WO2016193997A2 - Process for the preparation of 6-(3-chloro-2-fluorobenzyl)-1-[(2s)-1-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and pharmaceutically acceptable salts thereof - Google Patents

Process for the preparation of 6-(3-chloro-2-fluorobenzyl)-1-[(2s)-1-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and pharmaceutically acceptable salts thereof Download PDF

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WO2016193997A2
WO2016193997A2 PCT/IN2016/000142 IN2016000142W WO2016193997A2 WO 2016193997 A2 WO2016193997 A2 WO 2016193997A2 IN 2016000142 W IN2016000142 W IN 2016000142W WO 2016193997 A2 WO2016193997 A2 WO 2016193997A2
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formula
compound
chloro
fluorobenzyl
oxo
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PCT/IN2016/000142
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French (fr)
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WO2016193997A3 (en
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Srinivasan Thirumalai Rajan
Sajja Eswaraiah
Ghojala Venkat Reddy
Mallepally VENKAT REDDY
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Msn Laboratories Private Limited
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Publication of WO2016193997A3 publication Critical patent/WO2016193997A3/en

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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
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • C07D215/32—Esters
    • C07D215/34—Carbamates

Definitions

  • the present invention provides a process for the preparation of 6-(3-chloro-2- fluorobenzyl)- 1 - [(25)- 1 -hydroxy-3 -methylbutan-2-yl] -7-methoxy-4-oxo- 1 ,4-dihydro quinoline-3-carboxylic acid represented by the following structural formula- 1 and pharmaceutically acceptable salts thereof.
  • 6-(3 -Chloro-2-fluorobenzyl)- 1 -[(2S)- 1 -hydroxy-3 -methylbutan-2-yl] -7-methoxy-4- oxo-l ,4-dihydroquinoline-3-carboxylic acid is commonly known as Elvitegravir.
  • Elvitegravir is a drug used for the treatment of HIV infection. It acts as an integrase inhibitor. It was developed by the pharmaceutical company Gilead Sciences. This drug gained approval by U.S. Food and Drug Administration on August 27, 2012 for use in adult patients starting HIV treatment for the first time as part of the fixed dose combination known as Stribild.
  • the first aspect of the present invention is to provide a process for the preparation of 6-(3 -chloro-2-fluorobenzyl)- 1 - [(25)- 1 -hydroxy-3 -methylbutan-2-yl]-7-methoxy-4-oxo- 1 ,4- dihydroquinoline-3-carboxylic acid compound of formula- 1.
  • the second aspect of the present invention is to provide a process for the preparation of 6-(3 -chloro-2-fluorobenzyl)- 1 - [(25)- 1 -hydroxy-3 -methylbutan-2-yl] -7-methoxy-4-oxo- l,4-dihydroquinoline-3-carboxylic acid compound of formula- 1.
  • the third aspect of the present invention is to provide a process for the preparation of stable crystalline form-I of 6-(3-chloro-2-fluorobenzyl)-l -[(25)- 1 -hydroxy-3 -methylbutan-2- yl]-7-methoxy-4-oxo-l ,4-dihydroquinoline-3-carboxylic acid compound of formula-1.
  • the fourth aspect of the present invention is to provide alternate process for the preparation of crystalline form-I of 6-(3-chloro-2-fluorobenzyl)-l- [(25)- 1 -hydroxy-3 - methylbutan-2-yl]-7-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula-1.
  • the fifth aspect of the present invention is to provide a process for the preparation of crystalline form-II of 6-(3-chloro-2-fiuorobenzyl)-l-[(25)-l-hydroxy-3-methylbutan-2-yl]-7- methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula-1.
  • the sixth aspect of the present invention is to provide alternative process for the preparation of crystalline form-II of 6-(3-chloro-2-fluorobenzyl)-l-[(25)-l-hydroxy-3- methylbutan-2-yl]-7-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula-1.
  • the seventh aspect of the present invention is to provide process for the preparation of amorphous form of 6-(3-chloro-2-fluorobenzyl)-l-[(25)-l-hydroxy-3-methylbutan-2-yl]-7- methoxy-4-oxo- 1 ,4-dihydroquinoline-3 -carboxylic acid compound of formula- 1.
  • suitable solvent refers to "hydrocarbon solvents” such as n-pentane, n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents” such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents” such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents” such as dimethylacetamide, dimethylformamide, dimethylsulfox
  • suitable base refers to "inorganic bases” selected from “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium methoxide, lithium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; “alkali metal amides” such as sodium amide, potassium amide, lithium amide and the like; alkali metal carbonates” such as sodium
  • the first aspect of the present invention provides a process for the preparation of
  • 'R' represents Q-Q alkyl group
  • the suitable halogenating agent is selected from but not limited to N-halosuccinimides such as N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, Cl 2 , Br 2 , 1 2 and the like; and the suitable acid is selected from sulfuric acid, hydrochloric acid, formic acid, acetic acid, trifluoroacetic acid or a Lewis acid.
  • N-halosuccinimides such as N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, Cl 2 , Br 2 , 1 2 and the like
  • the suitable acid is selected from sulfuric acid, hydrochloric acid, formic acid, acetic acid, trifluoroacetic acid or a Lewis acid.
  • the suitable esterification catalyst is selected from thionyl chloride, oxalyl chloride, sulfuric acid, hydrochloric acid, trifluoroacetic acid and the like;
  • step-c) the suitable catalyst is selected from but not limited to Pd(PPh 3 )2Cl 2,
  • Pd(PPh 3 ) 4 Pd(OAc) 2 , PdCl 2 , Pd(OH) 2 , Pd(dba) 2 , Pd 2 (dba) 3 , Pd(dppe) 2 Cl 2 , Pd(dppf)Cl 2 , Pd(dppf)Cl 2 .CH 2 Cl 2 , Pd(dcypp)Cl 2 , Pd(PhCN) 2 Cl 2 , Pd(CH 3 CN) 2 Cl 2 and the like;
  • the suitable base is selected from hydroxides, alkoxides and carbonates of alkali metals;
  • the suitable coupling agent is selected from but not limited to l ,l '-carbonyl diimidazole (CDI), ⁇ , ⁇ '-dicyclohexylcarbodiimide (DCC), ⁇ , ⁇ '-diisopropyl carbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluoro phosphate (HATU), 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluoro phosphate (HBTU), lH-benzo tria
  • the suitable base is selected from organic bases, inorganic bases or their mixtures;
  • step-h) the conversion of compound of general formula- 10 to compound of formula- 1 can be carried out by reacting it with a suitable alkali metal methoxide in a suitable solvent in presence of catalytic amount of water; on the other hand, the said conversion can also be done by hydrolysis of ester group of compound of general formula- 10 to corresponding acid followed by reacting the obtained compound with a suitable alkali metal methoxide to provide compound of formula- 1 ;
  • the said conversion can be carried out by reacting the compound of formula- 10 with a suitable alkali meal methoxide to convert the fiuoro group to methoxide followed by hydrolysis of obtained compound to provide compound of formula- 1.
  • the suitable solvent wherever necessary is selected from but not limited to hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid or their mixtures.
  • the 2,4-difluorobenzoic acid compound of formula-2 utilized in the present invention can be prepared by any of the known processes or it can be procured from commercial sources.
  • the second aspect of the present invention provides a process for the preparation of 6-(3-chloro-2-fluorobenzyl)-l -[(2S)- 1 -hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo- 1 ,4- dihydroquinoline-3-carboxylic acid compound of formula- 1, comprising of reacting the compound of general formula- 10
  • alkali metal methoxide is selected from sodium methoxide, potassium methoxide, lithium methoxide, cesium methoxide and the like; and the suitable solvent is selected from alcohol solvents.
  • a preferred embodiment of the present invention provides a process for the preparation of 6-(3 -chloro-2-fluorobenzyl)- 1 - [(2S)- 1 -hydroxy-3 -methylbutan-2-yl]-7- methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula-1, comprising of reacting the (S)-ethyl 6-(3-chloro-2-fluorobenzyl)-l-[(2S)-l-hydroxy-3-methylbutan-2-yl]- 7-fluoro-4-oxo-l,4-dihydroquinoline-3-carboxylate compound of formula- 10a with sodium methoxide in presence of methanol and water to provide compound of formula-1.
  • the third aspect of the present invention provides a process for the preparation of stable crystalline form-I of 6-(3-chloro-2-fluorobenzyl)-l-[(2S)-l-hydroxy-3-methylbutan-2- yl]-7-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula-1, comprising of;
  • step-a) adding the solution obtained in step-a) to pre-cooled water at a suitable temperature, c) filtering the solid and drying to provide crystalline form-I of compound of formula- 1.
  • step-a) the dissolution of compound of formula-1 in methanol is carried out at a temperature ranges from 50°C to 65 °C;
  • step-b) the suitable temperature is 20 ⁇ 2°C.
  • a preferred embodiment of the present invention provides a process for the preparation of stable crystalline form-I of 6-(3-chloro-2-fluorobenzyl)-l-[(2S -l-hydroxy-3- methylbutan-2-yl]-7-methoxy-4-oxo-l ,4-dihydroquinoline-3-carboxylic acid compound of formula-1, comprising of;
  • step-a) adding the solution obtained in step-a) to pre-cooled water at 20 ⁇ 2°C,
  • the fourth aspect of the present invention provides alternate process for the preparation of crystalline form-I of 6-(3-chloro-2-fluorobenzyl)-l-[(25)-l-hydroxy-3- methylbutan-2-yl]-7-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula- 1, comprising of;
  • the suitable solvent is selected from hydrocarbon solvents, preferably toluene and xylene.
  • a preferred embodiment of the present invention provides a process for the preparation of crystalline form-I of 6-(3-chloro-2-fluorobenzyl)-l-[(25 -l-hydroxy-3- methylbutan-2-yl]-7-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula- 1 , comprising of;
  • crystalline form-I of compound of formula- 1 used as seeding material can be synthesized by any of the known processes or it can be synthesized by the process described in the present invention.
  • the fifth aspect of the present invention provides a process for the preparation of crystalline form-II of 6-(3-chloro-2-fluorobenzyl)-l-[(25')-l-hydroxy-3-methylbutan-2-yl]-7- methoxy-4-oxo-l ,4-dihydroquinoline-3-carboxylic acid compound of formula- 1, comprising of;
  • step-a) combining the solution obtained in step-a) with a suitable anti-solvent selected from n-hexane or n-heptane to provide crystalline form-II of compound of formula- 1.
  • a suitable anti-solvent selected from n-hexane or n-heptane
  • step-a) the dissolution of compound of formula- 1 in the solvent is carried out by refluxing compound of formula- 1 in the said solvent;
  • step-b) after combining the solution obtained in step-a) with anti-solvent, the reaction mixture is cooled to a suitable temperature ranges from 0°C to 30°C, preferably to 25-30°C to precipitate crystalline form-II which is further filtered and dried.
  • a preferred embodiment of the present invention provides a process for preparation of crystalline form-II of 6-(3-chloro-2-fluorobenzyl)-l-[(2iS -l-hydroxy-3-methylbutan-2-yl]-7- methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula-1, comprising; a) Dissolving the compound of formula-1 by refluxing in toluene,
  • the present inventors were able to achieve compound of formula-1 with excellent impurity profile and the formation of dimer impurity is drastically reduced to minimum level which makes the process highly advantageous.
  • the sixth aspect of the present invention provides alternative process for the preparation of crystalline form-II of 6-(3-chloro-2-fluorobenzyl)-l-[(2S)-l-hydroxy-3- methylbutan-2-yl]-7-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula- 1, comprising of recrystallizing the compound of formula-1 from xylene.
  • the seventh aspect of the present invention provides process for the preparation of amorphous form of 6-(3 -chloro-2-fluorobenzyl)- 1 - [(25)- 1 -hydroxy-3 -methylbutan-2-yl] -7- methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula-1, comprising of;
  • the suitable solvent is selected from chloro solvents, ketone solvents, ester solvents, ether solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents or their mixtures.
  • suitable techniques which may be used for the removal of solvent from the reaction mixture includes but not limited to evaporation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, vacuum distillation, distillation by using a rotational distillation device such as a Buchi Rotavapor, agitated thin film drying, melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, addition of suitable anti-solvent to the reaction mixture fqllowed by filtration of the precipitated solid, cooling the clear solution to lower temperatures such as below 20°C to precipitate the solid followed by filtration or by any other suitable techniques.
  • a rotational distillation device such as a Buchi Rotavapor
  • agitated thin film drying melt extrusion
  • spray drying freeze drying (lyophilization)
  • spray-freeze drying addition of suitable anti-solvent to the reaction mixture fqllowed by filtration of the precipitated solid, cooling the clear solution to lower temperatures such as below 20°C to precipitate the solid followed by filtration
  • a preferred embodiment of the present invention provides a process for the preparation of amorphous form of 6-(3-chloro-2-fluorobenzyl)-l -[(2 ⁇ S)-l-hydroxy-3- methylbutan-2-yl]-7-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula- 1, comprising of;
  • the compound of general formula- 10 of the present invention can also be converted to compound of formula- 1 by below sequence of steps as shown in scheme-2.
  • the O-protecting group 'Pi' is selected from but not limited to benzyloxycarbonyl (Cbz), Ci-C 6 straight chain or branched chain alkoxy carbonyl such as methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl (Boc), acetyl (Ac), trichloroacetyl, trifluoroacetyl (TFA), 1 -ethoxyethyl (EE), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), methylthiomethyl (MTM), pivaloyl (Piv), trityl (triphenylmethyl or Tr), methoxy- iso-propanyl, tri(C 1 -C 6 straight chain or branched chain alkyl)silyl groups such as frimethyl silyl (TMS), tri-ethylsilyl (TES), triisopropyl
  • the suitable deprotecting agent in the present invention is selected from but not limited to acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aqueous phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, alkyl/aryl sulfonic acids such as methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid and the like; acetyl chloride in combination with alcohols; bases such as alkali metal hydroxides, alkali metal carbonates, cesium carbonate/imidazole, alkali metal bicarbonates; sodium bisulfate, tetra-n- butylammonium fluoride (TBAF), ammonia, cerium(IV) ammonium nitrate (CAN), Fe or Zn in combination with HC1,
  • the conversion of compound of formula- 11 to compound of formula- 12 can be done in the same manner as described above for the conversion of compound of formula- 10 to compound of formula- 1.
  • the compound of formula- 1 obtained in the above process can be optionally converted to its pharmaceutically acceptable salts using conventional manners and the obtained salts can be further neutralized to provide pure compound of formula- 1.
  • the compound of formula- 1 in various polymorphic forms produced by the process of the present invention is well suitable for the preparation of pharmaceutical compositions.
  • the compound of formula- 1 produced by the process of the present invention was analyzed by HPLC under the following conditions;
  • Apparatus A liquid chromatographic system equipped with variable wavelength UV detector; Column: YMC pack Pro CI 8, 150 x 4.6 mm, S-3 ⁇ , 12 nm or equivalent; Flow rate: 1.0 mL/min; Column temperature: 35°C; Wave length: 260 nm; Injection volume: 5 ⁇ ; Run time: 52 min; Elution: Gradient; Diluent: acetonitrile : water (9:1 v/v); Buffer: Weigh accurately about 1.74 gm of dipotassium hydrogen phosphate and add 2 mL of triethylamine into 1000 mL of milli-Q-water and adjust its pH to 6.0 with dil.orthophosphoric acid, filter this solution through 0.22 ⁇ Nylon membrane filter paper; Mobile phase-A: Buffer: methanol (90:10 v/v); Mobile phase-B: Acetonitrile: water (90:10 v/v).
  • the compound of formula- 1 produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
  • the present invention is schematically represented as follows. Scheme-1:
  • 'X' represents halogen
  • 'R' represents Cj-C 6 straight chain or branched chain alkyl group
  • 'Pi' represents O-protecting group.
  • N-iodosuccinimide (71.1 gm) was slowly added to a pre-cooled mixture of 2,4-difluorobenzoic acid compound of formula-2 (50 gm) and conc.H 2 S0 4 (150 ml) at 0-5°C and stirred the reaction mixture for 3 hrs at the same temperature. Quenched the reaction mixture by pouring it slowly into ice water. Aqueous sodium sulfite solution was added to the reaction mixture and stirred for 1 hr. Filtered the solid and washed with water. 250 ml of water was added to the obtained compound and adjusted the pH to 3.5 using ammonia solution and stirred the reaction mixture for 30 min. Filtered the solid and washed with water.
  • reaction mixture was slowly added to a pre-heated mixture of tetrahydrofuran (50 ml), methyl 2,4-difluoro-5- iodobenzoate compound of formula-4b (50 gm) and dichlorobis(triphenylphosphine) palladium (II) (1.17 gm) at 60-65 °C under nitrogen atmosphere and stirred the reaction mixture for 2 hrs at the same temperature. Cooled the reaction mixture to 25-30°C, water (250 ml) and sodium hydroxide (33.5 gm) were added at the same temperature. Heated the reaction mixture to 60-65°C and stirred for 2 hrs at the same- temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure.
  • N,N-Dimethylformamide (0.37 gm) was slowly added to a mixture of 5-(3-chloro-2- fluorobenzyl)-2,4-difluorobenzoic acid compound of formula-6 (7.8 gm), oxalyl chloride (4.45 ml) and dichloromethane (39 ml) at 25-30°C under nitrogen atmosphere and stirred the reaction mixture for 2 hrs at the same temperature. Distilled off the solvent completely form the reaction mixture under reduced pressure and co-distilled with dichloromethane. 19.5 ml of dichloromethane was added to the obtained compound at 25-30°C.
  • Example-6 Preparation of 6-(3-chloro-2-fluorobenzyl)-l-[(2S)-l-hydroxy-3-methyl butan-2-yl]-7-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid (Formula-1)
  • Example-7 Purification of 6-(3-chloro-2-fluorobenzyl)-l-[(2S)-l-hydroxy-3-methyl butan-2-yl]-7-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid (Formula-1)
  • Fluoro ester impurity Not detected, Desbenzyl impurity: Not detected, Ethoxy impurity: Not detected, Desbenzyl bromo impurity: Not detected, R-isomer impurity: Not detected, Dimer impurity: 0.01%, Deschloro impurity: 0.02%.
  • D(0.1) is 6.81 ⁇
  • D(0.5) is 24.92 ⁇
  • D(0.9) is 58.33 ⁇ ⁇ .
  • Charcoal (10 gm) was added to the obtained compound at 60-65°C and stirred for 20 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with methanol. Reduced the temperature of the filtrate to 50-55°C and was added to pre-cooled water (1000 ml) at 15-20°C and stirred the reaction mixture for 6 hrs at the same temperature. Filtered the precipitated solid, washed with water and dried the material.
  • the obtained hot solution was slowly added to pre-cooled toluene (500 ml) containing seeding material of crystalline form-I of compound of formula- 1 (20 gm) at 10-15 °C and stirred the reaction mixture for 5 hrs at the same temperature. Filtered the solid, washed with toluene and dried the material to provide the title compound.

Abstract

The present invention relates to a process for the preparation of 6-(3-chloro-2-fluorobenzyl)-1-[(2S)-1-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid represented by the following structural formula-1 and pharmaceutically acceptable salts thereof.

Description

Process for the preparation of 6-(3-chloro-2-fluorobenzyn-l-r(2$)-l-hvdroxy-3- methylbutan-2-yll-7-methoxy-4-oxo-l,4-dihvdroquinoline-3-carboxylic acid and pharmaceutically acceptable salts thereof
Related Application:
This application claims the benefit of priority of our Indian patent application 2784/CHE/2015 filed on 3rd June 2015 which is incorporated herein by reference.
Field of the Invention:
The present invention provides a process for the preparation of 6-(3-chloro-2- fluorobenzyl)- 1 - [(25)- 1 -hydroxy-3 -methylbutan-2-yl] -7-methoxy-4-oxo- 1 ,4-dihydro quinoline-3-carboxylic acid represented by the following structural formula- 1 and pharmaceutically acceptable salts thereof.
Figure imgf000003_0001
Formula- 1
Background of the Invention:
6-(3 -Chloro-2-fluorobenzyl)- 1 -[(2S)- 1 -hydroxy-3 -methylbutan-2-yl] -7-methoxy-4- oxo-l ,4-dihydroquinoline-3-carboxylic acid is commonly known as Elvitegravir.
Elvitegravir is a drug used for the treatment of HIV infection. It acts as an integrase inhibitor. It was developed by the pharmaceutical company Gilead Sciences. This drug gained approval by U.S. Food and Drug Administration on August 27, 2012 for use in adult patients starting HIV treatment for the first time as part of the fixed dose combination known as Stribild.
Elvitegravir, its pharmaceutically acceptable salts and process for their preparation first described in US7176220B2. Brief description of the invention:
The first aspect of the present invention is to provide a process for the preparation of 6-(3 -chloro-2-fluorobenzyl)- 1 - [(25)- 1 -hydroxy-3 -methylbutan-2-yl]-7-methoxy-4-oxo- 1 ,4- dihydroquinoline-3-carboxylic acid compound of formula- 1.
The second aspect of the present invention is to provide a process for the preparation of 6-(3 -chloro-2-fluorobenzyl)- 1 - [(25)- 1 -hydroxy-3 -methylbutan-2-yl] -7-methoxy-4-oxo- l,4-dihydroquinoline-3-carboxylic acid compound of formula- 1. The third aspect of the present invention is to provide a process for the preparation of stable crystalline form-I of 6-(3-chloro-2-fluorobenzyl)-l -[(25)- 1 -hydroxy-3 -methylbutan-2- yl]-7-methoxy-4-oxo-l ,4-dihydroquinoline-3-carboxylic acid compound of formula-1.
The fourth aspect of the present invention is to provide alternate process for the preparation of crystalline form-I of 6-(3-chloro-2-fluorobenzyl)-l- [(25)- 1 -hydroxy-3 - methylbutan-2-yl]-7-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula-1.
The fifth aspect of the present invention is to provide a process for the preparation of crystalline form-II of 6-(3-chloro-2-fiuorobenzyl)-l-[(25)-l-hydroxy-3-methylbutan-2-yl]-7- methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula-1.
The sixth aspect of the present invention is to provide alternative process for the preparation of crystalline form-II of 6-(3-chloro-2-fluorobenzyl)-l-[(25)-l-hydroxy-3- methylbutan-2-yl]-7-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula-1.
The seventh aspect of the present invention is to provide process for the preparation of amorphous form of 6-(3-chloro-2-fluorobenzyl)-l-[(25)-l-hydroxy-3-methylbutan-2-yl]-7- methoxy-4-oxo- 1 ,4-dihydroquinoline-3 -carboxylic acid compound of formula- 1. Detailed description of the Invention:
The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-pentane, n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents" such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, t-butanol, ethane- 1,2-diol, propane- 1 ,2-diol and the like; "polar solvents" such as water; formic acid, acetic acid or mixture of any of the aforementioned solvents.
The term "suitable base" used in the present invention refers to "inorganic bases" selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium methoxide, lithium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal amides" such as sodium amide, potassium amide, lithium amide and the like; alkali metal and alkali earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate and the like; ammonia; "organic bases" like dimethylamine, diethylamine, diisopropylamine, diisopropylethylamine, diisobutylamine, triethylamine, triisopropyl amine, tributylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), imidazole, N-methylimidazole, l ,8-diazabicyclo[5.4.0] undec-7-ene (DBU), l ,5-diazabicyclo[4.3.0]non-
5- ene (DBN), N-methylmorpholine (NMM), l ,4-diazabicyclo[2.2.2]octane (DABCO), 2,6-lutidine and the like; "organolithium bases" such as methyl lithium, n-butyl lithium, lithium diisopropylamide (LDA) and the like; "organosilicon bases" such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or their mixtures.
The first aspect of the present invention provides a process for the preparation of
6- (3-chloro-2-fluorobenzyl)- l -[(2S)- 1 -hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo- 1 ,4- dihydroquinoline-3-carboxylic acid compound of formula- 1 , comprising of;
a) Halogenation of 2,4-difluorobenzoic acid compound of formula-2
Figure imgf000006_0001
Formula-2
by treating it with a suitable halogenating agent optionally in presence of a suitable acid and/or a suitable solvent to provide 2,4-difluoro-5-halobenzoic acid compound of general formula-3,
Figure imgf000006_0002
Formula-3
wherein, 'X' represents halogen;
b) esterification of compound of general formula-3 by reacting it with a suitable Ci-C alcohol in presence of a suitable esterification catalyst optionally in presence of a suitable solvent to provide compound of general formula-4,
Figure imgf000006_0003
Formula-4
wherein, 'R' represents Cj-C6 straight chain or branched chain alkyl group; c) converting the 3-chloro-2-fluoro benzyl halide to the corresponding zinc derivative and reacting the obtained compound with compound of general formula-4 in presence of a suitable catalyst in a suitable solve und of general formula-5,
Figure imgf000007_0001
Formula-5
d) hydrolyzing the compound of general formula-5 in presence of a suitable base optionally in presence of a solvent to provide 5-(3-chloro-2-fluorobenzyl)-2,4-difluorobenzoic acid compound of formula-6,
Figure imgf000007_0002
Formula-6
e) reacting the compound of formula-6 with alkyl-3-(dimethylamino)acrylate compound of general formula-7
Figure imgf000007_0003
Formula-7
wherein, 'R' represents Q-Q alkyl group;
in a suitable solvent optionally in presence of a suitable coupling agent and/or a suitable base to provide compound of general formula-8,
Figure imgf000007_0004
f) - reacting the compound of general formula-8 with L-valinol in a suitable solvent to provide compound of general formula-9,
Figure imgf000008_0001
Formula-9
g) cyclizing the compound of general formula-9 by treating it with a suitable base in a suitable solvent to provide compound of general formula- 10,
Figure imgf000008_0002
Formula- 10
h) converting the compound of general formula- 10 to compound of formula- 1,
i) purifying the compound of formula- 1 from a suitable solvent or mixture of solvents to provide pure compound of formula- 1.
Wherein, in step-a) the suitable halogenating agent is selected from but not limited to N-halosuccinimides such as N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, Cl2, Br2, 12 and the like; and the suitable acid is selected from sulfuric acid, hydrochloric acid, formic acid, acetic acid, trifluoroacetic acid or a Lewis acid.
In step-b) the suitable esterification catalyst is selected from thionyl chloride, oxalyl chloride, sulfuric acid, hydrochloric acid, trifluoroacetic acid and the like;
In step-c) the suitable catalyst is selected from but not limited to Pd(PPh3)2Cl2,
Pd(PPh3)4, Pd(OAc)2, PdCl2, Pd(OH)2, Pd(dba)2, Pd2(dba)3, Pd(dppe)2Cl2, Pd(dppf)Cl2, Pd(dppf)Cl2.CH2Cl2, Pd(dcypp)Cl2, Pd(PhCN)2Cl2, Pd(CH3CN)2Cl2 and the like;
In step-d) the suitable base is selected from hydroxides, alkoxides and carbonates of alkali metals; In step-e) the suitable coupling agent is selected from but not limited to l ,l '-carbonyl diimidazole (CDI), Ν,Ν'-dicyclohexylcarbodiimide (DCC), Ν,Ν'-diisopropyl carbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluoro phosphate (HATU), 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluoro phosphate (HBTU), lH-benzo triazolium l-[bis(dimethylamino)methylene]-5chloro- hexafluorophosphate (1 -) 3-oxide (HCTU), 0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyl uronium tetrafluoroborate (TBTU), alkyl/aryl haloformates selected from but not limited to ethyl chloroformate, benzylchloroformate; diphenylphosphoroazidate (DPPA), thionyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, 4-methyl-2- oxopentanoyl chloride (i-BuCOCOCl), (benzotriazol-l-yloxy) tris(dimethylamino) phosphonium hexafluorophosphate (BOP), benzotriazol-l-yl-oxy tripyrrolidinophosphonium hexafluorophosphate (PyBOP), methane sulfonyl chloride, p-toluenesulfonyl chloride and the like; the suitable base is selected from organic bases, inorganic bases, organolithium bases, organosilicon bases or their mixtures;
In step-g) the suitable base is selected from organic bases, inorganic bases or their mixtures;
In step-h) the conversion of compound of general formula- 10 to compound of formula- 1 can be carried out by reacting it with a suitable alkali metal methoxide in a suitable solvent in presence of catalytic amount of water; on the other hand, the said conversion can also be done by hydrolysis of ester group of compound of general formula- 10 to corresponding acid followed by reacting the obtained compound with a suitable alkali metal methoxide to provide compound of formula- 1 ;
In the other embodiment the said conversion can be carried out by reacting the compound of formula- 10 with a suitable alkali meal methoxide to convert the fiuoro group to methoxide followed by hydrolysis of obtained compound to provide compound of formula- 1.
In step-a) to step-i) the suitable solvent wherever necessary is selected from but not limited to hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid or their mixtures. The 2,4-difluorobenzoic acid compound of formula-2 utilized in the present invention can be prepared by any of the known processes or it can be procured from commercial sources.
The second aspect of the present invention provides a process for the preparation of 6-(3-chloro-2-fluorobenzyl)-l -[(2S)- 1 -hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo- 1 ,4- dihydroquinoline-3-carboxylic acid compound of formula- 1, comprising of reacting the compound of general formula- 10
Figure imgf000010_0001
Formula- 10
wherein, 'R' is as defined above;
with alkali metal methoxide in a suitable solvent in presence of catalytic amount of water to provide compound of formula-1.
Wherein, alkali metal methoxide is selected from sodium methoxide, potassium methoxide, lithium methoxide, cesium methoxide and the like; and the suitable solvent is selected from alcohol solvents.
A preferred embodiment of the present invention provides a process for the preparation of 6-(3 -chloro-2-fluorobenzyl)- 1 - [(2S)- 1 -hydroxy-3 -methylbutan-2-yl]-7- methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula-1, comprising of reacting the (S)-ethyl 6-(3-chloro-2-fluorobenzyl)-l-[(2S)-l-hydroxy-3-methylbutan-2-yl]- 7-fluoro-4-oxo-l,4-dihydroquinoline-3-carboxylate compound of formula- 10a with sodium methoxide in presence of methanol and water to provide compound of formula-1. US7635704B2 assigned to Japan Tobacco Inc., has described three crystalline polymorphs of compound of formula-1 viz., crystalline form-I, form-II & form-Ill and also disclosed their process fof preparation. In US7635704B2 patent, the applicant has disclosed that crystalline form-I of compound of formula- 1 was found to be unstable.
However, it is highly recommended for a formulation scientist to have stable API to develop a better finished product.
The third aspect of the present invention provides a process for the preparation of stable crystalline form-I of 6-(3-chloro-2-fluorobenzyl)-l-[(2S)-l-hydroxy-3-methylbutan-2- yl]-7-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula-1, comprising of;
a) Dissolving the compound of formula-1 in methanol,
b) adding the solution obtained in step-a) to pre-cooled water at a suitable temperature, c) filtering the solid and drying to provide crystalline form-I of compound of formula- 1. Wherein, in step-a) the dissolution of compound of formula-1 in methanol is carried out at a temperature ranges from 50°C to 65 °C;
In step-b) the suitable temperature is 20±2°C.
A preferred embodiment of the present invention provides a process for the preparation of stable crystalline form-I of 6-(3-chloro-2-fluorobenzyl)-l-[(2S -l-hydroxy-3- methylbutan-2-yl]-7-methoxy-4-oxo-l ,4-dihydroquinoline-3-carboxylic acid compound of formula-1, comprising of;
a) Dissolving the compound of formula-1 by refluxing in methanol,
b) adding the solution obtained in step-a) to pre-cooled water at 20±2°C,
c) filtering the solid and drying to provide crystalline form-I of compound of formula-1.
By developing the above described process, the present inventors were able to isolate stable crystalline form-I of compound of formula-1 which is highly advantageous when compared to the prior known process. The fourth aspect of the present invention provides alternate process for the preparation of crystalline form-I of 6-(3-chloro-2-fluorobenzyl)-l-[(25)-l-hydroxy-3- methylbutan-2-yl]-7-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula- 1, comprising of;
a) Providing a solution of compound of formula- 1 in a suitable solvent,
b) seeding the reaction mixture with crystalline form-I of compound of formula- 1.
Wherein, the suitable solvent is selected from hydrocarbon solvents, preferably toluene and xylene.
A preferred embodiment of the present invention provides a process for the preparation of crystalline form-I of 6-(3-chloro-2-fluorobenzyl)-l-[(25 -l-hydroxy-3- methylbutan-2-yl]-7-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula- 1 , comprising of;
a) Dissolving compound of formula- 1 by refluxing in toluene,
b) slowly adding the obtained solution to pre-cooled toluene containing seeding material of crystalline form-I at 10-15°C,
c) filtering the solid and drying to provide crystalline form-I of compound of formula- 1. In the above process, crystalline form-I of compound of formula- 1 used as seeding material can be synthesized by any of the known processes or it can be synthesized by the process described in the present invention.
The fifth aspect of the present invention provides a process for the preparation of crystalline form-II of 6-(3-chloro-2-fluorobenzyl)-l-[(25')-l-hydroxy-3-methylbutan-2-yl]-7- methoxy-4-oxo-l ,4-dihydroquinoline-3-carboxylic acid compound of formula- 1, comprising of;
a) Dissolving the compound of formula- 1 in a suitable solvent selected from toluene or xylene,
b) combining the solution obtained in step-a) with a suitable anti-solvent selected from n-hexane or n-heptane to provide crystalline form-II of compound of formula- 1. Wherein, in step-a) the dissolution of compound of formula- 1 in the solvent is carried out by refluxing compound of formula- 1 in the said solvent;
In step-b) after combining the solution obtained in step-a) with anti-solvent, the reaction mixture is cooled to a suitable temperature ranges from 0°C to 30°C, preferably to 25-30°C to precipitate crystalline form-II which is further filtered and dried.
A preferred embodiment of the present invention provides a process for preparation of crystalline form-II of 6-(3-chloro-2-fluorobenzyl)-l-[(2iS -l-hydroxy-3-methylbutan-2-yl]-7- methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula-1, comprising; a) Dissolving the compound of formula-1 by refluxing in toluene,
b) combining the solution obtained in step-a) with n-heptane,
c) cooling the reaction mixture to 25-30°C
d) filtering the precipitated solid and drying to provide crystalline form-II of compound of formula-1.
By developing the above described process, the present inventors were able to achieve compound of formula-1 with excellent impurity profile and the formation of dimer impurity is drastically reduced to minimum level which makes the process highly advantageous.
The sixth aspect of the present invention provides alternative process for the preparation of crystalline form-II of 6-(3-chloro-2-fluorobenzyl)-l-[(2S)-l-hydroxy-3- methylbutan-2-yl]-7-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula- 1, comprising of recrystallizing the compound of formula-1 from xylene.
The seventh aspect of the present invention provides process for the preparation of amorphous form of 6-(3 -chloro-2-fluorobenzyl)- 1 - [(25)- 1 -hydroxy-3 -methylbutan-2-yl] -7- methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula-1, comprising of;
a) Providing a solution of compound of formula-1 in a suitable solvent,
b) removing the solvent from the reaction mixture to provide amorphous form of compound of formula-1. Wherein, the suitable solvent is selected from chloro solvents, ketone solvents, ester solvents, ether solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents or their mixtures.
In step-b) suitable techniques which may be used for the removal of solvent from the reaction mixture includes but not limited to evaporation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, vacuum distillation, distillation by using a rotational distillation device such as a Buchi Rotavapor, agitated thin film drying, melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, addition of suitable anti-solvent to the reaction mixture fqllowed by filtration of the precipitated solid, cooling the clear solution to lower temperatures such as below 20°C to precipitate the solid followed by filtration or by any other suitable techniques.
A preferred embodiment of the present invention provides a process for the preparation of amorphous form of 6-(3-chloro-2-fluorobenzyl)-l -[(2<S)-l-hydroxy-3- methylbutan-2-yl]-7-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula- 1, comprising of;
a) Providing a solution of compound of formula- 1 in dichloromethane,
b) distilling off the solvent completely from the reaction mixture under reduced pressure to provide amorphous form of compound of formula- 1.
By developing the above described process for the preparation of compound of formula- 1, the present inventors were able to get compound of formula- 1 in excellent yield and quality with all the impurities and residual solvents controlled well within the limits as defined by ICH and most of the impurities in non-detectable level.
The below impurities are observed during the synthesis of compound of formula- 1 by the process of the present invention.
Figure imgf000015_0001
All the above impurities have been identified, characterized and well controlled within the limits in compound of formula- 1 as suggested by ICH guidelines.
The compound of general formula- 10 of the present invention can also be converted to compound of formula- 1 by below sequence of steps as shown in scheme-2.
In the present invention, the O-protecting group 'Pi' is selected from but not limited to benzyloxycarbonyl (Cbz), Ci-C6 straight chain or branched chain alkoxy carbonyl such as methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl (Boc), acetyl (Ac), trichloroacetyl, trifluoroacetyl (TFA), 1 -ethoxyethyl (EE), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), methylthiomethyl (MTM), pivaloyl (Piv), trityl (triphenylmethyl or Tr), methoxy- iso-propanyl, tri(C1-C6 straight chain or branched chain alkyl)silyl groups such as frimethyl silyl (TMS), tri-ethylsilyl (TES), triisopropylsilyl (TIPS), tri-iso-propylsilyloxymethyl (TOM), tert-butyl-dimethylsilyl (TBS or TBDMS), tert-butyl- biphenylsilyl (TBDIPS), furanidinyl, dihydropyran (DHP), tetrahydropyran (THP), trichloroethoxy carbonyl (Troc) and the like and it can be removed by treating the corresponding O-protected compound with a suitable deprotecting agent selected from an acid or a base or by hydrogenolysis depending on the nature of the protecting group employed. The suitable deprotecting agent in the present invention is selected from but not limited to acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aqueous phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, alkyl/aryl sulfonic acids such as methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid and the like; acetyl chloride in combination with alcohols; bases such as alkali metal hydroxides, alkali metal carbonates, cesium carbonate/imidazole, alkali metal bicarbonates; sodium bisulfate, tetra-n- butylammonium fluoride (TBAF), ammonia, cerium(IV) ammonium nitrate (CAN), Fe or Zn in combination with HC1, acetic acid or NH4C1; organic bases, pyridine-HF, pyridine-THF and the like; hydrogenating agents such as Pd/C, Pd(OH)2/C (Pearlman's catalyst), palladium acetate, platinum oxide, platinum black, sodium borohydride, Na-liq.NH3, Raney-Ni, tri(C1-C6)alkylsilanes, tri(Ci-C6)alkylsilyl halides and the like. In this process, the conversion of compound of formula- 11 to compound of formula- 12 can be done in the same manner as described above for the conversion of compound of formula- 10 to compound of formula- 1. The compound of formula- 1 obtained in the above process can be optionally converted to its pharmaceutically acceptable salts using conventional manners and the obtained salts can be further neutralized to provide pure compound of formula- 1.
The compound of formula- 1 in various polymorphic forms produced by the process of the present invention is well suitable for the preparation of pharmaceutical compositions.
The compound of formula- 1 produced by the process of the present invention was analyzed by HPLC under the following conditions;
Apparatus: A liquid chromatographic system equipped with variable wavelength UV detector; Column: YMC pack Pro CI 8, 150 x 4.6 mm, S-3 μιη, 12 nm or equivalent; Flow rate: 1.0 mL/min; Column temperature: 35°C; Wave length: 260 nm; Injection volume: 5 μί; Run time: 52 min; Elution: Gradient; Diluent: acetonitrile : water (9:1 v/v); Buffer: Weigh accurately about 1.74 gm of dipotassium hydrogen phosphate and add 2 mL of triethylamine into 1000 mL of milli-Q-water and adjust its pH to 6.0 with dil.orthophosphoric acid, filter this solution through 0.22 μηι Nylon membrane filter paper; Mobile phase-A: Buffer: methanol (90:10 v/v); Mobile phase-B: Acetonitrile: water (90:10 v/v).
The compound of formula- 1 produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product. The present invention is schematically represented as follows. Scheme-1:
Figure imgf000018_0001
Figure imgf000018_0002
Formula-10 Formula- 1 10a: R= C2H5
Figure imgf000019_0001
Forraula-1
Wherein, in the above schemes, 'X' represents halogen; 'R' represents Cj-C6 straight chain or branched chain alkyl group; 'Pi' represents O-protecting group.
The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.
Examples:
Example-1: Preparation of 2,4-difluoro-5-iodobenzoic acid (FormuIa-3b)
N-iodosuccinimide (71.1 gm) was slowly added to a pre-cooled mixture of 2,4-difluorobenzoic acid compound of formula-2 (50 gm) and conc.H2S04 (150 ml) at 0-5°C and stirred the reaction mixture for 3 hrs at the same temperature. Quenched the reaction mixture by pouring it slowly into ice water. Aqueous sodium sulfite solution was added to the reaction mixture and stirred for 1 hr. Filtered the solid and washed with water. 250 ml of water was added to the obtained compound and adjusted the pH to 3.5 using ammonia solution and stirred the reaction mixture for 30 min. Filtered the solid and washed with water. Ethyl acetate (25 ml) and cyclohexane (300 ml) were added to the obtained compound at 25-30°C. Heated the reaction mixture to 70-75°C and stirred for 15 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 40 min at the same temperature. Filtered the solid, washed with cyclohexane and dried the material to get the title compound.
Yield: 74.6 gm; MR: 155-159°C.
Example-2: Preparation of methyl 2,4-difluoro-5-iodobenzoate (Formula-4b)
Thionyl chloride (5.1 ml) was slowly added to a pre-cooled mixture of 2,4-difluoro-5- iodobenzoic acid compound of formula-3b (20 gm) and methanol (60 ml) at 0-5 °C under nitrogen atmosphere. Heated the reaction mixture to 60-65°C and stirred for 4 hrs at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. Water and dichloromethane were added to the obtained compound at 25-30°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with aqueous sodium bicarbonate solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 19.0 gm.
Example-3: Preparation of 5-(3-chloro-2-fluorobenzyl)-2,4-difluorobenzoic acid (Formula-6)
1 ,2-Dibromoethane (2.1 gm) and trimethylsilyl chloride (1.8 gm) were added to a pre-heated mixture of Zinc (24.1 gm) and tetrahydrofuran (50 ml) at 60-65°C under nitrogen atmosphere. A solution of 3-chloro-2-fluoro benzyl bromide (67.5 gm) in tetrahydrofuran (50 ml) was slowly added to the reaction mixture at 60-65°C and stirred for 30 min at the same temperature. Cooled the reaction mixture to 25-30°C. The obtained reaction mixture was slowly added to a pre-heated mixture of tetrahydrofuran (50 ml), methyl 2,4-difluoro-5- iodobenzoate compound of formula-4b (50 gm) and dichlorobis(triphenylphosphine) palladium (II) (1.17 gm) at 60-65 °C under nitrogen atmosphere and stirred the reaction mixture for 2 hrs at the same temperature. Cooled the reaction mixture to 25-30°C, water (250 ml) and sodium hydroxide (33.5 gm) were added at the same temperature. Heated the reaction mixture to 60-65°C and stirred for 2 hrs at the same- temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. Water was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Filtered the reaction mixture through hyflow bed, dichloromethane was added and stirred for 15 min. Both the organic and aqueous layers were separated and acidified the aqueous layer using aqueous hydrochloric acid. Filtered the precipitated solid, washed with water and dried the material to get the title compound.
Yield: 40.0 gm.
Example-4: Preparation of (S)-ethyl 2-(5-(3-chloro-2-fluorobenzyl)-2,4-difhioro benzoyl)-3-(l-hydroxy-3-methylbutan-2-ylamino)acrylate (Formula-9a)
N,N-Dimethylformamide (0.37 gm) was slowly added to a mixture of 5-(3-chloro-2- fluorobenzyl)-2,4-difluorobenzoic acid compound of formula-6 (7.8 gm), oxalyl chloride (4.45 ml) and dichloromethane (39 ml) at 25-30°C under nitrogen atmosphere and stirred the reaction mixture for 2 hrs at the same temperature. Distilled off the solvent completely form the reaction mixture under reduced pressure and co-distilled with dichloromethane. 19.5 ml of dichloromethane was added to the obtained compound at 25-30°C. A mixture of diisopropylethyl amine (5.5 ml), ethyl-3-(dimethylamino)acrylate compound of formula-7a (4.1 gm) and dichloromethane (19.5 ml) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 45-50°C and stirred for 2 hrs at the same temperature. Cooled the reaction mixture to 25-30°C, water was added and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated and dried the organic layer over sodium sulfate. L-Valinol (2.67 gm) was added to the organic layer at 25-30°C and stirred for 2 hrs at the same temperature. Water was added to the reaction mixture and stirred for 10 min. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer to get the title compound.
Yield: 11.3 gm.
Example-5: Preparation of (S)-ethyl 6-(3-chloro-2-fluorobenzyl)-l-[(2S)-l-hydroxy-3- methylbutan-2-yl]-7-fluoro-4-oxo-l,4-dihydroquinoline-3-carboxylate (Formula-lOa)
A mixture of (S)-ethyl 2-(5-(3-chloro-2-fluorobenzyl)-2,4-difluorobenzoyl)-3-(l- hydroxy-3-methylbutan-2-ylamino)acrylate compound of formula-9a (11.2 gm), potassium carbonate (8 gm) and acetonitrile (44.8 ml) was heated to 80-85°C and stirred the reaction mixture for 16 hrs at the same temperature. Water was added to the reaction mixture at 50-55°C and cooled the reaction mixture to 25-30°C. Filtered the solid, washed with water and then dried the material to get the title compound.
Yield: 5.0 gm.
Example-6: Preparation of 6-(3-chloro-2-fluorobenzyl)-l-[(2S)-l-hydroxy-3-methyl butan-2-yl]-7-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid (Formula-1)
28% Sodium methoxide solution in methanol (37.4 ml) was added to a mixture of (S)-ethyl 6-(3-chloro-2-fluorobenzyl)-l-[(2S)-l-hydroxy-3-methylbutan-2-yl]-7-fluoro-4- oxo-l,4-dihydroquinoline-3-carboxylate compound of formula- 10a (9 gm) and methanol (54 ml) at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 24 hrs at the same temperature. Cooled the reaction mixture to 25-30°C, charcoal was added and stirred for 30 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with methanol. Distilled off the solvent completely from the reaction mixture under reduced pressure. Ethyl acetate was added to the reaction mixture at 25-30°C. Acidified the reaction mixture using 20% aqueous hydrochloric acid solution and stirred the reaction mixture for 15 min. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced pressure. The obtained compound was purified by column chromatography using 90% ethyl acetate in cyclohexane to get pure title compound.
Yield: 5.0 gm; Purity by HPLC: 99%. Example-7: Purification of 6-(3-chloro-2-fluorobenzyl)-l-[(2S)-l-hydroxy-3-methyl butan-2-yl]-7-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid (Formula-1)
A mixture of 6-(3-chloro-2-fluorobenzyl)-l-[(2S)-l-hydroxy-3-methylbutan-2-yl]-7- methoxy-4-oxo- l ,4-dihydroquinoline-3-carboxylic acid compound of formula-1 (4 gm) and methanol (40 ml) was heated to 60-65°C and stirred the reaction mixture for 20 min at the same temperature. The obtained solution was slowly added to pre-heated water (40 ml) at 35-40°C. Cooled the reaction mixture to 25-30°C and stirred for 20 hrs at the same temperature. Filtered the precipitated solid, washed with methanol and then dried the material to get the title compound.
Yield: 2.8 gm.
Example-8: Preparation of 5-(3-chloro-2-fluorobenzyl)-2,4-difluorobenzoic acid
(Formula-6)
Step-1:
A mixture of 5-bromo-2,4-difluorobenzoic acid compound of formula-3a (100 gm) and methanol (500 ml) was stirred for 15 min at 25-30°C under nitrogen atmosphere and thionyl chloride (36.9 ml) was slowly added to it. Heated the reaction mixture to 55-60°C and stirred for 6 hrs at the same temperature. Reduced the temperature of the reaction mixture to 40-45°C and distilled off the solvent completely under reduced pressure. The residue obtained was cooled to 25-30°C, dichloromethane was added to it and stirred the reaction mixture for 15 min at the same temperature. Water was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with aqueous sodium bicarbonate solution. Distilled off the solvent completely from the organic layer. Tetrahydrofuran (300 ml) was added to the obtained compound at 25-30°C and stirred the reaction mixture for 20 min at the same temperature and the obtained reaction mixture was kept aside.
Step-2:
In another RBF, a mixture of Zinc dust (55.1 gm) and tetrahydrofuran (300 ml) was heated to 60-65°C under nitrogen atmosphere. Ethylene dibromide (5.94 gm) and trimethylsilyl chloride (4.58 gm) were slowly added to the reaction mixture at 60-65°C and stirred the reaction mixture for 20 min at the same temperature. A solution of 3-chloro-2-fluoro benzyl bromide (130.5 gm) in tetrahydrofuran (200 ml) was slowly added to the reaction mixture at 60-65°C and stirred the reaction mixture for 2 hrs at the same temperature. The reaction mixture was cooled to 25-30°C and kept aside.
Step-3:
A mixture of dichlorobis(triphenylphosphine)palladium (II) (2.96 gm) and tetrahydrofuran (200 ml) was heated to 60-65°C under nitrogen atmosphere. Tetrahydrofuran solution obtained in step-1 was slowly added to the reaction mixture at 60-65°C and stirred the reaction mixture for 15 min at the same temperature. Zinc bromide complex obtained in step-2 was slowly added to the reaction mixture at 60-65 °C and stirred the reaction mixture for 3 hrs at the same temperature. Cooled the reaction mixture to 25-30°C, aqueous sodium hydroxide solution (84 gm of sodium hydroxide dissolved in 500 ml of water) was added to it and stirred for 10 hrs at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with tetrahydrofuran. Distilled off the solvent completely from the filtrate. Water was added to the obtained compound at 25-30°C and stirred for 15 min at the same temperature. Charcoal (5 gm) was added to the reaction mixture at 25-30°C and stirred for 30 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with toluene. Acidified the filtrate using aqueous HC1 solution at 25-30°C and stirred the reaction mixture for 4 hrs at the same temperature. Filtered the precipitated solid, washed with water and suck dried the material. Cyclohexane (200 ml) was added to the obtained compound at 25-30°C and stirred the reaction mixture for 1 hr at the same temperature. Filtered the solid, washed with cyclohexane and dried the material to provide the title compound.
Yield: 93.0 gm; M.R: 170.6-172.9°C. Example-9: Preparation of (S)-ethyl 6-(3-chloro-2-fluorobenzyl)-l-[(2S)-l-hydroxy-3- methylbutan-2-yI]-7-fluoro-4-oxo-l,4-dihydroquinoline-3-carboxyIate (Formula-lOa)
A mixture of 5-(3-chloro-2-fluorobenzyl)-2,4-difluorobenzoic acid compound of formula-6 (100 gm) and dichloromethane (500 ml) was stirred for 15 min at 25-30°C under nitrogen atmosphere. Dimethylformamide (0.5 ml) was added to the reaction mixture at 25-30°C and cooled the reaction mixture to 0-5°C. Oxalyl chloride (42.2 gm) was slowly added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Distilled off the solvent completely from the reaction mixture and co-distilled with dichloromethane. Dichloromethane (300 ml) was added to the obtained compound at 25-30°C. A solution of ethyl-3-(dimethylamino) acrylate compound of formula- 7a (47.62 gm) and diisopropylethyl amine (51.5 gm) in dichloromethane (200 ml) was slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 40-45 °C and stirred for 6 hrs at the same temperature. Cooled the reaction mixture to 25-30°C, water was added and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with water. Distilled off the solvent completely from the organic layer. Cyclohexane (450 ml) was added to the obtained compound at 25-30°C and stirred the reaction mixture for 4 hrs at the same temperature. Ethyl acetate (50 ml) was added to the reaction mixture and stirred for 2 hrs. Filtered the solid, washed with cyclohexane and suck dried the material. Acetonitrile (350 ml) and L-Valinol (24 gm) were added to the obtained compound at 25-30°C and stirred the reaction mixture for 2 hrs at the same temperature. Potassium carbonate (137.9 gm) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 75-80°C and stirred for 14 hrs at the same temperature. Cooled the reaction mixture to 25-30°C, water was added and stirred for 3 hrs at the same temperature. Filtered the solid, washed with water and suck dried the material. Water (500 ml) was added to the obtained compound at 25-30°C and stirred for 30 min at the same temperature. Filtered the solid, washed with water and dried the material to provide the title compound.
Yield: 83.0 gm; M.R: 197-200°C.
Example-10: Preparation of 6-(3-chloro-2-fluorobenzyl)-l-[(2S)-l-hydroxy-3-methyl butan-2-yl]-7-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid (Formula-1)
A mixture of (S)-ethyl 6-(3-chloro-2-fluorobenzyl)-l-[(2S)-l-hydroxy-3-methyl butan-2-yl]-7-fluoro-4-oxo-l,4-dihydroquinoline-3-carboxylate compound of formula- 10a (100 gm) and methanol (2000 ml) was stirred for 15 min at 25-30°C under nitrogen atmosphere and water (5 ml) was added to it. 28% Sodium methoxide solution in methanol (207.8 ml) was slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 3 hrs at the same temperature. 28% Sodium methoxide solution in methanol (207.8 ml) was slowly added to the reaction mixture at 60-65°C and stirred for 3 hrs at the same temperature. 28% Sodium methoxide solution in methanol (207.8 ml) was slowly added to the reaction mixture at 60-65 °C. Further heated the reaction mixture to 70-75°C and stirred for 3 hrs at the same temperature. 28% Sodium methoxide solution in methanol (207.8 ml) was slowly added to the reaction mixture at 70-75°C and stirred for 10 hrs at the same temperature. Distilled off half of the solvent from the reaction mixture. Cooled the reaction mixture to 10-15°C, water and dichloromethane were added to it. Acidified the reaction mixture using aqueous HCl solution at 10-15°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and distilled off the solvent from the organic layer under reduced pressure. Toluene (250 ml) was added to the obtained compound at 25-30°C and stirred for 10 min at the same temperature. Heated the reaction mixture to 90-95 °C and stirred for 20 min at the same temperature. Charcoal (10 gm) was added to the reaction mixture at 90-95 °C and stirred for 30 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with hot toluene. Cooled the filtrate to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid, washed with toluene and dried the material to provide the title compound.
Yield: 70.0 gm; Purity by HPLC: 99.22%.
Example-11: Preparation of crystalline form-II of compound of formula-1
The purification process exemplified in example- 10 was carried out by using o-xylene as solvent instead of toluene.
Yield: 88.6%.
Example-12: Preparation of crystalline form-II of compound of formula-1
A mixture of 6-(3-chloro-2-fluorobenzyl)-l-[(2S)-l-hydroxy-3-methylbutan-2-yl]-7- methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula-1 (50 gm) and toluene (1000 ml) was stirred for 10 min at 25-30°C. Heated the reaction mixture to 90-95°C and stirred for 30 min at the same temperature. n-Heptane (250 ml) was added to the reaction mixture at 90-95°C and stirred for 20 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hrs at the same temperature. Filtered the precipitated solid, washed with n-heptane and dried the material to provide pure title compound. Yield: 45.0 gm; Purity by HPLC: 99.8%.
Fluoro ester impurity: Not detected, Desbenzyl impurity: Not detected, Ethoxy impurity: Not detected, Desbenzyl bromo impurity: Not detected, R-isomer impurity: Not detected, Dimer impurity: 0.01%, Deschloro impurity: 0.02%.
Particle size distribution (before micronization): D(0.1) is 6.81 μιη; D(0.5) is 24.92 μπι; D(0.9) is 58.33 μιη.
Particle size distribution (after micronization): D(0.1) is 2.07 μη ; D(0.5) is 4.39 μπι; D(0.9) is 8.35 μπι. Example-13: Preparation of crystalline form-II of compound of formula-1
The process described in example- 12 was carried out by using toluene as solvent and n-hexane as anti-solvent.
Yield: 77%. Example-14: Preparation of crystalline form-II of compound of formula-1
The process described in example- 12 was carried out by using o-xylene as solvent and n-heptane as anti-solvent.
Yield: 88%. Example-15: Preparation of crystalline form-I of compound of formula-1
A mixture of 6-(3-chloro-2-fiuorobenzyl)-l-[(2S)-l-hydroxy-3-methylbutan-2-yl]-7- methoxy-4-oxo-l ,4-dihydroquinoline-3-carboxylic acid compound of formula-1 (10 gm) and methanol (100 ml) was stirred for 10 min at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 20 min at the same temperature. Reduced the temperature of the reaction mixture to 50-55°C and was slowly added to pre-cooled water (100 ml) at 15-20°C and stirred for 6 hrs at the same temperature. Filtered the precipitated solid, washed with aqueous methanol and then dried the material to provide the title compound.
Yield: 7.9 gm. Example-16: Preparation of crystalline form-I of compound of formula-1
A mixture of (S)-ethyl 6-(3-chloro-2-fluorobenzyl)-l-[(2S)-l-hydroxy-3-methyl butan-2-yl]-7-fluoro-4-oxo-l,4-dihydroquinoline-3-carboxylate compound of formula-10a (100 gm) and methanol (2000 ml) was stirred for 15 min at 25-30°C and water (5 ml) was added to it. 28% Sodium methoxide solution in methanol (207.8 ml) was slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 3 hrs at the same temperature. 28% Sodium methoxide solution in methanol (207.8 ml) was slowly added to the reaction mixture at 60-65 °C and stirred for 3 hrs at the same temperature. 28% Sodium methoxide solution in methanol (207.8 ml) was slowly added to the reaction mixture at 60-65°C. Further heated the reaction mixture to 70-75°C and stirred for 3 hrs at the same temperature. 28% Sodium methoxide solution in methanol (207.8 ml) was slowly added to the reaction mixture at 70-75 °C and stirred for 3 hrs at the same temperature. 28% Sodium methoxide solution in methanol (207.8 ml) was slowly added to the reaction mixture at 70- 75°C and stirred for 10 hrs at the same temperature. Reduced the temperature of the reaction mixture to 55-60°C and distilled off half of the solvent from the reaction mixture. Cooled the reaction mixture to 10-15°C, water and dichloromethane were added to it. Acidified the reaction mixture using aqueous hydrochloric acid solution at 10-15°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and distilled off the solvent from the organic layer. Methanol (800 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 20 min at the same temperature. Charcoal (10 gm) was added to the obtained compound at 60-65°C and stirred for 20 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with methanol. Reduced the temperature of the filtrate to 50-55°C and was added to pre-cooled water (1000 ml) at 15-20°C and stirred the reaction mixture for 6 hrs at the same temperature. Filtered the precipitated solid, washed with water and dried the material.
Yield: 70.0 gm.
Example-17: Preparation of crystalline form-I of compound of formula-1
A mixture of 6-(3-chloro-2-fluorobenzyl)-l-[(2S)-l-hydroxy-3-methylbutan-2-yl]-7- methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula-1 (50 gm) and toluene (800 ml) was stirred for 15 min at 25-30°C. Heated the reaction mixture to 90-95°C and stirred for 20 min at the same temperature. Filtered the reaction mixture through hyflow bed and Washed the hyflow bed with hot toluene. The obtained hot solution was slowly added to pre-cooled toluene (500 ml) containing seeding material of crystalline form-I of compound of formula- 1 (20 gm) at 10-15 °C and stirred the reaction mixture for 5 hrs at the same temperature. Filtered the solid, washed with toluene and dried the material to provide the title compound.
Yield: 51.0 gm.
Example-18: Preparation of crystalline form-Ill of compound of formula-1
A mixture of 6-(3-chloro-2-fluorobenzyl)-l-[(2S)-l-hydroxy-3-methylbutan-2-yl]-7- methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula-1 (100 gm) and methanol (1000 ml) was stirred for 10 min at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 20 min at the same temperature. Slowly cooled the reaction mixture to 25-30°C and stirred for 6 hrs at the same temperature. Filtered the precipitated solid, washed with methanol and dried the material to provide the title compound.
Yield: 72.0 gm; M.R: 162-163°C.
Example-19: Preparation of amorphous form of compound of formula-1
A mixture of 6-(3-chloro-2-fluorobenzyl)-l-[(2S)-l-hydroxy-3-methylbutan-2-yl]-7- methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula-1 (15 gm) and methanol (150 ml) was stirred for 10 min at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 20 min at the same temperature. Reduced the temperature of the reaction mixture to 50-55°C and was slowly added to pre-cooled water (750 ml) at Q-5°C and stirred the reaction mixture for 6 hrs at the same temperature. Filtered the precipitated solid, washed with water and then dried the material to provide the title compound.
Yield: 14.0 gm.
Example-20: Preparation of compound of formula-1
A mixture of acetic anhydride (20.3 ml), Zinc chloride (0.005 gm) and boric acid (2 gm) was stirred for 45 min at 25-3Q°C under nitrogen atmosphere. (S)-Ethyl 6-(3-chloro-2- fluorobenzyl)- 1-[(2S)-1 -hydroxy-3 -methylbutan-2-yl] -7-fluoro-4-oxo- 1 ,4-dihydroquinoline- 3-carboxylate compound of formula- 10a (10 gm) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 90-95°C and stirred for 4 hrs at the same temperature. Toluene was added to the reaction mixture at 90-95 °C. Distilled off the solvent from the reaction mixture under reduced pressure and co-distilled with toluene. Methanol (100 ml) followed by 28% sodium methoxide solution in methanol (20.7 ml) were slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 3 hrs at the same temperature. Slowly added 28% sodium methoxide solution in methanol (20.7 ml) to the reaction mixture at 55-60°C and stirred the reaction mixture for 15 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and water was added. Acidified the reaction mixture using aqueous hydrochloric acid solution at 25-30°C. Dichloromethane was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and distilled off the solvent from the organic layer under reduced pressure to provide the title compound.
Yield: 7.2 gm.

Claims

We Claim:
1. A process for the preparation of 6-(3-chloro-2-fluorobenzyl)-l-[(2S)-l-hydroxy-3- methylbutan-2-yl] -7-methoxy-4-oxo- 1 ,4-dihydroquinoline-3 -carboxylic acid compound of formula- 1 , comprising of;
a) Halogenation of 2,4-difluorobenzoic acid compound of formula-2
Figure imgf000031_0001
Formula-2
by reacting it with a suitable halogenating agent optionally in presence of a suitable acid and/or a suitable solvent to provide 2,4-difluoro-5-halobenzoic acid compound of general formula-3,
Figure imgf000031_0002
Formula-3
wherein, 'X' represents halogen;
b) esterification of compound of general formula-3 by reacting it with a suitable Q-Ce alcohol in presence of a suitable esterification catalyst optionally in presence of a suitable solvent to provide compound of general formula-4,
Figure imgf000031_0003
Formula-4
wherein, 'R' represents C!-C6 straight chain or branched chain alkyl group;
c) converting the 3-chloro-2-fluoro benzyl halide to the corresponding zinc derivative and reacting the obtained compound with compound of general formula-4 in presence of a suitable catalyst in a suitable solvent to provide compound of general formula-5,
Figure imgf000031_0004
Formula-5 d) hydrolyzing the compound of general formula-5 in presence of a suitable base optionally in presence of a solvent to provide 5-(3-chloro-2-fluorobenzyl)-2,4- difluorobenzoic acid compound of formula-6,
Figure imgf000032_0001
Formula-6
e) reacting the compound of formula-6 with alkyl-3-(dimethylamino)acrylate compound of general formula-7
Figure imgf000032_0002
Formula-7
wherein, 'R' represents Ci-C6 alkyl group;
in a suitable solvent optionally in presence of a suitable coupling agent and/or a suitable base to provide compound of general formula-8,
Figure imgf000032_0003
Formula-8
f) reacting the compound of general formula-8 with L-valinol in a suitable solvent to provide compound of general formula-9,
Figure imgf000032_0004
g) cyclizing the compound of general formula-9 by treating it with a suitable base in a suitable solvent to provide compound of general formula- 10,
Figure imgf000033_0001
Formula- 10
h) reacting the compound of general formula- 10 with suitable alkali metal methoxide in a suitable solvent in presence of catalytic amount of water to provide compound of formula- 1,
i) purifying the compound of formula- 1 from a suitable solvent or mixture of solvents to provide pure compound of formula- 1.
The process according to claim 1 , wherein,
in step-a) the suitable halogenating agent is selected from N-halosuccinimides, Cl2, Br2, 12; and the suitable acid is selected from sulfuric acid, hydrochloric acid, formic acid, acetic acid, trifluoroacetic acid, a Lewis acid;
In step-b) the suitable esterification catalyst is selected from thionyl chloride, oxalyl chloride, sulfuric acid, hydrochloric acid, trifluoroacetic acid;
In step-c) the suitable catalyst is selected from Pd(PPh3)2Cl2, Pd(PPh3)4, Pd(OAc)2, PdCl2, Pd(OH)2, Pd(dba)2, Pd2(dba)3, Pd(dppe)2Cl2, Pd(dppf)Cl2, Pd(dppf)Cl2.CH2Cl2, Pd(dcypp)Cl2, Pd(PhCN)2Cl2, Pd(CH3CN)2Cl2;
In step-d) the suitable base is selected from hydroxides, alkoxides and carbonates of alkali metals;
In step-e) the suitable coupling agent is selected from Ι,Γ-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, Ν,Ν'-diisopropylcarbodiimide, 1 -ethyl-3 -(3 -dimethyl aminopropyl)carbodiimide hydrochloride (EDC.HC1), l-[bis(dimethylamino) methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluoro phosphate (HATU), 2-( 1 H-benzotriazol- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyluronium hexafluorophosphate (HBTU), lH-benzotriazolium l-[bis(dimethylamino)methylene]-5chloro-hexafluorophosphate (1-) 3 -oxide (HCTU), 0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), alkyl/aryl haloformates; diphenylphosphoroazidate (DPPA), thionyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, 4-methyl-2- oxopentanoyl chloride (i-BuCOCOCl), (benzotriazol-l-yloxy)tris(dimethylamino) phosphonium hexafluorophosphate (BOP), benzotriazol-l-yl-oxy tripyrrolidinophosphonium hexafluorophosphate (PyBOP), methanesulfonyl chloride, p-toluenesulfonyl chloride; the suitable base is selected from organic bases, inorganic bases, organolithium bases, organosilicon bases or their mixtures;
In step-g) the suitable base is selected from organic bases, inorganic bases or their mixtures;
In step-a) to step-i) the suitable solvent is selected from hydrocarbon solvents, ether, solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid or their mixtures.
3. A process for the preparation of 6-(3-chloro-2-fluorobenzyl)-l-[(25)-l-hydroxy-3- methylbutan-2-yl]-7-methoxy-4-oxo-l ,4-dihydroquinoline-3-carboxylic acid compound of formula- 1, comprising of reacting the compound of general formula- 10
Figure imgf000034_0001
Formula- 10
wherein, 'R' represents C!-C6 straight chain or branched chain alkyl group;
with alkali metal methoxide in a suitable solvent in presence of catalytic amount of water to provide compound of formula- 1.
4. The process according to claim 3, wherein the alkali metal methoxide is selected from sodium methoxide, potassium methoxide, lithium methoxide and the suitable solvent is selected from alcohol solvents. The process according to claim 4, wherein the suitable alkali metal methoxide is selected from sodium methoxide, potassium methoxide and the suitable solvent is methanol.
The process according to claim 5, wherein the suitable alkali metal methoxide is sodium methoxide.
A process for the preparation of 6-(3-chloro-2-fluorobenzyl)-l-[(2S)-l -hydroxy-3- methylbutan-2-yl]-7-methoxy-4-oxo-l ,4-dihydroquinoline-3-carboxylic acid compound of formula-1, comprising of reacting the (S)-ethyl 6-(3-chloro-2-fluorobenzyl)-l-[(2S)-l- hydroxy-3-methylbutan-2-yl]-7-fluoro-4-oxo-l,4-dihydroquinoline-3-carboxylate compound of formula-10a
Figure imgf000035_0001
Formula- 10a
with sodium methoxide in presence of methanol and catalytic amount of water to provide compound of formula-1.
A process for the preparation of stable crystalline form-I of 6-(3-chloro-2-fluorobenzyl)- 1 - [(25)- 1 -hydroxy-3 -methylbutan-2-yl]-7-methoxy-4-oxo- 1 ,4-dihydroquinoline-3 - carboxylic acid compound of formula-1 , comprising of;
a) Dissolving the compound of formula-1 in methanol,
b) adding the solution obtained in step-a) to pre-cooled water at a suitable temperature, c) filtering the solid and drying to provide crystalline form-I of compound of formula-1.
The process according to claim 8, wherein
in step-a) the dissolution of compound of formula-1 in methanol is carried out at a temperature ranges from 50°C to 65°C;
in step-b) the suitable temperature is 20±2°C.
10. A process for the preparation of stable crystalline form-I of 6-(3-chloro-2-fluorobenzyl)- 1 -[(25)- 1 -hydroxy-3 -methylbutan-2-yl] -7-methoxy-4-oxo- 1 ,4-dihydroquinoline-3 - carboxylic acid compound of formula- 1, comprising of;
a) Dissolving the compound of formula- 1 by refluxing in methanol,
b) adding the solution obtained in step-a) to pre-cooled water at 20±2°C,
c) filtering the solid and drying to provide crystalline form-I of compound of formula- 1.
11. A process for the preparation of crystalline form-I of 6-(3-chloro-2-fluorobenzyi)-l-[(2S)- l-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula- 1, comprising of;
a) Providing a solution of compound of formula- 1 in a suitable solvent,
b) seeding the reaction mixture with crystalline form-I of compound of formula- 1.
12. The process according to claim 11, wherein the suitable solvent is selected from hydrocarbon solvents.
13. The process according to claim 12, wherein the suitable solvent is preferably selected from toluene, xylene.
14. A process for the preparation of crystalline form-I of 6-(3-chloro-2-fluorobenzyl)-l-[(2iS - l-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo-l ,4-dihydroquinoline-3-carboxylic acid compound of formula- 1 , comprising of;
a) Dissolving compound of formula- 1 by refluxing in toluene,
b) slowly adding the obtained solution to pre-cooled toluene containing seeding material of crystalline form-I at 10-15°C,
c) filtering the solid and drying to provide crystalline form-I of compound of formula- 1.
15. A process for the preparation of crystalline form-II of 6-(3-chloro-2-fluorobenzyl)-l- [(2S)- 1 -hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo- 1 ,4-dihydroquinoline-3- carboxylic acid compound of formula- 1, comprising of;
a) Dissolving the compound of formula- 1 in a suitable solvent selected from toluene, xylene, b) combining the solution obtained in step-a) with a suitable anti-solvent selected from n-hexane, n-heptane to provide crystalline form-II of compound of formula- 1.
16. The process according to claim 15, wherein the dissolution of compound of formula- 1 in the solvent is carried out by refluxing compound of formula- 1 in the said solvent.
17. A process for the preparation of crystalline form-II of 6-(3-chloro-2-fluorobenzyl)-l- [(25)- 1 -hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo- 1 ,4-dihydroquinoline-3- carboxylic acid compound of formula- 1, comprising of;
a) Dissolving the compound of formula- 1 by refluxing in toluene,
b) combining the solution obtained in step-a) with n-heptane,
c) cooling the reaction mixture to 25-30°C,
d) filtering the precipitated solid and drying to provide crystalline form-II of compound of formula- 1.
18. A process for the preparation of crystalline form-II of 6-(3-chloro-2-fluorobenzyl)-l- [(25)-l-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo-l,4-dihydroquinoline-3- carboxylic acid compound of formula- 1, comprising of recrystallizing the compound of formula- 1 from xylene to provide crystalline form-II of compound of formula- 1.
PCT/IN2016/000142 2015-06-03 2016-06-03 Process for the preparation of 6-(3-chloro-2-fluorobenzyl)-1-[(2s)-1-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and pharmaceutically acceptable salts thereof WO2016193997A2 (en)

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