PROCESS FOR THE PREPARATION OF 4-DIMETHYLAMINOCROTONIC
ACID
Field of the Invention
The present invention provides a process for the preparation of 4-
dimethylaminocrotonic acid of Formula II or its salts, which is used as an intermediate for
t e preparation of afatinib or its salts.
Formula II
Background of the Invention
Afatinib is a tyrosine kinase inhibitor disclosed in U.S. Patent Nos. RE43,43 1 and
6,251,912. Afatinib is depicted by Formula la:
Formula la
Afatinib is presented as the dimaleate salt and is chemically designated as 2-
butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(35)-tetrahydro-3-furanyl]oxy]-6-
quinazolinyl]-4-(dimethylamino)-,(2£)-,(2Z)-2-butenedioate (1:2) having the structure
depicted by Formula I :
Formula I
Processes for the preparation of 4-dimethylaminocrotonic acid or its salts are
disclosed in U.S. Patent No. 7,126,025 and U.S. Publication No. 2012/0046494.
U.S. Patent No. 7,126,025 discloses a process for t e preparation of 4-
dimethylaminocrotonic acid or its salts by reacting but-2-enoic acid with
chlorotrimethylsilane in pyridine to obtain trimethylsilylcrotonate, which is brominated
with a brominating agent under free radical conditions and in the presence of methylene
chloride, acetonitrile, 1,2-dichloroethane, carbon tetrachloride, or ethyl acetate to give
trimethylsilyl-4-bromocrotonate. The bromocrotonate compound is treated with
dimethylamine in tetrahydrofuran to provide the 4-dimethylaminocrotonic acid.
U.S. Patent No. 7,126,025 also discloses aprocess forthe preparation of 4-
dimethylaminocrotonic acid by treating methyl or ethyl 4-bromocrotonate with
dimethylamine to provide methyl or ethyl 4-dimethylaminocrotonate, which is hydrolyzed
to provide the 4-dimethylaminocrotonic acid.
U.S. Publication No. 2012/0046494 discloses a process for the preparation of 4-
dimethylaminocrotonic acid or its salts by converting alkyl 4-chloro-3-hydroxy butyrate to
alkyl 4-hydroxy crotonate, which is brominated to obtain alkyl 4-bromo crotonate. The
alkyl 4-bromo crotonate is treated with dimethyl amine to provide alkyl 4-
dimethylaminocrotonate, which is hydrolyzed to get the 4-dimethylaminocrotonic acid.
The use of pyridine or carbon tetrachloride is toxic to humans and therefore their
use for the manufacture of a drug substance is not advisable. The bromocrotonate
compounds, being lachrymatory in nature, are difficult to handle on an industrial scale.
The present invention provides a faster, more efficient, and industrially feasible
process for the preparation of 4-dimethylaminocrotonic acid of Formula II, which is used
as an intermediate for the preparation of afatinib or its salts.
Summary of the Invention
A first aspect of the present invention provides a process for the preparation of 4-
dimethylaminocrotonic acid of Formula II or its salts,
Formula II
comprising t e steps of:
i) converting 2,2-diethoxy-N,N-dimethylethanamine of Formula III
Formula III
to ethyl-4-(dimethylamino)crotonate of Formula IV; and
Formula IV
ii) hydrolyzing the ethyl-4-(dimethylamino)crotonate of Formula IV.
A second aspect of the present invention provides a process for the preparation of
afatinib of Formula la or its salts,
Formula la
comprising the steps of:
i) converting 2,2-diethoxy-N,N-dimethylethanamine of Formula III
Formula III
to ethyl-4-(dimethylamino)crotonate of Formula IV;
Formula IV
ii) hydrolyzing t e ethyl-4-(dimethylamino)crotonate of Formula IV to obtain 4-
dimethylaminocrotonic acid of Formula II or its salts; and
Formula II
iii) converting the 4-dimethylaminocrotonic acid of Formula II or its salts to
afatinib of Formula la or its salts.
Detailed Description of the Invention
Various embodiments and variants of the present invention are described
hereinafter.
The term "about," as used herein, refers to any value which lies within the range
defined by a number up to ±10% of the value .
The term "salts," as used herein, refers to an acid addition salt of a compound,
wherein the acid can be selected from inorganic acids and organic acids. Examples of
inorganic acids include hydrochloric acid, hydrobromic acid, or t e like. Examples of
organic acids include formic acid, acetic acid, lactic acid, malonic acid, citric acid, quinic
acid, succinic acid, oxalic acid, maleic acid, tartaric acid, fumaric acid, camphor sulfonic
acid, and the like.
The conversion of 2,2-diethoxy-N,N-dimethylethanamine of Formula III to ethyl-
4-(dimethylamino)crotonate of Formula IV is carried out in t e presence of an acid to
provide (dimethylamino)acetaldehyde in-situ, followed by its treatment with ethyl
(diethoxyphosphoryl)acetate in the presence of a base and a solvent.
The acid to be used for the in-situ generation of (dimethylamino)acetaldehyde can
be selected from sulphuric acid, hydrochloric acid, nitric acid, and mixtures thereof. A
preferred acid is hydrochloric acid.
The base to be used for the reaction (dimethylamino)acetaldehyde with ethyl
(diethoxyphosphoryl)acetate to produce ethyl-4-(dimethylamino)crotonate of Formula IV
can be selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate,
potassium bicarbonate, and mixtures thereof. A preferred base is potassium hydroxide.
The solvent to be used for the reaction (dimethylamino)acetaldehyde with ethyl
(diethoxyphosphoryl)acetate to produce ethyl-4-(dimethylamino)crotonate of Formula IV
can be selected from 2-methyltetrahydrofuran, diethyl ether, ethyl -butyl ether, and
mixtures thereof. A preferred solvent is 2-methyltetrahydrofuran.
The hydrolysis of ethyl-4-(dimethylamino)crotonate of Formula IV to 4-
dimethylaminocrotonic acid of Formula II or its salts is carried out in the presence of a
base or an acid, and a solvent.
The base to be used for the hydrolysis can be selected from sodium hydroxide,
potassium hydroxide, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.
The acid to be used for the hydrolysis can be selected from sulphuric acid, hydrochloric
acid, nitric acid, and mixtures thereof. A preferred base is sodium hydroxide; a preferred
acid is hydrochloric acid.
The solvent to be used for t e hydrolysis can be selected from water, methanol,
ethanol, «-propanol, isopropanol, butanol, or mixtures thereof.
The conversion of 4-dimethylaminocrotonic acid of Formula II or its salts to
afatinib of Formula la or its salts can be carried out by processes known in the art, such as
those disclosed in U.S. Publication No. 2012/0046494.
In the foregoing section, embodiments are described by way of examples to
illustrate t e process of the present invention. However, these are not intended in any way
to limit the scope of the present invention. Several variants of these examples would be
evident to persons ordinarily skilled in the art which are within the scope of the present
invention.
EXAMPLES
Example 1: Preparation of ethyl-4-(dimethylamino)crotonate (Formula IV)
In a round bottom flask, 2,2-diethoxy-N,N-dimethylethanamine (Formula III, 200
g) and deionized water (100 mL) were added at about 20°C to about 25°C. To the
solution, concentrated hydrochloric acid (240 mL) was added at about 25°C to about
50°C. The temperature of the reaction mixture was raised to about 70°C. The reaction
mixture was stirred at about 60°C to about 70°C for about 12 hours. The reaction mixture
was cooled to about 0°C. To the reaction mixture, about 200 mL of aqueous potassium
hydroxide (240 g in 250 mL water) was added at about 0°C to about 10°C to attain a pH of
9.0. To the reaction mixture, ethyl(diethoxyphosphoryl) acetate (200 g) and 2-
methyltetrahydrofuran (600 mL) were added at about 0°C to about 5°C. Further, 50 mL of
aqueous potassium hydroxide was added to the reaction mixture at about -5°C to about
0°C to attain a pH of about 13.5. The reaction mixture was stirred at about -5°C to about
0°C for about 1 hour. The reaction mixture was filtered, and then the filtrate was
recovered under vacuum at about 45°C to about 50°C to obtain ethyl-4-
(dimethylamino)crotonate as an oily mass.
Yield: 89%
Example 2 : Preparation of 4-dimethylaminocrotonic acid hydrochloride (Formula I
In a round bottom flask, ethyl-4-(dimethylamino)crotonate (Formula IV, 120 g)
and ethanol (480 mL) were added at about 25°C to about 35°C. To t e solution, aqueous
sodium hydroxide (30.5 g in 60 mL water) was added at about 10°C to about 20°C. The
temperature of the reaction mixture was raised to about 50°C. The reaction mixture was
stirred at about 50°C to about 55°C for about 1 hour. The reaction mixture was cooled to
about 5°C. To the reaction mixture, concentrated hydrochloric acid (120 mL) was added
to attain a pH of 1.5. The reaction mixture was filtered on Celite® and washed with
ethanol (50 mL). The filtrate was recovered under vacuum at about 55°C to about 60°C to
obtain a crude mass. Ethanol (240 mL) was added to the crude mass, and then the reaction
mixture was stirred at about 55°C to about 60°C for about 15 minutes to obtain a solution.
In the solution, sodium chloride was obtained as a byproduct. The solution was filtered to
discard sodium chloride. The filtrate was recovered under vacuum at about 55°C to about
60°C to obtain a residue. To the residue, isopropanol (400 mL) was added, and then the
reaction mixture was stirred at about 55°C to about 60°C to obtain a clear solution. The
solution was gradually cooled to about 25°C to about 30°C. The solution was further
stirred at the same temperature for about 2 hours. The solid obtained was filtered, and
then washed with isopropanol (50 mL). The solid was dried under vacuum at about 55°C
to about 60°C to provide 4-dimethylaminocrotonic acid hydrochloride.
Yield: 63%

WE CLAIM:
1. A proccss for thc preparation of 4-di1~~etI~ylami1iocso~aoci1di iocf 1:ormula I1 01. its salts,
Formula 11
comprising the steps of:
i) converting 2,2-diethoxy-N,N-dimelhyletl1a1la1i1oif1 eF ormula I11
Formula 111
to ethyl-4-(dimethyla~nino)crolonate of Formula IV; and
CH3
H3C ,Ad OEt
Formula 1V
ii) hydrolyzing the ethyl-4-(dimethylamino)crotonate of Formula IV.
2. A process for the preparation afatinib of Formula Ia or its salts,
Formula la
cornprising the steps oi':
i) converting 2,2-dictl~oxy-N,N-dimet1iylethanamioncf Formula 111
Formula 111
to etl1yl-4-(dimcthylai~iii1o)cr~aotef l:or~nula 1V:
Formula IV
ii) hydrolyzing the ethyl-4-(di11~ethy1amino)crotonatco f For~liula1 V to obtain 4-
ditnethylaminocrotonic acid of Formula I1 or its salts; and
Formula Ii
iii) converting the 4-dimethylarninocrotonic acid of Formula I1 or its salts to afatinib of
Formula la or its salts.
3. The process according to claim 1 or claim 2, wherein the conversion of the 2,2-dicthoxy-N,Ndimethylethanarnirle
of For~nula1 11 to the ethyl-4-(dirncthy1amino)crotonate of Forrnula IV
is carried out in the presence of an acid to provide (din~ethylamino)acetaldehyde in-situ,
followed by its treatlnent with ethyl (diethoxyphosphory1)acetate in the presence of a base
and a solvent.
4. The process according to claitn 3, wherein the acid is selected frotn sulphuric acid,
hydrochloric acid, nitric acid, or mixtures thereof.
5. The proccss according to claim 3, wherein the base is selected from the group consisting of
sodium hydroxide, potassiuin hydroxide, sodium bicarbonate, potassium bicarbonate, or
tnixtures thereof:
6. Tlie process according to claiiii 3, whcrein the solvent is selected ti-om tlic group consisting
of2-1iicthyltctrahyd1~furand,i ethyl ethcr, ethyl let-1-butyl cthcr, or ~iiixturcstl iercoi:
7. The process according to claiin I or claim 2, whercin thc hydrolysis of thc cttiyl-4-
(diil~ethylarnii~o)croto~o~fa Fteo rmula 1V to thc 4-din~ethylamii~ocrotoa~c~idic o f Formula I1
or its salts is carried out in the presence of a base or an acid, and a solvent.
8. The process according to claim 7, wherein the base is selected from the group consisting of
sodium hydroxide, potassiuin hydroxide, sodium bicarbonate, potassiuln bicarbonate or
mixtures thereof.
9. The process according to claim 7, wherein the acid is selccted from the group consisting of
sulphuric acid, hydrochloric acid, nitric acid, or mixtures thereof.
10. The process according to claim 7, wherein the solvent is selected from the group consisting
of water, methanol, ethanol, n-propanol, isopropanol, butanol, or mixtures thereof.