PROCESS-FOR THE PREPARATION OF 4-BROMO-1-CHLORO-2-(4-
Field of the Invention
The present invention provides a for the preparation of 4-bromo- 1 -chloro-2-(4-
ethoxybenzy1)benzene of Formula 111, which can be used as an intermediate for the preparation
of dapagliflozin, or solvates
Formula 111
Background of the Invention
Dapagliflozin propanediol monohydrate is chemically designated as (1 9 - 1 ,5-anhydro- 1 -
~-[4-chloro-3-[(4-ethox~~hen~l)meth~l]~henl]-~-~l(9u-cpirtooply,le ne glycol, monohydrate
and is marketed in Europe for the treatment of type 2 Diabetes mellitus. Its chemical structure is
represented by Formula I:
Formula I
U.S. Patent No. 6,5 15,117 ("the ' 1 17 patent") discloses a process for the preparation of
I
I 4-bromo- 1 -chloro-2-(4-ethoxybenzy1)benzene of Formula 111, comprising the reaction of '5-
I
bromo-2-chlorobenzoyl chloride with phenetole thereby isolating 5-bromo-2-chloro-4'-
ethoxybenzophenone,. which upon reduction in acetonitrile at 50°C gives 4-bromo-l-chloro-2-
(4-ethoxybenzy1)benzene of Formula 111. The '1 17 patent discloses that fbrther increasing the,
temperature during the reduction step results in the formation of N-acetyl-5-bromo-2-chloro-4'-
-x p3
ethpxyd2j h e3_ngy_3lm-et0hy5jam-inZe_-u a3n_6 im L~uSrirtyouf FCo rmula VI. This impurity may be formed by the
. .
,, .a . nucleophilic addition of acetonitrile t'o 5-bromo-2-chloro-4'-ethoxybenzophenonef,o llowed by
hydrolysis of the addition product.
I
I Formula VI
1 The present invention provides a one 'pot process for the preparation of 4-bromo-1-
I
I~~ csohllvoerno-t 2-(4-thetuhso xybeanvzoy1id)ibnegn zene tohfe Formfuolram Ia11ti othna t cirocfu mvenNts-a tcheet yul-s5e- borfo macoe-t2o-ncihtrliolero a-4s '-a
I
I ethoxydiphenylmethylamine, an impurity of Formula VI.
I
I
Summary of the Invention
The present invention provides a process for the preparation of 4-bromo- 1 -chloro-2-(4-
ethoxybenzy1)benzene of Formula 111, which can be used as an intermediate for the preparation
of dapagliflozin of Formula 11, or solvates thereof.
Formula I1 Formula I11
An aspect of the present invention provides a process for the preparation of a compound
of Formula 111,
Formula I11
- - -DEe~-x 30-05- 2OJs 3 5 533
3
comprising reacting a compound of Formula IV with phenetole and reducing the reaction
product thus obtained,
Formula IV
wherein 'X' is a leaving group and the reaction proceeds without isolating the reaction product
obtained by the reaction of a compound of Formula IV with phenetole.
Detailed Description of the Invention
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 "substantially free of N-acetyl-5-bromo-2-chloro-4'-
ethoxydiphenylmethylamine", as used herein, refers to a compound having less than 1%,
preferably less than 0.5%, and most preferably less than 0.1% of N-acetyl-5-bromo-2-chloro-4'-
ethoxydiphenylmethylamine, an impurity of Formula VI. The term "substantially free of Nacetyl-
5-bromo-2-chloro-4'-ethoxydiphenylmethylamine" includes a compound having no
detectable amount of ~-acet~l-5-bromo-2-chloro-4~~ethox~di~hen~lmethan~ limampiunriety, of
Formula VI.
The term "leaving group", as used herein, refers to a halogen or an alkoxy group.
Examples of halogens include fluorine, chlorine, bromine, and iodine. Examples of alkoxy
groups include methoxy, ethoxy, propoxy, and butoxy.
'In the context of the present invention, "solvates" refer to complexes of dapagliflozin
with water, methanol, ethanol, n-propanol, propanediol, and butynediol.
The compound of Formula IV is prepared by reacting 5-bromo-2-chlorobenzoic acid
with a reagent selected from the group consisting of thionyl chloride, phosphorus trichloride,
phosphorus pentachloride, triphenylphosphine in carbontetrachloride, and cyanuric chloride in
dimethylformamide.
In an embodiment of the present invention, the compound of Formula I11 is prepared by
the reaction of a compound of Formula IV with phenetole in the presence of a Lewis acid
- - -fe_llowed-.by Izzsitu ~eductio t - e re chon uct obtained. EPO rrkrrra 5 ~u s-- L W ~ &1 : , . @fOP
4
In another embodiment of the present invention, the reduction is ,carried out in the
presence of a solvent.
- . In another embodiment of the present invention, the reduction is carried out in the
absence of acetonitrile.
In another embodiment of the present invention, the reaction of the compound. of
Formula IV with phenetole and the reduction of the reaction product formed proceeds without
the isolation of a compound of Formula V.
Formula V
Examples' of Lewis acids include aluminum trichloride (AlCh), ferric chloride (FeCl3),
gallium trichloride (GaC13), boron trifluoride (BF3), antimony pentachloride (SbCls), bismuth
chloride (BiC13) and bismuth tris(trifluoromethanesu1fonate) (Bi(OTQ3).
The reducing agent, used for performing the reduction, is selected fiom the group
consisting of metal hydrides and organosilanes. Examples of metal hydrides include lithium
aluminum hydride, lithium diethoxyaluminum. hydride, lithium triethoxyaluminum hydride,
lithium tributoxyaluminum hydride, lithium dibutoxyaluminum hydride, lithium
diethylaluminum hydride, lithium triethylaluminum hydride, K-selectride, L-selectride,
diisobutylaluminum hydride, sodium borohydride, sodium cyanoborohydride, and tri-n-butyltin
hydride. Examples of organosilanes include triethylsilane, tris(trimethylsilyl)silane, , and
diphenylsilane.
The solvent is selected fiom the group consisting of saturated hydrocarbons, halogenated
,
. hydrocarbons, ethers, ,polar organic solvents, or mixtures thereof. Examples of halogenated
hydrocarbons include dichloromethane, carbon tetrachloride, and chloroform. Examples of
saturated hydrocarbons include hexanes, heptanes, benzene, and toluene. Examples of ethers
include diethylether, diisopropylether, tetrahydrofuran, and dioxane. Examples of polar organic
solvents include dimethylformamide, N-methylpyridine, dimethylsulfoxide, and
dimethylacetamide.
i
!
. " In another embodiment of the present invention, the compound of Formula I11 is I
substantially free of N-acetyl-5-bromo-2-chloro-4'-ethoxydiphenylmethylamine,a n impurity of I
1
Formula VI. I
1
In another embodiment of the present invention, the compound of Formula I11 is
converted to dapagliflozin using the processes disclosed in our earlier filed applications
(PCTlIB20 141064639, filed on September 18, 20 14, and PCTlIB20 141064676, filed on
September 19,2014), the contents of both of which are incorporated herein by reference for their
disclosure of the process of converting the compound of Formula I11 to dapagliflozin.
In yet other embodiment of the present invention, the dapagliflozin prepared using the
compound of Formula I11 is substantially free of the impurity of Formula VI.
In general, 5-bromo-2-chlorobenzoic acid is reacted with oxalyl chloride to obtain a
compound of Formula IV, which upon reaction with phenetole in the presence of aluminum
chloride and reduction in the presence of sodium borohydride or triethylsilane gives the
I compound of Formula 111. The synthesis of the compound of Formula I11 is carried out without
the isolation of the intermediate of Formula V.
The conversion of the compound of Formula I11 into dapagliflozin can be carried out by ,
!
following the processes described in U.S. Patent Nos. 6;5 15,117, 7,375,2 13, 7,932,379, and
7,9 19,598, which are incorporated herein by reference. ~
Methods: I
i
The HPLC purity of dapagliflozin was determined using a ~uros~herS@TA R RP-18e ~
(150 x 4.6 mm), 3pm column with a flow rate 1.0 to 1.5 mL1minute (flow gradient and organic I
gradient); column oven temperature: 2'5°C; sample tray temperature: 25°C; detector: UV at 225 I
nm; injection volume: 10 pL; run time: 60 min. I
The following examples are set forth to aid the understanding of the invention but are not
intended to and should not be construed to limit its scope in any way.
. EXAMPLES
Example 1 A: Preparation of 4-Bromo- 1 -chloro-2-(4-ethoxybenzy1)benzene
Oxalyl chloride (0.8 mL) was added to a solution of 5-bromo-2-chlorobenzoic acid (2 g)
in dichloromethane (20 mL) and dimethylformamide (0.2 mL) under a nitrogen atmosphere.
The reaction mixture was stirred for one hour at 25°C to 30°C. After completion of the reaction,
-xp O a ~ ~ H36E- 05-2 6x6 15 - 3 2
6
the reaction mixture was concentrated under vacuum at 40°C to 45°C to obtain an oily residue.
The oily residue was dissolved in dichloromethane (20 mL) and allowed to cool to 0°C. To this
solution, phenetole (1.1 mL) and aluminum chloride (2.3 g) were added at 0°C to 5°C. The
reaction mixture was stirred at 0°C to"S°C for 2 hours. The reaction mixture was allowed to
warm to a temperature of about 20°C and triethylsilane (3.4 mL) was slowly added to it at the
same temperature. The reaction mixture was stirred for about 36 hours at 20°C to 25°C. After
completion of the reaction, the reaction mixture was washed with an aqueous solution of sodium
bicarbonate (8%; 20 mL). The layers were separated and the aqueous layer was extracted with
dichloromethane (10 mL). The organic layers were combined and washed with water (20 mL).
The organic layer was concentrated under vacuum to obtain 4-bromo-1-chloro-2-(4-
ethoxybenzy1)benzene.
Yield: 2.5 g
Example 1 B: Preparation of 4-Bromo- 1 -chloro-2-(4-ethoxybenzvl)benzene
Oxalyl chloride (0.8 mL) was added to' a solution of 5-bromo-2-chlorobenzoic acid (2 g)
in dichloromethane (20 mL) and dimethylformamide (0.2 mL) under an atmosphere of nitrogen.
The reaction mixture was stirred for one hour at -25°C to 30°C. After completion of the reaction,
the reaction mixture was concentrated under vacuum at 40°C to 45°C to obtain an oily residue.
The oily residue was dissolved in dichloromethane (2 mL) and allowed to cool to 0°C. To this
solution, phenetole (1.1 mL) and aluminum chloride (1.25 g) were added at 0°C to 5°C. The
reaction mixture was stirred at 0°C to 5°C for one hour and tetrahydrofuran (20 mL) was added
to the reaction mixture. Sodium borohydride (0.65 g) and aluminum chloride (2.3 g) were
slowly added to the reaction mixture at 0°C to 5°C. The reaction mixture was stirred for about
16 hours at 60°C to 65°C. After completion of the reaction, the reaction mixture was
concentrated at 50°C to 55°C and quenched with water (40 mL) at 0°C to 15°C. The reaction
mixture was extracted with toluene (2 x 20 mL). The organic layer was washed with water (10
- - mL) and concentrated under-vacuum to obtain an oily residue. The residue was again dissolved
in ethanol (10 mL) and concentrated under vacuum at 50°C to 55°C to obtain an oily residue.
The residue was then dissolved in ethanol (10 mL) and stirred for 2 hours at
-20°C to -15°C to obtain a solid. The solid was filtered, washed with pre-cooled ethanol (2 mL),
and dried under vacuum at 25°C to 30°C for 3 hours to obtain 4-bromo-1-chloro-2-(4-

WE CLAIM:
1. A proce-ss for the preparation ofa compound of Formula 111,
Formula I11
comprising reacting a compound of Formula IV with phenetole and reducing the reaction
product thus obtained,
Formula IV
wherein 'X' is a leaving group and the reaction proceeds without isolating the reaction
product obtained by the reaction ofa compound of Formula IV with phenetole.
2. The process according to claim 1, wherein the process is carried out in the presence of a
Lewis acid selected from the group consisting of AlCb, FeC13, GaC13, BF3, SbCls, BiC13,
and Bi(OTf)3.
3. The process according to claim 1, wherein the reduction is carried out in the presence of
a reducing agent selected from the group consisting of metal. hydrides and organosilanes.
4. The process according to claim 1, wherein the process is carried out in the absence of
acetonitrile.