Description:FIELD OF THE INVENTION
5 The present invention relates to substantially pure ethyl 2-(5-amino-2-bromo-4-
fluorophenyl) acetate of formula (1) having undesired impurity of formula (5) less than
0.2%.
The invention further relates to a process for the preparation of substantially pure ethyl
10 2-(5-amino-2-bromo-4-fluorophenyl) acetate of formula (1) having undesired impurity
of formula (5) less than 0.2%.
BACKGROUND OF THE INVENTION
15 The following discussion of the prior art is intended to present the invention in an
appropriate technical context and allows its significance to be properly appreciated.
Unless clearly indicated to the contrary, reference to any prior art in this specification
should not be construed as an expressed or implied admission that such art is widely
known or forms part of common general knowledge in the field.
20
Ethyl 2-(5-amino-2-bromo-4-fluorophenyl) acetate of formula (1) is an important
intermediate for the preparation of dihydronaphthyridines and related compounds
which are type of kinase inhibitors that treat or prevent diseases such as gastrointestinal
stromal tumors, acute myeloid leukemia, and systemic hypertrophy.
25
It is essential to prepare ethyl 2-(5-amino-2-bromo-4-fluorophenyl) acetate of formula
(1) with desired chemical purity and yield to avoid further purification and yield loss
3
during the preparation of final compounds. The desired purity and yield of
dihydronaphthyridines based kinase inhibitors is achieved by preparation of
substantially pure Ethyl 2-(5-amino-2-bromo-4-fluorophenyl) acetate (1).
5 The Chinese patent application CN110845337A of Jiming Medical Science and
Technology (suzhou) Co Ltd uses conditions such as reaction temperature less than “-
25 0C” with reaction time of less than 30 seconds which is extremely difficult to handle
on industrial scale and leads to formation of major impurity like di-bromo impurity
viz. ethyl 2-(3-amino-2, 6-dibromo-4-fluorophenyl) acetate (5) which is difficult to
10 remove (scheme-1).
Scheme-1
The examples described in CN`337 depicts formation of di-bromo impurity ranging
15 from 7.8% to 0.3% with respect to ethyl 2-(3-amino-2, 6-dibromo-4-fluorophenyl)
acetate (1) when detected by HPLC.
The inventors of the present invention have developed a substantially pure Ethyl 2-(5-
amino-2-bromo-4-fluorophenyl) acetate (1) having undesired impurity of formula (5)
20 less than 0.2% and process for preparation thereof.
The instant two-step process is easy to perform on industrial scale which further controls
the formation of undesired impurity during the reaction transformation, thereby the desired
pure compound of formula (1) is obtained with desired chemical yield (>70%) and
25 chemical purity (>99.8%).
4
SUMMARY OF THE INVENTION
One aspect of the present invention is to provide a substantially pure Ethyl 2-(5-amino-
2-bromo-4-fluorophenyl) acetate (1) having undesired impurity of formula (5) less
than 0.2%.
5
In another aspect, the present invention relates a process for the preparation of
substantially pure ethyl 2-(5-amino-2-bromo-4-fluorophenyl) acetate of formula (1)
having undesired impurity of formula (5) less than 0.2%.
10 In another aspect, the present invention relates to a process for the preparation of
substantially pure ethyl 2-(5-amino-2-bromo-4-fluorophenyl) acetate of formula (1)
having undesired impurity of formula (5) less than 0.2%; comprising,
a) reacting ethyl 2-(3-amino-4-fluorophenyl) acetate (2) with brominating agent
in a solvent, to give ethyl 2-(5-amino-2-bromo-4-fluoro phenyl) acetate (1),
15 which may or may not be isolated;
b) treating ethyl 2-(5-amino-2-bromo-4-fluoro phenyl) acetate (1) with an
aqueous base, to give 2-(5-amino-2-bromo-4-fluoro phenyl) acetic acid (4);
20 c) esterification of 2-(5-amino-2-bromo-4-fluoro phenyl) acetic acid (4) by
treating it with a suitable C1-C6 straight chain or branched chain alcohol in
presence of a catalyst to give corresponding pure ethyl 2-(5-amino-2-bromo-4-
fluorophenyl) acetate of formula (1).
5
DETAILED DESCRIPTION OF THE INVENTION
Before the present invention is described, it is to be understood that this invention is
not limited to particular methodologies and materials described, as these may vary as
per the person skilled in the art. It 5 is also to be understood that the terminology used
in the description is for the purpose of describing the particular embodiments only and
is not intended to limit the scope of the present invention.
Before the present invention is described, it is to be understood that unless defined
otherwise, all technical and scientific terms used herein have the same meaning as
10 commonly understood by one of ordinary skill in the art to which this invention
belongs. Further, it is to be understood that the present invention is not limited to the
methodologies and materials similar or equivalent to those described herein can be
used in the practice or testing of the present invention, the preferred methods and
materials are described, as these may vary within the specification indicated. Unless
15 stated to the contrary, any use of the words such as "including," "containing,"
"comprising," "having" and the like, means "including without limitation" and shall
not be construed to limit any general statement that it follows to the specific or similar
items or matters immediately following it. Embodiments of the invention are not
mutually exclusive but may be implemented in various combinations. The described
20 embodiments of the invention and the disclosed examples are given for the purpose of
illustration rather than limitation of the invention as set forth the appended claims.
Further the terms disclosed embodiments are merely exemplary methods of the
invention, which may be embodied in various forms.
The term “about,” as used herein, is intended to qualify the numerical values, which it
25 modifies, denoting such a value as variable within a margin of error. When no
particular margin of error, such as a standard deviation to a mean value given in a chart
6
or table of data, is recited, the term “about” should be understood to mean that range
which would encompass the recited value and the range which would be included by
rounding up or down to that figure as well, taking into account significant figures.
The term undesired impurity of formula (5) used herein, refers to ethyl 2-(3-amino-2,
5 6-dibromo-4-fluorophenyl) acetate as shown below.
The term “substantially pure” used herein, refers to the purity of desired compound of
formula (1) greater than 99.8% by HPLC.
The content of undesired impurity of formula (5) used herein, refer to less than 0.2%.
10 The term “heating”, as used herein, is heating the solution gradually to a temperature
in the range of 50-150°C.
In an embodiment, the present invention relates to a process for the preparation of
substantially pure ethyl 2-(5-amino-2-bromo-4-fluorophenyl) acetate of formula (1)
having undesired impurity of formula (5) less than 0.2%; comprising,
15 a) reacting ethyl 2-(3-amino-4-fluorophenyl) acetate (2) with brominating agent
in a solvent, to give ethyl 2-(5-amino-2-bromo-4-fluoro phenyl) acetate (1),
which may or may not be isolated;
b) treating ethyl 2-(5-amino-2-bromo-4-fluoro phenyl) acetate (1) with an
20 aqueous base, to give 2-(5-amino-2-bromo-4-fluoro phenyl) acetic acid (4);
7
c) esterification of 2-(5-amino-2-bromo-4-fluoro phenyl) acetic acid (4) by
treating it with a suitable C1-C6 straight chain or branched chain alcohol in
presence of a catalyst to give corresponding pure ethyl 2-(5-amino-2-bromo-4-
5 fluorophenyl) acetate of formula (1).
The present invention also relates to the process, wherein step (b) can be carried out
without isolating the compound of formula (1) of step (a).
10 The solvent used in step (a) is an ether solvent selected from tetrahydrofuran,
cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, dioxane, 1,4-
dioxane, 1,2-dioxane or 1,3-dioxane; an alcoholic solvent selected from methanol,
ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol or hexanol; an ester solvent
selected from ethyl acetate, methyl acetate, isopropyl acetate, hexyl acetate, butyl
15 acetate, sec-butyl acetate or tert-butyl acetate; a halogenated solvent selected from
dichloromethane (DCM), 4-bromotoluene, diiodomethane, carbon tetrachloride,
chlorobenzene or chloroform; a ketone solvent selected form acetone, propanone,
methyl ethyl ketone or methyl isobutyl ketone; an aprotic solvent selected from
acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl
20 sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from
toluene, xylene or benzene; water or a mixture thereof.
The brominating agent used for bromination in step (a) is selected from bromine, Nbromosuccinimide
[NBS], hydrogen bromide [HBr], sodium bromide, cyanogen
bromide [BrCN], 1,3-dibromo-5,5-dimethyl hydantoin [DBH], 2,4,4,6-tetrabromo-
25 2,5-cyclohexadien-1-one [TBCD], bromine gas, bromine in acetic acid, aqueous
8
hydrobromic acid, tetra alkyl ammonium tribromide, dioxane dibromide, carbon tetrabromide or phosphoroustribromide.
According to another embodiment of the present invention, the work-up of step (a) further comprises the steps of: 5 (i) quenching the bromine in the reaction with aqueous sodium bicarbonate; (ii) separating both organic and aqueous layer; (iii) washing the organic layer with saturated sodium chloride solution and then with water; and (iv) concentrating the layer to obtain the compound of formula (1), which is used 10 directly in next step. The base used in step (b) is an alkali metal hydroxide selected from lithium hydroxide, sodium hydroxide or potassium hydroxide; an alkali metal carbonate selected from lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate; an alkali metal bicarbonate selected from sodium bicarbonate or potassium bicarbonate; 15 an alkali metal alkoxides selected from sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or potassium tert-butoxide, or an organic amines selected from triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).
20
According to another embodiment of the present invention, the work-up of step (b) further comprises the steps of: (i) cooling reaction mass to 28-32? C; (ii) washing the reaction mass with dichloromethane (DCM); (iii)adjusting pH of aqueous layer to about 1 by using aqueous hydrochloric acid; 25 (iv) filtering the precipitated the compound of formula (4); and (v) purifying the compound of formula (4) by using aqueous methanol. The catalyst used in step (c) is selected from thionyl chloride, hydrochloric acid, cone, sulfuric acid, trifluoro acetic acid or methane sulfonic acid. 30
9
The C1-C6 straight chain or branched chain alcohol used in step (c) is selected from
methanol. ethanol, isopropanol (IPA), n-butanol or isobutanol.
The complete synthetic scheme of preparation of ethyl 2-(5-amino-2-bromo-4-
5 fluorophenyl) acetate of formula (1) according to the present invention can be
represented as below:
10
In a specific embodiment, the process for the preparation of substantially pure ethyl 2-
(5-amino-2-bromo-4-fluorophenyl) acetate of formula (1) having undesired impurity
of formula (5) less than 0.2%; comprising,
a) reacting ethyl 2-(3-amino-4-fluorophenyl) acetate (2) with bromine or N15
Bromosuccinimide (NBS) in ethyl aetate, to give ethyl 2-(5-amino-2-bromo-4-
fluoro phenyl) acetate (1) in-situ;
b) treating ethyl 2-(5-amino-2-bromo-4-fluoro phenyl) acetate (1) in-situ with an
aqueous sodium hydroxide, to give 2-(5-amino-2-bromo-4-fluoro phenyl)
10
acetic acid (4);
c) esterification of 2-(5-amino-2-bromo-4-fluoro phenyl) acetic acid (4) by
treating it with ethanol in presence of thionyl chloride to give ethyl 2-(5-amino-
2-bromo-5 4-fluorophenyl) acetate of formula (1).
The process of the instantly disclosed invention refers to the formation of pure ethyl
2-(5-amino-2-bromo-4-fluorophenyl) acetate of formula (1) wherein the content of
undesired impurity of formula (5) viz. dibromo impurity is less than 0.2%.
10 The inventors studied the content of the dibromo impurity (%) at every step of the
reaction during preparation of compound of formula (1). The table 1 consolidates the
observations for the content of the dibromo impurity (%) at every step of the reaction
during preparation of compound of formula (1).
Description/Step
(%) dibromo impurity of formula (5)
During reaction monitoring of step (a) 4.45
After work-up of step (a) 10.89
After ester hydrolysis of (1) i.e., step
(b)
2.04%
After work-up of step (b) i.e., after
purification in aqueous methanol
0.4%
After step (c) 0.2%
15
11
Advantageously, the above identified elements of the process of the instant invention effectively contribute to the reduction of overall cost of the process.
The invention is further illustrated by the following examples which are provided to be exemplary of the invention, and do not limit the scope of the invention. While the 5 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. EXAMPLES
EXAMPLE-1 10
PREPARATION OF ETHYL 2-(5-AMINO-2-BROMO-4-FLUORO PHENYL) ACETATE (1) – BROMINATION
ethyl 3-amino-4-fluorophenylacetate (2) (100 g) was dissolved in ethyl acetate (500 ml). To this obtained solution bromine (1 equivalent) was added at -5 to 0°C. After completion of the reaction, the bromine was quenched with aqueous sodium 15 bicarbonate. Both organic and aqueous layers were separated, and the organic layer was washed sodium chloride solution, followed by water. Distilled off the solvent completely from the organic layer.
[Yield = 50.48 to 80 %; undesired impurity viz. ethyl 2-(3-amino-2,6-dibromo-4-20 fluorophenyl) acetate (II) = 10.89%]
EXAMPLE-2
PREPARATION OF ETHYL 2-(5-AMINO-2-BROMO-4-FLUORO PHENYL) ACETATE (1) – BROMINATION 25
ethyl 3-amino-4-fluorophenylacetate (2) (100 g) was dissolved in ethyl acetate (500 ml). To this obtained solution bromine (1 eq) was added at room temperature. After completion of the reaction, the bromine was quenched with aqueous sodium bicarbonate. Both organic and aqueous layers were separated, and the organic layer was washed sodium chloride solution, followed by water. Distilled off the solvent 30 completely from the organic layer.
12
[Yield = 50.48 to 80 %; undesired impurity viz. ethyl 2-(3-amino-2,6-dibromo-4-fluorophenyl) acetate (II) = 10.89%]
EXAMPLE-3 PRPRATION OF COMPOUND OF FORMULA (4) 5
ethyl 2-(3-amino-4-fluoro phenyl)acetate (2) (1000 g) was added in ethyl acetate (4500 ml) and the content were cooled to -5 to 0 °C. To this obtained solution N-bromosuccinimide (0.812 kg) was added. After completion of the reaction, sodium carbonate solution was added. Both organic and aqueous layers were separated, and aqueous sodium hydroxide was added at room temperature. After completion 10 hydrolysis of compound (1), the reaction mixture was cooled to 28-32°C and washed with DCM. The pH of the resulting mixture was adjusted to 1 by adding aqueous hydrochloric acid. Filtered the precipitated solid of compound of formula (4) and washed with water which was further purified in aqueous methanol to get the pure compound 4. 15
Yield: 900g; undesired impurity viz. ethyl 2-(3-amino-2,6-dibromo-4-fluorophenyl) acetate (II) = 0.4%]
EXAMPLE-4 PREPARATION OF COMPOUND OF FORMULA (1) 20
2-(5-amino-2-bromo-4-fluorophenyl)acetic acid (4) (100 g), methanol (500 ml) and thionyl chloride (1eq) were heated until 2-(5-amino-2-bromo-4-fluorophenyl)acetic acid (4) was reacted. After completion of reaction, contents were cooled to room temperature and precipitated hydrochloride salt was filtered, washed with ethanol (100 mL). The wet cake was suspended in water (500 ml) and aqueous sodium carbonate 25 solution was added. The precipitated solid of compound (1) was filtered and dried.
[Yield = > 70 %); Purity (HPLC) = > 99.8 %, Impurity, ethyl 2-(3-amino-2,6-dibromo-4-fluorophenyl) acetate (5) = < 0.2%] , Claims:1. A process for the preparation of substantially pure ethyl 2-(5-amino-2-bromo-
5 4-fluorophenyl) acetate of formula (1) having undesired impurity of formula
(5) less than 0.2%; comprising,
a) reacting ethyl 2-(3-amino-4-fluorophenyl) acetate (2) with brominating agent
in a solvent, to give ethyl 2-(5-amino-2-bromo-4-fluoro phenyl) acetate (1),
and optionally isolating compound of formula (1);
10
b) treating ethyl 2-(5-amino-2-bromo-4-fluoro phenyl) acetate (1) with an
aqueous base, to give 2-(5-amino-2-bromo-4-fluoro phenyl) acetic acid (4);
c) esterification of 2-(5-amino-2-bromo-4-fluoro phenyl) acetic acid (4) by
15 treating it with a suitable C1-C6 straight chain or branched chain alcohol in
presence of a catalyst to give corresponding ethyl 2-(5-amino-2-bromo-4-
fluorophenyl) acetate of formula (1).
20 wherein -
the process of step (b) can be carried out without isolating the intermediate
compound of formula (1) of step (a).
14
2. The process as claimed in claim 1, wherein the solvent used in step (a) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, dioxane, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; an alcoholic solvent selected from methanol, ethanol, isopropanol, t-5 amyl alcohol, t-butyl alcohol or hexanol; an ester solvent selected from ethyl acetate, methyl acetate, isopropyl acetate, hexyl acetate, butyl acetate, sec-butyl acetate or tert-butyl acetate; a halogenated solvent selected from dichloromethane (DCM), 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected form 10 acetone, propanone, methyl ethyl ketone or methyl isobutyl ketone; an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; water or a mixture thereof. 15
3. The process as claimed in claim 1, wherein the brominating agent used for bromination in step (a) is selected from bromine, N-bromosuccinimide [NBS], hydrogen bromide [HBr], sodium bromide, cyanogen bromide [BrCN], 1,3-dibromo-5,5-dimethyl hydantoin [DBH], 2,4,4,6-tetrabromo-2,5-20 cyclohexadien-1-one [TBCD], bromine gas, bromine in acetic acid, aqueous hydrobromic acid, tetra alkyl ammonium tribromide, dioxane dibromide, carbon tetrabromide or phosphoroustribromide.
4. The process as claimed in claim 1, wherein the base used in step (b) is an alkali 25 metal hydroxide selected from lithium hydroxide, sodium hydroxide or potassium hydroxide; an alkali metal carbonate selected from lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate; an alkali metal bicarbonate selected from sodium bicarbonate or potassium bicarbonate; an alkali metal alkoxides selected from sodium methoxide or 30 potassium methoxide, sodium ethoxide or potassium ethoxide or potassium
15
tert-butoxide, or an organic amines selected from triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).
5. The process as claimed in claim 1, wherein the catalyst used in step (c) is 5 selected from thionyl chloride, hydrochloric acid, cone, sulfuric acid, trifluoro acetic acid or methane sulfonic acid.
6. The process as claimed in claim 1, wherein the C1-C6 straight chain or branched chain alcohol used in step (c) is selected from methanol. ethanol, isopropanol 10 (IPA), n-butanol or isobutanol.
7. The process as claimed in claim 1, wherein the work-up of step (a) further comprises the steps of:
(i) quenching the bromine in the reaction with aqueous sodium 15 bicarbonate; (ii) separating both organic and aqueous layer; (iii) washing the organic layer with saturated sodium chloride solution and then with water; and (iv) concentrating the layer to obtain the compound of formula (4), which is 20 used directly in next step.
8. The process as claimed in claim 1, wherein the work-up of step (b) further comprises the steps of:
(i) cooling reaction mass to 28-32? C; 25 (ii) washing the reaction mass with halogenated solvent selected from dichloromethane (DCM), toluene, or aromatic hydrocarbons; (iii) adjusting pH of aqueous layer to about 1 by using aqueous hydrochloric acid; (iv) filtering the precipitated the compound of formula (4) obtained in step 30 (iii); and (v) purifying the compound of formula (4) by using aqueous methanol.
16
9. A process for the preparation of substantially pure ethyl 2-(5-amino-2-bromo-
4-fluorophenyl) acetate of formula (1) having undesired impurity of formula
(2) less than 0.2%; comprising,
a) reacting ethyl 2-(3-amino-4-fluorophenyl) acetate (2) with bromine or N5
Bromosuccinimide (NBS) in ethyl aetate, to give ethyl 2-(5-amino-2-bromo-4-
fluoro phenyl) acetate (1) in-situ;
b) treating ethyl 2-(5-amino-2-bromo-4-fluoro phenyl) acetate (1) in-situ with an
aqueous sodium hydroxide, to give 2-(5-amino-2-bromo-4-fluoro phenyl)
10 acetic acid (4);
c) esterification of 2-(5-amino-2-bromo-4-fluoro phenyl) acetic acid (4) by
treating it with ethanol in presence of thionyl chloride to give ethyl 2-(5-amino-
2-bromo-4-fluorophenyl) acetate of formula (1).
15 wherein -
the process of step (b) can be carried out without isolating the intermediate
compound of formula (1) of step (a).
17
10. A substantially pure ethyl 2-(5-amino-2-bromo-4-fluorophenyl) acetate of
formula (1) having undesired impurity of formula (5) less than 0.2%.
11. A compound having the structure