Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• the present disclosure relates to a method of preparation of Zolpidem, particularly to a method of preparation of Zolpidem using a novel intermediate.
• Zolpidem an imidazo pyridine represented by Formula 6, is one of the most commonly prescribed hypnotics for the treatment of insomnia and other brain disorders such as convulsions and anxiety.
• Zolpidem has a short half-life and is a non-benzodiazepine, fast-acting hypnotic that binds selectively to the GABA A receptor subtypes, the usual onset of action being within 15 minutes of administration.
• 6-Methyl-2-(4-methylphenyl)imidazo[l,2-a]pyridine a compound represented by Formula 1, is the basic starting material for the preparation of Zolpidem.
• the Tschitschibabin reaction represented by Scheme 1, is a method conventionally followed for the preparation of the compound of Formula 1.
• toluene is reacted with chloroacetylchloride under Friedel-Crafts acylation conditions followed by condensation with 2-amino-5- methylpyridine to provide the compound of Formula 1.
• EP0050563 suggests a process for the preparation of Zolpidem as schematically represented in Scheme 2.
• EP0050563 uses low boiling, highly expensive and toxic reagents such as methyl iodide that makes the process cost-inefficient and non-amenable to large scale.
• US 4492695 avoids the use of expensive and toxic reagent i.e., methyl iodide; however it involves a relatively more number of steps. Further, the reaction time of some of the steps of US4492695 is relatively long, thereby making the process energy inefficient. Still further, the yield of Zolpidem is relatively low and the workup procedure to isolate Zolpidem is complex.
• WO2009007995 suggests a process represented in Scheme 4 for the preparation of Zol idem.
• WO2009007995 uses alkyl chloroformates which are as toxic as methyl iodide. Further, the alkyl chloroformates are difficult to handle due to their low vapor pressure and lachrymatic properties. Even further, the process suffers from tedious work-up method which is undesirable for commercial production.
• the inventors of the present disclosure thus, provide a process for the preparation of Zolpidem that can be readily scaled up, does not require special purification steps and which employs inexpensive, readily available, easy to handle and non-toxic reagents.
• an intermediate for the preparation of Zolpidem said intermediate having a structure of Formula 3, wherein R is selected from the group comprising ethyl, methyl, propyl, butyl, isopropyl, isobutyl and tertiary butyl group.
• a process for the preparation of an intermediate of Formula 3 by alkylating a compound of Formula 2 comprising the following steps: first, a solution comprising Formula 2 and a first solvent is prepared; then a compound of Formula 7 is added to the prepared solution at a temperature ranging from -5 °C to 15 °C to obtain a reaction mixture; the reaction mixture is refluxed at a temperature ranging from 35 °C to the boiling point of the first solvent to obtain a compound of Formula 3.
• the compound of Formula 4 is hydrolyzed said using an aqueous solution of at least one base and at least one second solvent to obtain a compound of Formula 5;
• Zolpidem an imidazo pyridine is one of the most commonly prescribed hypnotics for the treatment of insomnia and other brain disorders such as convulsions and anxiety.
• Zolpidem has a short half-life and is a non-benzodiazepine, fast-acting hypnotic that binds selectively to the GABA A receptor subtypes, the usual onset of action being within 15 minutes of administration.
• the basic starting material for preparation of Zolpidem is 6-Methyl-2- (4-methylphenyl)imidazo[l,2-a]pyridine (compound of Formula 1).
• compounds of Formula 1 6-Methyl-2- (4-methylphenyl)imidazo[l,2-a]pyridine.
• the present disclosure therefore, provides a process for preparation of Zolpidem that can be easily scaled up, does not require additional purification steps and employs inexpensive, readily available, easy to handle and non-toxic reagents.
• the present disclosure provides a novel intermediate having a structure of compound of formula 3, for the preparation of Zolpidem and a process for preparing the novel intermediate.
• a compound of Formula 7 i.e., dialkyl sulfate is added at a temperature ranging from -5 °C to 15 °C to the solution of compound of Formula 2 i.e., (2-(4-methylphenyl)-6-methyl-3-dimethylaminomethyl imidazo [l,2-a]pyridine) and solvent/s to obtain a reaction mixture.
• the reaction mixture is then heated to a boiling point of the solvent being used in the first step to obtain a compound of Formula 3 (a quaternary ammonium salt of Mannich base of the compound of Formula 2) after heating the reaction mixture for a time period of 15 to 480 minutes.
• the R group in the compound of Formula 7 is selected from a group comprising ethyl, methyl, propyl butyl, isopropyl, isobutyl and tertiary butyl group.
• the molar ratio of the compound of Formula 2 to the compound of Formula 7 is optimized in the range of 1:0.5 to 1:3.
• the optimized molar ratio of the compound of Formula 2 to the compound of Formula 7 ranges from 1:1 to 1:1.5.
• Solvents that can be used in the present disclosure include halogenated solvent, alcohol solvent and ketone solvent.
• Non-limiting examples of the solvent include dichloromethane, dichloroethane, chloroform, acetone, methanol, ethanol, ethyl acetate and the like.
• Non-limiting examples of the dialkyl sulfate represented by Formula 7 include diethyl sulfate, dipropyl sulfate, dibutyl sulfate, di-isopropyl sulfate, di-isobutyl sulfate, dimethyl sulfate and the like.
• dialkyl sulfate is dimethyl sulfate.
• the compound of Formula 3 prepared in accordance with the process of the present disclosure is subjected to cyanation reaction using an aqueous solution of sodium cyanide to obtain a nitrile derivative represented by Formula 4 (6-methyl-2-(4- methylphenyl)imidazo[l,2-a]pyridine-3-acetonitrile).
• the cyanation reaction is carried out at a temperature ranging from 10 °C to 100 °C for a time period of 1 to 6 hours.
• the compound of Formula 3 is isolated from the solvent prior to cyanation with sodium cyanide.
• the compound of Formula 3 is reacted as such, in-situ, for cyanation with sodium cyanide.
• the compound of Formula 3 is dissolved in water and the pH is adjusted in the range of 6.0 to 10.0 using a pH adjusting agent before subjecting it to the cyanation reaction.
• Non-limiting examples of pH adjusting agent include potassium carbonate, sodium bicarbonate, sodium hydride and sodium hydroxide.
• the compound of Formula 4 prepared in accordance with the present disclosure is further hydrolyzed using an aqueous solution of a base and at least one solvent to obtain an acid represented by the Formula 5 (6-methyl-2-(4- methylphenyl)imidazo[l,2-a]pyridine-3- acetic acid).
• Non-limiting examples of the base include potassium hydroxide, sodium hydroxide, barium hydroxide, sodium carbonate and ammonia.
• Non-limiting examples of the solvent include methanol, ethanol and acetone.
• the compound of Formula 5 prepared in accordance with the present disclosing is initially reacted with an acyl halide forming agent to obtain an acyl halide derivative represented by formula 8.
• the compound of Formula 8 is moisture sensitive and therefore not isolated, though it can be, and is further reacted with dimethyl amine to obtain Zolpidem having the structure of Formula 6 (6-methyl-2-(4- methylphenyl)imidazo[l,2-a]pyridine-3-N,N-dimethylacetamide).
• the acyl halide forming agent in accordance with the present disclosure is phosphorus oxychloride, phosphorus penta chloride, phosphorus trichloride, thionyl chloride and combinations thereof.
• the process of the present disclosure prepares the compound of Formula 5 (6-methyl- 2-(4-methylphenyl)imidazo[l,2-a]pyridine-3-acetic acid) without isolation and purification of intermediate products thereby saving the time and increasing the productivity.
• the overall progression of the reaction for the preparation of Zolpidem in accordance with the present disclosure is represented in Scheme 5.
• reaction mass was cooled to 10 °C, the product was filtered and taken in a reactor containing 1200 ml of 6.25%sodium cyanide solution.
• the resultant reaction mass was heated and then maintained at 85 °C for 4 hours and then cooled to about 25 °C, filtered and washed thoroughly with water to remove excess sodium cyanide.
• the filtered compound was dried at 100 °C to yield 133 g of title compound, 6-methyl-2-(4- methylphenyl)imidazo[l,2-a]pyridine-3-acetonitrile.
• HPLC High Performance Liquid Chromatography
• the reaction mass was then heated slowly to 80-85 °C and maintained for 2 hours to distill out methanol.
• the reaction mass was cooled to about 25 °C, filtered and washed thoroughly with water to remove excess sodium cyanide.
• the filtered compound was dried at 100 °C to yield 95 g of the compound of Formula 4. HPLC purity of the compound was found to be 87%.
• the compound prepared in Example 1 was taken into a reactor containing 600 ml of methanol and 600 ml of water along with 100 g of potassium hydroxide.
• the reaction mixture was refluxed for 15 hours till the completion of the reaction and was followed by distillation with methanol (600-700 ml of methanol-water).
• the aqueous reaction mass was cooled to about 25 °C and washed thrice with methylene chloride.
• the aqueous layer was then acidified with acetic acid to precipitate the product.
• the white solid material obtained was filtered and washed with water.
• 121 g (0.432 mol) of 6- methyl-2-(4-methylphenyl)imidazo[l,2-a]pyridine-3- acetic acid was the yield obtained having 99.70%HPLC purity.
• reaction mass was then cooled to 10 °C and dimethylamine gas was purged into the reaction mass at 10-15 °C, till the pH ranged between 9 and 10.
• the reaction mass was further heated to 50 °C and maintained for 1 hour.
• the reaction mass was cooled to 25 °C and a solution of sodium bicarbonate (12 g in 240 ml water) was added to the reaction mass.
• the reaction mass was maintained at 25-30 °C for 2 hours and further cooled to 5-10 °C and maintained at this temperature for 4 hours.
• the reaction mass was filtered and washed with 1 liter of hot water and further with 100 ml of chilled ethyl acetate.
• the filtered material was dried under vacuum at 75 °C until constant weight was reached. Dry weight of the resultant compound (Zolpidem) was found to be 120.0 grams.
• the process of present disclosure also provides a process for the preparation of Zolpidem in less number of steps which reduces time and increases the productivity.
• the process of present disclosure provides a process for preparation of Zolpidem using inexpensive, readily available and non-toxic reagents.

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• Chemical & Material Sciences (AREA)
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• Nitrogen Condensed Heterocyclic Rings (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 2014
  • 2014-07-22 WO PCT/IN2014/000481 patent/WO2015011722A2/en not_active Ceased
  • 2014-07-22 IN IN2428MU2013 patent/IN2013MU02428A/en unknown

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