Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members

Definitions

• the present invention relates to an improved process for the preparation of
• XO xanthine oxidase
• compound of formula VI can be prepared, either via ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5- carboxylate of formula III or ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5- carboxylate of formula V, starting from ethyl 2-(3-formyl-4-hydroxyphenyl)-4- methylthiazole-5-carboxylate of formula II, as described in scheme 1.
• the resulting a compound of formula VI is converted to Febuxostat.
• the process comprises full isolation of each intermediate at each step of the reaction, resulting in an overall low yield and high solvent consumption, at the end of the process. Under the described conditions the process requires a large molar excess of isobutyl bromide whose disposal procedure is not environmentally friendly.
• Febuxostat salt can contain extraneous compounds or impurities that can come from many sources. They can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Impurities in Febuxostat or any active pharmaceutical ingredient (API) are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API.
• API active pharmaceutical ingredient
• impurities in an API may arise from degradation of the API itself, which is related to the stability of the pure API during storage, and the manufacturing process, including the chemical synthesis.
• Process impurities include unreacted starting materials, chemical derivatives of impurities contained in starting materials, synthetic by-products, and degradation products.
• the purity of the API produced in the commercial manufacturing process is clearly a necessary condition for commercialization. Impurities introduced during commercial manufacturing processes must be limited to very small amounts, and are preferably substantially absent.
• the ICH Q7A guidance for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
• the product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and byproducts of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product mixture.
• an API such as febuxostat
• it must be analyzed for purity, typically, by HPLC analysis, to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product.
• the API need not be absolutely pure, as absolute purity is a theoretical ideal that is typically unattainable. Rather, purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and, thus, are as safe as possible for clinical use.
• the Food and Drug Administration guidelines recommend that the amounts of some impurities be limited to less than 0.1 percent.
• the present invention provides an improved process to prepare 2-(3- cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid of formula I as well as its ethyl intermediate of formula VI; where preferred processes are simple, environmentally friendly, result in a high overall yield and can be easily applied to large scale manufacture.
• the present invention encompasses a one-pot process for preparing a compound of formula VI
• the present invention comprises a process for preparing Febuxostat comprising preparing a compound of formula VI by any of the processes described in the present invention and further converting it to Febuxostat.
• the present invention further encompasses an improved process for preparing Febuxostat of formula I,
• Febuxostat or “compound of formula I” relates to 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid, having the formula:
• compound of formula ⁇ relates to ethyl 2-(3- formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate, having the formula:
• compound of formula III relates to ethyl 2-(3- formyl-4-isobutoxyphenyl)-4-meth lthiazole-5-carboxylate, having the formula:
• a compound of formula VI relates to ethyl 2-(3- cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylate, having the formula:
• compound of formula IV relates to ethyl 2-(3- carboxamido-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate, having the formula:
• Compound of formula VIII relates to [2-(3- carboxamido-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid] having the formula:
• the term "purity" refers to the weight percentage of a compound in a sample. It is typically determined by the w/w percentage under the peak of the compound relative to the total area in the HPLC chromatogram.
• substantially pure refers to Febuxostat having a purity of about 99.0% w/w by HPLC or more, for example, to Febuxostat having a purity of about 99.5% w/w by HPLC or more.
• Febuxostat refers to Febuxostat containing less than about 0.2 % w/w by HPLC of amide impurity of formula VIII.
• Febuxostat contains less than about 0.15 % w/w by HPLC of amide impurity of formula VIII, Febuxostat containing less than about 0.1 % w/w by HPLC of amide impurity of formula VIII, or Febuxostat containing less than about 0.05% w/w.
• Febuxostat containing an undetectable amount of amide impurity of formula VIII as measured by HPLC.
• the term "isolated" in reference, for example, to the compound of formula IV corresponds to the compound of formula IV that is physically separated from the reaction mixture, where it is formed.
• the separation can be done by filtering the precipitated compound of formula IV.
• compound of formula IV is separated from a compound of formula VI.
• the term "isolated” in reference, for example, to the compound of formula VIII corresponds to the compound of formula VIII that is physically separated from the reaction mixture, where it is formed. For example, the separation can be done by filtering the precipitated compound of formula VIII. In a preferred embodiment, compound of formula VIII is separated from Febuxostat.
• reduced pressure or “vacuum” refers to a pressure of less than 100 mmHg.
• distillation refers to a distillation process done at a pressure of no more than about 760 mmHg.
• solvent exchange refers to the process of adding a second solvent to a mixture comprising a compound, such as a compound of formula VI, in a first solvent, and concentrating the mixture.
• concentration of the mixture is preferably done by distillation.
• the distillation may be azeotropic distillation.
• azeotrope refers to a liquid mixture of at least two components that boils at constant temperature without change in composition. The temperature at which the azeotrope boils differs from the boiling points of its individual components.
• azeotropic distillation refers to the removal of residual solvent from the reaction mixture using a second solvent, wherein the second solvent forms an azeotrope with at least one of the residual solvents, and removes the azeotrope from the reaction mixture.
• water scavenger refers to chemical scavenger which works by destroying structure of water, for example, a molecule of anhydride which decomposes to form corresponding carboxylic groups.
• the present invention encompasses substantially pure Febuxostat.
• the present invention encompasses a compound of formula VI essentially free from the compound of formula IV.
• the present invention encompasses Febuxostat essentially free from the compound of formula Compound of formula VIII.
• the present invention encompasses isolated compound of formula IV and substantially pure compound of formula IV.
• the present invention encompasses isolated compound of formula VIII and substantially pure compound of formula VIII.
• the present invention encompasses a one-pot process for preparing a compound of formula VI comprising combining a compound of formula II with isobutyl halide, for example, isobutyl bromide and an organic solvent in the presence of an inorganic base selected from: alkali carbonate, alkali bicarbonate, ammonium carbonate and ammonium bicarbonate, an alkali iodide, and an alkali metal hydroxide, to obtain a compound of formula III; and adding hydroxylamine base or hydroxylamine HC1 to obtain a compound of formula VI.
• an inorganic base selected from: alkali carbonate, alkali bicarbonate, ammonium carbonate and ammonium bicarbonate, an alkali iodide, and an alkali metal hydroxide
• the organic solvent may be toluene or a polar aprotic solvent selected from: dimethylformamide (“DMF”), dimethylamide (“DMA”), acetonitrile, acetone and dimethylsulfoxide (“DMSO”), for example, the organic solvent may be toluene or DMF.
• DMF dimethylformamide
• DMA dimethylamide
• DMSO dimethylsulfoxide
• the inorganic base may be alkali carbonate, alkali bicarbonate or alkali metal hydroxide.
• the alkali carbonate is potassium carbonate or sodium carbonate.
• the alkali hydroxide is potassium hydroxide or sodium hydroxide.
• the combining step is typically done at a temperature of about 50°C to about 100°C, for example, from about 70°C to about 110°C, typically, until complete dissolution is obtained.
• inorganic by-products such as inorganic salts are formed.
• these inorganic salts are: alkali or ammonium bromides, residue of the used carbonates and alkali iodide.
• Such inorganic by-products may be removed, for example, by phase separation or by hot filtration.
• the hydroxylamine base or hydroxylamine HC1 may be added in an excess amount, for example, in an amount of about 1.1 equivalents compared to formula III or more.
• the hydroxylamine base or hydroxylamine HC1 may be added in the presence of alkali formate and either formic acid or acetic acid.
• the alkali formate may be sodium formate or potassium formate.
• the formic acid may be partially distilled. The distillation may be done for a time interval such as from about 3 hours to about 18 hours, or from about 4 hours to about 10 hours.
• hydroxylamine base or hydroxylamine HC1 may be done at a temperature of about 50°C to about reflux temperature, for a time interval of from about 2 hours to about 24 hours, or from about 3 hours to about 18 hours, for example, from about 4 hours to about 10 hours.
• aqueous washing step is performed to obtain a two phase system.
• the aqueous washing may be done with water and an organic solvent selected from: n-butanol, iso- butanol, ethyl acetate and toluene, for example, ethyl acetate or toluene.
• the phases obtained may be further separated.
• the organic phase is concentrated.
• the concentration may be done by distillation, for example, by atmospheric distillation.
• the distillation may be done at a temperature such as of from about 90°C to about 110°C, or at about 100°C. Typically, the distillation is done until dryness.
• the obtained dry organic phase may be further dehydrated by combining with a water scavenger, for example, anhydride.
• a water scavenger for example, anhydride.
• the dehydration may be done by adding anhydride such as acetic anhydride in the presence of acetic acid or any alkali acetate salt.
• the dehydration may be done at a temperature such as from about 70°C to about reflux, for a time interval of from about 5 hours to about 24, or from about 8 hours to about 12 hours, for example, from about 10 hours to about 11 hours.
• acetic acid used in the reaction may be removed, for example, by distillation.
• a seeding step may be performed.
• the seeding may be done with a compound of formula VI.
• a maintaining step may be performed, for a time interval of from about 10 minutes to about 5 hours, for example, from about 1 hour to about 3 hours.
• a temperature such as about 50°C to about 20°C, or about 40°C to about 30°C, for example, about 30°C, may be performed.
• washing for example with water
• the washing may be repeated.
• the washing may be done at a temperature of about 50°C to about 100°C, for example, of about 50°C to about 80°C.
• cooling is done prior and/or after the washing.
• the cooling may be done to a temperature of from about 65°C to about 10°C, for example, to a temperature of from about 50°C to about 10°C.
• a maintaining step for a time interval such as from about 10 minutes to about 5 hours, for example, from about 1 hour to about 3 hours, may be done.
• the washed organic phase may be concentrated to obtain a solid; and crystallized.
• the concentration may be done by distillation.
• the crystallization may be done with the same solvent used for the aqueous washing to obtain a compound of formula VI.
• the obtained compound of formula VI may be further cooled to a temperature such as about 25°C.
• the dehydration step may be done by alkali formate such as sodium formate or potassium formate, for example, sodium formate, and either formic acid or acetic acid.
• HC1 may be added in the presence of alkali formate and either formic acid or acetic acid.
• a concentrating step may be performed, for example, by distillation.
• the formic acid or acetic acid used in the reaction can be removed.
• the removal may be done by distillation followed by solvent exchange.
• the solvent exchange may be done with the same solvent used in the above process. Said solvent exchange steps may be repeated until the acid is completely removed.
• the organic solvent used in the process can be removed.
• the removal may be done by distillation followed by solvent exchange.
• the solvent exchange may be done with a Ci- C 4 alcohol, such as ethanol, for example, ethanol containing at least 5% water or more. Said solvent exchange steps may be repeated.
• the process may further comprise a recovery step.
• the recovery may be done by methods known in the art such as drying.
• drying is done under vacuum.
• drying is done at a temperature of about 35°C to about 80°C, more preferably, from about 40°C to about 75°C.
• the recovery step may additionally comprise filtering and washing prior to the drying.
• the washing may be done with the same solvent used for the aqueous washing.
• the present invention comprises a process for preparing Febuxostat comprising preparing a compound of formula VI by any of the processes described in the present invention and further converting it to Febuxostat.
• the compound of formula Vl-a is prepared essentially as described above by a one-pot process comprising: combining a compound of formula II with isobutyl bromide and an organic solvent in the presence of an inorganic base selected from: alkali carbonate, alkali bicarbonate, ammonium carbonate and ammonium bicarbonate, an alkali iodide, and alkali metal hydroxide; and adding hydroxylamine base or hydroxylamine HC1.
• the organic solvent may be a polar aprotic solvent selected from: dimethylformamide (“DMF”), dimethylamide (“DMA”), acetonitrile, acetone and dimethylsulfoxide (“DMSO”), for example, DMF.
• DMF dimethylformamide
• DMA dimethylamide
• DMSO dimethylsulfoxide
• the inorganic base may be alkali carbonate, such as potassium carbonate or sodium carbonate, for example, potassium carbonate, or alkali bicarbonate.
• the process may be done while heating to a temperature such as from about 50°C to about 100°C, or from about 60°C to about 80°C, for example, 70°C.
• the hydroxylamine base or hydroxylamine HC1 is typically added during about 2 hours to about 24, or, about 3 hours to about 18 hours, for example, during about 4 hours to about 10 hours.
• a maintaining step for a time interval of from about 30 minutes to about 6 hours, for example, for about 4 hours.
• an aqueous washing step is performed to obtain a two phase system.
• the aqueous washing may be done with water and an organic solvent such as: n-butanol, iso-butanol, ethyl acetate and toluene, for example, ethyl acetate or toluene.
• the phases obtained may be further separated, washed and cooled to obtain the compound of formula Vl-a.
• the washing may be done with water.
• the washing may be repeated.
• the cooling may be to a temperature of about 60°C to about 50°C, for example, to about 55°C.
• a maintaining at the same temperature achieved in the previous step, for a time interval of from about 30 minutes to about 3 hours, for example, for about 1 hour, may be done.
• Further cooling step may be performed.
• the cooling may be done to a temperature of about 30°C to about 10°C, for example, to about 10°C.
• the process may further comprise a recovery step.
• the recovery may be done by methods known in the art, for example by filtering; washing; and drying.
• the washing may be done with the same organic solvent used for the aqueous washing.
• the drying may be done under vacuum, at a temperature of about 30°C to about 50°C, for example, at about 40°C.
• the present invention comprises a process for preparing Febuxostat comprising preparing a compound of formula Vl-a by the processes described above and further converting it to Febuxostat.
• the present invention encompasses a process for preparing a compound of formula VI comprising: combining a compound of formula Vl-a with anhydride such as acetic anhydride optionally in the presence of acetic acid or alkali or ammonium acetate.
• the process may be done while heating to a temperature such as from about 70°C to about reflux, for a time interval of about 2 hours to about 24, or about 3 hours to about 18 hours, for example, for about 4 hours to about 10 hours.
• the final synthesis step of the process described in WO '279 comprises preparing Febuxostat from a compound of formula VI, using aqueous sodium hydroxide ethanol and tetrahydrofuran ("THF"), as depicted in scheme 2.
• THF tetrahydrofuran
• the process utilizes numerous solvents.
• the product obtained in WO '279 is further recovered with ethyl acetate and concentrated to dryness. The concentration is done by distillation. Said distillation to dryness is not applicable on an industrial scale.
• the present invention provides an improved process for preparing Febuxostat from a compound of formula VI, using a solvent system of one organic solvent only.
• the process preferably avoids the need for multiple drying steps, and preferably results in a pure product.
• the present invention encompasses an improved process for preparing
• a compound of formula VI can be obtained for example by any of the processes described above or according to WO '279.
• the alkali metal hydroxide may be sodium hydroxide or potassium hydroxide.
• the alkali metal hydroxide may be either in its solid form or as an aqueous solution.
• the aqueous alkali hydroxide solution concentration can be of about 4% to about 50% w/w, about 4% to about 25% w/w, or about 4% to about 10% w/w, for example, about 4% to about 6% w/w.
• the organic solvent may be selected from: a C 1 -C 3 alcohol, such as ethanol and a C 2 -C 3 ketone, such as acetone.
• the ethanol may comprise about 0% to about 10% w/w water, or about 5% to about 10% w/w, for example, about 5% w/w.
• the organic solvent may be selected from: a C4-C6 alcohol and a C3-C5 ketone, such as methyl ethyl ketone ("MEK”) or methyl isobutyl ketone (“MIBK”), for example, the organic solvent is n-butanol or iso-butanol.
• MEK methyl ethyl ketone
• MIBK methyl isobutyl ketone
• the process may be done in the absence of tetrahydrofuran
• the reaction may be done while heating.
• the heating may be done to a temperature of from about 20°C to about 60°C, or from about 30°C to about 50°C, for example, from about 40°C to about 50°C, for a time interval of from about 1 hour to about 48 hours, or from about 2 hours to about 24 hours.
• the process may further comprise a recovery step.
• the recovery step may comprise adding an acid; heating; cooling; filtering; and drying.
• the acid may be an inorganic acid, such as HC1, HBr, H 2 SO 4 , H 3 PO 4 , or an organic acid such as acetic acid and formic acid.
• the acid is added in excess amount, for example, the amount of acid is about 1.1 equivalents compared to formula VI or more.
• heating may be done to about reflux temperature.
• the heating may be followed by a filtration step.
• the obtained filtrate can be further heated and cooled thereafter.
• the cooling may be done to a temperature of about 25°C to about -10°C, or of about 20°C to about 0°C, for example, to a temperature of about 10°C to about 0°C.
• a two phase system can be obtained. Additional amount of water may be further added. The acid may be added to the water. The two phase system may further be separated, and the obtained organic phase may be heated and cooled. Prior to the heating, the organic phase may be further washed with water. Typically, the heating may be to a temperature of from about 40°C to about 90°C, or, from about 50°C to about 80°C, for example, to a temperature of from about 60°C to about 70°C. The heating is typically until complete dissolution is obtained.
• the organic phase is concentrated, for example, by distillation. The cooling may be done to a temperature of from about 25°C to about -10°C, or from about 20°C to about 0°C, for example, from about 10°C to about 0°C.
• drying may be done under vacuum at a temperature of about
• a compound of formula VI (1.0 gr, 2.9 mmol) was hydrolysed under anhydrous conditions using solid sodium hydroxide (0.2 gr, 4.8 mmol) in 15 ml absolute ethanol. The reaction was performed at 60°C during 2.5 hours. The Febuxostat purity in the reaction mixture was 96.15% (by HPLC).
• a compound of formula VI (1.0 gr, 2.9 mmol) was hydrolysed using aqueous (4.7%) sodium hydroxide (4.13 gr, 4.8 mmol) solution in 20 ml n-butanol. The reaction was performed at 40°C during 4 hours. The Febuxostat purity in the reaction mixture was 97.87% (by HPLC).
• Example 3 Preparation of Febuxostat by aqueous hydrolysis
• a compound of formula VI (1.0 gr, 2.9 mmol) was hydro lysed using aqueous (4.7%) sodium hydroxide (4.13 gr, 4.8 mmol) solution in 20 ml iso-butanol. The reaction was performed at 40°C during 9.5 hours. The Febuxostat purity in the reaction mixture was 96.22% (by HPLC).
• a compound of formula VI (10.0 gr, 29 mmol) was hydro lysed under anhydrous conditions using solid sodium hydroxide (1.9 gr, 48 mmol) in 50 ml ethanol (95%)). The reaction was performed at 40°C during 6 hours. Concentrated aqueous HC1 solution (4.5 ml) was added to the reaction mixture to get pH ⁇ 3. The resulting mixture was heated to reflux ( ⁇ 78°C). A hot filtration of inorganic salts was performed. The filtrate was heated to reflux again in order to complete product dissolution. The mixture was cooled slowly to obtain precipitation. After cooling to about 5°C, the Febuxostat suspension was filtered and the separated crude product was dried at 75 °C under reduced pressure to provide Febuxostat (8.64 gr, yield - 94%>; purity - 99.33%>).
• a compound of formula VI (10.0 gr, 29 mmol) was hydro lysed using aqueous (4.7%) sodium hydroxide (41.3 gr, 48 mmol) solution in 200 ml n-butanol. The reaction was performed at 40°C during 4 hours. Water (200 ml) was added to the reaction mixture, which then was acidified to about pH 1-3 with aqueous HC1 (32%). Organic phase was separated and washed with 200 ml water. The separated organic phase was heated to 60°C and cooled slowly to about 5°C and stirred during about 18 hours. The precipitated Febuxostat was separated by filtration and dried at 50°C under reduced pressure to provide crude product (5.8 gr, yield - 63%>; purity by HPLC test - 99.27%).
• a compound of formula II (10.0 gr, 34.33 mmol) was reacted with iso- butyl bromide (18.9 gr, 137.3 mmol) in the presence of potassium carbonate (19.0 gr, 137.3 mmol) and potassium iodide (2.3 gr, 13.7 mmol) in 60 ml dimethylformamide.
• the reaction was performed at about 70°C during 4 hours.
• the reaction mixture was extracted at 70°C using 300 ml ethyl acetate and 600 ml water.
• the separated aqueous phase was washed twice with 100 ml ethyl acetate.
• the combined organic phase was washed twice with 100 ml water and then concentrated to dryness.
• a compound of formula II (10.0 gr, 34.33 mmol) was reacted with iso- butyl bromide (18.9 gr, 137.3 mmol) in the presence of potassium carbonate (19.0 gr, 137.3 mmol) and potassium iodide (2.3 gr, 13.7 mmol) in 60 ml dimethylformamide.
• the reaction was performed at about 70°C during 4 hours.
• the reaction mixture was diluted with 100 ml toluene at about 70°C and washed first time with 300 ml water, second time with 150 ml water and finally with 75 ml water.
• the separated organic phase was cooled to about 10°C, filtered and dried under reduced pressure at about 40°C to provide a compound of formula III (7.7 gr, yield - 72%).
• the Compound of formula III purity is 99.4% (by HPLC).
• a compound of formula II (30.0 gr, 103.0 mmol) was reacted with iso- butyl bromide (56.7 gr, 412.0 mmol) in the presence of potassium carbonate (57.0 gr, 412.0 mmol) and potassium iodide (6.9 gr, 41.1 mmol) in 180 ml dimethylformamide.
• the reaction was performed at about 70°C during 4 hours.
• the reaction mixture was diluted with 180 ml toluene at about 70°C and washed first time with 600 ml water, second time with 300 ml water and finally with 150 ml water.
• the separated organic phase was cooled to about 5°C, filtered and dried under reduced pressure at about 40°C to provide a compound of formula III (25.2 gr, yield - 78.5%).
• the Compound of formula III purity is 99.35% (by HPLC).
• a compound of formula III (10.0 gr, 28.8 mmol) was reacted with hydroxylamine hydrochloride (2.4 gr, 34.5 mmol) in the presence of sodium formate (3.1 gr, 46.1 mmol) in 100 ml formic acid.
• the reaction was performed at reflux conditions during 3 hours.
• the reaction mixture was cooled to about 50°C, diluted with 100 ml toluene and 100 ml water and allowed for the phase separation.
• the organic phase was washed with 50 ml water at about 50°C and concentrated to dryness.
• the solid residue was re-crystallized from 40 ml toluene, cooled to about 25°C, filtered and dried under reduced pressure at about 75°C to provide a compound of formula VI (8.6 gr, yield - 87%).
• the compound of formula VI purity is 99.6% (by HPLC).
• a compound of formula III (10.0 gr, 28.8 mmol) was reacted with hydroxylamine hydrochloride (2.4 gr, 34.5 mmol) in the presence of sodium formate (3.1 gr, 46.1 mmol) in 100 ml formic acid. About 50 ml of the formic acid were distilled out under atmospheric pressure during 3 hours of the reaction time. The reaction mixture was cooled to about 50°C, diluted with 60 ml toluene and 100 ml water. The mixture was heated to about 72°C and allowed for the phase separation.
• the organic phase was washed first time with 100 ml water and second time with 50 ml water at about 72°C, cooled to about 10°C, filtered, washed with 10 ml toluene and dried under reduced pressure at about 40°C to provide a compound of formula VI (7.7 gr, yield - 78%).
• the compound of formula VI purity is 99.75%) (by HPLC).
• a compound of formula III (10.0 gr, 28.8 mmol) was reacted with hydroxylamine hydrochloride (2.4 gr, 34.5 mmol) in the presence of sodium formate (3.1 gr, 46.1 mmol) in 50 ml formic acid.
• the reaction was performed at reflux conditions during 3 hours.
• the reaction mixture was cooled to about 70°C, diluted in 170 ml ethyl acetate and 100 ml water and allowed for the phase separation.
• the organic phase was cooled to about 10°C, filtered, washed with 10 ml ethyl acetate and dried under reduced pressure at about 40°C to provide a compound of formula VI (9.5 gr, yield - 96%>).
• the compound of formula VI purity is 99.8%> (by HPLC).
• a compound of formula III (10.0 gr, 28.8 mmol) was reacted with hydroxylamine hydrochloride (2.4 gr, 34.5 mmol) in the presence of sodium formate (3.1 gr, 46.1 mmol) in 50 ml formic acid.
• the reaction was performed at reflux conditions during 3 hours.
• the reaction mixture was cooled to about 70°C, diluted in 80 ml toluene and 100 ml water and allowed for the phase separation.
• the organic phase was washed twice with 100 ml water at about 70°C, cooled to about 50°C, stirred at this temperature during 1 hour to deepen precipitation and then cooled to about 10°C, filtered, washed with 5 ml toluene and dried under reduced pressure at about 40°C to provide a compound of formula VI (9.3 gr, yield - 94%).
• the compound of formula VI purity is 99.7% (by HPLC).
• a compound of formula II (10.0 gr, 34.33 mmol) was reacted with iso- butyl bromide (18.9 gr, 137.3 mmol) in the presence of potassium carbonate (19.0 gr, 137.3 mmol) and potassium iodide (2.3 gr, 13.7 mmol) in 100 ml dimethylformamide.
• the reaction was performed at about 70°C during 4 hours. Hydroxylamine hydrochloride (Then 3.6 gr, 51.8 mmol) was then added at about 70°C and stirred at this temperature during 7 hours.
• the reaction mixture was diluted with 80 ml toluene, 100 ml water was added and the mixture was allowed for the phase separation.
• the organic phase was washed first time with 100 ml water and second time with 50 ml water at about 70°C, cooled to about 55°C, stirred at this temperature during 1 hour to deepen precipitation and then cooled to about 10°C, filtered, washed with 10 ml toluene and dried under reduced pressure at about 40°C to provide a compound of formula Vl-a (8.2 gr, yield - 73%).
• the Compound of formula Vl-a purity is 96.4% (by HPLC).
• Example 14 Preparation of a compound of formula VI from Compound of formula Vl-a [00102] A compound of formula Vl-a (0.3 gr, 0.83 mmol) was refluxed (about
• a compound of formula II (10.0 gr, 34.33 mmol) was reacted with iso- butyl bromide (18.9 gr, 137.3 mmol) in the presence of potassium carbonate (19 gr, 137.3 mmol) and potassium iodide (2.3 gr, 13.7 mmol) in 100 ml dimethylformamide. The reaction was performed at about 70°C during 4 hours. Then hydroxylamine hydrochloride (3.6 gr, 51.8 mmol) was added and the reaction mixture was stirred at 70°C during additional 4 hours.
• the reaction mixture was diluted with 90 ml toluene and washed twice with 100 ml water and finally with 50 ml water each time allowing for the phase separation at about 70°C.
• the separated organic phase was partially distilled using Dean- Stark trap under atmospheric pressure in order to remove water residue in the mixture (about 4 ml were distilled to reach boiling temperature more than 100°C).
• Acetic anhydride (15 ml) and glacial acetic acid (8 ml) were then added to the dried organic phase.
• the reaction mixture was refluxed at about 107°C during 11 hours to complete reaction.
• the reaction solvent (about 20 ml) was distilled out and the residual mixture was cooled to about 30°C, seeded with a compound of formula VI, stirred at this temperature during 1 hour to deepen precipitation and then cooled to about 10°C and dried under reduced pressure at about 40°C to provide a compound of formula VI (6.4 gr, yield - 60%).
• the compound of formula VI purity is 96.3% (by HPLC).

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