and
b) Subsequently treating the reaction product of step a)
with a source of hydrochloric acid in a suitable solvent
to give Erlotinib hydrochloride,
12
wherein the reacting of the compound of formula (II) with
the compound of formula (III) is carried out in the
presence of trifluoroacetic acid and formamidine
acetate, in an aprotic solvent.
2. The process of claim 1, wherein the aprotic polar
Solvent is selected from the group consisting of acetonitrile,
isopropanol, N,N-dimethyl-formamide, N,N-dimethylacet
amide and tetrahydrofuran.
10 3. The process of claim 2, wherein the solvent is acetoni
trile.
4. The process of claim 1, wherein the source of hydro
chloric acid is a solution of hydrochloric acid or an amine
hydrochloride salt.
15 5. The process of claim 4, wherein the amine hydrochlo
ride Salt is selected from the group consisting of benzylam
ine hydrochloride, trimethylamine hydrochloride and trieth
ylamine hydrochloride.
6. The process of claim 4, wherein the source of hydro
chloric acid is an aqueous Solution of concentrated hydro
chloric acid.
7. The process of claim 1, wherein the treating with a
source of hydrochloric acid is carried out in a solvent
25 selected from the group consisting ofisopropanol, methanol,
butanol, ethyl acetate and tetrahydrofuran.
8. The process of claim 7, wherein the solvent is isopro
panol or ethyl acetate.
9. The process of claim 1, wherein the reacting of the
30
compounds of formula (II) and (III) is carried out in the
presence of formamidine acetate and trifluoroacetic acid in
acetonitrile at a temperature above room temperature and the
Subsequent treating with concentrated hydrochloric acid is
carried out in ethyl acetate as solvent, at room temperature
or slightly lower temperature.
10. The process of claim 1, wherein the reacting of the
compounds of formula (II) and (III) is carried out in the
40 acetonitrile at the reflux temperature of the solvent and the
Subsequent treating with concentrated hydrochloric acid is
carried out in ethyl acetate as solvent, at room temperature
or slightly lower temperature.
k k k k k