WO2015087239A1 - Processes for the preparation of darapladib and its intermediates - Google Patents

Processes for the preparation of darapladib and its intermediates Download PDF

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Publication number
WO2015087239A1
WO2015087239A1 PCT/IB2014/066730 IB2014066730W WO2015087239A1 WO 2015087239 A1 WO2015087239 A1 WO 2015087239A1 IB 2014066730 W IB2014066730 W IB 2014066730W WO 2015087239 A1 WO2015087239 A1 WO 2015087239A1
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formula
fluorobenzyl
sulfanyl
cyclopenta
pyrimidin
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PCT/IB2014/066730
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French (fr)
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Md Abul Kalam AZAD
Amit K. Jain
Gyanendra Pandey
Kaptan Singh
Mohan Prasad
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Ranbaxy Laboratories Limited
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Publication of WO2015087239A1 publication Critical patent/WO2015087239A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems

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  • the present invention provides a process for the preparation of ethyl ⁇ 2-[(4- fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl ⁇ acetate of Formula 4, ⁇ 2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH- cyclopenta[d]pyrimidin-l-yl ⁇ acetic acid of Formula 1, and NN-diethyl-N'- ⁇ [4'- (trifluoromethyl)biphenyl-4-yl]methyl ⁇ ethane-l,2-diamine of Formula 2, which are
  • the present invention also provides a process for the
  • Darapladib of Formula A chemically known as N-[2-(diethylamino)ethyl]-2- ⁇ 2- [(4-fluorobenzyl)sulfanyl] -4-oxo-4,5 ,6,7-tetrahydro- lH-cyclopenta[d]pyrimidin- 1 -yl ⁇ -N- ⁇ [4'-(trifluoromethyl)biphenyl-4-yl]methyl ⁇ acetamide, is a Lp-PLA 2 inhibitor.
  • Darapladib is currently in clinical trials for the treatment of atherosclerosis.
  • PCT Publication No. WO 01/60805 provides a process for the preparation of ⁇ 2- [(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l- yl ⁇ acetic acid and NN-diethyl-N'- ⁇ [4'-(trifluoromethyl)biphenyl-4-yl]methyl ⁇ ethane-l,2- diamine intermediates and darapladib.
  • NN-diethyl-N'- ⁇ [4'-(trifluoromethyl)biphenyl-4- yl]methyl ⁇ ethane- 1,2-diamine requires reacting 4-(4-trifluoromethylphenyl)benzaldehyde with N,N-diethylethane- 1,2-diamine in the presence of molecular sieves to obtain an imine intermediate, which is then reduced with sodium borohydride to obtain NN-diethyl-N'- ⁇ [4'-(trifluoromethyl)biphenyl-4-yl]methyl ⁇ ethane-l,2-diamine.
  • Darapladib is prepared by reacting ⁇ 2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7- tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl ⁇ acetic acid with N,N-diethyl-N'- ⁇ [4'- (trifluoromethyl)biphenyl-4-yl]methyl ⁇ ethane-l,2-diamine in the presence of 1- hydroxybenzotriazole and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in dichloromethane, followed by a lengthy work up procedure for isolation and recrystallization. The present inventors found that the yield of darapladib obtained by this process is only 12.5%.
  • PCT Publication No. WO 03/016287 provides a process for the preparation of ⁇ 2- [(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l- yl ⁇ acetic acid and NN-diethyl-N'- ⁇ [4'-(trifluoromethyl)biphenyl-4-yl]methyl ⁇ ethane-l,2- diamine intermediates and darapladib.
  • ⁇ 2-[(4-Fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH- cyclopenta[d]pyrimidin-l-yl ⁇ acetic acid is prepared by reacting 2-[(4- fluorobenzyl)sulfanyl]-l,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one with hexamethyldisilazane in the presence of saccharin and treating the obtained reaction product with (trifluoromethanesulfonyloxy)acetic acid methyl ester to obtain the corresponding methyl ester, which is then hydrolyzed with a solution of 10% (w/v) sodium hydroxide.
  • NN-Diethyl-N'- ⁇ [4'-(trifluoromethyl)biphenyl-4-yl]methyl ⁇ ethane-l,2-diamine is prepared by stirring 4-(4-trifluoromethylphenyl)benzaldehyde with N,N-diethylethane- 1,2- diamine in toluene at 17°C to 21°C for 96 hours to obtain a solution.
  • This solution is then transferred to a hydrogenation vessel containing 5% palladium on alumina and is hydrogenated at 19°C to 27°C and a hydrogen pressure of 50 psi for 1 hour to obtain NN- diethyl-N'- ⁇ [4'-(trifluoromethyl)biphenyl-4-yl]methyl ⁇ ethane- 1 ,2-diamine .
  • Darapladib can then be prepared by reacting ⁇ 2-[(4-fluorobenzyl)sulfanyl]-4-oxo- 4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl ⁇ acetic acid in dichloromethane with NN-diemyl-N- ⁇ [4'-(trifluoromemyl)biphenyl-4-yl]methyl ⁇ emane-l,2-diamine in the presence of ⁇ , ⁇ -diisopropylethylamine and 0-Benzotriazol-l-yl-N,NN',N'- tetramethyluronium tetrafluoroborate (TBTU) at 20°C to 29°C for 4 hours.
  • TBTU 0-Benzotriazol-l-yl-N,NN',N'- tetramethyluronium tetrafluoroborate
  • PCT Publication No. WO 2011/146494 provides a process for the preparation of ⁇ 2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l- yl ⁇ acetic acid and NN-diemyl-N'- ⁇ [4'-(trifluoromethyl)biphenyl-4-yl]methyl ⁇ ethane-l,2- diamine intermediates and darapladib.
  • ⁇ 2-[(4-Fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH- cyclopenta[d]pyrimidin-l-yl ⁇ acetic acid is prepared by reacting (4-oxo-2-thioxo- 2,3,4,5, 6,7-hexahydro-lH-cyclopenta[d]pyrimidin-l-yl)acetic acid with 4- fluorobenzylchloride in a mixture of water and isopropyl alcohol in the presence of potassium carbonate at 40°C ⁇ 3°C to obtain ⁇ 2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7- tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl ⁇ acetic acid.
  • NN-Diethyl-N'- ⁇ [4'-(trifluoromethyl)biphenyl-4-yl]methyl ⁇ ethane-l,2-diamine is prepared by hydrogenating a mixture of 4-(4-trifluoromethylphenyl)benzaldehyde and NN-diethylethane-l,2-diamine in the presence of 5% Pd/C in toluene under hydrogen at 50 psi at 20°C ⁇ 3°C to obtain NN-diethyl-N'- ⁇ [4'-(trifluoromethyl)biphenyl-4- yl]methyl ⁇ ethane- 1,2-diamine.
  • darapladib can be prepared by reacting ⁇ 2- [(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l- yl ⁇ acetic acid with carbonyldiimidazole in methylisobutylketone at 70°C ⁇ 3°C to obtain an imidazole intermediate which can then be reacted with NN-diethyl-N'- ⁇ [4'-
  • the present inventors have observed that the preparation of ethyl ⁇ 2-[(4- fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl ⁇ acetate, which is an intermediate of darapladib, resulted in the formation of multiple impurities, particularly one at a relative retention time (RRT) 0.92, which is difficult to remove.
  • RRT relative retention time
  • the present invention provides an efficient, industrially preferable, and economic process for the preparation of ethyl ⁇ 2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7- tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl ⁇ acetate with a reduced level of impurities.
  • the present inventors have observed that preparation of NN-diethyl-N'- ⁇ [4'- (trifluoromethyl)biphenyl-4-yl]methyl ⁇ ethane- 1,2-diamine, which is an intermediate of darapladib, in the presence of an organic acid or zeolite resulted in better yields than the prior art processes and required a shorter reaction time.
  • the present invention further avoids the usage of environmentally hazardous reagents and organic solvents, thereby promoting green chemistry.
  • the present invention provides a process for the preparation of darapladib and its intermediates.
  • reacting includes adding, dissolving, slurrying, stirring, or a combination thereof.
  • organic base includes hydroxides, carbonates, and bicarbonates of alkali or alkaline earth metals.
  • hydroxides, carbonates, and bicarbonates of alkali or alkaline earth metals within the scope of the present invention include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate.
  • boric acid or its derivatives includes boric acid, boronic acid, or mixtures thereof.
  • organic acid includes acetic acid, boric acid, fumaric acid, propionic acid, and butyric acid.
  • solvent includes any solvent or solvent mixture, for example, water, esters, alkanols, halogenated hydrocarbons, aromatic hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • esters within the scope of the present invention include ethyl acetate, ⁇ -propyl acetate, isopropyl acetate, and «-butyl acetate.
  • alkanols within the scope of the present invention include primary, secondary, and tertiary alcohols having from one to six carbon atoms, for example, methanol, ethanol, n- propanol, isopropanol, and butanol.
  • halogenated hydrocarbons within the scope of the present invention include dichloromethane, chloroform, and 1,2- dichloroethane.
  • aromatic hydrocarbons within the scope of the present invention include toluene and xylene.
  • ketones within the scope of the present invention include acetone and methyl ethyl ketone.
  • ethers within the scope of the present invention include diethyl ether and tetrahydrofuran.
  • polar aprotic solvents within the scope of the present invention include NN- dimethylformamide, NN-dimethylacetamide, dimethylsulphoxide, acetonitrile, and N- methylpyrrolidone.
  • a first aspect of the present invention provides a process for the preparation of darapladib of Formula A
  • the starting materials 2-[(4- fluorobenzyl)sulfanyl]-l,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one of
  • Formula 3 and NN-diethyl-N'- ⁇ [4'-(trifluoromethyl)biphenyl-4-yl]methyl ⁇ ethane- 1,2- diamine of Formula 2 can be prepared by the methods known in the art, for example, as in PCT Publication Nos. WO 01/60805, WO 03/016287, or WO 2011/146494.
  • step a) can be performed at a
  • the organic solvent in step a) is selected from NN-dimethylformamide, dimethylsulphoxide, or N-methylpyrrolidone.
  • ethyl ⁇ 2-[(4-fluorobenzyl)sulfanyl]-4-oxo- 4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl ⁇ acetate of Formula 4 can be isolated by employing an isolation technique such as cooling, extraction, washing, crystallization, precipitation, filtration, filtration under vacuum, decantation, centrifugation, or combinations thereof.
  • step b) of hydrolysing ethyl ⁇ 2-[(4- fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl ⁇ acetate of Formula 4 involves treating ethyl ⁇ 2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7- tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl ⁇ acetate of Formula 4 with an aqueous sodium hydroxide solution at about 70°C to 75°C for a time period sufficient to complete the reaction.
  • ⁇ 2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7- tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl ⁇ acetic acid of Formula 1 can be isolated by washing the reaction mixture with toluene at a temperature of about 40°C to 50°C to remove the impurities, cooling the reaction mixture to about 20°C to 35°C, and precipitating the solid by adjusting the pH to about 1.2 with 6N hydrochloric acid. The reaction mixture is then stirred for about 2 hours, filtered under vacuum, and dried at about 45°C to about 50°C.
  • step c) of reacting ⁇ 2-[(4- fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l- yl ⁇ acetic acid of Formula 1 with NN-diethyl-N'- ⁇ [4'-(trifluoromethyl)biphenyl-4- yl]methyl ⁇ ethane- 1,2-diamine of Formula 2 can be performed in one or more solvents at a temperature of about 25°C to reflux in the presence of boric acid or its derivatives for a time period sufficient to complete the reaction.
  • darapladib of Formula A can be isolated by employing an isolation technique such as cooling, extraction, washing, crystallization, precipitation, filtration, filtration under vacuum, decantation, centrifugation, or a combination thereof.
  • an isolation technique such as cooling, extraction, washing, crystallization, precipitation, filtration, filtration under vacuum, decantation, centrifugation, or a combination thereof.
  • a second aspect of the present invention provides a process for the preparation of darapladib of Formula A
  • the starting materials, ⁇ 2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro- lH-cyclopenta[d]pyrimidin-l-yl ⁇ acetic acid of Formula 1 and NN-diethyl-N'- ⁇ [4'- (trifluoromethyl)biphenyl-4-yl]methyl ⁇ ethane- 1,2-diamine of Formula 2 can be prepared by the processes provided herein or by the methods known in the art, for example, as in PCT Publication Nos. WO 01/60805, WO 03/016287, or WO
  • the step of reacting ⁇ 2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro- lH-cyclopenta[d]pyrimidin-l-yl ⁇ acetic acid of Formula 1 with N,N-diethyl-N'- ⁇ [4'- (trifluoromethyl)biphenyl-4-yl]methyl ⁇ ethane- 1,2-diamine of Formula 2 may be performed in one or more solvents at a temperature of about 25°C to reflux in the presence of boric acid or its derivatives for a time period sufficient to complete the reaction.
  • darapladib of Formula A can be isolated by employing an isolation technique such as cooling, extraction, washing, crystallization, precipitation, filtration, filtration under vacuum, decantation, centrifugation, or a combination thereof.
  • an isolation technique such as cooling, extraction, washing, crystallization, precipitation, filtration, filtration under vacuum, decantation, centrifugation, or a combination thereof.
  • a third aspect of the present invention provides a process for the preparation of ethyl ⁇ 2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin- 1-yl ⁇ acetate of Formula 4
  • the starting material 2-[(4-fluorobenzyl)sulfanyl]-l,5,6,7-tetrahydro-4H- cyclopenta[d]pyrimidin-4-one of Formula 3, can be prepared by the methods known in the art, for example, PCT Publication Nos. WO 01/60805, WO 03/016287, or WO 2011/146494.
  • the step of reacting 2-[(4-fluorobenzyl)sulfanyl]-l,5,6,7-tetrahydro-4H- cyclopenta[d]pyrimidin-4-one of Formula 3 with ethyl bromoacetate can be performed at a temperature of about 25 °C to reflux for a time period sufficient to complete the reaction.
  • the organic solvent is selected from the group comprising NN- dimethylformamide, dimethylsulphoxide, or N-methylpyrrolidone.
  • ethyl ⁇ 2-[(4-fluorobenzyl)sulfanyl]-4-oxo- 4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl ⁇ acetate of Formula 4 can be isolated by cooling, extraction, washing, crystallization, precipitation, filtration, filtration under vacuum, decantation, centrifugation, or combinations thereof.
  • a fourth aspect of the present invention provides a process for the preparation of ⁇ 2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l- yl ⁇ acetic acid of Formula 1
  • the starting material, 2-[(4-fluorobenzyl)sulfanyl]-l,5,6,7-tetrahydro-4H- cyclopenta[d]pyrimidin-4-one of Formula 3 can be prepared by the methods known in the art, for example, as described in PCT Publication Nos. WO 01/60805, WO
  • Step a) of reacting 2-[(4-fluorobenzyl)sulfanyl]-l,5,6,7-tetrahydro-4H- cyclopenta[d]pyrimidin-4-one of Formula 3 with ethyl bromoacetate can be performed at a temperature of about 25 °C to reflux for a time period sufficient to complete the reaction.
  • the organic solvent in step a) is selected from N,N-dimethylformamide, dimethylsulphoxide, or N-methylpyrrolidone.
  • 4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl ⁇ acetate of Formula 4 can be isolated by cooling, extraction, washing, crystallization, precipitation, filtration, filtration under vacuum, decantation, centrifugation, or combinations thereof.
  • Step b) of hydrolysing ethyl ⁇ 2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7- tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl ⁇ acetate of Formula 4 involves treating ethyl ⁇ 2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l- yl ⁇ acetate of Formula 4 with aqueous sodium hydroxide solution at a temperature of about 70°C to 75°C for a time period sufficient to complete the reaction.
  • ⁇ 2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7- tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl ⁇ acetic acid of Formula 1 can be isolated by washing the reaction mixture with toluene at a temperature of about 40°C to 50°C to remove the impurities, cooling the reaction mixture to about 20°C to 35°C, and precipitating the solid by adjusting the pH to about 1.2 with 6N hydrochloric acid. The reaction mixture is then stirred for about 2 hours, filtered under vacuum, and dried at about 45°C to about 50°C.
  • a fifth aspect of the present invention provides a process for the preparation of NN-diemyl-N'- ⁇ [4'-(trifluoromethyl)biphenyl-4-yl]methyl ⁇ ethane-l,2-diamine of Formula 2
  • the starting material, 4-(4-trifluoromethylphenyl)benzaldehyde of Formula 5 can be prepared by the processes provided herein or by methods known in the art, for example, as in PCT Publication Nos. WO 01/60805 and WO 03/016287.
  • the step of treating 4-(4-trifluoromethylphenyl)benzaldehyde of Formula 5 with N,N-diethylethane-l,2-diamine, hydrogen, and a hydrogenation catalyst in the presence of an organic acid or zeolite includes adding, dissolving, slurrying, stirring, or combinations thereof.
  • the hydrogenation catalyst is selected from the group comprising Raney nickel, palladium on carbon, or palladium on alumina.
  • the step of treating 4-(4-trifluoromethylphenyl)benzaldehyde of Formula 5 with NN-diethylethane-l,2-diamine, hydrogen, and a hydrogenation catalyst in the presence of an organic acid or zeolite may be performed in one or more solvents at a hydrogen pressure of about 40 psi to 60 psi and a temperature of about 20°C to 35°C for a time period sufficient to complete the reaction.
  • NN-diethyl-N'- ⁇ [4'-(trifluoromethyl)biphenyl-4- yl]methyl ⁇ ethane- 1,2-diamine of Formula 2 can be isolated by filtration through Hyflo ® , washing with toluene, adjusting the pH of the filtrate with acetic acid, stirring, extraction, adjusting the pH to about 9.6 with 20% sodium carbonate solution, extraction, and recovering the organic layer under vacuum.
  • the isolated NN-diethyl-N'- ⁇ [4'-(trifluoromethyl)biphenyl-4-yl]methyl ⁇ ethane- 1,2-diamine of Formula 2 may be purified by crystallization, chromatography, or a combination thereof.
  • the organic layer was again extracted with a saturated 1 :3:0.2 mixture of sodium carbonate, water, and saturated brine (115 mL). The organic layer was washed with 1 : 1 mixture of saturated brine: water (115 mL). The organic layer was dried on sodium sulphate in presence of decolorizing charcoal (4.0 g), filtered, and the solvent was recovered under vacuum to obtain a dark brown foam. The residue was dissolved in isopropyl acetate (11.5 mL) and the solvent was recovered under vacuum to obtain a gummy residue. Isopropyl acetate (57.5 mL) was added to the gummy residue and the temperature of the reaction mixture was raised to reflux.
  • the reaction mixture was cooled to 25°C, seeded (darapladib crystallized from isopropyl acetate), and stirred overnight.
  • the reaction mixture was filtered and the solid was washed with isopropyl acetate (11.5 mL).
  • the solid was suck dried and was recrystallized using isopropyl acetate (46 mL).
  • the reaction mixture was stirred overnight.
  • the reaction mixture was filtered, and then the solid was washed with isopropyl acetate (9 mL). The solid was dried under vacuum for 15 hours at 45°C to 50°C to obtain the title compound.
  • NN-dimethylformamide (300 mL) and 2-[(4-fluorobenzyl)sulfanyl]- 1,5,6,7- tetrahydro-4H-cyclopenta[d]pyrimidin-4-one (Formula 3; 60 g) were mixed at 25°C.
  • Potassium carbonate (36 g) and ethyl bromoacetate (43.6 g) were added to the reaction mixture at 25°C.
  • the reaction mixture was heated to 70°C to 75°C and stirred for 4 hours.
  • the reaction was monitored by TLC until completion.
  • the reaction mixture was cooled to 20°C and de-ionized water (1200 mL) was added slowly to the reaction mixture over 45 minutes at 20°C to 30°C.
  • the reaction mixture was stirred at 20°C to 25 °C for 60 minutes.
  • the reaction mixture was filtered, and then the wet solid was washed with de- ionized water (600 mL).
  • the wet solid was dried overnight at 40°C to 45°C under vacuum to obtain the title compound.
  • Toluene (120 mL) was added at 45 °C to the reaction mixture and the reaction mixture was stirred at 40°C to 45 °C for 15 minutes. The reaction mixture was allowed to settle and the layers were separated. The aqueous layer was washed with toluene (120 mL) at 30°C to 40°C. The aqueous layer was cooled to 20°C and the pH was adjusted to 1.24 by the addition of 6N HC1 solution (52 mL) slowly over 30 minutes at 20°C to 25°C. The reaction mixture was stirred at 20°C to 25°C for 2 hours, and then filtered. The wet solid was washed with de-ionized water (400 mL). The wet solid was suck dried for 60 minutes, and then was dried at 45°C to 50°C under vacuum for 15 hours to obtain the title compound.
  • Toluene (100 mL) was added at 45 °C to the reaction mixture, then the reaction mixture was stirred at 40°C to 45°C for 15 minutes. The reaction mixture was allowed to settle and the layers were separated. The aqueous layer was washed with toluene (100 mL) at 30°C to 35°C. The aqueous layer was cooled to 20°C, then the pH was adjusted to 1.18 with 6N HC1 solution (65 mL) at 20°C to 25°C slowly over 30 minutes. The reaction mixture was stirred at 20°C to 25 °C for 90 minutes, and then filtered. The wet solid was washed with de-ionized water (500 mL). The wet solid was suck dried for 60 minutes, and then was dried at 45°C to 50°C under vacuum for 15 hours to obtain the title compound.
  • NN'-diethylethane-l,2-diamine (2.95 g) were mixed at 25°C.
  • Acetic acid (0.7 mL) was added at 25°C.
  • 10% Pd/C (0.7 g, 50% wet) was added at 25°C and the reaction mixture was stirred in a Parr apparatus at 25°C under hydrogen gas pressure (2.5 kg) for 20 hours.
  • the catalyst was filtered through a Hyflo ® bed and washed with toluene (10 mL).
  • De- ionized water (50 mL) was added to the filtrate, and then the pH was adjusted to 3.7 with acetic acid (20 mL).
  • the reaction mixture was stirred for 1 hour at 25°C.
  • the reaction mixture was allowed to settle, and then the organic layer was separated.
  • the pH of the organic layer was adjusted to 9.6 using a 20% aqueous sodium carbonate solution (40 mL).
  • the reaction mixture was stirred for 45 minutes, and then allowed to settle, and then the organic layer was separated.
  • the organic layer was washed with de-ionized water (50 mL), and toluene was recovered under vacuum at 50°C to obtain the title compound as an oily product.
  • De-ionized water 50 mL was added to the filtrate and the pH was adjusted to 3.7 using acetic acid (22 mL). The reaction mixture was stirred for 1 hour at 25°C, and then allowed to settle, and then the organic layer was separated. The pH of the organic layer was adjusted to 9.5 with a 30% aqueous sodium carbonate solution (50 mL). The reaction mixture was stirred for 1 hour, then the mixture settled, then the organic layer was separated. The organic layer was was washed with de-ionized water (50 mL), and then the toluene layer was recovered under vacuum at 50°C to obtain the title compound as an oily product.
  • reaction mixture was cooled to 25 °C, and then 5% aqueous sodium hydroxide solution (50 mL) was added to the reaction mixture at 25 °C. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was allowed to settle, and then the layers were separated. The organic layer was washed with 10% sodium chloride solution (50 mL). Toluene was recovered under vacuum at 48°C to 50°C to obtain an oily residue (10 g). n- Heptane (50 mL) was added to the oily residue and the mixture was heated to 50°C to
  • reaction mixture was stirred for 15 minutes at 50°C, then cooled to 25°C, then stirred for 4 hours.
  • the reaction mixture was filtered, and then the solid was washed with «-heptane (5 mL).
  • the wet material was dried under vacuum at 40°C to 45 °C for 15 hours to obtain the title compound.
  • NN-diethyl-N'- ⁇ [4'-(trifluoromethyl)biphenyl-4- yl]methyl ⁇ ethane- 1,2-diamine (Formula 2; 5.75 g; obtained in Example 6) was added to the reaction mixture and the reaction mixture was refluxed at 108°C to 110°C for 5.5 hours. The completion of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was cooled to 25 °C, and then a 5% aqueous sodium hydroxide solution (100 mL) was added to the reaction mixture at 25°C. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was allowed to settle, and then the layers were separated.
  • Toluene (400 mL) and NN-diethyl-N'- ⁇ [4'-(trifluoromethyl)biphenyl-4- yl]methyl ⁇ ethane- 1,2-diamine (Formula 2; 50 g) were mixed in a round bottom flask at 25°C and stirred.
  • the reaction mixture was allowed to settle, and then the organic layer was collected. The organic layer was washed with water (200 mL), and then toluene was recovered completely under vacuum at 50°C to obtain an oily residue. Methanol (350 mL) was added to the oily residue at 50°C, and the mixture was stirred for 15 minutes. The reaction mixture was cooled to 25 °C, then the solid was precipitated out, then water (200 mL) was added, and the mixture was stirred for 4 hours at 25 °C. The solid was filtered, and then washed with a mixture of methanol (75 mL) and water (25 mL). The wet solid was unloaded, then dried under vacuum at 45 °C for overnight to obtain the title compound.

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Abstract

The present invention provides a process for the preparation of ethyl {2-[(4- fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl}acetate of Formula 4, {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta [d]pyrimidin-1-yl}acetic acid of Formula 1, and N,N-diethyl-N'-{[4'- (trifluoromemyl)biphenyl-4-yl]methyl}ethane-1,2-diamine of Formula 2, which are intermediates of darapladib. The present invention also provides a process for the preparation of darapladib.

Description

PROCESSES FOR THE PREPARATION OF DARAPLADIB AND ITS INTERMEDIATES
Field of the Invention
The present invention provides a process for the preparation of ethyl {2-[(4- fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl}acetate of Formula 4, {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH- cyclopenta[d]pyrimidin-l-yl}acetic acid of Formula 1, and NN-diethyl-N'-{[4'- (trifluoromethyl)biphenyl-4-yl]methyl}ethane-l,2-diamine of Formula 2, which are
intermediates of darapladib. The present invention also provides a process for the
preparation of darapladib.
Background of the Invention
Darapladib of Formula A, chemically known as N-[2-(diethylamino)ethyl]-2-{2- [(4-fluorobenzyl)sulfanyl] -4-oxo-4,5 ,6,7-tetrahydro- lH-cyclopenta[d]pyrimidin- 1 -yl } -N- {[4'-(trifluoromethyl)biphenyl-4-yl]methyl}acetamide, is a Lp-PLA2 inhibitor. Darapladib is currently in clinical trials for the treatment of atherosclerosis.
Figure imgf000002_0001
Formula A
PCT Publication No. WO 01/60805 provides a process for the preparation of {2- [(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l- yl}acetic acid and NN-diethyl-N'-{[4'-(trifluoromethyl)biphenyl-4-yl]methyl}ethane-l,2- diamine intermediates and darapladib.
The process disclosed by WO 01/60805 for the preparation of {2-[(4- fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl}acetic acid requires reacting 2-[(4-fluorobenzyl)sulfanyl]-l,5,6,7-tetrahydro-4H- cyclopenta[d]pyrimidin-4-one with fert-butyl iodoacetate to obtain fert-butyl {2-[(4- fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl}acetate, which is then hydrolysed with trifluoroacetic acid to obtain {2-[(4-fluorobenzyl)sulfanyl]- 4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl}acetic acid.
The process for the preparation of NN-diethyl-N'-{[4'-(trifluoromethyl)biphenyl-4- yl]methyl} ethane- 1,2-diamine requires reacting 4-(4-trifluoromethylphenyl)benzaldehyde with N,N-diethylethane- 1,2-diamine in the presence of molecular sieves to obtain an imine intermediate, which is then reduced with sodium borohydride to obtain NN-diethyl-N'- {[4'-(trifluoromethyl)biphenyl-4-yl]methyl}ethane-l,2-diamine.
Darapladib is prepared by reacting{2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7- tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl}acetic acid with N,N-diethyl-N'-{[4'- (trifluoromethyl)biphenyl-4-yl]methyl}ethane-l,2-diamine in the presence of 1- hydroxybenzotriazole and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in dichloromethane, followed by a lengthy work up procedure for isolation and recrystallization. The present inventors found that the yield of darapladib obtained by this process is only 12.5%.
PCT Publication No. WO 03/016287 provides a process for the preparation of {2- [(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l- yl}acetic acid and NN-diethyl-N'-{[4'-(trifluoromethyl)biphenyl-4-yl]methyl}ethane-l,2- diamine intermediates and darapladib.
{2-[(4-Fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH- cyclopenta[d]pyrimidin-l-yl}acetic acid is prepared by reacting 2-[(4- fluorobenzyl)sulfanyl]-l,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one with hexamethyldisilazane in the presence of saccharin and treating the obtained reaction product with (trifluoromethanesulfonyloxy)acetic acid methyl ester to obtain the corresponding methyl ester, which is then hydrolyzed with a solution of 10% (w/v) sodium hydroxide.
NN-Diethyl-N'-{[4'-(trifluoromethyl)biphenyl-4-yl]methyl}ethane-l,2-diamine is prepared by stirring 4-(4-trifluoromethylphenyl)benzaldehyde with N,N-diethylethane- 1,2- diamine in toluene at 17°C to 21°C for 96 hours to obtain a solution. This solution is then transferred to a hydrogenation vessel containing 5% palladium on alumina and is hydrogenated at 19°C to 27°C and a hydrogen pressure of 50 psi for 1 hour to obtain NN- diethyl-N'- { [4'-(trifluoromethyl)biphenyl-4-yl]methyl } ethane- 1 ,2-diamine . Darapladib can then be prepared by reacting {2-[(4-fluorobenzyl)sulfanyl]-4-oxo- 4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl}acetic acid in dichloromethane with NN-diemyl-N-{[4'-(trifluoromemyl)biphenyl-4-yl]methyl}emane-l,2-diamine in the presence of Ν,Ν-diisopropylethylamine and 0-Benzotriazol-l-yl-N,NN',N'- tetramethyluronium tetrafluoroborate (TBTU) at 20°C to 29°C for 4 hours.
PCT Publication No. WO 2011/146494 provides a process for the preparation of {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l- yl}acetic acid and NN-diemyl-N'-{[4'-(trifluoromethyl)biphenyl-4-yl]methyl}ethane-l,2- diamine intermediates and darapladib.
{2-[(4-Fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH- cyclopenta[d]pyrimidin-l-yl}acetic acid is prepared by reacting (4-oxo-2-thioxo- 2,3,4,5, 6,7-hexahydro-lH-cyclopenta[d]pyrimidin-l-yl)acetic acid with 4- fluorobenzylchloride in a mixture of water and isopropyl alcohol in the presence of potassium carbonate at 40°C ±3°C to obtain{2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7- tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl}acetic acid.
NN-Diethyl-N'-{[4'-(trifluoromethyl)biphenyl-4-yl]methyl}ethane-l,2-diamine is prepared by hydrogenating a mixture of 4-(4-trifluoromethylphenyl)benzaldehyde and NN-diethylethane-l,2-diamine in the presence of 5% Pd/C in toluene under hydrogen at 50 psi at 20°C ±3°C to obtain NN-diethyl-N'-{[4'-(trifluoromethyl)biphenyl-4- yl]methyl} ethane- 1,2-diamine. The present inventors found that this process resulted in low yields.
The publication further discloses that darapladib can be prepared by reacting {2- [(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l- yl} acetic acid with carbonyldiimidazole in methylisobutylketone at 70°C ±3°C to obtain an imidazole intermediate which can then be reacted with NN-diethyl-N'-{ [4'-
(trifluoromethyl)biphenyl-4-yl]methyl} ethane- 1,2-diamine at 92°C ±3°C to obtain darapladib.
The processes described in the prior art for the preparation of {2-[(4- fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl}acetic acid and N,N-diethyl-N'-{[4'-(trifluoromethyl)biphenyl-4-yl]methyl}ethane-l,2-diamine intermediates and darapladib suffer from one or more of disadvantages such as low yield, difficulties in isolation of the products, formation of impurities, the necessity for column chromatography, and usage of hazardous/costly reagents such as hydroxybenzotriazole, O- Benzotriazol-l-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), and trifluoroacetic acid. Therefore, processes described in the prior art for the preparation of {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l- yljacetic acid, N,N-diethyl-N'-{[4'-(trifluoromethyl)biphenyl-4-yl]methyl}ethane-l,2- diamine, and darapladib are not commercially viable.
The present inventors have observed that the preparation of ethyl {2-[(4- fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl}acetate, which is an intermediate of darapladib, resulted in the formation of multiple impurities, particularly one at a relative retention time (RRT) 0.92, which is difficult to remove. Thus, the present invention provides an efficient, industrially preferable, and economic process for the preparation of ethyl {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7- tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl}acetate with a reduced level of impurities.
The present inventors have observed that preparation of NN-diethyl-N'-{[4'- (trifluoromethyl)biphenyl-4-yl]methyl} ethane- 1,2-diamine, which is an intermediate of darapladib, in the presence of an organic acid or zeolite resulted in better yields than the prior art processes and required a shorter reaction time.
The present invention further avoids the usage of environmentally hazardous reagents and organic solvents, thereby promoting green chemistry.
Summary of the Invention
The present invention provides a process for the preparation of darapladib and its intermediates.
Detailed Description of the Invention
The term "reacting" includes adding, dissolving, slurrying, stirring, or a combination thereof.
The term "inorganic base" includes hydroxides, carbonates, and bicarbonates of alkali or alkaline earth metals. Examples of hydroxides, carbonates, and bicarbonates of alkali or alkaline earth metals within the scope of the present invention include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate. The term "boric acid or its derivatives" includes boric acid, boronic acid, or mixtures thereof.
The term "organic acid" includes acetic acid, boric acid, fumaric acid, propionic acid, and butyric acid.
The term "solvent" includes any solvent or solvent mixture, for example, water, esters, alkanols, halogenated hydrocarbons, aromatic hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
Examples of esters within the scope of the present invention include ethyl acetate, ^-propyl acetate, isopropyl acetate, and «-butyl acetate. Examples of alkanols within the scope of the present invention include primary, secondary, and tertiary alcohols having from one to six carbon atoms, for example, methanol, ethanol, n- propanol, isopropanol, and butanol. Examples of halogenated hydrocarbons within the scope of the present invention include dichloromethane, chloroform, and 1,2- dichloroethane. Examples of aromatic hydrocarbons within the scope of the present invention include toluene and xylene. Examples of ketones within the scope of the present invention include acetone and methyl ethyl ketone. Examples of ethers within the scope of the present invention include diethyl ether and tetrahydrofuran. Examples of polar aprotic solvents within the scope of the present invention include NN- dimethylformamide, NN-dimethylacetamide, dimethylsulphoxide, acetonitrile, and N- methylpyrrolidone.
A first aspect of the present invention provides a process for the preparation of darapladib of Formula A
Figure imgf000006_0001
comprising the steps of: a) reacting 2-[(4-fluorobenzyl)sulfanyl]-l,5,6,7-tetrahydro-4H- cyclopenta[d]pyrimidin-4-one of Formula 3
Figure imgf000007_0001
Formula 3
with ethyl bromoacetate in an organic solvent in the presence of an inorganic base to obtain ethyl {2-[(4-fluorobenzyl)sulfanyl]-4-oxo- 4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl}acetate of Formula 4;
Figure imgf000007_0002
Formula 4
b) hydrolysing ethyl {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro- lH-cyclopenta[d]pyrimidin-l-yl} acetate of Formula 4 to obtain {2-[(4- fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH- cyclopenta[d]pyrimidin-l-yl} acetic acid of Formula 1; and
Figure imgf000007_0003
Formula 1
c) reacting {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH- cyclopenta[d]pyrimidin-l-yl} acetic acid of Formula 1 with NN-diethyl- N'-{[4'-(trifluoromethyl)biphenyl-4-yl]methyl}ethane-l,2-diarnine of
Formula 2
Figure imgf000008_0001
Formula 2
in the presence of boric acid or its derivatives to obtain darapladib of
Formula A.
In one embodiment of this aspect, the starting materials, 2-[(4- fluorobenzyl)sulfanyl]-l,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one of
Formula 3 and NN-diethyl-N'-{[4'-(trifluoromethyl)biphenyl-4-yl]methyl} ethane- 1,2- diamine of Formula 2, can be prepared by the methods known in the art, for example, as in PCT Publication Nos. WO 01/60805, WO 03/016287, or WO 2011/146494.
In another embodiment of this aspect, step a) can be performed at a
temperature of about 25 °C to reflux for a time period sufficient to complete the reaction.
In another embodiment of this aspect, the organic solvent in step a) is selected from NN-dimethylformamide, dimethylsulphoxide, or N-methylpyrrolidone.
After completion of the reaction, ethyl {2-[(4-fluorobenzyl)sulfanyl]-4-oxo- 4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl}acetate of Formula 4 can be isolated by employing an isolation technique such as cooling, extraction, washing, crystallization, precipitation, filtration, filtration under vacuum, decantation, centrifugation, or combinations thereof.
In another embodiment of this aspect, step b) of hydrolysing ethyl {2-[(4- fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl}acetate of Formula 4 involves treating ethyl {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7- tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl}acetate of Formula 4 with an aqueous sodium hydroxide solution at about 70°C to 75°C for a time period sufficient to complete the reaction.
After completion of the reaction, {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7- tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl}acetic acid of Formula 1 can be isolated by washing the reaction mixture with toluene at a temperature of about 40°C to 50°C to remove the impurities, cooling the reaction mixture to about 20°C to 35°C, and precipitating the solid by adjusting the pH to about 1.2 with 6N hydrochloric acid. The reaction mixture is then stirred for about 2 hours, filtered under vacuum, and dried at about 45°C to about 50°C.
In yet another embodiment of this aspect, step c) of reacting {2-[(4- fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l- yl}acetic acid of Formula 1 with NN-diethyl-N'-{[4'-(trifluoromethyl)biphenyl-4- yl]methyl} ethane- 1,2-diamine of Formula 2 can be performed in one or more solvents at a temperature of about 25°C to reflux in the presence of boric acid or its derivatives for a time period sufficient to complete the reaction.
After completion of the reaction, darapladib of Formula A can be isolated by employing an isolation technique such as cooling, extraction, washing, crystallization, precipitation, filtration, filtration under vacuum, decantation, centrifugation, or a combination thereof.
A second aspect of the present invention provides a process for the preparation of darapladib of Formula A
Figure imgf000009_0001
Formula A
which comprises reacting {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH- cyclopenta[d]pyrimidin-l-yl}acetic acid of Formula 1
Figure imgf000009_0002
Formula 1 with N,N-diethyl-N'- { [4'-(trifluoromethyl)biphenyl-4-yl]methyl } ethane- 1 ,2-diamine of Formula 2
Figure imgf000010_0001
Formula2
in the presence of boric acid or its derivatives.
The starting materials, {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro- lH-cyclopenta[d]pyrimidin-l-yl} acetic acid of Formula 1 and NN-diethyl-N'-{[4'- (trifluoromethyl)biphenyl-4-yl]methyl} ethane- 1,2-diamine of Formula 2, can be prepared by the processes provided herein or by the methods known in the art, for example, as in PCT Publication Nos. WO 01/60805, WO 03/016287, or WO
2011/146494.
The step of reacting {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro- lH-cyclopenta[d]pyrimidin-l-yl} acetic acid of Formula 1 with N,N-diethyl-N'-{[4'- (trifluoromethyl)biphenyl-4-yl]methyl} ethane- 1,2-diamine of Formula 2 may be performed in one or more solvents at a temperature of about 25°C to reflux in the presence of boric acid or its derivatives for a time period sufficient to complete the reaction.
After completion of the reaction, darapladib of Formula A can be isolated by employing an isolation technique such as cooling, extraction, washing, crystallization, precipitation, filtration, filtration under vacuum, decantation, centrifugation, or a combination thereof.
A third aspect of the present invention provides a process for the preparation of ethyl {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin- 1-yl} acetate of Formula 4
Figure imgf000011_0001
Formula 4
which comprises reacting 2-[(4-fluorobenzyl)sulfanyl]-l,5,6,7-tetrahyd]
cyclopenta[d]pyrimidin-4-one of Formula 3
Figure imgf000011_0002
Formula 3
with ethyl bromoacetate in an organic solvent in the presence of an inorganic base.
The starting material, 2-[(4-fluorobenzyl)sulfanyl]-l,5,6,7-tetrahydro-4H- cyclopenta[d]pyrimidin-4-one of Formula 3, can be prepared by the methods known in the art, for example, PCT Publication Nos. WO 01/60805, WO 03/016287, or WO 2011/146494.
The step of reacting 2-[(4-fluorobenzyl)sulfanyl]-l,5,6,7-tetrahydro-4H- cyclopenta[d]pyrimidin-4-one of Formula 3 with ethyl bromoacetate can be performed at a temperature of about 25 °C to reflux for a time period sufficient to complete the reaction.
The organic solvent is selected from the group comprising NN- dimethylformamide, dimethylsulphoxide, or N-methylpyrrolidone.
After completion of the reaction, ethyl {2-[(4-fluorobenzyl)sulfanyl]-4-oxo- 4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl}acetate of Formula 4 can be isolated by cooling, extraction, washing, crystallization, precipitation, filtration, filtration under vacuum, decantation, centrifugation, or combinations thereof. A fourth aspect of the present invention provides a process for the preparation of {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l- yl} acetic acid of Formula 1
Figure imgf000012_0001
Formula 1
comprising the steps of:
a) reacting 2-[(4-fluorobenzyl)sulfanyl]-l,5,6,7-tetrahydro-4H- cyclopenta[d]pyrimidin-4-one of Formula 3
Figure imgf000012_0002
Formula 3
with ethyl bromoacetate in an organic solvent in the presence of an inorganic base to obtain ethyl {2-[(4-fluorobenzyl)sulfanyl]-4-oxo- 4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl}acetate of Formula 4;
Figure imgf000012_0003
Formula 4
b) hydrolysing the ethyl {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7- tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl} acetate of Formula 4; and c) isolating {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH- cyclopenta[d]pyrimidin-l-yl} acetic acid of Formula 1.
Figure imgf000013_0001
Formula 1
The starting material, 2-[(4-fluorobenzyl)sulfanyl]-l,5,6,7-tetrahydro-4H- cyclopenta[d]pyrimidin-4-one of Formula 3 can be prepared by the methods known in the art, for example, as described in PCT Publication Nos. WO 01/60805, WO
03/016287, or WO 2011/146494.
Step a) of reacting 2-[(4-fluorobenzyl)sulfanyl]-l,5,6,7-tetrahydro-4H- cyclopenta[d]pyrimidin-4-one of Formula 3 with ethyl bromoacetate can be performed at a temperature of about 25 °C to reflux for a time period sufficient to complete the reaction.
The organic solvent in step a) is selected from N,N-dimethylformamide, dimethylsulphoxide, or N-methylpyrrolidone.
After completion of the reaction, ethyl {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-
4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl}acetate of Formula 4 can be isolated by cooling, extraction, washing, crystallization, precipitation, filtration, filtration under vacuum, decantation, centrifugation, or combinations thereof.
Step b) of hydrolysing ethyl {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7- tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl}acetate of Formula 4 involves treating ethyl {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l- yl} acetate of Formula 4 with aqueous sodium hydroxide solution at a temperature of about 70°C to 75°C for a time period sufficient to complete the reaction.
After completion of the reaction, {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7- tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl}acetic acid of Formula 1 can be isolated by washing the reaction mixture with toluene at a temperature of about 40°C to 50°C to remove the impurities, cooling the reaction mixture to about 20°C to 35°C, and precipitating the solid by adjusting the pH to about 1.2 with 6N hydrochloric acid. The reaction mixture is then stirred for about 2 hours, filtered under vacuum, and dried at about 45°C to about 50°C.
A fifth aspect of the present invention provides a process for the preparation of NN-diemyl-N'-{[4'-(trifluoromethyl)biphenyl-4-yl]methyl}ethane-l,2-diamine of Formula 2
Figure imgf000014_0001
Formula 2
which comprises treating 4-(4-trifluoromethylphenyl)benzaldehyde of Formula 5
Figure imgf000014_0002
with N,N-diethylethane-l,2-diamine, hydrogen, and a hydrogenation catalyst in the presence of an organic acid or zeolite.
The starting material, 4-(4-trifluoromethylphenyl)benzaldehyde of Formula 5, can be prepared by the processes provided herein or by methods known in the art, for example, as in PCT Publication Nos. WO 01/60805 and WO 03/016287.
The step of treating 4-(4-trifluoromethylphenyl)benzaldehyde of Formula 5 with N,N-diethylethane-l,2-diamine, hydrogen, and a hydrogenation catalyst in the presence of an organic acid or zeolite includes adding, dissolving, slurrying, stirring, or combinations thereof.
The hydrogenation catalyst is selected from the group comprising Raney nickel, palladium on carbon, or palladium on alumina.
The step of treating 4-(4-trifluoromethylphenyl)benzaldehyde of Formula 5 with NN-diethylethane-l,2-diamine, hydrogen, and a hydrogenation catalyst in the presence of an organic acid or zeolite may be performed in one or more solvents at a hydrogen pressure of about 40 psi to 60 psi and a temperature of about 20°C to 35°C for a time period sufficient to complete the reaction. After completion of the reaction, NN-diethyl-N'-{[4'-(trifluoromethyl)biphenyl-4- yl]methyl} ethane- 1,2-diamine of Formula 2 can be isolated by filtration through Hyflo®, washing with toluene, adjusting the pH of the filtrate with acetic acid, stirring, extraction, adjusting the pH to about 9.6 with 20% sodium carbonate solution, extraction, and recovering the organic layer under vacuum.
The isolated NN-diethyl-N'-{ [4'-(trifluoromethyl)biphenyl-4-yl]methyl}ethane- 1,2-diamine of Formula 2 may be purified by crystallization, chromatography, or a combination thereof.
While the present invention has been described in terms of its specific aspects, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be within the scope of the present invention.
EXAMPLES
Reference Example 1: Preparation of darapladib as per WO 01/60805
{2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH- cyclopenta[d]pyrimidin-l-yl}acetic acid (Formula 1; 10 g), hydroxybenzotriazole (4.04 g), and N-Ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (11.45 g) were added to dichloromethane (33 mL) at 25 °C to obtain a suspension, and the mixture was stirred for 30 minutes to obtain a clear solution. A solution of N,N-diethyl-N'-{[4'- (trifluoromethyl)biphenyl-4-yl]methyl} ethane- 1,2-diamine in dichloromethane (Formula 2; 10.47 g in 12 mL dichloromethane) was added at 25°C and the reaction mixture was stirred for 4 hours at 25 °C. A saturated 1 : 1 mixture of ammonium chloride and water (115 mL) was added, the mixture was stirred, and the organic layer was separated. The organic layer was extracted with a 1 : 1 mixture of ammonium chloride and water (115 mL), and extracted with a 10% acetic acid aqueous solution (115 mL). The organic layer was again extracted with a saturated 1 :3:0.2 mixture of sodium carbonate, water, and saturated brine (115 mL). The organic layer was washed with 1 : 1 mixture of saturated brine: water (115 mL). The organic layer was dried on sodium sulphate in presence of decolorizing charcoal (4.0 g), filtered, and the solvent was recovered under vacuum to obtain a dark brown foam. The residue was dissolved in isopropyl acetate (11.5 mL) and the solvent was recovered under vacuum to obtain a gummy residue. Isopropyl acetate (57.5 mL) was added to the gummy residue and the temperature of the reaction mixture was raised to reflux. The reaction mixture was cooled to 25°C, seeded (darapladib crystallized from isopropyl acetate), and stirred overnight. The reaction mixture was filtered and the solid was washed with isopropyl acetate (11.5 mL). The solid was suck dried and was recrystallized using isopropyl acetate (46 mL). The reaction mixture was stirred overnight. The reaction mixture was filtered, and then the solid was washed with isopropyl acetate (9 mL). The solid was dried under vacuum for 15 hours at 45°C to 50°C to obtain the title compound.
Yield: 2.5 g (12.5%)
Example 1 : Preparation of Ethyl {2-r(4-fluorobenzyl)sulfanvH-4-oxo-4.5.6.7-tetrahydro- lH-cyclopentardlpyrimidin-l-yl} acetate (Formula 4)
NN-dimethylformamide (300 mL) and 2-[(4-fluorobenzyl)sulfanyl]- 1,5,6,7- tetrahydro-4H-cyclopenta[d]pyrimidin-4-one (Formula 3; 60 g) were mixed at 25°C. Potassium carbonate (36 g) and ethyl bromoacetate (43.6 g) were added to the reaction mixture at 25°C. The reaction mixture was heated to 70°C to 75°C and stirred for 4 hours. The reaction was monitored by TLC until completion. The reaction mixture was cooled to 20°C and de-ionized water (1200 mL) was added slowly to the reaction mixture over 45 minutes at 20°C to 30°C. The reaction mixture was stirred at 20°C to 25 °C for 60 minutes. The reaction mixture was filtered, and then the wet solid was washed with de- ionized water (600 mL). The wet solid was dried overnight at 40°C to 45°C under vacuum to obtain the title compound.
Yield: 77 g (97.70%)
Purity (by HPLC): 96.26%
Impurity at RRT 0.92 (by HPLC): 2.41%
Example 2: Preparation of Ethyl {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4.5.6.7-tetrahydro- lH-cyclopentardlpyrimidin-l-yl} acetate (Formula 4)
NN-dimethylformamide (250 mL) and 2-[(4-fluorobenzyl)sulfanyl]- 1,5,6,7- tetrahydro-4H-cyclopenta[d]pyrimidin-4-one (Formula 3; 50 g) were mixed at 25°C.
Potassium carbonate (30 g) and ethyl bromoacetate (36.33 g) were added to the reaction mixture at 25°C. The reaction mixture was heated to 70°C to 75°C, and then stirred for 3.5 hours. The completion of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was cooled to 20°C and de-ionized water (1000 mL) was added slowly to the reaction mixture over 30 minutes at 20°C to 30°C. The reaction mixture was stirred at 20°C to 30°C for 60 minutes. The reaction mixture was filtered, then the wet solid was washed with de-ionized water (500 mL). The wet solid was dried at 40°C to 45°C under vacuum for 15 hours to obtain the title compound.
Yield: 62.5 g (95.41%)
Purity (by HPLC): 96.26%
Impurity at RRT 0.92 (by HPLC): 2.41%
Example 3: Preparation of {2-r(4-Fluorobenzyl)sulfanvH-4-oxo-4.5.6.7-tetrahvdro-lH- cvclopentardlpyrimidin-l-yljacetic acid (Formula 1)
Ethyl {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH- cyclopenta[d]pyrimidin-l-yl}acetate (Formula 4; 40 g, obtained in Example 1) and de- ionized water (200 mL) were mixed at 25°C. Aqueous sodium hydroxide solution (11.04 g in 200 mL de-ionized water) was added at 20°C to 25 °C. The reaction mixture was heated to 70°C to 75 °C and stirred for 3 hours. The completion of reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was cooled to 45°C. Toluene (120 mL) was added at 45 °C to the reaction mixture and the reaction mixture was stirred at 40°C to 45 °C for 15 minutes. The reaction mixture was allowed to settle and the layers were separated. The aqueous layer was washed with toluene (120 mL) at 30°C to 40°C. The aqueous layer was cooled to 20°C and the pH was adjusted to 1.24 by the addition of 6N HC1 solution (52 mL) slowly over 30 minutes at 20°C to 25°C. The reaction mixture was stirred at 20°C to 25°C for 2 hours, and then filtered. The wet solid was washed with de-ionized water (400 mL). The wet solid was suck dried for 60 minutes, and then was dried at 45°C to 50°C under vacuum for 15 hours to obtain the title compound.
Yield: 33 g (89.67%)
Purity (by HPLC): 99.15%
Example 4: Preparation of {2-r(4-Fluorobenzyl)sulfanvH-4-oxo-4.5.6.7-tetrahvdro-lH- cvclopentardlpyrimidin-l-yljacetic acid (Formula 1)
Ethyl {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH- cyclopenta[d]pyrimidin-l-yl}acetate (Formula 4; 50 g, obtained in Example 2) and de- ionized water (250 mL) were mixed at 25°C. Aqueous sodium hydroxide solution (13.81 g in 250 mL de-ionized water) was added slowly over 30 minutes at 20°C to 25°C. The reaction mixture was heated to 70°C to 75°C, and then stirred for 3 hours. The completion of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was cooled to 45 °C. Toluene (100 mL) was added at 45 °C to the reaction mixture, then the reaction mixture was stirred at 40°C to 45°C for 15 minutes. The reaction mixture was allowed to settle and the layers were separated. The aqueous layer was washed with toluene (100 mL) at 30°C to 35°C. The aqueous layer was cooled to 20°C, then the pH was adjusted to 1.18 with 6N HC1 solution (65 mL) at 20°C to 25°C slowly over 30 minutes. The reaction mixture was stirred at 20°C to 25 °C for 90 minutes, and then filtered. The wet solid was washed with de-ionized water (500 mL). The wet solid was suck dried for 60 minutes, and then was dried at 45°C to 50°C under vacuum for 15 hours to obtain the title compound.
Yield: 40 g (86.95%)
Purity (by HPLC): 98.64%
Example 5: Preparation ofN,N-Diethyl-N,-{ r4'-(trifluoromethyl)biphenyl-4- vHmethyl}ethane-1.2-diamine (Formula 2)
4-(4-trifluoromethylphenyl)benzaldehyde (Formula 5; 7 g), toluene (50 mL), and
NN'-diethylethane-l,2-diamine (2.95 g) were mixed at 25°C. Acetic acid (0.7 mL) was added at 25°C. 10% Pd/C (0.7 g, 50% wet) was added at 25°C and the reaction mixture was stirred in a Parr apparatus at 25°C under hydrogen gas pressure (2.5 kg) for 20 hours. The catalyst was filtered through a Hyflo® bed and washed with toluene (10 mL). De- ionized water (50 mL) was added to the filtrate, and then the pH was adjusted to 3.7 with acetic acid (20 mL). The reaction mixture was stirred for 1 hour at 25°C. The reaction mixture was allowed to settle, and then the organic layer was separated. The pH of the organic layer was adjusted to 9.6 using a 20% aqueous sodium carbonate solution (40 mL). The reaction mixture was stirred for 45 minutes, and then allowed to settle, and then the organic layer was separated. The organic layer was washed with de-ionized water (50 mL), and toluene was recovered under vacuum at 50°C to obtain the title compound as an oily product.
Yield: 8.0 g (82%)
Chemical Purity (by HPLC): 97.75% Example 6: Preparation ofN,N-Diethyl-N,-{ r4'-(trifluoromethyl)biphenyl-4- yllmethyl} ethane- 1.2-diamine (Formula 2)
4-(4-trifluoromethylphenyl)benzaldehyde (Formula 5; 7g), toluene (50 mL), and NN'-diethylethylenediamine (2.95 g) were mixed at 25°C. Zeolite (CBV 712) (3.50 g) was added at 25°C and 10% Pd/C (0.7 g, 50% wet) was added at 25°C. The reaction mixture was stirred in a Parr apparatus at 25°C under hydrogen gas pressure (2.5 kg) for 20 hours. The catalyst was filtered through a Hyflo® bed and washed with toluene (10 mL). De-ionized water (50 mL) was added to the filtrate and the pH was adjusted to 3.7 using acetic acid (22 mL). The reaction mixture was stirred for 1 hour at 25°C, and then allowed to settle, and then the organic layer was separated. The pH of the organic layer was adjusted to 9.5 with a 30% aqueous sodium carbonate solution (50 mL). The reaction mixture was stirred for 1 hour, then the mixture settled, then the organic layer was separated. The organic layer was washed with de-ionized water (50 mL), and then the toluene layer was recovered under vacuum at 50°C to obtain the title compound as an oily product.
Yield: 8.0 g (82%)
Purity (by HPLC): 96.30%
Example 7: Preparation of darapladib
Toluene (50 mL), {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH- cyclopenta[d]pyrimidin-l-yl}acetic acid (Formula 1; 5g; obtained in Example 4), and boric acid (0.45g) were mixed at 25°C. NN-diethyl-N'-{[4'-(trifluoromethyl)biphenyl-4- yl]methyl} ethane- 1,2-diamine (Formula 2; 5.75 g; obtained in Example 5) was added to the reaction mixture and the reaction mixture was refluxed at 108°C to 110°C for 9 hours. The completion of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was cooled to 25 °C, and then 5% aqueous sodium hydroxide solution (50 mL) was added to the reaction mixture at 25 °C. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was allowed to settle, and then the layers were separated. The organic layer was washed with 10% sodium chloride solution (50 mL). Toluene was recovered under vacuum at 48°C to 50°C to obtain an oily residue (10 g). n- Heptane (50 mL) was added to the oily residue and the mixture was heated to 50°C to
55°C. The reaction mixture was stirred for 15 minutes at 50°C, then cooled to 25°C, then stirred for 4 hours. The reaction mixture was filtered, and then the solid was washed with «-heptane (5 mL). The wet material was dried under vacuum at 40°C to 45 °C for 15 hours to obtain the title compound.
Yield: 7.30 g (74%)
Purity (by HPLC): 97.54%
Example 8: Preparation of darapladib
Toluene (50 mL), {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH- cyclopenta[d]pyrimidin-l-yl}acetic acid (Formula 1; 5 g; obtained in Example 4), and boric acid (0.45 g) were mixed at 25°C. NN-diethyl-N'-{[4'-(trifluoromethyl)biphenyl-4- yl]methyl} ethane- 1,2-diamine (Formula 2; 5.75 g; obtained in Example 6) was added to the reaction mixture and the reaction mixture was refluxed at 108°C to 110°C for 5.5 hours. The completion of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was cooled to 25 °C, and then a 5% aqueous sodium hydroxide solution (100 mL) was added to the reaction mixture at 25°C. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was allowed to settle, and then the layers were separated. The organic layer was washed with a 10% sodium chloride solution (100 mL). Toluene was recovered under vacuum at 48°C to 50°C to obtain an oily residue. «-Heptane (50 mL) was added to the oily residue and the mixture was heated to 50°C to 55°C. The reaction mixture was stirred for 15 minutes at 50°C, and then the mixture was cooled to 25 °C, and then stirred for 5 hours. The reaction mixture was filtered, and then the solid was washed with «-heptane (5 mL). The wet material was dried under vacuum at 40°C to 45°C for 15 hours to obtain the title compound.
Yield: 7.8 g (79%)
Chemical Purity (by HPLC): 97.59%
Example 9: Preparation of darapladib
Toluene (400 mL) and NN-diethyl-N'-{ [4'-(trifluoromethyl)biphenyl-4- yl]methyl} ethane- 1,2-diamine (Formula 2; 50 g) were mixed in a round bottom flask at 25°C and stirred. {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH- cyclopenta[d]pyrimidin-l-yl}acetic acid (Formula 1; 50g), boric acid (4.45 g), and trifluoromethyl phenyl boronic acid (2.71 g) were added to the reaction mixture at 25°C. The temperature of the reaction mixture was raised to 110°C and refluxed for 6 hours. The reaction mixture was monitored by HPLC until the reaction was completed. The reaction mixture was cooled to 25°C and a 5% NaOH solution (350 mL) was added, and then the mixture was stirred for 30 minutes at 25°C. The reaction mixture was allowed to settle, and then the organic layer was collected. The organic layer was washed with water (200 mL), and then toluene was recovered completely under vacuum at 50°C to obtain an oily residue. Methanol (350 mL) was added to the oily residue at 50°C, and the mixture was stirred for 15 minutes. The reaction mixture was cooled to 25 °C, then the solid was precipitated out, then water (200 mL) was added, and the mixture was stirred for 4 hours at 25 °C. The solid was filtered, and then washed with a mixture of methanol (75 mL) and water (25 mL). The wet solid was unloaded, then dried under vacuum at 45 °C for overnight to obtain the title compound.
Yield: 78.60 (82.63%)
Chemical Purity (by HPLC): 97.89%

Claims

CLAIMS:
1. A process for the preparation of darapladib of Formula A
Figure imgf000022_0001
Formula A
comprising the steps of:
a) reacting 2-[(4-fluorobenzyl)sulfanyl]-l,5,6,7-tetrahydro-4H- cyclopenta[d]pyrimidin-4-one of Formula 3
Figure imgf000022_0002
Formula 3
with ethyl bromoacetate in an organic solvent in the presence of an inorganic base to obtain ethyl {2-[(4-fluorobenzyl)sulfanyl]-4-oxo- 4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl}acetate of Formula 4;
Figure imgf000022_0003
Formula 4
b) hydrolyzing the ethyl {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7- tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl} acetate of Formula 4 to obtain {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH- cyclopenta[d]pyrimidin- 1 -yl } acetic acid of Formula 1 ; and
Figure imgf000023_0001
Formula 1
c) reacting the {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH- cyclopenta[d]pyrimidin-l-yl} acetic acid of Formula 1 with NN-diethyl- N'-{[4'-(trifluoromethyl)biphenyl-4-yl]methyl}ethane-l,2-diamine of Formula 2
Figure imgf000023_0002
Formula 2
in the presence of boric acid or its derivatives to obtain darapladib of Formula A.
2. The process according to claim 1, wherein the organic solvent is selected from NN-dimethylformamide, dimethylsulphoxide, or N-methylpyrrolidone.
3. The process according to claim 1, wherein the inorganic base is selected from hydroxides, carbonates, and bicarbonates of alkali or alkaline earth metals.
4. The process according to claim 1, wherein step a) is performed at a temperature of 25°C to reflux.
5. The process according to claim 1, wherein step b) involves treating ethyl {2- [(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l- yl} acetate of Formula 4 with an aqueous sodium hydroxide solution at a temperature of 70°C to 75°C.
6. The process according to claim 1, wherein step c) is performed in one or more solvents at a temperature of 25 °C to reflux in the presence of boric acid or its derivatives.
7. The process according to claim 1, wherein boric acid or its derivatives are selected from boric acid, boronic acid, or mixtures thereof.
8. The process according to claim 6, wherein the solvent is selected from water, esters, alkanols, halogenated hydrocarbons, aromatic hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
9. A process for the preparation of darapladib of Formula A
Figure imgf000024_0001
Formula A
which comprises reacting {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH- cyclopenta[d]pyrimidin-l-yl}acetic acid of Formula 1
Figure imgf000024_0002
Formula 1
with N,N-diethyl-N'-{[4'-(trifluoromethyl)biphenyl-4-yl]methyl}ethane-l,2-diamine of Formula 2
Figure imgf000024_0003
Formula 2
in the presence of boric acid or its derivatives.
10. The process according to claim 9, wherein the reaction is performed at a temperature of 25 °C to reflux.
11. The process according to claim 9 or claim 10, wherein the reaction is performed in one or more solvents.
12. The process according to claim 11, wherein the solvent is selected from water, esters, alkanols, halogenated hydrocarbons, aromatic hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
13. A process for the preparation of ethyl {2-[(4-fluorobenzyl)sulfanyl]-4-oxo- 4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl}acetate of Formula 4
Figure imgf000025_0001
Formula 4
which comprises reacting 2-[(4-fluorobenzyl)sulfanyl]-l,5,6,7-tetrahydro-4H- cyclopenta[d]pyrimidin-4-one of Formula 3
Figure imgf000025_0002
Formula 3
with ethyl bromoacetate in an organic solvent in the presence of an inorganic base.
14. The process according to claim 13, wherein the organic solvent is selected from NN-dimethylformamide, dimethylsulphoxide, or N-methylpyrrolidone.
15. The process according to claim 13, wherein the inorganic base is selected from hydroxides, carbonates, and bicarbonates of alkali or alkaline earth metals.
16. The process according to claim 13, wherein the process is performed at a temperature of 25 °C to reflux.
17. A process for the preparation of {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7- tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl}acetic acid of Formula 1
Figure imgf000026_0001
Formula 1
comprising the steps of:
a) reacting 2-[(4-fluorobenzyl)sulfanyl]-l,5,6,7-tetrahydro-4H- cyclopenta[d]pyrimidin-4-one of Formula 3
Figure imgf000026_0002
Formula 3
with ethyl bromoacetate in an organic solvent in the presence of an inorganic base to obtain ethyl {2-[(4-fluorobenzyl)sulfanyl]-4-oxo- 4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl}acetate of Formula 4;
Figure imgf000026_0003
Formula 4
b) hydrolyzing the ethyl {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7- tetrahydro- lH-cyclopenta[d]pyrimidin- 1 -yl } acetate of Formula 4; and c) isolating {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH- cyclopenta[d]pyrimidin- 1 -yl } acetic acid of Formula 1.
Figure imgf000027_0001
Formula 1
18. The process according to claim 17, wherein step a) is performed at a temperature of 25°C to reflux.
19. The process according to claim 17, wherein step b) involves treating the ethyl {2- [(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l- yl} acetate of Formula 4 with aqueous sodium hydroxide solution at a temperature of 70°C to 75°C.
20. A process for the preparation of NN-diethyl-N-{ [4'-(trifluoromethyl)biphenyl- 4-yl]methyl}ethane-l,2-diamine of Formula 2
Figure imgf000027_0002
Formula 2
which comprises treating 4-(4-trifluoromethylphenyl)benzaldehyde of Formula 5
Figure imgf000027_0003
Formula 5
with N,N-diethylethane- 1,2-diamine, hydrogen, and a hydrogenation catalyst in the presence of an organic acid or zeolite.
21. The process according to claim 20, wherein the organic acid is selected from acetic acid, boric acid, fumaric acid, propionic acid, or butyric acid.
22. The process according to claim 20, wherein the hydrogenation catalyst is selected from the group consisting of raney nickel, palladium on carbon, and
palladium on alumina.
23. The process according to claim 20, wherein the process is performed at a hydrogen pressure of 40 psi to 60 psi and a temperature of 20°C to 35°C.
24. The process according to claim 20, wherein the process is performed in one or more solvents.
25. The process according to claim 20, wherein the solvent is selected from water, esters, alkanols, halogenated hydrocarbons, aromatic hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
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