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Preparation of (±)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl-2-ethoxy-1-[[2’-(1H-tetrazol-5-yl)1,1’biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate in an inorganic acid

IP.com Disclosure Number: IPCOM000032366D
Publication Date: 2004-Nov-03
Document File: 3 page(s) / 105K

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) cyclohexyloxy [[( - 1 - ) ± ( Preparation of

     
] carbonyl

  
] oxy

- ' 2 [[ - 1 - ethoxy - 2 - ethyl

 
] yl - 4 - biphenyl ' ,1 1
) yl - 5 - tetrazol - H 1 ( an inorganic acid
2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7- carboxylic acid (CND) is a potent, long-acting, selective AT1 subtype angiotensin II receptor antagonist. CND meets the requirement of high potency but it is poorly absorbed by the body when administered orally. To overcome the poor absorption, the prodrug (±)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl-2-ethoxy-1-[[2'-(1H- tetrazol-5-yl)1,1'biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate (CND- Cil) was developed.

    A process for preparing CND-Cil comprises deprotecting trityl CND-Cil. This process comprises: using a mixture of at least one organic solvent and at least one inorganic acid under substantially aqueous conditions for a suitable time and at a suitable temperature to form CND-Cil; neutralizing the reaction mixture with at least one base; and isolating the CND-Cil.

 The deprotecting step : Scheme I

N

        in carboxylate - 7 - benzimidazole - H 1 - ] methyl

N

OEt

N

OEt

N

O O

Me O

O O

 N N

N

N

Trityl

O O

Me O

O O

 N N

N

NH

    Typically, inorganic acids include HF, HCl, HBr, HI, or H2SO4. Preferably, the inorganic acid is HCl.

    The reaction temperature is less than about 40ΕC, preferably, from about 5ΕC to about 30ΕC.

    The term "neutralizing" means adjusting the pH of a solution to 6-7.5, preferably 6.3-7.

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    Organic solvents include, at least one alcohol, ketone, ether, hydrocarbon, or chlorinated solvent. Preferably, organic solvents include at least one C1-C4 alkyl alcohol, ketone, ether, or chlorinated solvent. In particular, organic solvents include, but are not limited to, dichloromethane, methanol, toluene, or tert-butyl methyl ether. In one embodiment, wherein more than one solvent is used, the ratio of first to second solvents is from about 1:10 to about 10:1.

After the trityl group has been removed, the reaction mixture is neutralized using a base. Preferred bases include inorganic base or an organic base: Inorganic bases used in the reaction include lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, and silver carbonate. Organic bases used in the reaction include, but are not limited to, triethylamine, diisopropylethylamine, pyridine, N,N- dimethylaniline, N-methyl-morpholine, 4-dimethylaminopyridine, 1,5-diazabicyclo- [4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or 1,4- diazabicyclo[2.2.2]octane (DABCO). Preferably, the base is potassium carbonate.

     The isolation of the CND-Cil can be carried out by extraction, evaporation, crystallization, or other techniques commonly used to isolate an organic compound of interest f...