FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of
highly pure Erlotinib hydrochloride (I)
BACKGROUND OF THE INVENTION:
Erlotinib hydrochloride (I) is chemically named as N-(3-ethynylphenyl)-6,
7-bis (2-methoxy ethoxy)-4-quinazolinamine hydrochloride
Erlotinib hydrochloride (I) is an inhibitor of oncogenic and proto-oncogenic
protein tyrosine kinases viz, Epidermal growth factor receptor (EGFR).
Erlotinib is therefore useful in the treatment of proliferative disorders and is
currently marketed as Xeloda® for the treatment of lung cancer and pancreatic
cancer.
It is indicated for the treatment of patients with locally advanced or
metastatic non-small cell lung cancer after failure of at least one prior chemotherapy
regimen, and in combination with gemcitabine is indicated for the first-line
3
treatment of patients with locally advanced, unresectable or metastatic pancreatic
cancer.
Schnur, et al in US5747498B2 discloses a process for the preparation of
Erlotinib free base and its HCl salt, which follows the pathway as given in the
Scheme-1.
Scheme -1: Process as per US 5747498
Kalvins Ivars et al in WO2015023170A2 discloses the preparation method
of Erlotinib hydrochloride according to the pathway as given in the Scheme -2:
4
Scheme -2: Process as per WO2015023170A2
Murugesan et al in US8440823B2 disclosed the preparation method of
Erlotinib hydrochloride according to the pathway as given in the Scheme-3:
Scheme -3: Process as per US8440823B2
Baratella et al in US9428468B2 discloses the preparation method of
Erlotinib hydrochloride according to the pathway as given in the Scheme -4:
5
Scheme -4: Process as per US9428468B2
Simhadri Srinivas et al in WO2013156835A2 discloses the preparation
method of Erlotinib hydrochloride according to the pathway as given in the Scheme
-5:
Scheme -5: Process as per WO2013156835A2
Gore et al in US8952022B2 discloses the preparation method of Erlotinib
hydrochloride according to the pathway as given in the Scheme -6:
6
Scheme-6: Process as per US8952022
The present inventors have repeated the above process and found the
following disadvantages:
In most of the patent literature, the rate of reaction is very low, which
parallel yield in the formation of by-products, which is tedious for the removal as
well as unwanted reactions are observed during the formation of Erlotinib, as the
reaction in carried out at very high temperature.
In view of the above, to overcome the prior-art problems the present
inventors have now developed an improved process for the preparation of Erlotinib
hydrochloride, using industrially feasible and viable process, with the use of
industrially friendly solvents, which does not include tedious work up.
Being Erlotinib hydrochloride as an important anticancer therapeutic agent,
additional and improved ways of preparing Erlotinib hydrochloride salt may be of
7
immense value to pharmaceutical science and the healthcare of cancer patients.
Hence, there exists a need in the development of economically viable processes
providing highly pure active, which may be commercially up scalable, viable, safer
for handling, less time consuming and with better and
consistent quality parameters.
The present inventors have now developed an improved process for the
preparation of highly pure Erlotinib hydrochloride (I), which is stable and devoid
of process related impurities.
SUMMARY OF THE INVENTION
Particular aspects of the present invention relates to a process for the
preparation of Erlotinib or its hydrochloride salt of Formula (I).
Different aspects of the present application are summarized herein below
individually.
In one aspect of the present application, the present invention relates to a
process for preparation of highly pure or substantially Erlotinib hydrochloride (I),
comprising the steps of
a) aminating the compound of formula (A) at temperature ranging between 45-65°C
in the presence of alkali metal dithionite and an organic solvent to obtain the
compound of formula(B)
8
b) reacting compound of formula (B) with N, N-Dimethyl formamide dimethyl
acetal (DMFDMA) in the presence of non-polar organic solvent and an organic acid
to get an intermediate of compound of formula (C), which in-situ reacted with
ethynylaniline hydrochloride to isolate the compound of formula (D)
c) hydrochlorinating the compound of formula (D) in polar organic solvent to get
Erlotinib hydrochloride (I).
In yet another aspect according to the present invention, it relates to highly
pure Erlotinib hydrochloride having purity of greater than 99.8% (area % by
HPLC).
Further specific aspects of the invention are detailed in the description part
of the specification, wherever appropriate.
DETAILED DESCRIPTION:
As set forth herein, embodiments of the present invention relate to a process
for preparation of Erlotinib hydrochloride (I). The present invention deals with a
simple and industrially amenable process for making the compound of formula (I),
9
which exhibits various advantages over other processes known in the state of arts.
The advantages are discussed on the relevant places of further description.
Individual embodiments of the present invention are detailed herein below
separately.
In one embodiment according to the present application, it provides a
process for preparing highly pure Erlotinib or its hydrochloride salt of Formula (I).
In another embodiment according to present application, it provides a
process for preparation of highly pure or substantially pure Erlotinib or its
hydrochloride salt of Formula (I),
comprising the steps of:
a) aminating the compound of formula (A) at temperature ranging between 45-
65°C in the presence of alkali metal dithionite and an organic solvent to
obtain the compound of formula (B)
b) reacting compound of formula (B) with N, N-Dimethyl formamide dimethyl
acetal (DMFDMA) in the presence of non-polar organic solvent and an
organic acid to get an intermediate of compound of formula (C), which insitu reacted with ethynylaniline hydrochloride to isolate the compound of
formula (D)
10
c) hydrochlorinating the compound of formula (D) in polar organic solvent
to get Erlotinib hydrochloride (I).
Individual steps of the embodiments are detailed herein below.
In step a) process of aminating the 4, 5-bis (2-methoxyethoxy) -2-
nitrobenzonitrile (A) is carried out at temperature ranging between 45-65°C in the
presence of alkali metal dithionite and an organic solvent to obtain 4, 5-bis (2-
methoxyethoxy)-2-aminobenzonitrile (B). The alkali metal dithionite used is
selected from sodium or potassium dithionate.
The addition of the alkali metal dithionite is preferably carried out in two or
more different lots in order to ensure improved yields, since single lot dumping of
alkali metal dithionite resulted in significantly reduction of yield (yield >50% loss)
and process efficiencies including high exothermicity.
The organic solvent used is selected from ethylacetate, dichloromethane,
chloroform, carbon tetrachloride or a combination thereof. The organic solvent used
in this step is for the for the purpose of extraction of aminated compound of Formula
(B).
11
In step b), reaction is carried out of 4, 5-bis (2-methoxyethoxy)-2-
aminobenzonitrile (B) with N, N-Dimethyl formamide dimethyl acetal
(DMFDMA) in the presence of non-polar organic solvent and an organic acid to get
an intermediate of compound of formula (C), which is further in-situ reacted with
ethynylaniline hydrochloride to isolate the compound of formula (D). The organic
acid used is selected from aliphatic acid like acetic acid, propionic acid, butanoic
acid, citric acid or tartaric acid.
In-situ reaction has advantages over handling multiple steps of isolation and
subsequently processing for the next stages besides improved yields/efficiencies
and minimizing steps of plant operations. The present invention resides in avoiding
step of isolating an intermediate (C) without compromising on the quality
characteristics of final API (Active Pharmaceutical Ingredient) and improved
process efficiencies and yields.
The non-polar organic solvent is selected from toluene (methyl benzene),
ethyl benzene or xylene.
The step b) is advantageously carried out at temperature ranging between
95˚C to 120˚C, while necessary to obtain the desired quality and yields. It was
surprisingly observed by inventors that reaction carried out lower temperatures does
not results in acceptable quality of intermediate which was found to generate
impurities in the subsequent stages more particularly process related impurities.
Hence a control on process parameters was observed significantly important by
inventors of the present application.
In the subsequent step of the process of the present invention a treatment
with a source of hydrochloric acid is carried out to obtain Erlotinib hydrochloride.
Step c) provides process for the preparation of Erlotinib hydrochloride from
Erlotinib free base (D) which involved use of a polar organic solvent selected from
isopropanol, ethanol, dimethylformamide or methyl isobutyl ketone (MIBK) or
mixture thereof.
12
In a particular embodiment, the solvent used was isopropanol or a mixture
of IPA and MIBK and 10-15% IPA-HCl solution was added slowly i.e. not less
than 2 - 5 hours at a temperature ranging between 60˚C to 65˚C.
In step c), the hydrochloride salt formed- the washing of the cake (wet API)
was conducted with a mixture of isopropyl alcohol and methyl isobutyl ketone
(MIBK) which may be in the ratio ranging between 20-70: 80-30 respectively.
In a particular embodiment, the ratio of solvent used for washing was in the
range of 50:50 v/v.
The product obtained by the present invention is free of process related
impurities, including unreacted intermediates, side products, degradation products
and other medium dependent impurities. The Erlotinib and its hydrochloride salt
obtained by the process according to the present invention is highly pure having a
substantially purity of greater than 99.8% and having total impurities of ~0.2%
selected from A and/or C and process related reactants (key starting material) and
intermediates.

In yet further embodiment the steps of combining isopropanol and
Hydrochloride mixture, it comprises of slow addition of isopropanol (IPA) and
hydrochloride mixture, wherein isopropanol and hydrochloride prepared earlier by
13
combining Hydrochloride gas and isopropanol comprises of hydrochloride strength
ranging between 5 to 20% w/v.
After combining this acidic alcohol mixture, the solution may preferably be
maintained under stirring for a time duration between 10-45 minutes for complete
hydrochlorination of Erlotinib base and in order to get the higher yield of Erlotinib
hydrochloride salt
The step of cooling the reaction mixture may be carried out for the mixture
upto about 25-30°C to attain the crystalline material precipitated out with no or
minimal possible degradation for achieving the pure crystal form.
In another embodiment of the present invention, it provides a highly pure or
substantially pure Erlotinib hydrochloride having purity exceeding of 99.8%
(area% by HPLC).
The crystalline form obtained is a thermodynamically stable Form B
exhibits an X-ray powder diffraction pattern having characteristics diffraction angle
peaks expressed in 2Өºat approximately 6.29, 12.68, 13.39, 16.79, 20.30, 21.12,
22.98, 24.46, 25.29, and 26.98 ± 0.2 Өº and having the melting point range between
223-225ºC.
Form B is disclosed in US 6900221 along with characteristic X-Ray powder
diffraction, IR and melting point.
The process related impurities, including unreacted intermediates, side
products, degradation products and other medium dependent impurities, that
appears in the impurity profile of the Erlotinib hydrochloride can substantially be
removed by the process of the present invention resulting in the formation highly
pure Erlotinib, which parallel leads to the formation of highly pure and stable
Erlotinib hydrochloride.
Erlotinib hydrochloride obtained according to present invention shall be
dried under vacuum to attain water content in the range between 0.1 to 0.5% w/w.
14
In yet further another embodiment isolation of the Erlotinib and Erlotinib
hydrochloride may be carried out by filtration, solvent removal (extraction), layer
separation, concentration, distillation, or a combination thereof.
Process of the present invention avoids the formation of by-products and
process related impurities in the formation of substantially pure Erlotinib or
hydrochloride salt.
In yet further another embodiment, it provides that the Erlotinib
hydrochloride obtained by the processes of the present application may be
formulated as solid compositions for oral administration in the form of capsules,
tablets, pills, powders or granules useful in the treatment lung cancer and pancreatic
cancer.
Erlotinib hydrochloride of the present invention may have one or more
advantageous and desirable properties compared to the known Erlotinib
hydrochloride, which are not limited to better stability, solubility and quality
parameter leading to improved storage and distribution.
In another embodiment, the Erlotinib hydrochloride obtained by the
processes of the present application may be formulated as solid compositions for
oral administration in the form of capsules, tablets, pills, powders or granules. In
these compositions, the active product is mixed with one or more pharmaceutically
acceptable excipients. The drug substance can be formulated as liquid compositions
for oral administration including solutions, suspensions, syrups, elixirs and
emulsions, containing solvents or vehicles such as water, sorbitol, glycerin,
propylene glycol or liquid paraffin.
The compositions for parenteral administration can be suspensions,
emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle,
propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and
injectable organic esters, e.g. ethyl oleate, may be employed. These compositions
can contain adjuvants, especially wetting, emulsifying and dispersing agents. The
sterilization may be carried out in several ways, e.g. using a bacteriological filter,
15
by incorporating sterilizing agents in the composition, by irradiation or by heating.
They may be prepared in the form of sterile compositions, which can be dissolved
at the time of use in sterile water or any other sterile injectable medium.
Pharmaceutically acceptable excipients used in the compositions
comprising Erlotinib Hydrochloride of the present application include, but are but
not limited to diluents such as starch, pregelatinized starch, lactose, powdered
cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate,
mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth,
gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium
starch glycolate, pregelatinized starch, croscarmellose sodium, colloidal silicon
dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc
stearate and the like; glidants such as colloidal silicon dioxide and the like;
solubility or wetting enhancers such as anionic or cationic or neutral surfactants,
waxes and the like. Other pharmaceutically acceptable excipients that are of use
include but not limited to film formers, plasticizers, colorants, flavoring agents,
sweeteners, viscosity enhancers, preservatives, antioxidants and the like.
Pharmaceutically acceptable excipients used in the compositions derived
from Erlotinib hydrochloride of the present application may also comprise to
include the pharmaceutically acceptable carrier used for the preparation of solid
dispersion, wherever utilized in the desired
dosage form preparation.
While the present invention has been described in terms of its specific
embodiments, certain modifications and equivalents will be apparent to those
skilled in the art and are intended to be included within the scope of the present
invention.
Certain specific aspects and embodiments of the present application will be
explained in more detail with reference to the below examples, which are provided
by way for illustration purpose only and should not be construed as limiting the
scope of the invention in any manner.
16
The following examples illustrate the nature of the invention and are
provided for illustrative purposes only and should not be construed to limit the
scope of the present invention.
Example:
Step-a) Preparation of 4, 5-bis (2-methoxyethoxy)-2-aminobenzonitrile (B):
Charged first lot of 4,5-bis-(2-methoxyethoxy)-2-nitrobenzo nitrile
(100gm) of the compound of formula (A), Purified water (1682 ml) and sodium
dithionite (187 gm) at 20-30°C in a reaction flask. Stirred the reaction mass for 5-
10 min. Charged second lot (48 gm) of 4, 5-bis-(2-methoxyethoxy)-2-nitrobenzo
nitrile of the compound of formula (A) at 20-30°C. Added purified water (18 ml)
at 20-30°C. The reaction mixture was heated at 50-55°C and maintained this
temperature for 1.0 hr. Raised the temperature of reaction mass to 60-65°C. Added
conc hydrochloric acid (208.4 ml) in 45-60 min at 60-65°C. Stirred the reaction
mass for 30 min. at 60-65°C. The reaction mass was cooled down to 15-20°C and
used sodium hydroxide solution (215 ml) to adjust the pH of the reaction mass to
10-12. Raised the temperature of reaction mass to 25-30°C (if not in range).
Charged ethyl acetate (804 ml) and stirred for 30 min at 25-30°C and separate the
organic layer. The aqueous layer was extracted two times with ethyl acetate (350
ml). Combined all three ethyl acetate layers and charged purified water (252 ml)
for washing. Stirred for 30 min at 30°C and separate the organic layer. Washed the
organic layer with brine solution (504 ml). Stirred the mass for 30 min at 30°C.
Add activated Charcoal (10 g) and stirred for 30 min at 25-30°C. Filtered the mass
through hyflo and washed by ethyl acaetate (196 ml). Distilled out ethyl acetate
under vacuum below 55°C. Cooled the residue to 25-30°C. Charged hexane (400
ml) and stirred for 1hr at 30°C. Filtered and washed by 47 ml ethyl acetate. Dried
the material for 12 hrs at 50-55°C.
17
Yield: Dry wt 85 gm (95%)
Step-b) Preparation of Erlotinib (D):
Charged 4, 5-bis (2-methoxyethoxy) -2- aminobenzonitrile (B) (100 g),
toluene (1000 ml) and N, N-Dimethyl formamide dimethyl acetal (DMFDMA) (100
ml) into a reaction flask under stirring at 20-30°C. Added 1.4 ml Acetic acid at 20-
30°C. Raised the temperature of reaction mass to 105-110°C and maintained for 2
hr.
Cool the reaction mass to 95-100°C. Distilled out the toluene completely
under vacuum at temperature below 100°C. Degassed the material for 30 min at 95-
100°C. Cool the reaction mass to 25-30°C.
Charged Acetic acid (741.7 ml) and Ethynyl aniline hydrochloride (57.78
g) under stirring into the reaction flask in 30 min. at 20-30°C. Raised the
temperature of reaction mass to 115-120°C and maintained it for 4 hr. Cooled down
the reaction mass to 90-95°C and distilled toluene completely under vacuum at
temperature below 95°C. The reaction mass cooled to 25-30°C and added purified
water (1900 ml). Stirred the reaction mass for 30 min at 25-35°C. Cooled the
reaction mass to 15-20°C and pH was adjusted to 9.0-10.0 using 20-25% of 300 ml
Aqueous ammonia at 15-20°C. Raised the temperature to 25-35°C and added ethyl
acetate (500 ml) at the same temperature. Stirred the reaction mass for 2.0 hours at
25-35°C. Filtered and washed the material with purified water (670 ml) at 25-35°C.
Suck dried for 1-2 hours and unload the wet material.
Charged purified water (1500 ml) in another reactor and added the wet
material at 25-30°C. Stirred the reaction mass at 25-35°C. Charged aqueous
ammonia solution (32 ml) at 25-35°C. Stir the reaction mass for 2.0 hours at 25-
18
35°C. Filtered and washed the material with purified water (670 ml) at 25-35°C.
Suck dried for 1-2 hours and unload the wet material.
Charged purified water (1500 ml) in another reactor. Charged the wet
material at 25-30°C. Stirred the reaction mass at 25-35°C. Charged aqueous
ammonia solution (32 ml) at 25-35°C. Stirred the reaction mass for 2.0 hrs at 25-
35°C. Filtered and washed the material with purified water (670 ml) at 25-35°C.
Suck dried for 1-2 hrs. Unload the wet material. Dried the material at 55-60°C for
12 hrs.
Charged Toluene (2200 ml) into the reaction flask and added dried
compound of formula (D) under stirring at 20-30°C. Raised the temperature of the
reaction mixture upto 105 - 110°C and maintained for 1 hr. Cooled the mass to 40-
45°C. Filtered and washed the solid material by toluene (12 ml) to obtain Erlotinib.
Dry the material at 70-75°C for 16 hrs.
Yield: Dry wt 89 gm (61%)
HPLC purity: 99.74%
Step-c) Preparation of Erlotinib hydrochloride (I)
Charged Isopropyl alcohol (2500 ml), Methyl isobutyl ketone (2500 ml) and
Erlotinib free base (100 g) into the reaction flask under stirring at 20-30°C. Flushed
the reaction flask with Methyl isobutyl ketone (7.2 ml). Raised the temperature of
the reaction mixture upto 60-65°C. Stirred the reaction mass for 30 min. Charged
activated charcoal (10 gm) and stirred the reaction mass for 30 min at 60-65°C.
Filtered the material at 60-65°C. Washed the Hyflo bed with 200 ml 1:1 mixture of
IPA (100 ml) and MIBK (100ml). Filtered the above mother liquor through micron
filtration. Transferred and combined main and filtrated mother liquor into the
19
reactor. Maintained the temperature to 60-65°C. Added (already micron filtered)
15% Isopropyl alcohol Hydrochloride solution at 60-65°C in 2-3 hrs. Stir the
reaction mass for 10-15 min. Cool the reaction mass to 25-30°C. Stirred the reaction
mass for 2 hrs at 25-30°C. Filtered and washed the material with 200 ml 1:1 mixture
of Isopropyl alcohol (100 ml) and Methyl isobutyl ketone (100ml). Unload the
material. Dried the material at 70-75°C for 20 hrs to obtain Erlotinib hydrochloride.
Yield: Dry wt 100 gm (92%)
HPLC purity: 99.8%
The above mentioned examples, which are provided by way of illustration, should
not be construed as limiting the scope of the invention with respect to parameter/s,
ingredient/s and quantities use etc.

We Claims:
1. A process for the preparation of substantially pure Erlotinib hydrochloride (I)
comprising the steps of:
a) aminating the compound of formula (A) at temperature ranging between
45-65°C in the presence of alkali metal dithionite and an organic solvent
to obtain the compound of formula (B)
b) reacting compound of formula (B) with N, N-Dimethyl formamide dimethyl
acetal (DMFDMA) in the presence of non-polar organic solvent and an organic
acid to get an intermediate of compound of formula (C), which in-situ reacted
with ethynylaniline hydrochloride to isolate the compound of formula (D)
c) hydrochlorinating the compound of formula (D) in a polar organic solvent
to get Erlotinib hydrochloride (I).
~ "o. ~. • · .... o· .·· .·m·· .· ..·· ... · .N .·.H organic solvent
0 l~·"N
/ ~o· ·~ . .)
(D) N
'~ '&--. '
,,,;:,
NHHCI
'o~ ~N /o~oUNJ
Erlotinib Hydrochloride
(I)
2. A process for the preparation of the compound offormula (B)according to
claim 1, wherein organic solvent used in step a) is selected from
ethylacetate~ dichloromethane, chloroform, . carbon tetrachloride qr a
combination thereof.
3. A process for the preparation of the compound of formula (B) according to
claim 1, in step (a) wherein alkali metal dithfonite used is selected from
sodium or potassium dithionate.
4. A process for the preparation of the compound offormula(C) according to
claim l, wherein non-polar organic solvent in step (b) is selected from
toluene, ethylbenzene or xylene.
5. A process for the preparation of the compound· of formula (D) according to
claim 1, wherein organic acid in step (b )is selected from aliphatic acid like
acetic acid, propionic acid, butanoic acid, citric acid or tartaric acid.
6. A Process for the preparation of Erlotinib and its hydrochloride salt of
formula (I) according to claim l, whereinpolar organic solvent used in step
( c) is selected from isopropanol, ethanol or dimethylformamide.
7. Substantially pure Erlotinib hydrochloride having purity of greater than
99.8% (area%
byHPLC).