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WO2007047838A2 - Procede de preparation de l'olmesartan medoxomil - Google Patents

Procede de preparation de l'olmesartan medoxomil Download PDF

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Publication number
WO2007047838A2
WO2007047838A2 PCT/US2006/040883 US2006040883W WO2007047838A2 WO 2007047838 A2 WO2007047838 A2 WO 2007047838A2 US 2006040883 W US2006040883 W US 2006040883W WO 2007047838 A2 WO2007047838 A2 WO 2007047838A2
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Prior art keywords
formula
compound
phenyl
methyl
olmesartan medoxomil
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WO2007047838A3 (fr
Inventor
Sonny Sebastian
Srinivas Reddy Gade
Srinivasa Reddy Mallepalli
Nageswara Rao Koduri
Ravindranath Tagore Amirisetty
Sri Hari Babu Karrothu
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Dr Reddys Laboratories Ltd
Dr Reddys Laboratories Inc
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Dr Reddys Laboratories Ltd
Dr Reddys Laboratories Inc
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    • 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

Definitions

  • the present invention relates to a process for the preparation of olmesartan medoxomil and intermediates thereof.
  • it relates to a process for the preparation of methyl 4-(1 -hydroxy-1 -methylethyl)-2-propyl-1- ⁇ 4-2-(trityltetrazol-5- yl) phenyl ⁇ methyl imidazole-5-carboxylate and its use in the preparation of olmesartan medoxomil.
  • Olmesartan medoxomil is described chemically as 2,3-dihydroxy-2-butenyl 4-(1 -hydroxy-1 -methylethyl)-2-propyl-1 -[p-(o-1 H-tetrazol-
  • Olmesartan is a selective angiotensin Il receptor antagonist, pharmaceutically used as an antihypertensive for the treatment and prophylaxis of hypertension. It is commercially available in the form of the prodrug olmesartan medoxomil in products sold under the trademark BENICAR for oral administration as film-coated tablets containing 5 mg, 20 mg, or 40 mg of olmesartan medoxomil. Olmesartan medoxomil and other related imidazole derivatives have been disclosed in U.S. Patent No. 5,616,599. The patent also describes a process for the preparation of imidazole derivatives useful for the synthesis of olmesartan.
  • the present invention relates to a process for the preparation of olmesartan medoxomil and intermediates thereof.
  • it relates to a process involving the preparation of methyl 4-(1-hydroxy-1-methylethyl)-2-propyl 1- ⁇ 4-2-
  • a process for the preparation of methyl 4-(1-hydroxy-1- methylethyl)-2-propyl 1- ⁇ 4-2-(trityltetrazol-5-yl) phenyl ⁇ methyl imidazole-5- carboxylate of Formula V and its salts comprises: a) reacting dimethyl-2-propylimidazole-4,5-dicarboxylate compound of
  • Formula Il Formula III b) reacting dimethyl 2-propyl-1-[4-(2-trityltetrazol-5-yl) phenyl] phenylmethyl imidazole-4,5-carboxylate of compound Formula IV with methyl magnesium halide to yield methyl 4-(1-hydroxy-1-methylethyl)-2-propyl 1 - ⁇ 4-2-(trityltetrazol-5-yl) phenyl ⁇ methyl imidazole-5-carboxylate of Formula V; and
  • step b) is carried out in situ followed by isolation of the salt of the compound of Formula V.
  • Another aspect of the present invention provides methyl 4-(1 -hydroxy- 1- methylethyl)-2-propyl 1 - ⁇ 4-2-(trityltetrazol-5-yl) phenyl ⁇ methyl imidazole-5- carboxylate of Formula V and its base addition salts.
  • Still another aspect of the present invention provides a process for the conversion of methyl 4-(1-hydroxy-1-methylethyl)-2-propyl 1 - ⁇ 4-2-(trity ltetrazol-5- yl) phenyl ⁇ methyl imidazole-5-carboxylate of Formula V to olmesartan medoxomil of Formula I.
  • An embodiment of the invention includes a process for preparing olmesartan medoxomil, comprising reacting a compound having a formula:
  • Ph represents a phenyl group, with a compound having a formula CH 3 MgX, wherein X is a halogen, to form a compound having a formula:
  • Another embodiment of the invention includes a process for preparing olmesartan medoxomil, comprising reacting a compound having a formula:
  • a further embodiment of the invention includes a process for preparing olmesartan medoxomil, comprising reacting a compound having a formula:
  • Ph represents a phenyl group, with a compound having a formula CHsMgX, wherein X is a halogen, to form a compound having a formula:
  • Fig. 1 is a differential scanning calorimetry ("DSC") thermogram of the crystalline sodium salt of 4-(1 -hydroxy- 1 -methylethyl)-2-propyl-1 -[4-[2-
  • Fig. 2 is a thermogravimetric analysis ("TGA") thermogram of the crystalline sodium salt of 4-(1 -hydroxy- 1 -methylethyl)-2-propyl-1 -[4-[2-(trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid of Formula Vl, prepared according to Example 4.
  • TGA thermogravimetric analysis
  • Fig. 3 is an X-ray powder diffraction ("XRPD") pattern of the crystalline sodium salt of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid of Formula Vl, prepared according to Example 4.
  • XRPD X-ray powder diffraction
  • Fig. 4 is an infrared ("IR") absorption spectrum of the crystalline sodium salt of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid of Formula Vl, prepared according to Example 4.
  • Fig. 5 is a DSC thermogram of olmesartan medoxomil of Formula I, prepared according to Method 1 of Example 6.
  • Fig. 6 is an XRPD pattern of olmesartan medoxomil of Formula I, prepared according to Method 1 of Example 6.
  • Fig. 7 is an IR spectrum of olmesartan medoxomil of Formula I 1 prepared according to Method 1 of Example 6.
  • Fig. 8 is a schematic representation of a process for the preparation of olmesartan medoxomil.
  • the present invention relates to a process for the preparation of olmesartan medoxomil and intermediates thereof.
  • it relates to a process for the preparation of methyl 4-(1-hydroxy-1-methylethyl)-2-propyl 1- ⁇ 4-2-(trityltetrazol-5- yl) phenyl ⁇ methyl imidazole-5-carboxylate and it's use in the preparation of olmesartan medoxomil.
  • One aspect of the present invention provides a process for the preparation of the imidazole derivative, methyl 4-(1 ⁇ hydroxy-1-methylethyl)-2-propyl 1- ⁇ 4-2- (trityltetrazol-5-yl) phenyl ⁇ methyl imidazole-5-carboxylate of Formula V and its salts.
  • the process for preparation of the imidazole derivative, methyl 4-(1-hydroxy-1-methylethyl)-2-propyl 1- ⁇ 4-2-(trityltetrazol-5-yl) phenyl ⁇ methyl imidazole-5-carboxylate of Formula V and its salts comprises: a) reacting dimethyl-2-propylimidazole-4, 5-dicarboxylate compound of Formula Il with 4-[2-(trityltetrazol-5-yl) phenyl] benzyl bromide of Formula III in the presence of a suitable base and a suitable solvent to give dimethyl 2-propyl-1-[4- (2-trityltetrazol-5-yl) phenyl] phenylmethyl imidazole-4,5-carboxylate of Formula IV;
  • Formula IV Formula V c) reacting methyl 4-(1-hydroxy-1-methylethyl)-2-propyl 1- ⁇ 4-2- (trityltetrazol-5yl) phenyl ⁇ methyl imidazole-5-carboxylate of Formula V with a suitable base in a suitable solvent to obtain a salt of 4-(1-hydroxy-1-methylethyl)- 2-propyl-1-[4-[2-(trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid), exemplified by the sodium salt being shown in the compound of Formula Vl.
  • step b) is carried out in situ followed by isolation of the salt of the compound of Formula Vl.
  • Step a) involves reaction of dimethyl-2-propylimidazole-4,5-dicarboxylate of Formula Il with 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide of Formula III in the presence of a suitable base, and a suitable solvent to get the dimethyl 2-propyl-1- [4-(2-trityltetrazol-5-yl)phenyl]phenyl methylimidazole-4,5-carboxylate of Formula IV.
  • Suitable solvents which can be used include but are not limited to: alcoholic solvents such as Ci to C 4 alcohols; C 2 to C 6 ketone solvents including acetone, ethyl methyl ketone, and diethyl ketone; chlorinated solvents, such as Ci to Ce straight chain or branched chlorohydrocarbons, including dichloromethane, ethylene dichloride, chloroform, carbon tetrachloride, chloro benzene, dichlorobenzene, and the like; dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide and the like; and mixtures thereof.
  • alcoholic solvents such as Ci to C 4 alcohols
  • C 2 to C 6 ketone solvents including acetone, ethyl methyl ketone, and diethyl ketone
  • chlorinated solvents such as Ci to Ce straight chain or branched chlorohydrocarbons, including dichloromethane
  • the temperature for conducting the reaction can range from about 20 to about 130° C, or from about 110 to about 115° C, or at the reflux temperature of the solvent used.
  • the lower boiling solvent is distilled off and the product is isolated from the reaction mixture containing the product in the higher boiling solvent by addition of water.
  • the isolated solid can be optionally purified by recrystallization or slurrying in a suitable solvent.
  • Suitable solvents which can be used for recrystallization or slurrying include, but are not limited to: hydrocarbons such as toluene, xylene, n-hexane, cyclohexane, n-heptane and the like; ether solvents such as diethyl ether, dimethyl ether, di-isopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, 1 ,4- dioxane and the like; and mixtures thereof or their combinations with water in various proportions without limitation.
  • hydrocarbons such as toluene, xylene, n-hexane, cyclohexane, n-heptane and the like
  • ether solvents such as diethyl ether, dimethyl ether, di-isopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, 1 ,4- dio
  • Step b) involves reacting dimethyl 2-propyl-1-[4-(2-trityltetrazol-5-yl)phenyl] phenylmethyl imidazole-4,5-carboxylate of Formula IV with a methyl magnesium halide to give methyl 4-(1-hydroxy-1-methylethyl)-2-propyl 1- ⁇ 4-2-(trityltetrazol-5- yl) phenyl ⁇ methyl imidazole-5-carboxylate of Formula V.
  • one of the ester groups is sterically hindered by a bulky aromatic group, and the other has less steric hindrance. Because of the different environments present for the two ester groups, the Grignard reagent selectively reacts with the ester carbon having less steric hindrance, which is the desired ester carbon. This results in forming a high purity intermediate having Formula V, and a high purity final product.
  • Grignard reagents that can be used include, but are not limited to, methyl magnesium chloride, methyl magnesium bromide, or methyl magnesium iodide.
  • Suitable solvents that can be used for the reaction include: hydrocarbons, which can be aliphatic or aromatic, such as hexane and toluene; halogenated hydrocarbons, including halogenated aliphatic hydrocarbons such as methylene chloride or 1 ,2-dichloromethane; ethers such as tetrahydrofuran or diethyl ether; and the like.
  • the moisture can be removed by azeotropic distillation, or by using dehydrating agents like sodium sulphate or magnesium sulphate, or molecular sieves or other suitable methods. Suitable temperatures for conducting the reaction range from about -20 °C to about 70 0 C.
  • Methyl 4-(1-hydroxy-1-methylethyl)-2-propyl 1 - ⁇ 4-2-(trity ltetrazol-5-y I) phenyl ⁇ methyl imidazole-5-carboxylate of Formula V may or may not be isolated.
  • Step c) involves reacting methyl 4-(1-hydroxy-1-methylethyl)-2-propyl 1- ⁇ 4-
  • the salt is the sodium salt of 4-(1 -hydroxy- 1- methylethyl)-2-propyl-1-[4-[2 ⁇ (trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -
  • Suitable solvents include but are not limited to: alcoholic solvents such as
  • Ci Ci to C 4 alcohols
  • C 2 -Ce ketone solvents including acetone, ethyl methyl ketone, and diethyl ketone
  • chlorinated solvents such as Ci-C ⁇ straight chain or branched chlorohydrocarbons, including dichloromethane, ethylene dichloride, chloroform, carbon tetrachloride, chlorobenzene, dichlorobenzene, and the like; and mixtures thereof.
  • Suitable bases include, but are not limited to, sodium hydroxide, sodium carbonate, sodium bicarbonate, and the like.
  • other base addition salts can be prepared by reaction with: organic bases such as triethylamine, trimethylamine, di-isopropylethylamine and the like; and with inorganic bases such as potassium hydroxide, potassium carbonate, potassium bicarbonate and the like.
  • organic bases such as triethylamine, trimethylamine, di-isopropylethylamine and the like
  • inorganic bases such as potassium hydroxide, potassium carbonate, potassium bicarbonate and the like.
  • Another aspect of the present invention provides an imidazole derivative, methyl 4-(1-hydroxy-1-methylethyl)-2-propyl 1 - ⁇ 4-2-(trityltetrazol-5-yl) phenyl ⁇ methyl imidazole-5-carboxylate of Formula V and its salts.
  • the present invention provides a crystalline sodium salt of the compound 4-(1 -hydroxy-1 -methylethyl)-2-propyl-1 -[4-[2-(trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid of Formula V, represented by Formula Vl.
  • the crystalline sodium salt of 4-(1 -hydroxy-1 -methylethyl)-2-propyl-1-[4-[2- (trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid of Formula Vl is characterized by its X-ray powder diffraction pattern ("XRPD") pattern. All XRPD data reported herein were obtained using Cu K ⁇ -1 radiation, having the wavelength 1.541 A, and were obtained using a Bruker Axe D8 Advance Powder X-ray Diffractometer.
  • the crystalline sodium salt of 4-(1 -hydroxy-1 -methylethyl)-2-propyl-1 -[4-[2- (trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid of Formula Vl is characterized by its XRPD pattern substantially in accordance with the pattern of Fig. 3. It is also characterized by an XRPD pattern having significant peaks at about 13.2, 21.0, 21.7, 19.0, and 18.2, ⁇ 0.2 degrees two-theta. It is also characterized by the additional XRPD peaks at about 10.5, 9.9, 11.4, 12.2, 14.9, and 16.0, ⁇ 0.2 degrees two-theta.
  • the crystalline sodium salt of 4-(1 -hydroxy-1 -methylethyl)-2-propyl-1-[4-[2- (trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid of Formula Vl is characterized by an infrared absorption spectrum in potassium bromide substantially in accordance with Fig. 4. It is also characterized by an infrared absorption spectrum in potassium bromide comprising peaks at about 3392, 2966, 1586, 1492, 1174, 750, and 759, ⁇ 5 c ⁇ f 1 .
  • the crystalline sodium salt of 4-(1 -hydroxy-1 -methylethyl)-2-propyl-1- [4-[2- (trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid of Formula Vl is characterized by a differential scanning calorimetry curve substantially in accordance with Figure 1.
  • the crystalline sodium salt of 4-(1 -hydroxy-1 -methylethyl)-2-propyl-1- [4-[2- (trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid of Formula Vl is characterized by a TGA thermogram curve substantially in accordance with Figure 2. It is desirable to obtain the intermediates in the individual steps in highly purified form for use in the succeeding steps. Crystallinity of intermediates reflects their purity and is highly desirable since unwanted side reactions involving impurities can be avoided in the subsequent steps of the overall process.
  • the crystalline sodium salt of 4-(1-hydroxy-1-methylethyl)-2-propyl-1- [4-[2- (trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid of Formula Vl of the present invention has a purity of more than about 95%, or more than about 98%, by high performance liquid chromatography ("HPLC").
  • Still another aspect of the present invention provides a process for the conversion of methyl 4-(1-hydroxy-1-methylethyl)-2-propyl 1- ⁇ 4-2-(trityltetrazol-5- yl) phenyl ⁇ methyl imidazole-5-carboxylate of Formula V or its salts to olmesartan medoxomil of Formula I.
  • the compound of Formula Vl can be progressed to the next stage without isolation.
  • An embodiment of a process for the preparation of olmesartan medoxomil of Formula I from 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid) of Formula Vl comprises; a) reacting the sodium salt of 4-(1 -hydroxy- 1 -methylethyl)-2-propyl-1 - [4-[2-(trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid) of Formula Vl with 5-methyl-4-chloromethyl-1 ,3-dioxolen-2-one of Formula VII to give (5-methyl-2-oxo-1 , 3-dioxolen-4-yl) methyl-4 (1 -hydroxy 1-methylethyl) 2-propyl1- ⁇ phenyl
  • Formula VII Formula VII b) deprotection of (5-methyl-2-oxo-1 , 3-dioxolen-4-yl) methyl-4 (1- hydroxymethylethyl) 2-propyl1 - ⁇ phenyl ⁇ 4-[2-(trityltetrazol-5-yl) phenyl] methylimidazol-5-carboxylate of Formula VIII to give olmesartan medoxomil of Formula I.
  • Step a) involves reaction of the sodium salt of 4-(1-hydroxy-1-methylethyl)- 2-propyl-1-[4-[2-(trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid) of Formula Vl with 5-methyl-4-chloromethyl-1 ,3-dioxolen-2-one of Formula VII in the presence of a suitable base to give (5-methyl-2-oxo-1 , 3-dioxolen-4-yl) methyl-4 (1-hydroxy1-methylethyl) 2-propyl 1 - ⁇ phenyl ⁇ 4-[2-(trity ltetrazol-5-yl) phenyl]methylimidazol-5-carboxylate of Formula VIII.
  • Suitable bases which can be used include, but are not limited to: sodium methoxide, sodium ethoxide or their solutions in alcohol, potassium methoxide, potassium ethoxide or their solutions in alcohol, sodium tertiary butoxide, and potassium tertiary butoxide; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide, alkali metal carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate and the like; alkali metal hydrides such as sodium hydride; and the like.
  • Suitable solvents which can be used include but are not limited to: hydrocarbon solvents such as toluene, xylene, n-heptane, cyclohexane, n-hexane and the like; nitrile solvents such as acetonitrile, propionitrile and the like; dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N, N- dimethylacetamide and the like; and mixtures thereof in various proportions without limitation.
  • hydrocarbon solvents such as toluene, xylene, n-heptane, cyclohexane, n-hexane and the like
  • nitrile solvents such as acetonitrile, propionitrile and the like
  • DMSO dimethylsulfoxide
  • DMF N,N-dimethylformamide
  • N- dimethylacetamide and the like and mixtures thereof in various proportions without limitation.
  • Suitable temperatures for conducting the reaction range from about 35 0 C to about 200 0 C.
  • the product obtained can be optionally purified by recrystallization or slurrying in a suitable solvent.
  • Suitable solvents that can be used for recrystallization or slurrying include but are not limited to: hydrocarbon solvents such as toluene, xylene, n-heptane, cyclohexane, n-hexane and the like; and nitrile solvents such as acetonitrile, propionitrile and the like.
  • Step b) involves deprotection of (5-methyl-2-oxo-1 , 3-dioxolen-4-yl) methyl- 4 (1 -hydroxy 1-methylethyl) 2-propyl-1 - ⁇ phenyl ⁇ 4-[2-(trityltetrazol-5-yl) phenyl] methylimidazol-5-carboxylate of Formula VIII to give olmesartan medoxomil.
  • Deprotection can be suitably carried out in acidic environment.
  • Suitable acids which can be used for providing the acidic environment include, but are not limited to: inorganic acids such as hydrochloric acid, sulphuric acid, and the like; and organic acids such as oxalic acid, tartaric acid, formic acid, acetic acid, para-toluene sulfonic acid and the like.
  • Suitable solvents which can be used include but are not limited to: water; alcoholic solvents like methanol, ethanol, isopropyl alcohol and the like; hydrocarbon solvents such as toluene, xylene, heptane, hexane and the like; nitrile solvents such as acetonitrile, propionitrile and the like; and mixtures thereof or their combination with water in various proportions without limitation.
  • Olmesartan medoxomil obtained above can be further purified by recrystallization or slurrying in suitable solvents. Recrystallization involves providing a solution of crude olmesartan medoxomil in a suitable solvent and then crystallizing the solid from the solution.
  • Suitable solvents which can be used for recrystallization and slurrying include, but are not limited to: halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like; ketonic solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbon solvents such as toluene, xylene, heptane, hexane and the like; nitrile solvents such as acetonitrile, propionitrile and the like; and mixtures thereof in various proportions.
  • halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like
  • ketonic solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like
  • hydrocarbon solvents such as
  • the concentration of olmesartan medoxomil in the solvent can range from 40 to 80% or more.
  • the solution can be prepared at an elevated temperature if desired to achieve a desired concentration. Any temperature is acceptable for the dissolution as long as a clear solution of the olmesartan medoxomil is obtained and is not detrimental to the drug substance chemically or physically.
  • the solution may be brought down to room temperature for further processing if required or an elevated temperature may be used. A higher temperature will allow the precipitation from solutions with higher concentrations of Zolpidem resulting in better economy of manufacture.
  • the compound obtained can be further dried suitably using a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like.
  • the drying can be carried out at temperatures of about 35° C to about 70° C.
  • the drying can be carried out for any desired time period until the required solvent removal is obtained, times from about 1 to 20 hours frequently being suitable.
  • the compound 4-(1 -hydroxy-1 -methylethyl)-2-propyl-1 -[4-[2-(trityltetrazol-5- yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid) of Formula V or its salts obtained above can also be converted to olmesartan medoxomil by processes known in the art, for example one being given in U.S. Patent No. 5,616,599.
  • Olmesartan medoxomil prepared according to the process of the present invention has a low level of impurities as determined by HPLC. For example, it contains less than about 0.15%, or less than about 0.05%, of 4-(1 -hydroxy-1 - methylethyl)-2-propyl-1- [4-[2-(tetrazol-5-yl) phenyl] phenyl] methylimidazole-5- carboxylic acid of Formula Il A, hereinafter referred to as "olmesartan acid impurity";
  • Formula MA less than about 0.15%, or less than about 0.03%, of (5-Methyl-2-oxo-1 ,3-dioxolen- 4-yl)methyl 4-isopropenyl-2-butyl-1-[4-[2-(tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate of Formula HB, hereinafter referred to as "olmesartan dehydro impurity";
  • Formula HB less than about 0.15% of 5-Acetyl-4-(1 ⁇ hydroxy1-methylethyl)-2-propyl1-1-[4-[2- tetrazol-5-yl)phenyl]phenyl]methyl imidazole of Formula HC, hereinafter referred to as "5-acetyl olmesartan"; and
  • Formula IIC less than about 0.15% of (5- methyl-2-oxo-1 ,3-dioxolen-4-yl)methyl4 -(1-hydroxy- 1 -methyl ethyl)-2-propyl-1-[4- [2-((5-methyl-2-oxo-1 ,3-dioxolen-4-yl)methyltetrazol- 5-yl)phenyl]phenyl]methylimidazole-5-carboxylate derivative of Formula HD, hereinafter referred to as "bis dioxolene impurity.”
  • Olmesartan medoxomil prepared according to the process of the present invention contains less than about 5000 ppm, or less than about 3000 ppm, or less than about 1000 ppm of methanol, and less than about 200 ppm, or less than about 100 ppm, of individual residual organic solvents like hexane, acetone, tetrahydrofuran, ethyl acetate, methanol, dichloromethane, acetonitrile, toluene, ortho-xylene, N,N-dimethylformamide, N,N-dimethylacetamide, and acetic acid.
  • Olmesartan medoxomil prepared according to the process of the present invention has particle sizes less than about 500 ⁇ m and a bulk density of about 0.5 to about 1 g/ml.
  • D 90 refers to the value for the particle size for which at least 90 volume percent of the particles have a size smaller than the value.
  • D50 and D 10 refer to the values for the particle size for which 50 volume percent, and 10 volume percent, of the particles have a size smaller than the value.
  • Methods for determining Di 0 , D 50 and D 90 include laser diffraction, such as using Malvern Instruments Ltd. (of Malvern, Worcestershire, United Kingdom) equipment.
  • Olmesartan medoxomil prepared according to the process of the present invention has D 10 less than about 50 ⁇ m, or less than about 30 ⁇ m, D 50 less than about 150 ⁇ m, or less than about 100 ⁇ m, and D 90 less than about 250 ⁇ m, or less than about 200 ⁇ m. There is no specific lower limit for any of the D values.
  • Olmesartan medoxomil prepared according to the process of the present invention has a bulk density of less than 0.5 g/ml or less than 1 g/ml before tapping, and bulk density of less than 0.5 g/ml, or less than 1 g/ml after tapping. The bulk densities are determined using Test 616 "Bulk Density and Tapped Density," United States Pharmacopeia 24, pages 1913-4 (United States Pharmacopeial Convention, Inc., Rockville, Maryland, 1999).
  • the solvent was distilled from the organic layer at a temperature of 43 0 C and a pressure of 300-400 mm Hg, and the residue co-distilled with 200 ml toluene twice.
  • 270 ml heptane was added and stirred for solid separation for 30 minutes.
  • Solvent was removed by decantation and the product was again washed with 100 ml of heptane.
  • the product was dried under a vacuum of 300 mm Hg at 29 0 C to yield 112 g of the title compound. Purity by HPLC: 98.89%.
  • the reaction mixture was diluted with water, neutralized with sodium hydroxide solution and stirred with a mixture of 250 ml toluene and 10 ml ethyl acetate.
  • the precipitated product was filtered, and washed with water.
  • the compound was dried at 70 to 80° C for 2 to 3 hours to get 5.2 g of the title compound.
  • reaction mass was then cooled to 36 0 C and 240 liters of water was added, and a vacuum of 680 mm Hg was applied to distill off the remaining acetone.
  • the remaining reaction mass was filtered and the solid was washed with 60 liters of water.
  • 152 liters of toluene was taken into a reactor and the wet solid obtained after filtration was added to it.
  • the mixture was heated to 84 0 C to get clear dissolution. After clear dissolution was obtained, the solution was cooled to 34 0 C. The solution was maintained at that temperature for 1 hour for complete isolation of the solid. It was then filtered and the wet solid was washed with 38 liters of toluene.
  • the reaction mass was stirred for another 10 minutes.
  • the organic layer was separated and the aqueous layer was extracted with 55 liters of toluene.
  • the combined organic layer was washed with 345 liters of water in three equal lots.
  • the organic layer was distilled at 35 °C under a vacuum of 700 mm Hg.
  • the residue was cooled to 40 0 C and 190 liters of acetone was added to it.
  • the reaction mass was stirred at 43 0 C for clear dissolution.
  • the reaction mass was then cooled to 36 0 C and 200 liters of acetone was added to it.
  • a solution of 3.1 kg of sodium hydroxide flakes in 275 liters of water was prepared and added to the above reaction mass at 29 0 C.
  • reaction mass was maintained at this temperature for 1 hour. Reaction completion was checked using thin layer chromatography. After the reaction was completed, a solution of 0.9 liters of acetic acid in 8.5 liters of water was prepared and the pH of the reaction mass was adjusted to 8.7 using this solution. 330 liters of ethyl acetate was added, followed by a solution of 42.7 kg of sodium chloride in 170 liters of water. The reaction mass was stirred for 10 minutes. The organic layer was separated and the aqueous layer was extracted with 55 liters of ethyl acetate. The combined organic layer was washed with a solution of 56.9 kg of sodium chloride in 230 liters of water in two equal lots.
  • the organic layer was distilled completely at a temperature of 23 0 C and a vacuum of 700 mm Hg. To the residue obtained, 55 liters of toluene was added to dissolve the residue. The toluene was distilled completely under a vacuum of 700 mm Hg and a temperature of 40 0 C. 170 liters of dimethylacetamide was added and the reaction mass was heated to 49 0 C and stirred for 20 minutes. 5 kg of sodium carbonate, and 15.2 kg of 4-ch!oromethyl-5 ⁇ methyl-1 ,3-dioxolene-2-one were added. The reaction mass was maintained at 44 0 C for 5 hours. Reaction completion was checked using thin layer chromatography. After the reaction was completed, the reaction mass was cooled to 33 °C.
  • the dry material obtained was taken into another reactor and 173 liters of acetonitrile was added to it.
  • the mixture was heated to 81 0 C to obtain clear dissolution and maintained for 15 minutes. Then the mixture was cooled to 29 0 C and maintained for 1.5 hours.
  • the separated solid was filtered and washed with 35 liters of acetonitrile.
  • the wet compound was taken into another reactor and another 173 liters of acetonitrile was added to it.
  • the mixture was heated to 81 0 C to obtain clear dissolution and maintained for 45 minutes.
  • the mixture was cooled to 29 0 C and maintained for 1.5 hours.
  • the separated solid was filtered and washed with 35 liters of acetonitrile.
  • the wet material was dried at 71 0 C and a vacuum of 660 mm Hg for 3 hours to yield 25.7 kg of the title compound. (Yield 41.1 %).
  • reaction mass was cooled to 33 0 C and a solution of 18.9 kg of sodium chloride in 375 liters of water was added. The reaction mass was maintained at 33 0 C for 30 minutes. The reaction mass was filtered and the filter bed was washed with a solution of 10 liters of acetic acid in 15 liters of water. The filtrate was taken into another reactor and 250 liters of dichloromethane was added. The reaction mass was stirred for 10 minutes and the organic layer was separated. The aqueous layer was extracted with 375 liters of dichloromethane in 3 equal lots.
  • the combined organic layer was washed with a solution of 15 kg of sodium chloride, and 15 kg of sodium bicarbonate in 598 liters of water in two equal lots.
  • the organic layer was again washed with a solution of 5 kg of sodium chloride in 100 liters of water in two equal lots.
  • the organic layer was distilled off atmospherically and then under a vacuum of 650 mm Hg at a temperature of 40 0 C to distill dichloromethane completely.
  • the residue was then co-distilled with 50 liters of toluene in two equal lots.
  • To the residue 242 liters of acetone was added .
  • the reaction mass was heated to 55 0 C and 140 liters of acetone was distilled from the reaction mass.
  • the remaining reaction mass was cooled to 39 0 C and 25 liters of acetone was distilled atmospherically. The reaction mass was then cooled to 35 0 C and maintained for 1.5 hours. The reaction mass was filtered and the wet material was washed with 13 liters of acetone. The wet compound was taken into another reactor and 158 liters of acetone was added. The mixture was heated to 57 0 C and maintained for 10 minutes. The reaction mass was filtered through a candy filter and 50 liters of solvent was distilled from it atmospherically. Another 25 liters of solvent was distilled from the reaction mass and it was cooled to 30 °C and maintained for 1.5 hours. The separated solid was filtered and washed with 5 liters of acetone. The wet material was dried at a temperature of 80 0 C for 3 hours to yield 9 kg of the title compound. (Yield 51.4%).
  • Olmesartan acetyl impurity below LOD.
  • Olmesartan dehydro impurity 0.06%.
  • Bis dioxolene impurity less than 0.1 %.
  • Olmesartan acetyl impurity below LOD.
  • Bis dioxolene impurity below 0.1 %.
  • Residual solvents acetone 585 ppm, methanol 50 ppm. Other solvents not detected.
  • Particle size distribution D 10 25 ⁇ m, D 50 80 ⁇ m, Dg 0 178 ⁇ m.
  • Bulk Density 0.5 g/ml.
  • LOQ is limit of quantitation

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

Abstract

L'invention porte sur un procédé de préparation de l'olmésartan médoxomil.
PCT/US2006/040883 2005-10-20 2006-10-18 Procede de preparation de l'olmesartan medoxomil Ceased WO2007047838A2 (fr)

Applications Claiming Priority (4)

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IN1517CH2005 2005-10-20
IN1517/CHE/2005 2005-10-20
US74567006P 2006-04-26 2006-04-26
US60/745,670 2006-04-26

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WO2007047838A3 WO2007047838A3 (fr) 2007-12-06

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008149160A1 (fr) * 2007-06-07 2008-12-11 Generics [Uk] Limited Olmésartan médoxomil amorphe
WO2009151016A1 (fr) 2008-06-09 2009-12-17 第一三共株式会社 Procédé de fabrication d’un composé de 1-biphénylméthylimidazole
WO2010026255A1 (fr) * 2008-09-05 2010-03-11 Krka, Tovarna Zdravil, D.D., Novo Mesto Procédé de préparation d'un intermédiaire d'olmésartan médoxomil
WO2011007368A2 (fr) 2009-07-14 2011-01-20 Cadila Healthcare Limited Procédé amélioré de préparation d'olmésartan
WO2011045760A2 (fr) 2009-10-13 2011-04-21 Ranbaxy Laboratories Limited Compositions d'olmésartan médoxomil micronisé
WO2011021224A3 (fr) * 2009-08-19 2011-04-28 Msn Laboratories Limited Procédé de préparation de (5-méthyl-2-oxo- 1,3-dioxolen-4-yl)méthyl-4-(1-hydroxy- 1 -méthyléthyl)-2-propyl- l-[4-[2-(tétrazol-5-yl)phényl]phényl]méthyl imidazole-5-carboxylate
WO2012055994A1 (fr) 2010-10-29 2012-05-03 Interquim, S.A. Procédé de préparation d'olmésartan médoxomil
WO2014030082A1 (fr) 2012-08-22 2014-02-27 Lupin Limited Nouveau procédé d'obtention de l'olmésartan médoxomil avec une taille de particule réduite
US8859600B2 (en) 2009-04-28 2014-10-14 Daiichi Sankyo Company, Limited Acetone solvate crystals of trityl olmesartan medoxomil
US8933241B2 (en) 2009-04-28 2015-01-13 Daiichi Sankyo Company, Limited Method for producing olmesartan medoxomil
JP2016065007A (ja) * 2014-09-24 2016-04-28 株式会社トクヤマ オルメサルタンメドキソミルの製造方法
CN106749195A (zh) * 2016-12-30 2017-05-31 青岛黄海制药有限责任公司 一种奥美沙坦酯中间体杂质合成、鉴定的方法
CN112337419A (zh) * 2020-10-27 2021-02-09 浙江花蝶染料化工有限公司 一种4-（1-羟基-1-甲基乙基）-2-丙基咪唑-5-羧酸乙酯的制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5616599A (en) * 1991-02-21 1997-04-01 Sankyo Company, Limited Angiotensin II antagosist 1-biphenylmethylimidazole compounds and their therapeutic use
TW259786B (fr) * 1992-12-17 1995-10-11 Sankyo Co
US5674879A (en) * 1993-09-24 1997-10-07 G.D. Searle & Co. Compositions including and methods of using conformationally restricted angiotensin II antagonist
ATE324890T1 (de) * 2000-11-21 2006-06-15 Sankyo Co Zusammensetzung enthaltend einen angiotensin-ii- rezeptor-antagonist und einen diuretikum und deren verwendung zur behandlung von bluthochdruck

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008149160A1 (fr) * 2007-06-07 2008-12-11 Generics [Uk] Limited Olmésartan médoxomil amorphe
WO2009151016A1 (fr) 2008-06-09 2009-12-17 第一三共株式会社 Procédé de fabrication d’un composé de 1-biphénylméthylimidazole
KR20110015428A (ko) 2008-06-09 2011-02-15 다이이찌 산쿄 가부시키가이샤 1-비페닐메틸이미다졸 화합물의 제조 방법
US8735598B2 (en) 2008-06-09 2014-05-27 Daiichi Sankyo Company, Limited Method for producing 1-biphenylmethylimidazole compound
WO2010026255A1 (fr) * 2008-09-05 2010-03-11 Krka, Tovarna Zdravil, D.D., Novo Mesto Procédé de préparation d'un intermédiaire d'olmésartan médoxomil
EP2426127B1 (fr) * 2009-04-28 2019-09-04 Daiichi Sankyo Company, Limited Nouveaux cristaux solvates
US8859600B2 (en) 2009-04-28 2014-10-14 Daiichi Sankyo Company, Limited Acetone solvate crystals of trityl olmesartan medoxomil
US8933241B2 (en) 2009-04-28 2015-01-13 Daiichi Sankyo Company, Limited Method for producing olmesartan medoxomil
WO2011007368A2 (fr) 2009-07-14 2011-01-20 Cadila Healthcare Limited Procédé amélioré de préparation d'olmésartan
WO2011021224A3 (fr) * 2009-08-19 2011-04-28 Msn Laboratories Limited Procédé de préparation de (5-méthyl-2-oxo- 1,3-dioxolen-4-yl)méthyl-4-(1-hydroxy- 1 -méthyléthyl)-2-propyl- l-[4-[2-(tétrazol-5-yl)phényl]phényl]méthyl imidazole-5-carboxylate
WO2011045760A2 (fr) 2009-10-13 2011-04-21 Ranbaxy Laboratories Limited Compositions d'olmésartan médoxomil micronisé
WO2012055994A1 (fr) 2010-10-29 2012-05-03 Interquim, S.A. Procédé de préparation d'olmésartan médoxomil
WO2014030082A1 (fr) 2012-08-22 2014-02-27 Lupin Limited Nouveau procédé d'obtention de l'olmésartan médoxomil avec une taille de particule réduite
JP2016065007A (ja) * 2014-09-24 2016-04-28 株式会社トクヤマ オルメサルタンメドキソミルの製造方法
CN106749195A (zh) * 2016-12-30 2017-05-31 青岛黄海制药有限责任公司 一种奥美沙坦酯中间体杂质合成、鉴定的方法
CN112337419A (zh) * 2020-10-27 2021-02-09 浙江花蝶染料化工有限公司 一种4-（1-羟基-1-甲基乙基）-2-丙基咪唑-5-羧酸乙酯的制备方法

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