WO2015063726A1 - Process for the preparation of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene - Google Patents

Process for the preparation of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene Download PDF

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WO2015063726A1
WO2015063726A1 PCT/IB2014/065726 IB2014065726W WO2015063726A1 WO 2015063726 A1 WO2015063726 A1 WO 2015063726A1 IB 2014065726 W IB2014065726 W IB 2014065726W WO 2015063726 A1 WO2015063726 A1 WO 2015063726A1
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formula
bromo
chloro
compound
preparation
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PCT/IB2014/065726
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French (fr)
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Suresh Babu Jayachandra
Devendra Prakash NAGDA
Tarun Kumar SINGH
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Ranbaxy Laboratories Limited
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Priority to EP14802506.7A priority Critical patent/EP3063116A1/en
Priority to US15/033,088 priority patent/US20160280619A1/en
Publication of WO2015063726A1 publication Critical patent/WO2015063726A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/46—Friedel-Crafts reactions

Definitions

  • the present invention provides a process for the preparation of 4-bromo- l-chloro- 2-(4-ethoxybenzyl)benzene of Formula III, which can be used as an intermediate for the preparation of dapagliflozin, or solvates thereof.
  • Dapagliflozin propanediol monohydrate is chemically designated as ( IS)- 1,5- anhydro-l-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol, ( ⁇ S)-propylene glycol, monohydrate and is marketed in Europe for the treatment of type 2 Diabetes mellitus. Its chemical structure is represented by Formula I:
  • U.S. Patent No. 6,515, 1 17 discloses a process for the preparation of 4-bromo- l-chloro-2-(4-ethoxybenzyl)benzene of Formula III, comprising the reaction of 5-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-ethoxybenzyl)benzene of Formula III.
  • the ⁇ 17 patent discloses that further increasing the temperature during the reduction step results in the formation of N-acetyl-5-bromo-2-chloro-4'-ethoxydiphenylmethylamine - an impurity of Formula VI.
  • This impurity may be formed by the nucleophilic addition of acetonitrile to 5-bromo-2-chloro-4'-ethoxybenzophenone, followed by hydrolysis of the addition product.
  • the present invention provides a one pot process for the preparation of 4-bromo-l- chloro-2-(4-ethoxybenzyl)benzene of Formula III that circumvents the use of acetonitrile as a solvent thus avoiding the formation of N-acetyl-5-bromo-2-chloro-4'- ethoxydiphenylmethylamine, an impurity of Formula VI.
  • the present invention provides a process for the preparation of 4-bromo-l-chloro- 2-(4-ethoxybenzyl)benzene of Formula III, which can be used as an intermediate for the preparation of dapagliflozin of Formula II, or solvates thereof.
  • substantially free of N-acetyl-5-bromo-2-chloro-4'- ethoxydiphenylmethylamine 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.
  • substantially free of N-acetyl-5-bromo-2-chloro-4'-ethoxydiphenylmethylamine includes a compound having no detectable amount of N-acetyl-5-bromo-2-chloro-4'- ethoxydiphenylmethylamine, an impurity of Formula VI.
  • leaving group refers to a halogen or an alkoxy group.
  • halogens include fluorine, chlorine, bromine, and iodine.
  • alkoxy groups include methoxy, ethoxy, propoxy, and butoxy.
  • 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.
  • a reagent selected from the group consisting of thionyl chloride, phosphorus trichloride, phosphorus pentachloride, triphenylphosphine in carbontetrachloride, and cyanuric chloride in dimethylformamide.
  • the compound of Formula III is prepared by the reaction of a compound of Formula IV with phenetole in the presence of a Lewis acid followed by in situ reduction of the reaction product obtained.
  • the reduction is carried out in the presence of a solvent.
  • the reduction is carried out in the absence of acetonitrile.
  • 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.
  • Lewis acids examples include aluminum trichloride (AICI 3 ), ferric chloride (FeCl 3 ), gallium trichloride (GaCl 3 ), boron trifluoride (BF 3 ), antimony pentachloride (SbCls), bismuth chloride (B1CI 3 ) and bismuth tris(trifluoromethanesulfonate) (Bi(OTf) 3 ).
  • AICI 3 aluminum trichloride
  • FeCl 3 ferric chloride
  • GaCl 3 gallium trichloride
  • BF 3 boron trifluoride
  • SbCls antimony pentachloride
  • B1CI 3 bismuth chloride
  • Bi(OTf) 3 bismuth tris(trifluoromethanesulfonate
  • the reducing agent, used for performing the reduction is selected from the group consisting of metal hydrides and organosilanes.
  • 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.
  • organosilanes include triethylsilane,
  • the solvent is selected from the group consisting of saturated hydrocarbons, halogenated hydrocarbons, ethers, polar organic solvents, or mixtures thereof.
  • halogenated hydrocarbons include dichloromethane, carbon tetrachloride, and chloroform.
  • saturated hydrocarbons include hexanes, heptanes, benzene, and toluene.
  • ethers include diethylether, diisopropylether, tetrahydrofuran, and dioxane.
  • polar organic solvents include dimethylformamide, N- methylpyridine, dimethylsulfoxide, and dimethylacetamide.
  • the compound of Formula III is substantially free of N-acetyl-5-bromo-2-chloro-4'-ethoxydiphenylmethylamine, an impurity of Formula VI.
  • the compound of Formula III is converted to dapagliflozin using the processes disclosed in our earlier filed applications (PCT/IB2014/064639, filed on September 18, 2014, and PCT/IB2014/064676, 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 III to dapagliflozin.
  • the dapagliflozin prepared using the compound of Formula III is substantially free of the impurity of Formula VI.
  • 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 compound of Formula III.
  • the synthesis of the compound of Formula III is carried out without the isolation of the intermediate of Formula V.
  • the HPLC purity of dapagliflozin was determined using a Purospher ® STAR RP- 18e (150 x 4.6 mm), 3 ⁇ column with a flow rate 1.0 to 1.5 mL/minute (flow gradient and organic gradient); column oven temperature: 25°C; sample tray temperature: 25°C; detector: UV at 225 nm; injection volume: 10 ⁇ ; run time: 60 min.
  • 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, 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.
  • reaction mixture was stirred at 0°C to 5°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.
  • 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

Abstract

The present invention provides a process for the preparation of 4-bromo-1-chloro- 2-(4-ethoxybenzyl)benzene of Formula III, which can be used as an intermediate for the preparation of dapagliflozin, or solvates thereof.

Description

PROCESS FOR THE PREPARATION OF 4-BROMO-l-CHLORO-2-(4- ETHOXYBENZYL)BENZENE
Field of the Invention
The present invention provides a process for the preparation of 4-bromo- l-chloro- 2-(4-ethoxybenzyl)benzene of Formula III, which can be used as an intermediate for the preparation of dapagliflozin, or solvates thereof.
Figure imgf000002_0001
Formula III
Background of the Invention
Dapagliflozin propanediol monohydrate is chemically designated as ( IS)- 1,5- anhydro-l-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol, (<S)-propylene glycol, monohydrate and is marketed in Europe for the treatment of type 2 Diabetes mellitus. Its chemical structure is represented by Formula I:
Figure imgf000002_0002
Formula I
U.S. Patent No. 6,515, 1 17 ("the ' 1 17 patent") discloses a process for the preparation of 4-bromo- l-chloro-2-(4-ethoxybenzyl)benzene of Formula III, comprising the reaction of 5-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-ethoxybenzyl)benzene of Formula III. The Ί 17 patent discloses that further increasing the temperature during the reduction step results in the formation of N-acetyl-5-bromo-2-chloro-4'-ethoxydiphenylmethylamine - an impurity of Formula VI. This impurity may be formed by the nucleophilic addition of acetonitrile to 5-bromo-2-chloro-4'-ethoxybenzophenone, followed by hydrolysis of the addition product.
Figure imgf000003_0001
Formula VI
The present invention provides a one pot process for the preparation of 4-bromo-l- chloro-2-(4-ethoxybenzyl)benzene of Formula III that circumvents the use of acetonitrile as a solvent thus avoiding the formation of N-acetyl-5-bromo-2-chloro-4'- ethoxydiphenylmethylamine, an impurity of Formula VI.
Summary of the Invention
The present invention provides a process for the preparation of 4-bromo-l-chloro- 2-(4-ethoxybenzyl)benzene of Formula III, which can be used as an intermediate for the preparation of dapagliflozin of Formula II, or solvates thereof.
Figure imgf000003_0002
Formula II Formula III An aspect of the present invention provides a process for the preparation of a compound of Formula III,
Figure imgf000003_0003
Formula III comprising reacting a compound of Formula IV with phenetole and reducing the reaction product thus obtained,
Figure imgf000004_0001
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 N-acetyl-5-bromo-2-chloro-4'-ethoxydiphenylmethylamine" includes a compound having no detectable amount of N-acetyl-5-bromo-2-chloro-4'- ethoxydiphenylmethylamine, an impurity 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 III is prepared by the reaction of a compound of Formula IV with phenetole in the presence of a Lewis acid followed by in situ reduction of the reaction product obtained.
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.
Figure imgf000005_0001
Formula V
Examples of Lewis acids include aluminum trichloride (AICI3), ferric chloride (FeCl3), gallium trichloride (GaCl3), boron trifluoride (BF3), antimony pentachloride (SbCls), bismuth chloride (B1CI3) and bismuth tris(trifluoromethanesulfonate) (Bi(OTf)3).
The reducing agent, used for performing the reduction, is selected from 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 from 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.
In another embodiment of the present invention, the compound of Formula III is substantially free of N-acetyl-5-bromo-2-chloro-4'-ethoxydiphenylmethylamine, an impurity of Formula VI.
In another embodiment of the present invention, the compound of Formula III is converted to dapagliflozin using the processes disclosed in our earlier filed applications (PCT/IB2014/064639, filed on September 18, 2014, and PCT/IB2014/064676, 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 III to dapagliflozin.
In yet other embodiment of the present invention, the dapagliflozin prepared using the compound of Formula III 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 compound of Formula III. The synthesis of the compound of Formula III is carried out without the isolation of the intermediate of Formula V.
The conversion of the compound of Formula III into dapagliflozin can be carried out by following the processes described in U.S. Patent Nos. 6,515, 117, 7,375,213, 7,932,379, and 7,919,598, which are incorporated herein by reference.
Methods:
The HPLC purity of dapagliflozin was determined using a Purospher® STAR RP- 18e (150 x 4.6 mm), 3μπι column with a flow rate 1.0 to 1.5 mL/minute (flow gradient and organic gradient); column oven temperature: 25°C; sample tray temperature: 25°C; detector: UV at 225 nm; injection volume: 10 μί; run time: 60 min.
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 1A: Preparation of 4-Bromo-l-chloro-2-(4-ethoxybenzyl)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, 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 5°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-l-chloro-2-(4- ethoxybenzyl)benzene .
Yield: 2.5 g
Example IB: Preparation of 4-Bromo-l-chloro-2-(4-ethoxybenzyl)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 tetrahydroiuran (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-l-chloro- 2-(4-ethoxybenzyl)benzene .
Yield: 1.2 g; HPLC: 95.21%

Claims

We claim:
1. A process for the preparation of a compound of Formula III,
Figure imgf000009_0001
comprising reacting a compound of Formula IV with phenetole and reducing the reaction product thus obtained,
Figure imgf000009_0002
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.
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 AICI3, FeCl3, GaCl3, BF3, SbCls, BiCl3, 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.
PCT/IB2014/065726 2013-10-31 2014-10-30 Process for the preparation of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene WO2015063726A1 (en)

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US15/033,088 US20160280619A1 (en) 2013-10-31 2014-10-30 Process for the preparation of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene

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WO2021176096A1 (en) 2020-03-05 2021-09-10 Krka, D.D., Novo Mesto Pharmaceutical composition comprising sglt2 inhibitor
WO2021245253A1 (en) 2020-06-05 2021-12-09 Krka, D.D., Novo Mesto Preparation of highly pure amorphous dapagliflozin
US20220267238A1 (en) * 2020-12-04 2022-08-25 Wisdom Pharmaceutical Co., Ltd Preparation of 4-bromo-2-(4'-ethoxyphenyl)-1-chlorobenzene

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Publication number Priority date Publication date Assignee Title
CN105061373A (en) * 2015-09-06 2015-11-18 合肥华方医药科技有限公司 Synthesis method of dapagliflozin isomer impurity
CN105294624A (en) * 2015-11-16 2016-02-03 山东罗欣药业集团股份有限公司 Preparation method for dapagliflozin
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WO2021245253A1 (en) 2020-06-05 2021-12-09 Krka, D.D., Novo Mesto Preparation of highly pure amorphous dapagliflozin
US20220267238A1 (en) * 2020-12-04 2022-08-25 Wisdom Pharmaceutical Co., Ltd Preparation of 4-bromo-2-(4'-ethoxyphenyl)-1-chlorobenzene
US11565990B2 (en) * 2020-12-04 2023-01-31 Wisdom Pharmaceutical Co., Ltd Preparation of 4-bromo-2-(4′-ethoxyphenyl)-1-chlorobenzene

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