Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

• the present invention relates to processes for preparing olmesartan medoxomil.
• olmesartan medoxomil is 4-(l -hydroxy- 1 -methylethyl)-2- propyl-l-[[2'-(lH-tetrazol-5-yl)[l,r-biphenyl]-4-yl]methyl]-lH-imidazole-5-carboxylic acid (5-methyl ⁇ 2-oxo-l,3-dioxol-4-yi)methyl ester (Merck Index 13th ed.).
• the empirical formula is C 29 H 30 N 6 O 6 .
• the molecular weight is 558.58.
• Olmesartan medoxomil is a prodrug that is hydrolyzed during absorption, and it is a selective ATi subtype angiotensin II receptor antagonist.
• Olmesartan medoxomil is disclosed by U.S. Patent No. 5,616,599 to Yanagisawa et al. It is marketed as BENICAR® in film- coated tablets of 5 mg, 20 mg, and 40 mg for treatment of hypertension in a human.
• ODM-Mod olmesartan medoxomil
• Step (vi) (the deprotection step) of the prior art synthesis is illustrated as follows:
• Example 61(b) of the '599 patent discloses a process for preparing crude olmesartan medoxomil from a mixture of trityl olmesartan medoxomil (MTT) and aqueous acetic acid. Col. 176, lines 24-37. Triphenyl carbinol (TPC) is removed, and olmesartan medoxomil is isolated by evaporation. in solution
• the impurity OLM-acid is also formed during the reaction by hydrolysis of the ester bond.
• the prior art process yields crude olmesartan medoxomil containing 2.2% OLM-acid per area percent HPLC.
• the present invention provides a process for preparing olmesartan medoxomil including the steps of: contacting trityl olmesartan medoxomil with an acid in a water miscible organic solvent, with or without water, preferably acetone and water, to obtain a solution of olmesartan medoxomil and a precipitate of triphenyl carbinol; separating the precipitate of triphenyl carbinol from the solution of olmesartan medoxomil; and contacting the solution of olmesartan medoxomil with a base to obtain a precipitate of olmesartan medoxomil.
• the present invention provides a process for preparing olmesartan medoxomil including the steps of: contacting trityl olmesartan medoxomil with an acid in a water miscible organic solvent, with or without water, to obtain a solution of olmesartan medoxomil and a precipitate of triphenyl carbinol; separating the precipitate of triphenyl carbinol from the solution of olmesartan medoxomil; and contacting the solution of olmesartan medoxomil with a base to obtain a precipitate of olmesartan medoxomil.
• Preferred water miscible organic solvents include, but are not limited to, acetone, acetonitrile, and t-butanol. Acetone is especially preferred.
• the trityl olmesartan medoxomil is contacted with a mixture of a water miscible organic solvent and water. Most preferably, the trityl olmesartan medoxomil is contacted with a mixture of acetone and water.
• the ratio of water to the water miscible organic solvent e.g., acetone, is preferably about 1 :3 to about 3:1 by volume.
• the acid that is contacted with the trityl olmesartan medoxomil removes the triphenyl carbinol to form an acid salt of olmesartan medoxomil.
• the acid is a strong acid having a pH of about 0 to about 4.
• Suitable acids include, but are not limited to, organic acids such as formic acid, acetic acid, benzoic acid, and oxalic acid; oxoacids such as perchloric acid, chloric acid, chlorous acid, hypochlorous acid, sulfuric acid, sulfurous acid, p-toluene sulfonic acid, nitric acid, nitrous acid, phosphoric acid, and carbonic acid; and binary acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydrocyanic acid, and hydrosulfuric acid. Hydrochloric acid, p-toluene sulfonic acid, and especially sulfuric acid are preferred.
• the amount of acid is about 2 to about 8 equivalents, more preferably about 3 to about 4 equivalents, and most preferably about 3 equivalents.
• the temperature is preferably about 10°C to about 60°C, more preferably about 40°C.
• the combination of trityl olmesartan medoxomil, the water miscible organic solvent, and the acid is maintained for about 3 to about 15 hours.
• the combination is maintained for about 4 to about 6 hours, most preferably for about 4 hours.
• water is added prior to separating the triphenyl carbinol to avoid the formation of undesired by-products.
• the amount of added water is about 2 volumes per gram of trityl olmesartan medoxomil. Precipitation can be perceived visually as a clouding of the solution or formation of distinct particles of the precipitate suspended in the solution or collected at the bottom the vessel containing the solution.
• Separating the triphenyl carbinol from the solution can be performed by any means known in the art, such as filtration or centrifugation.
• Suitable bases include, but are not limited to, alkali and alkaline earth metal hydroxides, carbonates, and hydrogen carbonate salts.
• Specific exemplary bases include, but are not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and calcium carbonate. Potassium carbonate and especially sodium bicarbonate are preferred.
• the equivalents of base used is about equal to the equivalents of acid used, that is, the amount of base used is preferably about 0.8 to 1.5 equivalents compared to the amount of acid used.
• the base preferably increases the pH of the solution, but the solution need not reach a basic pH.
• the solution is preferably maintained at a temperature of about 2 0 C to about 25 0 C, preferably at about room temperature.
• room temperature refers to a temperature of about 2O 0 C to 3O 0 C, preferably 2O 0 C to 25 0 C.
• the solution is maintained until olmesartan medoxomil is precipitated.
• the precipitate of olmesartan medoxomil can then be recovered by any means known in the art, such as filtration or centrifugation. Olmesartan medoxomil is recovered in its free base form, i.e., the nitrogen on the tetrazole is free.
• reaction progress can be detected by any method known in the art, such as, for example, HPLC, GC, TLC, NMR, and mass spectroscopy.
• olmesartan medoxomil can be obtained directly, without the evaporation step required by the prior art process, which is an inconvenient industrial method. See U.S. Patent No. 5,616,599 Example 61(b). Also, the product of the '599 process is obtained in a gel-like form, which is difficult to handle in an industrial process. In addition to presenting industrial disadvantages, the '599 process achieves a lower yield than that obtained by the present invention. Additionally, the olmesartan medoxomil obtained according to the present invention has a lower amount of the impurity olmesartan acid (OLM-acid).
• Crude olmesartan medoxomil prepared according to the '599 process contains 2.2% OLM-acid.
• crude olmesartan medoxomil prepared according the present invention contains less than about 1% OLM-acid, e.g., only about 0.89% OLM-acid. All percentages of impurities described herein are provided as area percentage HPLC at 220 nm.
• Example 2 Preparation of crude olmesartan medoxomil A lL reactor, equipped with mechanical stirrer and thermometer, was charged with MTT (70 g), acetone (140 ml), water (140 ml), and H 2 SO 4 (19.47 g). The reactor was heated to 40°C for 2.5 hrs (at EOR, MTT is LT 1%). Water (140 ml) was added at 40°C, and the reaction was stirred for 1.5 hrs or until MTT is LT 0.1%. After cooling to 15°C and stirring for 1 hr, the TPC was filtered and washed with water (70 ml).

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Plural Heterocyclic Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 2005
  • 2005-09-02 CN CNA2005800262573A patent/CN1993355A/zh active Pending
  • 2005-09-02 CA CA002573800A patent/CA2573800A1/en not_active Abandoned
  • 2005-09-02 JP JP2006538570A patent/JP4511550B2/ja not_active Expired - Fee Related
  • 2005-09-02 WO PCT/US2005/031481 patent/WO2006029056A1/en not_active Ceased
  • 2005-09-02 EP EP05797758A patent/EP1706401A1/en not_active Withdrawn
  • 2005-09-02 US US11/217,472 patent/US7528258B2/en not_active Expired - Fee Related
  • 2005-09-02 CN CNA2005800219037A patent/CN1976926A/zh active Pending
• 2007
  • 2007-02-26 IL IL181549A patent/IL181549A0/en unknown

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