WO2018011676A1 - Novel processes for the preparation of 2-oxy-benzoxazinone derivatives - Google Patents

Novel processes for the preparation of 2-oxy-benzoxazinone derivatives Download PDF

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WO2018011676A1
WO2018011676A1 PCT/IB2017/054068 IB2017054068W WO2018011676A1 WO 2018011676 A1 WO2018011676 A1 WO 2018011676A1 IB 2017054068 W IB2017054068 W IB 2017054068W WO 2018011676 A1 WO2018011676 A1 WO 2018011676A1
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formula
group
solvent
mixtures
cetilistat
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PCT/IB2017/054068
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French (fr)
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Dodda Mohan Rao
Aadepu Jithender
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Symed Labs Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/24—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in positions 2 and 4
    • C07D265/26—Two oxygen atoms, e.g. isatoic anhydride
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups

Definitions

  • the present invention relates to novel, commercially viable and industrially advantageous processes for the preparation of 2-hexadecyloxy-6-methyl-4H-3,l- benzoxazin-4-one, and its intermediates, in high yield and purity.
  • U.S. Patent No. 6,624,161 (hereinafter referred to as the US '161 patent), assigned to Alizyme Therapeutics Limited, discloses a variety of 2-oxy-benzoxazinone derivatives, processes for the preparation, pharmaceutical compositions, and methods of use thereof. These compounds are useful for the prevention and/or treatment of obesity or an obesity-related disorder.
  • Cetilistat chemically named as 2- hexadecyloxy-6-methyl-4H-3,l-benzoxazin-4-one, is a orally active gastrointestinal and pancreatic lipase inhibitor. Cetilistat is useful for the prevention and/or treatment of a medical condition such as obesity, hyper lip aemia, hyperlipidaemia and related diseases. Cetilistat is represented by the following structural formula 1:
  • Cetilistat has been approved in Japan by the Japanese Ministry of Health, Labour and Welfare for the treatment of obesity and it is sold under the trade name OBLEAN®. It is orally administered as tablets containing 120 mg of Cetilistat.
  • OBLEAN® trade name for the preparation of Cetilistat.
  • Various processes for the preparation of Cetilistat are disclosed in U.S. Patent Nos. US 6,624,161; US 7,396,952; and Chinese Patent Application Nos. CN103936687A and CN104341370 A.
  • the USM 61 patent describes various synthetic routes for the preparation of Cetilistat.
  • Cetilistat is prepared by the reaction of a solution of 1-hexadecanol in tetrahydrofuran with a solution of phosgene in toluene (20%, 1.5 equivalents) under nitrogen to produce 1- hexadecyloxycarbonyl chloride, which is then condensed with 2-amino-5-methylbenzoic acid in presence of pyridine (5 equivalents), followed by tedious work-up to produce crude Cetilistat as a residue.
  • Cetilistat is prepared by the process as depicted in below scheme 2:
  • Cetilistat is prepared by the reaction of a solution of 1-hexadecanol in tetrahydrofuran with a solution of phosgene in toluene (20%, 3 equivalents) under nitrogen to produce 1-hexadecyloxycarbonyl chloride, which is then reacted with 2- amino-5-methylbenzoic acid in the presence of pyridine (1.15 equivalents) to produce a reaction mass, followed by subsequent reaction with methyl chloro formate (8.5 equivalents) and then subjecting to tedious work-up to produce crude Cetilistat as a residue. The resulting crude compound is then purified by flash chromatography on silica (1.5% diisopropylethylamine in dichloromethane) to produce Cetilistat as a white solid.
  • Cetilistat may be prepared by a process as depicted in below Scheme-4:
  • Cetilistat may be prepared by a process as depicted in below Scheme-5:
  • Cetilistat may be prepared by a process as depicted in below Scheme-6:
  • Cetilistat According to the synthetic route described in U.S. Patent No. 7,396,952 (hereinafter referred to as US'952 patent), Cetilistat is prepared by reacting 1-hexadecanol with p-tolyl isocyanate to produce hexadecyl 4-methylphenylcarbamate, followed by reacting with bromine to produce hexadecyl (2-bromo-4-methylphenyl)carbamate, which is further reacted with carbon monoxide using bis(triphenylphosphine)palladium dichloride and triphenylphosphine to produce 2-hexadecyloxycarbonylamino-5-methylbenzoic acid, which is finally reacted with ethyl chloroformate to produce Cetilistat.
  • the synthetic route is depicted in below Scheme-7:
  • the prior art processes involve the use of highly flammable solvents like tetrahydrofuran; d) the prior art processes involve the use of expensive reagents like tetraethyl tin, bis(triphenylphosphine)-palladium(II)dichloride and benzyl(chloro)bis(triphenyl- pho sphine)palladium; e) the prior art processes involve the use of tedious and cumbersome procedures like prolonged reaction time periods, multiple process steps, column chromatographic purifications, multiple isolation /re-crystallizations resulting the product with low yields and purity.
  • the object of the present invention is to provide novel, commercially viable and industrially advantageous processes for the preparation of Cetilistat and its intermediates in high yield and purity.
  • Cetilistat can be prepared in high yield and with high purity by reacting 1-hexadecanol with carbonyl diimidazole in presence of a suitable solvent to produce 1- hexadecyloxycarbonylimidazole, which is then reacted with 2-amino-5-methylbenzoic acid to produce 2-hexadecyloxycarbonylamino-5-methylbenzoic acid, followed by cyclization with a suitable cyclizing agent or a dehydrating agent to produce Cetilistat.
  • provided herein is a novel, commercially viable and industrially advantageous process for the preparation of Cetilistat of formula 1, in high yield and high purity.
  • the process disclosed herein avoids the tedious and cumbersome procedures of the prior art processes, thereby resolving the problems associated with the processes described in the prior art, which is more convenient to operate at laboratory scale and on a commercial scale.
  • the processes avoid the use of highly flammable solvents like tetrahydrofuran; d) the processes avoid the use of highly expensive reagents like tetraethyl tin, bis(triphenylphosphine)-palladium(II)dichloride and benzyl(chloro)bis(triphenyl- pho sphine)palladium.
  • the solvent used for isolating, purifying and/or recrystallizing the compounds obtained by the processes described in the present invention is selected from the group consisting of water, an alcohol, an ether, an ester, a hydrocarbon, a halogenated hydrocarbon, a nitrile solvent, and mixtures thereof.
  • the solvent used for isolating, purifying and/or recrystallizing the compounds obtained by the processes described herein is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, acetonitrile, and mixtures thereof.
  • the carbon treatment is carried out by the methods known in the art, for example, by stirring the reaction mass/solution with finely powdered carbon at a temperature of about 40°C to the reflux temperature for at least 5 minutes, specifically at the reflux temperature; and filtering the resulting mixture through charcoal bed to obtain a filtrate containing compound by removing charcoal.
  • finely powdered carbon is a special carbon or an active carbon.
  • 'base' as used herein includes, but is not limited to, organic bases and inorganic bases such as carbonates, bicarbonates, hydroxides, alkoxides, acetates and amides of alkali or alkali earth metals.
  • the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tertbutoxide, potassium tertbutoxide, sodium amide, potassium amide, lithium amide, ammonia, sodium acetate, potassium acetate, magnesium acetate, calcium acetate, and mixtures thereof.
  • the organic base is selected from the group consisting of dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, di n- butylamine, diisobutylamine, triethylamine, tributylamine, tert-butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5- diazabicyclo[4.3.0]non-5-ene(DBN), N-methylmorpholine (NMM), 1,4- diazabicyclo [2.2.2] octane (DABCO), 2,6-lutidine, lithium diisopropylamide, n- butyllithium, lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazi
  • phase transfer catalyst' as used herein includes, but are not limited to, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, benzyltrimethyl ammonium chloride, benzyltriethyl ammonium chloride, methyltributyl ammonium chloride, crown ethers and the like.
  • salts may include acid addition salts and base addition salts.
  • Acid addition salts may be derived from organic and inorganic acids.
  • the acid addition salts are derived from a therapeutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, acetic acid, propionic acid, phosphoric acid, succinic acid, maleic acid, fumaric acid, citric acid, glutaric acid, tartaric acid, benzenesulfonic acid, toluenesulfonic acid, malic acid, ascorbic acid, and the like.
  • a therapeutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, acetic acid, propionic acid, phosphoric acid, succinic acid, maleic acid, fumaric acid, citric acid, glutaric acid, tartaric acid, benzenesulfonic acid, toluenesulfonic acid, malic acid, ascorbic acid, and the like
  • Exemplary acid addition salts include, but are not limited to, hydrochloride, hydrobromide, sulphate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate, tartrate, and the like.
  • a most specific acid addition salt is hydrochloride salt.
  • Base addition salts may be derived from an organic or an inorganic base.
  • the base addition salts are derived from alkali or alkaline earth metals such as sodium, calcium, potassium and magnesium, ammonium salt and the like.
  • the highly pure Cetilistat or a pharmaceutically acceptable thereof obtained by the process disclosed herein has a purity of greater than about 99%, specifically greater than about 99.3%, more specifically greater than about 99.5%, and most specifically greater than about 99.9% as measured by HPLC.
  • the purity of the highly pure Cetilistat or a pharmaceutically acceptable thereof obtained by the processes disclosed herein is about 99% to about 99.99% as measured by HPLC.
  • reflux temperature means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
  • room temperature refers to a temperature of about 20°C to about 35°C.
  • room temperature can refer to a temperature of about 25°C to about 30°C.
  • the reaction in step-(a) is carried out in the presence of a reaction inert solvent.
  • exemplary solvents used in step-(a) include, but are not limited to, a cyclic ether, a hydrocarbon solvent, a halogenated hydrocarbon solvent, a nitrile, a polar aprotic solvent, and mixtures thereof.
  • the solvent used in step-(a) is selected from the group consisting of tetrahydrofuran, toluene, dichloromethane, acetonitrile, ⁇ , ⁇ -dimethylformamide, and mixtures thereof.
  • a most specific solvent is acetonitrile.
  • the reaction in step-(a) is carried out at a temperature of about 20°C to the reflux temperature of the solvent used, specifically at a temperature of about 30°C to the reflux temperature of the solvent used, and more specifically the reflux temperature of the solvent used.
  • the reaction time may vary from about 30 minutes to about 5 hours.
  • the reaction mass containing the 1-hexadecyloxy-carbonylimidazole of formula 4 obtained in step-(a) may be subjected to usual work up methods such as a washing, a quenching, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, a carbon treatment, or a combination thereof.
  • the reaction mass may be used directly in the next step to produce 2-hexadecyloxycarbonylamino-5- methylbenzoic acid of formula 2, or the compound of formula 4 may be isolated and/or recrystallized and then used in the next step.
  • the compound of formula 4 may be isolated and/or re- crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
  • the solvent used for work up, isolation and/or recrystallization of the compound of formula 4 obtained by the process described herein is selected from the group as described hereinabove.
  • the base used in step-(b) is selected from the group consisting of triethylamine, diisopropylethylamine, 4-N,N-dimethylaminopyridine, and the like.
  • a most specific base is triethylamine.
  • the reaction in step-(b) is carried out in the presence of a suitable solvent.
  • suitable solvents used in step-(b) include, but are not limited to, a cyclic ether, a hydrocarbon solvent, a halogenated hydrocarbon solvent, a nitrile, a polar aprotic solvent, and mixtures thereof.
  • the solvent used in step-(b) is selected from the group consisting of tetrahydrofuran, toluene, dichloromethane, acetonitrile, ⁇ , ⁇ -dimethylformamide, and mixtures thereof.
  • a most specific solvent is selected from the group consisting of acetonitrile, dichloromethane and mixtures thereof.
  • reaction in step-(b) may be optionally carried out in the presence of a suitable phase transfer catalyst.
  • the phase transfer catalyst can be selected from the group as described hereinabove.
  • the reaction in step-(b) is carried out at a temperature of about 20°C to about 100°C, specifically at a temperature of about 80°C to about 90°C.
  • the reaction time may vary from about 1 hour to about 10 hours.
  • the reaction mass containing the 2-hexadecyloxycarbonylamino-5- methylbenzoic acid of formula 2 obtained in step-(b) may be subjected to usual work up methods as described hereinabove.
  • the reaction mass may be used directly in the next step to produce the compound of formula 1, or the compound of formula 2 may be isolated and/or recrystallized and then used in the next step.
  • the compound of formula 2 or a salt thereof is isolated and/or re-crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
  • the solvent used for work up, isolation and/or recrystallization of the compound of formula 2 is selected from the group as described hereinabove. Specifically, the solvent used for work up, isolation and/or recrystallization of the compound of formula 2 is water, ethyl acetate, acetonitrile, and mixtures thereof.
  • Exemplary reagents used in step-(c) include, but are not limited to, methyl chloroformate, ethyl chloroformate, benzyl chloroformate, phenyl chloroformate, carbonyl diimidazole, acetic anhydride, dicyclohexylcarbodiimide, acetic anhydride, concentrated sulphuric acid, concentrated hydrochloric acid, oxalyl chloride, thionyl chloride, acetyl chloride, trichloro acetyl chloride and the like.
  • the reagent used in step-(c) is selected from the group consisting of ethyl chloroformate, carbonyl diimidazole and acetyl chloride.
  • the reaction in step-(c) is carried out in a reaction inert solvent.
  • exemplary solvents used in step-(c) include, but are not limited to, a cyclic ether, an ester, a hydrocarbon solvent, a halogenated hydrocarbon solvent, a nitrile solvent, a polar aprotic solvent, and mixtures thereof.
  • reaction inert solvent used in step-(c) is selected from the group consisting of tetrahydrofuran, ethyl acetate, toluene, dichloromethane, acetonitrile, ⁇ , ⁇ -dimethylformamide, and mixtures thereof.
  • a most specific solvent is selected from the group consisting of dichloromethane, ethyl acetate and mixtures thereof.
  • the reaction in step-(c) is carried out in the presence of a base.
  • the base is selected from the group as described hereinabove.
  • the base is selected from the group consisting of triethylamine, diisopropylethylamine, 4-N,N-dimethylaminopyridine, and the like.
  • the reaction in step-(c) is carried out at a temperature of about 0°C to about 100°C, and specifically at a temperature of about 0°C to about 50°C.
  • the reaction time may vary from about 2 hours to about 15 hours.
  • the reaction mass containing the cetilistat of formula 1 obtained in step-(c) may be subjected to usual work up methods such as a washing, a quenching, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, a carbon treatment, or a combination thereof.
  • the Cetilistat of formula 1 obtained in step-(c) may be isolated and/or re-crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti- solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
  • the solvent used for work up, isolation and/or recrystallization of the Cetilistat of formula 1 is selected from the group as described hereinabove. Specifically, the solvent used for work up, isolation and/or recrystallization of the Cetilistat of formula 1 is selected from the group consisting of water, ethyl acetate, acetonitrile, dichloromethane, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, toluene, and mixtures thereof.
  • Removal of solvent is accomplished, for example, by substantially complete evaporation of the solvent, concentrating the solution or distillation of solvent.
  • the solids obtained in the above process steps can be collected by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof.
  • the highly pure Cetilistat obtained by the above processes may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines.
  • ICH International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use
  • the drying is carried out at atmospheric pressure or reduced pressures, such as below about 200 mm Hg, or below about 50 mm Hg, at temperatures such as about 35°C to about 90°C, and specifically at about 75°C to about 85°C.
  • the drying can be carried out for any desired time period that achieves the desired result, such as times about 1 to 20 hours. Drying may also be carried out for shorter or longer periods of time depending on the product specifications. Temperatures and pressures will be chosen based on the volatility of the solvent being used and the foregoing should be considered as only a general guidance. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer, and the like.
  • Cetilistat of formula 1 or a pharmaceutically acceptable salt thereof is produced by reacting the compound of formula 2 or a salt thereof with a suitable reagent, optionally in the presence of a base, to produce Cetilistat of formula 1 or a pharmaceutically acceptable salt thereof.
  • a suitable reagent optionally in the presence of a base
  • the preparation of Cetilistat of formula 1 or a pharmaceutically acceptable salt thereof as described in the above process steps-(a) and (b) can be carried out by using the suitable solvents, reagents, methods, parameters and conditions as described hereinabove.
  • Cetilistat of formula 1 or a pharmaceutically acceptable salt thereof with a suitable reagent, optionally in the presence of a base, to produce Cetilistat of formula 1 or a pharmaceutically acceptable salt thereof.
  • Cetilistat of formula 1 or a pharmaceutically acceptable salt thereof as described in the above process can be carried out by using the suitable solvents, reagents, methods, parameters and conditions as described hereinabove.
  • 2-Amino-5-methylbenzoic acid (18 g), 1-hexadecyloxycarbonylimidazole (30 g) and triethylamine (46.5 g) were taken into a reaction flask at 25-30°C, and the contents were heated to 85-90°C, followed by maintaining the reaction mass for 7 hours at the same temperature. After completion of the reaction, the resulting mass was cooled to 25-30°C. To the resulting mass, water (100 ml) was added at 25-30°C and maintained for 15 minutes at the same temperature. Dichloro methane (90 ml) was added to the resulting mass at 25-30°C and the stirred for 15 minutes at the same temperature.

Abstract

Provided herein are novel, commercially viable and industrially advantageous processes for the preparation of 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one, and its intermediates, in high yield and purity.

Description

NOVEL PROCESSES FOR THE PREPARATION OF 2-OXY- BENZOXAZINONE DERIVATIVES
CROSS REFERENCE TO RELATED APPLICATION
This patent application claims the benefit of priority to Indian Provisional Patent Application No. 201641023598 filed on July 11, 2016, which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
The present invention relates to novel, commercially viable and industrially advantageous processes for the preparation of 2-hexadecyloxy-6-methyl-4H-3,l- benzoxazin-4-one, and its intermediates, in high yield and purity.
BACKGROUND OF THE INVENTION
U.S. Patent No. 6,624,161 (hereinafter referred to as the US '161 patent), assigned to Alizyme Therapeutics Limited, discloses a variety of 2-oxy-benzoxazinone derivatives, processes for the preparation, pharmaceutical compositions, and methods of use thereof. These compounds are useful for the prevention and/or treatment of obesity or an obesity-related disorder. Among them, Cetilistat, chemically named as 2- hexadecyloxy-6-methyl-4H-3,l-benzoxazin-4-one, is a orally active gastrointestinal and pancreatic lipase inhibitor. Cetilistat is useful for the prevention and/or treatment of a medical condition such as obesity, hyper lip aemia, hyperlipidaemia and related diseases. Cetilistat is represented by the following structural formula 1:
Figure imgf000002_0001
Cetilistat has been approved in Japan by the Japanese Ministry of Health, Labour and Welfare for the treatment of obesity and it is sold under the trade name OBLEAN®. It is orally administered as tablets containing 120 mg of Cetilistat. Various processes for the preparation of Cetilistat are disclosed in U.S. Patent Nos. US 6,624,161; US 7,396,952; and Chinese Patent Application Nos. CN103936687A and CN104341370 A. The USM 61 patent describes various synthetic routes for the preparation of Cetilistat. According to the synthetic route described in Preparation 1 of Example 4 of the US ' 161 Patent, Cetilistat is prepared by the reaction of a solution of 1-hexadecanol in tetrahydrofuran with a solution of phosgene in toluene (20%, 1.5 equivalents) under nitrogen to produce 1- hexadecyloxycarbonyl chloride, which is then condensed with 2-amino-5-methylbenzoic acid in presence of pyridine (5 equivalents), followed by tedious work-up to produce crude Cetilistat as a residue. The resulting crude compound is purified by flash chromatography on silica, eluting with 1:5:94 diisopropylethylamine/ ethyl acetate/ hexane to afford Cetilistat as a white solid. The synthetic route is depicted in scheme 1 :
Scheme- 1:
Figure imgf000003_0001
Tetrahydrofuran i-Hexadecyloxycarbonyl 2-Amino-5-methyl 1-Hexadecanol chloride benzoic acid
. .. Purification by
Pyridine (5 eq) flash chromatography
Figure imgf000003_0002
Crude Cetilistat
Figure imgf000003_0003
Pure Cetilistat
According to another synthetic route described in Preparation 2 of Example 4 of the US' 161 patent, Cetilistat is prepared by the process as depicted in below scheme 2:
Scheme-2:
2-Amino-5-methyl
Figure imgf000003_0004
benzoic acid
Pyridine (1.15 eq)
Methyl
Ethyl acetate
Figure imgf000003_0005
Crude Cetilistat
Figure imgf000003_0006
Pure Cetilistat As per the above synthetic route, Cetilistat is prepared by the reaction of a solution of 1-hexadecanol in tetrahydrofuran with a solution of phosgene in toluene (20%, 3 equivalents) under nitrogen to produce 1-hexadecyloxycarbonyl chloride, which is then reacted with 2- amino-5-methylbenzoic acid in the presence of pyridine (1.15 equivalents) to produce a reaction mass, followed by subsequent reaction with methyl chloro formate (8.5 equivalents) and then subjecting to tedious work-up to produce crude Cetilistat as a residue. The resulting crude compound is then purified by flash chromatography on silica (1.5% diisopropylethylamine in dichloromethane) to produce Cetilistat as a white solid.
According to another synthetic route described in the US' 161 patent (column- 29, lines 3-20 and lines 62-67; column-30, lines 1-17), Cetilistat is prepared by a process as depicted in below Scheme- 3:
Scheme-3: loxycarbonylchloride
2-Amino-5-methyl benzoic acid
Phosgene
(or) triphosgene
Figure imgf000004_0001
(or) thionyl chloride
2-Hexadecyloxycarbonylamino-5-methylbenzoic acid
Figure imgf000004_0002
Cetilistat
According to another synthetic route described in the US ' 161 patent (column- 29, lines 36-48; column-30, lines 34-54), Cetilistat may be prepared by a process as depicted in below Scheme-4:
Scheme-4:
Figure imgf000004_0003
. . , 6-Methyl-lH-benzo[d][l,3]- 2-Chloro-6-Methyl-benzo[d] 2-Amino-5-methylbenzoicacid oxazine-2 4-dione [l,3]-oxazin-4-one
Figure imgf000004_0004
According to another synthetic route described in the US' 161 patent (column-29, lines 22-34; and column-30, lines 18-31), Cetilistat may be prepared by a process as depicted in below Scheme-5:
Scheme-5:
Figure imgf000005_0001
acid alkyl ester
LiOH in aq. Tetrahydrofuran
(or) LiOH on aq. dioxane
Figure imgf000005_0002
2-Hexadecyloxycarbonylamino-5-methylbenzoic
alkyl ester
Figure imgf000005_0003
2-Hexadecyloxycarbonylamino-5-methylbenzoic acid Cetilistat
According to another synthetic route described in the US' 161 patent (column-29, lines 52-61 and column-30, lines 55-65), Cetilistat may be prepared by a process as depicted in below Scheme-6:
Scheme-6:
Figure imgf000005_0004
(X = halogen or alkenyl or alkynyl)
H2, 10%Pd7C in alcohol solvent PhCH2Pd(PPh3)2Cl in HPMA
(when X is alkenyl or alkynyl) (When Xis halogen)
(OR) (CH3)4Sn
Figure imgf000005_0005
Cetilistat According to the synthetic route described in U.S. Patent No. 7,396,952 (hereinafter referred to as US'952 patent), Cetilistat is prepared by reacting 1-hexadecanol with p-tolyl isocyanate to produce hexadecyl 4-methylphenylcarbamate, followed by reacting with bromine to produce hexadecyl (2-bromo-4-methylphenyl)carbamate, which is further reacted with carbon monoxide using bis(triphenylphosphine)palladium dichloride and triphenylphosphine to produce 2-hexadecyloxycarbonylamino-5-methylbenzoic acid, which is finally reacted with ethyl chloroformate to produce Cetilistat. The synthetic route is depicted in below Scheme-7:
Scheme-7:
Figure imgf000006_0001
p-Tolyl isocyanate Hexadecyl 4-Methylphenylcarbamate
Figure imgf000006_0002
Hexadecyl (2-Bromo-4-Methylphenyl) Carbon monoxide
2-Hexadecyloxycarbonylamino-5- carbamate methyl benzoic acid
Figure imgf000006_0003
Cetilistat
The processes for the preparation of Cetilistat as described in the aforementioned prior art suffer from the following disadvantages and limitations:
a) the prior art processes involve the use of highly corrosive reagents like phosgene and triphosgene;
b) the prior art processes involve the use of excess amount of reagents and solvents like methylchloro formate, hexadecylchloro formate and pyridine;
c) the prior art processes involve the use of highly flammable solvents like tetrahydrofuran; d) the prior art processes involve the use of expensive reagents like tetraethyl tin, bis(triphenylphosphine)-palladium(II)dichloride and benzyl(chloro)bis(triphenyl- pho sphine)palladium; e) the prior art processes involve the use of tedious and cumbersome procedures like prolonged reaction time periods, multiple process steps, column chromatographic purifications, multiple isolation /re-crystallizations resulting the product with low yields and purity.
A need remains for novel, commercially viable and environmentally friendly processes for the preparation of Cetilistat and its intermediates with high yields and purity, to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation.
SUMMARY OF THE INVENTION
The object of the present invention is to provide novel, commercially viable and industrially advantageous processes for the preparation of Cetilistat and its intermediates in high yield and purity.
The present inventors have surprisingly and unexpectedly found that Cetilistat can be prepared in high yield and with high purity by reacting 1-hexadecanol with carbonyl diimidazole in presence of a suitable solvent to produce 1- hexadecyloxycarbonylimidazole, which is then reacted with 2-amino-5-methylbenzoic acid to produce 2-hexadecyloxycarbonylamino-5-methylbenzoic acid, followed by cyclization with a suitable cyclizing agent or a dehydrating agent to produce Cetilistat.
In one aspect, provided herein is a novel, commercially viable and industrially advantageous process for the preparation of Cetilistat of formula 1, in high yield and high purity. The process disclosed herein avoids the tedious and cumbersome procedures of the prior art processes, thereby resolving the problems associated with the processes described in the prior art, which is more convenient to operate at laboratory scale and on a commercial scale.
The processes for the preparation of Cetilistat disclosed herein have the following advantages over the processes described in the prior art:
a) the processes avoid the use of highly corrosive and toxic reagents like phosgene and triphosgene;
b) the processes avoid the use of excess amount of reagents and solvents like methylchloro formate, hexadecylchloro formate and pyridine;
c) the processes avoid the use of highly flammable solvents like tetrahydrofuran; d) the processes avoid the use of highly expensive reagents like tetraethyl tin, bis(triphenylphosphine)-palladium(II)dichloride and benzyl(chloro)bis(triphenyl- pho sphine)palladium.
e) the processes avoid the use of excess amounts of reagents and solvents, tedious and cumbersome procedures like prolonged reaction time periods, multiple process steps, column chromatographic purifications, multiple isolation /re-crystallizations thereby resulting the product with high yield and purity.
DETAILED DESCRIPTION OF THE INVENTION
According to one aspect, there is provided a novel process for the preparation of Cetilistat of formula 1 :
Figure imgf000008_0001
or a pharmaceutically acceptable salt thereof, which comprises:
a) reacting 1-hexadecanol of formula 5:
Figure imgf000008_0002
with carbonyl diimidazole in a suitable solvent to produce 1-hexadecyloxycarbonyl- imidazole of formula 4:
Figure imgf000008_0003
b) reacting the 1-hexadecyloxycarbonylimidazole of formula 4 with 2-amino-5- methylbenzoic acid of formula 3:
3
Figure imgf000008_0004
or a salt thereof, in presence of a base to produce 2-hexadecyloxycarbonylamino-5- methylbenzoic acid of formula 2:
Figure imgf000009_0001
or a salt thereof; and
c) reacting the compound of formula 2 or a salt thereof with a suitable reagent, optionally in the presence of a base, to produce Cetilistat of formula 1 or a pharmaceutically acceptable salt thereof.
Unless otherwise specified, the solvent used for isolating, purifying and/or recrystallizing the compounds obtained by the processes described in the present invention is selected from the group consisting of water, an alcohol, an ether, an ester, a hydrocarbon, a halogenated hydrocarbon, a nitrile solvent, and mixtures thereof. Specifically, the solvent used for isolating, purifying and/or recrystallizing the compounds obtained by the processes described herein is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, acetonitrile, and mixtures thereof.
Unless otherwise specified, the carbon treatment is carried out by the methods known in the art, for example, by stirring the reaction mass/solution with finely powdered carbon at a temperature of about 40°C to the reflux temperature for at least 5 minutes, specifically at the reflux temperature; and filtering the resulting mixture through charcoal bed to obtain a filtrate containing compound by removing charcoal. Specifically, finely powdered carbon is a special carbon or an active carbon.
Unless otherwise specified, the term 'base' as used herein includes, but is not limited to, organic bases and inorganic bases such as carbonates, bicarbonates, hydroxides, alkoxides, acetates and amides of alkali or alkali earth metals.
Specifically, the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tertbutoxide, potassium tertbutoxide, sodium amide, potassium amide, lithium amide, ammonia, sodium acetate, potassium acetate, magnesium acetate, calcium acetate, and mixtures thereof.
Specifically, the organic base is selected from the group consisting of dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, di n- butylamine, diisobutylamine, triethylamine, tributylamine, tert-butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5- diazabicyclo[4.3.0]non-5-ene(DBN), N-methylmorpholine (NMM), 1,4- diazabicyclo [2.2.2] octane (DABCO), 2,6-lutidine, lithium diisopropylamide, n- butyllithium, lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS), and mixtures thereof.
Unless otherwise specified, the term 'phase transfer catalyst' as used herein includes, but are not limited to, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, benzyltrimethyl ammonium chloride, benzyltriethyl ammonium chloride, methyltributyl ammonium chloride, crown ethers and the like.
Unless otherwise specified, the term 'salt' as used herein may include acid addition salts and base addition salts.
Acid addition salts may be derived from organic and inorganic acids. For example, the acid addition salts are derived from a therapeutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, acetic acid, propionic acid, phosphoric acid, succinic acid, maleic acid, fumaric acid, citric acid, glutaric acid, tartaric acid, benzenesulfonic acid, toluenesulfonic acid, malic acid, ascorbic acid, and the like.
Exemplary acid addition salts include, but are not limited to, hydrochloride, hydrobromide, sulphate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate, tartrate, and the like. A most specific acid addition salt is hydrochloride salt. Base addition salts may be derived from an organic or an inorganic base. For example, the base addition salts are derived from alkali or alkaline earth metals such as sodium, calcium, potassium and magnesium, ammonium salt and the like.
The highly pure Cetilistat or a pharmaceutically acceptable thereof obtained by the process disclosed herein has a purity of greater than about 99%, specifically greater than about 99.3%, more specifically greater than about 99.5%, and most specifically greater than about 99.9% as measured by HPLC. For example, the purity of the highly pure Cetilistat or a pharmaceutically acceptable thereof obtained by the processes disclosed herein is about 99% to about 99.99% as measured by HPLC.
As used herein, the term "reflux temperature" means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
As used herein, the term "room temperature" refers to a temperature of about 20°C to about 35°C. For example, "room temperature" can refer to a temperature of about 25°C to about 30°C.
In one embodiment, the reaction in step-(a) is carried out in the presence of a reaction inert solvent. Exemplary solvents used in step-(a) include, but are not limited to, a cyclic ether, a hydrocarbon solvent, a halogenated hydrocarbon solvent, a nitrile, a polar aprotic solvent, and mixtures thereof.
Specifically, the solvent used in step-(a) is selected from the group consisting of tetrahydrofuran, toluene, dichloromethane, acetonitrile, Ν,Ν-dimethylformamide, and mixtures thereof. A most specific solvent is acetonitrile.
In one embodiment, the reaction in step-(a) is carried out at a temperature of about 20°C to the reflux temperature of the solvent used, specifically at a temperature of about 30°C to the reflux temperature of the solvent used, and more specifically the reflux temperature of the solvent used. The reaction time may vary from about 30 minutes to about 5 hours.
The reaction mass containing the 1-hexadecyloxy-carbonylimidazole of formula 4 obtained in step-(a) may be subjected to usual work up methods such as a washing, a quenching, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, a carbon treatment, or a combination thereof. The reaction mass may be used directly in the next step to produce 2-hexadecyloxycarbonylamino-5- methylbenzoic acid of formula 2, or the compound of formula 4 may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula 4 may be isolated and/or re- crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
The solvent used for work up, isolation and/or recrystallization of the compound of formula 4 obtained by the process described herein is selected from the group as described hereinabove.
In one embodiment, the base used in step-(b) is selected from the group consisting of triethylamine, diisopropylethylamine, 4-N,N-dimethylaminopyridine, and the like. A most specific base is triethylamine.
In another embodiment, the reaction in step-(b) is carried out in the presence of a suitable solvent. Exemplary solvents used in step-(b) include, but are not limited to, a cyclic ether, a hydrocarbon solvent, a halogenated hydrocarbon solvent, a nitrile, a polar aprotic solvent, and mixtures thereof.
Specifically, the solvent used in step-(b) is selected from the group consisting of tetrahydrofuran, toluene, dichloromethane, acetonitrile, Ν,Ν-dimethylformamide, and mixtures thereof. A most specific solvent is selected from the group consisting of acetonitrile, dichloromethane and mixtures thereof.
In another embodiment, the reaction in step-(b) may be optionally carried out in the presence of a suitable phase transfer catalyst. The phase transfer catalyst can be selected from the group as described hereinabove.
In one embodiment, the reaction in step-(b) is carried out at a temperature of about 20°C to about 100°C, specifically at a temperature of about 80°C to about 90°C. The reaction time may vary from about 1 hour to about 10 hours.
The reaction mass containing the 2-hexadecyloxycarbonylamino-5- methylbenzoic acid of formula 2 obtained in step-(b) may be subjected to usual work up methods as described hereinabove. The reaction mass may be used directly in the next step to produce the compound of formula 1, or the compound of formula 2 may be isolated and/or recrystallized and then used in the next step. In one embodiment, the compound of formula 2 or a salt thereof is isolated and/or re-crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
The solvent used for work up, isolation and/or recrystallization of the compound of formula 2 is selected from the group as described hereinabove. Specifically, the solvent used for work up, isolation and/or recrystallization of the compound of formula 2 is water, ethyl acetate, acetonitrile, and mixtures thereof.
Exemplary reagents used in step-(c) include, but are not limited to, methyl chloroformate, ethyl chloroformate, benzyl chloroformate, phenyl chloroformate, carbonyl diimidazole, acetic anhydride, dicyclohexylcarbodiimide, acetic anhydride, concentrated sulphuric acid, concentrated hydrochloric acid, oxalyl chloride, thionyl chloride, acetyl chloride, trichloro acetyl chloride and the like.
Specifically, the reagent used in step-(c) is selected from the group consisting of ethyl chloroformate, carbonyl diimidazole and acetyl chloride.
In one embodiment, the reaction in step-(c) is carried out in a reaction inert solvent. Exemplary solvents used in step-(c) include, but are not limited to, a cyclic ether, an ester, a hydrocarbon solvent, a halogenated hydrocarbon solvent, a nitrile solvent, a polar aprotic solvent, and mixtures thereof.
Specifically, the reaction inert solvent used in step-(c) is selected from the group consisting of tetrahydrofuran, ethyl acetate, toluene, dichloromethane, acetonitrile, Ν,Ν-dimethylformamide, and mixtures thereof. A most specific solvent is selected from the group consisting of dichloromethane, ethyl acetate and mixtures thereof.
In one embodiment, the reaction in step-(c) is carried out in the presence of a base. The base is selected from the group as described hereinabove.
Specifically, the base is selected from the group consisting of triethylamine, diisopropylethylamine, 4-N,N-dimethylaminopyridine, and the like.
In one embodiment, the reaction in step-(c) is carried out at a temperature of about 0°C to about 100°C, and specifically at a temperature of about 0°C to about 50°C. The reaction time may vary from about 2 hours to about 15 hours. The reaction mass containing the cetilistat of formula 1 obtained in step-(c) may be subjected to usual work up methods such as a washing, a quenching, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, a carbon treatment, or a combination thereof.
In one embodiment, the Cetilistat of formula 1 obtained in step-(c) may be isolated and/or re-crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti- solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
The solvent used for work up, isolation and/or recrystallization of the Cetilistat of formula 1 is selected from the group as described hereinabove. Specifically, the solvent used for work up, isolation and/or recrystallization of the Cetilistat of formula 1 is selected from the group consisting of water, ethyl acetate, acetonitrile, dichloromethane, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, toluene, and mixtures thereof.
Removal of solvent is accomplished, for example, by substantially complete evaporation of the solvent, concentrating the solution or distillation of solvent.
The solids obtained in the above process steps can be collected by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof.
The highly pure Cetilistat obtained by the above processes may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines.
In one embodiment, the drying is carried out at atmospheric pressure or reduced pressures, such as below about 200 mm Hg, or below about 50 mm Hg, at temperatures such as about 35°C to about 90°C, and specifically at about 75°C to about 85°C. The drying can be carried out for any desired time period that achieves the desired result, such as times about 1 to 20 hours. Drying may also be carried out for shorter or longer periods of time depending on the product specifications. Temperatures and pressures will be chosen based on the volatility of the solvent being used and the foregoing should be considered as only a general guidance. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer, and the like.
According to another aspect, there is provided a novel process for the preparation of 2-hexadecyloxycarbonylamino-5-methylbenzoic acid of formula 2:
Figure imgf000015_0001
or a salt thereof, which comprises:
a) reacting 1-hexadecanol of formula 5:
Figure imgf000015_0002
with carbonyl diimidazole in a suitable solvent to produce 1-hexadecyloxycarbonyl- imidazole of formula 4:
Figure imgf000015_0003
b) reacting the 1-hexadecyloxycarbonylimidazole of formula 4 with 2-amino-5- methylbenzoic acid of formula 3:
Figure imgf000015_0004
or a salt thereof, in presence of a base to produce the 2-hexadecyloxycarbonylamino- 5-methylbenzoic acid of formula 2 or a salt thereof. The preparation of the 2-hexadecyloxycarbonylamino-5-methylbenzoic acid of formula 2 or a salt thereof as described in the above process steps-(a) and (b) can be carried out by using the suitable solvents, reagents, methods, parameters and conditions as described hereinabove.
According to another aspect, there is provided a novel process for the preparation of Cetilistat of formula 1:
Figure imgf000016_0001
or a pharmaceutically acceptable salt thereof, which comprises:
a) reacting the 1-hexadecyloxycarbonylimidazole of formula 4:
Figure imgf000016_0002
with 2-amino-5-methylbenzoic acid of formula 3:
Figure imgf000016_0003
or a salt thereof, in presence of a base to produce 2-hexadecyloxycarbonylamino-5- methylbenzoic acid of formula 2:
Figure imgf000016_0004
or a salt thereof; and
b) reacting the compound of formula 2 or a salt thereof with a suitable reagent, optionally in the presence of a base, to produce Cetilistat of formula 1 or a pharmaceutically acceptable salt thereof. The preparation of Cetilistat of formula 1 or a pharmaceutically acceptable salt thereof as described in the above process steps-(a) and (b) can be carried out by using the suitable solvents, reagents, methods, parameters and conditions as described hereinabove.
According to another aspect, there is provided a novel process for the preparation of Cetilistat of formula 1 :
Figure imgf000017_0001
or a pharmaceutically acceptable salt thereof, which comprises:
reacting 2-hexadecyloxycarbonylamino-5-methylbenzoic acid of formula 2:
Figure imgf000017_0002
or a salt thereof with a suitable reagent, optionally in the presence of a base, to produce Cetilistat of formula 1 or a pharmaceutically acceptable salt thereof.
The preparation of Cetilistat of formula 1 or a pharmaceutically acceptable salt thereof as described in the above process can be carried out by using the suitable solvents, reagents, methods, parameters and conditions as described hereinabove.
The following examples are given only to illustrate the present invention. However, they should not be considered as limitation on the scope or spirit of the invention.
EXAMPLES
Example 1
Preparation of 1-Hexadecyloxycarbonylimidazole
1-Hexadecanol (25 g), acetonitrile (250 ml) and carbonyldiimidazole (23.5 g) were taken into a reaction flask at 25-30°C, and the contents were heated to 60-65°C to obtain a clear solution. The reaction mass was stirred for 2 hours at 60-65°C. The reaction mass was cooled to 25-35°C, followed by stirring for 30 minutes at the same temperature. The separated solid was filtered, washed with acetonitrile (25 ml) and then air-dried the material to produce 33 g of 1-hexadecyloxycarbonylimidazole (Yield: 95.4%, Purity by HPLC: 99.6%).
Example 2
Preparation of 2-Hexadecyloxycarbonylamino-5-methylbenzoic acid
2-Amino-5-methylbenzoic acid (18 g), 1-hexadecyloxycarbonylimidazole (30 g) and triethylamine (46.5 g) were taken into a reaction flask at 25-30°C, and the contents were heated to 85-90°C, followed by maintaining the reaction mass for 7 hours at the same temperature. After completion of the reaction, the resulting mass was cooled to 25-30°C. To the resulting mass, water (100 ml) was added at 25-30°C and maintained for 15 minutes at the same temperature. Dichloro methane (90 ml) was added to the resulting mass at 25-30°C and the stirred for 15 minutes at the same temperature. The layers were separated and the resulting organic layer was washed with water (90 ml), followed by distillation off the solvent to obtain a residue (residue weight: 40 g). Acetonitrile (300 ml) was added to the resulting residue at 25-30°C, followed by heating the resulting mass at 65-70°C to obtain a clear solution. Activated carbon (3 g) was added to the resulting solution at 65-70°C and then stirred for 10 minutes at the same temperature. The resulting mass was filtered and then washed with acetonitrile (20 ml). The resulting filtrate was cooled to room temperature and then stirred for 30 minutes at the same temperature. The separated solid was filtered, washed with acetonitrile (20 ml) and then dried the material at 40-45°C under vacuum to produce 27 g of 2-hexadecyloxycarbonylamino-5-methylbenzoic acid (Yield: 72.2%, Purity by HPLC: 99.5%). Example 3
Preparation of Cetilistat
2-Hexadecyloxycarbonylamino-5-methylbenzoic acid (4 g), pyridine (24 ml) and dichloromethane (120 ml) were taken into a reaction flask at 25-30°C and maintained for 10 minutes at the same temperature. The resulting mass was cooled to 0-5°C and acetyl chloride (6 ml) was added drop-wise at the same temperature. The resulting mass was maintained for 2-3 hours at 0-5°C. The temperature of reaction mass was raised to 25-35°C and maintained for 10-12 hours at the same temperature. To the resulting mass, water (120 ml) was added at room temperature and maintained for 10 minutes at the same temperature. The layers were separated and the organic layer was washed with water (120 ml) and distilled under vacuum to obtain a residue (weight: 6 g). To the resulting residue, acetonitrile (60 ml) was added at room temperature. The resulting mass was heated to 65-70°C and maintained for 15-20 minutes at the same temperature. The resulting solution was cooled to room temperature and then stirred for 30 minutes at the same temperature. The separated solid was filtered, washed with acetonitrile (10 ml) and then air-dried for 16-18 hours to produce 3.5 g of crude Cetilistat. Ethyl acetate (17.5 ml) was added to the crude Cetilistat at room temperature, followed by heating the resulting mass at 70-75 °C to obtain a clear solution. The resulting solution was cooled to 0-5°C and maintained for 30 minutes at the same temperature. The solid obtained was filtered, washed with ethyl acetate (5 ml) and then dried for 8 hours at 50- 55°C to produce 3 g of pure Cetilistat (Yield: 78.5%, Purity by HPLC: 99.5%). Example 4
Preparation of Cetilistat
2-Hexadecyloxycarbonylamino-5-methylbenzoic acid (10 g), pyridine (30 ml) and dichloromethane (150 ml) were taken into a reaction flask at 25-30°C and the resulting mass was stirred for 10 minutes at the same temperature. The resulting solution was cooled to 0-5°C and then ethyl chloro formate (10 ml) was added drop-wise at the same temperature. The resulting mass was stirred for 2 hours at 0-5°C. The temperature of reaction mass was raised to 25-35°C and then stirred for 2 hours at the same temperature. To the resulting mass, water (100 ml) was added at room temperature and then stirred for 15 minutes at the same temperature. The layers were separated and the organic layer was distilled under vacuum up to 60°C to obtain a residue (weight: 10 g). To the resulting residue, ethyl acetate (50 ml) was added at room temperature, followed by heating the mass at 65°C to obtain a clear solution. To the resulting solution, activated carbon (2 g) was added at 65°C and then stirred for 10 minutes at the same temperature. The resulting mass was filtered and the filtrate was cooled to 0-5°C. The separated solid was filtered, washed with ethyl acetate (10 ml) and then dried for 8 hours at 50-55°C to produce 8 g of Cetilistat (Yield: 83.3%, Purity by HPLC: 99.5%).

Claims

We Claim:
1. A process for the preparation of Cetilistat of formula 1:
Figure imgf000020_0001
or a pharmaceutically acceptable salt thereof, which comprises:
a) reacting 1-hexadecanol of formula 5:
Figure imgf000020_0002
with carbonyl diimidazole in a suitable solvent to produce 1-hexadecyloxy carbonylimidazole of formula 4:
Figure imgf000020_0003
reacting the 1-hexadecyloxycarbonylimidazole of formula 4 with 2-amino- methylbenzoic acid of formula 3:
Figure imgf000020_0004
or a salt thereof, in presence of a base to produce 2 hexadecyloxycarbonylamino-5-methylbenzoic acid of formula 2:
Figure imgf000020_0005
or a salt thereof; and c) reacting the compound of formula 2 or a salt thereof with a suitable reagent, optionally in presence of a base, to produce Cetilistat of formula 1 or a pharmaceutically acceptable salt thereof.
2. The process of claim 1, wherein the solvent used in step-(a) is selected from the group consisting of tetrahydrofuran, toluene, dichloromethane, acetonitrile, N,N- dimethylformamide, and mixtures thereof; wherein the base used in step-(b) is selected from the group consisting of triethylamine, diisopropylethylamine and 4- Ν,Ν-dimethylaminopyridine; wherein the reaction in step-(b) is carried out in the presence of a solvent selected from the group consisting of tetrahydrofuran, toluene, dichloromethane, acetonitrile, Ν,Ν-dimethylformamide, and mixtures thereof; wherein the reaction in step-(b) is optionally carried out in the presence of a phase transfer catalyst selected from the group consisting of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, benzyltrimethyl ammonium chloride, benzyltriethyl ammonium chloride, methyltributyl ammonium chloride and crown ethers; wherein the reagent used in step-(c) is selected from the group consisting of methyl chloroformate, ethyl chloroformate, benzyl chloroformate, phenyl chloroformate, carbonyl diimidazole, acetic anhydride, dicyclohexylcarbodiimide, acetic anhydride, concentrated sulphuric acid, concentrated hydrochloric acid, oxalyl chloride, thionyl chloride, acetyl chloride and trichloro acetyl chloride; wherein the reaction in step-(c) is carried out in a reaction inert solvent selected from the group consisting of tetrahydrofuran, ethyl acetate, toluene, dichloromethane, acetonitrile, N,N- dimethylformamide, and mixtures thereof; wherein the reaction in step-(c) is carried out in the presence of a base selected from the group consisting of triethylamine, diisopropylethylamine, and 4-N,N-dimethylaminopyridine; and wherein the Cetilistat of formula 1 obtained in step-(c) is isolated and/or re- crystallized from a solvent selected from the group consisting of water, an alcohol, an ether, an ester, a hydrocarbon, a halogenated hydrocarbon, a nitrile solvent, and mixtures thereof.
3. The process of claim 2, wherein the solvent used in step-(a) is acetonitrile; wherein the base used in step-(b) is triethylamine; wherein the solvent used in step-(b) is selected from the group consisting of acetonitrile, dichloromethane and mixtures thereof; wherein the solvent used in step-(c) is dichloromethane, ethyl acetate and mixtures thereof; wherein the reagent used in step-(c) is selected from the group consisting of ethyl chloro formate, carbonyl diimidazole and acetyl chloride; and wherein the Cetilistat of formula 1 obtained in step-(c) is isolated and/or re- crystallized from a solvent selected from the group consisting of water, ethyl acetate, acetonitrile, dichloromethane, methanol, ethanol, isopropyl alcohol, and mixtures thereof.
4. A process for the preparation of 2-hexadecyloxycarbonylamino-5-methylbenzoic acid of formula 2:
Figure imgf000022_0001
or a pharmaceutically acceptable salt thereof, which comprises:
a) reacting 1-hexadecanol of formula 5:
Figure imgf000022_0002
with carbonyl diimidazole in a suitable solvent to produce 1-hexadecyloxy- carbonylimidazole of formula 4:
Figure imgf000022_0003
b) reacting the 1-hexadecyloxycarbonylimidazole of formula 4 with 2-amino-5- methylbenzoic acid of formula 3:
Figure imgf000022_0004
or a salt thereof, in presence of a base to produce the 2-hexadecyloxy- carbonylamino-5-methylbenzoic acid of formula 2 or a salt thereof.
5. The process of claim 4, wherein the solvent used in step-(a) is selected from the group consisting of tetrahydrofuran, toluene, dichloromethane, acetonitrile, N,N- dimethylformamide, and mixtures thereof; wherein the base used in step-(b) is selected from the group consisting of triethylamine, diisopropylethylamine and 4- Ν,Ν-dimethylaminopyridine; wherein the reaction in step-(b) is carried out in the presence of a solvent selected from the group consisting of tetrahydrofuran, toluene, dichloromethane, acetonitrile, Ν,Ν-dimethylformamide, and mixtures thereof; wherein the reaction in step-(b) is optionally carried out in the presence of a phase transfer catalyst selected from the group consisting of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, benzyltrimethyl ammonium chloride, benzyltriethyl ammonium chloride, methyltributyl ammonium chloride and crown ethers.
6. The process of claim 5, wherein the solvent used in step-(a) is acetonitrile; wherein the base used in step-(b) is triethylamine; wherein the solvent used in step-(b) is selected from the group consisting of acetonitrile, dichloromethane and mixtures thereof.
7. A process for preparation of process for the preparation of Cetilistat of formula 1:
Figure imgf000023_0001
or a pharmaceutically acceptable salt thereof, which comprises:
a) reacting the 1-hexadecyloxycarbonylimidazole of formula 4:
Figure imgf000023_0002
with 2-amino-5-methylbenzoic acid of formula 3:
Figure imgf000024_0001
or a salt thereof, in presence of a base to produce 2- hexadecyloxycarbonylamino-5-methylbenzoic acid of formula 2:
Figure imgf000024_0002
or a salt thereof; and
b) reacting the compound of formula 2 or a salt thereof with a suitable reagent, optionally in the presence of a base, to produce Cetilistat of formula 1 or a pharmaceutically acceptable salt thereof.
8. The process of claim 7, wherein the base used in step-(a) is selected from the group consisting of triethylamine, diisopropylethylamine and 4-N,N- dimethylaminopyridine; wherein the reaction in step-(a) is carried out in the presence of a solvent selected from the group consisting of tetrahydrofuran, toluene, dichloromethane, acetonitrile, Ν,Ν-dimethylformamide, and mixtures thereof; wherein the reaction in step-(a) is optionally carried out in the presence of a phase transfer catalyst selected from the group consisting of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, benzyltrimethyl ammonium chloride, benzyltriethyl ammonium chloride, methyltributyl ammonium chloride and crown ethers; wherein the reagent used in step-(b) is selected from the group consisting of methyl chloroformate, ethyl chloroformate, benzyl chloroformate, phenyl chloroformate, carbonyl diimidazole, acetic anhydride, dicyclohexylcarbodiimide, acetic anhydride, concentrated sulphuric acid, concentrated hydrochloric acid, oxalyl chloride, thionyl chloride, acetyl chloride and trichloro acetyl chloride; wherein the reaction in step-(b) is carried out in a reaction inert solvent selected from the group consisting of tetrahydrofuran, ethyl acetate, toluene, dichloromethane, acetonitrile, N,N- dimethylformamide, and mixtures thereof; wherein the reaction in step-(b) is carried out in the presence of a base selected from the group consisting of triethylamine, diisopropylethylamine and 4-N,N-dimethylaminopyridine; and wherein the Cetilistat of formula 1 obtained in step-(b) is isolated and/or re- crystallized from a solvent selected from the group consisting of water, an alcohol, an ether, an ester, a hydrocarbon, a halogenated hydrocarbon, a nitrile solvent, and mixtures thereof.
9. The process of claim 8, wherein the base used in step-(a) is triethylamine; wherein the solvent used in step-(a) is selected from the group consisting of acetonitrile, dichloromethane and mixtures thereof; wherein the reagent used in step-(b) is selected from the group consisting of ethyl chloroformate, carbonyl diimidazole and acetyl chloride; wherein the solvent used in step-(b) is dichloromethane, ethyl acetate and mixtures thereof; and wherein the Cetilistat of formula 1 obtained in step-(b) is isolated and/or re-crystallized from a solvent selected from the group consisting of water, ethyl acetate, acetonitrile, dichloromethane, methanol, ethanol, isopropyl alcohol, and mixtures thereof.
10. A process for the preparation of Cetilistat of formula 1:
Figure imgf000025_0001
or a pharmaceutically acceptable salt thereof, which comprises:
reacting 2-hexadecyloxycarbonylamino-5-methylbenzoic acid of formula 2:
Figure imgf000025_0002
or a salt thereof with a suitable reagent, optionally in the presence of a base, to produce Cetilistat of formula 1 or a pharmaceutically acceptable salt thereof.
The process of claim 10, wherein the reagent used in the reaction is selected from the group consisting of methyl chloroformate, ethyl chloroformate, benzyl chloroformate, phenyl chloroformate, carbonyl diimidazole, acetic anhydride, dicyclohexylcarbodiimide, acetic anhydride, concentrated sulphuric acid, concentrated hydrochloric acid, oxalyl chloride, thionyl chloride, acetyl chloride and trichloro acetyl chloride; wherein the reaction is carried out in a reaction inert solvent selected from the group consisting of tetrahydrofuran, ethyl acetate, toluene, dichloromethane, acetonitrile, Ν,Ν-dimethylformamide, and mixtures thereof; wherein the reaction is carried out in the presence of a base selected from the group consisting of triethylamine, diisopropylethylamine and 4-N,N- dimethylaminopyridine; and wherein the Cetilistat of formula 1 obtained is isolated and/or re-crystallized from a solvent selected from the group consisting of water, an alcohol, an ether, an ester, a hydrocarbon, a halogenated hydrocarbon, a nitrile solvent, and mixtures thereof.
12. The process of claim 11, wherein the solvent used is dichloromethane, ethyl acetate and mixtures thereof; wherein the reagent used is selected from the group consisting of ethyl chloroformate, carbonyl diimidazole and acetyl chloride; and wherein the Cetilistat of formula 1 obtained is isolated and/or re-crystallized from a solvent selected from the group consisting of water, ethyl acetate, acetonitrile, dichloromethane, methanol, ethanol, isopropyl alcohol, and mixtures thereof.
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Citations (1)

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Publication number Priority date Publication date Assignee Title
US7858617B2 (en) * 1999-01-08 2010-12-28 Norgine B.V. 2-oxy-benzoxazinone derivatives for the treatment of obesity

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7858617B2 (en) * 1999-01-08 2010-12-28 Norgine B.V. 2-oxy-benzoxazinone derivatives for the treatment of obesity

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Title
THOMAS WERNER ET AL.: "Simple Method for the Preparation of Esters from Grignard Reagents and Alkyl 1-Imidazolecarboxylates", J. ORG. CHEM. , 2006, vol. 71, no. 11, 3 May 2006 (2006-05-03), pages 4302 - 4304, XP055458714 *

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