WO2011004389A2 - An improved process for the preparation of elvitegravir - Google Patents

An improved process for the preparation of elvitegravir Download PDF

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WO2011004389A2
WO2011004389A2 PCT/IN2010/000420 IN2010000420W WO2011004389A2 WO 2011004389 A2 WO2011004389 A2 WO 2011004389A2 IN 2010000420 W IN2010000420 W IN 2010000420W WO 2011004389 A2 WO2011004389 A2 WO 2011004389A2
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formula
compound
acid
solvent
methoxide
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PCT/IN2010/000420
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French (fr)
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WO2011004389A3 (en
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Siva Rama Prasad Vellanki
Vilas Nathu Dhake
Satyanarayana Ravi
Ravi Nuchu
Ravindra Puliyala
Mahaboob Basha Shaik
Debashish Datta
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Matrix Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to an improved process for the preparation of Elvitegravir.
  • the present invention includes novel intermediates for the preparation of Elvitegravir.
  • Elvitegravir also known as GS 9137 or JTK 303, is an investigational new drug and a novel oral integrase inhibitor that is being evaluated for the treatment of HIV-1 infection. After HIVs genetic material is deposited inside a cell, its RNA must be converted (reverse transcribed) into DNA. A viral enzyme called integrase then helps to hide HIVs DNA inside the cell's DNA. Once this happens, the cell can begin producing genetic material for new viruses. Integrase inhibitors, such as elvitegravir, are designed to block the activity of the integrase enzyme and to prevent HIV DNA from entering healthy cell DNA.
  • Elvitegravir has the chemical name: 6-(3-chloro-2-fluorobenzyl)-1-[(S)-1 -hydroxy -methyl-2- methylpropyl]-7-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid and has the following structural formula:
  • WO 2000040561 , WO 2000040563 and WO 2001098275 disclose 4-oxo-1 , 4-dihydro-3- quinoline which is useful as antiviral agents.
  • WO2004046115 provides certain 4- oxoquinoline compounds that are useful as HIV Integrase inhibitors.
  • Elvitegravir (residue) US 7635704 patent discloses certain specific crystalline forms of elvitegravir. The specific crystalline forms are reported to have superior physical and chemical stability compared to other physical forms of the compound. Further, process for the preparation of elvitegravir also disclosed and is depicted below in the Scheme B. The given processes involve the isolation of the intermediates at almost all the stages.
  • Elvitegravir WO 2007102499 discloses a compound which is useful as an intermediate for the synthesis of an anti-HIV agent having an integrase-inhibiting activity; a process for production of the compound; and a process for production of an anti-HIV agent using the intermediate.
  • WO 2009036161 also discloses synthetic processes and synthetic intermediates that can be used to prepare 4-oxoquinolone compounds having useful integrase inhibiting properties.
  • the present invention relates to process for the preparation of elvitegravir without isolating some of the intermediates.
  • the present invention provides a time saving process for the preparation of elvitegravir without compromising the yields and purity.
  • the main object of the present invention is to provide an improved process for the preparation of elvitegravir.
  • Another object of the present invention is to provide novel intermediates of elvitegravir and process for preparation thereof.
  • the main aspect of the present invention provides an improved process for the preparation of elvitegravir, which involves the preparation of elvitegravir without isolating some of the intermediates.
  • the main aspect of the present invention provides preparation of elvitegravir (12), wherein 7- fluoro-1-(1 -(S)-I -hydroxymethyl-2-methylpropyl)-6-iodo-4-oxo-1 ,4-dihydroquinoline-3- carboxylic acid ethyl ester (6) is protected with suitable protecting agents and further reacted with 3-chloro-2-fluorobenzylzinc bromide (9) in the presence of tetrakis(triphenylphosphine)- palladium (0) catalyst in tetrahydofuran to get corresponding condensed products, which are subjected to hydrolysis, de-protection to get 6-(3-chloro-2-fluorobenzyl)-7-fluoro-1-((S)
  • the compound of formula (11) is optionally treated with amine to get amine addition salt of 6-(3- chloro-2-fluorobenzyl)-7-fluoro-1-((S)-1-hydroxymethyl-2-methylpropyl)-4-oxo-1, 4- dihydroquinoline-3-carboxylic acid, amine salt (11D), then setting free of amine salt in the presence of acid to get pure compound of formula (11).
  • the pure compound of formula (11) is reacted with sodium alkoxide to get pure elvitegravir (12).
  • Yet another aspect of the present invention provides a process disclosed herein involving one pot Negishi coupling of tetrahydropyranyl intermediates of 4-oxoquinolones with organozinc compounds in presence of zero valent homogenous catalyst tetrakis(triphenylphosphine)palladium (0) or bis(triphenylphosphine)palladium dichloride (II) catalyst.
  • Yet another aspect of the present invention provides novel intermediates of elvitegravir and processes for preparation thereof.
  • Yet another aspect of the present invention provides 6-(3-chloro-2-fluorobenzyl)-7-fluoro-1- ((S)-I -hydroxymethyl-2-methylpropyl)-4-oxo-1 , 4-dihydroquino-line-3-carboxylic acid dicyclohexyl amine salt (11A), an intermediate in the preparation of elvitegravir and process for its preparation.
  • Yet another aspect of the present invention provides 1 -(S)-I- [1-(tert- butyldimethylsilanyloxymethyl)-2-methylpropyl]-6-(3-chloro-2-fluoro benzyl)-7-fluoro-4-oxo-1 , 4-dihydroquinoline-3-carboxylic acid (11B) and process for its preparation thereof.
  • Yet another aspect of the present invention provides 6-(3-chloro-2-fluoro-benzyl)-7-fluoro-1- ⁇ -methyM-Ctetrahydro-pyran ⁇ -yloxymethyO-propylH-oxo-'M-dihydro-quinoline-S- carboxylic acid (11C) and process for its preparation thereof.
  • Yet another aspect of the present invention provides 1 -(S)-I- [1-(tert- butyldimethylsilanyloxymethyl)-2-methylpropyl]-6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo- 1 , 4-dihydroquinoline-3-carboxylic acid (12B) and process for its preparation thereof.
  • Yet another aspect of the present invention provides 6-(3-chloro-2-fluoro-benzyl)-7-methoxy- 1-[1-(S)-2-methyl-1-(tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo-1 ,4-dihydro-quinoline-3- carboxylic acid (12C) and process for its preparation thereof.
  • Yet another aspect of the present invention provides 1-[(2S)-1-( ⁇ 3-carboxy-6-(3-chloro-2- fluorobenzyl)-1 -[(2S)-1 -hydroxy-3-methylbutan-2-yl]-4-oxo-1 , 4-dihydroquinolin-7-yl ⁇ oxy)-3- methylbutan-2-yl-6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1 , 4-dihydroquinoline-3- carboxylic acid (elvitegravir dinner impurity, 13) and process for its preparation thereof.
  • FIG. 1 is a representative X-ray diffraction pattern of dicyclohexyl amine salt of formula 11 A.
  • FIG. 2 is a representative DSC thermogram of dicyclohexyl amine salt of formula 11 A.
  • FIG. 3 is a representative X-ray diffraction pattern of silyl intermediate of elvitegravir of formula 11 B.
  • FIG. 4 is a representative DSC thermogram of silyl intermediate of elvitegravir of formula 11B.
  • FIG. 5 is a representative X-ray diffraction pattern of silyl intermediate of elvitegravir of formula 11 C.
  • FIG. 6 is a representative X-ray diffraction pattern of silyl intermediate of elvitegravir of formula 12B.
  • FIG. 7 is a representative DSC thermogram of silyl intermediate of elvitegravir of formula 12B.
  • the X-ray powder diffraction data was collected on Bruker axs D8 ADVANCE powder diffractometer.
  • the Copper anode is used as radiation source with scintillation counter as detector.
  • the Differential scanning calorimetric (DSC) was recorded on Mettler Toledo DSC 822e. The experiment was performed at a heating rate of 10°C/min. over a temperature range of 50- 300°C purging with nitrogen at a flow rate of 50mL/min.
  • the present invention relates to improved process for the preparation of elvitegravir (12), wherein the compound of formula (6) is protected with suitable protecting agents and further reacted with formula (9) in the presence of tetrakis(triphenylphosphine)-palladium (0) catalyst in tetrahydofuran to get corresponding condensed products, which are subjected to hydrolysis, de-protection to get compound of formula (11).
  • the compound of formula (11) is optionally treated with amine to get amine addition salt of formula (11D), then setting free of amine salt in the presence of acid to get pure compound of formula (11).
  • the pure compound of formula (11) is reacted with sodium alkoxide to get pure elvitegravir (12).
  • the present invention provides a process for the preparation of elvitegravir (12) comprising the steps of: a) protecting the hydroxyl group of the compound of formula 6
  • the compound of formula 6 is dissolving in solvent and reacting with a suitable hydroxyl group protecting agent in the presence of base at 10-35 0 C for 2-3h to isolate 1-((S)-1-tert-butyldimethylsilyloxymethyl-2-methylpropyl)-7-fluoro-6-iodo- 4-OXO-1 ,4-dihydro-quinoline-3-carboxylic acid ethyl ester (7).
  • the suitable hydroxyl group protecting agent is selected from tert-butyldimethylsilyl chloride, methyl chloroformate or chloromethyl methyl ether.
  • the organic solvent used in protection is selected from chlorinated solvents such as dichloromethane or hydrocarbon solvent such as toluene, xylene or mixture thereof and the base is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium bicarbonate or imidazole
  • the compound of formula 7 is reacted with 3-chloro-2- fluoro-benzyl zinc bromide (9) in the presence of tetrakis(triphenyl-phosphine)palladium (0) catalyst in tetrahydrofuran 30-60 0 C for 4-8h to isolate 6-(3-chloro-2-fluoro-benzyl)-7-fluoro-1- [1-(S) tert-butyldimethylsilyloxymethyl-2-methylpropyl)-4-oxo-1 ,4-dihydro-quinoline-3- carboxylic acid ethyl ester (10).
  • the obtained compound of formula 10 is subjected to hydrolysis, de-protection in the presence of base in solvent at 10 0 C to reflux to isolate 6- (3-chloro-2-fluorobenzyl)-7-fluoro-1-((S)-1-hydroxymethyl-2-methylpropyl)-4-oxo-1 , 4- dihydro-quinoline-3-carboxylic acid (11).
  • the organic solvent used in hydrolysis, de-protection is selected from methanol, ethanol, isopropyl alcohol or butanol.
  • the base is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium bicarbonate or imidazole.
  • the compound of formula 11 is, optionally, treating with amine in solvent at ambient temperature to isolate an amine addition salt, compound formula of 11D in a crystalline form.
  • the solvent used for amine salt formation is selected from ethyl acetate, toluene, xylene or mixture thereof.
  • the amine is selected from cyclohexylamine or dicyclohexyl amine.
  • the compound of formula 11D is treating with acid at ambient temperature to isolate compound of formula 11 in the pure form.
  • the acid is selected from hydrochloric acid, sulfuric acid, acetic acid or formic acid
  • compound of formula 11 or 11 D is then treated with alkali methoxide in methanol and heated to reflux for 16-2Oh to introduce methoxy functionality to get elvitegravir (12).
  • the alkali methoxide is selected from sodium methoxide, potassium methoxide or lithium methoxide.
  • the present invention relates process for the preparation of 1- (S)-1 - [i-(tert-butyldimethylsilanyloxymethyl) 2-methylpropyl]-6-(3-chloro-2-fluorobenzyl)-7- methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (12B) as shown in the Scheme 3,
  • the elvitegravir is dissolving in an organic solvent and reacted with tert-butyldimethylsilyl chloride in presence of a base at room temperature for 3h to get compound of formula 12B.
  • the organic solvent used for dissolution is selected from chlorinated solvent such as dichloromethane.
  • the base is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium bicarbonate or imidazole.
  • the above obtained protected elvitegravir is further subjected to de-protection to get pure elvitegravir.
  • the present invention provides a process for the preparation of elvitegravir (12)
  • the compound of formula 6 is dissolved in solvent and reacted with 3,4-dihydro-2H-pyran in the presence of an acid at 10-35 0 C for 2-3h to isolate 7-fluoro-6-iodo-1 -[1 -(S)-2-methyl-1 -(tetrahydro-pyran-2-yloxymethyl)propyl]-4-oxo-1 ,4- dihydro-quinoline-3-carboxylic acid ethyl ester (7A).
  • the solvent used for protection reaction is selected from chlorinated solvents such as dichloromethane, dichloroethane or chlorobenzene or hydrocarbon solvent such as toluene, xylene or mixture thereof.
  • the acid is selected from hydrochloric acid, hydrochloric acid, sulfuric acid, acetic acid, formic acid, boron trifluoride etherate (BF 3 O(Et) 2 ) or p- tolue ⁇ esulfonic acid.
  • the compound of formula 7A is reacted with 3-chloro-2- fluoro-benzyl zinc bromide (9) in the presence of tetrakis(triphenyl-phosphine)palladium (0) catalyst in tetrahydrofuran at 30-60 0 C for 4-8h to isolate 6-(3-chloro-2-fluoro-benzyl)-7-fluoro- 1 -(S)-I - ⁇ -methyl-i- ⁇ etrahydro-pyran ⁇ -ylo'xymethylJ-propyll ⁇ -oxo-i ⁇ -dihydro-quinoline-S- carboxylic acid ethyl ester (10A).
  • the obtained compound of formula 10A is subjected to hydrolysis, de-protection in the presence of acid in solvent at 1O 0 C to reflux to give 6-(3- chloro-2-f luorobenzyl)-7-fluoro-1 -((S)-1 -hydroxymethyl-2-methylpropyl)-4-oxo-1 , 4-dihydro- quinoline-3-carboxylic acid (11).
  • the solvent used for hydrolysis, de-protection is selected from methanol, ethanol, isopropyl alcohol or butanol.
  • the acid is selected from hydrochloric acid, sulfuric acid, acetic acid or formic acid.
  • the compound of formula 11 is, optionally, treating with amine in solvent at ambient temperature to isolate an amine addition salt, compound formula of 11 D in a crystalline form.
  • the solvent used for amine salt formation is selected from ethyl acetate, toluene, xylene or mixture thereof.
  • the amine is selected from cyclohexylamine or dicyclohexyl amine.
  • the compound of formula 11D is treating with acid at ambient temperature to isolate compound of formula 11 in the pure form.
  • the acid is selected from hydrochloric acid, sulfuric acid, acetic acid or trifluoro acetic acid.
  • compound of formula 11 or 11D is treated with alkali methoxide in methanol to introduce methoxy group to give elvitegravir (12).
  • the alkali methoxide is selected from sodium methoxide, potassium methoxide or lithium methoxide.
  • the present invention provides a process for the preparation of elvitegravir (12)
  • compound of formula 10A is treated with alkali methoxide in methanol to introduce methoxy group followed by hydrolysis of ethyl ester to afford compound of formula 12C.
  • the alkali methoxide is selected from sodium methoxide, potassium methoxide or lithium methoxide.
  • compound of formula 12C is deprotected with an acid in solvent to afford compound of formula 12.
  • the acid is selected from hydrochloric acid, sulfuric acid, acetic acid, trifluoro acetic acid, boron trifluoride etherate (BF 3 O(Et) 2 ) or p- toluenesulfonic acid.
  • the present invention provides a process for the preparation of elvitegravir (12) comprising the steps of:
  • compound of formula 1OA is subjected to hydrolysis in the presence of base in solvent at 40-70 0 C for 2-8h to afford 6-(3-chloro-2-fluoro-benzyl)-7- fluoro-1 -[2-methyl-1 -(tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo-1 ,4-dihydro-quinoline-3- carboxylic acid (11C).
  • the base used for hydrolysis reaction is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide or potassium bicarbonate.
  • the solvent is selected from methanol, ethanol, isopropyl alcohol or butanol.
  • compound of formula 11C is treated with alkali methoxide in methanol to introduce methoxy group to afford 6-(3-chloro-2-fluoro-benzyl)-7- methoxy-1-[1-(S)-2-methyl-1-(tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo-1 ,4-dihydro- quinoline-3-carboxylic acid (12C).
  • the alkali methoxide is selected from sodium methoxide, potassium methoxide or lithium methoxide.
  • compound of formula 12C is treated with an acid in a solvent for deprotection to give elvitegravir (12).
  • the solvent used for deprotection reaction is selected from methanol, ethanol, isopropyl alcohol or butanol and the acid is selected from hydrochloric acid, sulfuric acid, acetic acid, trifluoro acetic acid, boron trifluoride etherate (BF 3 O(Et) 2 ) or p-toluenesulfonic acid.
  • the present invention provides a process for the preparation of elvitegravir (12) comprising the steps of:
  • compound of formula 1OA is subjected to hydrolysis in the presence with base in solvent at 40-70 0 C for 2-8h to afford 6-(3-chloro-2-fluoro-benzyl)-
  • the solvent used for hyrolysis reaction is selected from methanol, ethanol, isopropyl alcohol or butanol and base is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide or potassium bicarbonate.
  • base is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide or potassium bicarbonate.
  • the obtained compound of formula 11C is deprotected with an acid in solvent at 1O 0 C to reflux to get 6-(3-chloro-2-fluorobenzyl)-7-fluoro-1-((S)-1- hydroxymethyl-2-methylpropyl)-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid (11).
  • the organic solvent used for deprotection reaction is selected from methanol, ethanol, isopropyl alcohol or butanol and acid is selected from hydrochloric acid, sulfuric acid, acetic acid, trifluoro acetic acid, boron trifluoride etherate (BF 3 O(Et) 2 ) or p-toluenesulfonic acid.
  • compound of formula 11 is then treated with alkali methoxide in methanol to introduce methoxy group to give elvitegravir (12).
  • the alkali methoxide is selected from sodium methoxide, potassium methoxide or lithium methoxide.
  • the present invention encompasses process for the preparation of 6-(3-chloro-2-fluorobenzyl)-1-[(S)-1-hydroxymethyl-2-methylpropyl]-7-methoxy-4-oxo-1, 4- dihydroquinoline-3-carboxylic acid sodium (elvitegravir sodium), a compound of the formula 12A, as shown in the Scheme 1 ,
  • elvitegravir is dissolved in methanol and treated with source of sodium ion is selected from sodium hydroxide, sodium bicarbonate, sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium butoxide or sodium tertiary butoxide
  • source of sodium ion is selected from sodium hydroxide, sodium bicarbonate, sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium butoxide or sodium tertiary butoxide
  • elvitegravir sodium is further converting to elvitegravir by conventional method to get pure elvitegravir.
  • the present invention provides processes for the preparation of elvitegravir as depicted in the following schemes below (Scheme 2 and 3).
  • X is halo, preferably fluoro and R denotes both straight & branched groups.
  • 6-(3-chloro-2-fluoro-benzyl)- 7-fluoro-1-[1-(S)-2-methyl-1-(tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo-1 ,4-dihydro- quinoline-3-carboxylic acid ethyl ester is represented by compound of formula 1OA.
  • the present invention relates to 6-(3-chloro-2-fluorobenzyl)-7- fluoro-1-((S)-1-hydroxymethyl-2-methylpropyl)-4-oxo-1 , 4-dihydroquino-line-3-carboxylic acid dicyclohexyl amine salt, a novel intermediate of elvitegravir, represented by compound of formula 11 A.
  • the present invention relates to crystallization of compound of formula 11 A, using solvents such as ethyl acetate, dimethyl formamide, dichloromethane, acetonitrile, acetone, methanol, ethanol and isopropanol.
  • solvents such as ethyl acetate, dimethyl formamide, dichloromethane, acetonitrile, acetone, methanol, ethanol and isopropanol.
  • the present invention provides crystalline 6-(3-chloro-2- fluorobenzyl)-7-fluoro-1 -((S)-1 -hydroxymethyl-2-methylpropyl)-4-oxo-1 ,4-dihydroquinoline-3- carboxylic acid dicyclohexyl amine salt (11A) characterized by an X-ray diffraction pattern having three or more peaks at 2 ⁇ values selected from 7.43, 14.97, 15.85, 17.08, 22.91 ,24.08, ⁇ 0.2 degrees 2-Theta, is shown in FIG. 1.
  • the present invention provides crystalline 6-(3-chloro-2- fluorobenzyl)-7-fluoro-1 -((S)-1 -hydroxymethyl-2-methylpropyl)-4-oxo-1 ,4-dihydroquinoline-3- carboxylic acid dicyclohexyl amine salt (11A) is further characterized by a Differential Scanning Calorimetry (DSC) thermogram having onset 181.08°C, Peak 183.60 ⁇ 2 0 C and End set 186.61°C. The typical DSC thermogram is shown in figure FIG. 2.
  • DSC Differential Scanning Calorimetry
  • the present invention relates to 1-(S)-1- [1-(tert- butyldimethylsilanyloxymethyl)-2-methylpropyl]-6-(3-chloro-2-fluoro benzyl)-7-fluoro-4-oxo-1 , 4-dihydroquinoline-3-carboxylic acid (11B), a novel intermediate of elvitegravir.
  • the silyl protected intermediate of compound of 11B have the X- ray powder diffraction pattern with characteristic peaks at 9.15, 10.54, 13.37, 14.47, 18.38, 18.70, 19.24, 20.86, 21.23 ⁇ 0.2 degrees 2-Theta, shown in FIG. 3.
  • compound of 11B is further characterized by a Differential Scanning Calorimetry (DSC) thermogram having onset 137.72°C, Peak 140.62 ⁇ 2 0 C and End set 142.41 °C. The typical DSC thermogram is shown in figure FIG. 4.
  • DSC Differential Scanning Calorimetry
  • the present invention relates to 6-(3-chloro-2-fluoro-benzyl)-7- fluoro-1 -[1 -(S)-2-methyl-1 -(tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo-1 , 4-dihydro- quinoline-3-carboxylic acid, represented by compound of formula 11C novel intermediate of elvitegravir.
  • the present invention relates to crystallization of 6-(3-chloro-2- fluoro-benzyl)-7-fluoro-1-[2-methyl-1-(tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo-1 ,4- dihydro-quinoline-3-carboxylic acid (11C), using solvents such as ethyl acetate, dichloromethane, acetonitrile.
  • the crystalline form of 6-(3-chloro-2-fluoro-benzyl)-7-fluoro-1-[2- methyl-i- ⁇ etrahydro-pyran ⁇ -yloxymethyO-propylJ ⁇ -oxo-i ⁇ -dihydro-quinoline-S-carboxylic acid (11C), prepared according to the present invention have the X-ray powder diffraction pattern with characteristic peaks at 3.84, 7.67, 8.12, 11.98, 12.42, 15.37, 18.1 , 19.13, 19.75, 20.54, 21.10, 23.66 & 24.47 ⁇ 0.2 degrees 2-Theta, shown in FIG.5.
  • the present invention relates to 1-(S)-1- [1-(tert- butyldimethyl silanyloxymethyl) 2-methylpropyl]-6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1 , A- dihydroquinoline-3-carboxylic acid, a novel intermediate of elvitegravir, represented by the compound of formula 12B
  • the present invention provides crystalline 1 -(S)-I- [1- (tertbutyldimethylsilanyloxymethyl)-2-methylpropyl]-6-(3-chloro-2-fluorobenzyl)-7-methoxy-4- oxo-1 , 4-dihydroquinoline-3-carboxylic acid (12B) characterized by an X-ray diffraction pattern having three or more peaks at 2 ⁇ values selected from 9.99, 11.19, 16.37, 17.16, 17.94,18.63,19.81 , 20.48, 21.10, 26.26, 27.87 ⁇ 0.2 degrees 2-Theta, is shown in FIG. 6.
  • the present invention provides crystalline 1 -(S)-I- [1- (tertbutyldimethylsilanyloxymethyl)-2-methylpropyl]-6-(3-chloro-2-fluorobenzyl)-7-methoxy-4- oxo-1, 4-dihydroquinoline-3-carboxylic acid (12B) is further characterized by a Differential Scanning Calorimetry (DSC) thermogram having onset 144.29°C, Peak 146.40 ⁇ 2°C and End set 148.36 0 C. The typical DSC thermogram is shown in FIG.7.
  • DSC Differential Scanning Calorimetry
  • the present invention relates to 6-(3-chloro-2-fluoro-benzyl)-7- methoxy-1-[2-methyl-1-(tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo-1 ,4-dihydro-quinoline- 3-carboxylic acid, represented by compound of formula 12C a novel intermediate of elvitegravir.
  • elvitegravir having the dimmer impurity of formula 13 is less than 0.1% and HPLC purity is more than 99%, which is obtained by recrystallizing from a mixture of ethyl acetate - hexane to give pure elvitegravir of formula 12.
  • the situ reactions followed in the present process save the time as well the increase the purity of the final compound.
  • the elvitegravir prepared according to present invention containing dimmer impurity of formula 13 is less than 0.1% and HPLC purity more than 99%.
  • the present invention relates to a process for the preparation of L-valinol by reacting L-valine with sodium borohydride and sulfuric acid followed by isolation using isopropyl alcohol.
  • Example-1 is provided for illustrative purposes only and are not intended to limit the scope of the in any way.
  • the wet cake was suspended in purified water (500 mL) at 25 to 35°C and the pH of the reaction was adjusted to 3.0 to 3.5 with ammonia solution and stirred for an hour.
  • the product was collected by filtered and washed with purified water (100 mL).
  • the wet cake (250 g) was dissolved in 50% aqueous methanol (500 mL) at 70 to 8O 0 C and stirred for the dissolution for 30 min.
  • the reaction mass was cooled to 25 to 35°C in 2 h., further cooled to 15 to 20°C and maintained for an hour.
  • the separated solid was filtered, washed with purified water (50 mL) and dried at 50 to 55°C for 10 to 12 h. to afford 2,4-difluoro-5-iodobenzoic acid (2, 155 g, HPLC Purity: 99.1%).
  • Step 1 2, 4-Difluoro-5-iodobenzoic acid (2, 100 g) was dissolved in toluene (200 mL) and thionyl chloride (50 mL) and dimethylformamide (3 mL) were added respectively under nitrogen atmosphere. The mixture was heated to 85 to 90 0 C and maintained for 2 to 3 h. The reaction mixture was cooled to below 50 0 C and concentrated under reduced pressure. The resultant residue was dissolved in toluene (50 mL) and concentrated under reduced pressure to remove traces of thionyl chloride and repeated the same. The resultant 2, 4- difluoro-5-iodobenzoyl chloride (3) residue was dissolved in toluene (100 mL).
  • Step 2 The solution obtained in step 1 was added to a solution of ethyl 3,3- dimethylaminoacrylate (56 g) and diisopropylethyl amine (56 g) in toluene (100 mL) over a period of 30 min., raised the temperature of the reaction mass to 90 to 95°C and maintained for 4 h. to form 2-(2,4-difluoro-5-iodobenzoyl)-3-dimethylamino acrylic acid ethyl ester (4).
  • Step 3 (S)-(+)-Valinol (40 g) was added to the cooled solution of step 2 and stirred at room temperature for one and half hour. Toluene (400 mL) and purified water (200 mL) were added to the reaction mixture and the mixture was partitioned. The aqueous layer was extracted with toluene (50 ml). The combined organic layer was washed twice with water (2
  • Step 4 The crude product obtained in step 3 was dissolved in ⁇ /, ⁇ /-dimethylformamide (250 mL) and potassium carbonate (150 g) was added. The mixture was stirred at room temperature for 24 to 30 h. The reaction mixture was added to ice water (1.4 L) and the mixture was stirred for 45 min. The precipitate was collected by filtration and washed with water (200 ml_). The wet cake was suspended into water (500 mL) and stirred for an hour. The precipitate was collected by filtration, washed with water (100 mL) and vacuum-dried till MC become not more than 2.0%.
  • the obtained compound (145 g) was treated with methanol (200 mL) at 45 to 50 0 C and maintained the slurry for 30 min.
  • the reaction mixture was cooled to ambient temperature and maintained for 1 h.
  • the precipitated solid was collected by filtration, washed with methanol (25 mL) and dried at 45 to 50°C for 6 to 8 h. to afford 7-fluoro-1-(1 -(S)-I -hydroxymethyl-2-methylpropyl)-6-iodo-4-oxo-1,4-dihydroquinoline- 3- carboxylic acid ethyl ester (6, 125 g, purity by HPLC 98. 0%).
  • Hexane (100 mL) was added to the obtained residue and distilled under reduced pressure.
  • the separated compound was filtered, washed with chilled hexane (100 mL) and dried at 40 to 45°C for 8 h.
  • reaction mass was cooled to ambient temperature after distilling tetrahydrofuran (-300 mL) from the reaction mass under reduced pressure.
  • the reaction mass poured into 25% ammonium chloride (500 mL) solution, toluene (500 mL) was added and stirred for 45 min.
  • the layers were separated and the organic layer was washed with 25% ammonium chloride (2 X 500 mL) solution, 3.5 % sodium bicarbonate (2 X 500 mL) solution and saturated sodium chloride (100 & 50 mL) respectively.
  • Step 1 The compound of formula 6 (100 g) was dissolved in dichloromethane (500 mL) and added with imidazole (30 g), tert-butyl dimethylsilyl chloride (50 g) and stirred for 2 to 3 h. The reaction mixture was twice washed with water (2 X 100 mL). The dichloromethane layer was concentrated under atmospheric pressure, finally, under reduced pressure.
  • Step 2 Under nitrogen stream, zinc powder (33 g) was suspended in tetrahydrofuran (105 mL), and iodine (0.1 g) and trimethylsilyl chloride (8.88 mL, 70.00 mmol) were added and raised the temperature to 65°C. The mixture was stirred with heating for 30 min and cooled to 30 0 C. A solution of 3-chloro-2-fluorobenzyl bromide (8, 95 g) in tetrahydrofuran (210 mL) was added dropwise at 30°C and, during addition, the temperature of the reaction has been increase to 60 0 C. The reaction mass was cooled to 30°C in 2 h.
  • Step 3 To the step 2 solution, 3.0 g of tetrakis(triphenylphosphine)palladium (0) catalyst was added under nitrogen atmosphere followed by step 1 solution. The temperature of the reaction was raised to 40 0 C and maintained for 6 h. The reaction mass was cooled to ambient temperature after distilling tetrahydrofuran ( ⁇ 300 mL) from the reaction mass under reduced pressure. The reaction mass poured into 25% ammonium chloride (500 mL) solution, toluene (500 ml) was added and stirred for 45 min.
  • the layers were separated and the organic layer was washed with 25% ammonium chloride (2 X 500 mL) solution, 3.5 % sodium bicarbonate (2 X 500 mL) solution and saturated sodium chloride (100 & 50 mL).
  • the organic layer was concentrated; isopropanol (20 mL) was added again and concentrated. Isopropanol (130 mL) was added to the obtained residue to get a solution of compound of 10 and it's in process purity is around 70 to 80%.
  • Step 4 4N Sodium hydroxide (125 mL) solution was added to the step 3 reaction mass, and raised the temperature to 55°C and maintained for 4 to 6 h.
  • the reaction mass was cooled to ambient temperature, filtered through hyflow bed and washed with 50% aqueous isopropyl alcohol (26 mL).
  • the reaction mass further cooled to 10 to 15°C and adjusted the pH to 3 to 3.5 with 50% aqueous HCI (-110 mL).
  • Ethyl acetate (375 mL) was added and stirred for 30 min. The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was washed with 10% sodium chloride (200 mL) solution.
  • the 6-(3-chloro-2-f luoro-benzyl)-7-fluoro-1 -[2-methyl-1 -(tetrahydro-pyran-2-yloxy methyl)- propyl]-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (10) was added to a pre- cooled (20 to 25°C) mixture of concentrated hydrochloric acid (50 g) and methanol (5000 mL). The resultant mixture was heated under reflux for 16 to 20 h. The reaction mass concentrated and cooled. Water (1000 mL) and ethyl acetate (450 mL) were added to the obtained residue under stirring.
  • Step 1 The compound of formula 6 (100 g) was dissolved in dichloromethane (500 mL) and added imidazole (30 g) and tert-butyl dimethylsilyl chloride (50 g) and stirred 2 to 3 h. The reaction mixture was twice washed with water (2 X 100 mL). The dichloromethane layer was concentrated under reduced pressure. Hexane (100 mL) was added to the obtained residue and distilled under reduced pressure. The residue seeded with compound of formula 7 (1 g), stirred for 6 to 8 h. at 0 to 5°C. Hexane (500 mL) was added to the reaction mass and continued the stirring at the same temperature for 12 h.
  • Step 2 Under nitrogen stream, zinc powder (33 g) was suspended in tetrahydrofuran (105 mL), iodine (0.1 g) and trimethylsilyl chloride (8.88 mL, 70.00 mmol) were added and raised the temperature to 65°C. The mixture was stirred with heating for 30 min. and cooled to
  • Step 3 To the solution obtained in step 2, 3.0 g of tetrakis(triphenylphosphine)palladium (0) catalyst was added under nitrogen atmosphere followed by addition of solution obtained in step 1. The temperature of the reaction mass was raised to 40 0 C and maintained for 6 h. The reaction mass was cooled to ambient temperature after distilling tetrahydrofuran ( ⁇ 300 mL) from the reaction mass under reduced pressure. The resultant solution was poured into 25% ammonium chloride solution (500 mL) and added toluene (500 mL) and stirred for 45 min.
  • the layers were separated and the organic layer was washed with 25% ammonium chloride (2 X 500 mL) solution, 3.5 % sodium bicarbonate (2 X 500 mL) solution and saturated sodium chloride (100 & 50 mL) solution.
  • the organic layer was concentrated, isopropanol (20 mL) was added to the obtained residue and concentrated completely, lsopropanol (130 mL) was added to dissolve the resultant residue and it's in process purity of around 70 to 80%.
  • Step 4 4N Sodium hydroxide (125 mL) solution was added to the compound obtained in the step 3 and raised the temperature to 55°C and maintained for 4 to 6 h.
  • the reaction mass was cooled to ambient temperature, filtered through hyflow bed and washed with 50% aqueous isopropylalcohol (26 mL).
  • the reaction mass was further cooled to 10 to 15°C and adjusted the pH to 3 to 3.5 with 50% aqueous HCI (-110 mL).
  • Ethyl acetate (375 mL) was added to the reaction mixture and stirred for 30 min. The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL).
  • the compound of formula 11 (100 g) was dissolved in dichloromethane (500 mL) and added imidazole (30 g, 0.436 mmol) and tert-butyldimethylsilyl chloride (50 g) and the mixture was stirred at room temperature for 3 h.
  • Water (100 mL) was added to the reaction mixture under stirring and separated the layers after 30 min.
  • Organic layer was washed with water (100 mL) and concentrated under reduced pressure.
  • Hexane (100 mL) was added to the obtained residue and concentrated under reduced pressure to remove the traces of dichloromethane.
  • Hexane (200 mL) was added to the obtained residue and stirred for 10 to 12 h.
  • reaction mass was cooled to ambient temperature after distilling tetrahydrofuran ( ⁇ 300 mL) from the reaction mass under reduced pressure.
  • the reaction mass poured into 25% ammonium chloride (500 mL) solution, toluene (500 mL) was added and stirred for 45 min.
  • the layers were separated and the organic layer was washed with 25% ammonium chloride (2 X 500 mL) solution, 3.5 % sodium bicarbonate (2 X 500 mL) solution and saturated sodium chloride (100 & 50 mL) respectively.
  • the organic layer was concentrated; isopropanol (20 mL) was added and concentrated to remove the toluene traces.
  • Isopropanol 130 mL was added to the obtained residue and it's in process purity is around 70 to 80%.
  • 4N Sodium hydroxide (125 mL) solution was added the IPA solution, raised the temperature to 55°C and maintained for 4 to 6 h.
  • the reaction mass was cooled to ambient temperature, filtered through hyflow bed and washed the bed with 50% aqueous isopropyl alcohol (26 mL).
  • the filtrate cooled to 10 to 15°C and adjusted the pH to 8 to 8.5 with 50% aqueous HCI (-110 mL).
  • Ethyl acetate 375 mL was added under stirring and maintained for 30 min.
  • Step 1 Sodium methoxide (124 g) and purified water (5 mL) were added to methanol (1000 mL) under nitrogen atmosphere. The resultant mass was cooled to 20 to 25°C and compound of formula 11 was added. The resultant mixture was heated under reflux for 16 to 20 hours. Methanol (350 to 400 mL) was distilled out thefrom the reaction mass and cooled. To the reaction mass was added a mixture of water (1000 mL) and toluene (1000 mL) under stirring. The sodium salt of elvitegravir separated was filtered after 30 min at 10-15 0 C and washed with chilled purified water (12A, 100 mL).
  • Step 2 The wet cake obtained in stepi of example 10, was suspended into water (500 mL) and adjusted the pH to 8 to 8.5 with 50% aqueous HCI at 10 to 15°C. Ethyl acetate (450 mL) was added to the reaction mass and further the pH was adjusted to 3 to 3.5 with 50% aqueous HCI. The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was washed with water (250 mL). BW 280
  • Step 3 The residue product obtained in step 2 of example 10, was dissolved in ethyl acetate (200 mL) by heating under reflux, hexane (100 mL) was added at 60 to 65°C over a period of 30 min. and maintained for an hour. The reaction mass was cooled to 25 to 30 0 C over a period of 2 to 3 h. and maintained for 30 min. The precipitated solid was collected by filtration, washed with a mixture of ethyl acetate and hexane (1 :1 , 25 mL).
  • Step 4 The obtained crude product in. step 3 of example 10, was dissolved in ethyl acetate (150 mL) by heating under reflux.
  • Hexane (75 mL) was added at a temperature of about 60 to 75°C over a period of 30 min and maintained for an hour.
  • the reaction mass cooled to 25 to 3O 0 C over a period of 2 to 3 h. and maintained for 30 min.
  • the obtained residue was dissolved in ethyl acetate (200 mL) by heating under reflux; hexane (100 ml) was added at 60 to 65°C over a period of 30 min. and maintained for an hour.
  • the reaction mass was cooled to 25 to 30 0 C over a period of 2 to 3 h. and maintained for 30 min.
  • the precipitated solid was collected by filtration, washed with a mixed solvent of ethyl acetate and hexane (1:1 , 25 mL).
  • the obtained crude product was dissolved in ethyl acetate (150 ml) by heating under reflux.
  • Hexane (75 mL) was added at a temperature of about 60 to 75°C over a period of 30 min and maintained for an hour.
  • the reaction mass cooled to 25 to 30 0 C over a period of 2 to 3 h. and maintained for 30 min.
  • the precipitated solid was collected by filtration, washed with a mixed solvent of ethyl acetate and hexane (1 :1, 25 mL) and dried at 50-55°C to get pure 6-(3-chloro-2- fluorobenzyl)-1-[(S)-1-hydroxymethyl-2-methylpropyl]-7-methoxy-4-oxo-1 ,4-dihydroquinoline- 3-carboxylic acid(12) as white solid ( 60 g) with HPLC Purity 99.35.
  • the obtained residue was dissolved in ethyl acetate (200 mL) by heating under reflux; hexane (100 mL) was added at 60 to 65°C over a period of 30 min. and maintained for an hour.
  • the reaction mass was cooled to 25 to 30°C over a period of 2 to 3 h. and maintained for 30 min.
  • the precipitated crude solid was collected by filtration, washed with a mixed solvent of ethyl acetate and hexane (1 :1, 25 ml).
  • the obtained crude product was dissolved in ethyl acetate (150 mL) by heating under reflux and hexane (75 mL) at a temperature of about 60 to 75°C over a period of 30 min.
  • the obtained residue was dissolved in ethyl acetate (100 mL) by heating under reflux; hexane (50 mL) was added at 60 to 65°C over a period of 30 min. and maintained for an hour.
  • the reaction mass was cooled to 25 to 30°C over a period of 2 to 3 h. and maintained for 30 min.
  • the precipitated crude solid was collected by filtration, washed with a mixed solvent of ethyl acetate and hexane (1 :1 , 12.5 mL).
  • the obtained crude product was dissolved in ethyl acetate (75 mL) by heating under reflux.
  • Hexane (37 mL) was added at a temperature of about 60 to 75°C over a period of 30 min and maintained for an hour.
  • the reaction mass cooled to 25 to 30°C over a period of 2 to 3 h. and maintained for 30 min.
  • the obtained residue was dissolved in methanol (500 mL) and pTSA (10 g). The resultant mixture was heated for 35-40°C and maintain for 6-8 h. The methanol was distilled out from the reaction mass and cooled. To the reaction mass, a mixture of water (500 mL) and ethyl acetate (500 mL) was added. The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with water (250 mL). BW 280 Carbon (5 g) was added to the reaction mixture.
  • the mixture was stirred at room temperature for 30 minutes, filtered through hyflow bed, washed thoroughly with ethyl acetate (50 mL) and the mixture was concentrated under reduced pressure.
  • the residue product obtained was dissolved in ethyl acetate (200 mL) by heating under reflux; hexane (100 mL) was added at 60 to 65°C over a period of 30 min. and maintained for an hour.
  • the reaction mass was cooled to 25 to 3O 0 C over a period of 2 to 3 hours and maintained for 30 min.
  • the precipitated crude solid was collected by filtration, washed with a mixed solvent of ethyl acetate and hexane (1 :1 , 25 mL).
  • the obtained crude product was dissolved in ethyl acetate (150 mL) by heating under reflux. Added hexane (75 mL) at a temperature of about 60 to 75°C over a period of 30 min and maintained for an hour. The reaction mass cooled to 25 to 30°C over a period of 2 to 3 hours and maintained for 30 min.
  • 6-(3-Chloro-2-fluorobenzyl)-1-[(S)-1-hydroxymethyl-2-methylpropyl]-7-fluoro-4-oxo- i ⁇ dihydroquinoline-S-carboxylic acid (11 , 100 g, 0.229 moles) was dissolved in methanol (500 ml_). Sodium methoxide (54 g, 2.29 moles) and water (5 mL) were added and the mixture was heated under reflux for 20 h. The reaction mixture was allowed to cool to room temperature and filtered through celite. The filtered reaction mixture was concentrated to half of the volume and diluted by adding one liter of water and one liter of toluene.
  • the compound of formula 12 (100 g) was dissolved in dichloromethane (500 mL) and added imidazole (30 g, 0.436 mmol) and tert-butyldimethylsilyl chloride (50 g) and the mixture was stirred at room temperature for 3 h. Water (100 mL) was added to the reaction mixture under stirring and separated the layers after 30 min. Organic layer was washed with water (100 mL) and concentrated under reduced pressure. Methyl t-butyl ether (100 mL) was added to the obtained residue and concentrated under reduced pressure to remove the traces of dichloromethane.
  • Example 14 Isolation of 1-[(2S)-1-( ⁇ 3-carboxy-6-(3-chloro-2-fluorobenzyl)-1 -[(2S)-I- hydroxy-3-methylbutan-2-yl]-4-oxo-1 , 4-dihydroquinolin-7-yl ⁇ oxy)-3- methylbutan-2-yl 6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1 , 4-dihydroquinoline-3-carboxylic acid (elvitegravir dimer impurity, 13)
  • Example 15 Preparation of L-valinol Sodium borohydride (79 g) was suspended in tetrahydrofuran (662 mL) and L-valine (100 g, 0.85 mol) was added and stirred the mixture for 15 min. and cooled to 0 0 C. A pre-cooled solution of sulfuric acid (105 mL) in tetrahydrofuran (76 mL) was added to the reaction mass at 0 to 5 0 C over a period of 3 to 5 h. and stirred at ambient temperature for 18 h. The reaction mixture was concentrated under reduced pressure to remain about 400 mL of solvent. The resultant residue was cooled to ambient temperature and quenched with methanol (66 mL).
  • reaction mass was heated to 50 0 C and sodium hydroxide (12.5N, 260 mL) solution was added to the reaction mass at the same temperature.
  • the reaction mixture was concentrated under reduced pressure till temperature of the reaction mass reached 100 to 105°C.
  • the reaction mass was cooled to 40 0 C and charged isopropanol (330 mL) under stirring.
  • the slurry was filtered and wet mass was treated twice with isopropanol (2 X 200 mL) at 80°C for 30 min and filtered.
  • the combined isopropanol layer was concentrated under atmospheric pressure till reaction mass temperature reached to 100 to 105°C.

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Abstract

The present invention relates to improved process for the preparation of elvitegravir (12), wherein the compound of formula (6) is protected with suitable protecting agents and further reacted with formula (9) in the presence of tetrakis(triphenylphosphine)-palladium (0) catalyst in tetrahydofuran to get corresponding condensed products, which are subjected to hydrolysis, de-protection to get compound of formula (11). The compound of formula (11) is optionally treated with amine to get amine addition salt of formula (11D), then setting free of amine salt in the presence of acid to get pure compound of formula (11). The pure compound of formula (11) is reacted with sodium alkoxide to get pure elvitegravir (12).

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF ELVITEGRAVIR
This patent application claims priorities from Indian patent applications 1435/CHE/2009 dated Jun 18, 2009 and 2558/CHE/2009 dated Oct 23, 2009, the contents of which are incorporated by reference in their entirety.
Field of the Invention
The present invention relates to an improved process for the preparation of Elvitegravir. The present invention includes novel intermediates for the preparation of Elvitegravir.
Background of the Invention
Elvitegravir, also known as GS 9137 or JTK 303, is an investigational new drug and a novel oral integrase inhibitor that is being evaluated for the treatment of HIV-1 infection. After HIVs genetic material is deposited inside a cell, its RNA must be converted (reverse transcribed) into DNA. A viral enzyme called integrase then helps to hide HIVs DNA inside the cell's DNA. Once this happens, the cell can begin producing genetic material for new viruses. Integrase inhibitors, such as elvitegravir, are designed to block the activity of the integrase enzyme and to prevent HIV DNA from entering healthy cell DNA. Elvitegravir has the chemical name: 6-(3-chloro-2-fluorobenzyl)-1-[(S)-1 -hydroxy -methyl-2- methylpropyl]-7-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid and has the following structural formula:
Figure imgf000002_0001
WO 2000040561 , WO 2000040563 and WO 2001098275 disclose 4-oxo-1 , 4-dihydro-3- quinoline which is useful as antiviral agents. WO2004046115 provides certain 4- oxoquinoline compounds that are useful as HIV Integrase inhibitors.
US 7176220 patent discloses elvitegravir, solvate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof or pharmaceutical composition containing them and their method of treatment. The chemistry involved in the above said patent is depicted below in the Scheme A. Scheme-A
Toluene, DIPEA
SOCl2 ,COCl (S)-(+)-Valinol
Toluene
Figure imgf000003_0001
,4-Difluoro-5-iodo- benzoic acid
Figure imgf000003_0003
Figure imgf000003_0002
THF
dichlorobis(triphenylphosphine)
palladium argon stream,
Figure imgf000003_0004
Elvitegravir Form ] Elvitegravir (residue) US 7635704 patent discloses certain specific crystalline forms of elvitegravir. The specific crystalline forms are reported to have superior physical and chemical stability compared to other physical forms of the compound. Further, process for the preparation of elvitegravir also disclosed and is depicted below in the Scheme B. The given processes involve the isolation of the intermediates at almost all the stages.
Scheme B
2,
-
Figure imgf000004_0001
Zn THF,
CK Br THF CU "ZnBr dιchlorobis(trιphenylphos
phine)palladium
Figure imgf000004_0002
Elvitegravir WO 2007102499 discloses a compound which is useful as an intermediate for the synthesis of an anti-HIV agent having an integrase-inhibiting activity; a process for production of the compound; and a process for production of an anti-HIV agent using the intermediate.
WO 2009036161 also discloses synthetic processes and synthetic intermediates that can be used to prepare 4-oxoquinolone compounds having useful integrase inhibiting properties.
The said processes are tedious in making and the purity of the final compound is affected because of the number of steps, their isolation, purification etc., thus, there is a need for new synthetic methods for producing elvitegravir which process is cost effective, easy to practice, increase the yield and purity of the final compound, or that eliminate the use of toxic or costly reagents.
The present invention relates to process for the preparation of elvitegravir without isolating some of the intermediates. Thus the present invention provides a time saving process for the preparation of elvitegravir without compromising the yields and purity.
Object of the Invention
The main object of the present invention is to provide an improved process for the preparation of elvitegravir.
Another object of the present invention is to provide novel intermediates of elvitegravir and process for preparation thereof.
Summary of the Invention
The main aspect of the present invention provides an improved process for the preparation of elvitegravir, which involves the preparation of elvitegravir without isolating some of the intermediates. The main aspect of the present invention provides preparation of elvitegravir (12), wherein 7- fluoro-1-(1 -(S)-I -hydroxymethyl-2-methylpropyl)-6-iodo-4-oxo-1 ,4-dihydroquinoline-3- carboxylic acid ethyl ester (6) is protected with suitable protecting agents and further reacted with 3-chloro-2-fluorobenzylzinc bromide (9) in the presence of tetrakis(triphenylphosphine)- palladium (0) catalyst in tetrahydofuran to get corresponding condensed products, which are subjected to hydrolysis, de-protection to get 6-(3-chloro-2-fluorobenzyl)-7-fluoro-1-((S)-1- hydroxymethyl-2-methylpropy- l)-4-oxo-1 , 4-dihydroquinoline-3-carboxylic acid (11). The compound of formula (11) is optionally treated with amine to get amine addition salt of 6-(3- chloro-2-fluorobenzyl)-7-fluoro-1-((S)-1-hydroxymethyl-2-methylpropyl)-4-oxo-1, 4- dihydroquinoline-3-carboxylic acid, amine salt (11D), then setting free of amine salt in the presence of acid to get pure compound of formula (11). The pure compound of formula (11) is reacted with sodium alkoxide to get pure elvitegravir (12).
Yet another aspect of the present invention provides a process disclosed herein involving one pot Negishi coupling of tetrahydropyranyl intermediates of 4-oxoquinolones with organozinc compounds in presence of zero valent homogenous catalyst tetrakis(triphenylphosphine)palladium (0) or bis(triphenylphosphine)palladium dichloride (II) catalyst.
Yet another aspect of the present invention provides novel intermediates of elvitegravir and processes for preparation thereof. Yet another aspect of the present invention provides 6-(3-chloro-2-fluorobenzyl)-7-fluoro-1- ((S)-I -hydroxymethyl-2-methylpropyl)-4-oxo-1 , 4-dihydroquino-line-3-carboxylic acid dicyclohexyl amine salt (11A), an intermediate in the preparation of elvitegravir and process for its preparation.
Figure imgf000006_0001
HA
Yet another aspect of the present invention provides 1 -(S)-I- [1-(tert- butyldimethylsilanyloxymethyl)-2-methylpropyl]-6-(3-chloro-2-fluoro benzyl)-7-fluoro-4-oxo-1 , 4-dihydroquinoline-3-carboxylic acid (11B) and process for its preparation thereof.
Figure imgf000007_0001
HB
Yet another aspect of the present invention provides 6-(3-chloro-2-fluoro-benzyl)-7-fluoro-1- β-methyM-Ctetrahydro-pyran^-yloxymethyO-propylH-oxo-'M-dihydro-quinoline-S- carboxylic acid (11C) and process for its preparation thereof.
Figure imgf000007_0002
HC
Yet another aspect of the present invention provides 1 -(S)-I- [1-(tert- butyldimethylsilanyloxymethyl)-2-methylpropyl]-6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo- 1 , 4-dihydroquinoline-3-carboxylic acid (12B) and process for its preparation thereof.
Figure imgf000007_0003
12B
Yet another aspect of the present invention provides 6-(3-chloro-2-fluoro-benzyl)-7-methoxy- 1-[1-(S)-2-methyl-1-(tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo-1 ,4-dihydro-quinoline-3- carboxylic acid (12C) and process for its preparation thereof.
Figure imgf000007_0004
Yet another aspect of the present invention provides 1-[(2S)-1-({3-carboxy-6-(3-chloro-2- fluorobenzyl)-1 -[(2S)-1 -hydroxy-3-methylbutan-2-yl]-4-oxo-1 , 4-dihydroquinolin-7-yl}oxy)-3- methylbutan-2-yl-6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1 , 4-dihydroquinoline-3- carboxylic acid (elvitegravir dinner impurity, 13) and process for its preparation thereof.
Figure imgf000008_0001
Brief description of the figures
FIG. 1 is a representative X-ray diffraction pattern of dicyclohexyl amine salt of formula 11 A. FIG. 2 is a representative DSC thermogram of dicyclohexyl amine salt of formula 11 A.
FIG. 3 is a representative X-ray diffraction pattern of silyl intermediate of elvitegravir of formula 11 B. FIG. 4 is a representative DSC thermogram of silyl intermediate of elvitegravir of formula 11B.
FIG. 5 is a representative X-ray diffraction pattern of silyl intermediate of elvitegravir of formula 11 C.
FIG. 6 is a representative X-ray diffraction pattern of silyl intermediate of elvitegravir of formula 12B.
FIG. 7 is a representative DSC thermogram of silyl intermediate of elvitegravir of formula 12B.
The X-ray powder diffraction data was collected on Bruker axs D8 ADVANCE powder diffractometer. The Copper anode is used as radiation source with scintillation counter as detector. The Differential scanning calorimetric (DSC) was recorded on Mettler Toledo DSC 822e. The experiment was performed at a heating rate of 10°C/min. over a temperature range of 50- 300°C purging with nitrogen at a flow rate of 50mL/min. Detailed Description of the Invention
The present invention relates to improved process for the preparation of elvitegravir (12), wherein the compound of formula (6) is protected with suitable protecting agents and further reacted with formula (9) in the presence of tetrakis(triphenylphosphine)-palladium (0) catalyst in tetrahydofuran to get corresponding condensed products, which are subjected to hydrolysis, de-protection to get compound of formula (11). The compound of formula (11) is optionally treated with amine to get amine addition salt of formula (11D), then setting free of amine salt in the presence of acid to get pure compound of formula (11). The pure compound of formula (11) is reacted with sodium alkoxide to get pure elvitegravir (12).
In one embodiment, the present invention provides a process for the preparation of elvitegravir (12) comprising the steps of: a) protecting the hydroxyl group of the compound of formula 6
Figure imgf000009_0001
X = F, R' = Et
with tert-butyldimethylsilyl chloride in the presence of base in solvent to get compound of formula 7,
Figure imgf000009_0002
7 - X = F, R' = Et, R" = TBDMS
b) reacting the compound of formula 7 with compound of formula 9 in the presence of tetrakis(triphenylphosphine)-palladium (0) catalyst in tetrahydrofuran get compound of formula 10,
Figure imgf000010_0002
10 - X = F, R' = Et, R" = TBDMS c) hydrolyzing and deprotecting the compound formula 10 in the presence of base in solvent to get compound of formula 11 ,
Figure imgf000010_0003
1 1 - X = F
d) optionally treating the compound of formula 11 with an amine in solvent to isolate an amine addition salt of compound of formula 11 D,
Figure imgf000010_0004
e) treating the amine addition salt with acid in solvent to get the compound of formula 11 in a pure form
f) reacting the compound of formula 11 or 11D with alkali methoxide in methanol to introduce methoxy functionality to isolate elvitegravir (12). According to the present invention, the compound of formula 6 is dissolving in solvent and reacting with a suitable hydroxyl group protecting agent in the presence of base at 10-350C for 2-3h to isolate 1-((S)-1-tert-butyldimethylsilyloxymethyl-2-methylpropyl)-7-fluoro-6-iodo- 4-OXO-1 ,4-dihydro-quinoline-3-carboxylic acid ethyl ester (7).
The suitable hydroxyl group protecting agent is selected from tert-butyldimethylsilyl chloride, methyl chloroformate or chloromethyl methyl ether. The organic solvent used in protection is selected from chlorinated solvents such as dichloromethane or hydrocarbon solvent such as toluene, xylene or mixture thereof and the base is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium bicarbonate or imidazole
According to the present invention, the compound of formula 7 is reacted with 3-chloro-2- fluoro-benzyl zinc bromide (9) in the presence of tetrakis(triphenyl-phosphine)palladium (0) catalyst in tetrahydrofuran 30-600C for 4-8h to isolate 6-(3-chloro-2-fluoro-benzyl)-7-fluoro-1- [1-(S) tert-butyldimethylsilyloxymethyl-2-methylpropyl)-4-oxo-1 ,4-dihydro-quinoline-3- carboxylic acid ethyl ester (10).
According to the present invention, the obtained compound of formula 10 is subjected to hydrolysis, de-protection in the presence of base in solvent at 100C to reflux to isolate 6- (3-chloro-2-fluorobenzyl)-7-fluoro-1-((S)-1-hydroxymethyl-2-methylpropyl)-4-oxo-1 , 4- dihydro-quinoline-3-carboxylic acid (11).
The organic solvent used in hydrolysis, de-protection is selected from methanol, ethanol, isopropyl alcohol or butanol. The base is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium bicarbonate or imidazole.
According to the present invention, the compound of formula 11 is, optionally, treating with amine in solvent at ambient temperature to isolate an amine addition salt, compound formula of 11D in a crystalline form. The solvent used for amine salt formation is selected from ethyl acetate, toluene, xylene or mixture thereof. The amine is selected from cyclohexylamine or dicyclohexyl amine.
According to the present invention, the compound of formula 11D is treating with acid at ambient temperature to isolate compound of formula 11 in the pure form. The acid is selected from hydrochloric acid, sulfuric acid, acetic acid or formic acid According to the present invention, compound of formula 11 or 11 D is then treated with alkali methoxide in methanol and heated to reflux for 16-2Oh to introduce methoxy functionality to get elvitegravir (12). The alkali methoxide is selected from sodium methoxide, potassium methoxide or lithium methoxide.
In yet another embodiment, the present invention relates process for the preparation of 1- (S)-1 - [i-(tert-butyldimethylsilanyloxymethyl) 2-methylpropyl]-6-(3-chloro-2-fluorobenzyl)-7- methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (12B) as shown in the Scheme 3,
Scheme 1
Figure imgf000012_0001
comprising the steps of:
a) dissolving the elvitegravir in solvent,
b) reacting with tert-butyldimethylsilyl chloride in the presence of base and c) isolating a compound of formula 12B
According to the present invention, the elvitegravir is dissolving in an organic solvent and reacted with tert-butyldimethylsilyl chloride in presence of a base at room temperature for 3h to get compound of formula 12B.
The organic solvent used for dissolution is selected from chlorinated solvent such as dichloromethane. The base is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium bicarbonate or imidazole.
According to the present invention the above obtained protected elvitegravir is further subjected to de-protection to get pure elvitegravir.
In yet another embodiment, the present invention provides a process for the preparation of elvitegravir (12)
Figure imgf000013_0001
comprising the steps of:
a) protecting the hydroxyl group of the compound of formula 6
Figure imgf000013_0002
6 - X = F, R1 = Et
with 3,4-dihydro-2H-pyran in solvent in the presence of acid to get compound of formula 7A,
Figure imgf000013_0003
7A - X = F, R' = Et1 R" = THP
b) reacting compound of formula 7A with compound of formula 9 in the presence of tetrakis(triphenylphosphine)-palladium (0) catalyst in a tetrahydrofuran to get compound of formula 1OA,
Figure imgf000013_0004
10A - X = F, R' = Et, R" = THP
c) hydrolyzing and deprotecting the compound of formula 1OA in solvent to get compound of formula 11,
Figure imgf000013_0005
d) optionally treating the compound of formula 11 with an amine in solvent to get amine addition salt of compound of formula 11 D,
Figure imgf000014_0001
e) treating the compound of formula 11D with amine addition salt with an acid in solvent to get the compound of formula 11 in a pure form
f) reacting the compound of formula 11 or 11D with alkali methoxide in methanol to introduce methoxy functionality to isolate elvitegravir (12).
According to the present invention, the compound of formula 6 is dissolved in solvent and reacted with 3,4-dihydro-2H-pyran in the presence of an acid at 10-350C for 2-3h to isolate 7-fluoro-6-iodo-1 -[1 -(S)-2-methyl-1 -(tetrahydro-pyran-2-yloxymethyl)propyl]-4-oxo-1 ,4- dihydro-quinoline-3-carboxylic acid ethyl ester (7A).
The solvent used for protection reaction is selected from chlorinated solvents such as dichloromethane, dichloroethane or chlorobenzene or hydrocarbon solvent such as toluene, xylene or mixture thereof. The acid is selected from hydrochloric acid, hydrochloric acid, sulfuric acid, acetic acid, formic acid, boron trifluoride etherate (BF3 O(Et)2) or p- tolueπesulfonic acid.
According to the present invention, the compound of formula 7A is reacted with 3-chloro-2- fluoro-benzyl zinc bromide (9) in the presence of tetrakis(triphenyl-phosphine)palladium (0) catalyst in tetrahydrofuran at 30-600C for 4-8h to isolate 6-(3-chloro-2-fluoro-benzyl)-7-fluoro- 1 -(S)-I -^-methyl-i-^etrahydro-pyran^-ylo'xymethylJ-propyll^-oxo-i ^-dihydro-quinoline-S- carboxylic acid ethyl ester (10A).
According to the present invention, the obtained compound of formula 10A is subjected to hydrolysis, de-protection in the presence of acid in solvent at 1O0C to reflux to give 6-(3- chloro-2-f luorobenzyl)-7-fluoro-1 -((S)-1 -hydroxymethyl-2-methylpropyl)-4-oxo-1 , 4-dihydro- quinoline-3-carboxylic acid (11).
The solvent used for hydrolysis, de-protection is selected from methanol, ethanol, isopropyl alcohol or butanol. The acid is selected from hydrochloric acid, sulfuric acid, acetic acid or formic acid.
According to the present invention, the compound of formula 11 is, optionally, treating with amine in solvent at ambient temperature to isolate an amine addition salt, compound formula of 11 D in a crystalline form. The solvent used for amine salt formation is selected from ethyl acetate, toluene, xylene or mixture thereof. The amine is selected from cyclohexylamine or dicyclohexyl amine.
According to the present invention, the compound of formula 11D is treating with acid at ambient temperature to isolate compound of formula 11 in the pure form. The acid is selected from hydrochloric acid, sulfuric acid, acetic acid or trifluoro acetic acid.
According to the present invention, compound of formula 11 or 11D is treated with alkali methoxide in methanol to introduce methoxy group to give elvitegravir (12). The alkali methoxide is selected from sodium methoxide, potassium methoxide or lithium methoxide.
In yet another embodiment, the present invention provides a process for the preparation of elvitegravir (12)
Figure imgf000015_0001
comprising the steps of:
a) reacting the compound of formula 1OA
Figure imgf000015_0002
with alkali methoxide in methanol to give formula 12C,
b) hydrolyzing the compound of formula 12C with an acid in solvent to get elvetegravie
Figure imgf000016_0001
According to the present invention, compound of formula 10A is treated with alkali methoxide in methanol to introduce methoxy group followed by hydrolysis of ethyl ester to afford compound of formula 12C.The alkali methoxide is selected from sodium methoxide, potassium methoxide or lithium methoxide.
According to the present invention, compound of formula 12C is deprotected with an acid in solvent to afford compound of formula 12.The acid is selected from hydrochloric acid, sulfuric acid, acetic acid, trifluoro acetic acid, boron trifluoride etherate (BF3 O(Et)2) or p- toluenesulfonic acid.
In yet another embodiment, the present invention provides a process for the preparation of elvitegravir (12) comprising the steps of:
a) hydrolyzing the compound of formula 10A
Figure imgf000016_0002
1OA - X = F, R' = Et, R" = THP
with base in solvent to obtain compound of formula 11C
Figure imgf000016_0003
IIC b) reacting the compound of 11C with alkali methoxide in methanol to get the compound of formula 12C,
Figure imgf000017_0001
c) deprotecting the compound of formula 12C with acid in solvent to get elvitegravir (12).
According to the present invention, compound of formula 1OA is subjected to hydrolysis in the presence of base in solvent at 40-700C for 2-8h to afford 6-(3-chloro-2-fluoro-benzyl)-7- fluoro-1 -[2-methyl-1 -(tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo-1 ,4-dihydro-quinoline-3- carboxylic acid (11C).
The base used for hydrolysis reaction is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide or potassium bicarbonate. The solvent is selected from methanol, ethanol, isopropyl alcohol or butanol. According to the present invention, compound of formula 11C is treated with alkali methoxide in methanol to introduce methoxy group to afford 6-(3-chloro-2-fluoro-benzyl)-7- methoxy-1-[1-(S)-2-methyl-1-(tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo-1 ,4-dihydro- quinoline-3-carboxylic acid (12C). The alkali methoxide is selected from sodium methoxide, potassium methoxide or lithium methoxide.
According to the present invention, compound of formula 12C is treated with an acid in a solvent for deprotection to give elvitegravir (12). The solvent used for deprotection reaction is selected from methanol, ethanol, isopropyl alcohol or butanol and the acid is selected from hydrochloric acid, sulfuric acid, acetic acid, trifluoro acetic acid, boron trifluoride etherate (BF3 O(Et)2) or p-toluenesulfonic acid.
In yet another embodiment, the present invention provides a process for the preparation of elvitegravir (12) comprising the steps of:
Figure imgf000018_0001
comprising the steps of;
a) hydrolyzing the compound of formula 1OA
Figure imgf000018_0002
1 OA - X = F, R' = Et, R" = THP
with base in solvent to obtain compound of formula 11C
Figure imgf000018_0003
b) deprotecting the resultant 11C with acid in solvent to get the compound of formula
Figure imgf000018_0004
1 1 - X = F
c) reacting the compound formula 11 with alkali methoxide in methanol to get elvitegravir
According to the present invention, compound of formula 1OA is subjected to hydrolysis in the presence with base in solvent at 40-700C for 2-8h to afford 6-(3-chloro-2-fluoro-benzyl)-
7-fluoro-1-[2-methyl-1-(tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo-1 ,4-dihydro-quinoline-
3-carboxylic acid (11C).
The solvent used for hyrolysis reaction is selected from methanol, ethanol, isopropyl alcohol or butanol and base is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide or potassium bicarbonate. According to the present invention, the obtained compound of formula 11C is deprotected with an acid in solvent at 1O0C to reflux to get 6-(3-chloro-2-fluorobenzyl)-7-fluoro-1-((S)-1- hydroxymethyl-2-methylpropyl)-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid (11).
The organic solvent used for deprotection reaction is selected from methanol, ethanol, isopropyl alcohol or butanol and acid is selected from hydrochloric acid, sulfuric acid, acetic acid, trifluoro acetic acid, boron trifluoride etherate (BF3 O(Et)2) or p-toluenesulfonic acid. According to the present invention, compound of formula 11 is then treated with alkali methoxide in methanol to introduce methoxy group to give elvitegravir (12). The alkali methoxide is selected from sodium methoxide, potassium methoxide or lithium methoxide.
In yet another embodiment, the present invention encompasses process for the preparation of 6-(3-chloro-2-fluorobenzyl)-1-[(S)-1-hydroxymethyl-2-methylpropyl]-7-methoxy-4-oxo-1, 4- dihydroquinoline-3-carboxylic acid sodium (elvitegravir sodium), a compound of the formula 12A, as shown in the Scheme 1 ,
Scheme 2
Figure imgf000019_0001
comprising the steps of:
a) dissolving the compound of formula 11 in methanol,
b) adding a source of sodium ion, under stirring and
c) isolating compound of elvitegravir sodium.
According to the present invention, elvitegravir is dissolved in methanol and treated with source of sodium ion is selected from sodium hydroxide, sodium bicarbonate, sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium butoxide or sodium tertiary butoxide According to the present invention, elvitegravir sodium is further converting to elvitegravir by conventional method to get pure elvitegravir.
In yet another embodiment, the present invention provides processes for the preparation of elvitegravir as depicted in the following schemes below (Scheme 2 and 3). According to the present invention, X is halo, preferably fluoro and R denotes both straight & branched groups.
Scheme 3
solvent
agent
Figure imgf000020_0001
Figure imgf000020_0002
7 - X = F, R' - Et, R- = TBDMS
7 A - X = F, R' = Et, R" = THP
Figure imgf000020_0003
Scheme 4
Figure imgf000021_0001
In yet another embodiment, according to the present invention, 6-(3-chloro-2-fluoro-benzyl)- 7-fluoro-1-[1-(S)-2-methyl-1-(tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo-1 ,4-dihydro- quinoline-3-carboxylic acid ethyl ester is represented by compound of formula 1OA.
Figure imgf000021_0002
In yet another embodiment, the present invention relates to 6-(3-chloro-2-fluorobenzyl)-7- fluoro-1-((S)-1-hydroxymethyl-2-methylpropyl)-4-oxo-1 , 4-dihydroquino-line-3-carboxylic acid dicyclohexyl amine salt, a novel intermediate of elvitegravir, represented by compound of formula 11 A.
Figure imgf000022_0001
In yet another embodiment, the present invention relates to crystallization of compound of formula 11 A, using solvents such as ethyl acetate, dimethyl formamide, dichloromethane, acetonitrile, acetone, methanol, ethanol and isopropanol.
- In yet another embodiment, the present invention provides crystalline 6-(3-chloro-2- fluorobenzyl)-7-fluoro-1 -((S)-1 -hydroxymethyl-2-methylpropyl)-4-oxo-1 ,4-dihydroquinoline-3- carboxylic acid dicyclohexyl amine salt (11A) characterized by an X-ray diffraction pattern having three or more peaks at 2Θ values selected from 7.43, 14.97, 15.85, 17.08, 22.91 ,24.08, ± 0.2 degrees 2-Theta, is shown in FIG. 1.
In yet another embodiment, the present invention provides crystalline 6-(3-chloro-2- fluorobenzyl)-7-fluoro-1 -((S)-1 -hydroxymethyl-2-methylpropyl)-4-oxo-1 ,4-dihydroquinoline-3- carboxylic acid dicyclohexyl amine salt (11A) is further characterized by a Differential Scanning Calorimetry (DSC) thermogram having onset 181.08°C, Peak 183.60 ± 2 0C and End set 186.61°C. The typical DSC thermogram is shown in figure FIG. 2. In yet another embodiment, the present invention relates to 1-(S)-1- [1-(tert- butyldimethylsilanyloxymethyl)-2-methylpropyl]-6-(3-chloro-2-fluoro benzyl)-7-fluoro-4-oxo-1 , 4-dihydroquinoline-3-carboxylic acid (11B), a novel intermediate of elvitegravir.
Figure imgf000022_0002
UB In yet another embodiment, the silyl protected intermediate of compound of 11B have the X- ray powder diffraction pattern with characteristic peaks at 9.15, 10.54, 13.37, 14.47, 18.38, 18.70, 19.24, 20.86, 21.23 ± 0.2 degrees 2-Theta, shown in FIG. 3. In yet another embodiment, compound of 11B is further characterized by a Differential Scanning Calorimetry (DSC) thermogram having onset 137.72°C, Peak 140.62 ± 2 0C and End set 142.41 °C. The typical DSC thermogram is shown in figure FIG. 4.
In yet another embodiment, the present invention relates to 6-(3-chloro-2-fluoro-benzyl)-7- fluoro-1 -[1 -(S)-2-methyl-1 -(tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo-1 , 4-dihydro- quinoline-3-carboxylic acid, represented by compound of formula 11C novel intermediate of elvitegravir.
Figure imgf000023_0001
lie
In yet another embodiment, the present invention relates to crystallization of 6-(3-chloro-2- fluoro-benzyl)-7-fluoro-1-[2-methyl-1-(tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo-1 ,4- dihydro-quinoline-3-carboxylic acid (11C), using solvents such as ethyl acetate, dichloromethane, acetonitrile.
In yet another embodiment, the crystalline form of 6-(3-chloro-2-fluoro-benzyl)-7-fluoro-1-[2- methyl-i-^etrahydro-pyran^-yloxymethyO-propylJ^-oxo-i ^-dihydro-quinoline-S-carboxylic acid (11C), prepared according to the present invention have the X-ray powder diffraction pattern with characteristic peaks at 3.84, 7.67, 8.12, 11.98, 12.42, 15.37, 18.1 , 19.13, 19.75, 20.54, 21.10, 23.66 & 24.47 ± 0.2 degrees 2-Theta, shown in FIG.5. In yet another embodiment, the present invention relates to 1-(S)-1- [1-(tert- butyldimethyl silanyloxymethyl) 2-methylpropyl]-6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1 , A- dihydroquinoline-3-carboxylic acid, a novel intermediate of elvitegravir, represented by the compound of formula 12B
Figure imgf000024_0001
12B
In yet another embodiment, the present invention provides crystalline 1 -(S)-I- [1- (tertbutyldimethylsilanyloxymethyl)-2-methylpropyl]-6-(3-chloro-2-fluorobenzyl)-7-methoxy-4- oxo-1 , 4-dihydroquinoline-3-carboxylic acid (12B) characterized by an X-ray diffraction pattern having three or more peaks at 2Θ values selected from 9.99, 11.19, 16.37, 17.16, 17.94,18.63,19.81 , 20.48, 21.10, 26.26, 27.87 ± 0.2 degrees 2-Theta, is shown in FIG. 6.
In yet another embodiment, the present invention provides crystalline 1 -(S)-I- [1- (tertbutyldimethylsilanyloxymethyl)-2-methylpropyl]-6-(3-chloro-2-fluorobenzyl)-7-methoxy-4- oxo-1, 4-dihydroquinoline-3-carboxylic acid (12B) is further characterized by a Differential Scanning Calorimetry (DSC) thermogram having onset 144.29°C, Peak 146.40 ± 2°C and End set 148.360C. The typical DSC thermogram is shown in FIG.7.
In yet another embodiment, the present invention relates to 6-(3-chloro-2-fluoro-benzyl)-7- methoxy-1-[2-methyl-1-(tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo-1 ,4-dihydro-quinoline- 3-carboxylic acid, represented by compound of formula 12C a novel intermediate of elvitegravir.
Figure imgf000024_0002
In another embodiment, elvitegravir having the dimmer impurity of formula 13 is less than 0.1% and HPLC purity is more than 99%, which is obtained by recrystallizing from a mixture of ethyl acetate - hexane to give pure elvitegravir of formula 12.
In yet another embodiment, the situ reactions followed in the present process save the time as well the increase the purity of the final compound. The elvitegravir prepared according to present invention containing dimmer impurity of formula 13 is less than 0.1% and HPLC purity more than 99%.
Figure imgf000025_0001
In yet another embodiment, the present invention relates to a process for the preparation of L-valinol by reacting L-valine with sodium borohydride and sulfuric acid followed by isolation using isopropyl alcohol.
Figure imgf000025_0002
In yet another embodiment, for the preparation of organo zinc reagent, the activation of zinc" using iodine instead of trimethylsilyl chloride and 1 , 2-dibromoethane moves the reaction fast and feasible at industrial level.
The following examples are provided for illustrative purposes only and are not intended to limit the scope of the in any way. Example-1
Preparation of 2, 4-difluoro-S-iodobenzoic acid (2)
Dichloromethane (400 mL) and 2,4-difluoro benzoic acid (1, 100 g) were added respectively to pre-cooled (0 - 5°C) sulfuric acid (184 g) under stirring and maintained for 30 min. N- lodosuccinamide (142 g) was added in 5 equal portions at below 5°C and maintained for 8 to 1O h. The reaction mass was poured onto crushed ice (500 g) and 3% sodium sulfite (50 mL) solution was added. The slurry was stirred at 5 to 10°C for an hour, filtered and the wet cake was washed with water (100 mL). The wet cake was suspended in purified water (500 mL) at 25 to 35°C and the pH of the reaction was adjusted to 3.0 to 3.5 with ammonia solution and stirred for an hour. The product was collected by filtered and washed with purified water (100 mL). The wet cake (250 g) was dissolved in 50% aqueous methanol (500 mL) at 70 to 8O0C and stirred for the dissolution for 30 min. The reaction mass was cooled to 25 to 35°C in 2 h., further cooled to 15 to 20°C and maintained for an hour. The separated solid was filtered, washed with purified water (50 mL) and dried at 50 to 55°C for 10 to 12 h. to afford 2,4-difluoro-5-iodobenzoic acid (2, 155 g, HPLC Purity: 99.1%).
Example-2
Preparation of 7-fluoro-1-(1-(S)-1-hydroxymethyl-2-methylpropyl)-6-iodo-4-oxo-1,4- dihydroquinoline-3- carboxylic acid ethyl ester (6)
Step 1 : 2, 4-Difluoro-5-iodobenzoic acid (2, 100 g) was dissolved in toluene (200 mL) and thionyl chloride (50 mL) and dimethylformamide (3 mL) were added respectively under nitrogen atmosphere. The mixture was heated to 85 to 900C and maintained for 2 to 3 h. The reaction mixture was cooled to below 500C and concentrated under reduced pressure. The resultant residue was dissolved in toluene (50 mL) and concentrated under reduced pressure to remove traces of thionyl chloride and repeated the same. The resultant 2, 4- difluoro-5-iodobenzoyl chloride (3) residue was dissolved in toluene (100 mL).
Step 2: The solution obtained in step 1 was added to a solution of ethyl 3,3- dimethylaminoacrylate (56 g) and diisopropylethyl amine (56 g) in toluene (100 mL) over a period of 30 min., raised the temperature of the reaction mass to 90 to 95°C and maintained for 4 h. to form 2-(2,4-difluoro-5-iodobenzoyl)-3-dimethylamino acrylic acid ethyl ester (4).
Step 3: (S)-(+)-Valinol (40 g) was added to the cooled solution of step 2 and stirred at room temperature for one and half hour. Toluene (400 mL) and purified water (200 mL) were added to the reaction mixture and the mixture was partitioned. The aqueous layer was extracted with toluene (50 ml). The combined organic layer was washed twice with water (2
X 100 mL) and concentrated under reduced pressure at below 600C to obtain a crude 2-(2,4- difluoro-5-iodobenzoyl)-3-(1-hydroxymethyl-3-methylpropylamino)acrylic acid ethyl ester (5, 165 g) as a brown oil.
Step 4: The crude product obtained in step 3 was dissolved in Λ/, Λ/-dimethylformamide (250 mL) and potassium carbonate (150 g) was added. The mixture was stirred at room temperature for 24 to 30 h. The reaction mixture was added to ice water (1.4 L) and the mixture was stirred for 45 min. The precipitate was collected by filtration and washed with water (200 ml_). The wet cake was suspended into water (500 mL) and stirred for an hour. The precipitate was collected by filtration, washed with water (100 mL) and vacuum-dried till MC become not more than 2.0%. The obtained compound (145 g) was treated with methanol (200 mL) at 45 to 500C and maintained the slurry for 30 min. The reaction mixture was cooled to ambient temperature and maintained for 1 h. The precipitated solid was collected by filtration, washed with methanol (25 mL) and dried at 45 to 50°C for 6 to 8 h. to afford 7-fluoro-1-(1 -(S)-I -hydroxymethyl-2-methylpropyl)-6-iodo-4-oxo-1,4-dihydroquinoline- 3- carboxylic acid ethyl ester (6, 125 g, purity by HPLC 98. 0%).
Example 3
Preparation of 1-((S)-1-tert-butyldimethylsilyloxymethyl-2-methylpropyl)-7-fluoro-6- iodo-4-oxo-1 , 4-dihydroquinoline-3-carboxylic acid ethyl ester (7). The compound of formula 6 (100 g) was dissolved in dichloromethane (500 mL) followed by addition of imidazole (30 g) and tert-butyl dimethylsilyl chloride (50 g) and stirred for 2 to 3 h. The reaction mixture was washed twice with water (2 X 100 mL). The dichloromethane layer was concentrated, finally under reduced pressure. Hexane (100 mL) was added to the obtained residue and distilled under reduced pressure. The residue seeded with compound of formula 7 (1 g), stirred for 6 to 8 h. at 0 to 5°C, hexane (500 mL) was charged and continued the stirring at the same temperature for 12 h. The separated compound was filtered, washed with chilled hexane (100 mL) and dried at 40 to 45°C for 8 h. to get 1-((S)-1- tert-butyldimethylsilyloxymethyl-2-methylpropyl)-7-fluoro-6-iodo-4-oxo-1 ,4-dihydroquinoline- 3-carboxylic acid ethyl ester (7, 110 g).
Example-4
Preparation of 7-f luoro-6-iodo-1 -[1 -(S)-2-methyl-1 -(tetrahydropyran-2-yloxymethyl)- propyl]-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid ethyl ester (7A). Method A
7-Fluoro-1-(1 -(S)-I -hydroxymethyl-2-methyl-propyl)-6-iodo-4-oxo-1,4-dihydro-quinoline-3- carboxylic acid ethyl ester (6, 100 g) and pTSA (1 g) were dissolved in dichloromethane (1000 mL) at 10 - 15°C. 3, 4-Dihydro-2/-/-pyran (43 mL) was added to reaction mass at same temperature over a period of 30 min and maintained for 4-6 h. The dichloromethane layer was washed with purified water (1000 mL) followed by 5% sodium bicarbonate solution (125 mL x 2). The organic layer was concentrated to get 7-fluoro-6-iodo-1-[1-(S)-2-methyl-1- (tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo-1 , 4-dihydro-quinoline-3-carboxylic acid ethyl ester (7A) as a sticky liquid (120 g).
Method B
7-Fluoro-1-(1-hydroxymethyl-2-methyl-propyl)-6-iodo-4-oxo-1 ,4-dihydro-quinoline-3- carboxylic acid ethyl ester (6, 100 g), boron trifluoroetherate (1 g) and hydrochloric acid (0.5 g) were dissolved in toluene (1000 mL) at 10-15°C. 3, 4-Dihydro-2H-pyran (43 mL) was added at same temperature over a period of 30 min. and maintained for 4-6 h. The dichloromethane layer was washed with purified water (1000 mL) followed by 5% sodium bicarbonate solution (125 mL x 2). The organic layer was concentrated to get 7-fluoro-6- iodo-1 -[2-methyl-1 -(tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo-1 ,4-dihydro-quinoline-3- carboxylic acid ethyl ester (7A) as a sticky liquid (116 g).
Method C
7-Fluoro-1-(1-hydroxymethyl-2-methyl-propyl)-6-iodo-4-oxo-1 ,4-dihydro-quinoline-3- carboxylic acid ethyl ester (6, 100 g) and hydrochloric acid (1 g) were dissolved in dichloromethane (1000 mL) at 10 - 15°C. 3, 4-Dihydro-2H-pyran (43 mL) was added at same temperature over a period of 30 min. and maintained for 4-6. The dichloromethane layer was washed with purified water (1000 mL) followed by 5% sodium bicarbonate solution (125 mL x 2). The organic layer was concentrated to get 7-fluoro-6-iodo-1-[2-methyl-1- (tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid ethyl ester (7A) as a sticky liquid (105 g).
Example-5
Preparation of 6-(3-chloro-2-fluoro-benzyl)-7-fluoro-1-[2-methyl-1-(tetrahydropyran-2- yloxymethyl)-propyl]-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (10A). 7-Fluoro-6-iodo-1 -[2-methyl-1 -(tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo-1 ,4-dihydro- quinoline-3-carboxylic acid ethyl ester of (7A) was dissolved in 300 mL of tetrahydrofuran and 3.0 g of tetrakis(triphenylphosphine)palladium (0) catalyst was added under nitrogen atmosphere followed by 3-chloro-2-fluoro-benzyl zinc bromide (9) in tetrahydrofuran. The temperature of the reaction was raised to 40cC and maintained for 6 h. The reaction mass was cooled to ambient temperature after distilling tetrahydrofuran (-300 mL) from the reaction mass under reduced pressure. The reaction mass poured into 25% ammonium chloride (500 mL) solution, toluene (500 mL) was added and stirred for 45 min. The layers were separated and the organic layer was washed with 25% ammonium chloride (2 X 500 mL) solution, 3.5 % sodium bicarbonate (2 X 500 mL) solution and saturated sodium chloride (100 & 50 mL) respectively. The organic layer was concentrated, isopropanol (20 mL) was added and concentrated to get 6-(3-chloro-2-fluoro-benzyl)-7-fluoro-1-[2-methyl-1- (tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid ethyl ester (10 A) as a residue (110 g).
Example 6:
Preparation of 6-(3-chloro-2-fluorobenzyl)-7-fluoro-1-((S)-1-hydroxymethyl-2- methylpropy- l)-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (11) Method A
Step 1: The compound of formula 6 (100 g) was dissolved in dichloromethane (500 mL) and added with imidazole (30 g), tert-butyl dimethylsilyl chloride (50 g) and stirred for 2 to 3 h. The reaction mixture was twice washed with water (2 X 100 mL). The dichloromethane layer was concentrated under atmospheric pressure, finally, under reduced pressure. The residue -1-((S)-1-tert-butyldimethylsilyloxymethyl-2-methylpropyl)-7-fluoro-6-iodo-4-oxo-1 ,4- dihydroquinoline-3-carboxylic acid ethyl ester was dissolved in tetrahydrofuran (7, 25 mL) and concentration under reduced pressure at below 40°C. The obtained residue was dissolved in tetrahydrofuran (300 mL) and it's in process purity is around 90 to 95% by HPLC.
Step 2: Under nitrogen stream, zinc powder (33 g) was suspended in tetrahydrofuran (105 mL), and iodine (0.1 g) and trimethylsilyl chloride (8.88 mL, 70.00 mmol) were added and raised the temperature to 65°C. The mixture was stirred with heating for 30 min and cooled to 300C. A solution of 3-chloro-2-fluorobenzyl bromide (8, 95 g) in tetrahydrofuran (210 mL) was added dropwise at 30°C and, during addition, the temperature of the reaction has been increase to 600C. The reaction mass was cooled to 30°C in 2 h. to give a solution of 3- chloro-2-fluorobenzylzinc bromide (9). Step 3: To the step 2 solution, 3.0 g of tetrakis(triphenylphosphine)palladium (0) catalyst was added under nitrogen atmosphere followed by step 1 solution. The temperature of the reaction was raised to 400C and maintained for 6 h. The reaction mass was cooled to ambient temperature after distilling tetrahydrofuran (~300 mL) from the reaction mass under reduced pressure. The reaction mass poured into 25% ammonium chloride (500 mL) solution, toluene (500 ml) was added and stirred for 45 min. The layers were separated and the organic layer was washed with 25% ammonium chloride (2 X 500 mL) solution, 3.5 % sodium bicarbonate (2 X 500 mL) solution and saturated sodium chloride (100 & 50 mL). The organic layer was concentrated; isopropanol (20 mL) was added again and concentrated. Isopropanol (130 mL) was added to the obtained residue to get a solution of compound of 10 and it's in process purity is around 70 to 80%.
Step 4: 4N Sodium hydroxide (125 mL) solution was added to the step 3 reaction mass, and raised the temperature to 55°C and maintained for 4 to 6 h. The reaction mass was cooled to ambient temperature, filtered through hyflow bed and washed with 50% aqueous isopropyl alcohol (26 mL). The reaction mass further cooled to 10 to 15°C and adjusted the pH to 3 to 3.5 with 50% aqueous HCI (-110 mL). Ethyl acetate (375 mL) was added and stirred for 30 min. The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was washed with 10% sodium chloride (200 mL) solution. The organic layer was treated with activated carbon (5 g) and concentrated to dryness under reduced pressure. Methanol (50 mL) was charged to the obtained residue and distilled to remove the traces of ethyl acetate. Methanol (100 mL) was charged and heated to 55 to 600C and maintained for 15 to 30 min. The slurry mass was cooled to 0 to 5°C, filtered after 30 min., washed with chilled methanol (25 mL) and dried at about 500C for 6 to 8 h. to afford 60 g of 6-(3-chloro-2-fluorobenzyl)-7-fluoro-1-((S)-1-hydroxymethyl-2-methylpropy-l)-4-oxo- 1,4-dihydro quinoline-3-carboxylic acid (11) having HPLC purity not less than 95.0%.
Method B
The 6-(3-chloro-2-f luoro-benzyl)-7-fluoro-1 -[2-methyl-1 -(tetrahydro-pyran-2-yloxy methyl)- propyl]-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (10) was added to a pre- cooled (20 to 25°C) mixture of concentrated hydrochloric acid (50 g) and methanol (5000 mL). The resultant mixture was heated under reflux for 16 to 20 h. The reaction mass concentrated and cooled. Water (1000 mL) and ethyl acetate (450 mL) were added to the obtained residue under stirring. The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined ethyl acetate layer was washed with water (250 mL). BW 280 Carbon (5 g) was added to the reaction mixture. The mixture was stirred at room temperature for 30 minutes, filtered through hiflow bed, washed thoroughly with ethyl acetate (50 mL) and the filtrate was concentrated under reduced pressure to get 6- (3-chloro-2-f luorobenzyl)-1 -[(S)-1 -hydroxymethyl-2-methylpropyl]-7-f luoro-4-oxo-1 ,4- dihydroquinoline-3-carboxylic acid (11) as a yellow colored material (50 g).
Example 7:
Preparation of 6-(3-chloro-2-fluorobenzyl)-7-fluoro-1 -((S)-1 -hydroxymethyl-2- methylpropyl)-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid dicyclohexyl amine salt (11A)
Step 1: The compound of formula 6 (100 g) was dissolved in dichloromethane (500 mL) and added imidazole (30 g) and tert-butyl dimethylsilyl chloride (50 g) and stirred 2 to 3 h. The reaction mixture was twice washed with water (2 X 100 mL). The dichloromethane layer was concentrated under reduced pressure. Hexane (100 mL) was added to the obtained residue and distilled under reduced pressure. The residue seeded with compound of formula 7 (1 g), stirred for 6 to 8 h. at 0 to 5°C. Hexane (500 mL) was added to the reaction mass and continued the stirring at the same temperature for 12 h. The separated compound was filtered, washed with chilled hexane (100 mL) and dried at 40 to 45°C for 8 h. to get the 1- ((S)-1-tert-butyldimethylsilyloxymethyl-2-methylpropyl)-7-fluoro-6-iodo-4-oxo-1 ,4- dihydroquinoline-3-carboxylic acid ethyl ester (7, 110 g).
Step 2: Under nitrogen stream, zinc powder (33 g) was suspended in tetrahydrofuran (105 mL), iodine (0.1 g) and trimethylsilyl chloride (8.88 mL, 70.00 mmol) were added and raised the temperature to 65°C. The mixture was stirred with heating for 30 min. and cooled to
30°C. A solution of 3-chloro-2-fluorobenzyl bromide (8, 95 g) in tetrahydrofuran (210 mL) was added drop-wise at 300C and, during addition, the temperature of the reaction has been increase to 600C. The reaction mass was cooled to 300C in 2 h. to get a solution of 3-chloro- 2-fluorobenzylzinc bromide (9).
Step 3: To the solution obtained in step 2, 3.0 g of tetrakis(triphenylphosphine)palladium (0) catalyst was added under nitrogen atmosphere followed by addition of solution obtained in step 1. The temperature of the reaction mass was raised to 400C and maintained for 6 h. The reaction mass was cooled to ambient temperature after distilling tetrahydrofuran (~300 mL) from the reaction mass under reduced pressure. The resultant solution was poured into 25% ammonium chloride solution (500 mL) and added toluene (500 mL) and stirred for 45 min. The layers were separated and the organic layer was washed with 25% ammonium chloride (2 X 500 mL) solution, 3.5 % sodium bicarbonate (2 X 500 mL) solution and saturated sodium chloride (100 & 50 mL) solution. The organic layer was concentrated, isopropanol (20 mL) was added to the obtained residue and concentrated completely, lsopropanol (130 mL) was added to dissolve the resultant residue and it's in process purity of around 70 to 80%.
Step 4: 4N Sodium hydroxide (125 mL) solution was added to the compound obtained in the step 3 and raised the temperature to 55°C and maintained for 4 to 6 h. The reaction mass was cooled to ambient temperature, filtered through hyflow bed and washed with 50% aqueous isopropylalcohol (26 mL). The reaction mass was further cooled to 10 to 15°C and adjusted the pH to 3 to 3.5 with 50% aqueous HCI (-110 mL). Ethyl acetate (375 mL) was added to the reaction mixture and stirred for 30 min. The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was washed with 10% sodium chloride (200 mL) solution and treated with activated carbon (5 g). Dicyclohexylamine (40 g) was added resultant solution and stirred for an hour. The separated solid was filtered, washed with ethyl acetate (50 mL) and dried at 45 to 500C for 8 h. to get 6-(3-chloro-2-fluorobenzyl)-7-fluoro-1-((S)-1-hydroxymethyl-2-methylpropyl)-4-oxo- 1 , 4-dihydroquinoline-3-carboxylic acid dicyclohexyl amine salt (11 A, 105 g).
Example 8:
Preparation of 1 -(S)-I- [1-(tert-butyldimethylsilanyloxymethyl)-2-methylpropyl]-6-(3- chloro-2-fluoro benzyl)-7-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (11B)
The compound of formula 11 (100 g) was dissolved in dichloromethane (500 mL) and added imidazole (30 g, 0.436 mmol) and tert-butyldimethylsilyl chloride (50 g) and the mixture was stirred at room temperature for 3 h. Water (100 mL) was added to the reaction mixture under stirring and separated the layers after 30 min. Organic layer was washed with water (100 mL) and concentrated under reduced pressure. Hexane (100 mL) was added to the obtained residue and concentrated under reduced pressure to remove the traces of dichloromethane. Hexane (200 mL) was added to the obtained residue and stirred for 10 to 12 h. at ambient temperature and further cooled to 0 to 5°C and stirred for 2 h. The separated solid was filtered, washed with hexane (50 mL) and dried at 45 to 500C for 8 h. to afford 1-(S)-1- [1- (tert-butyldimethylsilanyloxymethyl)-2-methylpropyl]-6-(3-chloro-2-fluoro benzyl)-7-fluoro-4- oxo-1 , 4-dihydroquinoline-3-carboxylic acid (11B).
Example-9
Preparation of 6-(3-chloro-2-fluoro-benzyl)-7-fluoro-1-[2-methyl-1-(tetrahydro-pyran-2- yloxy methyl)-propyl]-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (11C).
7-Fluoro-6-iodo-1 -[2-methyl-1 -(tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo-1 ,4-dihydro- quinoline-3-carboxylic acid ethyl ester of example 1 (7A) dissolved in 300 mL of tetrahydrofuran and 3.0 g of tetrakis(triphenylphosphine)palladium (0) catalyst was added under nitrogen atmosphere followed by 3-chloro-2-fluoro-benzyl zinc bromide solution (9). The temperature of the reaction was raised to 40°C and maintained for 6 h. The reaction mass was cooled to ambient temperature after distilling tetrahydrofuran (~300 mL) from the reaction mass under reduced pressure. The reaction mass poured into 25% ammonium chloride (500 mL) solution, toluene (500 mL) was added and stirred for 45 min. The layers were separated and the organic layer was washed with 25% ammonium chloride (2 X 500 mL) solution, 3.5 % sodium bicarbonate (2 X 500 mL) solution and saturated sodium chloride (100 & 50 mL) respectively. The organic layer was concentrated; isopropanol (20 mL) was added and concentrated to remove the toluene traces. Isopropanol (130 mL) was added to the obtained residue and it's in process purity is around 70 to 80%. 4N Sodium hydroxide (125 mL) solution was added the IPA solution, raised the temperature to 55°C and maintained for 4 to 6 h. The reaction mass was cooled to ambient temperature, filtered through hyflow bed and washed the bed with 50% aqueous isopropyl alcohol (26 mL). The filtrate cooled to 10 to 15°C and adjusted the pH to 8 to 8.5 with 50% aqueous HCI (-110 mL). Ethyl acetate (375 mL) was added under stirring and maintained for 30 min. The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined ethyl acetate was washed with 10% sodium chloride (200 mL) solution and treated with activated carbon (5 g) followed by concentrated to get 6-(3-chloro-2-fluoro-benzyl)-7- fluoro-1 -[2-methyl-1 -(tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo-1 ,4-dihydro-quinoline-3- carboxylic acid (11C) as a sticky liquid (90 g). Method B
6-(3-Chloro-2-fluorobenzyl)-1-[(S)-1-hydroxymethyl-2-methylpropyl]-7-fluoro-4-oxo-1, 4- dihydro- quinoline-3-carboxylic acid (11 , 100 g) and pTSA (1 g) were dissolved in dichloromethane (1000 mL) at 10 - 15°C then added 3,4-dihydro-2H-pyran (43 mL) at same temperature over a period of 30 min. The resultant mixture was maintained for 4-6 h. The dichloromethane layer was washed with purified water (500 mL x 2) followed by 5% sodium bicarbonate solution (125 mL x 2). The organic layer was concentrated to get residue, which is crystallized from a mixture of ethyl acetate and hexane to get 6-(3-chloro-2-fluoro-benzyl)- 7-fluoro-1-[2-methyl-1-(tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo-1 ,4-dihydro-quinoline- 3-carboxylic acid (11C) as a off white colored material (100 g).
Example-10
Preparation of 6-(3-chloro-2-fluorobenzyl)-1-[(S)-1-hydroxymethyl-2-methylpropyl]-7-meth- oxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (12) Method A
Step 1: Sodium methoxide (124 g) and purified water (5 mL) were added to methanol (1000 mL) under nitrogen atmosphere. The resultant mass was cooled to 20 to 25°C and compound of formula 11 was added. The resultant mixture was heated under reflux for 16 to 20 hours. Methanol (350 to 400 mL) was distilled out thefrom the reaction mass and cooled. To the reaction mass was added a mixture of water (1000 mL) and toluene (1000 mL) under stirring. The sodium salt of elvitegravir separated was filtered after 30 min at 10-150C and washed with chilled purified water (12A, 100 mL).
Step 2: The wet cake obtained in stepi of example 10, was suspended into water (500 mL) and adjusted the pH to 8 to 8.5 with 50% aqueous HCI at 10 to 15°C. Ethyl acetate (450 mL) was added to the reaction mass and further the pH was adjusted to 3 to 3.5 with 50% aqueous HCI. The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was washed with water (250 mL). BW 280
Carbon (5 g) was added to the reaction mixture. The mixture was stirred at room temperature for 30 min. filtered through hyflow bed, washed thoroughly with ethyl acetate
(50 mL) and the mixture was concentrated under reduced pressure.
Step 3: The residue product obtained in step 2 of example 10, was dissolved in ethyl acetate (200 mL) by heating under reflux, hexane (100 mL) was added at 60 to 65°C over a period of 30 min. and maintained for an hour. The reaction mass was cooled to 25 to 300C over a period of 2 to 3 h. and maintained for 30 min. The precipitated solid was collected by filtration, washed with a mixture of ethyl acetate and hexane (1 :1 , 25 mL). Step 4: The obtained crude product in. step 3 of example 10, was dissolved in ethyl acetate (150 mL) by heating under reflux. Hexane (75 mL) was added at a temperature of about 60 to 75°C over a period of 30 min and maintained for an hour. The reaction mass cooled to 25 to 3O0C over a period of 2 to 3 h. and maintained for 30 min. The precipitated solid was collected by filtration, washed with a mixture of ethyl acetate and hexane (1:1 , 25 mL) and dried at 50-550C to get pure 6-(3-chloro-2-fluorobenzyl)-1-[(S)-1-hydroxymethyl-2- methylpropyl]-7-methoxy-4-oxo-1,4-dihydro quinoline-3-carboxylic acid in 70 g with HPLC Purity not less than 99.0%.
Method B
6-(3-Chloro-2-fluoro-benzyl)-7-fluoro-1 -[2-methyl-1 -(tetrahydro-pyran-2-yloxymethyl)-propyl]- 4-OXO-1 ,4-dihydro-quinoline-3-carboxylic acid ethyl ester (10 A) and pTSA (10 g) were dissolved in methanol (500 mL). The resultant mixture was heated to 35-4O0C and maintain for 6-8 h. The reaction mass was concentrated and cooled. A mixture of water (500 mL) and ethyl acetate (500 mL) was added to the reaction mass. The layers were separated and the aqueous layer was extracted with (100 mL). The combined ethyl acetate was washed with water (250 mL) and BW 280 Carbon (5 g) was added. The mixture was stirred at room temperature for 30 min., filtered through hyflow bed, washed the bed thoroughly with ethyl acetate (50 mL) and the filtrate was concentrated under reduced pressure. The obtained residue dissolved in methanol (1000 mL) and sodium methoxide (60 g) and purified water (2.5 mL) were added under nitrogen atmosphere at 25 - 35°C. The resultant mixture was heated under reflux for 16 to 20 h. The reaction mass was concentrated and cooled. To the reaction mass, water (1000 mL) was added and adjusted the pH to 2.5 to 3.0 with 50% aqueous HCI at 10 to 15°C and ethyl acetate (250 mL) was added. The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined ethyl acetate layer was washed with water (250 mL) and BW 280 Carbon (5 g) was added. The mixture was stirred at room temperature for 30 min., filtered through hyflow bed, washed the bed thoroughly with ethyl acetate (50 mL) and the mixture was concentrated under reduced pressure to get residue. The obtained residue was dissolved in ethyl acetate (200 mL) by heating under reflux; hexane (100 ml) was added at 60 to 65°C over a period of 30 min. and maintained for an hour. The reaction mass was cooled to 25 to 300C over a period of 2 to 3 h. and maintained for 30 min. The precipitated solid was collected by filtration, washed with a mixed solvent of ethyl acetate and hexane (1:1 , 25 mL).The obtained crude product was dissolved in ethyl acetate (150 ml) by heating under reflux. Hexane (75 mL) was added at a temperature of about 60 to 75°C over a period of 30 min and maintained for an hour. The reaction mass cooled to 25 to 300C over a period of 2 to 3 h. and maintained for 30 min. The precipitated solid was collected by filtration, washed with a mixed solvent of ethyl acetate and hexane (1 :1, 25 mL) and dried at 50-55°C to get pure 6-(3-chloro-2- fluorobenzyl)-1-[(S)-1-hydroxymethyl-2-methylpropyl]-7-methoxy-4-oxo-1 ,4-dihydroquinoline- 3-carboxylic acid(12) as white solid ( 60 g) with HPLC Purity 99.35.
Method C
6-(3-chloro-2-fluoro-benzyl)-7-fluoro-1-[2-methyl-1-(tetrahydro-pyran-2-yloxy methyl)-propyl]- 4-OXO-1 ,4-dihydro-quinoline-3-carboxylic acid ethyl ester (10A) and hydrochloric acid (10 ml) dissolved in methanol (500 mL). The resultant mixture was heated for 35-400C and maintain for 6-8 h. The reaction mass was concentrated and cooled. To the reaction mass, water (500 mL) and ethyl acetate (500 mL) were added under stirring. The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with water (250 mL) and BW 280 Carbon (5 g) was added. The mixture was stirred at room temperature for 30 min., filtered through hyflow bed, washed the bed thoroughly with ethyl acetate (50 mL) and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (1000 ml) and sodium methoxide (60 g) and purified water (2.5 ml) were added under nitrogen atmosphere at 25 - 35°C. The resultant mixture was heated under reflux for 16 to 20 h. The reaction mass was concentrated and cooled. To the reaction mass, water (1000 mL) was added, adjusted the pH to 2.5 to 3.0 with 50% aqueous HCI at 10 to 15°C and ethyl acetate (250 mL) was added. The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was washed with water (250 ml) and BW 280 Carbon (5 g) was added. The mixture was stirred at room temperature for 30 min. filtered through hyflow bed, washed the bed thoroughly with ethyl acetate (50 mL) and the mixture was concentrated under reduced pressure to get residue. The obtained residue was dissolved in ethyl acetate (200 mL) by heating under reflux; hexane (100 mL) was added at 60 to 65°C over a period of 30 min. and maintained for an hour. The reaction mass was cooled to 25 to 30°C over a period of 2 to 3 h. and maintained for 30 min. The precipitated crude solid was collected by filtration, washed with a mixed solvent of ethyl acetate and hexane (1 :1, 25 ml). The obtained crude product was dissolved in ethyl acetate (150 mL) by heating under reflux and hexane (75 mL) at a temperature of about 60 to 75°C over a period of 30 min. and maintained for an hour. The reaction mass cooled to 25 to 30°C over a period of 2 to 3 h. and maintained for 30 min. The precipitated solid was collected by filtration, washed with a mixed solvent of ethyl acetate and hexane (1 :1 , 25 ml) and dried at 50-550C to get pure 6-(3- chloro-2-fluorobenzyl)-1-[(S)-1-hydroxymethyl-2-methylpropyl]-7-meth- oxy-4-oxo-1,4- dihydroquinoline-3-carboxylic acid (12) as a white solid (76 g) with HPLC Purity 99.38%.
Method D
Sodium methoxide (60 g) and purified water (2.5 mL) were added to methanol (1000 mL) under nitrogen atmosphere. The resultant mass was cooled to 20 to 25°C and the 6-(3- chloro-2-fluorobenzyl)-1-[(S)-1-hydroxymethyl-2-methylpropyl]-7-fluoro-4-oxo-1 , 4- dihydroquinoline-3-carboxylic acid (11) was added. The resultant mixture was heated under reflux for 16 to 20 h. The methanol was distilled about 700 to 800 mL from the reaction mass and remaining mass was cooled. To the mass, water (1000 mL) was added, adjusted the pH to 2.5 to 3.0 with 50% aqueous HCI at 10 to 15°C and ethyl acetate (250 mL) was added. The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with water (250 mL). BW 280 Carbon (5 g) was added to the reaction mixture. The mixture was stirred at room temperature for 30 minutes, filtered through hyflow bed, washed thoroughly with ethyl acetate (50 mL) and the mixture was concentrated under reduced pressure to get residue. The obtained residue was dissolved in ethyl acetate (100 mL) by heating under reflux; hexane (50 mL) was added at 60 to 65°C over a period of 30 min. and maintained for an hour. The reaction mass was cooled to 25 to 30°C over a period of 2 to 3 h. and maintained for 30 min. The precipitated crude solid was collected by filtration, washed with a mixed solvent of ethyl acetate and hexane (1 :1 , 12.5 mL). The obtained crude product was dissolved in ethyl acetate (75 mL) by heating under reflux. Hexane (37 mL) was added at a temperature of about 60 to 75°C over a period of 30 min and maintained for an hour. The reaction mass cooled to 25 to 30°C over a period of 2 to 3 h. and maintained for 30 min. The precipitated solid was collected by filtration, washed with a mixed solvent of ethyl acetate and hexane (1 :1 , 12.5 mL) and dried at 50-55°C to get pure 6-(3-chloro-2-fluorobenzyl)-1-[(S)-1-hydroxymethyl-2-methylpropyl]-7- methoxy-4-oxo-1 ,4-dihydroquinoline-3-carboxylic acid (12) as a white solid (26 g) with HPLC Purity 99.51%. Method E
Sodium methoxide (120 g) and purified water (5 mL) were added to methanol (2000 mL) under nitrogen atmosphere. The resultant mass was cooled to 20 to 25°C and 6-(3-chloro-2- fluoro-benzyl)-7-fluoro-1-[1-(S)-2-methyl-1-(tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo- i ^-dihydro-quinoline-S-carboxylic acid (11) was added. The resultant mixture was heated under reflux for 16 to 20 h. The reaction was distilled out to remove the methanol (700 to 800 mL) and cooled. Water (1000 mL) was added to the reaction mass, adjusted the pH to 6.8 to 7.0 with 50% aqueous hydrochloric acid at 10 to 15°C and ethyl acetate (500 mL) was added under stirring. The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with water (250 mL). BW 280 Carbon (5 g) was added to the reaction mixture. The mixture was stirred at room temperature for 30 minutes, filtered through hyflow bed, washed thoroughly with ethyl acetate (50 mL) and the mixture was concentrated under reduced pressure to get residue. The obtained residue was dissolved in methanol (500 mL) and pTSA (10 g). The resultant mixture was heated for 35-40°C and maintain for 6-8 h. The methanol was distilled out from the reaction mass and cooled. To the reaction mass, a mixture of water (500 mL) and ethyl acetate (500 mL) was added. The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with water (250 mL). BW 280 Carbon (5 g) was added to the reaction mixture. The mixture was stirred at room temperature for 30 minutes, filtered through hyflow bed, washed thoroughly with ethyl acetate (50 mL) and the mixture was concentrated under reduced pressure. The residue product obtained was dissolved in ethyl acetate (200 mL) by heating under reflux; hexane (100 mL) was added at 60 to 65°C over a period of 30 min. and maintained for an hour. The reaction mass was cooled to 25 to 3O0C over a period of 2 to 3 hours and maintained for 30 min. The precipitated crude solid was collected by filtration, washed with a mixed solvent of ethyl acetate and hexane (1 :1 , 25 mL). The obtained crude product was dissolved in ethyl acetate (150 mL) by heating under reflux. Added hexane (75 mL) at a temperature of about 60 to 75°C over a period of 30 min and maintained for an hour. The reaction mass cooled to 25 to 30°C over a period of 2 to 3 hours and maintained for 30 min. The precipitated solid was collected by filtration, washed with a mixed solvent of ethyl acetate and hexane (1 :1 , 25 mL) and dried at 50-55°C to get pure 6-(3-chloro-2- fluorobenzyl)-1-[(S)-1-hydroxymethyl-2-methylpropyl]-7-methoxy-4-oxo-1 ,4-dihydroquinoline- 3-carboxylic acid (12) as white solid (60 g) with HPLC Purity 99.60%. Example 11:
Preparation of elvitegravir sodium salt (12A)
6-(3-Chloro-2-fluorobenzyl)-1-[(S)-1-hydroxymethyl-2-methylpropyl]-7-fluoro-4-oxo- i ^dihydroquinoline-S-carboxylic acid (11 , 100 g, 0.229 moles) was dissolved in methanol (500 ml_). Sodium methoxide (54 g, 2.29 moles) and water (5 mL) were added and the mixture was heated under reflux for 20 h. The reaction mixture was allowed to cool to room temperature and filtered through celite. The filtered reaction mixture was concentrated to half of the volume and diluted by adding one liter of water and one liter of toluene. The resultant slurry was stirred for an hour at room temperature and collected the precipitated material by filtration. The wet product was washed with chilled water and dried under vacuum to give 78.5 g of 6-(3-chloro-2-fluorobenzyl)-1-[(S)-1-hydroxymethyl-2-methylpropyl]-7-methoxy-4- oxo-1 , 4-dihydroquinoline-3-carboxylic acid sodium (12A, yield - 77%). Example 12:
Preparation of 1 -(S)-I- [1-(tert- butyldimethylsilanyloxymethyl) 2-methylpropyl]-6-(3- chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (12B)
The compound of formula 12 (100 g) was dissolved in dichloromethane (500 mL) and added imidazole (30 g, 0.436 mmol) and tert-butyldimethylsilyl chloride (50 g) and the mixture was stirred at room temperature for 3 h. Water (100 mL) was added to the reaction mixture under stirring and separated the layers after 30 min. Organic layer was washed with water (100 mL) and concentrated under reduced pressure. Methyl t-butyl ether (100 mL) was added to the obtained residue and concentrated under reduced pressure to remove the traces of dichloromethane. Methyl t-butyl ether (200 mL) was added to the obtained residue and stirred for 10 to 12 h. at ambient temperature. The reaction mass further cooled to 0 to 5°C and stirred for 2 h. The separated solid was filtered, washed with methyl t-butyl ether (50 mL) and dried at 45 to 500C for 8 h. to get 1-(S)-1- [i-(tert-butyldimethylsilanyloxymethyl) 2- methylpropyl]-6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1 , 4-dihydroquinoline-3- carboxylic acid (12B, 115 g).
Example-13
Preparation of 6-(3-chloro-2-fluoro-benzyl)-7-methoxy-1-[1-(S)-2-methyl-1-(tetrahydro- pyran-2-yloxymethyl)-propyl]-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (12C). Method A
Sodium methoxide (124 g) and purified water (5 mL) were added to methanol (1000 mL) under nitrogen atmosphere. The resultant mass was cooled to 20 to 25°C and 6-(3-chloro-2- fluoro-benzyl)-7-fluoro-1 -[2-methyl-1 -(tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo-1 ,4- dihydro-quinoline-3-carboxylic acid (11C) was added. The resultant mixture was heated under reflux for 16 to 20 h. The reaction mixture was concentrated and cooled. To the obtained residue, water (1000 mL) was added and adjusted the pH to 6.8 to 7.0 with 50% aqueous HCI at 10 to 15°C and ethyl acetate (450 mL) was added. The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined ethyl acetate layer was washed with water (250 mL) and BW 280 Carbon (5 g) was added. The mixture was stirred at room temperature for 30 min. filtered through hyflow bed, washed the bed thoroughly with ethyl acetate (50 mL) and the filtrate was concentrated under reduced pressure to get 6-(3-chloro-2-fluoro-benzyl)-7-methoxy-1-[1-(S)-2-methyl-1- (tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (12C) as a sticky liquid (90 g).
Method B
Sodium methoxide (124 g) and purified water (5 mL) were added to methanol (1000 mL) under nitrogen atmosphere. The resultant mass was cooled to 20 to 25°C and 6-(3-chloro-2- fluoro-benzyl)-7-fluoro-1-[2-methyl-1-(tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo-1 ,4- dihydro-quinoline-3-carboxylic acid ethyl ester (10) was added. The resultant mixture was heated under reflux for 16 to 20 h. The reaction mass was concentrated and cooled. To the reaction mass, water (1000 mL) was added, adjusted the pH to 6.8 to 7.0 with 50% aqueous hydrochloric acid at 10 to 15°C and ethyl acetate (450 mL) was added. The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was washed with water (250 mL). BW 280 Carbon (5 g) was added to the reaction mixture and stirred at room temperature for 30 min., filtered through hyflow bed, washed the bed thoroughly with ethyl acetate (50 mL) and the mixture was concentrated under reduced pressure to get e-^-chloro^-fluoro-benzyO^-methoxy-HHS^-methyl-i- (tetrahydro-pyran-2-yloxymethyl)-propyl]-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid 16 as a sticky liquid (12C, 90 g). Method C
6-(3-Chloro-2-fluorobenzyl)-1-[(S)-1-hydroxymethyl-2-methylpropyl]-7-methoxy-4-oxo-1 , 4- dihydroquinoline-3-carboxylic acid (12, 100 g) and pTSA (1 g) were dissolved in dichloromethane (1000 mL) at 10 - 15°C and 3,4-dihydro-2H-pyran (43 mL) was added at same temperature over a period of 30 min. The resultant mixture was maintained for 4-6 h. The dichloromethane layer was washed with purified water (500 mL x 2) followed by 5% sodium bicarbonate solution (2 x 125 mL). The organic layer was concentrated to get 6-(3- chloro-2-fluoro-benzyl)-7-methoxy-1 -[1 -(S)-2-methyl-1 -(tetrahydro-pyran-2-yloxymethyl)- propyl]-4-oxo-1 , 4-dihydro-quinoline-3-carboxylic acid (12C) as a sticky liquid (120 g).
Example 14: Isolation of 1-[(2S)-1-({3-carboxy-6-(3-chloro-2-fluorobenzyl)-1 -[(2S)-I- hydroxy-3-methylbutan-2-yl]-4-oxo-1 , 4-dihydroquinolin-7-yl}oxy)-3- methylbutan-2-yl 6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1 , 4-dihydroquinoline-3-carboxylic acid (elvitegravir dimer impurity, 13)
After isolation of the elvitegravir from the mixture of ethyl acetate-hexane, solvent from the filtrate was removed under reduced pressure. The resultant residue purified by column chromatography using a mixture of ethyl acetate-hexane (gradient, 20-80% EtOAc in hexane) as an eluent. Upon concentration of the required fractions, a thick solid was obtained which was further purified on slurry washing with ethyl acetate to get pure elvitegravir dimer impurity (13). The 1H-NMR, 13C-NMR and mass spectral data complies with proposed structure.
Figure imgf000041_0001
1H-NMR (DMSO-Cf6, 300 MHz, ppm) - δ 0.79 (m, d=6.3 Hz, 6H, 20 & 2O')\ 1.18 & 1.20 (d, J=6.3 Hz & J=6.2 Hz, 6H, 21 & 21')1, 2.42-2.49 (m, 2H, 19 & 19'), 3.81-3.89 (m, 3H, T & 17'Ha), 3.94-4.01 (m, 1 H, 17'Hb), 4.01 (s, 3H, 23), 4.11 (s, 2H, 7), 4.83-4.85 (m, 3H, 17 & 18'), 5.22 (t, J=4.7 Hz, 1H, OH), 5.41-5.44 (m, 1 H, 18), 6.73-6.78 (t, J=7.1 Hz, 1 H, 11)1' 2, 6.92-6.98 (t, J=8.0 Hz, 1H, 3') 1'2, 7.12-7.22 (m, 2H, 1 & 3), 7.34-7.39 (m, 1H, 2'),
7.45-7.48 (m, 1 H, 2), 7.49, 7.56 (s, 2H, 15 & 15'), 7.99, 8.02 (s, 2H, 9 & 9'), 8.89, 9.01 (s, 2H, 13 & 13'), 15.30, 15.33 (s, 2H, COOH' & COOH").
13C-NMR (DMSO-Cf6, 75 MHz, ppm)- δ 18.87, 19.03 (2OC, 20'C), 19.11 , 19.24 (21 C, 21 'C), 27.94 (7'C), 28.40 (7C), 28.91 , 30.08 (19C, 19'C), 56.80(23C), 60.11 (171C), 63.59 (18C), 66.52 (18'C), 68.53 (17C), 97.86, 98.97 (15, 15'), 107.43, 108.16 (12C, 12'C),
118.77, 119.38 (1OC, 10'C), 119.57 (d, J=17.6 Hz, 41C), 119.61 (d, J=17.9 Hz, 4C),
124.88 (d, J=4.3 Hz, 31C), 125.18 (d, J=4.2 Hz, 3C), 126.59, 126.96 (9C1 9'C), 127.14 (8'C), 127.62 (d, J=15.9 Hz, 61C), 127.73 (8C), 127.99 (d, J=15.2 Hz, 6C), 128.66 (2'C),
128.84 (11C), 128.84 (2C), 130.03 (d, J=3.4 Hz, 1C), 142.14, 142.44 (14C, 14'C), 144.37, 145.56 (13C, 131C), 155.24 (d, J=245.1 Hz, 5'C)1 155.61 (d, J=245.1 Hz, 5C),
160.17 (16'C), 162.04 (16C), 166.00, 166.14 (22C, 22'C), 176.17, 176.22 (11C, 111C).
DIP MS: m/z (%)- 863 [M+H]+, 885 [M+Na]+.
Example 15: Preparation of L-valinol Sodium borohydride (79 g) was suspended in tetrahydrofuran (662 mL) and L-valine (100 g, 0.85 mol) was added and stirred the mixture for 15 min. and cooled to 00C. A pre-cooled solution of sulfuric acid (105 mL) in tetrahydrofuran (76 mL) was added to the reaction mass at 0 to 50C over a period of 3 to 5 h. and stirred at ambient temperature for 18 h. The reaction mixture was concentrated under reduced pressure to remain about 400 mL of solvent. The resultant residue was cooled to ambient temperature and quenched with methanol (66 mL). The reaction mass was heated to 500C and sodium hydroxide (12.5N, 260 mL) solution was added to the reaction mass at the same temperature. The reaction mixture was concentrated under reduced pressure till temperature of the reaction mass reached 100 to 105°C. The reaction mass was cooled to 400C and charged isopropanol (330 mL) under stirring. The slurry was filtered and wet mass was treated twice with isopropanol (2 X 200 mL) at 80°C for 30 min and filtered. The combined isopropanol layer was concentrated under atmospheric pressure till reaction mass temperature reached to 100 to 105°C. The fractions were collected at 80 to 11O0C under reduced pressure [bath temp 150 to170°C] to get the L-valinol (75 g, SOR:+ 9.0° to + 11.0°, Purity by GC: NLT 95.0%).

Claims

We claim:
1. A process for preparing elvitegravir, a compound of formula 12,
Figure imgf000043_0001
comprising the steps of;
a) protecting the hydroxyl group of the compound of formula 6
Figure imgf000043_0002
6 - X = F, R' = Et
with tert-butytldimethylsilyl chloride in the presence of base in solvent to get formula 7,
Figure imgf000043_0003
' ^ - X = F, R' = Et, R" = TBDM S
b) reacting the compound of formula 7 with compound of formula 9 in the presence of tetrakis(triphenylphosphine)-palladium (0) catalyst in tetrahydrofuran to get compound of formula 10,
Figure imgf000043_0005
10 - X = F, R' = Et, R- = TBDM S
c) hydrolyzing and deprotecting the compound of formula 10 in the presence of base and solvent to get formula 11,
Figure imgf000044_0001
U - X = F
d) optionally treating the compound of formula 11 with amine in solvent to give amine addition salt of compound of formula 11 D,
HD
e) treating the compound of formula 11 D with an acid to get pure compound of formula 11,
f) reacting the compound of formula 11 or 11D with alkali methoxide in methanol to get elvitegravir (12).
2. The process according to claim 1 , wherein the solvent in step a) is selected from toluene, xylene or mixture thereof.
3. The process according to claim 1 , wherein the step a) and step c) the base is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate or potassium t-butoxide.
4. The process according to claim 1, wherein the said solvent in step c) is selected from methanol, ethanol, isopropyl alcohol or butanol.
5. The process according to claim 1 , wherein the said amine in step d) is selected from cyclohexylamine or dicyclohexyl amine.
6. The process according to claim 1 , wherein the said solvent in step d) is selected from ethylacetate, toluene or xylene.
7. The process according to claim 1, wherein the said acid in step e) is selected from hydrochloric acid, boron trifluoride etherate (BF3O(Et)2) or p-toluenesulfonic acid.
8. The process according to claim 1 , wherein alkali methoxide in step f) is selected from sodium methoxide, potassium methoxide or lithium methoxide.
9. A process for preparing elvitegravir, a compound of formula 12,
Figure imgf000045_0001
comprising the steps of;
a) reacting the compound of formula 6
Figure imgf000045_0002
6 - X = F, R' = Et with suitable protecting agent like 3-4-dihydro-2H-pyran in the presence of acid in solvent to get compound of formula 7A,
Figure imgf000045_0003
7A - X = F, R' = Et, R" = THP
b) reacting the compound of formula 7A with compound of formula 9
Figure imgf000045_0004
9
in the presence tetrakis(triphenylphosphine)-palladium (0) catalyst in tetrahydrofuran to get compound of formula 1OA,
Figure imgf000045_0005
10A - X = F, R1 = Et, R" = TH P
c) hydrolyzing and deprotecting the compound of formula 1OA in the presence of acid in solvent to get formula 11 ,
Figure imgf000046_0001
1 1 - X = F g) optionally treating the compound of formula 11 with amine in solvent to get amine addition salt of compound of formula 11 D,
Figure imgf000046_0002
HD
I O h) optionally treating the compound of formula 11D with acid in solvent to get pure formula 11 ,
i) reacting the compound of formula 11 or 11D with alkali methoxide in methanol to get elvitegravir (12).
10. The process according to claim 9, wherein the said solvent in step a) is selected from 15 dichloromethane, dichloroethane, chlorobenzene or mixture thereof.
11. The process according to claim 9, wherein the acid in step a), step d) and step h) is selected from hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, boron trifluoride etherate (BF3«O(Et)2) or p-toluenesulfonic acid.
12. The process according to claim 9, wherein said solvent in step c) is selected from 0 methanol, ethanol, isopropanol or butanol.
13. The process according to claim 9, wherein the amine in step g) is selected from cyclohexylamine or dicyclohexyl amine.
14. The process according to step g) of claim 9, wherein the said solvent is selected from ethylacetate, toluene, xylene.
5 15. The process according to claim 9, wherein alkali methoxide in step i) is selected from sodium methoxide, potassium methoxide or lithium methoxide.
16. A process for preparing elvitegravir, a compound of formula 12,
Figure imgf000047_0001
comprising the steps of;
a) reacting the compound of formula 1OA
Figure imgf000047_0002
with alkali methoxide in methanol to get formula 12C1
Figure imgf000047_0003
b) deprotecting the compound of formula 12C in the presence of an acid in solvent to get elvitegravir 12.
17. The process according to claim 16, wherein alkali methoxide in step a) is selected from sodium methoxide, potassium methoxide or lithium methoxide.
18. The process according to claim 16, wherein the acid in step b) is selected from hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, boron trifluoride etherate (BF3«O(Et)2) or p-toluenesulfonic.
19. A process for preparing elvitegravir, a compound of formula 12,
Figure imgf000047_0004
comprising the steps of;
a) hydrolysis of the compound of formula 1OA
Figure imgf000048_0001
1OA - X = F, R' = Et, R" = THP
with base in solvent to obtain compound of formula 11C
Figure imgf000048_0002
lie
b) reacting the compound formula 11C with alkali methoxide in methanol to get compound of formula 12C,
Figure imgf000048_0003
c) deprotecting the resultant 12C with acid in solvent to get elvitegravir (12).
20. The process according to claim 19, wherein the said solvent in step a) and step c) is selected from methanol, ethanol, isopropyl alcohol, butanol or water.
21. The process according to claim 19, wherein the said base in step a) is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate or potassium t-butoxide.
22. The process according to claim 19, wherein the said alkali methoxide in step b) is selected from sodium methoxide, potassium methoxide or lithium methoxide.
23. The process according to claim 19, wherein the acid in step c) is selected from hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, boron trifluoride etherate (BF3«O(Et)2) or p-toluenesulfonic acid.
24. A process for preparing elvitegravir, a compound of formula 12,
Figure imgf000049_0001
comprising the steps of;
a) hydrolyzing the compound of formula 1OA
Figure imgf000049_0002
I OA - X = F, R' = Et, R" = TH P
with base in solvent to obtain compound of formula 11C
Figure imgf000049_0003
UC
b) deprotecting the compound of formula 11C with acid in solvent to get the compound of formula 11
Figure imgf000049_0004
1 1 - X = F
c) reacting the compound formula 11 with alkali methoxide in methanol to get elvitegravir (12).
25. The process according to claim 24, wherein the said solvent in step a) and step b) is selected from methanol, ethanol, isopropyl alcohol, butanol or water.
26. The process according to claim 24, wherein the base in step a) is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate or potassium t-butoxide.
27. The process according to claim 24, wherein the acid in step b) is selected from hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, boron trifluoride etherate (BF3-O(Et)2) or p-toluenesulfonic acid.
28. The process according to claim 24, wherein alkali methoxide in step c) is selected from sodium methoxide, potassium methoxide or lithium methoxide.
29. A compound of formula 7A or solvate, stereoisomer, tautomer or it's pharmaceutically acceptable salts:
Figure imgf000050_0001
7A
30. A compound of formula 10A or solvate, stereoisomer, tautomer or it's pharmaceutically acceptable salts:
Figure imgf000050_0002
1OA
31. A compound of formula 11 A or solvate, stereoisomer or tautomer
Figure imgf000050_0003
32. The compound according to claim 31 , wherein the compound of formula 11 A is characterized by X-ray diffraction having at least three peaks at 7.43, 14.97, 15.85, 17.08, 22.91 , 24.08, ± 0.2Θ.
33. A compound of formula 11B or solvate, stereoisomer, tautomer or it's pharmaceutically acceptable salt thereof:
Figure imgf000051_0001
UB
34. A compound of formula 11C or solvate, stereoisomer, tautomer, or it's pharmaceutically acceptable salt thereof:
Figure imgf000051_0002
lie
35. A compound of formula 12B or solvate, stereoisomer, tautomer or it's pharmaceutically acceptable salts:
Figure imgf000051_0003
12B
36. A compound of formula 12C or solvate, stereoisomer, tautomer, or it's pharmaceutically acceptable salts :
Figure imgf000051_0004
37. A compound of formula 13 or solvate, stereoisomer, tautomer or it's pharmaceutically acceptable salts thereof:
Figure imgf000052_0001
38. Elvitegravir containing the dimmer impurity of formula (13) is less then 0.1%.
39. Elvitegravir having the HPLC purity more than 99%.
40. A pharmaceutical composition comprising: (a) a therapeutically effective amount of Elvitegravir free base or pharmaceutically acceptable salt; and (b) at least one pharmaceutically acceptable carrier.
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