US20040235854A1 - 1H-imidazole derivatives having cb1 agonistic, cb1 partial agonistic or cb1 antagonistic activity - Google Patents

1H-imidazole derivatives having cb1 agonistic, cb1 partial agonistic or cb1 antagonistic activity Download PDF

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US20040235854A1
US20040235854A1 US10/490,019 US49001904A US2004235854A1 US 20040235854 A1 US20040235854 A1 US 20040235854A1 US 49001904 A US49001904 A US 49001904A US 2004235854 A1 US2004235854 A1 US 2004235854A1
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substituted
imidazole
alkyl group
dichlorophenyl
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Cornelis Kruse
Josephus Lange
Arnoldus Herremans
Herman van Stuivenberg
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Abbott Healthcare Products BV
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Solvay Pharmaceuticals BV
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Assigned to SOLVAY PHARMACEUTICALS B.V. reassignment SOLVAY PHARMACEUTICALS B.V. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KRUSE, CORNELIS G., LANGE, JOSEPHUS H.M., VAN STUIVENBERG, HERMAN H., HERREMANS, ARNOLDUS H.J.
Priority to US10/912,171 priority Critical patent/US7109216B2/en
Publication of US20040235854A1 publication Critical patent/US20040235854A1/en
Priority to US12/203,113 priority patent/US8729101B2/en
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    • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
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Definitions

  • the present invention relates to a group of novel 1H-imidazole derivatives, to methods for the preparation of these compounds, and to pharmaceutical compositions containing one or more of these compounds as an active component.
  • 1H-imidazole derivatives are potent cannabinoid-CB 1 receptor agonists, partial agonists or antagonists, useful for the treatment of psychiatric and neurological disorders, as well as and other diseases involving cannabinoid neurotransmission.
  • Cannabinoids are present in the Indian hemp Cannabis sativa and have been used as medicinal agents for centuries (Mechoulam, R. and Feigenbaum, J. J. Prog. Med. Chem. 1987, 24, 159). However, only within the past ten years the research in the cannabinoid area has revealed pivotal information on cannabinoid receptors and their (endogenous) agonists and antagonists. The discovery and the subsequent cloning of two different subtypes of cannabinoid receptors (CB 1 and CB 2 ) stimulated the search for novel cannabinoid receptor antagonists (Munro, S. et al., Nature 1993, 365, 61. Matsuda, L. A. and Bonner, T. I.
  • Cannabinoid Receptors Pertwee, R. G. Ed. 1995, 117, Academic Press, London).
  • pharmaceutical companies became interested in the development of cannabinoid drugs for the treatment of diseases connected with disorders of the cannabinoid system (Consroe, P. Neurobiology of Disease 1998, 5, 534. Pop, E. Curr. Opin. In CPNS Investigational Drugs 1999, 1, 587. Greenberg, D. A. Drug News Perspect. 1999, 12, 458. Pertwee, R. G., Progress in Neurobiology 2001, 63, 569).
  • CB, receptor antagonists are known. Sanofi disclosed their diarylpyrazole congeners as selective CB, receptor antagonists.
  • SR-141716A Dutta, A. K. et al., Med. Chem. Res. 1994, 5, 54. Lan, R. et al., J. Med. Chem. 1999, 42, 769. Nakamura-Palacios, E. M. et al., CNS Drug Rev. 1999, 5, 43).
  • CP-272871 is a pyrazole derivative, like SR141716A, but less potent and less CB, receptor subtype-selective than SR141716A (Meschler, J. P. et al., Biochem. Pharmacol. 2000, 60, 1315). Aminoalkylindoles have been dis-closed as CB 1 receptor antagonists.
  • a representative example is Iodopravadoline (AM-630), which was introduced in 1995.
  • AM-630 is a moderately active CB, receptor antagonist, in some assays behaving as a weak partial agonist (Hosohata, K. et al., Life Sc. 1997, 61, PL115).
  • aryl-aroyl substituted benzofurans as selective CB, receptor antagonists (e.g. LY-320135) (Felder, C. C. et al., J. Pharmacol. Exp. Ther. 1998, 284, 291).
  • 3-Alkyl-5,5′-diphenylimidazolidine-diones were described as cannabinoid receptor ligands, which were indicated to be cannabinoid antagonists (Kanyonyo, M.
  • CB Pyrazole cannabinoids
  • a number of classes of CB, receptor agonists are known such as for example the classical cannabinoids (e.g. ⁇ 9 -THC), non-classical cannabinoids, aminoalkylindoles and eicosanoids (e.g. anandamide).
  • Reviews provide a nice overview of the cannabinoid research area (Mechoulam, R. et al., Prog. Med. Chem. 1998, 35, 199.
  • novel 1H-imidazole derivatives of the formula (I), prodrugs thereof and salts thereof are potent agonists, partial agonists or antagonists on cannabinoid-CB, receptors
  • R represents phenyl, thienyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, which groups may be substituted with 1, 2, 3 or 4 substituents Y, which can be the same or different, from the group C 1-3 -alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C 1-2 )-amino, mono- or dialkyl (C 12 )-amido, (C 1-3 )-alkoxycarbonyl, carboxyl, cyano, carbamoyl and acetyl, or R represents naphtyl, with the proviso that when R is 4-pyridinyl, R 4 represents a halogen atom or a cyano, carbamoyl and
  • R 1 represents phenyl or pyridinyl, which groups may be substituted with 1-4 substituents Y, which can be the same or different, wherein Y has the above mentioned meaning, or R 1 represents pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, which groups may be substituted with 1-2 substituents Y, which can be the same or different or R 1 represents a five-membered aromatic heterocyclic ring having one or two heteroatoms from the group (N, O, S), which heteroatoms can be the same or different, which five-membered aromatic heterocyclic ring may be substituted with 1-2 substituents Y, which can be the same or different or R 1 represents naphtyl,
  • R 2 represents H, branched or unbranched C 1-8 alkyl, C 3-8 cycloalkyl, C 3-8 alkenyl, C 5-8 cycloalkenyl which groups may contain a sulfur, oxygen or nitrogen atom,
  • R 3 represents branched or unbranched C 2-8 alkyl, C 1-8 alkoxy, C 5-8 cycloalkyloxy, C 3-8 cycloalkyl, C 5-10 bicycloalkyl, C 6-10 tricycloalkyl, C 3-8 alkenyl, C 5-8 cycloalkenyl, which groups may optionally contain one or more heteroatoms from the group (O, N, S) and which groups may be substituted with a hydroxy group or 1-2 C 1-3 alkyl groups or 1-3 fluoro atoms, or R 3 represents a benzyl or phenethyl group which aromatic rings may be substituted with 1-5 substituents Z, which can be the same or different, from the group C 1-3 -alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C 12 )-amino, mono- or dialkyl
  • R 3 represents a pyridinyl group, or R 3 represents a phenyl group, with the proviso that R 4 represents a halogen atom or a cyano, carbamoyl, formyl, acetyl, trifluoroacetyl, fluoroacetyl, propionyl, sulfamoyl, methanesulfonyl, methylsulfanyl or C 1-4 alkyl group, which C 1-4 alkyl group may be substituted with 1-3 fluoro atoms or with a bromo, chloro, iodo, cyano or hydroxy group, or R 3 represents a group NR 5 Rr with the proviso that R 2 represents a hydrogen atom or a methyl group, wherein
  • R 5 and R 6 are the same or different and represent branched or unbranched C 1-4 alkyl, or R 5 and R 6 — together with the nitrogen atom to which they are bonded—form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4 to 10 ring atoms which heterocyclic group contains one or two heteroatoms from the group (N, O, S), which heteroatoms can be the same or different, which heterocyclic group may be substituted with a C 1-3 alkyl group or a hydroxy group, or R 2 and R 3 — together with the nitrogen atom to which they are bonded—form a saturated or unsaturated heterocyclic group having 4 to 10 ring atoms which heterocyclic group contains one or two heteroatoms from the group (N, O, S), which heteroatoms can be the same or different, which heterocyclic group may be substituted with a C 1-3 alkyl group or a hydroxy group,
  • R 4 represents a hydrogen or halogen atom or a cyano, carbamoyl, formyl, acetyl, trifluoroacetyl, fluoroacetyl, propionyl, sulfamoyl, methanesulfonyl, methylsulfanyl or branched or unbranched C 1-4 alkyl group, which C 1-4 alkyl group may be substituted with 1-3 fluoro atoms or with a bromo, chloro, iodo, cyano or a hydroxy group,
  • the compounds according to the invention are suitable for use in the treatment of psychiatric disorders such as psychosis, anxiety, depression, attention deficits, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, appetence, drug dependence and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischaemia, cerebral apoplexy, craniocerebral trauma, stroke, spinal cord injury, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, demyelinisation related disorders, as well as for the treatment of pain disorders, including neuropathic pain disorders, and other diseases involving cannabinoid neurotransmission, including the treatment of septic shock, glaucoma, diabetes, cancer, emesis, nausea, gastrointestinal disorders, etc.
  • the affinity of the compounds of the invention for cannabinoid CB 1 receptors was determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabinoid CB, receptor is stably transfected in conjunction with [ 3 H]CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [ 3 H]-ligand, with or without addition of compounds of the invention, separation of bound and free ligand was performed by filtration over glassfiber filters. Radioactivity on the filter was measured by liquid scintillation counting.
  • the cannabinoid CB 1 antagonistic activity of compounds of the invention was determined by functional studies using CHO cells in which human cannabinoid CB, receptors are stably expressed. Adenylyl cyclase was stimulated using forskolin and measured by quantifying the amount of accumulated cyclic AMP. Concomitant activation of CB, receptors by CB 1 receptor agonists (e.g. CP-55,940 or (R)—WIN-55,212-2) can attenuate the forskolin-induced accumulation of cAMP in a concentration-dependent manner. This CB 1 receptor-mediated response can be antagonized by CB, receptor antagonists such as the compounds of the invention.
  • CB 1 receptor agonists e.g. CP-55,940 or (R)—WIN-55,212-2
  • Cannabinoid agonistic of partial agonistic activity of compounds of the invention can be determined according to published methods, such as assessment of in vivo cannabimimetic effects (Wiley, J. L. et al., J. Pharmacol. Exp. Ther. 2001, 296, 1013).
  • the invention relates both to racemates, mixtures of diastereomers and the individual stereoisomers of the compounds having formula (I).
  • the compounds of the invention can be brought into forms suitable for administration by means of usual processes using auxiliary substances and/or liquid or solid carrier materials.
  • Suitable synthetic routes for the compounds of the invention are the following: Synthetic route A
  • Step 1 ester hydrolysis of a compound having formula (II) wherein R 7 represents a branched or unbranched alkyl group (C 1-4 ) or benzyl group
  • R, R 1 and R 4 have the meanings as described above.
  • Step 2 reaction of a compound having formula (III) with a compound having formula R 2 R 3 NH wherein R 2 and R 3 have the meanings as described above via activating and coupling methods such as formation of an active ester, or in the presence of a coupling reagent such as DCC, HBTU, BOP or similar reagents.
  • This reaction gives a desired 1H-imidazole derivative having formula (I).
  • This reaction is preferably carried out in the presence of an organic base such as for example diisopropylethylamine (DIPEA) or triethylamine.
  • DIPEA diisopropylethylamine
  • triethylamine triethylamine
  • This reaction is carried out in the presence of a strong non-nucleophilic base such as lithium diisopropylamide (LDA), preferably under anhydrous conditions in an inert organic solvent, for example tetrahydrofuran, and yields a compound having formula (II)
  • a strong non-nucleophilic base such as lithium diisopropylamide (LDA)
  • LDA lithium diisopropylamide
  • an inert organic solvent for example tetrahydrofuran
  • R, R 1 and R 7 have the meanings as described hereinabove and R 4 represents a C 1-4 alkyl group, which alkyl group may be substituted with 1-3 fluoro atoms or wherein R 4 represents a cyano, formyl, acetyl, trifluoroacetyl, fluoroacetyl, methylsulfanyl or propionyl group, or a halogen atom.
  • R 4 represents a branched or unbranched C 1-4 alkyl group, which C 1-4 alkyl group may be substituted with 1-3 fluoro substituents and wherein R, R 1 have the meanings given above and R 7 represents a branched or unbranched alkyl group (C 1-4 ) or benzyl group can be synthesized by reacting a compound having formula (V) or its tautomer
  • R 4 represents a branched or unbranched C 1-4 alkyl group, which C 1-4 alkyl group may be substituted with 1-3 fluoro atoms and RB represents a leaving group, for example a bromo substituent, and R 7 represents a branched or unbranched alkyl group (C 1-4 ) or benzyl group.
  • the reaction is preferably carried out in an organic solvent, for example in 2-propanol or in N-methyl-2-pyrrolidinone (NMP).
  • NMP N-methyl-2-pyrrolidinone
  • the addition of an acid like trifluoroacetic acid (TFA) during the reaction may enhance the formation of the compounds having formula (II).
  • R 4 represents a methyl group and R, R 1 have the meanings given above and R 7 represents a branched or unbranched alkyl group (C 1-4 ) or benzyl group with a regioselective brominating compound such as N-bromo-succinimide (NBS) in an organic solvent such as CCl 4 in the presence of a free-radical initiator like dibenzoyl peroxide gives a compound of formula (VII)
  • R, R 1 and R 7 have the meanings given hereinabove and Nu represents a chloro, iodo, fluoro or cyano group.
  • the reaction is preferably carried out in the presence of a weak base like NaHCO 3 or in the presence of a crown ether or a cryptand.
  • a weak base like NaHCO 3
  • a crown ether or a cryptand for more information on crown ethers and cryptands see: M. B. Smith and J. March: Advanced organic chemistry , p. 105, 5 th ed., (2001) John Wiley & Sons, New York, ISBN: 0-471-58589-0).
  • Part A To a 1M solution of sodium bis(trimethylsilyl) amide in THF (70 mL) is added dropwise a solution of 4-chloroaniline (8.86 gram, 69.5 mmol) in anhydrous THF in a nitrogen atmosphere. After the mixture is stirred for 20 minutes a solution of 2,4-dichlorobenzonitrile (12 gram, 70 mmol) in THF is added. The resulting mixture is stirred overnight, poured into ice-water (400 mL) and extracted with dichloromethane, dried over Na 2 SO 4 and concentrated in vacuo to give a yellow oil (15.7 gram).
  • Part B A mixture of N-(4-chlorophenyl)-2,4-dichlorobenzenecarboxamidine (2.00 gram, 6.68 mmol), ethyl 3-bromo-2-oxopropanoate (2.65 gram, 13.6 mmol) and NaHCO 3 (1.12 gram, 13.3 mmol) in 2-propanol is stirred at reflux temperature for 20 hours. After cooling to room temperature the mixture is concentrated in vacuo and the residue suspended in dichloromethane, washed with water (3 ⁇ 50 mL) and brine (3 ⁇ 50 mL). The aqueous layers are extracted with dichloromethane.
  • Part C Ethyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate (0.810 gram, 2.06 mmol) and LiOH (0.173 g, 7.20 mmol) are dissolved in a H 2 O/THF (20 mL/20 mL) mixture and stirred at 50° C. for 16 hours. The mixture is concentrated in vacuo to give 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylic acid.
  • Part D Crude 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carbonyl chloride (919 mg, 2.39 mmol), 1-aminopiperidine (0.469 g, 4.69 mmol) and triethylamine (0.363 g, 3.59 mmol) are dissolved in dichloromethane and stirred for one hour at room temperature.
  • Part A Diisopropylamine (2.30 gram, 22.8 mmol) is added dropwise to anhydrous THF (100 mL) in a nitrogen atmosphere at 0° C. n-BuLi is added dropwise (7.34 mL, 2.5 M solution in hexane, 18.4 mmol). The resulting solution is cooled to ⁇ 78° C. A solution of ethyl 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate (6.0 gram, 15.2 mmol) in anhydrous THF is added dropwise. The colour of the mixture changes from yellow to purple brown.
  • Part B Ethyl 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxylate (0.250 gram, 0.61 mmol) and LiOH (0.052 gram, 2.17 mmol) are dissolved in H 2 O/THF (1:1 (v/v); 50 mL) and stirred at 50° C. for one hour. The mixture is concentrated to give crude 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxylic acid.
  • Part C 2-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-imidazole4-carbonyl chloride (1.5 gram, 3.75 mmol), 1-aminopiperidine (0.725 gram, 7.25 mmol) and triethylamine (0.549 gram, 5.44 mmol) are dissolved in dichloromethane and stirred for one hour at room temperature.
  • Part A To a stirred solution of ethyl 1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate (6.10 gram, 0.0139 mol) in THF (70 mL) is added LiOH (0.67 gram, 0.0278 mol) and water (70 mL). The resulting mixture is stirred for 16 hours at 50° C. to give a clear solution. After cooling to room temperature, HCl (1 N solution, 28 mL) is added to give an oily precipitate which completely solidifies on continued stirring and addition of water (70 mL).
  • Part B To a stirred suspension of 1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylic acid (1.23 gram, 2.99 mmol) in dry acetonitrile (40 mL) is successively added diisopropylethylamine (DIPEA) (1.15 mL, 6.6 mmol), O-benzotriazol-1-yl-N,N, N′,N′-tetramethyluronium hexafluorophos-phate (HBTU) (1.36 gram, 3.6 mmol) and 1-aminopiperidine (0.39 mL, 3.6 mmol).
  • DIPEA diisopropylethylamine
  • HBTU O-benzotriazol-1-yl-N,N, N′,N′-tetramethyluronium hexafluorophos-phate
  • Part A 2,4-Dichlorobenzoyl chloride (40.0 g, 0.19 mol) is dissolved in tetrahydrofuran (1 L). To the resulting stirred solution is successively added diisopropylethylamine (DIPEA) (73.4 mL, 2.2 molar equivalent) and 4-(trifluoromethyl)phenylamine (30.7 g, 0.19 mol). After one hour the mixture is concentrated in vacuo to give an oil. This oil is crystallised from ethanol to give pure 2,4-dichloro-N-(4-(trifluoromethyl)phenyl)benzamide (53.2 g, 83% yield).
  • DIPEA diisopropylethylamine
  • Part B 2,4-Dichloro-N-(4-(trifluoromethyl)phenyl)benzamide (19.0 g, 0.057 mol) is dissolved in benzene (150 mL) and PCI 5 (13.0 g, 1.1 molar equivalent) is added. The resulting mixture is heated at reflux temperature for two hours, allowed to attain room temperature and concentrated in vacuo to give a residue. The residue is dissolved in anhydrous THF, cooled to 0° C. and transferred into an autoclave. Excess NH 3 is quickly added from a lecture bottle and the mixture is stirred at room temperature for 50 hours. A mixture of ethylacetate and aqueous NaHCO 3 is added.
  • Part C 2,4-Dichloro-N-(4-(trifluoromethyl)phenyl)benzenecarboxamidine (15.0 g, 0.0450 mol) is dissolved in 2-propanol and ethyl 3-bromo-2-oxobutanoate (20.8 g, 2 molar equivalent) and NaHCO 3 are successively added. The resulting mixture is heated at reflux temperature for 40 hours and allowed to attain room temperature. The 2-propanol is removed in vacuo, ethyl acetate is added to the residue and the resulting organic layer is washed with NaHCO 3 (5% aqueous solution).
  • Part D The formed ethyl 2-(2,4-dichlorophenyl)-5-methyl-1-(4-(trifluoromethyl) phenyl)-1H-imidazole-4-carboxylate is converted to 2-(2,4-dichlorophenyl)-5-methyl-1-(4-(trifluoromethyl)phenyl)-1H-imidazole-4-carboxylic acid (melting point: 224-226° C.), which carboxylic acid is converted to 2-(2,4-dichlorophenyl)-5-methyl-N-(piperidin-1-yl)-1-(4-(trifluoromethyl)phenyl)-1H-imidazole-4-carboxamide (melting point: 173-174° C.) according to the procedure described in example 22 above.
  • Part B To a stirred solution of ethyl 2-(2,4-dichlorophenyl)-5-methyl-1-(4-methoxyphenyl)-1H-imidazole4-carboxylate (8.00 gram, 0.0198 mol) in THF (80 mL) is added LiOH (0.59 gram, 2 molar equivalents) and water (80 mL). The resulting mixture is stirred for 16 hours at 80° C. After cooling to room temperature, HCl (2N solution, 12.3 mL) is added to give an oily precipitate. After addition of water and extraction with ethylacetate, the ethylacetate layer is collected, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Part C To 2-(2,4-dichlorophenyl)-5-methyl-1-(4-methoxyphenyl)-1H-imidazole-4-carboxylic acid (1.00 gram, 2.65 mmol) in dry acetonitrile (25 mL) is successively added diisopropylethylamine (DIPEA) (1.02 mL, 2.2 molar equivalents), O-benzotriazol-1-yl-N,N, N′,N′-tetramethyluronium hexafluoro-phosphate (HBTU) (1.21 gram, 1.2 molar equivalents) and the resulting solution is stirred for 15 minutes.
  • DIPEA diisopropylethylamine
  • HBTU O-benzotriazol-1-yl-N,N, N′,N′-tetramethyluronium hexafluoro-phosphate
  • Part A Ethyl 1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate is converted to ethyl 1-(4-bromophenyl)-5-chloro-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate analogously to a published procedure (N. Kudo et al., Chem. Pharm. Bull. 1999, 47, 857-868) using excess of SO 2 Cl 2 in dichloroethane at reflux temperature for 50 hours.
  • Part B Ethyl 1-(4-bromophenyl)-5-chloro-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate is converted to 1-(4-bromophenyl)-5-chloro-2-(2,4-dichloro-phenyl)-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide (melting point: >150° C.; Rf (Silicagel, EtOAc) 0.35) analogously to the procedure described in example 22 above.
  • Part A To a stirred solution of 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylic acid (18.38 gram, 50 mmol) in toluene (200 mL) in a nitrogen atmosphere is added N,N-dimethylformamide di-tert-butyl acetal (50 mL) and the resulting mixture is heated at 80° C. for 4 hours. After cooling to room temperature the reaction mixture is concentrated and diethyl ether is added. The resulting solution is twice washed with water, dried over MgSO 4 , filtered and concentrated in vacuo.
  • Lithium diisopropyl amide (LDA) (5.25 mL of a 2 M solution in THF, 0.0105 mol) is added dropwise to a cooled solution ( ⁇ 70° C.) of tert-butyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate (4.24 gram, 0.010 mol) in anhydrous THF (80 mL) in a nitrogen atmosphere and the resulting mixture is stirred for one hour.
  • LDA Lithium diisopropyl amide
  • This oil is purified by column chromatography (dichloromethane, silicagel) to give 3.4 gram of tert-butyl 1-(4-chlorophenyl)-5-cyano-2-(2,4-dichlorophenyl)-1H-imidazole4-carboxylate. Recrystallisation from diisopropyl ether gave crystalline tert-butyl 1-(4-chlorophenyl)-5-cyano-2-(2,4-dichlorophenyl)-1H-imidazole4-carboxylate (2.57 gram, 57% yield). Melting point: 210-212° C.

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