WO2016067194A1 - Process for the preparation of anacetrapib and an intermediate thereof - Google Patents

Process for the preparation of anacetrapib and an intermediate thereof Download PDF

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Publication number
WO2016067194A1
WO2016067194A1 PCT/IB2015/058271 IB2015058271W WO2016067194A1 WO 2016067194 A1 WO2016067194 A1 WO 2016067194A1 IB 2015058271 W IB2015058271 W IB 2015058271W WO 2016067194 A1 WO2016067194 A1 WO 2016067194A1
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formula
trifluoromethyl
bis
process according
carbamate
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PCT/IB2015/058271
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French (fr)
Inventor
Sony Joseph
Durga SHANKAR
Vishwesh Pravinchandra Pandya
Hashim Nizar Poovanathil Nagoor Meeran
Neera Tewari
Mohan Prasad
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Sun Pharmaceutical Industries Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2

Definitions

  • the present invention provides a process for the preparation of anacetrapib and an intermediate thereof.
  • Anacetrapib is an inhibitor of cholesterol ester transfer protein (CETP). It is chemically designated as (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((4'-fluoro-5'- isopropyl-2 ' -methoxy-4-(trifluoromethyl)-[ 1 , ⁇ -biphenyl] -2-yl)methyl)-4- methyloxazolidin-2-one, having the structure as depicted in Formula I.
  • CETP cholesterol ester transfer protein
  • (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-l,3-oxazolidin-2-one of Formula II is a key intermediate used for the preparation of anacetrapib.
  • PCT Publication Nos. WO 2007/081569 and WO 2007/081571 disclose processes for the preparation of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-l,3-oxazolidin- 2-one of Formula II.
  • PCT Publication Nos. WO 2006/014413, WO 2007/005572, WO 2012/085133, WO 2013/066768, WO 2013/091696, WO 2013/064188, and WO 2014/111953 disclose processes for the preparation of anacetrapib and its intermediates.
  • the present invention provides an easy, cost-effective, and industrially advantageous process for the preparation of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4- methyl-l,3-oxazolidin-2-one of Formula II, and its use for the preparation of anacetrapib of Formula I.
  • a first aspect of the present invention provides a process for the preparation of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-l,3-oxazolidin-2-one of Formula II,
  • a second aspect of the present invention provides a process for the preparation of anacetrapib of Formula I,
  • ambient temperature refers to a temperature in the range of about 20°C to about 35°C.
  • alkyl or “alkoxy,” as used herein, refers to a C1-5 straight chain or branched chain hydrocarbon.
  • halide or halogen, as used herein, refers to fluorine, chlorine, bromine, or iodine.
  • N-[(benzyloxy)carbonyl]-L-alanine of Formula III, to be used as an intermediate for the preparation of benzyl [(2S)-l-(mo holin-4-yl)-l-oxopropan-2-yl]carbamate of Formula IV, is commercially available.
  • the reaction of the N-[(benzyloxy)carbonyl]-L-alanine of Formula III with morpholine to obtain benzyl [(2S)-l-(mo ⁇ holin-4-yl)-l-oxopropan-2-yl]carbamate of Formula IV is carried out in the presence of pivaloyl chloride, a base, and a solvent.
  • the base is selected from the group consisting of inorganic and organic bases. Examples of inorganic bases include hydroxides, carbonates, and bicarbonates of alkali and alkaline earth metals, or mixtures thereof.
  • alkali and alkaline earth metal hydroxides include lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, and barium hydroxide.
  • alkali and alkaline earth metal carbonates include sodium carbonate, potassium carbonate, calcium carbonate, and magnesium carbonate.
  • alkali metal bicarbonates include sodium bicarbonate and potassium bicarbonate.
  • organic bases examples include N,N- diisopropylethylamine, triethylamine, triisopropylamine, N,N-2-trimethyl-2-propanamine, N-methylmorpholine, 4-dimethylaminopyridine, 2,6-di-tert-butyl-4- dimethylaminopyridine, l,4-diazabicyclo[2.2.2]octane, and l,8-diazabicyclo[5.4.0]undec- 7-ene.
  • the base used is triethylamine.
  • the solvent may be selected from the group consisting of hydrocarbons, ethers, chlorinated hydrocarbons, ketones, amides, sulphoxides, and mixtures thereof.
  • hydrocarbons include benzene, toluene, and xylene.
  • ethers include diethyl ether, ethyl methyl ether, di-isopropyl ether, tetrahydrofuran, and 1,4-dioxane.
  • chlorinated hydrocarbons include dichloromethane and chloroform.
  • ketones include acetone, dimethyl ketone, ethyl methyl ketone, and methyl iso-butyl ketone.
  • amides include N,N-dimethylformamide and N,N- dimethylacetamide.
  • sulphoxides include dimethyl sulphoxide and diethyl sulphoxide.
  • the solvent used is
  • reaction of the N-[(benzyloxy)carbonyl]-L-alanine of Formula III with morpholine is carried out at a temperature of about 0°C to ambient temperature.
  • the reaction of the N-[(benzyloxy)carbonyl]-L-alanine of Formula III with morpholine is carried out for a period of about 30 minutes to about 2 hours. In an embodiment of the present invention, the reaction is carried out for a period of about 1 hour.
  • alkyl magnesium halides include methyl magnesium chloride, methyl magnesium bromide, ethyl magnesium chloride, n-propyl magnesium chloride, n-propyl magnesium bromide, iso-propyl magnesium chloride, and iso-propyl magnesium bromide.
  • iso-propyl magnesium chloride is used.
  • the solvent may be selected from the group consisting of hydrocarbons, ethers, chlorinated hydrocarbons, amides, sulphoxides, and mixtures thereof.
  • the solvent used is tetrahydrofuran.
  • the reaction of the benzyl [(2S)-l-(mo ⁇ holin-4-yl)-l-oxopropan-2-yl]carbamate of Formula IV with l-bromo-3,5-bis(trifluoromethyl)benzene of Formula V is carried out for a period of about 2 hours to about 20 hours. In an embodiment of the present invention, the reaction is carried out for a period of about 3 hours to about 8 hours.
  • the benzyl ⁇ (2S)-l-[3,5-bis(trifluoromethyl)phenyl]-l-oxopropan-2-yl ⁇ carbamate of Formula VI may or may not be isolated as a solid from the reaction mixture prior to its reaction with the tris(alkoxy)aluminum.
  • the benzyl ⁇ (2S)-l-[3,5- bis(trifluoromethyl)phenyl]-l-oxopropan-2-yl ⁇ carbamate of Formula VI, obtained as an oil, is reacted with tris(alkoxy)aluminum followed by treatment with an inorganic base in a solvent.
  • tris(alkoxy)aluminums include tris(methoxy)aluminum, tris(ethoxy)aluminum, and tris(iso-propoxy)aluminum.
  • tris(iso-propoxy)aluminum is used.
  • inorganic bases include hydroxides, carbonates, and bicarbonates of alkali and alkaline earth metals, or mixtures thereof.
  • the base used is potassium hydroxide.
  • the reaction may be carried out at a temperature of about 0°C to about 70°C for about 1 hour to about 10 hours.
  • Isolation of (4S,5R)-5-[3,5 -bis(trifluoromethyl)phenyl] -4-methy 1- 1 , 3 -oxazolidin-2- one of Formula II as a solid is carried out by stirring in a hydrocarbon solvent for about 30 minutes to about 10 hours, followed by filtration, and drying under reduced pressure for about 3 hours.
  • hydrocarbon solvents include benzene, toluene, xylenes, hexanes, and heptane. In an embodiment of the present invention, heptane is used.
  • Triethylamine (14.7 g) was added into a reaction vessel containing a solution of N- [(benzyloxy)carbonyl]-L-alanine (25 g; Formula III) in dichloromethane (125 mL) at ambient temperature.
  • the reaction mixture was cooled to 0°C to 5°C.
  • Pivaloyl chloride (16.2 g) was added over a period of 20 minutes while maintaining the temperature of the reaction mixture below about 10°C.
  • the reaction mixture was stirred at 0°C to 10°C for about 1 hour.
  • Morpholine 25 mL was added over a period of 30 minutes while maintaining the temperature of the reaction mixture below about 10°C.
  • the reaction mixture was stirred at 10°C to 25°C for 1 hour, and then quenched by adding deionized water (125 mL).
  • deionized water 125 mL
  • the organic layer and the aqueous layer were separated.
  • the aqueous layer was extracted with dichloromethane (50 mL).
  • the organic layers were combined, and washed sequentially with 15% aqueous acetic acid (125 mL), 7% aqueous sodium bicarbonate solution (125 mL), and deionized water (125 mL).
  • the organic layer was concentrated under reduced pressure to obtain an oil.
  • the reaction mixture was stirred for about 7 hours at 5°C to 20°C, and then quenched by adding 25% aqueous acetic acid solution (125 mL) while maintaining the temperature of the reaction mixture below about 10°C.
  • the organic layer and the aqueous layer were separated.
  • the aqueous layer was extracted with toluene (125 mL).
  • the organic layers were combined, then washed with deionized water (125 mL), and then concentrated under reduced pressure to obtain benzyl ⁇ (2S)-l-[3,5-bis(trifluoromethyl)phenyl]-l-oxopropan-2-yl ⁇ carbamate of Formula VI as an oil, which was used as such in the next step.
  • the benzyl ⁇ (2S)-l-[3,5-bis(trifluoromethyl)phenyl]-l-oxopropan-2-yl ⁇ carbamate of Formula VI was added into a mixture of toluene (75 mL) and isopropanol (35 mL) at ambient temperature. Tris(isopropoxy)aluminum (8.5 g) was added. The reaction mixture was heated to 60°C to 70°C, and then stirred for about 5 hours. The reaction mixture was cooled to 10°C to 15°C. Potassium hydroxide (8.1 g) was added in small lots while maintaining the temperature of the reaction mixture below about 25°C.
  • reaction mixture was stirred for about 3 hours.
  • the reaction mixture was cooled to 5°C, and then quenched by adding IN hydrochloric acid solution (150 mL) while maintaining the temperature of the reaction mixture below about 25°C.
  • the contents were stirred for 15 minutes, and then filtered.
  • the organic layer was separated, then washed once with 0.5 N hydrochloric acid solution (150 mL), and then washed twice with an isopropanol: water mixture (35 mL:200 mL).
  • the combined organic layers were concentrated under reduced pressure to obtain (4S,5R)-5-[3,5- bis(trifluoromethyl)phenyl]-4-methyl-l,3-oxazolidin-2-one as an oil.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The present invention provides a process for the preparation of anacetrapib and an intermediate thereof.

Description

PROCESS FOR THE PREPARATION OF ANACETRAPIB AND AN
INTERMEDIATE THEREOF
Field of the Invention
The present invention provides a process for the preparation of anacetrapib and an intermediate thereof.
Background of the Invention
Anacetrapib is an inhibitor of cholesterol ester transfer protein (CETP). It is chemically designated as (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((4'-fluoro-5'- isopropyl-2 ' -methoxy-4-(trifluoromethyl)-[ 1 , Γ -biphenyl] -2-yl)methyl)-4- methyloxazolidin-2-one, having the structure as depicted in Formula I.
Figure imgf000002_0001
Formula I
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-l,3-oxazolidin-2-one of Formula II is a key intermediate used for the preparation of anacetrapib.
Figure imgf000002_0002
Formula II
PCT Publication Nos. WO 2007/081569 and WO 2007/081571 disclose processes for the preparation of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-l,3-oxazolidin- 2-one of Formula II. PCT Publication Nos. WO 2006/014413, WO 2007/005572, WO 2012/085133, WO 2013/066768, WO 2013/091696, WO 2013/064188, and WO 2014/111953 disclose processes for the preparation of anacetrapib and its intermediates.
Summary of the Invention
The present invention provides an easy, cost-effective, and industrially advantageous process for the preparation of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4- methyl-l,3-oxazolidin-2-one of Formula II, and its use for the preparation of anacetrapib of Formula I.
A first aspect of the present invention provides a process for the preparation of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-l,3-oxazolidin-2-one of Formula II,
Figure imgf000003_0001
Formula II
comprising the steps of:
i) reacting N-[(benzyloxy)carbonyl]-L-alanine of Formula III
Figure imgf000003_0002
Formula III
with morpholine to obtain benzyl [(28)-1-^οφηο1ίη-4^1)-1-οχορκ^η-2- yl]carbamate of Formula IV;
Figure imgf000003_0003
Formula IV ii) reacting the benzyl [(2S)-l-(moφholin-4-yl)-l-oxopropan-2-yl]carbamate of Formula IV with l-bromo-3,5-bis(trifluoromethyl)benzene of Formula V
Figure imgf000004_0001
Formula V
to obtain benzyl {(2S)-l-[3,5-bis(trifluoromethyl)phenyl]-l-oxopropan-2- yl} carbamate of Formula VI; and
Figure imgf000004_0002
Formula VI
iii) reacting the benzyl {(2S)-l-[3,5-bis(trifluoromethyl)phenyl]-l-oxopropan-2- yl} carbamate of Formula VI with tris(alkoxy)aluminum, followed by treatment with a base to obtain the (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl- l,3-oxazolidin-2-one of Formula II.
A second aspect of the present invention provides a process for the preparation of anacetrapib of Formula I,
Figure imgf000004_0003
Formula I
comprising the steps of:
i) reacting N-[(benzyloxy)carbonyl]-L-alanine of Formula III
Figure imgf000005_0001
Formula III
with morpholine to obtain benzyl [(28)-1-^οφ1ιο1ίη-4^1)-1-οχορκ^η-2- yl]carbamate of Formula IV;
Figure imgf000005_0002
Formula IV
ii) reacting the benzyl [(2S)-l-(moφholin-4-yl)-l-oxopropan-2-yl]carbamate of Formula IV with l-bromo-3,5-bis(trifluoromethyl)benzene of Formula V
Figure imgf000005_0003
Formula V
to obtain benzyl {(2S)-l-[3,5-bis(trifluoromethyl)phenyl]-l-oxopropan-2- yl} carbamate of Formula VI;
Figure imgf000005_0004
Formula VI
iii) reacting the benzyl {(2S)-l-[3,5-bis(trifluoromethyl)phenyl]-l-oxopropan-2- yl} carbamate of Formula VI with tris(alkoxy)aluminum, followed by treatment with a base to obtain (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-l,3- oxazolidin-2-one of Formula II; and
Figure imgf000006_0001
Formula II
iv) reacting the (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-l,3- oxazolidin-2-one of Formula II with a biaryl halide of Formula VII
Figure imgf000006_0002
Formula VII (wherein X is halogen) to obtain anacetrapib of Formula I.
Detailed Description of the Invention
Various aspects and embodiments of the present invention are described hereafter.
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 "ambient temperature," as used herein, refers to a temperature in the range of about 20°C to about 35°C.
The term "alkyl" or "alkoxy," as used herein, refers to a C1-5 straight chain or branched chain hydrocarbon.
The term "halide" or "halogen," as used herein, refers to fluorine, chlorine, bromine, or iodine.
N-[(benzyloxy)carbonyl]-L-alanine of Formula III, to be used as an intermediate for the preparation of benzyl [(2S)-l-(mo holin-4-yl)-l-oxopropan-2-yl]carbamate of Formula IV, is commercially available.
The reaction of the N-[(benzyloxy)carbonyl]-L-alanine of Formula III with morpholine to obtain benzyl [(2S)-l-(moφholin-4-yl)-l-oxopropan-2-yl]carbamate of Formula IV is carried out in the presence of pivaloyl chloride, a base, and a solvent. The base is selected from the group consisting of inorganic and organic bases. Examples of inorganic bases include hydroxides, carbonates, and bicarbonates of alkali and alkaline earth metals, or mixtures thereof. Examples of alkali and alkaline earth metal hydroxides include lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, and barium hydroxide. Examples of alkali and alkaline earth metal carbonates include sodium carbonate, potassium carbonate, calcium carbonate, and magnesium carbonate. Examples of alkali metal bicarbonates include sodium bicarbonate and potassium bicarbonate. Examples of organic bases include N,N- diisopropylethylamine, triethylamine, triisopropylamine, N,N-2-trimethyl-2-propanamine, N-methylmorpholine, 4-dimethylaminopyridine, 2,6-di-tert-butyl-4- dimethylaminopyridine, l,4-diazabicyclo[2.2.2]octane, and l,8-diazabicyclo[5.4.0]undec- 7-ene. In an embodiment of the present invention, the base used is triethylamine. The solvent may be selected from the group consisting of hydrocarbons, ethers, chlorinated hydrocarbons, ketones, amides, sulphoxides, and mixtures thereof. Examples of hydrocarbons include benzene, toluene, and xylene. Examples of ethers include diethyl ether, ethyl methyl ether, di-isopropyl ether, tetrahydrofuran, and 1,4-dioxane. Examples of chlorinated hydrocarbons include dichloromethane and chloroform. Examples of ketones include acetone, dimethyl ketone, ethyl methyl ketone, and methyl iso-butyl ketone. Examples of amides include N,N-dimethylformamide and N,N- dimethylacetamide. Examples of sulphoxides include dimethyl sulphoxide and diethyl sulphoxide. In an embodiment of the present invention, the solvent used is
dichloromethane .
The reaction of the N-[(benzyloxy)carbonyl]-L-alanine of Formula III with morpholine is carried out at a temperature of about 0°C to ambient temperature.
The reaction of the N-[(benzyloxy)carbonyl]-L-alanine of Formula III with morpholine is carried out for a period of about 30 minutes to about 2 hours. In an embodiment of the present invention, the reaction is carried out for a period of about 1 hour.
The reaction of the benzyl [(28)-1-^οφηο1ίη-4^1)-1-οχορΓορ3η-2^1^Λ3η^ΐε of Formula IV with l-bromo-3,5-bis(trifluoromethyl)benzene of Formula V to obtain the benzyl {(2S)-l-[3,5-bis(trifluoromethyl)phenyl]-l-oxopropan-2-yl}carbamate of Formula VI is carried out in the presence of an alkyl magnesium halide in a solvent. Examples of alkyl magnesium halides include methyl magnesium chloride, methyl magnesium bromide, ethyl magnesium chloride, n-propyl magnesium chloride, n-propyl magnesium bromide, iso-propyl magnesium chloride, and iso-propyl magnesium bromide. In an embodiment of the present invention, iso-propyl magnesium chloride is used. The solvent may be selected from the group consisting of hydrocarbons, ethers, chlorinated hydrocarbons, amides, sulphoxides, and mixtures thereof. In an embodiment of the present invention, the solvent used is tetrahydrofuran.
The reaction of the benzyl [(2S)-l-(moφholin-4-yl)-l-oxopropan-2-yl]carbamate of Formula IV with l-bromo-3,5-bis(trifluoromethyl)benzene of Formula V is carried out at a temperature of about 0°C to ambient temperature.
The reaction of the benzyl [(2S)-l-(moφholin-4-yl)-l-oxopropan-2-yl]carbamate of Formula IV with l-bromo-3,5-bis(trifluoromethyl)benzene of Formula V is carried out for a period of about 2 hours to about 20 hours. In an embodiment of the present invention, the reaction is carried out for a period of about 3 hours to about 8 hours.
The benzyl {(2S)-l-[3,5-bis(trifluoromethyl)phenyl]-l-oxopropan-2-yl}carbamate of Formula VI may or may not be isolated as a solid from the reaction mixture prior to its reaction with the tris(alkoxy)aluminum.
In an embodiment of the present invention, the benzyl {(2S)-l-[3,5- bis(trifluoromethyl)phenyl]-l-oxopropan-2-yl}carbamate of Formula VI, obtained as an oil, is reacted with tris(alkoxy)aluminum followed by treatment with an inorganic base in a solvent. Examples of tris(alkoxy)aluminums include tris(methoxy)aluminum, tris(ethoxy)aluminum, and tris(iso-propoxy)aluminum. In an embodiment of the present invention, tris(iso-propoxy)aluminum is used. Examples of inorganic bases include hydroxides, carbonates, and bicarbonates of alkali and alkaline earth metals, or mixtures thereof. In an embodiment of the present invention, the base used is potassium hydroxide. The reaction may be carried out at a temperature of about 0°C to about 70°C for about 1 hour to about 10 hours.
Isolation of (4S,5R)-5-[3,5 -bis(trifluoromethyl)phenyl] -4-methy 1- 1 , 3 -oxazolidin-2- one of Formula II as a solid is carried out by stirring in a hydrocarbon solvent for about 30 minutes to about 10 hours, followed by filtration, and drying under reduced pressure for about 3 hours. Examples of hydrocarbon solvents include benzene, toluene, xylenes, hexanes, and heptane. In an embodiment of the present invention, heptane is used. The reaction of the (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-l,3- oxazolidin-2-one of Formula II with the biaryl halide of Formula VII to obtain anacetrapib of Formula I may be carried out by processes known in the literature, such as those disclosed in PCT Publication Nos. WO 2006/014413 and WO 2007/005572, which are incorporated herein by reference.
While the present invention has been described in terms of its specific aspects and 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.
The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.
Examples
Example 1 : Preparation of benzyl Γ(2S)-l-(moφholin-4-vΠ-l-oxopropan-2-yllcarbamate (Formula IV)
Triethylamine (14.7 g) was added into a reaction vessel containing a solution of N- [(benzyloxy)carbonyl]-L-alanine (25 g; Formula III) in dichloromethane (125 mL) at ambient temperature. The reaction mixture was cooled to 0°C to 5°C. Pivaloyl chloride (16.2 g) was added over a period of 20 minutes while maintaining the temperature of the reaction mixture below about 10°C. The reaction mixture was stirred at 0°C to 10°C for about 1 hour. Morpholine (25 mL) was added over a period of 30 minutes while maintaining the temperature of the reaction mixture below about 10°C. The reaction mixture was stirred at 10°C to 25°C for 1 hour, and then quenched by adding deionized water (125 mL). The organic layer and the aqueous layer were separated. The aqueous layer was extracted with dichloromethane (50 mL). The organic layers were combined, and washed sequentially with 15% aqueous acetic acid (125 mL), 7% aqueous sodium bicarbonate solution (125 mL), and deionized water (125 mL). The organic layer was concentrated under reduced pressure to obtain an oil. The oil was stirred in diisopropyl ether (75 mL) for about 3 hours, then filtered, and then dried under reduced pressure for about 3 hours to obtain benzyl [(28)-1-^οφηο1ίη-4^1)-1-οχορΓορ3η-2^1^ή^η^ΐε of Formula IV as a white solid.
Yield: 60 % Example 2: Preparation of (4S.5R)-5-r3.5-bis(trifluoromethyl)phenyll-4-methyl-1.3- oxazolidin-2-one (Formula II)
In a reaction vessel flushed with nitrogen gas, benzyl [(2S)-l-(morpholin-4-yl)-l- oxopropan-2-yl]carbamate (25 g; Formula IV), l-bromo-3,5-bis(trifluoromethyl)benzene (31.3 g; Formula V), and tetrahydrofuran (75 mL) were added at ambient temperature. The reaction mixture was cooled to -10°C. Isopropyl magnesium chloride (107 mL, 2M solution in tetrahydrofuran) was added over a period of 30 minutes while maintaining the temperature of the reaction mixture below about 0°C. The reaction mixture was stirred for about 7 hours at 5°C to 20°C, and then quenched by adding 25% aqueous acetic acid solution (125 mL) while maintaining the temperature of the reaction mixture below about 10°C. The organic layer and the aqueous layer were separated. The aqueous layer was extracted with toluene (125 mL). The organic layers were combined, then washed with deionized water (125 mL), and then concentrated under reduced pressure to obtain benzyl {(2S)-l-[3,5-bis(trifluoromethyl)phenyl]-l-oxopropan-2-yl}carbamate of Formula VI as an oil, which was used as such in the next step.
The benzyl {(2S)-l-[3,5-bis(trifluoromethyl)phenyl]-l-oxopropan-2-yl}carbamate of Formula VI was added into a mixture of toluene (75 mL) and isopropanol (35 mL) at ambient temperature. Tris(isopropoxy)aluminum (8.5 g) was added. The reaction mixture was heated to 60°C to 70°C, and then stirred for about 5 hours. The reaction mixture was cooled to 10°C to 15°C. Potassium hydroxide (8.1 g) was added in small lots while maintaining the temperature of the reaction mixture below about 25°C. After the addition of potassium hydroxide was complete, the reaction mixture was stirred for about 3 hours. The reaction mixture was cooled to 5°C, and then quenched by adding IN hydrochloric acid solution (150 mL) while maintaining the temperature of the reaction mixture below about 25°C. The contents were stirred for 15 minutes, and then filtered. The organic layer was separated, then washed once with 0.5 N hydrochloric acid solution (150 mL), and then washed twice with an isopropanol: water mixture (35 mL:200 mL). The combined organic layers were concentrated under reduced pressure to obtain (4S,5R)-5-[3,5- bis(trifluoromethyl)phenyl]-4-methyl-l,3-oxazolidin-2-one as an oil. Heptane (75 mL) was added to the oil. The contents were stirred for about 3 hours, then filtered, and then dried under reduced pressure for about 5 hours to obtain (4S,5R)-5-[3,5- bis(trifluoromethyl)phenyl]-4-methyl-l,3-oxazolidin-2-one of Formula II as a solid.
Yield: 84%

Claims

We claim:
1. A process for the preparation of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4- methyl-l,3-oxazolidin-2-one of Formula II
Figure imgf000011_0001
Formula II
comprising the steps of:
i) reacting N-[(benzyloxy)carbonyl]-L-alanine of Formula III
Figure imgf000011_0002
Formula III
with morpholine to obtain benzyl [(28)-1-^οφ1ιο1ίη-4^1)-1-οχορκ^η-2- yl]carbamate of Formula IV;
Figure imgf000011_0003
Formula IV
ii) reacting the benzyl [(2S)-l-(moφholin-4-yl)-l-oxopropan-2-yl]carbamate of Formula IV with l-bromo-3,5-bis(trifluoromethyl)benzene of Formula V
Figure imgf000011_0004
Formula V to obtain benzyl {(2S)-l-[3,5-bis(trifluoromethyl)phenyl]-l-oxopropan-2- yl} carbamate of Formula VI; and
Figure imgf000012_0001
Formula VI
iii) reacting the benzyl {(2S)-l-[3,5-bis(trifluoromethyl)phenyl]-l-oxopropan-2- yl} carbamate of Formula VI with tris(alkoxy)aluminum, followed by treatment with a base to obtain the (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl- l,3-oxazolidin-2-one of Formula II.
2. A process for the preparation of anacetrapib of Formula I
Figure imgf000012_0002
Formula I
comprising the steps of:
i) reacting N-[(benzyloxy)carbonyl]-L-alanine of Formula III
Figure imgf000012_0003
Formula III
with morpholine to obtain benzyl [(28)-1-^οφηο1ίη-4^1)-1-οχορκ^η-2- yl]carbamate of Formula IV;
Figure imgf000013_0001
Formula IV
ii) reacting the benzyl [(2S)-l-(moφholin-4-yl)-l-oxopropan-2-yl]carbamate of Formula IV with l-bromo-3,5-bis(trifluoromethyl)benzene of Formula V
Figure imgf000013_0002
Formula V
to obtain benzyl {(2S)-l-[3,5-bis(trifluoromethyl)phenyl]-l-oxopropan-2- yl} carbamate of Formula VI;
Figure imgf000013_0003
Formula VI
iii) reacting the benzyl {(2S)-l-[3,5-bis(trifluoromethyl)phenyl]-l-oxopropan-2- yl} carbamate of Formula VI with tris(alkoxy)aluminum, followed by treatment with a base to obtain (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-l,3- oxazolidin-2-one of Formula II: and
Figure imgf000013_0004
Formula II
iv) reacting the (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-l,3- oxazolidin-2-one of Formula II with a biaryl halide of Formula VII
Figure imgf000014_0001
Formula VII (wherein X is halogen) to obtain anacetrapib of Formula I.
3. The process according to claim 1 or 2, wherein the reaction of N- [(benzyloxy)carbonyl]-L-alanine of Formula III with morpholine in step i) is carried out in the presence of pivaloyl chloride, a base, and a solvent.
4. The process according to claim 3, wherein the base is selected from the group
consisting of inorganic and organic bases.
5. The process according to claim 4, wherein the base is triethylamine.
6. The process according to claim 3, wherein the solvent is selected from the group consisting of hydrocarbons, ethers, chlorinated hydrocarbons, ketones, amides, sulphoxides, and mixtures thereof.
7. The process according to claim 6, wherein the solvent is dichloromethane.
8. The process according to claim 1 or 2, wherein the reaction of the N- [(benzyloxy)carbonyl]-L-alanine of Formula III with morpholine in step i) is carried out at a temperature of 0°C to ambient temperature.
9. The process according to claim 1 or 2, wherein the reaction of the benzyl [(2S)-1- (mo holin-4-yl)-l-oxopropan-2-yl]carbamate of Formula IV with the l-bromo-3,5- bis(trifluoromethyl)benzene of Formula V in step ii) is carried out in the presence of an alkyl magnesium halide in a solvent.
10. The process according to claim 9, wherein the alkyl magnesium halide is selected from methyl magnesium chloride, methyl magnesium bromide, ethyl magnesium chloride, n-propyl magnesium chloride, n-propyl magnesium bromide, iso-propyl magnesium chloride, and iso-propyl magnesium bromide.
1 1. The process according to claim 9, wherein the solvent is selected from the group consisting of hydrocarbons, ethers, chlorinated hydrocarbons, ketones, amides, sulphoxides, and mixtures thereof.
12. The process according to claim 11, wherein the solvent is tetrahydrofuran.
13. The process according to claim 1 or 2, wherein the tris(alkoxy)aluminum in step iii) is selected from tris(methoxy)aluminum, tris(ethoxy)aluminum, and tris(iso- propoxy)aluminum.
14. The process according to claim 1 or 2, wherein the base in step iii) is selected from the group comprising of hydroxides, carbonates, and bicarbonates of alkali and alkaline earth metals, or mixtures thereof.
15. The process according to claim 14, wherein the base is potassium hydroxide.
16. The process according to claim 1 or 2, wherein the reaction of step iii) is carried out at a temperature of about 0°C to about 70°C.
PCT/IB2015/058271 2014-10-27 2015-10-27 Process for the preparation of anacetrapib and an intermediate thereof WO2016067194A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100041724A1 (en) * 2005-07-01 2010-02-18 Miller Ross A Process For Synthesizing A CETP Inhibitor
US20130109649A1 (en) * 2011-10-28 2013-05-02 Pengcheng Patrick Shao Fused bicyclic oxazolidinone cetp inhibitor
WO2014111953A1 (en) * 2013-01-17 2014-07-24 Glenmark Pharmaceuticals Limited; Glenmark Generics Limited Process for preparation of anacetrapib and intermediates thereof
US20140221383A1 (en) * 2004-07-02 2014-08-07 Merck Sharp & Dohme Corp. Cetp inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140221383A1 (en) * 2004-07-02 2014-08-07 Merck Sharp & Dohme Corp. Cetp inhibitors
US20100041724A1 (en) * 2005-07-01 2010-02-18 Miller Ross A Process For Synthesizing A CETP Inhibitor
US20130109649A1 (en) * 2011-10-28 2013-05-02 Pengcheng Patrick Shao Fused bicyclic oxazolidinone cetp inhibitor
WO2014111953A1 (en) * 2013-01-17 2014-07-24 Glenmark Pharmaceuticals Limited; Glenmark Generics Limited Process for preparation of anacetrapib and intermediates thereof

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