HK1063794B - Imidazole derivatives - Google Patents
Imidazole derivatives Download PDFInfo
- Publication number
- HK1063794B HK1063794B HK04106638.1A HK04106638A HK1063794B HK 1063794 B HK1063794 B HK 1063794B HK 04106638 A HK04106638 A HK 04106638A HK 1063794 B HK1063794 B HK 1063794B
- Authority
- HK
- Hong Kong
- Prior art keywords
- imidazol
- methyl
- phenyl
- methanol
- imidazole
- Prior art date
Links
Description
The invention relates to compounds of general formula (I) and pharmaceutically acceptable acid addition salts thereof
Wherein
A is phenyl, pyridin-2-yl, pyridin-3-yl or piperidin-1-yl;
R1/R2independently of one another, hydrogen, halogen, lower alkyl, cycloalkyl, lower alkenyl, trifluoromethyl, -O-trifluoromethyl, -S-trifluoromethyl, S-lower alkyl, lower alkoxy, -CHF2-C (lower alkyl) F2、-OCHF2Phenyl, nitro, benzyloxy, hydroxy or amino, or in any adjacent position together with the carbon atom to which it is attached, -CH-, -CH-N-, - (CH)2)3-、-O-CH2-O-、-O-CF2-O-、-CH2-O-CH2-or-CH2CH2-O-；
R3Is hydrogen, lower alkyl, cycloalkyl, phenyl, S-lower alkyl, amino, lower alkyl-amino, -nhc (o) -lower alkyl or hydroxy-lower alkyl;
R4/R5independently of one another, hydrogen or lower alkyl, or together with the carbon atom to which they are attached form a radical- (CH)2)4-，
R6/R6' independently of each other is hydrogen or lower alkyl;
x is-N < or
Y is-N-, -NH-, -N-CH-or-CH;
z is-CR7＝、-N＝、-NR7-、-N＝CR7-、＝CH-N＝C(R7) -or-N-CH-;
R7is hydrogen, -CH2OH or lower alkyl;
n is 0, 1 or 2;
m is 0 or 1; and is
The dotted line may be a bond.
Heterocyclic aromatic radicals in the formula I
May have the following structure:
thus, compounds of the following types are also included within formula I:
wherein the substituents are as described above.
The compounds of formula I and their salts have valuable therapeutic properties. The compounds of the present invention are NMDA (N-methyl-D-aspartate) -receptor subtype selective blockers, which have a key role in modulating neuronal activity and plasticity and are therefore critical for modulating fundamental processes in CNS development and learning and memory formation.
Under acute and chronic forms of neurodegenerative pathological conditions, over-activation of NMDA receptors is the major cause of triggering neuronal cell death. The NMDA receptor is composed of members of two subunit families, NR-1(8 different splice variants) and NR-2(A-D) derived from different genes. Members from both subunit families show different distributions in different brain regions. The combination of different species of NR-1 members with different NR-2 subunits results in NMDA receptors exhibiting different pharmacological properties. Possible therapeutic indications for NMDA NR-2B receptor subtype specific blockers include acute neurodegenerative diseases caused by, for example, stroke and brain trauma, and chronic neurodegenerative diseases such as alzheimer's disease, parkinson's disease, huntington's disease, ALS (amyotrophic lateral sclerosis) and neurodegenerative diseases associated with bacterial or viral infections, as well as depression and chronic and acute pain.
Objects of the present invention are the compounds of formula I and pharmaceutically acceptable acid addition salts thereof, the processes for the preparation of the compounds of formula I and salts thereof, medicaments comprising the compounds of formula I or pharmaceutically acceptable acid addition salts thereof, processes for the manufacture of the medicaments, as well as the use of the compounds of formula I and pharmaceutically acceptable salts thereof for the control or prevention of illnesses, especially of illnesses as mentioned above, and the use thereof for the manufacture of corresponding medicaments.
The invention includes racemic mixtures and all of their corresponding optical antipodes.
The following definitions of general terms used in the present application apply when the terms in question appear alone or in combination.
The term "lower alkyl" as used herein refers to a straight or branched chain alkyl group containing 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, and the like. Preferably, the lower alkyl group contains 1 to 4 carbon atoms.
The term "lower alkenyl" as used herein means C2-C7A carbon group having at least one double bond in its chain.
The term "halogen" refers to chlorine, iodine, fluorine and bromine.
The term "lower alkoxy" refers to a group wherein the alkyl residue is as defined above and the alkyl is attached via an oxygen atom.
The term "cycloalkyl" refers to a carbocyclic ring having 3 to 6 carbon atoms, preferably cyclopropyl.
The term "pharmaceutically acceptable acid addition salts" includes salts with inorganic and organic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
Preferred compounds of formula I are those wherein a is phenyl, for example the following group of compounds:
wherein
R1/R2Independently of one another, hydrogen, halogen, lower alkyl, trifluoromethyl, S-lower alkyl, lower alkoxy, -OCHF2Phenyl, nitro, benzyloxy, hydroxy or amino, or together with the carbon atom to which they are attached is- (CH)2)3-、-O-CH2-O-、-CH2-O-CH2-or-CH2CH2-O-；
R3Is hydrogen, lower alkyl, phenyl, S-lower alkyl, amino, lower alkyl-amino, -nhc (o) -lower alkyl or hydroxy-lower alkyl;
R4/R5independently of one another, hydrogen or lower alkyl, or together with the carbon atom to which they are attached form a radical- (CH)2)4-；
R6/R6' independently of each other is hydrogen or lower alkyl;
x is-N < or
Y is-N-, -NH-, -N-CH-or-CH;
z is-CR7＝、-N＝、-NHa-、-N＝CR7-、＝CH-N＝C(R7) -or-N-CH-;
R7is hydrogen or lower alkyl;
n is 0, 1 or 2;
m is 0 or 1; and is
The dotted line may be a bond;
and pharmaceutically acceptable acid addition salts thereof.
Of the compounds of the formula I, particular preference is given to compounds of the formula Ia
Wherein A is phenyl, R1And R2Independently of one another, lower alkyl, -CHF2-C (lower alkyl) F2、CF3Or halogen, or together with the corresponding carbon atom form- (CH)2)3-，R3Is lower alkyl or amino, and R4、R5And R6、R6' is hydrogen, for example the following compounds:
1- [ [1- (4-chloro-3-methylphenyl) -1H-imidazol-4-yl ] methyl ] -2-ethyl-1H-imidazole,
1- [ [1- (4-chloro-3-methylphenyl) -1H-imidazol-4-yl ] methyl ] -2-methyl-1H-imidazole,
1- [ [1- (2, 3-dihydro-1H-inden-5-yl) -1H-imidazol-4-yl ] methyl ] -2-methyl-1H-imidazole,
1- [ [1- [ 4-fluoro-3- (trifluoromethyl) phenyl ] -1H-imidazol-4-yl ] methyl ] -2-methyl-1H-imidazole,
1- [1- (4-chloro-3-methyl-phenyl) -1H-imidazol-4-yl-methyl ] -1H-imidazol-2-yl-amine,
1- [ [1- [3- (1, 1-difluoroethyl) phenyl ] -1H-imidazol-4-yl ] methyl ] -2-methyl-1H-imidazole,
1- [ [1- (3-difluoromethyl-4-fluorophenyl) -1H-imidazol-4-yl ] methyl ] -2-methyl-1H-imidazole, or
1- [ [1- [3- (1, 1-difluoroethyl) -4-fluorophenyl ] -1H-imidazol-4-yl ] methyl ] -2-methyl-1H-imidazole.
Other preferred compounds of formula I are compounds of formula Ib
Wherein A is phenyl, R1And R2Is halogen, R3Is lower alkyl or hydrogen, and R4、R5And R6、R6' is hydrogen, for example the following compounds:
1- (3, 4-dichloro-phenyl) -3- (2-methyl-imidazol-1-yl-methyl) -1H-pyrazole.
Other preferred compounds of formula I are compounds of formula Ic
Wherein A is phenyl, R1And R2Is halogen, R3Is lower alkyl or hydrogen, and R4、R5And R6、R6' is hydrogen, for example the following compounds:
1- (3, 4-dichloro-phenyl) -4-imidazol-1-yl-methyl-1H-pyrazole; or
1- (3, 4-dichloro-phenyl) -4- (2-methyl-imidazol-1-yl-methyl) -1H-pyrazole.
Other preferred compounds of formula I are compounds of formula Id
Wherein A is phenyl, R1And R2Is halogen, hydrogen, CF3Or lower alkyl; r3Is a lower alkaneA radical or a hydrogen atom,
and R is4、R5And R6、R6′、R7Hydrogen, for example the following compounds:
2-methyl-1- [ [4- [3- (trifluoromethyl) phenyl ] -1H-imidazol-2-yl ] methyl ] -1H-imidazole,
1- [ [4- (4-fluoro-3-methylphenyl) -1H-imidazol-2-yl ] methyl ] -2-methyl-1H-imidazole,
1- [ [4- (3, 4-difluorophenyl) -1H-imidazol-2-yl ] methyl ] -2-methyl-1H-imidazole, or
4- (4-fluoro-3-methylphenyl) -2- (1H-imidazol-1-yl-methyl) -1H-imidazole.
Other preferred compounds of formula I are compounds of formula Ie
Wherein A is phenyl, R1And R2Is lower alkyl, halogen or CF3，R3Is lower alkyl or hydrogen, and R4、R5And R6、R6' is hydrogen, for example the following compounds:
3- (3, 4-dimethyl-phenyl) -5- (2-methyl-imidazol-1-yl-methyl) -pyridine,
3- (4-fluoro-3-methyl-phenyl) -5- (2-methyl-imidazol-1-yl-methyl) -pyridine,
3- (4-chloro-3-methyl-phenyl) -5- (2-methyl-imidazol-1-yl-methyl) -pyridine,
3- (3-chloro-4-fluoro-phenyl) -5- (2-methyl-imidazol-1-yl-methyl) -pyridine, or
3- (4-chloro-3-trifluoromethyl-phenyl) -5- (2-methyl-imidazol-1-yl-methyl) -pyridine.
Other preferred compounds of formula I are compounds of formula If
Wherein A is phenyl, R1And R2Is halogen, R3Is lower alkyl, and R4、R5And R6、R6' is hydrogen, for example the following compounds:
4- (3, 4-dichloro-phenyl) -2- (2-methyl-imidazol-1-yl-methyl) -pyridine.
Other preferred compounds of formula I are those of formula Ig
Wherein A is phenyl, R1And R2Is halogen, R3Is lower alkyl, and R4、R5And R6、R6' is hydrogen, for example the following compounds:
2- (3, 4-dichloro-phenyl) -4- (2-methyl-imidazol-1-yl-methyl) -pyridine.
Preferred compounds of formula I also include those wherein A is pyridin-2-or 3-yl or A is piperidin-1-yl.
According to the invention, the compounds of formula I above can be produced by the following process:
a) reacting a compound of the formula
With a compound of the formula V
To give a compound of the formula
Wherein
A is phenyl or pyridin-2 or 3-yl, R1-R7Has the meaning given above, hal is Br or Cl, or
b) Cleavage of the N-protecting group from a compound of formula VI
To give a compound of the formula Id
Wherein, A and R1-R6Having the meaning given above, P is an N-protecting group, such as 2- (trimethylsilyl) -ethoxymethyl, or
c) Reacting a compound of the formula
With a compound of the formula V
To give a compound of the formula
Wherein A is phenyl or pyridin-2 or 3-yl, and R1-R6Has the meaning given above, hal is Cl or Br, and,
if desired, the compound of formula I obtained is converted into a pharmaceutically acceptable salt.
The preparation of the compounds of formula I is described in more detail below.
Compounds of formula I are prepared by known procedures according to the various methods described above, and using schemes 1-10 as described below, for example:
according to step a), sodium hydride is added to a DMF solution of an imidazole compound of formula V, for example 2-propylimidazole, 2-methylimidazole, imidazole, 4-methylimidazole or 4, 5, 6, 7-tetrahydrobenzimidazole. After 30 minutes at room temperature, the mixture is cooled in an ice bath and a compound of formula II, III or IV, for example 4-chloromethyl-1- (3, 4-dichloro-phenyl) -1H-imidazole, 4-chloromethyl-1- (3, 4-dichloro-phenyl) -1H-pyrazole or 4-chloromethyl-1- (3, 4-dichloro-phenyl) -3-methyl-1H-imidazole, is added. The resulting mixture is stirred at room temperature for 30 minutes, and after evaporation of the solvent, the compounds of the formulae Ia, Ib and Ic are obtained in a customary manner.
The compounds of the formula Id can be prepared according to reaction process b). A compound of formula VI, for example 2- [ (2-methyl-1H-imidazol-1-yl) methyl ] -4- [3- (trifluoromethyl) phenyl ] -1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-imidazole or 4- (4-fluoro-3-methylphenyl) - [ (2-methyl-1H-imidazol-1-yl) methyl ] -1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-imidazole is dissolved in ethanol and treated with HCl. The reaction mixture was then refluxed overnight, cooled to room temperature, concentrated and purified.
The compounds of the formula If, Ig or Ih can be prepared according to reaction process c). To a suspension of sodium hydride in mineral oil and DMF is added a compound of formula V, for example 2-propylimidazole, 2-methylimidazole, imidazole or 4-methylimidazole. The mixture was stirred at room temperature for 1.5 hours. Then, the compound of formula VIII, IX or X and triethylamine are added and the mixture is heated to about 100 ℃ for 4 hours. After cooling, the DMF is evaporated off and the residue is chromatographed directly.
Pharmaceutically acceptable salts can be produced according to methods well known and familiar to those skilled in the art. The acid addition salts of the compounds of formula I are particularly suitable for therapeutic use.
In schemes 1-10 below, processes for preparing compounds of formula I from well-known compounds, commercially available products, or compounds that can be prepared in a conventional manner are described.
The preparation of the compounds of formula I is described in more detail in examples 1-233 below.
Reaction scheme 1
Substituent R1-R5As mentioned above, THF is tetrahydrofuran. In the compounds of formula XI, the phenyl group may be replaced by a pyridin-2-or 3-yl group to give the corresponding compounds of formula Ia.
Alternatively, compounds of formula XIV may be prepared
Wherein R is1And R2DIBAH is diisobutylaluminum hydride and LAH is lithium aluminum hydride, as described above.
Reaction scheme 2
Substituent R1-R5And R7As mentioned above, LAH is lithium aluminum hydride.
In the compounds of formula XV the phenyl group may be replaced by a pyridin-2-or 3-yl group to give the corresponding compounds of formula Ia.
Reaction scheme 3
Substituent R1-R5As mentioned above, NBS is N-bromosuccinimide and AIBN is azobisisobutyronitrile.
In the compounds of formula XX, the phenyl group may be replaced by a pyridin-2-or-3-yl group to obtain the corresponding compounds of formula Ib.
Reaction scheme 4
Substituent R1-R5As mentioned above, THF is tetrahydrofuran.
In the compounds of the formula XXIII, the phenyl group can be replaced by a pyridin-2-or 3-yl group to give the corresponding compounds of the formula Ic.
Reaction scheme 5
Substituent R1-R5As mentioned above, DMF is N, N-dimethylformamide.
In the compounds of formula XV, the phenyl group may be replaced by a pyridin-2-or 3-yl group to give the corresponding compounds of formula Id.
Reaction scheme 6
Substituent R1-R5And R7As mentioned above, LAH is lithium aluminum hydride. Alternatively, the compound of formula XV may be replaced by
In the compounds of formula XV the phenyl group may be replaced by a pyridin-2-or 3-yl group to give the corresponding compounds of formula Ie.
Reaction scheme 7
Substituent R1-R5As described above.
In the compounds of formula XV the phenyl group may be replaced by a pyridin-2-or 3-yl group to give the corresponding compounds of formula If.
Reaction scheme 8
Substituent R1-R5As mentioned above, LAH is lithium aluminum hydride.
In the compounds of formula XV the phenyl group may be replaced by a pyridin-2-or 3-yl group to give the corresponding compounds of formula Ig.
Reaction scheme 9
The substituents are as described above, BINAP is 2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl.
Reaction scheme 10
In the compound of formula XV or another compound, the phenyl group may be replaced by a pyridin-2-or 3-yl group.
As mentioned previously, the compounds of formula I and their pharmaceutically acceptable acid addition salts possess valuable pharmacological properties. They are selective blockers of NMDA-receptor subtype 2B, which have a key role in regulating neuronal activity and plasticity and are therefore crucial for regulating fundamental processes in CNS development and learning and memory formation.
The compounds were studied according to the experiments given below.
Experimental methods
3 H-Ro 25-6981 binding(Ro 25-6981 is [ R- (R, S)]-alpha- (4-hydroxy-phenyl) -beta-methyl-4- (phenyl-methyl) -1-piperidinepropanol
Male F ü llinsdorf white rats weighing 150-. The whole brain with the cerebellum and medulla oblongata removed was homogenized with Polytron (10,000rpm, 30 seconds) in 25 volumes of cold Tris-HCl 50mM, EDTA 10mM, pH 7.1 buffer. The homogenate was centrifuged at 48,000g for 10 min at 4 ℃. The sediment was resuspended in the same volume of buffer using a Polytron and the homogenate incubated at 37 ℃ for 10 minutes. After centrifugation, the sediment was homogenized in the same buffer and frozen at-80 ℃ for at least 16 hours, but not more than 10 days. For binding experiments, the tissue homogenates were thawed at 37 ℃, centrifuged, and the sediment was washed three times in cold buffer Tris-HCl 5mM, pH 7.4 as described above. The final pellet was resuspended in the same buffer and used at a final concentration of 200mg protein/ml.
With Tris-HCl 50mM, pH 7.4 buffer3H-Ro 25-6981 binding assays. For the displacement experiments, 5nM of3H-Ro 25-6981, and measuring nonspecific binding with 10mM tetrahydroisoquinoline, which usually accounts for 10% of the total amount. The incubation time was 2 hours at 4 ℃ and the experiment was stopped by filtration on a Whatmann GF/B glass fibre filter (Unifilter-96, Packard, Zurich, Switzerland). The filter was washed 5 times with cold buffer. After addition of 40mL microscint40(Canberra Packard S.A., Zurich, Switzerland), radioactivity on the filters was counted using a Packard Top-count microplate scintillation counter.
The potency of the compounds was determined with at least 8 concentrations and the determination was repeated at least once. The collected normalized values were analyzed using a non-linear regression calculation program to obtain the IC defined by its upper and lower 95% confidence limits50The value is obtained.
IC of a preferred compound of formula I as determined by the above method50(mu.M) is < 0.1. mu.M. In the following table, some data of the binding activity are shown.
| Example No. 2 | IC(μM) | Example No. 2 | IC(μM) |
| 1 | 0.007 | 151 | 0.014 |
| 2 | 0.01 | 152 | 0.01 |
| 3 | 0.012 | 153 | 0.02 |
| 4 | 0.017 | 154 | 0.048 |
| 6 | 0.045 | 155 | 0.01 |
| Example No. 2 | IC(μM) | Example No. 2 | IC(μM) |
| 10 | 0.004 | 156 | 0.014 |
| 11 | 0.005 | 157 | 0.014 |
| 12 | 0.008 | 158 | 0.041 |
| 13 | 0.095 | 159 | 0.014 |
| 16 | 0.009 | 160 | 0.016 |
| 17 | 0.012 | 161 | 0.05 |
| 21 | 0.043 | 162 | 0.016 |
| 24 | 0.016 | 163 | 0.017 |
| 27 | 0.027 | 164 | 0.03 |
| 39 | 0.043 | 165 | 0.046 |
| 48 | 0.061 | 166 | 0.02 |
| 52 | 0.078 | 168 | 0.038 |
| 58 | 0.093 | 170 | 0.039 |
| 87 | 0.017 | 172 | 0.024 |
| 89 | 0.048 | 173 | 0.028 |
| 93 | 0.02 | 174 | 0.063 |
| 94 | 0.021 | 176 | 0.032 |
| 103 | 0.043 | 177 | 0.0375 |
| 105 | 0.001 | 178 | 0.074 |
| 109 | 0.085 | 180 | 0.05 |
| Example No. 2 | IC(μM) | Example No. 2 | IC(μM) |
| 111 | 0.011 | 181 | 0.053 |
| 119 | 0.046 | 183 | 0.052 |
| 130 | 0.065 | 186 | 0.052 |
| 136 | 0.08 | 189 | 0.053 |
| 139 | 0.065 | 192 | 0.055 |
| 140 | 0.04 | 194 | 0.079 |
| 141 | 0.039 | 199 | 0.098 |
| 143 | 0.0073 | 224 | 0.01 |
| 144 | 0.038 | 225 | 0.01 |
| 145 | 0.054 | 226 | 0.02 |
| 146 | 0.008 | 227 | 0.03 |
| 147 | 0.0092 | 229 | 0.012 |
| 149 | 0.0082 | 230 | 0.084 |
| 150 | 0.0135 | 232 | 0.04 |
The compounds of formula I and salts thereof as hereinbefore described may be incorporated into standard pharmaceutical dosage forms, for example in the form of oral or parenteral administration using conventional pharmaceutical adjuvant materials such as organic or inorganic inert carrier materials, for example water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols and the like. The pharmaceutical preparations may be in solid form, such as tablets, suppositories, capsules, or in liquid form, such as solutions, suspensions or emulsions. Pharmaceutical adjuvant materials which may be added include preservatives, stabilisers, wetting or emulsifying agents, salts for altering the osmotic pressure or acting as buffers. The pharmaceutical preparation may also comprise other pharmaceutically active substances.
The dosage can vary within wide limits and should, of course, be adapted to the individual requirements of each particular case. When administered orally, the dosage will range from about 0.1mg per dose to about 1000mg per day of the compound of formula I, although the upper limit may be exceeded where the indication may be exceeded.
The following examples illustrate the invention in more detail. They are not intended to limit the scope of the invention. All temperatures are in degrees celsius.
Example 1
1- [ [1- (3, 4-dichlorophenyl) -1H-imidazol-4-yl]Methyl radical]-2-propyl-1H-imidazole hydrochloride (1: 2)
Sodium hydride (0.44g of a 55% dispersion in mineral oil, 10mmol) was slowly added to a solution of 2-propylimidazole (0.55g, 5mmol) in DMF. After 30 min at 20 ℃ the mixture was cooled in an ice bath and 4-chloromethyl-1- (3, 4-dichloro-phenyl) -1H-imidazole (1.0g, 4mmol) was added in one portion. The resulting mixture was stirred at 20 ℃ for 30 minutes. After evaporation of the solvent, the residue was dissolved in ethyl acetate, washed with water, dried (sodium sulfate) and chromatographed [ silica, gradient elution: dichloromethane to 50% (dichloromethane/methanol/aqueous ammonium hydroxide solution ═ 90: 10: 1)]. The free base of the title compound was obtained as a brown oil (1.12g, 84%). Treatment with HCl in methanol and addition of diethyl ether isolated the title compound as a white crystal. Mp.241-243 ℃ (methanol/diethyl ether), MS: 334 (M/e)+)。
Examples 2-9 were prepared according to the general procedure described in example 1.
Example 2
1- [ [1- (3, 4-dichlorophenyl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride (1: 2)
Reacting 2-methylimidazole with sodium hydride followed by treatment with 4-chloromethyl-1- (3, 4-dichloro-phenyl) -1H-imidazole,after extractive workup and chromatography, the free base of the title compound is obtained and is converted into its white hydrochloride salt. Mp. > 250 ℃ (methanol/diethyl ether), MS: 306 (M/e)+)。
Example 3
1- [ [1- (3, 4-dichlorophenyl) -1H-imidazol-4-yl]Methyl radical]-2-ethyl-1H-imidazole hydrochloride (1: 2)
Reaction of 2-ethylimidazole with sodium hydride followed by treatment with 4-chloromethyl-1- (3, 4-dichloro-phenyl) -1H-imidazole led, after extractive workup and chromatography, to the free base of the title compound, which was converted into its white hydrochloride salt. Mp. > 250 ℃ (methanol/diethyl ether), MS: 320 (M/e) ═ M/e+)。
Example 4
1- [ [1- (3, 4-dichlorophenyl) -1H-imidazol-4-yl]Methyl radical]-2- (1-methylethyl) -1H-imidazole hydrochloride
(1∶2)
Reaction of 2-isopropylimidazole with sodium hydride followed by treatment with 4-chloromethyl-1- (3, 4-dichloro-phenyl) -1H-imidazole led, after extractive workup and chromatography, to the free base of the title compound, which was converted into its white hydrochloride salt. Mp.236-238 ℃ (decomposition) (methanol/ether), MS: 335(M + H) M/e+)。
Example 5
1- (3, 4-dichlorophenyl) -4- (1H-imidazol-1-yl-methyl) -1H-imidazole hydrochloride (1: 2)
Reaction of imidazole with sodium hydride followed by treatment with 4-chloromethyl-1- (3, 4-dichloro-phenyl) -1H-imidazole led, after extractive workup and chromatography, to the free base of the title compound, which was converted into its white hydrochloride salt. Mp. > 250 ℃ (methanol/diethyl ether), MS: 292 (M/e)+)。
Example 6
1- (3, 4-dichlorophenyl) -4- [ (4-methyl-1H-imidazol-1-yl) methyl]-1H-imidazole hydrochloride (1: 2) and
1- (3, 4-dichlorophenyl) -4- [ (5-methyl-1H-imidazol-1-yl) methyl]-1H-imidazole hydrochloride (1: 2) (ratio)
3∶2)
Reaction of 4-methylimidazole with sodium hydride followed by treatment with 4-chloromethyl-1- (3, 4-dichloro-phenyl) -1H-imidazole led, after extractive workup and chromatography, to the free base of the title compound, which was converted into its white hydrochloride salt. MS: 306 (M/e)+)。
Example 7
1- [1- (3, 4-dichloro-phenyl) -1H-imidazol-4-yl-methyl]-4, 5, 6, 7-tetrahydro-1H-benzimidazole, hydrochloric acid
Salt (1: 2)
Reaction of 4, 5, 6, 7-tetrahydrobenzimidazole with sodium hydride followed by treatment with 4-chloromethyl-1- (3, 4-dichloro-phenyl) -1H-imidazole led, after extractive workup and chromatography, to the free base of the title compound, which was converted into its white hydrochloride salt. Mp. > 250 ℃ (methanol/diethyl ether), MS: 346 (M/e)+)。
Example 8
1- [ [1- (3, 4-dichlorophenyl) -1H-imidazol-4-yl]Methyl radical]-4, 5-dimethyl-1H-imidazole hydrochloride (1: 2)
Reaction of 4, 5-dimethylimidazole with sodium hydride followed by treatment with 4-chloromethyl-1- (3, 4-dichloro-phenyl) -1H-imidazole led, after extractive workup and chromatography, to the free base of the title compound, which was converted into its white hydrochloride salt. Mp. > 250 ℃ (methanol/diethyl ether), MS: 320 (M/e) ═ M/e+)。
Example 9
1- [ [1- (3, 4-dichlorophenyl) -1H-imidazol-4-yl]Methyl radical]-2-phenyl-1H-imidazole hydrochloride (1: 2)
Reaction of 2-phenylimidazole with sodium hydride followed by treatment with 4-chloromethyl-1- (3, 4-dichloro-phenyl) -1H-imidazole led, after extractive workup and chromatography, to the free base of the title compound, which was converted into its white hydrochloride salt. Mp.197-198 ℃ (methanol/diethyl ether), MS: 369(M + H)+)。
Example 10
1- [ [1- (4-chloro-3-methylphenyl) -1H-imidazol-4-yl]Methyl radical]-2-ethyl-1H-imidazole hydrochloride (1: 2)
The [1- (4-chloro-3-methyl-phenyl) -1H-imidazol-4-yl ] -methanol was treated with thionyl chloride and the obtained 4-chloromethyl-1- (4-chloro-3-methyl-phenyl) -1H-imidazole was used directly in the next reaction as its hydrochloride.
As described in example 1, 2-ethylimidazole was reacted with sodium hydride followed by treatment with 4-chloromethyl-1- (4-chloro-3-methyl-phenyl) -1H-imidazole hydrochloride to give, after extractive workup and chromatography, the free base of the title compound which was converted to its white hydrochloride salt. Mp.186-187 ℃ (methanol/diethyl ether), MS: 300 (M/e)+)。
Examples 11-103 were prepared according to the general procedure described in example 10.
Example 11
1- [ [1- (4-chloro-3-methylphenyl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride (1: 2)
Reacting [1- (4-chloro-3-methyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.218-220 ℃ (methanol/diethyl ether), MS: 286M/e (M)+)。
Example 12
1- (4-chloro-3-methylphenyl) -4-(1H-imidazol-1-yl-methyl) -1H-imidazole hydrochloride (1: 2)
Reacting [1- (4-chloro-3-methyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and imidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.206-207 ℃ (methanol/diethyl ether), MS: 272 (M/e) ═ M/e+)。
Example 13
1- [ [1- (4-chloro-3-methylphenyl) -1H-imidazol-4-yl]Methyl radical]-4, 5-dimethyl-1H-imidazole hydrochloride
(1∶2)
Reacting [1- (4-chloro-3-methyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with a reaction mixture of sodium hydride and 4, 5-dimethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp. > 250 ℃ (methanol/diethyl ether), MS: 300 (M/e)+)。
Example 14
1- [1- (4-chloro-3-methyl-phenyl) -1H-imidazol-4-yl-methyl]-4, 5, 6, 7-tetrahydro-1H-benzimidazole, salts
Acid salt (1: 2)
Reacting [1- (4-chloro-3-methyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with a reaction mixture of sodium hydride and 4, 5, 6, 7-tetrahydro-benzimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp. > 250 ℃ (methanol/diethyl ether), MS: 326 (M/e)+)。
Example 15
1- [ [1- (4-chloro-3-methylphenyl) -1H-imidazol-4-yl]Methyl radical]-2- (methylthio) -1H-imidazole hydrochloride
(1∶2)
Reacting [1- (4-chloro-3-methyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylthioimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.202-204 ℃ (decomposition) (methanol/ether), MS: 319(M + H) M/e+)。
Example 16
1- [ [1- (2, 3-dihydro-1H-inden-5-yl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride
(1∶2)
(1-indan-5-yl-1H-imidazol-4-yl) -methanol is first treated with thionyl chloride and then with a reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.242-243 ℃ (methanol/diethyl ether), MS: 278 (M) M/e+)。
Example 17
1- [ [1- (2, 3-dihydro-1H-inden-5-yl) -1H-imidazol-4-yl]Methyl radical]-2-ethyl-1H-imidazole hydrochloride
(1∶2)
(1-indan-5-yl-1H-imidazol-4-yl) -methanol is first treated with thionyl chloride and then with a reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.240-241 ℃ (methanol/diethyl ether), MS: 292 (M/e)+)。
Example 18
1- (2, 3-dihydro-1H-inden-5-yl) -4- (1H-imidazol-1-yl-methyl) -1H-imidazole hydrochloride (1: 2)
(1-indan-5-yl-1H-imidazol-4-yl) -methanol is first treated with thionyl chloride and then with sodium hydrideAnd imidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.214-216 ℃ (methanol/diethyl ether), MS: 264 (M/e)+)。
Example 19
1- [ [1- (3, 4-dimethylphenyl) -1H-imidazol-4-yl ] methyl ester]Methyl radical]-2-ethyl-1H-imidazole hydrochloride (1: 2)
1- (3, 4-dimethyl-phenyl) -1H-imidazole-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp. > 250 ℃ (methanol/diethyl ether), MS: 280 parts M/e (M)+)。
Example 20
1- [ [1- (3, 4-dimethylphenyl) -1H-imidazol-4-yl ] methyl ester]Methyl radical]-2-methyl-1H-imidazole hydrochloride (1: 2)
Reacting [1- (3, 4-dimethyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.249-251 ℃ (methanol/diethyl ether), MS: 266M/e (M)+)。
Example 21
1- (3, 4-dimethylphenyl) -4- (1H-imidazol-1-yl-methyl) -1H-imidazole hydrochloride (1: 2)
Reacting [1- (3, 4-dimethyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and imidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.218-219 ℃ (methanol/diethyl ether), MS: m/e is 252(M+)。
Example 22
2-methyl-1- [ [1- (4-methylphenyl) -1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride (1: 2)
(1-p-tolyl-1H-imidazol-4-yl) -methanol was first treated with thionyl chloride and then with a reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp. > 250 ℃ (methanol/diethyl ether), MS: 252 (M/e)+)。
Example 23
4- (1H-imidazol-1-yl-methyl) -1- (4-methylphenyl) -1H-imidazole hydrochloride (1: 2)
(1-p-tolyl-1H-imidazol-4-yl) -methanol was first treated with thionyl chloride and then with a reaction mixture of sodium hydride and imidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.228-229 ℃ (methanol/diethyl ether), MS: 238 (M/e)+)。
Example 24
1- [ [1- (4-fluoro-3-methylphenyl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride (1: 2)
Reacting [1- (4-fluoro-3-methyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.210-212 ℃ (methanol/diethyl ether), MS: 270 (M/e)+)。
Example 25
2-ethyl-1- [ [1- (4-fluoro-3-methylphenyl) -1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloric acidSalt (1: 2)
Reacting [1- (4-fluoro-3-methyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.210-212 ℃ (methanol/diethyl ether), MS: 284 (M/e) (M)+)。
Example 26
1- (4-fluoro-3-methylphenyl) -4- (1H-imidazol-1-yl-methyl) -1H-imidazole hydrochloride (1: 2)
Reacting [1- (4-fluoro-3-methyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and imidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.242-243 ℃ (methanol/diethyl ether), MS: 256 (M/e)+)。
Example 27
2-methyl-1- [ [1- [4- (methylthio) phenyl ] methyl ester]-1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride (1: 2)
Reacting [1- (4-methylthio-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.242-243 ℃ (methanol/diethyl ether), MS: 284 (M/e) (M)+)。
Example 28
2-ethyl-1- [ [1- [4- (methylthio) phenyl ] methyl ester]-1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride (1: 2)
Reacting [1- (4-methylthio-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then reacted with sodium hydride and 2-ethylimidazoleAnd (4) treating the mixture. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted into its light yellow hydrochloride salt. Mp.161-162 ℃ (methanol/diethyl ether), MS: 298 (M) M/e+)。
Example 29
4- (1H-imidazol-1-yl-methyl) -1- [4- (methylthio) phenyl]-1H-imidazole hydrochloride (1: 2)
Reacting [1- (4-methylthio-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and imidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted into its light yellow hydrochloride salt. Mp.233-234 ℃ (methanol/diethyl ether), MS: 270 (M/e)+)。
Example 30
2-methyl-1- [ [1- [3- (trifluoromethyl) phenyl ] methyl ester]-1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride (1: 2)
Reacting [1- (3-trifluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.218-220 ℃ (methanol/diethyl ether), MS: 306 (M/e)+)。
Example 31
2-ethyl-1- [ [1- [3- (trifluoromethyl) phenyl ] methyl ester]-1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride (1: 2)
Reacting [1- (3-trifluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.216-218 ℃ (methanol/diethyl ether), MS: 320 (M/e) ═ M/e+)。
Example 32
4- (1H-imidazol-1-yl-methyl) -1- [3- (trifluoromethyl) phenyl]-1H-imidazole hydrochloride (1: 2)
Reacting [1- (3-trifluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and imidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.224-226 ℃ (methanol/diethyl ether), MS: 292 (M/e)+)。
Example 33
2-ethyl-1- [ [1- [ 4-fluoro-3- (trifluoromethyl) phenyl ] methyl ] phenyl]-1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride
(1∶2)
Reacting [1- (4-fluoro-3-trifluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted into its light yellow hydrochloride salt. Mp. > 238 deg.C (decomposed) (methanol/ether), MS: 338 (M/e)+)。
Example 34
1- [ [1- [ 4-fluoro-3- (trifluoromethyl) phenyl ] phenyl]-1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride
(1∶2)
Reacting [1- (4-fluoro-3-trifluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with a reaction mixture of sodium hydride and 2-methyl-imidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted into its light yellow hydrochloride salt. Mp. > 231 ℃ (decomposition) (methanol/ether), MS: 324 (M/e)+)。
Example 35
1- [ 4-fluoro-3- (trifluoromethyl) phenyl]-4- (1H-imidazol-1-yl-methyl) -1H-imidazole hydrochloride (1: 2)
1- (4-fluoro-3-trifluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and imidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted into its light yellow hydrochloride salt. Mp. > 246 ℃ (decomposed) (methanol/ether), MS: 310 (M/e)+)。
Example 36
1- [ 3-fluoro-4- (trifluoromethyl) phenyl]-4- (1H-imidazol-1-yl-methyl) -1H-imidazole hydrochloride (1: 2)
Reacting [1- (3-fluoro-4-trifluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and imidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.232-234 ℃ (methanol/diethyl ether), MS: 311(M + H) M/e+)。
Example 37
1- [ [1- [ 3-fluoro-4- (trifluoromethyl) phenyl ] phenyl]-1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole
Hydrochloride salt
(1∶2)
Reacting [1- (3-fluoro-4-trifluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with a reaction mixture of sodium hydride and 2-methyl-imidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.238-239 ℃ (methanol/diethyl ether), MS: 325(M + H) M/e+)。
Example 38
2-ethyl-1- [ [1- [ 3-fluoro-4- (trifluoromethyl) phenyl ] methyl ] phenyl]-1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride
(1∶2)
Reacting [1- (3-fluoro-4-trifluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.222-224 ℃ (decomposition) (methanol/ether), MS: 339(M + H) M/e+)。
Example 39
2-methyl-1- [ [1- [ 4-methyl-3- (trifluoromethyl) phenyl ] methyl ester]-1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloric acid
Salt (1: 2)
Reacting [1- (4-methyl-3-trifluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its yellow-white hydrochloride salt. Mp. > 235 ℃ (decomposed) (methanol/ether), MS: 320 (M/e) ═ M/e+)。
Example 40
2-ethyl-1- [ [1- [ 4-methyl-3- (trifluoromethyl) phenyl ] methyl ester]-1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloric acid
Salt (1: 2)
Reacting [1- (4-methyl-3-trifluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its yellow-white hydrochloride salt. Mp. > 250 ℃ (methanol/diethyl ether), MS: 334 (M/e)+)。
EXAMPLE 41
4- (1H-imidazol-1-yl-methyl) -1- [ 4-methyl-3- (trifluoromethyl) phenyl]-1H-imidazole hydrochloride (1: 2)
Reacting [1- (4-methyl-3-trifluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and imidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its yellow-white hydrochloride salt. Mp. > 250 ℃ (methanol/diethyl ether), MS: 306 (M/e)+)。
Example 42
1- [ [1- (4-chloro-3-methoxyphenyl) -1H-imidazol-4-yl]Methyl radical]-2-ethyl-1H-imidazole hydrochloride (1: 2)
Reacting [1- (4-chloro-3-methoxy-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its yellow-white hydrochloride salt. Mp.244-246 ℃ (decomposed) (methanol/ether), MS: 316 (M/e)+)。
Example 43
1- [ [1- (4-chloro-3-methoxyphenyl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride (1: 2)
Reacting [1- (4-chloro-3-methoxy-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its yellow-white hydrochloride salt. Mp. > 250 ℃ (methanol/diethyl ether), MS: 302 (M/e) ═ M+)。
Example 44
1- (4-chloro-3-methoxyphenyl) -4- (1H-imidazol-1-yl-methyl) -1H-imidazole hydrochloride (1: 2)
Reacting [1- (4-chloro-3-methoxy-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and imidazole. At the position of extractionAfter purification by chromatography and chromatography, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.221-222 ℃ (methanol/diethyl ether), MS: 288 (M/e)+)。
Example 45
2-Ethyl-1- [1- (4-fluoro-3-methoxyphenyl) -1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride (1: 2)
Reacting [ [1- (4-fluoro-3-methoxy-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its yellow-white hydrochloride salt. Mp. > 250 ℃ (decomposition) (methanol/ether), MS: 300 (M/e)+)。
Example 46
1- [ [1- (4-fluoro-3-methoxyphenyl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride (1: 2)
Reacting [ [1- (4-fluoro-3-methoxy-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its yellow-white hydrochloride salt. Mp. > 220 ℃ (decomposition) (methanol/ether), MS: 286M/e (M)+)。
Example 47
1- (4-fluoro-3-methoxyphenyl) -4- (1H-imidazol-1-yl-methyl) -1H-imidazole hydrochloride (1: 2)
Reacting [ [1- (4-fluoro-3-methoxy-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and imidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its yellow-white hydrochloride salt. Mp.174-178 ℃ (methanol/diethyl ether), MS: 272 (M/e) ═ M/e+)。
Example 48
1- [ [1- (4-chlorophenyl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride (1: 2)
Reacting [1- (4-chloro-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted into its light yellow hydrochloride salt. Mp.243-244 ℃ (methanol/diethyl ether), MS: 272 (M/e) ═ M/e+)。
Example 49
1- [ [1- (4-chlorophenyl) -1H-imidazol-4-yl]Methyl radical]-2-ethyl-1H-imidazole hydrochloride
1- (4-chloro-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.200-201 ℃ (methanol/diethyl ether), MS: 286M/e (M)+)。
Example 50
1- (4-chlorophenyl) -4- (1H-imidazol-1-yl-methyl) -1H-imidazole hydrochloride (1: 2)
Reacting [1- (4-chloro-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and imidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.228-229 ℃ (methanol/diethyl ether), MS: 258 (M/e)+)。
Example 51
1- [ [1- (1, 3-benzodioxol-5-yl) -1H-imidazol-4-yl]Methyl radical]-2-ethyl-1H-imidazole
Hydrochloride salt(1∶2)
1-benzo [1, 3 ]]dioxol-5-yl-1H-imidazol-4-yl) -methanol is first treated with thionyl chloride and then with a reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp. > 250 ℃ (methanol/diethyl ether), MS: 296 (M/e) ═ 296 (M)+)。
Example 52
1- [ [1- (1, 3-benzodioxol-5-yl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole
Hydrochloride (1: 2)
1-benzo [1, 3 ]]dioxol-5-yl-1H-imidazol-4-yl) -methanol is first treated with thionyl chloride and then with a reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp. > 250 ℃ (methanol/diethyl ether), MS: 282 (M/e)+)。
Example 53
1- (1, 3-benzodioxol-5-yl) -4- (1H-imidazol-1-yl-methyl) -1H-imidazole hydrochloride
(1∶2)
1-benzo [1, 3 ]]dioxol-5-yl-1H-imidazol-4-yl) -methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and imidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.197-198 ℃ (methanol/diethyl ether), MS: 268 (M/e)+)。
Example 54
1- [ [ - (3-fluoro-4-methylphenyl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride (1: 2)
Will 21- (3-fluoro-4-methyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp. > 250 ℃ (methanol/diethyl ether), MS: 270 (M/e)+)。
Example 55
2-ethyl-1- [ [1- (3-fluoro-4-methylphenyl) -1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride
(1∶2)
Reacting [1- (3-fluoro-4-methyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp. > 250 ℃ (methanol/diethyl ether), MS: 284 (M/e) (M)+)。
Example 56
1- (3-fluoro-4-methylphenyl) -4- (1H-imidazol-1-ylmethyl) -1H-imidazole hydrochloride (1: 2)
Reacting [1- (3-fluoro-4-methyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and imidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.223-224 ℃ (methanol/diethyl ether), MS: 256 (M/e)+)。
Example 57
1- [ [1- (3-chloro-4-methoxyphenyl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride (1: 2)
Reacting [1- (3-chloro-4-methoxy-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylimidazole. After extraction and chromatographic purificationAfter this time, the free base of the title compound was obtained. It was converted to its white hydrochloride salt. Mp.240-241 ℃ (methanol/diethyl ether), MS: 302 (M/e) ═ M+)。
Example 58
1- [ [1- (3-chloro-4-methoxyphenyl) -1H-imidazol-4-yl]Methyl radical]-2-ethyl-1H-imidazole, hydrochloride
(1∶2)
Reacting [1- (3-chloro-4-methoxy-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.220-221 ℃ (methanol/diethyl ether), MS: 316 (M/e)+)。
Example 59
1- (3-chloro-4-methoxyphenyl) -4- (1H-imidazol-1-yl-methyl) -1H-imidazole hydrochloride (1: 2)
Reacting [1- (3-chloro-4-methoxy-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and imidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.245-246 ℃ (methanol/diethyl ether), MS: 288 (M/e)+)。
Example 60
1- [ [1- (4-chloro-2-fluorophenyl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride (1: 2)
Reacting [1- (4-chloro-2-fluoro-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.235-236 ℃ (methanol/diethyl ether), MS: 290 (M/e)+)。
Example 61
1- [ [1- (4-chloro-2-fluorophenyl) -1H-imidazol-4-yl]Methyl radical]-2-ethyl-1H-imidazole hydrochloride (1: 2)
Reacting [1- (4-chloro-2-fluoro-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.248-249 ℃ (methanol/diethyl ether), MS: 304 (M/e)+)。
Example 62
1- (4-chloro-2-fluorophenyl) -4- (1H-imidazol-1-yl-methyl) -1H-imidazole hydrochloride (1: 2)
Reacting [1- (4-chloro-2-fluoro-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and imidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp. > 212 ℃ (decomposed) (methanol/ether), MS: 276 (M/e)+)。
Example 63
1- [ [1- (4-bromophenyl) -1H-imidazol-4-yl]Methyl radical]-2-ethyl-1H-imidazole hydrochloride (1: 2)
Reacting [1- (4-bromo-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp. > 250 ℃ (methanol/diethyl ether), MS: 330 (M/e) ═ M/e+)。
Example 64
1- [ [1- (4-bromophenyl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride
Reacting [1- (4-bromo-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp. > 250 ℃ (methanol/diethyl ether), MS: 316 (M/e)+)。
Example 65
1- (4-bromophenyl) -4- (1H-imidazol-1-yl-methyl) -1H-imidazole hydrochloride (1: 2)
Reacting [1- (4-bromo-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and imidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.237-239 ℃ (methanol/diethyl ether), MS: 302 (M/e) ═ M+)。
Example 66
1- [ [1- [4- (difluoromethoxy) phenyl ] phenyl]-1H-imidazol-4-yl]Methyl radical]-2-ethyl-1H-imidazole hydrochloride
(1∶2)
[ [1- (4-difluoromethoxy-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.199-200 ℃ (methanol/diethyl ether), MS: m/e is 318 (M)+)。
Example 67
1- [ [1- [4- (difluoromethoxy) phenyl ] phenyl]-1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride
(1∶2)
Reacting [ [1- (4-difluoromethoxy-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.228-229 ℃ (methanol/diethyl ether), MS: 304 (M/e)+)。
Example 68
2-methyl-1- [ [1- [4- (phenylmethoxy) phenyl ] methyl]-1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride
(1∶2)
Reacting [1- (4-benzyloxy-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.225-226 ℃ (methanol/diethyl ether), MS: 344 (M/e)+)。
Example 69
2-ethyl-1- [ [1- [4- (phenylmethoxy) phenyl ] methyl]-1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride
(1∶2)
Reacting [1- (4-benzyloxy-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.222-223 ℃ (methanol/diethyl ether), MS: 358 (M/e) (M/e)+)。
Example 70
4- (1H-imidazol-1-yl-methyl) -1- [4- (phenylmethoxy) phenyl]-1H-imidazole hydrochloride
Reacting [1- (4-benzyloxy-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and imidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.224-225 ℃ (methanol/diethyl ether), MS: 330 (M/e) ═ M/e+)。
Example 71
2-ethyl-1- [ [1- (3-methoxy-4-methylphenyl) -1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride
(1∶2)
Reacting [1- (3-methoxy-4-methyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp. > 250 ℃ (methanol/diethyl ether), MS: 296 (M/e) ═ 296 (M)+)。
Example 72
1- [ [1- (3-methoxy-4-methylphenyl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride
(1∶2)
Reacting [1- (3-methoxy-4-methyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.232-235 ℃ (methanol/diethyl ether), MS: 282 (M/e)+)。
Example 73
4- (1H-imidazol-1-yl-methyl) -1- (3-methoxy-4-methylphenyl) -1H-imidazole hydrochloride (1: 2)
Reacting [1- (3-methoxy-4-methyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and imidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.249-251 ℃ (methanol/diethyl ether), MS: 268 (M/e)+)。
Example 74
2-ethyl-1- [ [1- [4- (trifluoromethyl) phenyl ] methyl ester]-1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride (1: 2)
Reacting [1- (4-trifluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.240-242 ℃ (methanol/diethyl ether), MS: 320 (M/e) ═ M/e+)。
Example 75
2-methyl-1- [ [1- [4- (trifluoromethyl) phenyl ] methyl ester]-1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride (1: 2)
Reacting [1- (4-trifluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.246-248 ℃ (methanol/diethyl ether), MS: 306 (M/e)+)。
Example 76
4- (1H-imidazol-1-yl-methyl) -1- [4- (trifluoromethyl) phenyl]-1H-imidazole hydrochloride (1: 2)
Reacting [1- (4-trifluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and imidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.220-222 ℃ (methanol/diethyl ether), MS: 292 (M/e)+)。
Example 77
1- [ [1- (1, 3-dihydro-5-isobenzofuranyl) -1H-imidazol-4-yl]Methyl radical]-2-ethyl-1H-imidazole hydrochloric acid
Salt (1: 2)
Reacting [1- (1, 3-dihydro-isobenzofuran-5-yl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its yellow-white hydrochloride salt. Mp. > 108 ℃ (decomposed) (methanol/ether), MS: 294 (M/e)+)。
Example 78
1- [ [1- (1, 3-dihydro-5-isobenzofuranyl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloric acid
Salt (1: 2)
Reacting [1- (1, 3-dihydro-isobenzofuran-5-yl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its yellow-white hydrochloride salt. Mp. > 250 ℃ (methanol/diethyl ether), MS: 280 parts M/e (M)+)。
Example 79
1- [ [1- (3-fluoro-4-methoxyphenyl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride (1: 2)
Reacting [1- (3-fluoro-4-methoxy-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.238-240 ℃ (methanol/diethyl ether), MS: 286M/e (M)+)。
Example 80
2-ethyl-1- [ [1- (3-fluoro-4-methoxyphenyl) -1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride (1: 2)
Reacting [1- (3-fluoro-4-methoxy-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride,then, it was treated with a reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.218-220 ℃ (methanol/diethyl ether), MS: 300 (M/e)+)。
Example 81
1- [ [1- (4-methoxyphenyl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride (1: 2)
Reacting [1- (4-methoxy-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp. > 250 ℃ (methanol/diethyl ether), MS: 268 (M/e)+)。
Example 82
2-ethyl-1- [ [1- (3-methoxyphenyl) -1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride (1: 2)
Reacting [1- (3-methoxy-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.246-248 ℃ (methanol/diethyl ether), MS: 282 (M/e)+)。
Example 83
1- [ [1- (3-methoxyphenyl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride (1: 2)
Reacting [1- (3-methoxy-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.242-243 deg.C (methanol)Diethyl ether), MS: 268 (M/e)+)。
Example 84
4- (1H-imidazol-1-yl-methyl) -1- (3-methoxyphenyl) -1H-imidazole hydrochloride (1: 2)
Reacting [1- (3-methoxy-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and imidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.219-220 ℃ (methanol/diethyl ether), MS: 254 (M/e)+)。
Example 85
1- [ [1- [ 4-methoxy-3- (trifluoromethyl) phenyl group]-1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazolium salt
Acid salt (1: 2)
Reacting [1- (4-methoxy-3-trifluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its light brown hydrochloride salt. Mp. > 222 ℃ (decomposition) (methanol/ether), MS: 337(M + H) M/e+)。
Example 86
2-ethyl-1- [ [1- [ 4-methoxy-3- (trifluoromethyl) phenyl ] methyl ester]-1H-imidazol-4-yl]Methyl radical]-1H-imidazolium salts
Acid salt (1: 2)
Reacting [1- (4-methoxy-3-trifluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its light brown hydrochloride salt. Mp. > 226 ℃ (decomposition) (methanol/diethyl ether), MS: m/e is 351(M + H)+)。
Example 87
1- [ [1- (3-chloro-4-methylphenyl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride (1: 2)
Reacting [1- (3-chloro-4-methyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.242-243 ℃ (methanol/diethyl ether), MS: 286M/e (M)+)。
Example 88
1- [ [1- (3-chloro-4-methylphenyl) -1H-imidazol-4-yl]Methyl radical]-2-ethyl-1H-imidazole hydrochloride (1: 2)
Reacting [1- (3-chloro-4-methyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.178-179 ℃ (methanol/ether), MS: 300 (M/e)+)。
Example 89
1- (3-chloro-4-methylphenyl) -4- (1H-imidazol-1-yl-methyl) -1H-imidazole hydrochloride (1: 2)
Reacting [1- (3-chloro-4-methyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and imidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.218-220 ℃ (methanol/diethyl ether), MS: 272 (M/e) ═ M/e+)。
Example 90
1- [ [1- [ 4-chloro-3- (trifluoromethyl) phenyl ] phenyl]-1H-imidazol-4-yl]Methyl radical]-2-ethyl-1H-imidazole hydrochloride
(1∶2)
Reacting [1- (4-chloro-3-trifluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.179-180 ℃ (methanol/diethyl ether), MS: 354 (M/e)+)。
Example 91
1- [ [1- [ 4-chloro-3- (trifluoromethyl) phenyl ] phenyl]-1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride
(1∶2)
Reacting [1- (4-chloro-3-trifluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp. > 250 ℃ (methanol/diethyl ether), MS: 340 (M/e)+)。
Example 92
1- [ 4-chloro-3- (trifluoromethyl) phenyl]-4- (1H-imidazol-1-ylmethyl) -1H-imidazole hydrochloride (1: 2)
Reacting [1- (4-chloro-3-trifluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and imidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp. > 250 ℃ (methanol/diethyl ether), MS: 326 (M/e)+)。
Example 93
1- [ [1- (3-chloro-4-fluorophenyl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride (1: 2)
Reacting [1- (3-chloro-4-fluoro-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then withTreating the reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.224-225 ℃ (methanol/diethyl ether), MS: 290 (M/e)+)。
Example 94
1- [ [1- (3-chloro-4-fluorophenyl) -1H-imidazol-4-yl]Methyl radical]-2-ethyl-1H-imidazole hydrochloride (1: 2)
Reacting [1- (3-chloro-4-fluoro-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.248-250 ℃ (methanol/diethyl ether), MS: 304 (M/e)+)。
Example 95
1- (3-chloro-4-fluorophenyl) -4- (1H-imidazol-1-yl-methyl) -1H-imidazole hydrochloride (1: 2)
Reacting [1- (3-chloro-4-fluoro-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and imidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.210-212 ℃ (methanol/diethyl ether), MS: 276 (M/e)+)。
Example 96
1- [ (1- [1, 1' -biphenyl)]-4-yl-1H-imidazol-4-yl) methyl]-2-ethyl-1H-imidazole hydrochloride (1: 2)
(1-biphenyl-4-yl-1H-imidazol-4-yl) -methanol was first treated with thionyl chloride and then with a reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp.248-253 ℃ (methanol/diethyl ether), MS: 328 (M/e) ═ M/e (M)+)。
Example 97
1- [ (1- [1, 1' -biphenyl)]-4-yl-1H-imidazol-4-yl) methyl]-2-methyl-1H-imidazole hydrochloride (1: 2)
(1-biphenyl-4-yl-1H-imidazol-4-yl) -methanol was first treated with thionyl chloride and then with a reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted into its light yellow hydrochloride salt. Mp.169-175 ℃ (methanol/ether), MS: 314 (M/e)+)。
Example 98
2-ethyl-1- [ [1- [ 3-methyl-4- (1-methylethyl) phenyl ] ethyl]-1H-imidazol-4-yl]Methyl radical]-1H-imidazolium salts
Acid salt (1: 2)
Reacting [1- (4-isopropyl-3-methyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp. > 180 ℃ (decomposition) (methanol/ether), MS: 308 (M/e)+)。
Example 99
2-methyl-1- [ [1- [ 3-methyl-4- (1-methylethyl) phenyl ] methyl]-1H-imidazol-4-yl]Methyl radical]-1H-imidazolium salts
Acid salt (1: 2)
Reacting [1- (4-isopropyl-3-methyl-phenyl) -1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp. > 250 ℃ (methanol/diethyl ether), MS: 294 (M/e)+)。
Example 100
2-methyl-1- [ [1- (4-nitrophenyl) -1H-imidazol-4-yl]methyl-1H-imidazole hydrochloride (1: 2)
1- (4-Nitrophenyl) -1H-imidazole-4-methanol (prepared by the method I.Antonini et al, Synthesis, 1983,147-49) was first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its yellow hydrochloride salt. Mp. > 250 ℃ (methanol/diethyl ether), MS: 283 (M/e)+)。
Example 101
2-ethyl-1- [ [1- (4-nitrophenyl) -1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride (1: 2)
1- (4-Nitrophenyl) -1H-imidazole-4-methanol (prepared by the method I.Antonini et al, Synthesis, 1983,147-49) was first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-ethylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its yellow hydrochloride salt. Mp.196-197 ℃ (methanol/ether), MS: m/e is 297 (M)+)。
Example 102
4- (1H-imidazol-1-yl-methyl) -1- (4-nitrophenyl) -1H-imidazole hydrochloride (1: 2)
1- (4-Nitrophenyl) -1H-imidazole-4-methanol (prepared by I.Antonini et al Synthesis, 1983, 1, 47-49) was first treated with thionyl chloride and then with a reaction mixture of sodium hydride and imidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its yellow hydrochloride salt. Mp.245-246 ℃ (methanol/diethyl ether), MS: m/e269 (M)+)。
Example 103
1- (3, 4-dichlorophenyl) -5-methyl-4- [ (2-methyl-1H-imidazol-1-yl) methyl]-1H-imidazole hydrochloride
(1∶2)
Reacting [1- (3, 4-dichloro-phenyl) -5-methyl-1H-imidazol-4-yl]Methanol is first treated with thionyl chloride and then with the reaction mixture of sodium hydride and 2-methylimidazole. After extractive workup and chromatographic purification, the free base of the title compound is obtained. It was converted to its white hydrochloride salt. Mp. > 240 ℃ (decomposition) (methanol/ether), MS: 320 (M/e) ═ M/e+)。
Example 104
1- [1- (3, 4-dichloro-phenyl) -1H-imidazol-4-yl-methyl]-1H-imidazol-2-yl-amine hydrochloride (1: 2)
1- [ [1- (3, 4-dichlorophenyl) -1H-imidazol-4-yl ] will]Methyl radical]-2-Nitro-1H-imidazole (2.1g, 6.2mmol) was dissolved in acetic acid (50ml), iron powder (3.5g, 62mmol) was added and the resulting mixture was stirred at 60 ℃ for 2H. After addition of ethyl acetate (200ml), the hot mixture was heated to reflux and filtered. All volatile components were removed in vacuo and the residual acid was removed by co-evaporation with toluene. The obtained semi-solid was chromatographed [ silica, gradient elution: dichloromethane to 100% (dichloromethane/methanol/aqueous ammonium hydroxide solution ═ 90: 10: 1)]The free base of the title compound (1.9g, 100%) was isolated as an off-white solid. After treatment with HCl in methanol, ether was added to isolate the title compound as a white crystalline solid. Mp.164-165 ℃ (methanol/diethyl ether), MS: 308(M + H) M/e+)。
Example 105-107 was prepared according to the general procedure described in example 104.
Example 105
1- [1- (4-chloro-3-methyl-phenyl) -1H-imidazol-4-yl-methyl]-1H-imidazol-2-yl-amine hydrochloride (1: 2)
Will 1- [ [1-(4-chloro-3-methylphenyl) -1H-imidazol-4-yl]Methyl radical]-2-nitro-1H-imidazole was reacted with iron in acetic acid. After filtration, evaporation and chromatographic purification, the free base of the title compound is isolated. It was converted to its white hydrochloride salt. Mp.230-233 ℃ (methanol/diethyl ether), MS: 288(M + H)+)。
Example 106
1- (1-p-tolyl-1H-imidazol-4-yl-methyl) -1H-imidazol-2-yl-amine hydrochloride (1: 2)
1- [ [1- (4-methylphenyl) -1H-imidazol-4-yl]Methyl radical]-2-nitro-1H-imidazole was reacted with iron in acetic acid. After filtration, evaporation and chromatographic purification, the free base of the title compound is isolated. It was converted to its white hydrochloride salt. Mp.232-233 ℃ (methanol/diethyl ether), MS: 253 (M/e)+)。
Example 107
1- (1-phenyl-1H-imidazol-4-yl-methyl) -1H-imidazol-2-yl-amine hydrochloride (1: 2)
2-nitro-1- [ (1-phenyl-1H-imidazol-4-yl) methyl]-1H-imidazole is reacted with iron in acetic acid. After filtration, evaporation and chromatographic purification, the free base of the title compound is isolated. It was converted to its white hydrochloride salt. Mp.153-155 ℃ (methanol/diethyl ether), MS: 239 (M) for M/e+)。
Example 108
1- [ [1- (3, 4-dichlorophenyl) -1H-imidazol-4-yl]Methyl radical]-2, 5-dimethyl-1H-imidazole hydrochloride (1: 2)
Reacting N- [1- (3, 4-dichloro-phenyl) -1H-imidazol-4-ylmethyl]A suspension of thioacetamide (0.60g, 2.0mmol) in acetone (10ml) was treated with potassium carbonate (0.28g, 2.0mmol) and iodomethane (0.26g, 1.8 mmol). The mixture was refluxed for 1 hour, evaporated and suspended in ethanol (3 ml). After addition of propargylamine (1.1g, 20mmol), it was refluxed for 9 hours. After filtration and evaporation, the residue is purified by chromatography [ silica ]Gradient elution: dichloromethane to 30% (dichloromethane/methanol/aqueous ammonium hydroxide solution ═ 90: 10: 1)]The free base of the title compound (0.20g, 28%) was isolated as a light brown oil. After treatment with HCl in methanol, ether was added to isolate the title compound as a white crystal. Mp. > 250 ℃ (methanol/diethyl ether), MS: 321(M + H) M/e+)。
Example 109
{1- [1- (3, 4-dichloro-phenyl) -1H-imidazol-4-yl-methyl]-1H-imidazol-2-yl } -methanol
Reacting 1- [1- (3, 4-dichloro-phenyl) -1H-imidazol-4-ylmethyl]A solution of (E) -1H-imidazole-2-carbaldehyde (0.52g, 1.6mmol) in methanol (16ml) was treated with sodium borohydride (0.12g, 3.2 mmol). The mixture was stirred at room temperature for 2 hours. Then, all volatiles were evaporated and the residue was partitioned (ethyl acetate/water). The organic phase was dried (sodium sulfate) and concentrated to about 30 ml. The title compound was obtained as a white crystalline material (0.21g, 41%). Mp.202-203 ℃ (ethyl acetate), MS: 322 (M/e)+)。
Example 110
N- {1- [1- (3, 4-dichloro-phenyl) -1H-imidazol-4-yl-methyl]-1H-imidazol-2-yl } -acetamide
1- [1- (3, 4-dichloro-phenyl) -1H-imidazol-4-yl-methyl]A solution of (1.0g, 3.2mmol) of (1H) -imidazol-2-ylamine in THF (32ml) was treated with triethylamine (0.33g, 3.2mmol) and acetyl chloride (0.25g, 3.2mmol) at room temperature. The mixture was stirred at room temperature for 2 hours, filtered and the organic phase was evaporated to dryness. After chromatography [ silica, gradient elution: dichloromethane to 50% (dichloromethane/methanol/aqueous ammonium hydroxide solution ═ 90: 10: 1)]After this time, the title compound (0.19g, 17%) was isolated as a light brown solid. Mp. > 236 ℃ (decomposed) (ethyl acetate), MS: 350(M + H) M/e+)。
Example 111
{1- [1- (3, 4-dichloro-phenyl) -1H-imidazol-4-yl-methyl]-1H-imidazol-2-yl } -ethyl-amine hydrochloride
(1∶2)
Mixing N- {1- [1- (3, 4-dichloro-phenyl) -1H-imidazol-4-ylmethyl]-1H-imidazol-2-yl } -acetamide (0.30g, 0.86mmol) with 1M BH3THF complex (1.6ml) was treated and refluxed for 2 hours. The mixture was cooled to 5 ℃ and methanol (5ml) was added slowly. After all the volatiles were distilled off, the residue was added to 2N HCl solution (3ml) and refluxed for 20 min. The mixture was cooled and 2N NaOH solution (3ml) was added. After extraction with ethyl acetate (50ml), the organic phase was dried (sodium sulphate) and evaporated to dryness. Chromatographic purification [ silica, gradient elution: dichloromethane to 50% (dichloromethane/methanol/aqueous ammonium hydroxide solution ═ 90: 10: 1)]To give the free base of the title compound. After workup with HCl in methanol, the title compound was isolated as a yellow-white crystalline material by addition of diethyl ether (0.062g, 22%). Mp. > 250 ℃ (methanol/diethyl ether), MS: 336(M + H) M/e+)。
Example 112
1- (3, 4-dichloro-phenyl) -3- (2-methyl-imidazol-1-yl-methyl) -1H-pyrazole hydrochloride (1: 1)
A solution of 1- (3, 4-dichloro-phenyl) -3-methyl-1H-pyrazole (1.4g, 6.1mmol) in carbon tetrachloride was treated with N-bromosuccinimide (1.2g, 6.8mmol) and a catalytic amount of 2, 2' -azobis- (isobutyronitrile). The mixture was refluxed for 2 hours, cooled, filtered and evaporated. The oily residue was dissolved in DMF (10ml) and added to a solution of deprotonated 2-methylimidazole (0.60g, 7.3mmol) with sodium hydride (0.32g, 7.3mmol, see example 1) in DMF (10 ml). After stirring at room temperature for 12 hours, the volatiles were removed in vacuo and the resulting residue was dissolved in ethyl acetate. The organic phase was washed with water (3 times), dried (sodium sulfate) and concentrated. Chromatographic purification [ silica, gradient elution: dichloromethane to 60% (dichloromethane/methanol/aqueous ammonium hydroxide solution ═ 90: 10: 1)]The free base of the title compound (0.98g, 52%) was obtained as a light brown oil.After treatment with HCl in methanol, ether was added to isolate the title compound as a white crystal. Mp.204-205 ℃ (methanol/diethyl ether), MS: 306 (M/e)+)。
Example 113
1- (3, 4-dichloro-phenyl) -4-imidazol-1-yl-methyl-1H-pyrazole
Sodium hydride (0.24g of 55% dispersion in mineral oil, 5.5mmol) was slowly added to a solution of imidazole (0.19g, 2.8mmol) in DMF (15 ml). After 30 min at 60 ℃, the mixture was cooled in an ice bath and 4-chloromethyl-1- (3, 4-dichloro-phenyl) -1H-pyrazole (0.50g, 1.9mmol) was added in one portion. The resulting mixture was stirred at 20 ℃ for 1 hour. After evaporation of the solvent, the residue is dissolved in ethyl acetate, washed with water, dried (sodium sulfate) and chromatographed [ silica, gradient elution: dichloromethane to 30% (dichloromethane/methanol/aqueous ammonium hydroxide solution ═ 90: 10: 1)]0.23g (41%) of the title compound is obtained. Mp.103-104 ℃ (isopropyl ether), MS: m/e 293(M + H)+)
Example 114 was prepared by the general procedure of the method described in example 113.
Example 114
1- (3, 4-dichloro-phenyl) -4- (2-methyl-imidazol-1-yl-methyl) -1H-pyrazole
The 2-methylimidazole is deprotonated with sodium hydride and then treated with 4-chloromethyl-1- (3, 4-dichloro-phenyl) -1H-pyrazole. Extraction and chromatography gave the title compound as a white crystalline solid. Mp.176-177 ℃ (ethyl acetate), MS: 307(M + H) M/e+)。
Example 115
1- (3, 4-dichlorophenyl) -4- [1- (1H-imidazol-1-yl) ethyl]-1H-imidazole and
1- (3, 4-dichlorophenyl) -3-chloro-4- [1- (1H-imidazol-1-yl) ethyl]-1H-imidazole
1- [1- (3, 4-dichloro-phenyl) -1H-imidazol-4-yl]A mixture of ethanol (0.2g, 0.78mmol) and thionyl chloride (3ml, excess) was stirred at room temperature for 1.5 h. The solvent was removed by a gentle stream of air. Imidazole (3.5g, excess) was then added to the residue and the mixture was stirred at 90 ℃ for 30 minutes. After addition of water (10ml), the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and the solvent was evaporated. The residue is chromatographed (silica, eluent: dichloromethane/methanol/aqueous ammonium hydroxide 140: 10: 1) to give 1- (3, 4-dichlorophenyl) -4- [1- (1H-imidazol-1-yl) ethyl as a pale brown solid]-1H-imidazole (82mg, 34%) [ MS: 306.1 (M/e)+)]And a light yellow oily by-product (1- (3, 4-dichlorophenyl) -3-chloro-4- [1- (1H-imidazole-1-yl) ethyl)]-1H-imidazole, 102mg, 38%). MS: 341.1(M + H)+)。
Example 116 was prepared by the general procedure described in example 115.
Example 116
1- [1- [1- (3, 4-dichlorophenyl) -1H-imidazol-4-yl]Ethyl radical]-2-methyl-1H-imidazole
1- [1- (3, 4-dichloro-phenyl) -1H-imidazol-4-yl]Treatment of ethanol with thionyl chloride, followed by 2-methylimidazole, after extractive workup and chromatography, gives the title compound as a light brown solid. MS: 320.1 (M/e ═ M+)。
Example 117
1- (3, 4-dichlorophenyl) -4- [1- (1H-imidazol-1-yl) -1-methylethyl]-1H-imidazole
Reacting 2- [1- (3, 4-dichloro-phenyl) -1H-imidazol-4-yl]A mixture of propan-2-ol (150mg, 0.55mmol) and boron tribromide (1M in dichloromethane, 3ml) was stirred at room temperature for 2 hours. After removal of the solvent in an air stream, the residue was dried overnight. Imidazole (226mg, 33.2mmol) was added and the mixture was stirred at 100 deg.CStirring for 45 minutes. After addition of water, the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulphate), evaporated and the residue chromatographed (silica, eluting first with ethyl acetate and then with dichloromethane/methanol 95: 5) to give the title compound (15mg, 8%) as a pale yellow solid. MS: 320.0 (M/e ═ M+)。
Example 118
2-methyl-1- [ [4- [3- (trifluoromethyl) phenyl ] methyl ester]-1H-imidazol-2-yl]Methyl radical]-1H-imidazole hydrochloride (1: 2)
2- [ (2-methyl-1H-imidazol-1-yl) methyl]-4- [3- (trifluoromethyl) phenyl]-1- [ [2- (trimethylsilyl) ethoxy ] group]Methyl radical]-1H-imidazole (0.034g, 0.078mmol) was dissolved in ethanol (0.8ml) and treated with 2N HCl (0.86 ml). The reaction mixture was refluxed overnight, cooled to room temperature and concentrated. The crude residue was added to ethyl acetate and stirred at room temperature for 30 minutes. Filtering to obtain 2-methyl-1- [ [4- [3- (trifluoromethyl) phenyl group]-1H-imidazol-2-yl]Methyl radical]-1H-imidazole hydrochloride (24mg, 81%) as a light yellow solid, MS: 307.2(M + H) M/e+)。
Example 119-122 was prepared according to the general procedure described in example 118.
Example 119
1- [ [4- (4-fluoro-3-methylphenyl) -1H-imidazol-2-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride (1: 2)
The title compound, MS: 270.1 (M/e)+) From 4- (4-fluoro-3-methylphenyl) -2- [ (2-methyl-1H-imidazol-1-yl) methyl]-1- [ [2- (trimethylsilyl) ethoxy ] group]Methyl radical]-1H-imidazole preparation.
Example 120
1- [ [4- (3, 4-difluorophenyl) -1H-imidazol-2-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride (1: 2)
The title compound, MS: 275.2 (M/e ═ M+H+) From 4- (3, 4-difluorophenyl) -2- [ (2-methyl-1H-imidazol-1-yl) methyl]-1- [ [2- (trimethylsilyl) ethoxy ] group]Methyl radical]-1H-imidazole preparation.
Example 121
2-methyl-1- [ [4- [4- (methylthio) phenyl ] methyl ester]-1H-imidazol-2-yl]Methyl radical]-1H-imidazole hydrochloride (1: 2)
The title compound, MS: 285.2(M + H)+) From 2- [ (2-methyl-1H-imidazol-1-yl) methyl]-4- [4- (methylthio) phenyl]-1- [ [2- (trimethylsilyl) ethoxy ] group]Methyl radical]-1H-imidazole preparation.
Example 122
4- (4-fluoro-3-methylphenyl) -2- (1H-imidazol-1-yl-methyl) -1H-imidazole hydrochloride (1: 2)
The title compound, MS: 257.1(M + H)+) From 4- (4-fluoro-3-methylphenyl) -2- (1H-imidazol-1-yl-methyl) -1- [ [2- (trimethylsilyl) ethoxy]Methyl radical]-1H-imidazole preparation.
Example 123
3- (3, 4-dichloro-phenyl) -5- (2-methyl-imidazol-1-yl-methyl) -pyridine hydrochloride (1: 1)
To a solution of sodium hydride (17mg, 55% dispersion in mineral oil, 0.39mmol) in DMF (5ml) was added 2-methylimidazole (32mg, 0.39 mmol). The mixture was stirred at 20 ℃ for 1.5 hours. Subsequently, 3-chloromethyl-5- (3, 4-dichloro-phenyl) -pyridine hydrochloride (1: 1) (100mg, 0.32mmol) and triethylamine (78mg, 0.78mmol) were added and the mixture was heated at 100 ℃ for 4 hours. After cooling, DMF was distilled off and the residue was directly chromatographed [ silica, eluent: dichloromethane/(2 MNH)3Methanol solution) 85: 15]The free base of the title compound was obtained as a yellow oil. This material was dissolved in methanol, cooled to 4 ℃ with stirring, and treated with HCl/ethanol (1.46M, 1.1 equiv.) for 15 minutes. Evaporating the solvent, and vacuum drying at 50 deg.C for 2 hr to obtainTo the title compound (71mg, 62%) as a pale yellow solid. MS: 317.1 (M/e)+)。
Example 124-127 was prepared according to the general procedure described in example 123.
Example 124
4- (3, 4-dichloro-phenyl) -2- (2-methyl-imidazol-1-yl-methyl) -pyridine hydrochloride (1: 1)
Reaction of 2-chloromethyl-3- (3, 4-dichloro-phenyl) -pyridine hydrochloride (1: 1) with 2-methylimidazole using sodium hydride and triethylamine as bases followed by the formation of the hydrochloride salt gave the title compound, MS: 317.0 (M/e ═ M+) As a light brown solid (60% yield).
Example 125
2- (3, 4-dichloro-phenyl) -4- (2-methyl-imidazol-1-yl-methyl) -pyridine hydrochloride (1: 2)
Reaction of 4-chloromethyl-2- (3, 4-dichloro-phenyl) -pyridine hydrochloride (1: 1) with 2-methylimidazole using sodium hydride and triethylamine as bases followed by the formation of the hydrochloride salt gave the title compound, MS: 317.0 (M/e ═ M+) As a beige solid (51% yield).
Example 126
3- (3, 4-dichloro-phenyl) -5-imidazol-1-yl-methyl-pyridine hydrochloride (1: 1)
3-chloromethyl-5- (3, 4-dichloro-phenyl) -pyridine hydrochloride (1: 1) was reacted with imidazole using sodium hydride and triethylamine as bases followed by the hydrochloride salt to give the title compound as a solid (56% yield), MS: 304.1(M + H) M/e+)。
Example 127
3- (3, 4-dichloro-phenyl) -5- (2-ethyl-imidazol-1-yl-methyl) -pyridine hydrochloride (1: 1)
Reaction of 3-chloromethyl-5- (3, 4-dichloro-phenyl) -pyridine hydrochloride (1: 1) with 2-ethylimidazole using sodium hydride and triethylamine as bases followed by the formation of the hydrochloride salt gave the title compound, MS: 332.2(M + H) M/e+) As an orange solid (49% yield).
Example 128
5- (3, 4-dimethyl-phenyl) -2-methyl-3- (2-methyl-imidazol-1-yl-methyl) -pyridine hydrochloride (1: 1)
3-chloromethyl-5- (3, 4-dimethyl-phenyl) -2-methyl-pyridine hydrochloride (1: 1) was reacted with 2-methylimidazole (5 equivalents) using sodium hydride (3 equivalents) as the base followed by the formation of the hydrochloride salt to give the title compound, MS: 292.2(M + H)+) As a beige solid (77% yield).
Example 129
3- (4-chloro-phenyl) -5- (2-methyl-imidazol-1-yl-methyl) -pyridine hydrochloride (1: 1)
A mixture of 3-bromo-5- (2-methyl-imidazol-1-ylmethyl) -pyridine (120mg, 0.48mmol), bis (triphenylphosphine) palladium (II) chloride (10mg, 0.01mmol) and potassium acetate (140mg, 0.14mmol) was stirred in dioxane (10ml) at 20 ℃ for 1 hour. 4-Chlorophenylboronic acid (78mg, 0.05mmol) and a 2N sodium carbonate solution (1.2ml) were then added, and the mixture was heated at 100 ℃ for 7 to 24 hours under an argon atmosphere. After cooling, the solvent was evaporated, and 2N sodium hydroxide (5ml) and ethyl acetate were added. The mixture was shaken. The mixture was shaken and the aqueous phase was separated, further extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was chromatographed [ silica, eluent: dichloromethane/(2M NH)3Methanol solution) 97: 3]. The product was dissolved in methanol, cooled to 4 ℃ with stirring and treated with HCl/ethanol (1.46M, 1.1 eq.) for 45 minutes. The solvent was distilled off, and dried under high vacuum at 50 ℃ for 2 hours to give the title compound (98mg, 64%) as a pale brown solidAnd (3) a body. MS: 284.2(M + H) M/e+)。
Example 130-142 was prepared according to the general procedure described in example 129.
Example 130
3- (3, 4-dimethyl-phenyl) -5- (2-methyl-imidazol-1-yl-methyl) -pyridine hydrochloride (1: 1)
Reaction of 3-bromo-5- (2-methyl-imidazol-1-ylmethyl) -pyridine with 3, 4-dimethylphenylboronic acid gave the title compound as a pale yellow foam (54% yield), MS: m/e 277 (M)+)。
Example 131
3- (4-fluoro-3-methyl-phenyl) -5- (2-methyl-imidazol-1-yl-methyl) -pyridine hydrochloride (1: 1)
Reaction of 3-bromo-5- (2-methyl-imidazol-1-ylmethyl) -pyridine with 4-fluoro-3-methyl-phenylboronic acid gave the title compound as a light brown foam (63% yield), MS: 281.1 (M/e ═ M+)。
Example 132
3- (3, 4-difluoro-phenyl) -5- (2-methyl-imidazol-1-yl-methyl) -pyridine hydrochloride (1: 1)
Reaction of 3-bromo-5- (2-methyl-imidazol-1-ylmethyl) -pyridine with 3, 4-difluoro-phenylboronic acid gave the title compound as a light yellow foam (85% yield), MS: 286.2(M + H)+)。
Example 133
3- (4-fluoro-phenyl) -5- (2-methyl-imidazol-1-yl-methyl) -pyridine hydrochloride (1: 1)
Reaction of 3-bromo-5- (2-methyl-imidazol-1-ylmethyl) -pyridine with 4-fluorophenylboronic acid gave the title compound as a light yellow solid (90% yield), MS: 268.3(M + H)+)。
Example 134
3- (2-methyl-imidazol-1-yl-methyl) -5- (3-trifluoromethyl-phenyl) -pyridine hydrochloride (1: 1)
Reaction of 3-bromo-5- (2-methyl-imidazol-1-ylmethyl) -pyridine with 3-trifluoromethylphenylboronic acid gave the title compound as a beige foam (74% yield), MS: m/e 318.3(M + H)+)。
Example 135
3- (2-methyl-imidazol-1-yl-methyl) -5- (4-trifluoromethyl-phenyl) -pyridine hydrochloride (1: 1)
Reaction of 3-bromo-5- (2-methyl-imidazol-1-yl-methyl) -pyridine with 4-trifluoromethylphenylboronic acid gave the title compound as a beige solid (77% yield), MS: m/e 318.3(M + H)+)，。
Example 136
3- (3-chloro-4-methyl-phenyl) -5- (2-methyl-imidazol-1-yl-methyl) -pyridine hydrochloride (1: 1)
Reacting 3-bromo-5- (2-methyl-imidazol-1-yl-methyl) -pyridine with 2- (3-chloro-4-methyl-phenyl) -4, 4, 5, 5-tetramethyl [1, 3, 2]Dioxaborolane reaction to give the title compound as a beige solid (78% yield), MS: 298.3(M + H) M/e+)。
Example 137
3- (4-chloro-3-methyl-phenyl) -5- (2-methyl-imidazol-1-yl-methyl) -pyridine hydrochloride (1: 1)
Reacting 3-bromo-5- (2-methyl-imidazol-1-yl-methyl) -pyridine with 2- (4-chloro-3-methyl-phenyl) -4, 4, 5, 5-tetramethyl [1, 3, 2]Dioxaborolane reaction to give the title compound as a white solid (73% yield), MS: 298.3(M + H) M/e+)。
Example 138
3- (2, 3-dihydro-benzofuran-5-yl) -5- (2-methyl-imidazol-1-yl-methyl) -pyridine hydrochloride (1: 1)
Reacting 3-bromo-5- (2-methyl-imidazol-1-yl-methyl) -pyridine with 5- (4, 4, 5, 5-tetramethyl [1, 3, 2-methyl-)]Dioxaborolan-2-yl) -2, 3-dihydro-benzofuran to give the title compound as a pale yellow foam (18% yield), MS: 292.2(M + H)+)。
Example 139
3-indan-5-yl-5- (2-methyl-imidazol-1-yl-methyl) -pyridine hydrochloride (1: 1)
Reacting 3-bromo-5- (2-methyl-imidazol-1-ylmethyl) -pyridine with 2-indan-5-yl-4, 4, 5, 5-tetramethyl [1, 3, 2%]Dioxaborolane reaction to give the title compound as a white solid (91% yield), MS: 289.1 (M/e ═ M+)。
Example 140
3- (3-chloro-4-fluoro-phenyl) -5- (2-methyl-imidazol-1-yl-methyl) -pyridine hydrochloride (1: 1)
Reaction of 3-bromo-5- (2-methyl-imidazol-1-yl-methyl) -pyridine with 3-chloro-4-fluoro-phenylboronic acid gave the title compound as a yellow solid (53% yield), MS: 301.1 (M/e)+)。
Example 141
3- (4-chloro-3-trifluoromethyl-phenyl) -5- (2-methyl-imidazol-1-yl-methyl) -pyridine hydrochloride (1: 1)
Reacting 3-bromo-5- (2-methyl-imidazol-1-yl-methyl) -pyridine with 2- (4-chloro-3-trifluoromethyl-phenyl) -4, 4, 5, 5-tetramethyl- [1, 3, 2]Dioxaborolane reaction to give the title compound as a beige foam (49% yield), MS: 352.3(M + H)+)。
Example 142
3- (4-fluoro-3-trifluoromethyl-phenyl) -5- (2-methyl-imidazol-1-yl-methyl) -pyridine hydrochloride (1: 1)
Reacting 3-bromo-5- (2-methyl-imidazol-1-ylmethyl) -pyridine with 2- (4-fluoro-3-trifluoromethyl-phenyl) -4, 4, 5, 5-tetramethyl- [1, 3, 2]Dioxaborolane reaction to give the title compound as a white solid (60% yield), MS: 336.3(M + H) M/e+)。
Example 143
2-ethyl-1- [ [1- [3- (trifluoromethylthio) phenyl ] methyl ester]-1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride
(1∶2)
Following the general procedure described in example 10, [1- (3-trifluoromethylsulfanyl-phenyl) -1H-imidazol-4-yl]Reaction of methanol with thionyl chloride, then with 2-ethylimidazole and sodium hydride, followed by chromatography and crystallization of the hydrochloride salt gave the title compound as a white crystalline material, mp.234-236 ℃ (methanol/diethyl ether), MS: 353(M + H)+)。
Example 144
2-methyl-1- [ [1- [3- (trifluoromethylthio) phenyl ] methyl]-1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride
(1∶2)
Following the general procedure described in example 10, [1- (3-trifluoromethylsulfanyl-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-methylimidazole and sodium hydride, followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a white crystalline material, mp.169-170 ℃ (methanol/diethyl ether), MS: 339(M + H) M/e+)。
Example 145
4-Imidazol-1-ylmethyl-1- (3-methylsulfanyl-phenyl) -1H-imidazole hydrochloride (1: 2)
As described in example 10General procedure [1- (3-trifluoromethylsulfanyl-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then imidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt gave the title compound as a white crystalline material, mp.213-215 ℃ (methanol/diethyl ether), MS: 325(M + H) M/e+)。
Example 146
1- [ [1- [3- (1, 1-difluoroethyl) phenyl]-1H-imidazol-4-yl]Methyl radical]-2-ethyl-1H-imidazole hydrochloride
(1∶2)
Following the general procedure described in example 10, {1- [3- (1, 1-difluoro-ethyl) -phenyl ] -ethyl]-1H-imidazol-4-yl } -methanol was first reacted with thionyl chloride, then 2-ethylimidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt to give the title compound as an off-white crystalline material, mp.130-134 ℃ (decomposed) (methanol/ether), MS: 317(M + H) M/e+)。
Example 147
1- [ [1- [3- (1, 1-difluoroethyl) phenyl]-1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride
(1∶2)
Following the general procedure described in example 10, {1- [3- (1, 1-difluoro-ethyl) -phenyl ] -ethyl]-1H-imidazol-4-yl } -methanol was first reacted with thionyl chloride, then 2-methylimidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt to give the title compound as an off-white crystalline material, Mp. > 200 ℃ (decomposed) (methanol/ether), MS: m/e 303(M + H)+)。
Example 148
1- [3- (1, 1-difluoroethyl) -phenyl]-4-imidazol-1-ylmethyl-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, {1- [3- (1, 1-difluoro-ethyl)-phenyl radical]-1H-imidazol-4-yl } -methanol was first reacted with thionyl chloride, then imidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt to give the title compound as an off-white crystalline material, Mp. > 200 ℃ (decomposed) (methanol/ether), MS: m/e 303(M + H)+)。
Example 149
1- [ [1- [3- (1, 1-difluoroethyl) -4-fluorophenyl)]-1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazolium salt
Acid salt (1: 2)
Following the general procedure described in example 10, {1- [3- (1, 1-difluoro-ethyl) -4-fluoro-phenyl]-1H-imidazol-4-yl } -methanol was first reacted with thionyl chloride, then 2-methylimidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt to give the title compound as an off-white crystalline material, Mp. > 200 ℃ (decomposed) (methanol/ether), MS: 321(M + H) M/e+)。
Example 150
1- [3- (1, 1-difluoro-ethyl) -4-fluoro-phenyl]-4-imidazol-1-ylmethyl-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, {1- [3- (1, 1-difluoro-ethyl) -4-fluoro-phenyl]-1H-imidazol-4-yl } -methanol was first reacted with thionyl chloride, then imidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt to give the title compound as an off-white crystalline material, Mp. > 200 ℃ (decomposed) (methanol/ether), MS: 307(M + H) M/e+)。
Example 151
1- [ [1- [3- (1, 1-difluoroethyl) -4-fluorophenyl)]-1H-imidazol-4-yl]Methyl radical]-2-ethyl-1H-imidazolium salt
Acid salt (1: 2)
Following the general procedure described in example 10, {1- [3- (1, 1-difluoro-ethyl) -4-fluoro-Phenyl radical]-1H-imidazol-4-yl } -methanol was first reacted with thionyl chloride, then 2-ethylimidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt to give the title compound as an off-white crystalline material, Mp. > 200 ℃ (decomposed) (methanol/ether), MS: 335(M + H) M/e+)。
Example 152
1- [ [1- (3-isopropylphenyl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride
(1∶2)
Following the general procedure described in example 10, [1- (3-isopropyl-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride and then with 2-methylimidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a yellowish white crystalline material, Mp. > 200 ℃ (decomposition) (methanol/diethyl ether), MS: 281(M + H) M/e+)。
Example 153
2-ethyl-1- [ [1- (3-isopropylphenyl) -1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-isopropyl-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-ethylimidazole and sodium hydride, followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a yellowish white crystalline material, Mp. > 200 ℃ (decomposed) (methanol/diethyl ether), MS: 295(M + H)+)。
Example 154
4-Imidazol-1-ylmethyl-1- (3-isopropyl-phenyl) -1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-isopropyl-phenyl) -1H-imidazol-4-yl]Methanol is first reacted with thionyl chloride, then imidazole and sodium hydride, and subsequentlyChromatography and crystallization of the hydrochloride salt gave the title compound as a yellow-white crystalline material, mp.200-206 ℃ (methanol/diethyl ether), MS: 267(M + H)+)。
Example 155
2-methyl-1- [ [1- (naphthalen-2-yl) -1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, (1-naphthalen-2-yl-1H-imidazol-4-yl) -methanol was reacted first with thionyl chloride, then 2-methylimidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a white crystalline material, mp.247-248 ℃ (methanol/diethyl ether), MS: 288 (M/e)+)。
Example 156
1- [ [1- (3-bromo-4-fluorophenyl) -1H-imidazol-4-yl]Methyl radical]-2-ethyl-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-bromo-4-fluoro-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-ethylimidazole and sodium hydride, followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a white crystalline material, mp.238-239 ℃ (methanol/diethyl ether), MS: 349(M + H) M/e+)。
Example 157
1- [ [1- (3-bromo-4-fluorophenyl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-bromo-4-fluoro-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-methylimidazole and sodium hydride, followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a white crystalline material, mp.232-233 ℃ (methanol/diethyl ether), MS: 335(M + H) M/e+)
Example 158
1- (3-bromo-4-fluoro-phenyl) -4-imidazol-1-ylmethyl-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-bromo-4-fluoro-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then imidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt gave the title compound as a white crystalline material, mp.229-230 ℃ (methanol/diethyl ether), MS: 321(M + H) M/e+)。
Example 159
1- [ [1- (3-ethylphenyl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-ethyl-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride and then with 2-methylimidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a yellowish white crystalline material, Mp. > 200 ℃ (decomposition) (methanol/diethyl ether), MS: 267(M + H)+)。
Example 160
2-ethyl-1- [ [1- (3-ethylphenyl) -1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-ethyl-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-ethylimidazole and sodium hydride, followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a yellowish white crystalline material, Mp. > 200 ℃ (decomposed) (methanol/diethyl ether), MS: 281(M + H) M/e+)。
Example 161
1- (3-Ethyl group-phenyl) -4-imidazol-1-ylmethyl-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-ethyl-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with imidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a yellowish white crystalline material, Mp. > 190 ℃ (decomposition) (methanol/ether), MS: 253(M + H) M/e+)。
Example 162
1- [ [1- (3-cyclopropylphenyl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-cyclopropyl-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-methylimidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a light brown crystalline material, mp.174-175 ℃ (methanol/diethyl ether), MS: 279(M + H) M/e+)。
Example 163
1- [ [1- (3-difluoromethyl-4-fluorophenyl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride
(1∶2)
Following the general procedure described in example 10, [1- (3-difluoromethyl-4-fluorophenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-methylimidazole and sodium hydride, followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a white crystalline material, mp.223-225 ℃ (decomposition) (methanol/diethyl ether), MS: 306 (M/e)+)。
Example 164
1- [ [1- (3-difluoromethyl-4-fluorophenyl) -1H-imidazol-4-yl]Methyl radical]-2-ethyl-1H-imidazolium salt
Acid salts
(1∶2)
Following the general procedure described in example 10, [1- (3-difluoromethyl-4-fluorophenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-ethylimidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a white crystalline material, mp.229-232 ℃ (methanol/diethyl ether), MS: 320 (M/e) ═ M/e+)。
Example 165
1- (3-difluoromethyl-4-fluoro-phenyl) -4-imidazol-1-ylmethyl-1H-imidazole hydrochloride
Following the general procedure described in example 10, [1- (3-difluoromethyl-4-fluoro-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with imidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt gave the title compound as a white crystalline material, mp.239-241 ℃ (methanol/diethyl ether), MS: 292 (M/e)+)。
Example 166
2-ethyl-1- [ [1- [3- (methylthio) phenyl ] methyl ester]-1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-methylsulfanyl-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-ethylimidazole and sodium hydride, followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a yellowish white crystalline material, Mp. > 200 ℃ (decomposed) (methanol/diethyl ether), MS: 299(M + H)+)。
Example 167
2-methyl-1- [ [1- [3- (methylthio) phenyl ] methyl ester]-1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-methylsulfanyl-phenyl)) -1H-imidazol-4-yl]Methanol first with thionyl chloride and then with 2-methylimidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a yellowish white crystalline material, Mp. > 200 ℃ (decomposition) (methanol/diethyl ether), MS: 285(M + H) M/e+)。
Example 168
4-Imidazol-1-ylmethyl-1- (3-methylsulfanyl-phenyl) -1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-methylsulfanyl-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with imidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a yellowish white crystalline material, Mp. > 200 ℃ (decomposed) (methanol/ether), MS: 271(M + H)+)。
Example 169
2-ethyl-1- [ [1- [3- (trifluoromethoxy) phenyl ] phenyl]-1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride
(1∶2)
Following the general procedure described in example 10, [1- (3-trifluoromethoxy-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-ethylimidazole and sodium hydride, followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a white crystalline material, mp.237-239 ℃ (methanol/diethyl ether), MS: 336 (M/e)+)。
Example 170
2-methyl-1- [ [1- [3- (trifluoromethoxy) phenyl ] methyl ester]-1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride
(1∶2)
Following the general procedure described in example 10, [1- (3-trifluoromethoxy-phenyl) -1H-imidazol-4-yl]Methanol is first reacted with thionyl chloride and then with 2-methylimidazole and hydrogenSodium reaction followed by chromatography and crystallization of the hydrochloride salt gave the title compound as a white crystalline material, mp.221-223 ℃ (methanol/diethyl ether), MS: 322 (M/e)+)。
Example 171
4-Imidazol-1-ylmethyl-1- (3-trifluoromethoxy-phenyl) -1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-trifluoromethoxy-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then imidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt gave the title compound as a white crystalline material, mp.233-234 ℃ (methanol/diethyl ether), MS: 308 (M/e)+)。
Example 172
2-methyl-1- [ [1- (3-vinylphenyl) -1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-vinyl-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-methylimidazole and sodium hydride, followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a white crystalline material, mp.207-208 ℃ (methanol/diethyl ether), MS: 265(M + H) M/e+)。
Example 173
1- [ [1- (3-chlorophenyl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-chloro-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-methylimidazole and sodium hydride, followed by chromatography and crystallization of the hydrochloride to give the title compound as a yellowish white crystalline substance, Mp. > 200 ℃ (decomposition) (methanol/diethyl ether)，MS：m/e＝273(M+H+)。
Example 174
1- [ [1- (3-chlorophenyl) -1H-imidazol-4-yl]Methyl radical]-2-ethyl-1H-imidazole hydrochloride
Following the general procedure described in example 10, [1- (3-chloro-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-ethylimidazole and sodium hydride, followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a yellowish white crystalline material, Mp. > 200 ℃ (decomposed) (methanol/diethyl ether), MS: 287(M + H)+)。
Example 175
1- (3-chloro-phenyl) -4-imidazol-1-ylmethyl-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-chloro-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with imidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a yellowish white crystalline material, Mp. > 200 ℃ (decomposed) (methanol/ether), MS: m/e-259 (M + H)+)。
Example 176
1- [ [1- (3-iodophenyl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-iodo-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride and then with 2-methylimidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a yellowish white crystalline material, Mp. > 222 ℃ (decomposition) (methanol/diethyl ether), MS: m/e is 365(M + H)+)。
Example 177
2-ethyl-1- [ [1- [ 3-fluoro-5- (trifluoromethyl) phenyl ] methyl ] phenyl]-1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride
(1∶2)
Following the general procedure described in example 10, [1- (3-fluoro-5-trifluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-ethylimidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a white crystalline material, mp.243-244 ℃ (methanol/diethyl ether), MS: 338 (M/e)+)。
Example 178
1- [ [1- [ 3-fluoro-5- (trifluoromethyl) phenyl ] phenyl]-1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride
(1∶2)
Following the general procedure described in example 10, [1- (3-fluoro-5-trifluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride and then with 2-methylimidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a white crystalline material Mp. > 250 ℃ (methanol/diethyl ether), MS: 325(M + H) M/e+)。
Example 179
1- (3-fluoro-5-trifluoromethyl-phenyl) -4-imidazol-1-ylmethyl-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-fluoro-5-trifluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then imidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt gave the title compound as a white crystalline material, mp.233-234 ℃ (methanol/diethyl ether), MS: 310 (M/e)+)。
Example 180
1- [ [1- [ 3-methoxy-5- (trifluoromethyl) phenyl group]-1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole salts
Acid salt (1: 2)
Following the general procedure described in example 10, [1- (3-methoxy-5-trifluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-methylimidazole and sodium hydride, followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a white crystalline material, mp.246-247 ℃ (methanol/diethyl ether), MS: 337(M + H) M/e+)。
Example 181
2-ethyl-1- [ [1- [ 3-methoxy-5- (trifluoromethyl) phenyl ] methyl ] phenyl]-1H-imidazol-4-yl]Methyl radical]-1H-imidazolium salts
Acid salt (1: 2)
Following the general procedure described in example 10, [1- (3-methoxy-5-trifluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-ethylimidazole and sodium hydride, followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a white crystalline material, mp.245-246 ℃ (methanol/diethyl ether), MS: 350M/e (M)+)。
Example 182
4-Imidazol-1-ylmethyl-1- (3-methoxy-5-trifluoromethyl-phenyl) -1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-methoxy-5-trifluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then imidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt gave the title compound as a white crystalline material, mp.244-246 ℃ (methanol/diethyl ether), MS: 322 (M/e)+)。
Example 183
1- [ [1- (3-tert-butylphenyl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-tert-butyl-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride and then with 2-methylimidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a yellowish white crystalline material, Mp. > 200 ℃ (decomposition) (methanol/diethyl ether), MS: 295(M + H)+)。
Example 184
1- [ [1- (3-tert-butylphenyl) -1H-imidazol-4-yl]Methyl radical]-2-ethyl-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-tert-butyl-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-ethylimidazole and sodium hydride, followed by chromatography and crystallization of the hydrochloride salt gave the title compound as a light brown crystalline material, mp.205 ℃ (decomposition) (methanol/diethyl ether), MS: 309M/e (M + H)+)。
Example 185
1- (3-tert-butyl-phenyl) -4-imidazol-1-ylmethyl-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-tert-butyl-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with imidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a yellowish white crystalline material, Mp. > 200 ℃ (decomposed) (methanol/ether), MS: 281(M + H) M/e+)。
Example 186
1- [ [1- [ 3-chloro-4- (trifluoromethoxy) phenyl ]]-1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloric acid
Salt (1: 2)
Following the general procedure described in example 10, [1- (3-chloro-4-trifluoromethoxy) was reactedphenyl-1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-methylimidazole and sodium hydride, followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a white crystalline material, mp.221-222 ℃ (methanol/diethyl ether), MS: 357(M + H)+)。
Example 187
1- [ [1- [ 3-chloro-4- (trifluoromethoxy) phenyl ]]-1H-imidazol-4-yl]Methyl radical]-2-ethyl-1H-imidazole hydrochloric acid
Salt (1: 2)
Following the general procedure described in example 10, [1- (3-chloro-4-trifluoromethoxy-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-ethylimidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a white crystalline material, Mp. > 250 ℃ (methanol/diethyl ether), MS: 370 (M/e) ═ M/e+)。
Example 188
1- (3-chloro-4-trifluoromethoxy-phenyl) -4-imidazol-1-ylmethyl-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-chloro-4-trifluoromethoxy-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then imidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt gave the title compound as a white crystalline material, mp.212-213 ℃ (methanol/diethyl ether), MS: 342 (M/e)+)。
Example 189
1- [ [1- [3- (difluoromethoxy) phenyl ] phenyl]-1H-imidazol-4-yl]Methyl radical]-2-ethyl-1H-imidazole hydrochloride
(1∶2)
Following the general procedure described in example 10, [1- (3-difluoromethoxy-phenyl) -1H-imidazol-4-yl]Methanol is first reacted with thionyl chloride, thenReaction with 2-ethylimidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt gave the title compound as a white crystalline material, mp.216-217C (methanol/diethyl ether), MS: 319(M + H) M/e+)。
Example 190
1- [ [1- [3- (difluoromethoxy) phenyl ] phenyl]-1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride
(1∶2)
Following the general procedure described in example 10, [1- (3-difluoromethoxy-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-methylimidazole and sodium hydride, followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a white crystalline material, mp.220-222 ℃ (methanol/diethyl ether), MS: 305(M + H) M/e+)。
Example 191
1- (3-difluoromethoxy-phenyl) -4-imidazol-1-ylmethyl-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-difluoromethoxy-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then imidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt gave the title compound as a white crystalline material, mp.205-206 ℃ (methanol/diethyl ether), MS: 291(M + H) M/e+)。
Example 192
1- [ [1- (3-bromophenyl) -1H-imidazol-4-yl)]Methyl radical]-2-methyl-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-bromo-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-methylimidazole and sodium hydride, followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a brownish yellow solidCrystalline material, mp.205-207 ℃ (methanol/diethyl ether), MS: 317(M + H) M/e+)。
Example 193
1- [ [1- [3- (difluoromethyl) phenyl ] phenyl]-1H-imidazol-4-yl]Methyl radical]-2-ethyl-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-difluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-ethylimidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a white crystalline material, mp.219-220 ℃ (methanol/diethyl ether), MS: m/e 303(M + H)+)。
Example 194
1- [ [1- [3- (difluoromethyl) phenyl ] phenyl]-1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-difluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-methylimidazole and sodium hydride, followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a white crystalline material, mp.195-196 ℃ (methanol/diethyl ether), MS: 289(M + H) M/e+)。
Example 195
1- (3-difluoromethyl-phenyl) -4-imidazol-1-ylmethyl-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-difluoromethyl-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with imidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt gave the title compound as a white crystalline material, mp.216-217C (methanol/diethyl ether), MS: 275(M + H) M/e+)。
Example 196
{1- [1- (3, 4-dichloro-phenyl) -1H-imidazol-4-ylmethyl]-1H-imidazol-2-yl } -methyl-amine hydrochloride
(1∶1)
Reacting 1- [1- (3, 4-dichloro-phenyl) -1H-imidazol-4-ylmethyl]A suspension of (1H) -imidazol-2-ylamine (0.7g, 2.3mmol) in triethyl orthoformate (10ml) was stirred at reflux for 2H. The reaction mixture was evaporated to dryness, dissolved in ethanol (10ml) and cooled in an ice bath. Sodium borohydride (0.091g, 2.4mmol) was added and the mixture was slowly warmed to 20 ℃. After 18 hours, ethyl acetate and brine were added and the organic phase was separated, dried (sodium sulfate) and concentrated. Chromatography [ silica, gradient elution: dichloromethane to 100% (dichloromethane/methanol/aqueous ammonium hydroxide solution ═ 90: 10: 1)]To give the free base of the title compound. It was crystallized as an off-white hydrochloride salt (0.25g, 16%). Mp. > 250 ℃ (methanol/diethyl ether), MS: 322(M + H) with M/e+)。
Example 197
[3- (3, 4-dichloro-phenyl) -5- (2-methylamino-imidazol-1-ylmethyl) -3H-imidazol-4-yl]-methanolic hydrochloric acid
Salt (1: 1)
Reacting {1- [1- (3, 4-dichloro-phenyl) -1H-imidazol-4-ylmethyl]A solution of-1H-imidazol-2-yl } -methyl-amine (0.60g, 1.7mmol) in acetic acid (7ml) and aqueous formaldehyde (2ml, 37% solution) was stirred at 20 ℃ for 96 hours. The reaction mixture was evaporated to dryness and chromatographed [ silica, gradient elution: dichloromethane to 50% (dichloromethane/methanol/aqueous ammonium hydroxide solution ═ 90: 10: 1)]To give the free base of the title compound. It was crystallized as a yellow-white hydrochloride salt (0.030g, 5%). Mp. > 180 ℃ (decomposition) (methanol/ether), MS: 352(M + H)+)。
Example 198
1- [ [1- (3-bromo-5-fluorophenyl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-bromo-5-fluoro-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride and then with 2-methylimidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a yellowish white crystalline material, Mp. > 200 ℃ (decomposition) (methanol/diethyl ether), MS: 335(M + H) M/e+)。
Example 199
1- [ [1- (3-bromo-5-fluorophenyl) -1H-imidazol-4-yl]Methyl radical]-2-ethyl-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-bromo-5-fluoro-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-ethylimidazole and sodium hydride, followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a yellowish white crystalline material, Mp. > 200 ℃ (decomposed) (methanol/diethyl ether), MS: 349(M + H) M/e+)。
Example 200
1- (3-bromo-5-fluoro-phenyl) -4-imidazol-1-ylmethyl-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-bromo-5-fluoro-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with imidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a yellowish white crystalline material, Mp. > 200 ℃ (decomposed) (methanol/ether), MS: 321(M + H) M/e+)。
Example 201
1- [ [1- (2, 2-difluoro-1, 3-benzodioxol-5-yl) -1H-imidazol-4-yl]Methyl radical]-2-ethyl group
-1H-imidazole hydrochloride (1: 2)
As described in example 10General procedure, [1- (2, 2-difluoro-benzo [1, 3 ]]Dioxol-5-yl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-ethylimidazole and sodium hydride, followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a white crystalline material, mp.237-239 ℃ (decomposition) (methanol/diethyl ether), MS: 333(M + H) M/e+)。
Example 202
1- [ [1- (2, 2-difluoro-1, 3-benzodioxol-5-yl) -1H-imidazol-4-yl]Methyl radical]-2-methyl
-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (2, 2-difluoro-benzo [1, 3 ] -c]Dioxol-5-yl) -1H-imidazol-4-yl]Methanol first with thionyl chloride and then with 2-methylimidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a white crystalline material Mp. > 250 ℃ (methanol/diethyl ether), MS: 319(M + H) M/e+)。
Example 203
1- (2, 2-difluoro-benzo [1, 3 ]]Dioxol-5-yl) -4-imidazol-1-ylmethyl-1H-imidazole hydrochloride
Salt (1: 2)
Following the general procedure described in example 10, [1- (2, 2-difluoro-benzo [1, 3 ] -c]Dioxol-5-yl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then imidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt gave the title compound as a white crystalline material, mp.245-246 ℃ (methanol/diethyl ether), MS: 319(M + H) M/e+)。
Example 204
2- [4- (2-methyl-imidazol-1-ylmethyl) -imidazol-1-yl]-quinolines
Following the general procedure described in example 10, (1-quinolin-2-yl-1H-imidazol-4-yl) -methanol was reacted first with thionyl chloride, then 2-methylimidazole and sodium hydride followed by chromatography and crystallization of the free base to give the title compound as an off-white crystalline material, mp.160 ℃ (ethyl acetate/hexane), MS: 290(M + H)+)。
Example 205
2- [4- (2-Ethyl-imidazol-1-ylmethyl) -imidazol-1-yl]-quinolines
Following the general procedure described in example 10, (1-quinolin-2-yl-1H-imidazol-4-yl) -methanol was reacted first with thionyl chloride, then 2-ethylimidazole and sodium hydride followed by chromatography and crystallization of the free base to give the title compound as an off-white crystalline material, Mp. > 80 ℃ (decomposed) (ethyl acetate/hexane), MS: 304(M + H) M/e+)。
Example 206
2- (4-imidazol-1-ylmethyl-imidazol-1-yl) -quinoline
Following the general procedure described in example 10, (1-quinolin-2-yl-1H-imidazol-4-yl) -methanol was reacted first with thionyl chloride, then imidazole and sodium hydride, followed by chromatography and crystallization of the free base to give the title compound as an off-white crystalline material, Mp. > 150 ℃ (decomposed) (ethyl acetate/hexane), MS: 276(M + H) M/e+)。
Example 207
1- [ [1- [ 3-chloro-4- (trifluoromethylthio) phenyl ] methyl ester]-1H-imidazol-4-yl]Methyl radical]-2-ethyl-1H-imidazole hydrochloric acid
Salt (1: 2)
Following the general procedure described in example 10, [1- (3-chloro-4-trifluoromethylsulfanyl-phenyl) -1H-imidazol-4-yl]Methanol is first reacted with thionyl chloride and then with 2-ethylimidazole and sodium hydride,subsequent chromatography and crystallization of the hydrochloride salt gave the title compound as a white crystalline material, mp.214-215 ℃ (methanol/diethyl ether), MS: m/e 387(M + H)+)。
Example 208
1- [ [1- [ 3-chloro-4- (trifluoromethylthio) phenyl ] methyl ester]-1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloric acid
Salt (1: 2)
Following the general procedure described in example 10, [1- (3-chloro-4-trifluoromethylsulfanyl-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-methylimidazole and sodium hydride, followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a white crystalline material, mp.195-198 ℃ (methanol/diethyl ether), MS: 373(M + H) with M/e+)。
Example 209
1- (3-chloro-4-trifluoromethylsulfanyl-phenyl) -4-imidazol-1-ylmethyl-1H-imidazole hydrochloride (1: 2)
Following the general procedure described in example 10, [1- (3-chloro-4-trifluoromethylsulfanyl-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then imidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt gave the title compound as a white crystalline material, mp.244-245 ℃ (methanol/diethyl ether), MS: 359(M + H)+)。
Example 210
3- [4- (2-Ethyl-imidazol-1-ylmethyl) -imidazol-1-yl]-quinolines
Following the general procedure described in example 10, (1-quinolin-3-yl-1H-imidazol-4-yl) -methanol was reacted first with thionyl chloride, then 2-ethylimidazole and sodium hydride followed by chromatography and crystallization of the free base to give the title compound as a white yellow crystalline material, mp.132-136 ℃ (ethyl acetate)Ethyl acetate/hexane), MS: 304(M + H) M/e+)。
Example 211
3- [4- (2-methyl-imidazol-1-ylmethyl) -imidazol-1-yl]-quinolines
Following the general procedure described in example 10, (1-quinolin-3-yl-1H-imidazol-4-yl) -methanol was reacted first with thionyl chloride, then 2-methylimidazole and sodium hydride followed by chromatography and crystallization of the free base to give the title compound as an off-white crystalline material, mp.168-172 ℃ (ethyl acetate/hexane), MS: 290(M + H)+)。
Example 212
5-chloro-2- [4- (2-methyl-imidazol-1-ylmethyl) -imidazol-1-yl]-pyridine
Following the general procedure described in example 10, [1- (5-chloro-pyridin-2-yl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-methylimidazole and sodium hydride, followed by chromatography and crystallization of the free base to give the title compound as a yellowish white crystalline material, mp.192-196 ℃ (ethyl acetate/hexane), MS: 274(M + H) for M/e+)。
Example 213
5-chloro-2- [4- (2-ethyl-imidazol-1-ylmethyl) -imidazol-1-yl]-pyridine
Following the general procedure described in example 10, [1- (5-chloro-pyridin-2-yl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-ethylimidazole and sodium hydride, followed by chromatography and crystallization of the free base to give the title compound as an off-white crystalline material, mp.182-185 ℃ (ethyl acetate/hexane), MS: 288(M + H)+)。
Example 214
3-[4- (2-methyl-imidazol-1-ylmethyl) -imidazol-1-yl]-isoquinoline hydrochloride (1: 2)
Following the general procedure described in example 10, (1-isoquinolin-3-yl-1H-imidazol-4-yl) -methanol was reacted first with thionyl chloride, then 2-methylimidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a yellow-white crystalline material, Mp. > 250 ℃ (methanol/ether), MS: 290(M + H)+)。
Example 215
2-ethyl-1- [ [1- [4- (trifluoromethoxy) phenyl ] phenyl]-1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride
(1∶2)
Following the general procedure described in example 10, [1- (4-trifluoromethoxy-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-ethylimidazole and sodium hydride followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a white crystalline material, mp.216-218 ℃ (methanol/diethyl ether), MS: 337(M + H) M/e+)。
Example 216
2-methyl-1- [ [1- [4- (trifluoromethoxy) phenyl ] methyl ester]-1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride
(1∶2)
Following the general procedure described in example 10, [1- (4-trifluoromethoxy-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-methylimidazole and sodium hydride, followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a white crystalline material, mp.231-233 ℃ (methanol/diethyl ether), MS: 323(M + H)+)。
Example 217
1- [ [1- (1-biphenyl-3-yl) -1H-imidazol-4-yl]Methyl radical]-2-methyl-1H-imidazole hydrochloride (1: 2)
1- [ [1- (3-iodophenyl) -1H-imidazol-4-yl group]Methyl radical]A suspension of-2-methyl-1H-imidazole (0.20g, 0.55mmol) in toluene (10ml) was treated with tetrakis (triphenylphosphine) palladium (0.023g, 0.02mmol) under an argon atmosphere. After 30 min, phenylboronic acid (0.080g, 0.66mmol) and 2M aqueous potassium carbonate (2.0ml) were added. The reaction mixture was refluxed for 2 hours, then extracted with ethyl acetate and water. The organic phase was dried (sodium sulfate), concentrated and chromatographed [ silica, gradient elution: dichloromethane to 30% (dichloromethane/methanol/aqueous ammonium hydroxide solution ═ 90: 10: 1)]. The free base of the title compound was obtained as a colorless oil (0.13g, 75%). It was crystallized as a white hydrochloride salt. Mp.241-243 ℃ (methanol/diethyl ether), MS: 315(M + H) M/e+)。
Example 218
2-ethyl-1- [ [1- [4- (trifluoromethylthio) phenyl ] methyl ester]-1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride
(1∶2)
Following the general procedure described in example 10, [1- (4-trifluoromethylsulfanyl-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-ethylimidazole and sodium hydride, followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a pale yellow crystalline material, mp.183-185 ℃ (methanol/diethyl ether), MS: 352 (M/e)+)。
Example 219
2-methyl-1- [ [1- [4- (trifluoromethylthio) phenyl ] methyl]-1H-imidazol-4-yl]Methyl radical]-1H-imidazole hydrochloride
(1∶2)
Following the general procedure described in example 10, [1- (4-trifluoromethylsulfanyl-phenyl) -1H-imidazol-4-yl]Methanol first with thionyl chloride, then with 2-methylimidazole and sodium hydride, followed by chromatography and crystallization of the hydrochloride salt to give the title compound as a white crystalline material, mp.249-250 ℃ (methanol/diethyl ether), MS: m/e ═ 339(M +H+)。
Example 220
6- [4- (2-methyl-imidazol-1-ylmethyl) -imidazol-1-yl]-quinolines
Following the general procedure described in example 10, (1-quinolin-6-yl-1H-imidazol-4-yl) -methanol was reacted first with thionyl chloride, then 2-methylimidazole and sodium hydride followed by chromatography and crystallization of the free base to give the title compound as an off-white crystalline material, Mp. > 125 ℃ (decomposed) (ethyl acetate/hexane), MS: 290(M + H)+)。
Example 221
6- [4- (2-Ethyl-imidazol-1-ylmethyl) -imidazol-1-yl]-quinolines
Following the general procedure described in example 10, (1-quinolin-6-yl-1H-imidazol-4-yl) -methanol was reacted first with thionyl chloride, then 2-ethylimidazole and sodium hydride followed by chromatography and crystallization of the free base to give the title compound as an off-white crystalline material, Mp. > 79 ℃ (decomposed) (ethyl acetate/hexane), MS: 304(M + H) M/e+)。
Example 222
8- [4- (2-methyl-imidazol-1-ylmethyl) -imidazol-1-yl]-quinolines
Following the general procedure described in example 10, (1-quinolin-8-yl-1H-imidazol-4-yl) -methanol was reacted first with thionyl chloride, then 2-methylimidazole and sodium hydride followed by chromatography and crystallization of the free base to give the title compound as an off-white crystalline material, mp.150-154 ℃ (ethyl acetate/hexane), MS: 290(M + H)+)。
Example 223
8- [4- (2-Ethyl-imidazol-1-ylmethyl) -imidazol-1-yl]-quinolines
Following the general procedure described in example 10, (1-quinolin-8-yl-1H-imidazol-4-yl) -methanol was reacted first with thionyl chloride, then 2-ethylimidazole and sodium hydride followed by chromatography and crystallization of the free base to give the title compound as an off-white crystalline material, mp.78-81 ℃ (ethyl acetate/hexane), MS: 304(M + H) M/e+)。
Example 224
1- (1-benzo [1, 3 ]]dioxol-5-yl-1H-imidazol-4-ylmethyl) -1H-imidazol-2-ylamine salts
Acid salt (1: 2)
Following the general procedure described in example 104, 1- [ [1- (1, 3-benzodioxol-5-yl) -1H-imidazol-4-yl ] -was reacted]Methyl radical]-2-nitro-1H-imidazole was reacted with iron in acetic acid. After filtration, evaporation and chromatography, the free base of the title compound is isolated. It was converted into its light yellow hydrochloride salt. Mp. > 245 ℃ (decomposed) (methanol/ether), MS: 284(M + H) M/e+)。
Example 225
3- (3-difluoromethyl-4-fluoro-phenyl) -5- (2-methyl-imidazol-1-ylmethyl) -pyridine
Following the general method described in example 129 (substituting DMF for dioxane, 4 hours, 100 ℃), 2- (3-difluoromethyl-4-fluoro-phenyl) -4, 4, 5, 5-tetramethyl- [1, 3, 2]Reaction of dioxaborolane with 3-bromo-5- (2-methyl-imidazol-1-ylmethyl) -pyridine gave the title compound as a light brown solid (73% yield), MS: m/e 318.3(M + H)+)。
Example 226
3- [3- (1, 1-difluoro-ethyl) -phenyl]-5- (2-methyl-imidazol-1-ylmethyl) -pyridine
Following the general procedure described in example 129 (substituting DMF for dioxan)Alkane, 4 hours, 100 ℃ C.) 2- [3- (1, 1-difluoro-ethyl) -phenyl]-4, 4, 5, 5-tetramethyl- [1, 3, 2 [ ]]Reaction of dioxaborolane with 3-bromo-5- (2-methyl-imidazol-1-ylmethyl) -pyridine gave the title compound as a light brown oil (70% yield), MS: 314.3(M + H) M/e+)。
Example 227
3- (3-fluoro-5-trifluoromethyl-phenyl) -5- (2-methyl-imidazol-1-ylmethyl) -pyridine
Following the general method described in example 129 (substituting DMF for dioxane, 4 hours, 100 ℃), 2- (3-fluoro-5-trifluoromethyl-phenyl) -4, 4, 5, 5-tetramethyl- [1, 3, 2]Reaction of dioxaborolane with 3-bromo-5- (2-methyl-imidazol-1-ylmethyl) -pyridine gave the title compound as a light brown solid (67% yield), MS: 336.3(M + H) M/e+)。
Example 228
3- [3- (1, 1-difluoro-ethyl) -4-fluoro-phenyl]-5- (2-methyl-imidazol-1-ylmethyl) -pyridine
Following the general method described in example 129 (substituting DMF for dioxane, 4 hours, 100 ℃), 2- [3- (1, 1-difluoro-ethyl) -4-fluoro-phenyl]-4, 4, 5, 5-tetramethyl- [1, 3, 2 [ ]]Reaction of dioxaborolane with 3-bromo-5- (2-methyl-imidazol-1-ylmethyl) -pyridine gave the title compound as a light brown oil (73% yield), MS: 332.3(M + H) M/e+)。
Example 229
2-cyclopropyl-1- [ [1- (3, 4-dichlorophenyl) -1H-imidazol-4-yl]Methyl radical]-1H-imidazole
Following the general method described in example 1, 4-chloromethyl-1- (3, 4-dichloro-phenyl) -1H-imidazole was reacted with 2-cyclopropyl-1H-imidazole and sodium hydride followed by chromatography to give the title compound as a yellow oil. MS: 334(M + H) M/e+)。
Example 230
5- (4-fluoro-3-methyl-phenyl) -1-methyl-2- (2-methyl-imidazol-1-ylmethyl) -1H-imidazole hydrochloride (1: 1)
5-bromo-1-methyl-2- (2-methyl-imidazol-1-ylmethyl) -1H-imidazole (0.1g, 0.392mmol) was dissolved in toluene (4ml) and methanol (0.8ml) and treated with 2N aqueous sodium carbonate (0.2ml), 4-fluoro-3-methylphenylboronic acid (0.078g, 0.510mmol) and tetrakis (triphenylphosphine) palladium (0.023g, 0.020 mmol). The reaction mixture was refluxed for 12 hours under argon atmosphere, then cooled at room temperature and dried over sodium sulfate. After filtration and evaporation of the solvent, the residue is chromatographed (silica, eluent: dichloromethane/methanol 95: 5). The product was dissolved in methanol, cooled to 0 ℃ and treated with HCl/ether. The solvent was distilled off and dried under high vacuum to give the title compound (0.11g, 88%) as a pale yellow solid. MS: 285.2(M + H)+)。
Example 231
5- (4-fluoro-3-trifluoromethyl-phenyl) -1-methyl-2- (2-methyl-imidazol-1-ylmethyl) -1H-imidazole hydrochloride
(1∶1)
5-bromo-1-methyl-2- (2-methyl-imidazol-1-ylmethyl) -1H-imidazole (0.1g, 0.392mmol) was dissolved in DMF (1.5ml) and potassium carbonate (0.1g, 0.784mmol), 2- (4-fluoro-3-trifluoromethyl-phenyl) -4, 4, 5, 5-tetramethyl- [1, 3, 2]Dioxaborolane (0.148g, 0.510mmol) and tetrakis (triphenylphosphine) palladium (0.047g, 0.040 mmol). The reaction mixture was heated under argon at 100 ℃ for 12 hours, then cooled to room temperature and dried over sodium sulfate. Filtration and evaporation of the solvent are carried out and the residue is chromatographed (silica, eluent: dichloromethane/methanol 95: 5). The product was dissolved in methanol, cooled to 0 ℃ and treated with HCl/ether. The solvent was distilled off and dried under high vacuum to give the title compound (0.089g, 88%) as a pale brown solid. MS: 339.2(M + H) M/e+)。
Example 232
5- (4-chloro-3-methyl-phenyl) -1-methyl-2- (2-methyl-imidazol-1-ylmethyl) -1H-imidazole hydrochloride (1: 1)
Following the general method described in example 231, from 5-bromo-1-methyl-2- (2-methyl-imidazol-1-ylmethyl) -1H-imidazole and 2- (4-chloro-3-methyl-phenyl) -4, 4, 5, 5-tetramethyl- [1, 3, 2]Dioxaborolane to give the title compound. MS: 300.1 (M/e)+)。
Example 233
2- [5- (2-methyl-imidazol-1-ylmethyl) -pyridin-3-yl]-1, 2, 3, 4-tetrahydro-isoquinoline hydrochloride (1: 2)
The compound was prepared according to the methods described in the following documents:
S.Wagaw；S.L.Buchwald；J.Org.Chem.1996，61，7240-7241
3-bromo-5- (2-methyl-imidazol-1-ylmethyl) -pyridine (0.1g, 0.397mmol) was dissolved in toluene (1ml) and sequentially treated with 1, 2, 3, 4-tetrahydroisoquinoline (61. mu.l, 0.476mmol), sodium tert-butoxide (53mg, 0.556mmol), Pd2(dba)3Chloroform complex (8.2mg, 0.0079mmol) and R (+) -BINAP (10mg, 0.0159 mmol). The reaction mixture was heated at 70 ℃ under argon for 6 hours, cooled to room temperature and quenched with water. The aqueous layer was extracted 3 times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue is chromatographed (silica, eluent: dichloromethane/methanol 95: 05). The product was dissolved in methanol, cooled to 0 ℃ and treated with HCl/ether. The solvent was distilled off and dried under high vacuum to give the title compound (0.09g, 60%) as a yellow foam. MS: 305.3(M + H) M/e+)。
Process for the preparation of intermediates
Example 234
1- (3, 4-dichloro-phenyl) -1H-imidazole-4-carboxylic acid
A mixture of 3, 4-dichloroaniline (24.3g, 150mmol), triethyl orthoformate (24.0g, 162mmol), ethyl nitroacetate (20.0g, 150mmol) and acetic acid (1ml) was refluxed for 1 hour. After addition of triethyl orthoformate (300ml, 1.8mol), iron powder (25.1g, 450mmol) and acetic acid (300ml, 5.2mol), the mixture was refluxed for 5 hours. During this time, iron powder (25.1g, 450mmol) was added in 3 portions. The mixture was cooled to 60 ℃ and ethyl acetate (1 l) was added. After refluxing for 10 min, the precipitate was filtered and the filtrate was concentrated. The residual acetic acid was removed by azeotropic distillation with toluene (500 ml). The residue of crystallization was dissolved in dioxane (300ml) and 2N sodium hydroxide solution (300ml) and charcoal (about 10g) were added. The mixture was refluxed for 2 hours, filtered and cooled to 5 ℃. HCl solution (37%) was added until precipitation was complete. Filtration and drying gave the title compound (25.8g, 67%) as light brown crystals. Mp. > 235 ℃ (decomposed) (water), MS: m/e 255[ (M-H)-]。
Example 235-262 was prepared according to the general procedure described in example 234.
Example 235
1- (4-chloro-3-methyl-phenyl) -1H-imidazole-4-carboxylic acid
The title compound, MS, was prepared by the following procedure: 236 (M/e)+) Mp.231-236 ℃ (water/dioxane), a yellow-white crystalline material: 4-chloro-3-methylaniline was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 236
1-indan-5-yl-1H-imidazole-4-carboxylic acid
The title compound, MS, was prepared by the following procedure: m/e 227[ (M-H)-]Mp.243-251 deg.C (water/dioxane), is a compoundYellow-white crystalline material: reacting 5-aminoindane with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 237
1- (3, 4-dimethyl-phenyl) -1H-imidazole-4-carboxylic acid
The title compound, MS, was prepared by the following procedure: 216 (M/e)+) Mp. > 250 ℃ (water/dioxane), as a yellow-white crystalline material: 3, 4-dimethylaniline was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 238
1-p-tolyl-1H-imidazole-4-carboxylic acid
The title compound, MS, was prepared by the following procedure: 202 (M/e)+) Mp. > 250 ℃ (DMF), is a rose-colored crystalline material: p-toluidine was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 239
1- (4-fluoro-3-methyl-phenyl) -1H-imidazole-4-carboxylic acid
The title compound, MS, was prepared by the following procedure: m/e ═ 219[ (M-H)-]Mp.192-198 ℃ (water/dioxane), a yellow-white crystalline material: 4-fluoro-3-methylaniline was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 240
1- (4-methylthio-phenyl) -1H-imidazole-4-carboxylic acid
The title compound, MS, was prepared by the following procedure: m/e ═ 233[ (M-H)-]Mp.233-245 ℃ (water/dioxane), a red crystalline material: reacting 4- (methylthio) aniline with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 241
1- (3-trifluoromethyl-phenyl) -1H-imidazole-4-carboxylic acid
The title compound, MS, was prepared by the following procedure: 256M/e+Mp.233-245 ℃ (water/DMF), a light orange crystalline material: 3- (trifluoromethyl) aniline was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 242
1- (4-fluoro-3-trifluoromethyl-phenyl) -1H-imidazole-4-carboxylic acid
The title compound, MS, was prepared by the following procedure: 274M/e+Mp.188-193 ℃ (water/dioxane), a yellow-white crystalline material: 4-fluoro-3- (trifluoromethyl) aniline is reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 243
1- (3-fluoro-4-trifluoromethyl-phenyl) -1H-imidazole-4-carboxylic acid
The title compound, MS, was prepared by the following procedure: 274M/e+Mp. > 250 ℃ (water/dioxane), as a yellow-white crystalline material: 3-fluoro-4- (trifluoromethyl) aniline is reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 244
1- (4-methyl-3-trifluoromethyl-phenyl) -1H-imidazole-4-carboxylic acid
The title compound, MS, was prepared by the following procedure: m/e ═ 269[ (M-H)-]Mp. > 233 ℃ (decomposed) (water/dioxane), as a yellow-white crystalline material: 4-methyl-3- (trifluoromethyl) aniline was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 245
1- (4-chloro-3-methoxy-phenyl) -1H-imidazole-4-carboxylic acid
The title compound, MS, was prepared by the following procedure: 252 (M/e)+) Mp.232-236 ℃ (water/dioxane), a light red crystalline material: 4-chloro-3-methoxyaniline was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 246
1- (4-fluoro-3-methoxy-phenyl) -1H-imidazole-4-carboxylic acid
The title compound, MS, was prepared by the following procedure: 236 (M/e)+) Mp. > 182 ℃ (decomposed) (water/dioxane), as a light brown crystalline material: reacting 4-fluoro-3-methoxyaniline with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 247
1- (4-chloro-phenyl) -1H-imidazole-4-carboxylic acid
The title compound, MS, was prepared by the following procedure: 222 (M/e)+) Mp. > 250 ℃ (DMF/water), is a rose-colored crystalline material: reacting 4-chloroaniline with triethyl orthoformateEster, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 248
1-benzo [1, 3 ]]dioxol-5-yl-1H-imidazole-4-carboxylic acid
The title compound, MS, was prepared by the following procedure: 232 (M/e)+) Mp. > 250 ℃ (water/dioxane), as a gray crystalline material: 3, 4-methylenedioxyaniline was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 249
1- (3-fluoro-4-methyl-phenyl) -1H-imidazole-4-carboxylic acid
The title compound, MS, was prepared by the following procedure: 220 (M/e) ═ M+) Mp. > 250 ℃ (water/dioxane), as a yellow-white crystalline material: 3-fluoro-4-methylaniline was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 250
1- (3-chloro-4-methoxy-phenyl) -1H-imidazole-4-carboxylic acid
The title compound, MS, was prepared by the following procedure: 252 (M/e)+) Mp.224-226 ℃ (water/dioxane), a white crystalline material: 3-chloro-4-methoxyaniline was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 251
1- (4-chloro-2-fluoro-phenyl) -1H-imidazole-4-carboxylic acid
From belowThe title compound was prepared by the following procedure, MS: m/e 239[ (M-H)-]Mp.234-238 ℃ (water/dioxane), a light yellow crystalline material: 4-chloro-2-fluoroaniline was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 252
1- (4-bromo-phenyl) -1H-imidazole-4-carboxylic acid
The title compound, MS, was prepared by the following procedure: 266M/e (M)+) Mp. > 250 ℃ (water/dioxane), as a light yellow crystalline material: 4-bromoaniline was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 253
1- (4-difluoromethoxy-phenyl) -1H-imidazole-4-carboxylic acid
The title compound, MS, was prepared by the following procedure: 253[ (M-H) }/e ═ M/e-]Mp.218-225 ℃ (water/dioxane) as a white crystalline material: 4-Difluoromethoxyaniline was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 254
1- (4-benzyloxy-phenyl) -1H-imidazole-4-carboxylic acid
The title compound, MS, was prepared by the following procedure: m/e 293[ (M-H)-]Mp.238-243 ℃ (decomposed) (water/dioxane), a yellow-white crystalline material: 4-benzyloxyaniline was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 255
1- (3-methoxy-4-methyl-phenyl) -1H-imidazole-4-carboxylic acid
The title compound, MS, was prepared by the following procedure: 232 (M/e)+) Mp.226-230 ℃ (water/dioxane), a rose crystalline material: 3-methoxy-4-methylaniline was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 256
1- (4-trifluoromethyl-phenyl) -1H-imidazole-4-carboxylic acid
The title compound, MS, was prepared by the following procedure: 256 (M/e)+) Mp. > 250 ℃ (water/dioxane), as a light yellow crystalline material: 4- (trifluoromethyl) aniline was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 257
1- (1, 3-dihydro-isobenzofuran-5-yl) -1H-imidazole-4-carboxylic acid
The title compound, MS, was prepared by the following procedure: 230 (M/e)+) Mp.245-247 ℃ (DMF/water) as a light brown crystalline material: 1, 3-dihydro-5-isobenzofuranamine (prepared by t.y.shen et al, j.med.chem., 1978, 21, 965) was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 258
1- (4-fluoro-3-methoxy-phenyl) -1H-imidazole-4-carboxylic acid
The title compound, MS, was prepared by the following procedure: 236 (M/e)+) Mp. > 182 ℃ (decomposed) (water/dioxane), as a light brown crystalline material:reacting 4-fluoro-3-methoxyaniline with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 259
1-phenyl-1H-imidazole-4-carboxylic acid
The title compound, MS, was prepared by the following procedure: 188 (M/e)+) Mp.220-221 ℃ (DMF/water) as a white crystalline material: aniline is reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 260
1- (4-methoxy-phenyl) -1H-imidazole-4-carboxylic acid
The title compound, MS, was prepared by the following procedure: 218 (M/e)+) Mp. > 240 ℃ (decomposed) (water/dioxane), as a light brown crystalline material: p-anisidine is reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 261
1- (3-methoxy-phenyl) -1H-imidazole-4-carboxylic acid
The title compound, MS, was prepared by the following procedure: 218 (M/e)+) Mp.196-201 ℃ (water/dioxane), a light red crystalline material: meta-methoxyaniline is reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 262
1- (4-methoxy-3-trifluoromethyl-phenyl) -1H-imidazole-4-carboxylic acid
By the following processPreparation of the title compound, MS: 286M/e (M)+) Mp. > 141 ℃ (decomposed) (water/dioxane), as a light brown crystalline material: 4-methoxy-3- (trifluoromethyl) aniline was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis.
Example 263
1- (3, 4-dichloro-phenyl) -5-methyl-1H-imidazole-4-carboxylic acid ethyl ester and
3- (3, 4-dichloro-phenyl) -5-methyl-3H-imidazole-4-carboxylic acid ethyl ester
A suspension of 3, 4-dichlorophenylboronic acid (8.22g, 43.1mmol), ethyl 4-methyl-5-imidazolecarboxylate (6.64g, 43.1mmol) and copper (II) acetate (7.83g, 43.1mmol) in dichloromethane (86ml) was stirred at 20 ℃ for 48 h. All solids were filtered off and the organic phase was diluted with ethyl acetate (500ml) and stirred with saturated aqueous sodium potassium tartrate solution. After filtration and evaporation, the residue is chromatographed (silica, gradient elution: hexane to ethyl acetate) to give 2.8g (22%) of ethyl 3- (3, 4-dichloro-phenyl) -5-methyl-3H-imidazole-4-carboxylate [ mp.135-136 ℃ (ethyl acetate/hexane), MS: 298 (M) M/e+)]And 1.0g (8%) of 1- (3, 4-dichloro-phenyl) -5-methyl-1H-imidazole-4-carboxylic acid ethyl ester [ mp.163-164 ℃ (ethyl acetate/hexane), MS: 298 (M) M/e+)]。
Example 264
[1- (3, 4-dichloro-phenyl) -1H-imidazol-4-yl]-methanol
1- (3, 4-dichloro-phenyl) -1H-imidazole-4-carboxylic acid (20.0g, 77.8mmol) was reacted with 1M BH3THF complex (100ml) was treated and refluxed for 2 hours. The mixture was cooled to 5 ℃ and methanol (20ml) was added slowly. After distilling off all volatile substances, the residue was added to a 2N HCl solution (100ml) and refluxed for 2 hours. After filtration, the hot aqueous phase was slowly treated with 2N sodium hydroxide solution until pH 10. After cooling, the labelThe title compound crystallized as a white material (12.2g, 65%). Mp.146-147 ℃ (water), MS: 242 (M/e)+)。
Example 265-292 was prepared according to the general procedure described in example 264.
Example 265
[1- (4-chloro-3-methyl-phenyl) -1H-imidazol-4-yl]-methanol
The title compound, MS, was prepared by the following procedure: 222 (M/e)+) Mp.126-133 ℃ (water), a light brown crystalline material: reacting 1- (4-chloro-3-methyl-phenyl) -1H-imidazole-4-carboxylic acid with BH3The THF complex was reacted followed by hydrolytic workup.
Example 266
(1-indan-5-yl-1H-imidazol-4-yl) -methanol
The title compound, MS, was prepared by the following procedure: 214M/e (M)+) Mp.128-133 ℃ (water), a light brown crystalline material: reacting 1-indan-5-yl-1H-imidazole-4-carboxylic acid with BH3The THF complex was reacted followed by hydrolytic workup.
Example 267
[1- (3, 4-dimethyl-phenyl) -1H-imidazol-4-yl]-methanol
The title compound, MS, was prepared by the following procedure: 202 (M/e)+) Mp.110-116 ℃ (water), is an off-white crystalline material: reacting 1- (3, 4-dimethyl-phenyl) -1H-imidazole-4-carboxylic acid with BH3The THF complex was reacted followed by hydrolytic workup.
Example 268
(1-p-tolyl-1H-imidazol-4-yl) -methanol
The title compound, MS, was prepared by the following procedure: 188 (M/e)+)，Mp.101-102℃(water), an off-white crystalline material: reacting 1-p-tolyl-1H-imidazole-4-carboxylic acid with BH3The THF complex was reacted followed by hydrolytic workup.
Example 269
1- (4-fluoro-3-methyl-phenyl) -1H-imidazol-4-yl]-methanol
The title compound, MS, was prepared by the following procedure: 206 (M/e)+) Mp.138-144 ℃ (water), an off-white crystalline material: reacting 1- (4-fluoro-3-methyl-phenyl) -1H-imidazole-4-carboxylic acid with BH3The THF complex was reacted followed by hydrolytic workup.
Example 270
[1- (4-methylthio-phenyl) -1H-imidazol-4-yl]-methanol
The title compound, MS, was prepared by the following procedure: 220 (M/e) ═ M+) Mp.108-114 ℃ (water), a light brown crystalline material: reacting 1- (4-methylthio-phenyl) -1H-imidazole-4-carboxylic acid with BH3The THF complex was reacted followed by hydrolytic workup.
Example 271
[1- (3-trifluoromethyl-phenyl) -1H-imidazol-4-yl]-methanol
The title compound, MS, was prepared by the following procedure: 242 (M/e)+) Mp.96-100 ℃ (water), a white crystalline material: reacting 1- (3-trifluoromethyl-phenyl) -1H-imidazole-4-carboxylic acid with BH3The THF complex was reacted followed by hydrolytic workup.
Example 272
[1- (4-fluoro-3-trifluoromethyl-phenyl) -1H-imidazol-4-yl]-methanol
The title compound, MS, was prepared by the following procedure: 260 (M/e) ═ M/e (M)+) Mp.142-146 deg.C (water), is a white productCrystalline material: reacting 1- (4-fluoro-3-trifluoromethyl-phenyl) 1H-imidazole-4-carboxylic acid with BH3The THF complex was reacted followed by hydrolytic workup.
Example 273
[1- (3-fluoro-4-trifluoromethyl-phenyl) -1H-imidazol-4-yl]-methanol
The title compound, MS, was prepared by the following procedure: 260 (M/e) ═ M/e (M)+) Mp.142-144 ℃ (water), a white crystalline material: reacting 1- (3-fluoro-4-trifluoromethyl-phenyl) -1H-imidazole-4-carboxylic acid with BH3The THF complex was reacted followed by hydrolytic workup.
Example 274
[1- (4-methyl-3-trifluoromethyl-phenyl) -1H-imidazol-4-yl]-methanol
The title compound, MS, was prepared by the following procedure: 257(M + H) M/e+) Mp.116-119 ℃ (water), a white crystalline material: reacting 1- (4-methyl-3-trifluoromethyl-phenyl) -1H-imidazole-4-carboxylic acid with BH3The THF complex was reacted followed by hydrolytic workup.
Example 275
[1- (4-chloro-3-methoxy-phenyl) -1H-imidazol-4-yl]-methanol
The title compound, MS, was prepared by the following procedure: 238 (M/e)+) Mp.116-119 ℃ (water), a white crystalline material: reacting 1- (4-chloro-3-methoxy-phenyl) -1H-imidazole-4-carboxylic acid with BH3The THF complex was reacted followed by hydrolytic workup.
Example 276
[1- (4-fluoro-3-methoxy-phenyl) -1H-imidazol-4-yl]-methanol
The title compound, MS, was prepared by the following procedure: 222 (M/e)+) Mp.174-177 ℃ (water), an off-white crystalline material: make it1- (4-fluoro-3-methoxy-phenyl) -1H-imidazole-4-carboxylic acid and BH3The THF complex was reacted followed by hydrolytic workup.
Example 277
[1- (4-chloro-phenyl) -1H-imidazol-4-yl]-methanol
The title compound, MS, was prepared by the following procedure: 208 (M/e)+) Mp.115-116 ℃ (ethyl acetate), as a white crystalline material: reacting 1- (4-chloro-phenyl) -1H-imidazole-4-carboxylic acid with BH3The THF complex was reacted followed by hydrolytic workup.
Example 278
(1-benzo [1, 3 ]]dioxol-5-yl-1H-imidazol-4-yl) -methanol
The title compound, MS, was prepared by the following procedure: 218 (M/e)+) Mp.150-157 ℃ (water), a white crystalline material: reacting 1-benzo [1, 3 ]]dioxol-5-yl-1H-imidazole-4-carboxylic acid and BH3The THF complex was reacted followed by hydrolytic workup.
Example 279
[1- (3-fluoro-4-methyl-phenyl) -1H-imidazol-4-yl]-methanol
The title compound, MS, was prepared by the following procedure: 206 (M/e)+) Mp.115-122 ℃ (water), a pale yellow crystalline material: reacting 1- (3-fluoro-4-methyl-phenyl) -1H-imidazole-4-carboxylic acid with BH3The THF complex was reacted followed by hydrolytic workup.
Example 280
[1- (3-chloro-4-methoxy-phenyl) -1H-imidazol-4-yl]-methanol
The title compound, MS, was prepared by the following procedure: 238 (M/e)+) Mp.133-138 ℃ (water), an off-white crystalline material: reacting 1- (3-chloro-4-methoxy-phenyl) -1H-imidazole-4-carboxylic acid with BH3The THF complex was reacted followed by hydrolytic workup.
Example 281
[1- (4-chloro-2-fluoro-phenyl) -1H-imidazol-4-yl]-methanol
The title compound, MS, was prepared by the following procedure: 226 (M/e)+) Mp.120-130 ℃ (water), an off-white crystalline material: reacting 1- (4-chloro-2-fluoro-phenyl) -1H-imidazole-4-carboxylic acid with BH3The THF complex was reacted followed by hydrolytic workup.
Example 282
[1- (4-bromo-phenyl) -1H-imidazol-4-yl]-methanol
The title compound, MS, was prepared by the following procedure: 252 (M/e)+) Mp.132-139 ℃ (water), a light yellow crystalline material: reacting 1- (4-bromo-phenyl) -1H-imidazole-4-carboxylic acid with BH3The THF complex was reacted followed by hydrolytic workup.
Example 283
[ [1- (4-difluoromethoxy-phenyl) -1H-imidazol-4-yl]-methanol
The title compound, MS, was prepared by the following procedure: 240 (M/e)+) Mp.66-72 ℃ (water), a light brown crystalline material: reacting 1- (4-difluoromethoxy-phenyl) -1H-imidazole-4-carboxylic acid with BH3The THF complex was reacted followed by hydrolytic workup.
Example 284
[1- (4-benzyloxy-phenyl) -1H-imidazol-4-yl]-methanol
The title compound, MS, was prepared by the following procedure: 280 parts M/e (M)+) Mp.151-152 ℃ (ethyl acetate), as a white crystalline material: reacting 1- (4-benzyloxy-phenyl) -1H-imidazole-4-carboxylic acid with BH3Reaction of THF complex followed by hydrolysisAnd (6) processing.
Example 285
[1- (3-methoxy-4-methyl-phenyl) -1H-imidazol-4-yl]-methanol
The title compound, MS, was prepared by the following procedure: 218 (M/e)+) Mp.141-147 ℃ (water) as a white crystalline material: reacting 1- (3-methoxy-4-methyl-phenyl) -1H-imidazole-4-carboxylic acid with BH3The THF complex was reacted followed by hydrolytic workup.
Example 286
[1- (4-trifluoromethyl-phenyl) -1H-imidazol-4-yl]-methanol
The title compound, MS, was prepared by the following procedure: 242 (M/e)+) Mp.153-156 ℃ (water), an off-white crystalline material: reacting 1- (4-trifluoromethyl-phenyl) -1H-imidazole-4-carboxylic acid with BH3The THF complex was reacted followed by hydrolytic workup.
Example 287
[1- (1, 3-dihydro-isobenzofuran-5-yl) -1H-imidazol-4-yl]-methanol
The title compound, MS, was prepared by the following procedure: 216 (M/e)+) Mp.161-165 ℃ (ethyl acetate) as an off-white crystalline material: reacting 1- (1, 3-dihydro-isobenzofuran-5-yl) -1H-imidazole-4-carboxylic acid with BH3The THF complex was reacted followed by hydrolytic workup.
Example 288
[1- (3-fluoro-4-methoxy-phenyl) -1H-imidazol-4-yl]-methanol
The title compound, MS, was prepared by the following procedure: 222 (M/e)+) Mp.112-120 ℃ (dichloromethane/isopropyl ether), a white crystalline material: reacting 1- (4-fluoro-3-methoxy-phenyl) -1H-imidazole-4-carboxylic acid with BH3Reaction of THF complex, followed byAnd (5) performing hydrolysis treatment.
Example 289
[ (1-phenyl-1H-imidazol-4-yl) -methanol
The title compound, MS, was prepared by the following procedure: m/e-174 (M)+) Mp.116-118 ℃ (water), a white crystalline material: reacting 1-phenyl-1H-imidazole-4-carboxylic acid with BH3The THF complex was reacted followed by hydrolytic workup.
Example 290
[1- (4-methoxy-phenyl) -1H-imidazol-4-yl]-methanol
The title compound, MS, was prepared by the following procedure: 204 (M/e)+) Mp.107-109 ℃ (ethyl acetate) as a white crystalline material: reacting 1- (4-methoxy-phenyl) -1H-imidazole-4-carboxylic acid with BH3The THF complex was reacted followed by hydrolytic workup.
Example 291
[1- (3-methoxy-phenyl) -1H-imidazol-4-yl]-methanol
The title compound, MS, was prepared by the following procedure: 204 (M/e)+) Mp.80-85 ℃ (ethyl acetate/hexane) as a white crystalline material: reacting 1- (3-methoxy-phenyl) -1H-imidazole-4-carboxylic acid with BH3The THF complex was reacted followed by hydrolytic workup.
Example 292
[1- (4-methoxy-3-trifluoromethyl-phenyl) -1H-imidazol-4-yl]-methanol
The title compound, MS, was prepared by the following procedure: 272 (M/e) ═ M/e+) Mp.147-150 ℃ (water), is an off-white crystalline material: reacting 1- (4-methoxy-3-trifluoromethyl-phenyl) -1H-imidazole-4-carboxylic acid with BH3The THF complex was reacted followed by hydrolytic workup.
Example 293
[1- (3-chloro-4-methyl-phenyl) -1H-imidazol-4-yl]-methanol
3-chloro-4-methylaniline (21.5g, 150mmol) was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid as in example 234. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis. The isolated acid (10.0g) was reduced directly as in example 264 with BH3Reaction of the THF complex followed by hydrolytic workup yielded the title compound as a white crystalline solid (5.2g, 16%). Mp.126-133 ℃ (ethyl acetate/hexane), MS: 222 (M/e)+)。
Example 294-297 was prepared according to the general procedure described in example 293.
Example 294
[1- (4-chloro-3-trifluoromethyl-phenyl) -1H-imidazol-4-yl]-methanol
3-trifluoromethyl-4-chloroaniline was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis. The separated acid is directly used by BH3Reduction of the THF complex followed by hydrolytic workup yielded the title compound as a white crystalline solid, mp.148-153 ℃ (ethyl acetate/isopropyl ether), MS: 276 (M/e)+)。
Example 295
[1- (3-chloro-4-fluoro-phenyl) -1H-imidazol-4-yl]-methanol
3-chloro-4-fluoroaniline was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis. The separated acid is directly used by BH3Reduction of the THF complex followed by hydrolytic workup yielded the title compound, mp.130-135 ℃ (water), MS: 226 (M/e)+) It is a yellow-white crystalline solid.
Example 296
(1-Biphenyl-4-yl-1H-imidazol-4-yl) -methanol
4-phenylaniline was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis. The separated acid is directly used by BH3Reduction of the THF complex followed by hydrolytic workup yielded the title compound, mp.173-177 ℃ (dichloromethane/isopropyl ether), MS: 250 (M/e) ═ M/e+) It is a yellow crystalline solid.
Example 297
[1- (4-isopropyl-3-methyl-phenyl) -1H-imidazol-4-yl]-methanol
4-isopropyl-3-methylaniline was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis. The separated acid is directly used by BH3Reduction of the THF complex followed by hydrolytic workup yielded the title compound, mp.98-102 ℃ (dichloromethane/isopropyl ether), MS: 230 (M/e)+) It is a yellow crystalline solid.
Example 298
[1- (3, 4-dichloro-phenyl) -5-methyl-1H-imidazol-4-yl]-methanol
To a solution of ethyl 1- (3, 4-dichloro-phenyl) -5-methyl-1H-imidazole-4-carboxylate (0.82g, 2.7mmol) in THF (27ml) was added lithium aluminium hydride (0.21g, 5.4mmol) portionwise to keep the temperature below 10 ℃. The mixture was stirred in an ice bath for 2 hours, then 1ml of saturated aqueous sodium potassium tartrate solution was slowly added. After dilution with ethyl acetate (100ml), the mixture was filtered, concentrated and chromatographed [ silica, gradient elution: dichloromethane to 80% (dichloromethane/methanol ═ 9: 1)]. The title compound was obtained as a white crystalline solid (0.46g, 66%). Mp.174-175 deg.C (dichloromethane/isopropyl ether)，MS：m/e＝256(M+)
Example 299
4-chloromethyl-1- (3, 4-dichloro-phenyl) -1H-imidazole
Thionyl chloride (39.5ml, excess) was slowly added to [1- (3, 4-dichloro-phenyl) -1H-imidazol-4-yl in an ice bath]Methanol (9.6g, 39.5 mmol). The resulting mixture was stirred for 24 hours. After evaporation, the oily residue was triturated with ether to give 10.12g (86%) of the hydrochloride salt of the title compound as an off-white solid. To obtain the free base, it was carefully neutralized with aqueous sodium hydroxide (2N) and extracted with ethyl acetate. The organic phase was dried (sodium sulfate) and concentrated to give 8.43g (95%) of the title compound as an off-white solid. Mp.146-147 ℃ (decomposed) (ethyl acetate/hexane), MS: 260 (M/e) ═ M/e (M)+)
Example 300
1- [ [1- (3, 4-dichlorophenyl) -1H-imidazol-4-yl]Methyl radical]-2-nitro-1H-imidazole
4-chloromethyl-1- (3, 4-dichloro-phenyl) -1H-imidazole (2.0g, 7.5mmol) was dissolved in DMF (25ml), 2-nitroimidazole (1.0g, 8.8mmol) and cesium carbonate (1.43g, 4.4mmol) were added and the resulting mixture was stirred at 70 ℃ for 3 hours. After evaporation of the solvent, the residue was dissolved in ethyl acetate and washed with water. The organic phase was dried (sodium sulfate), concentrated and chromatographed [ silica, gradient elution: dichloromethane to 50% (dichloromethane/methanol ═ 9: 1)]2.48g (98%) of the title compound are obtained as an off-white solid. Mp.130-131 ℃ (dichloromethane/isopropyl ether), MS: 291[ (M-NO) }/e2)+]。
Example 301
1- [ [1- (4-chloro-3-methylphenyl) -1H-imidazol-4-yl]Methyl radical]-2-nitro-1H-imidazole
[1- (4-chloro-3-methyl-phenyl) -1H-imidazol-4-yl ] as in example 299]-methanol withThionyl chloride was reacted and the resulting 4-chloromethyl-1- (4-chloro-3-methyl-phenyl) -1H-imidazole was reacted directly in the form of its hydrochloride salt. Thus, 4-chloromethyl-1- (4-chloro-3-methyl-phenyl) -1H-imidazole hydrochloride was reacted with 2-nitroimidazole (1.2 eq) and cesium carbonate (1.2 eq) as described in example 300 to give, after evaporation and extraction, the crude product which was purified by chromatography. Mp.147-148 ℃ (dichloromethane/hexane), MS: 271[ (M-NO) }/e2)+]。
Examples 302 and 303 were prepared according to the general procedure described in example 301.
Example 302
1- [ [1- (4-methylphenyl) -1H-imidazol-4-yl]Methyl radical]-2-nitro-1H-imidazole
(1-p-tolyl-1H-imidazol-4-yl) -methanol was first treated with thionyl chloride and then reacted with 2-nitroimidazole and cesium carbonate. After evaporation, extractive workup and chromatography, the title compound was obtained as a white solid. Mp.147-148 ℃ (dichloromethane/isopropyl ether), MS: 237 ═ M/e [ (M-NO)2)+]。
Example 303
2-Nitro-1- [ (1-phenyl-1H-imidazol-4-yl) methyl]-1H-imidazole
(1-phenyl-1H-imidazol-4-yl) -methanol was first treated with thionyl chloride and then reacted with 2-nitroimidazole and cesium carbonate. After evaporation, extractive workup and chromatography, the title compound was obtained as a white solid. Mp.126-127 ℃ (dichloromethane/isopropyl ether), MS: m/e ═ 223[ (M-NO)2)+]。
Example 304
1- (3, 4-dichloro-phenyl) -1H-imidazole-4-carboxylic acid amide
Carbonyldiimidazole (0.49g, 3mmol) was added to the stirring 1- (3, 4-dichloro-phenyl) -1H-imidazole-4-Formic acid (0.64g, 2.5mmol) in DMF (10 ml). After 1 hour at 60 ℃, the reaction mixture was cooled to room temperature, aqueous ammonia (25%, 20ml) was added and stirring was continued for 12 hours. Then, water (100ml) was added and the precipitated product was filtered. Recrystallization from ethanol gave the title compound as a yellowish white crystal. Mp.244-245 ℃ (ethanol), MS: m/e 255 (M)+)。
Example 305
1- (3, 4-dichlorophenyl) -1H-imidazole-4-methylamine fumarate (1: 1)
1- (3, 4-dichloro-phenyl) -1H-imidazole-4-carboxylic acid amide (4.32g, 16.9mmol) was reacted with 1M BH3THF complex (100ml) was treated and refluxed for 6 hours. The mixture was cooled to 5 ℃ and methanol (50ml) was added slowly. After all volatiles were distilled off, the residue was taken up in 6N HCl solution (30ml) and refluxed for a further 15 minutes. The reaction mixture was filtered, treated slowly with 6N sodium hydroxide (30ml) and extracted with ethyl acetate (3X 200 ml). The organic phase is dried (sodium sulfate), concentrated and the crude product obtained is chromatographed [ silica, eluent: (dichloromethane/methanol/aqueous ammonium hydroxide 90: 10: 1)]The free base of the title compound was obtained as a light brown semi-solid (2.62g, 64%). After treatment with equimolar amounts of fumaric acid, the title compound is isolated as a white crystal. Mp.176-177 ℃ (methanol/ether), MS: 241M/e (M)+)。
Example 306
N-1- (3, 4-dichloro-phenyl) -1H-imidazol-4-yl-methyl]-acetamide
To a solution of 1- (3, 4-dichlorophenyl) -1H-imidazole-4-methanamine (0.20g, 0.83mmol) in THF (30ml) was added triethylamine (0.079g, 0.78mmol) and acetyl chloride (0.082mg, 1.0 mmol). The reaction mixture was stirred at room temperature for 12 hours. After evaporation of the solvent, the residue was dissolved in ethyl acetate and washed with water. The organic phase is dried (sodium sulphate), concentrated and the crude product obtained is chromatographed [ silica,gradient elution: dichloromethane to 100% (dichloromethane/methanol ═ 9: 1)]. The title compound was obtained as an off-white crystalline material (0.17g, 74%). Mp.177-180 ℃ (methanol/dichloromethane), MS: 284(M + H) M/e+)。
Example 307
N- [1- (3, 4-dichloro-phenyl) -1H-imidazol-4-yl-methyl]-thioacetamide
To N- [1- (3, 4-dichloro-phenyl) -1H-imidazol-4-ylmethyl]To a suspension of acetamide (1.1g, 3.7mmol) in 1, 2-dimethoxyethane (11ml) was added Lawesson's reagent (0.82g, 2.0mmol) and the mixture was refluxed for 90 min. After addition of saturated sodium bicarbonate solution (50ml), extraction with dichloromethane (3 × 100ml), drying of the combined organic phases (sodium sulphate), concentration and chromatography of the crude product obtained [ silica, gradient elution: dichloromethane to 100% (dichloromethane/methanol ═ 9: 1)]. The title compound was obtained as a brown crystalline material (0.75g, 68%). Mp.166-170 ℃ (methanol/dichloromethane), MS: 299 (M/e)+)。
Example 308
1- [1- (3, 4-dichloro-phenyl) -1H-imidazol-4-yl-methyl]-1H-imidazole-2-carbaldehyde
4-chloromethyl-1- (3, 4-dichloro-phenyl) -1H-imidazole (1.31g, 5.0mmol) was dissolved in DMF (10ml), 2-imidazolecarboxaldehyde (0.48g, 5.0mmol) and cesium carbonate (0.82g, 2.5mmol) were added and the resulting mixture was stirred at 60 ℃ for 12H. After evaporation of the solvent, the residue was dissolved in ethyl acetate and washed with water. The organic phase was dried (sodium sulfate), concentrated and chromatographed [ silica, gradient elution: dichloromethane to 100% (dichloromethane/methanol ═ 9: 1)]This gave 0.98g (61%) of the title compound as a yellowish white solid. Mp.130-131 ℃ (dichloromethane/isopropyl ether), MS: 320 (M/e) ═ M/e+)。
Example 309
1- (3, 4-diChloro-phenyl) -3-methyl-1H-pyrazole and 1- (3, 4-dichloro-phenyl) -5-methyl-1H-pyrazole
A solution of 3, 4-dichlorophenylhydrazine (4.27g, 20.0mmol) in ethanol (50ml) and water (50ml) was treated with 3-oxobutyraldehyde dimethyl acetal (2.64g, 20.0mmol) and refluxed for 1 hour. The alcohol was removed in vacuo and the aqueous residue was extracted with ethyl acetate (2X 150 ml). The organic phase was dried (sodium sulfate), filtered and evaporated. The remaining oil was chromatographed [ silica, gradient elution: hexane to 10% (hexane/ethyl acetate 1: 1)]To yield 3.01g (66%) of 1- (3, 4-dichloro-phenyl) -3-methyl-1H-pyrazole [ mp.57-58 ℃ (ethyl acetate/hexane), MS: 226 (M/e)+)]And 1.32g (29%) of 1- (3, 4-dichloro-phenyl) -5-methyl-1H-pyrazole [ mp.46-47 ℃ (hexane), MS: 226 (M/e)+)]。
Example 310
4-chloromethyl-1- (3, 4-dichloro-phenyl) -1H-pyrazole
1- (3, 4-dichloro-phenyl) -1H-pyrazole-4-carboxylic acid (3.0g, 12mmol) (US 5,064,851) was reacted with 1M BH3THF complex (50ml) was treated and refluxed for 90 minutes. The mixture was cooled to 5 ℃ and methanol (50ml) was added slowly. After evaporation of all volatiles, the residue was taken up in 25% HCl solution (50ml) and refluxed for 15 min. After filtration, the aqueous phase was cooled in an ice bath and slowly treated with 28% sodium hydroxide solution (50 ml). The title compound crystallized as a pale yellow material (2.6g, 86%). Mp.66-67 ℃ (water), MS: 260 (M/e) ═ M/e (M)+)。
Example 311
1- (3, 4-dichloro-phenyl) -1H-imidazole-4-carbaldehyde
Reacting [1- (3, 4-dichloro-phenyl) -1H-imidazol-4-yl]A solution of methanol (10.8g, 44.3mmol) in a mixture of THF (270ml) and water (30ml) was treated with manganese (IV) oxide (5g, 57.5mmol) and the mixture was refluxed for 4 hours. A second portion of manganese (IV) oxide (1.5g) was added and refluxing continued for 1.5 hours. The mixture was filtered through celite and the residue was washed with methanol. Toluene was added to the filtrate and water was azeotropically removed. The brown residue was taken up in dichloromethane and after standing a white crystal formed. Filtration yielded 1- (3, 4-dichloro-phenyl) -1H-imidazole-4-carbaldehyde (2.5g, 25%). MS: 240.0 (M/e)+)。
Example 312
1- [1- (3, 4-dichloro-phenyl) -1H-imidazol-4-yl]-ethanol
To a solution of methyl magnesium iodide in diethyl ether (3M, 13.7ml, 41.1mmol) and diethyl ether (40ml) was added 1- (3, 4-dichloro-phenyl) -1H-imidazole-4-carbaldehyde (2.58g, 10.7mmol) in portions. THF (50ml) was then added slowly and stirring continued at reflux for 1 hour. After addition of aqueous ammonium chloride (saturated, 30ml), the mixture was extracted with ethyl acetate. The organic phase was dried (sodium sulfate) and evaporated to give 1- [1- (3, 4-dichloro-phenyl) -1H-imidazol-4-yl]Ethanol (2.56g, 93%) as a light brown solid. MS: 257.0(M + H)+)。
Example 313
1- (3, 4-dichloro-phenyl) -1H-imidazole-4-carboxylic acid methyl ester
A mixture of 1- (3, 4-dichloro-phenyl) -1H-imidazole-4-carboxylic acid (7.0g, 27mmol), methanol (150ml) and concentrated sulfuric acid (25ml) was refluxed for 3 hours. The solution was then concentrated to about 80ml and an aqueous solution (500ml) of sodium carbonate (60g) at 0 ℃ was added. Extraction with dichloromethane, drying of the organic phase and evaporation of the solvent gave a brown residue which, after trituration with ether, gave the title compound (6.0g, 81%) as a pale brown solid. MS: 269.9 (M/e) ═ M/e+)。
Example 314
2- [1- (3, 4-dichloro-phenyl) -1H-imidazol-4-yl]-propan-2-ol
In analogy to example 312, 1- (3, 4-dichloro-phenyl) -1H-imidazole-4-carboxylic acid methyl ester (1.5g, 5.53mmol) was usedExcess methyl magnesium iodide. After extractive workup, the title compound was obtained (1.3g, 86%). MS: 270.1 (M/e)+)。
Example 315
2- [ (2-methyl-1H-imidazol-1-yl) methyl]-4- [3- (trifluoromethyl) phenyl]-1- [ [2- (trimethylsilane)
Yl) ethoxy]Methyl radical]-1H-imidazole
4-iodo-2- [ (2-methyl-1H-imidazol-1-yl) methyl]-1- [ [2- (trimethylsilyl) ethoxy ] group]Methyl radical]-1H-imidazole (0.080g, 0.191mmol) was dissolved in toluene (4ml) and methanol (0.8ml) and treated with 2N sodium carbonate (0.2ml), 3- (trifluoromethyl) phenylboronic acid (0.049g, 0.248mmol) and tetrakis (triphenylphosphine) palladium (0.0114g, 0.0095 mmol). The reaction mixture was refluxed for 150 hours under argon atmosphere, then cooled to room temperature and dried (sodium sulfate). Filtration and evaporation of the solvent followed by chromatography of the residue (silica, eluent: dichloromethane/methanol 95: 5) gave the title compound (0.036g, 43%) as a brown oil. MS: 437.4(M + H)+)。
Example 316-319 was prepared according to the general procedure described in example 315.
Example 316
4- (4-fluoro-3-methylphenyl) -2- [ (2-methyl-1H-imidazol-1-yl) methyl]-1- [ [2- (trimethylsilyl)
Ethoxy radical]Methyl radical]-1H-imidazole
From 4-iodo-2- [ (2-methyl-1H-imidazol-1-yl) methyl]-1- [ [2- (trimethylsilyl) ethoxy ] group]Methyl radical]-1H-imidazole and 4-fluoro-3-methylphenylboronic acid the title compound was prepared, MS: m/e 400.2 (M)+)。
Example 317
4- (3, 4-difluorophenyl) -2- [ (2-methyl-1H-imidazol-1-yl) methyl]-1- [ [2- (trimethylsilyl) ethane
Oxy radical]Methyl radical]-1H-imidazole
From 4-iodo-2- [ (2-methyl-1H-imidazol-1-yl) methyl]-1- [ [2- (trimethylsilyl) ethoxy ] group]Methyl radical]-1H-imidazole and 3, 4-difluorophenylboronic acid the title compound was prepared, MS: 404.2 (M/e)+)。
Example 318
2- [ (2-methyl-1H-imidazol-1-yl) methyl]-4- [4- (methylthio) phenyl]-1- [ [2- (trimethylsilyl)
Ethoxy radical]Methyl radical]-1H-imidazole
From 4-iodo-2- [ (2-methyl-1H-imidazol-1-yl) methyl]-1- [ [2- (trimethylsilyl) ethoxy ] group]Methyl radical]-1H-imidazole and 4-methylthiophenylboronic acid the title compound was prepared, MS: m/e 414.2 (M)+)。
Example 319
4- (4-fluoro-3-methylphenyl) -2- (1H-imidazol-1-ylmethyl) -1- [ [2- (trimethylsilyl) ethoxy]
Methyl radical]-H-imidazole
From 2- (1H-imidazol-1-ylmethyl) -4-iodo-1- [ [2- (trimethylsilyl) ethoxy]Methyl radical]-1H-imidazole and 4-fluoro-3-methylphenylboronic acid the title compound was prepared, MS: m/e 387.3(M + H)+)。
Example 320
4-iodo-2- [ (2-methyl-1H-imidazol-1-yl) methyl]-1- [ [2- (trimethylsilyl) ethoxy ] group]First of all
Base of]-1H-imidazole
Reacting [ 4-iodo-1- (2-trimethylsilyl-ethoxymethyl) -1H-imidazol-2-yl]Methanol (1.0g, 2.8mmol) and tetrabromomethane (1.3g, 4.0 mmol) were dissolved in THF (10.0ml) and cooled to 0 ℃. Triphenylphosphine (1.07g, 3.95mmol) was added portionwise over 30 min. The reaction mixture was stirred at 0 ℃ for 1 hour to give a white suspension. In a second flask, sodium hydride (0.615g, 14.1mmol, 55% dispersion in mineral oil) was suspended in DMF (20ml) and cooled to 0 ℃. 2-methylimidazole (1.16g, 14.1mmol) was added portionwise. Mixing the reaction mixtureStirred at 60 ℃ for 30 minutes, cooled to 0 ℃ and treated with the above suspension. After stirring at room temperature for 2 hours, the reaction mixture was quenched with saturated sodium bicarbonate (50 ml). The aqueous layer was extracted 3 times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was chromatographed (silica, eluent: dichloromethane/methanol 97: 3) to give the title compound (0.835g, 71%) as a brown oil. MS: 419.0(M + H)+)。
Example 321 was prepared according to the general procedure described in example 320.
Example 321
2- (1H-imidazol-1-ylmethyl) -4-iodo-1- [ [2- (trimethylsilyl) ethoxy]Methyl radical]-1H-imidazole
From [ 4-iodo-1- (2-trimethylsilyl-ethoxymethyl) -1H-imidazol-2-yl]Methanol and imidazole the title compound was prepared, MS: 405.3(M + H) M/e+)。
Example 322
[ 4-iodo-1- (2-trimethylsilyl-ethoxymethyl) -1H-imidazol-2-yl]-methanol
4-iodo-1- (2-trimethylsilyl-ethoxymethyl) -1H-imidazole-2-carbaldehyde (4.6g, 13.1mmol) was dissolved in ethanol (50ml) under argon atmosphere. Sodium borohydride (0.514g, 13.1mmol) was added and the mixture was stirred at room temperature for 45 min. Water (200ml) was added. The aqueous layer was extracted 3 times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude residue was added to hexane and stirred at room temperature. Filtration gives [ 4-iodo-1- (2-trimethylsilyl-ethoxymethyl) -1H-imidazol-2-yl]Methanol (4.0g, 87%) as a white solid. MS: 354.0 (M/e ═ M+)。
Example 323
4-iodo-1- (2-trimethylsilyl-ethoxymethyl) -1H-imidazole-2-carboxaldehyde
A solution of 4, 5-diiodo-1- (2-trimethylsilyl-ethoxymethyl) -1H-imidazole (8.86g, 19.68mmol) in dry THF (110ml) was cooled to-78 deg.C under argon and n-butyllithium (13.5ml, 21.65mmol, 1.6M in hexanes) was added dropwise. After stirring at-78 ℃ for 10 min and-45 ℃ for 30 min, the reaction mixture was cooled to-78 ℃ and treated once with DMF (10 ml). The mixture was warmed to room temperature, and saturated ammonium chloride (150ml) was added. The aqueous layer was extracted 2 times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was chromatographed (silica, eluent: hexane/ethyl acetate 98: 2) to give the title compound (5.18g, 75%) as a pale yellow oil. MS: m/e 352.1 (M)+)。
Example 324
4, 5-diiodo-1- (2-trimethylsilyl-ethoxymethyl) -1H-imidazole
4, 5-diiodoimidazole (prepared by D.S. Carver, S.D. Lindell, and E.A. Saville-Stones, Tetrahedron, 1997, 53, 42, 14481-propan 14496) (10.1g, 31.6mmol) was added portionwise to a suspension of sodium hydride (1.38g, 31.6mmol, 55% dispersion in mineral oil) in anhydrous DMF (45ml) at room temperature. The reaction mixture was stirred at room temperature for 90 minutes, then cooled to 0 ℃ and slowly treated with a solution of 2- (trimethylsilyl) -ethoxymethyl chloride (6.81ml, 34.7mmol) in DMF (10 ml). After stirring at 0 ℃ for 2 h, the reaction mixture was poured into a mixture of water (200ml) and ethyl acetate (50 ml). The mixture was filtered and the mother liquor was extracted 3 times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was chromatographed (silica, eluent: hexane/ethyl acetate 9: 1) to give the title compound (9.44g, 66.4%) as a pale yellow oil. MS: 450.0 (M/e) ═ M/e+)。
Example 325
3-chloromethyl-5- (3, 4-dichloro-phenyl) -pyridine hydrochloride (1: 1)
Reacting [5- (3, 4-dichloro-phenyl) -pyridin-3-yl]A solution of methanol (470mg, 1.9mmol) in thionyl chloride (4.9ml) was stirred at 20 ℃ for 15 h. Thionyl chloride was distilled off and dried at 50 ℃ under high vacuum for 2 hours to give the title compound (558mg, 98%) as a pale yellow solid. MS: 271.0 (M/e)+)。
Example 326-328 was prepared following the general procedure described in example 325.
Example 326
2-chloromethyl-3- (3, 4-dichloro-phenyl) -pyridine hydrochloride (1: 1)
Reacting [4- (3, 4-dichloro-phenyl) -pyridin-2-yl]Reaction of methanol with thionyl chloride at 20 ℃ for 15 hours gives the title compound, MS: 271.0 (M/e)+) As a light brown foam (99% yield).
Example 327
4-chloromethyl-2- (3, 4-dichloro-phenyl) -pyridine hydrochloride (1: 1)
Reacting [2- (3, 4-dichloro-phenyl) -pyridin-4-yl]Reaction of methanol with thionyl chloride at 20 ℃ for 1 hour to give the title compound, MS: 271.0 (M/e)+) As a light brown foam (100% yield).
Example 328
3-chloromethyl-5- (3, 4-dimethyl-phenyl) -2-methyl-pyridine hydrochloride (1: 1)
Reacting [5- (3, 4-dimethyl-phenyl) -2-methyl-pyridin-3-yl]Methanol hydrochloride (1: 1) with thionyl chloride at 20 ℃ for 1 hour, followed by reflux for 2 hours to give the title compound, MS: 245.1 (M/e) ═ M/e+) As a yellow solid (98% yield).
Example 329
[5- (3, 4-dichloro-phenyl) -pyridin-3-yl]-methanol
To a suspension of lithium aluminium hydride (161mg, 4.2mmol) in THF (20ml) was added dropwise methyl 5- (3, 4-dichloro-phenyl) -nicotinate (2.0g, 7.0mmol) in THF (20ml) at 0 deg.C and stirring continued at this temperature for 2 h. The reaction was stopped by careful addition of THF/water (9: 1), then dried directly over sodium sulfate, filtered and the solvent was evaporated. The residue was chromatographed [ silica, eluent: dichloromethane/(2M NH)3Methanol) 97: 3]To give the title compound (480mg, 27%) as an orange solid. MS: 254.0(M + H)+)。
Example 330-332 was prepared according to the general procedure described in example 329.
Example 330
[2- (3, 4-dichloro-phenyl) -pyridin-4-yl]-methanol
Methyl 2- (3, 4-dichloro-phenyl) -isonicotinate was reacted with lithium aluminium hydride in THF at 20 ℃ for 1 hour, followed by chromatography [ silica, eluent: dichloromethane/(2M NH)3Methanol) 19: 1]To give the title compound, MS: 252.0([ M-H) } M/e]-) As a pale yellow solid (53% yield).
Example 331
[4- (3, 4-dichloro-phenyl) -pyridin-2-yl]-methanol
4- (3, 4-dichloro-phenyl) -pyridine-2-carboxylic acid methyl ester was reacted with 1M lithium aluminum hydride/THF solution in THF at 20 ℃ for 1 hour, followed by chromatographic purification to give the title compound, MS: 252.0([ M-H) } M/e]-) It was a light brown oil (94% yield).
Example 332
[5- (3, 4-dimethyl-phenyl) -2-methyl-pyridin-3-yl]-methanol hydrochloride (1: 1)
Ethyl 5- (3, 4-dimethyl-phenyl) -2-methyl-nicotinate was stirred with sodium borohydride (5 equivalents) in ethanol (5ml) at 20 ℃ for 23 h and then chromatographed to give the title compound, MS: m/e 227.2 (M)+) As a beige solid (58% yield).
Example 333
5- (3, 4-dichloro-phenyl) -nicotinic acid methyl ester
To a solution of methyl 5-bromopyridine-3-carboxylate (2g, 9.3mmol) in toluene (50ml) was added tetrakis- (triphenylphosphine) -palladium (0) (320mg, 0.28mmol), lithium chloride (785mg, 18.5mmol) was added and the mixture was stirred at 20 ℃ for 30 min. Then, 3, 4-dichlorophenylboronic acid (50% by weight solution in THF/water 9: 1) (3.7g, 3.3ml, 9.7mmol) and 2N aqueous potassium carbonate solution (11.3ml, 2.5 equiv) were added, and the stirred mixture was heated under argon atmosphere at 100 ℃ for 23 hours. After cooling, water (25ml) was added, the aqueous phase was separated and extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and the solvent evaporated, and the product dried under high vacuum at 50 ℃ for 2 hours to give the title compound (2.48g, 95%) as a beige solid. MS: m/e ═ 281.0(M + H)+)。
Example 334-336 was prepared according to the general procedure described in example 333.
Example 334
4- (3, 4-dichloro-phenyl) -pyridine-2-carboxylic acid methyl ester
Reaction of 4-bromo-pyridine-2-carboxylic acid methyl ester with 3, 4-dichlorophenyl boronic acid gives the title compound, MS: m/e ═ 281.0 (M)+) As a pale yellow solid (10% yield).
Example 335
2- (3, 4-dichloro-phenyl) -isonicotinic acid methyl ester
Reaction of 2-iodo-isonicotinic acid methyl ester with 3, 4-dichlorophenyl boronic acid gave the title compound, MS: m/e ═ 281.0 (M)+) As a light brown solid (59% yield).
Example 336
6- (3, 4-dichloro-phenyl) -pyridine-2-carboxylic acid methyl ester
Reaction of 6-bromo-pyridine-2-carboxylic acid methyl ester with 3, 4-dichlorophenyl boronic acid gave the title compound, MS: 282.0 (M/e ═ M+) As a pale yellow solid (7% yield).
Example 337
2-iodo-isonicotinic acid methyl ester
A solution of 2-chloro-pyridine-4-carboxylic acid (5g, 31.7mmol) in butan-2-one (150ml) was heated under reflux with sodium iodide for 6 hours to afford 2-iodo-isonicotinic acid (7.3g, 92.4% yield) after extractive workup. This material was dissolved in THF (50ml) and esterified with fresh diazomethane ether solution (44ml, 0.55 mol/l). After evaporation of the solvent, filtration was performed using a silica gel pad, and the eluent: dichloromethane/(2M NH)3Methanol) 19: 1]The title compound (2.3g, 44%) was obtained as a dark yellow oil. MS: 263.0 (M/e)+)。
Example 338
3-bromo-5- (2-methyl-imidazol-1-ylmethyl) -pyridine
To a stirred suspension of sodium hydride (0.54g, 12.3mmol) in THF (40ml) was added 2-methylimidazole in portions over 45 min at 20 ℃. Then a solution of 3-bromo-5- (chloromethyl) -pyridine (1g, 4.1mmol) in ethanol (8ml) was added and the mixture was heated under argon at reflux for 1 hour. After cooling and evaporation of the solvent, the residue was suspended in methanol, filtered and adsorbed onto silica gel. Subjecting to chromatography with dichloromethane/(2M NH)3Methanol) 98: 2 to give the title compound (0.56g,53%) as a yellow oil. MS: 251.0 (M/e ═ M+)。
Example 339
3-bromo-5- (chloromethyl) -pyridine
To a cooled solution of thionyl chloride (41ml, 344mmol) at 0 deg.C was carefully added (highly exothermic reaction) in portions (5-bromo-pyridin-3-yl) -methanol (10g, 44.5 mmol). After the addition was complete, the mixture was heated to reflux to complete the reaction. After cooling, diethyl ether (50ml) was added and the mixture was cooled to 4 ℃. The precipitated solid was filtered off, washed with cold diethyl ether and then dried under vacuum at 50 ℃ for 2 hours to give the title compound (9.1g, 84%) as a pale yellow solid. MS: 206.9 (M/e ═ M+)。
Example 340
(5-bromo-pyridin-3-yl) -methanol hydrochloride (1: 1)
Ethyl 5-bromonicotinate (25g, 108mmol) was dissolved in ethanol (500ml) and fresh sodium borohydride (25g, 660mmol) was added portionwise over 30 min at 20 ℃. Stirring was continued overnight under argon. Subsequently, 1N HCl (50ml) was added slowly (over 20 min), followed by 2N sodium hydroxide (25ml) and water (75ml), and the mixture was stirred at room temperature for 2 hours. After evaporation of the alcohol, the aqueous phase was extracted with dichloromethane (4X 150ml), and the combined extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. The resulting yellow oil was dissolved in a small amount of ethanol and treated with 0.93M HCl/ethanol (62ml, 1.2 eq.) at 4 ℃ for 1 hour, the solvent was removed and dried under high vacuum at 50 ℃ for 16 hours to give the title compound (10.9g, 44%) as a pale yellow solid. MS: m/e 186.9 (M)+)。
Example 341
5- (3, 4-dimethyl-phenyl) -2-methyl-nicotinic acid ethyl ester
The title compound was prepared from [ 3-dimethylamino-2- (3, 4-dimethyl-phenyl) allylidene ] -dimethyl-ammonium tetrafluoroborate (1: 1) and the starting material was prepared from 3, 4-dimethyl-phenylacetic acid (prepared by a. j. liepa; aust. j. chem., 1981, 34(12), 2647-55).
Example 342
2- (4-chloro-3-trifluoromethyl-phenyl) -4, 4, 5, 5-tetramethyl- [1, 3, 2]Dioxaborolane
This compound was prepared according to a modification of the methods known in the literature (y. masuda, m.murata, s.watanabe, j.org.chem., 1997, 62, 6458-9). To the solution was added potassium acetate (3.4g, 34.7mmol), PdCl2(PPH3)2(234mg, 0.34mmol) and 4, 4, 4 ', 4 ', 5, 5, 5 ', 5 ' -octamethyl-2, 2 ' -1, 3, 2-dioxaborolane (3.2g, 12.7mmol) in a flask was added a solution of 5-bromo-2-chloro-trifluorotoluene (3g, 11.5mmol) in dioxane. The mixture was heated for 3 hours under argon at 100 ℃. After cooling, ethyl acetate was added, and then the organic mixture was washed with a saturated sodium chloride solution, then dried over sodium sulfate and the solvent was distilled off. The residue was chromatographed (silica, eluent: hexane/ethyl acetate 9: 1) to give the title compound (2.35g, 66%) as a pale brown solid. MS: 306.1 (M/e)+)。
Example 343-347 was prepared according to the general procedure described in example 342.
Example 343
2- (3-chloro-4-methyl-phenyl) -4, 4, 5, 5-tetramethyl [1, 3, 2 ]]-dioxaborolane
The title compound was prepared using 2-chloro-4-iodo-toluene as starting material, MS: 252.1 (M/e)+) It was a pale yellow semi-solid (30% yield).
Example 344
2- (4-chloro-3-methyl-phenyl) -4, 4, 5, 5-tetramethyl [1, 3, 2 ]]-twoOxaborolidines
The title compound was prepared using 5-bromo-2-chloro-toluene, MS: 252.1 (M/e)+) As a colorless liquid (16% yield).
Example 345
5- (4, 4, 5, 5-tetramethyl [1, 3, 2 ]]-dioxaborolan-2-yl) -2, 3-dihydro-benzofuran
Using 2, 3-dihydro-5-iodobenzo [ b ]]Furan preparation the title compound, MS: 246.1 (M/e)+) As a pale yellow oil (51% yield).
Example 346
2-indan-5-yl-4, 4, 5, 5-tetramethyl [1, 3, 2]-dioxaborolane
The title compound was prepared using indan-5-yl trifluoromethanesulfonate, MS: 244.1 (M/e)+) This is a pale yellow oil (96% yield) prepared from indan-5-ol by treatment with trifluoro-methanesulfonic anhydride, DMAP and triethylamine in dichloromethane at-70 ℃ to 20 ℃.
Example 347
2- (4-fluoro-3-trifluoromethyl-phenyl) -4, 4, 5, 5-tetramethyl- [1, 3, 2]-dioxaborolane
The title compound was prepared using 5-bromo-2-fluoro-trifluorotoluene, MS: m/e-290.1 (Me) as a colorless oil (76% yield).
Example 348
[1- (3-trifluoromethylsulfanyl-phenyl) -1H-imidazol-4-yl]-methanol
Following the general method described in example 293, 3- (trifluoromethylthio) aniline was reacted with triethyl orthoformate, ethyl nitroacetate, and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis. The isolated acid was directly reduced as in example 264, i.e. with BH3Reaction of the THF complex followed by hydrolytic workup yielded the title compound as a pale brown crystalline solid. Mp.73-75 ℃ (water), MS: 274 (M/e)+)。
Example 349
{1- [3- (1, 1-difluoro-ethyl) -phenyl]-1H-imidazol-4-yl } -methanol
Following the general method described in example 293, 3- (1, 1-difluoro-ethyl) -aniline [ r.o.neri, j.g.topliss, ger.offen. (1972), DE 213045219721221CAN 78: 124310]With triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis. The isolated acid was directly reduced as in example 264, i.e. with BH3The THF complex was reacted followed by hydrolytic workup to give the title compound as a white crystalline solid. Mp.104-108 ℃ (water), MS: 238 (M/e)+)。
Example 350
{1- [3- (1, 1-difluoro-ethyl) -4-fluoro-phenyl]-1H-imidazol-4-yl } -methanol
Following the general method described in example 293, 3- (1, 1-difluoro-ethyl) -4-fluoroanilines were reacted with triethyl orthoformate, ethyl nitroacetate, and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis. The isolated acid was directly reduced as in example 264, i.e. with BH3The THF complex was reacted followed by hydrolytic workup to give the title compound as a white crystalline solid. MS: 257(M + H) M/e+)。
Example 351
3- (1, 1-difluoro-ethyl) -4-fluoro-phenylamine
Towards 2-To a solution of (1, 1-difluoro-ethyl) -1-fluoro-4-nitro-benzene (10.4g, 50.6mmol) in methanol (200ml) was added palladium on charcoal (10%, 4g), the resulting mixture was hydrogenated at 20 ℃ for 2 hours, after filtering off the catalyst, the solvent was evaporated to give the title compound as a yellow semi-solid material (8.5g, 96%). MS: 175 (M/e)+)。
Example 352
2- (1, 1-difluoro-ethyl) -1-fluoro-4-nitro-benzene
A solution of 1- (2-fluoro-5-nitro-phenyl) -ethanone (10.8g, 59.0mmol) in diethylaminosulfur trifluoride (15.5ml, 118mmol) was stirred at 50 ℃ for 6 h. The mixture was cooled in an ice bath and slowly added to ice-cooled 2N aqueous sodium hydroxide solution (100 ml). After extraction with dichloromethane, the organic phase is dried (sodium sulfate) and concentrated. Chromatography (silica, eluent: ethyl acetate/hexane ═ 1: 4) gave the title compound as a dark brown oil (9.8g, 81%). MS: 205 (M/e) ═ M (M)+)。
Example 353
1- (3-isopropyl-phenyl) -1H-imidazole-4-carboxylic acid
Following the general method described in example 234, 3-isopropylaniline was reacted with triethyl orthoformate, ethyl nitroacetate, and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis. The title compound was obtained as a light brown crystalline solid. Mp. > 122 ℃ (decomposed) (water/dioxane), MS: m/e 231(M + H)+)。
Example 354
[1- (3-isopropyl-phenyl) -1H-imidazol-4-yl]-methanol
Following the general method described in example 264, 1- (3-isopropyl-phenyl) -1H-imidazole-4-carboxylic acid was reacted with BH3The THF complex was reacted followed by hydrolytic workup. The title compound was obtained as a light brownA colored crystalline solid. Mp.76-77 ℃ (water), MS: 216 (M/e)+)。
Example 355
1-Naphthalen-2-yl-1H-imidazole-4-carboxylic acid methyl ester
A suspension of 2-naphthylboronic acid (1.4g, 8mmol), methyl 1H-imidazole-4-carboxylate (1.0g, 8mmol) and copper acetate (1.4g, 8mmol) in dichloromethane (20ml) was stirred at 20 ℃ for 24H. Ethyl acetate (100ml) and saturated aqueous sodium potassium tartrate solution (50ml) were added to the solution, and the resulting mixture was stirred for further 2 hours. After separation, the organic phase is dried (sodium sulfate), concentrated and chromatographed (silica, eluent: dichloromethane/methanol 99: 1) to give the title compound (0.49g, 24%) as a white crystal. Mp.143-144 ℃ (ethyl acetate), MS: 252 (M/e)+)。
Example 356
(1-naphthalen-2-yl-1H-imidazol-4-yl) -methanol
Following the general method described in example 298, 1-naphthalen-2-yl-1H-imidazole-4-carboxylic acid methyl ester was reacted with lithium aluminum hydride followed by hydrolytic workup and chromatography. The title compound was obtained as a light brown gum. MS: 225 (M/e)+)。
Example 357
[1- (3-bromo-4-fluoro-phenyl) -1H-imidazol-4-yl]-methanol
Following the general method described in example 293, 3-bromo-4-fluoroaniline (k.s.y.lau et al, j.org.chem., 1981,462280-6) with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis. The isolated acid was directly reduced as in example 264, i.e. with BH3The THF complex was reacted followed by hydrolytic workup to give the title compound as a white crystalline solid. Mp.151-152 ℃ (water), MS: 270 (M/e)+)。
Example 358
1- (3-bromo-phenyl) -1H-imidazole-4-carboxylic acid
Following the general method described in example 234, 3-bromoaniline was reacted with triethyl orthoformate, ethyl nitroacetate, and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis. The title compound was obtained as a light brown crystalline solid. Mp.205-207 ℃ (water/dioxane), MS: 267 (M-H)-)。
Example 359
[1- (3-bromo-phenyl) -1H-imidazol-4-yl]-methanol
Following the general method described in example 264, 1- (3-bromo-phenyl) -1H-imidazole-4-carboxylic acid was reacted with BH3The THF complex was reacted followed by hydrolytic workup. The title compound was obtained as a yellow-white solid. MS: 253(M + H) M/e+)。
Example 360
[1- (3-vinyl-phenyl) -1H-imidazol-4-yl]-methanol
Reacting [1- (3-bromo-phenyl) -1H-imidazol-4-yl under argon]Methanol (3.0g, 12mmol) in DMF (90ml) in succession with PdCl2(PPH3)2(0.87g, 0.1mmol) and vinyltributylstannane (4.1g, 13 mmol). The resulting mixture was heated at 60 ℃ for 8 hours. After evaporation of the solvent, the residue was stirred with ethyl acetate (60ml) and 10% aqueous KF solution for 30 minutes. The organic phase was separated and the aqueous phase was extracted 3 times with ethyl acetate. The combined organic phases were dried (sodium sulfate), concentrated and chromatographed [ silica, gradient elution: dichloromethane to 40% (dichloromethane/methanol ═ 9: 1)]The title compound was obtained as a colorless oil (1.2g, 51%). MS: m/e is 201(M + H)+)。
Example 361
[1- (3-cyclopropyl-phenyl) -1H-imidazol-4-yl]-methanol
Reacting [1- (3-vinyl-phenyl) -1H-imidazol-4-yl under argon]A mixture of methanol (0.10g, 0.5mmol) in toluene (20ml) was treated with diethyl zinc (3.8ml, 1.1M in hexane, 4.2mmol) and diiodomethane (6.6g, 25mmol) in that order. The resulting mixture was stirred at 20 ℃ for 12 hours. The precipitate was filtered and stirred with ethyl acetate and saturated aqueous ammonium chloride for 30 minutes. The organic phase was separated, dried (sodium sulfate) and concentrated to give the title compound as a yellow oil (0.10g, 93%). MS: 215(M + H) M/e+)。
Example 362
2-fluoromethyl-1-fluoro-4-nitro-benzene
A solution of 2-fluoro-5-nitrobenzaldehyde (1.7g, 10mmol) in dichloromethane (50ml) was treated with diethylaminosulfur trifluoride (1.8ml, 14mmol) and stirred at 20 ℃ for 72 h. Then, saturated aqueous sodium hydrogencarbonate (200ml) was added, and the mixture was stirred for 1 hour. The organic phase was separated, dried (sodium sulfate) and chromatographed [ silica, gradient elution: hexane to 100% (hexane/ethyl acetate 3: 1)]The title compound was obtained as a colorless oil (1.4g, 74%). MS: 191 (M/e)+)。
Example 363
3-difluoromethyl-4-fluoroaniline hydrochloride (1: 1)
To a mixture of iron powder (88.0g, 1.58mol) in acetic acid (500ml) was slowly added 2-difluoromethyl-1-fluoro-4-nitro-benzene (25.0g, 131mmol) at 120 ℃. After the addition was complete, stirring was continued for 15 minutes, and the reaction mixture was cooled to 20 ℃, filtered and evaporated. The residue was stirred with ethyl acetate (1 l), filtered, evaporated and chromatographed [ silica, gradient elution: hexane to 100% (hexane/ethyl acetate 2: 1)]To give the free base of the title compound,as a dark brown oil (15.11g, 72%). An analytical sample was treated with HCl and crystallized as a white hydrochloride salt. Mp. > 240 ℃ (decomposition) (methanol/ether), MS: 161 (M/e) ═ 161 (M)+)。
Example 364
1- (3-difluoromethyl-4-fluoro-phenyl) -1H-imidazole-4-carboxylic acid
Following the general method described in example 234, 3-difluoromethyl-4-fluoroaniline was reacted with triethyl orthoformate, ethyl nitroacetate, and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis. The title compound was obtained as a light brown crystalline solid. Mp. > 247 ℃ (decomposed) (water/dioxane), MS: m/e 255 (M-H)-)。
Example 365
[1- (3-difluoromethyl-4-fluoro-phenyl) -1H-imidazol-4-yl]-methanol
Following the general method described in example 264, 1- (3-difluoromethyl-4-fluoro-phenyl) -1H-imidazole-4-carboxylic acid was reacted with BH3The THF complex was reacted followed by hydrolytic workup. The title compound was obtained as a yellow-white solid. Mp.133-134 ℃ (water), MS: 242 (M/e)+)。
Example 366
1- (3-methylthio-phenyl) -1H-imidazole-4-carboxylic acid
Following the general method described in example 234, 3- (methylthio) aniline was reacted with triethyl orthoformate, ethyl nitroacetate, and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis. The title compound was obtained as a grey crystalline solid. Mp.190-192 ℃ (water/dioxane), MS: 234 (M/e)+)。
Example 367
[1- (3-methylthio-phenyl) -1H-imidazol-4-yl]-methanol
Following the general method described in example 264, 1- (3-methylsulfanyl-phenyl) -1H-imidazole-4-carboxylic acid was reacted with BH3The THF complex was reacted followed by hydrolytic workup. The title compound was obtained as a yellow-white solid. Mp. > 120 ℃ (decomposed) (water), MS: 221(M + H) M/e+)。
Example 368
1- (3-trifluoromethoxy-phenyl) -1H-imidazole-4-carboxylic acid
Following the general method described in example 234, 3- (trifluoromethoxy) aniline was reacted with triethyl orthoformate, ethyl nitroacetate, and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis. The title compound was obtained as a grey crystalline solid. Mp.173-175 ℃ (water/dioxane), MS: 273(M + H) M/e+)。
Example 369
[1- (3-trifluoromethoxy-phenyl) -1H-imidazol-4-yl]-methanol
Following the general method described in example 264, 1- (3-trifluoromethoxy-phenyl) -1H-imidazole-4-carboxylic acid was reacted with BH3The THF complex was reacted followed by hydrolytic workup. The title compound was obtained as a yellow-white solid. MS: 258 (M/e)+)。
Example 370
[1- (3-chloro-phenyl) -1H-imidazol-4-yl]-methanol
Following the general method described in example 293, 3-chloroaniline was reacted with triethyl orthoformate, ethyl nitroacetate, and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis. The isolated acid was directly reduced as in example 264, i.e. with BH3The THF complex was reacted followed by hydrolytic workup to give the title compound as an off-white crystalline solid. Mp.78-79 deg.C (water),MS：m/e＝209(M+H+)。
example 371
1- (3-iodo-phenyl) -1H-imidazole-4-carboxylic acid
Following the general method described in example 234, 3-iodoaniline was reacted with triethyl orthoformate, ethyl nitroacetate, and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis. The title compound was obtained as an off-white crystalline solid. Mp.229-230 ℃ (water/dioxane), MS: 313 (M-H)-)。
Example 372
[1- (3-iodo-phenyl) -1H-imidazol-4-yl]-methanol
Following the general method described in example 264, 1- (3-iodo-phenyl) -1H-imidazole-4-carboxylic acid was reacted with BH3The THF complex was reacted followed by hydrolytic workup. The title compound was obtained as a yellow oil. MS: 301(M + H) with M/e+)。
Example 373
1- (3-fluoro-5-trifluoromethyl-phenyl) -1H-imidazole-4-carboxylic acid
Following the general method described in example 234, 3-fluoro-5-trifluoromethylaniline was reacted with triethyl orthoformate, ethyl nitroacetate, and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis. The title compound was obtained as a white crystalline solid. Mp. > 250 ℃ (water/dioxane), MS: 273 (M-H)-)。
Example 374
[1- (3-fluoro-5-trifluoromethyl-phenyl) -1H-imidazol-4-yl]-methanol
Following the general method described in example 264, 1- (3-fluoro-5-trifluoromethyl-phenyl) -1H-imidazole-4-carboxylic acid was reacted with BH3The THF complex is reacted with the reaction solution,followed by a hydrolysis treatment. The title compound was obtained as a white crystalline solid. Mp.144-145 ℃ (water), MS: 261(M + H) for M/e+)。
Example 375
[1- (3-methoxy-5-trifluoromethyl-phenyl) -1H-imidazol-4-yl]-methanol
Following the general method described in example 293, 3-methoxy-5-trifluoromethylaniline was reacted with triethyl orthoformate, ethyl nitroacetate, and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis. The isolated acid was directly reduced as in example 264, i.e. with BH3Reaction of the THF complex followed by hydrolytic workup yielded the title compound as a pale brown crystalline solid. Mp.133-134 ℃ (water), MS: 272 (M/e) ═ M/e+)。
Example 376
[1- (3-tert-butyl-phenyl) -1H-imidazol-4-yl]-methanol
Following the general method described in example 293, 3-tert-butylaniline was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis. The isolated acid was directly reduced as in example 264, i.e. with BH3The THF complex was reacted followed by hydrolytic workup to give the title compound as a colorless oil. MS: 230 (M/e)+)。
Example 377
1- (3-chloro-4-trifluoromethoxy-phenyl) -1H-imidazole-4-carboxylic acid
Following the general method described in example 234, 3-chloro-5- (trifluoromethoxy) aniline was reacted with triethyl orthoformate, ethyl nitroacetate, and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis. The title compound was obtained as a light brown crystalline solid. Mp 230-231 deg.C(water/dioxane), MS: 305 (M-H)-)。
Example 378
[1- (3-chloro-4-trifluoromethoxy-phenyl) -1H-imidazol-4-yl]-methanol
Following the general method described in example 264, 1- (3-chloro-4-trifluoromethoxy-phenyl) -1H-imidazole-4-carboxylic acid was reacted with BH3The THF complex was reacted followed by hydrolytic workup. The title compound was obtained as a white crystalline solid. Mp.115-116 ℃ (water), MS: 292 (M/e)+)。
Example 379
1- (3-difluoromethoxy-phenyl) -1H-imidazole-4-carboxylic acid
Following the general method described in example 234, 3- (difluoromethoxy) aniline was reacted with triethyl orthoformate, ethyl nitroacetate, and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis. The title compound was obtained as a light brown crystalline solid. Mp.190-191 ℃ (water/dioxane), MS: 253 (M-H) with M/e-)。
Example 380
[1- (3-difluoromethoxy-phenyl) -1H-imidazol-4-yl]-methanol
Following the general method described in example 264, 1- (3-difluoromethoxy-phenyl) -1H-imidazole-4-carboxylic acid was reacted with BH3The THF complex was reacted followed by hydrolytic workup. The title compound was obtained as a white crystalline solid. MS: 240 (M/e)+)。
Example 381
[1- (3-difluoromethyl-phenyl) -1H-imidazol-4-yl]-methanol
Following the general procedure described in example 293, 3-difluoromethylaniline (g.e.wright et al, j.med.chem., 1995,3849-57) with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis. The isolated acid was directly reduced as in example 264, i.e. with BH3Reaction of the THF complex followed by hydrolytic workup yielded the title compound as a pale brown solid. MS: 225(M + H) M/e+)。
Example 382
[1- (3-bromo-5-fluoro-phenyl) -1H-imidazol-4-yl]-methanol
Following the general method described in example 293, 3-bromo-5-fluoroaniline (k. yoshiizumi et al, bioorg.med.chem.lett., 1998,83397-3402) was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis. The isolated acid was directly reduced as in example 264, i.e. with BH3Reaction of the THF complex followed by hydrolytic workup yielded the title compound as a pale brown solid. Mp.134-138 ℃ (ethyl acetate/hexane), MS: 271(M + H)+)。
Example 383
[1- (2, 2-difluoro-benzo [1, 3 ]]Dioxol-5-yl) -1H-imidazol-4-yl]-methanol
Following the general method described in example 293, 2-difluoro-benzo [1, 3 ]]Dioxol-5-ylamine was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis. The isolated acid was directly reduced as in example 264, i.e. with BH3Reaction of the THF complex followed by hydrolytic workup yielded the title compound as a pale brown solid. Mp.163-164 ℃ (water), MS: 254 (M/e)+)。
Example 384
1-Quinolin-2-yl-1H-imidazole-4-carboxylic acid ethyl ester
A mixture of 2-aminoquinoline (10.0g, 69mmol), triethyl orthoformate (140ml, excess), ethyl nitroacetate (9.2g, 69mmol) and acetic acid (1ml) was refluxed for 3 hours. Acetic acid (140ml) and iron powder (11.6g, 208mmol) were added and the mixture was refluxed for 5 hours. Iron powder (11.6g each, 208mmol) was added in three portions during this period. The mixture was cooled to 60 ℃ and ethyl acetate (500ml) was added. After 10 minutes of reflux, the precipitate was filtered off and the filtrate was concentrated. Residual acetic acid was removed by azeotropic distillation with toluene (500 ml). Chromatography (silica, gradient elution: hexanes to ethyl acetate) afforded the title compound as an off-white crystalline material (12.2g, 66%). Mp.129-130 ℃ (ethyl acetate/hexane), MS: 268(M + H) M/e+)。
Example 385
(1-quinolin-2-yl-1H-imidazol-4-yl) -methanol
Following the general method described in example 298, 1-quinolin-2-yl-1H-imidazole-4-carboxylic acid ethyl ester was reacted with lithium aluminum hydride followed by hydrolytic workup and chromatography. The title compound was obtained as a yellow-white crystal. Mp.136-137 ℃ (ethanol), MS: 225 (M/e)+)。
Example 386
[1- (3-chloro-4-trifluoromethylsulfanyl-phenyl) -1H-imidazol-4-yl]-methanol
Following the general method described in example 293, 3-chloro-4- (trifluoromethylthio) aniline was reacted with triethyl orthoformate, ethyl nitroacetate, and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis. The isolated acid was directly reduced as in example 264, i.e. with BH3Reaction of the THF complex followed by hydrolytic workup yielded the title compound as a pale brown crystalline solid. Mp.105-106 ℃ (water), MS: 308 (M/e)+)。
Example 387
1-Quinolin-3-yl-1H-imidazole-4-carboxylic acid ethyl ester
Following the general method described in example 384, 2-aminoquinoline was reacted with triethyl orthoformate, ethyl nitroacetate, and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was performed. After work-up, chromatography gave the title compound as a beige crystalline solid. Mp.170-171 ℃ (ethyl acetate/hexane), MS: 267 (M/e)+)。
Example 388
(1-quinolin-3-yl-1H-imidazol-4-yl) -methanol
A suspension of ethyl 1-quinolin-3-yl-1H-imidazole-4-carboxylate (5.0g, 18.7mmol) in toluene (100ml) was cooled to-78 ℃. Diisobutylaluminum hydride (19ml of a 1M solution in THF, 19mmol) was added dropwise while maintaining the temperature below-70 ℃. The mixture was stirred at this temperature for 2 hours, then the reaction mixture was slowly raised to 0 ℃. After addition of saturated aqueous sodium potassium tartrate solution (10ml), stirring was continued for 1 hour. The mixture was diluted with ethyl acetate (100ml), filtered, concentrated and chromatographed [ silica, gradient elution: from dichloromethane to 80% (dichloromethane/methanol/aqueous ammonium hydroxide solution ═ 90: 10: 1)]]. The title compound was prepared as a light brown crystalline solid (1.20g, 28%). Mp.142-145 ℃ (ethyl acetate), MS: 226(M + H) M/e+)。
Example 389
1- (5-chloro-pyridin-2-yl) -1H-imidazole-4-carboxylic acid ethyl ester
Following the general method described in example 384, 2-amino-5-chloropyridine was reacted with triethyl orthoformate, ethyl nitroacetate, and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was performed. After work-up, chromatography gave the title compound as a beige crystalline solid. Mp.163-164 ℃ (ethyl acetate), MS: 252(M + H) M/e+)。
Example 390
[1- (5-chloro-pyridin-2-yl) -1H-imidazol-4-yl]-methanol
Following the general method described in example 388, 1- (5-chloro-pyridin-2-yl) -1H-imidazole-4-carboxylic acid ethyl ester was reacted with diisobutylaluminum hydride. After hydrolysis, chromatography gave the title compound as a pale brown crystalline solid. Mp.82-87 ℃ (ethyl acetate/diethyl ether), MS: 210(M + H) M/e+)。
Example 391
1-Isoquinolin-3-yl-1H-imidazole-4-carboxylic acid ethyl ester
Following the general method described in example 384, 3-aminoquinoline was reacted with triethyl orthoformate, ethyl nitroacetate, and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was performed. After work-up, chromatography gave the title compound as a beige crystalline solid. Mp.161-162 ℃ (ethyl acetate), MS: 268(M + H) M/e+)。
Example 392
(1-isoquinolin-3-yl-1H-imidazol-4-yl) -methanol
Following the general method described in example 298, 1-isoquinolin-3-yl-1H-imidazole-4-carboxylic acid ethyl ester was reacted with lithium aluminum hydride followed by hydrolytic workup and chromatography. The title compound was obtained as a yellow-white waxy solid. MS: 226(M + H) M/e+)。
Example 393
[1- (4-trifluoromethoxy-phenyl) -1H-imidazol-4-yl]-methanol
Following the general method described in example 293, 4- (trifluoromethoxy) aniline was reacted with triethyl orthoformate, ethyl nitroacetate, and acetic acid. Subsequently, treated with triethyl orthoformate, iron and acetic acidThen, alkaline hydrolysis is performed. The isolated acid was directly reduced as in example 264, i.e. with BH3The THF complex reaction followed by hydrolysis gave the title compound as a white crystal. Mp.105-106 ℃ (diethyl ether), MS: 258 (M/e)+)。
Example 394
1- (4-trifluoromethylsulfanyl-phenyl) -1H-imidazole-4-carboxylic acid
Following the general method described in example 234, 4- (trifluoromethylthio) aniline was reacted with triethyl orthoformate, ethyl nitroacetate, and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was followed by alkaline hydrolysis. The title compound was obtained as a light brown crystalline solid. Mp.247-248 ℃ (water/dioxane), MS: 288 (M/e)+)。
Example 395
[1- (4-trifluoromethylsulfanyl-phenyl) -1H-imidazol-4-yl]-methanol
Following the general method described in example 264, 1- (4-trifluoromethylsulfanyl-phenyl) -1H-imidazole-4-carboxylic acid was reacted with BH3The THF complex was reacted followed by hydrolytic workup. The title compound was obtained as an off-white crystalline solid. Mp.145-147 ℃ (water), MS: 275(M + H) M/e+)。
Example 396
1-quinolin-6-yl-1H-imidazole-4-carboxylic acid ethyl ester
Following the general method described in example 384, 6-aminoquinoline was reacted with triethyl orthoformate, ethyl nitroacetate, and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was performed. After work-up, chromatography gave the title compound as a brown crystalline solid. Mp.90-94 ℃ (ethyl acetate/hexane), MS: 268(M + H) M/e+)。
Example 397
(1-quinolin-6-yl-1H-imidazol-4-yl) -methanol
Following the general method described in example 388, 1-quinolin-6-yl-1H-imidazole-4-carboxylic acid ethyl ester was reacted with diisobutylaluminum hydride. After the hydrolysis treatment, chromatography was performed. The title compound was obtained as a light brown crystalline solid. Mp.183-187 ℃ (ethyl acetate/hexane), MS: 226(M + H) M/e+)。
Example 398
1-Quinolin-8-yl-1H-imidazole-4-carboxylic acid ethyl ester
Following the general method described in example 384, 8-aminoquinoline was reacted with triethyl orthoformate, ethyl nitroacetate, and acetic acid. Subsequently, treatment with triethyl orthoformate, iron and acetic acid was performed. After work-up, chromatography gave the title compound as a pale brown crystalline solid. Mp. > 92 ℃ (decomposed) (ethyl acetate/hexane), MS: 267 (M/e)+)。
Example 399
(1-quinolin-8-yl-1H-imidazol-4-yl) -methanol
Following the general method described in example 388, 1-quinolin-8-yl-1H-imidazole-4-carboxylic acid ethyl ester was reacted with diisobutylaluminum hydride. After the hydrolysis treatment, chromatography was performed. The title compound was obtained as a light brown crystalline solid. Mp.168-170 ℃ (diethyl ether), MS: 225 (M/e)+)。
Example 400
1- [ [1- (1, 3-benzodioxol-5-yl) -1H-imidazol-4-yl]Methyl radical]-2-nitro-1H-imidazole
Following the general procedure described in example 301, (1-benzo [1, 3 ]]dioxol-5-yl-1H-imidazol-4-yl) -methanol was first treated with thionyl chloride and then with 2-nitroimidazole and cesium carbonate. Evaporating, and extractingPhysical and chromatographic treatment afforded the title compound as a pale brown solid. Mp. > 156 ℃ (decomposed) (dichloromethane/isopropyl ether), MS: 314(M + H) M/e+)。
Example 401
2- (3-difluoromethyl-4-fluoro-phenyl) -4, 4, 5, 5-tetramethyl- [1, 3, 2]Dioxaborolane
The title compound was prepared as a colorless oil according to example 342, using 4-bromo-2-difluoromethyl-1-fluoro-benzene and 4, 4, 4 ', 4 ', 5, 5, 5 ', 5 ' -octamethyl-2, 2 ' -1, 3, 2-dioxaborolane as starting materials (54% yield), MS: 272 (M/e) ═ M/e+)。
Example 402
2- [3- (1, 1-difluoro-ethyl) -phenyl]-4, 4, 5, 5-tetramethyl- [1, 3, 2 [ ]]Dioxaborolane
The title compound was prepared as a colorless oil according to example 342, using 1-bromo-3- (1, 1-difluoro-ethyl) -benzene and 4, 4, 4 ', 4 ', 5, 5, 5 ', 5 ' -octamethyl-2, 2 ' -1, 3, 2-dioxaborolane as starting materials (60% yield), MS: 268 (M/e)+)。
Example 403
2- (3-fluoro-5-trifluoromethyl-phenyl) -4, 4, 5, 5-tetramethyl- [1, 3, 2]Dioxaborolane
The title compound was prepared as a colorless oil according to example 342, using 3-bromo-5-fluoro-trifluorotoluene and 4, 4, 4 ', 4 ', 5, 5, 5 ', 5 ' -octamethyl-2, 2 ' -1, 3, 2-dioxaborolane as starting materials (48% yield), MS: 290 (M/e)+)。
Example 404
2- [3- (1, 1-difluoro-ethyl) -4-fluoro-phenyl]-4, 4, 5, 5-tetramethyl- [1, 3, 2 [ ]]DioxaboronesHeterocyclopentane ring
The title compound was prepared as an orange oil (28% yield), MS: 286.2 (M/e ═ M+)。
Example 405
4-bromo-2-difluoromethyl-1-fluoro-benzene
5-bromo-2-fluorobenzaldehyde (2g, 9.85mmol) was dissolved in dichloromethane (50 ml). The reaction mixture was placed under argon and cooled to 0 ℃. Diethylaminosulfur trifluoride (2.04ml, 14.78mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. Then, the reaction was stopped with a saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and the solvent was distilled off. The brown oil was chromatographed (silica, eluent: hexane/ethyl acetate) to give the title compound (1.55g, 70%) as a colorless oil. MS: 226.0(M + H)+)。
Example 406
1-bromo-3- (1, 1-difluoro-ethyl) -benzene
The title compound was prepared as a colorless oil (15% yield) according to example 405 (diethylaminosulfur trifluoride alone) starting from 3-bromoacetophenone, MS: 220.0 (M/e)+)。
Example 407
1- (2-fluoro-5-nitro-phenyl) -ethanones
The title compound was prepared using the following literature methods: m.q.zhang, a.haemers, d.vanden Berghe, s.r.pattyn, w.bolaert, j.heterocyclic chem., 1991,28673-683, using 2' -fluoro acetophenone as raw material. Obtained as a pale yellow solid (85%). MS: m/e＝205.0(M+)。
Example 408
4-bromo-2- (1, 1-difluoro-ethyl) -1-fluoro-benzene
The title compound was prepared using procedures described in the literature (a. takahashi, t.agatsuma, m.matsuda, t.ohta, t.nuozawa, t.endo, s.nozoe, chem.pharm.bull., 1992,403185 and 3188), 3- (1, 1-difluoro-ethyl) -4-fluoro-phenylamine is used as a starting material. A dark red liquid was obtained (yield 46%).1H-NMR(400MHz)δ＝1.99(t，J＝11.75Hz，3H)，7.02(t，J＝6.0Hz，1H)，7.50-7.55(m，1H)，7.65-7.69(m，1H)。
Example 409
2-cyclopropyl-1H-imidazole
To a solution of ethyl cyclopropaneimidate (32.9g, 291mmol) in methanol (40ml) was added aminoacetaldehyde dimethyl acetal (34.5ml, 320mmol), and the reaction mixture was stirred for 2 days. The reaction mixture was concentrated, concentrated hydrochloric acid and water were added, and the mixture was concentrated again. The residue was dissolved in water, the pH adjusted to 8 by the addition of sodium carbonate and the mixture was concentrated. The brown residue was then suspended in ethanol and filtered. The filtrate was concentrated to give 30.6g (283mmol, 97%) of the title compound. MS: and M/e is 107.1 (M-H).
Example 410
Cyclopropane carboxylic acid ethyl ester hydrochloride
A steady stream of HCl was passed slowly through a solution of cyclopropanecarbonitrile (25g, 373mmol) in ethanol (17.2 ml). After 15 hours, the reaction mixture was cooled to 0 ℃ and diethyl ether was added dropwise. The precipitated title compound was filtered to give a colorless crystalline material (32.9g, 220mmol, 59%). MS: and M/e is 112.2 (M-H).
Example 411
5-bromo-1-methyl-2- (2-methyl-imidazol-1-ylmethyl) -1H-imidazole
(5-bromo-1-methyl-1H-imidazol-2-yl) -methanol (1.0g, 5.24mmol) and tetrabromomethane (2.48g, 7.33mmol) were dissolved in THF (10.0ml) and cooled to 0 ℃. Triphenylphosphine (1.98g, 7.33mmol) was added dropwise over 30 min. The reaction mixture was stirred at 0 ℃ for 1 hour to give a white suspension. In a second flask, sodium hydride (1.05g, 26.18mmol, 60% dispersion in mineral oil) was suspended in a solution of DMF (20ml) and cooled to 0 ℃. 2-methylimidazole (2.15g, 26.2mmol) was added portionwise. The reaction mixture was stirred at 60 ℃ for 30 minutes, cooled to 0 ℃ and treated with the above suspension. After stirring at room temperature for 2 hours, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (50 ml). The aqueous layer was extracted 3 times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was chromatographed (silica, eluent: dichloromethane/methanol 95: 5) to give the title compound (0.7g, 52%) as a brown solid. MS: m/e 255.0 (M)+)。
Example 412
(5-bromo-1-methyl-1H-imidazol-2-yl) -methanol
1-methylimidazole-2-methanol (3.15g, 28mmol) (R.J.Sundberg; P.V.Nguyen; Med.chem.Res.7, 2, 1997, 123-propanoic acid 136) was suspended in THF (75ml) at-20 ℃ and treated slowly (over 30 min) with N-bromosuccinimide (4.9g, 27 mmol). The reaction mixture was slowly warmed to room temperature and quenched with saturated aqueous sodium bicarbonate (50 ml). The aqueous layer was extracted 3 times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was chromatographed (silica, eluting first with ethyl acetate/hexane 1: 1 and then dichloromethane/methanol 95: 05) to give the title compound (2.11g, 67%) as a white solid. MS: m/e 191.2 (M)+)。
Example A
Tablet (Wet granulation)
Item ingredient mg/tablet
5mg 25mg 100mg 500mg
Formula 1 Compound 525100500
2 lactose anhydrous DTG 12510530150
3 Sta-Rx 1500 6 6 6 30
4 microcrystalline cellulose 303030150
5 magnesium stearate 1111
Total 167167167831
The production process comprises the following steps:
1. mixing the above items 1, 2, 3 and 4 and granulating with purified water.
2. The granules were dried at 50 ℃.
3. The granules are passed through a suitable milling apparatus.
4. Add item 5 and mix for 3 minutes; tabletting on a suitable tabletting machine.
Example B
Capsule
Project ingredient mg/capsule
5mg 25mg 100mg 500mg
Formula 1 Compound 525100500
2 aqueous lactose 159123148-
3 corn starch 25354070
4 Talc 10151025
5 magnesium stearate 1225
Total 200200300500
The production process comprises the following steps:
1. mix items 1, 2 and 3 above in a suitable mixer for 30 minutes.
2. Add items 4 and 5 and mix for 3 minutes.
3. Fill into a suitable capsule.
Claims (19)
1. A compound of the formula or a pharmaceutically acceptable acid addition salt thereof
Wherein
A is phenyl, pyridin-2-yl, pyridin-3-yl or piperidin-1-yl;
R1/R2independently of one another, hydrogen, halogen, C1-7Alkyl radical, C3-6Cycloalkyl radical, C2-7Alkenyl, trifluoromethyl, -O-trifluoromethyl, -S-trifluoromethyl, S-C1-7Alkyl radical, C1-7Alkoxy, -CHF2、-C(C1-7Alkyl) F2、-OCHF2Phenyl, nitro, benzyloxy, hydroxy or amino,
or in any adjacent position, together with the carbon atoms to which they are attached, is-CH-, -CH-N-, - (CH)2)3-、-O-CH2-O-、-O-CF2-O-、-CH2-O-CH2-or-CH2CH2-O-；
R3Is hydrogen, C1-7Alkyl radical, C3-6Cycloalkyl, phenyl, S-C1-7Alkyl, amino, C1-7Alkyl-amino, -NHC (O) -C1-7Alkyl or hydroxy-C1-7An alkyl group;
R4/R5independently of one another, hydrogen or C1-7Alkyl, or together with the carbon atom to which they are attached form a radical- (CH)2)4-，
R6/R6' independently of one another are hydrogen or C1-7An alkyl group;
R7is hydrogen, -CH2OH or C1-7An alkyl group, a carboxyl group,
is a 5-membered nitrogen-containing heteroaryl selected from:
2. the compound of claim 1 having the formula
Wherein the content of the first and second substances,a and R1-R7As defined in claim 1.
3. A compound of formula Ia according to claim 2, wherein A is phenyl and R is1And R2Independently of one another are C1-7Alkyl, -CHF2、-C(C1-7Alkyl) F2、CF3Or halogen, or together with the corresponding carbon atom form a radical- (CH)2)3-，R3Is C1-7Alkyl or amino; and R is4、R5、R6And R6' is hydrogen.
4. A compound of formula Ia according to claim 3, which is:
1- [ [1- (4-chloro-3-methylphenyl) -1H-imidazol-4-yl ] methyl ] -2-ethyl-1H-imidazole,
1- [ [1- (4-chloro-3-methylphenyl) -1H-imidazol-4-yl ] methyl ] -2-methyl-1H-imidazole,
1- [ [1- (2, 3-dihydro-1H-inden-5-yl) -1H-imidazol-4-yl ] methyl ] -2-methyl-1H-imidazole,
1- [ [1- [ 4-fluoro-3- (trifluoromethyl) phenyl ] -1H-imidazol-4-yl ] methyl ] -2-methyl-1H-imidazole,
1- [1- (4-chloro-3-methyl-phenyl) -1H-imidazol-4-yl-methyl ] -1H-imidazol-2-yl-amine,
1- [ [1- [3- (1, 1-difluoroethyl) phenyl ] -1H-imidazol-4-yl ] methyl ] -2-methyl-1H-imidazole,
1- [ [1- (3-difluoromethyl-4-fluorophenyl) -1H-imidazol-4-yl ] methyl ] -2-methyl-1H-imidazole, or
1- [ [1- [3- (1, 1-difluoroethyl) -4-fluorophenyl ] -1H-imidazol-4-yl ] methyl ] -2-methyl-1H-imidazole.
5. The compound of claim 1 having the formula
Wherein, A and R1-R6' as defined in claim 1.
6. A compound of formula Ib according to claim 5, wherein A is phenyl and R is1And R2Is halogen, R3Is C1-7Alkyl or hydrogen, R4、R5And R6、R6' is hydrogen.
7. A compound of formula Ib according to claim 6, which is 1- (3, 4-dichloro-phenyl) -3- (2-methyl-imidazol-1-yl-methyl) -1H-pyrazole.
8. The compound of claim 1 having the formula
Wherein, A and R1-R6' as defined in claim 1.
9. The compound of formula Ic according to claim 8, wherein A is phenyl and R is1And R2Is halogen, R3Is C1-7Alkyl or hydrogen, R4、R5And R6、R6' is hydrogen.
10. A compound of formula Ic according to claim 9, which is:
1- (3, 4-dichloro-phenyl) -4-imidazol-1-yl-methyl-1H-pyrazole; or
1- (3, 4-dichloro-phenyl) -4- (2-methyl-imidazol-1-yl-methyl) -1H-pyrazole.
11. The compound of claim 1 having the formula
Wherein, A and R1-R7As defined in claim 1.
12. A compound of formula Id according to claim 11 where A is phenyl and R is1And R2Is halogen, hydrogen, CF3Or C1-7Alkyl radical, R3Is C1-7Alkyl or hydrogen, R4、R5And R6、R6' is hydrogen.
13. The compound of formula Id according to claim 12, which is
2-methyl-1- [ [4- [3- (trifluoromethyl) phenyl ] -1H-imidazol-2-yl ] methyl ] -1H-imidazole,
1- [ [4- (4-fluoro-3-methylphenyl) -1H-imidazol-2-yl ] methyl ] -2-methyl-1H-imidazole,
1- [ [4- (3, 4-difluorophenyl) -1H-imidazol-2-yl ] methyl ] -2-methyl-1H-imidazole or
4- (4-fluoro-3-methylphenyl) -2- (1H-imidazol-1-yl-methyl) -1H-imidazole.
14. A medicament comprising one or more compounds of formula I according to any one of claims 1 to 13 or a pharmaceutically acceptable acid addition salt thereof together with an inert carrier for the treatment of diseases.
15. The medicament according to claim 14 for use in a medicament for the treatment of a disease based on therapeutic indications for NMDA receptor subtype specific blockers selected from the group consisting of: acute neurodegenerative diseases caused by stroke and brain trauma, chronic neurodegenerative diseases and neurodegenerative diseases associated with bacterial or viral infections, and depression and chronic or acute pain.
16. The medicament according to claim 15, wherein the chronic neurodegenerative disease is alzheimer's disease, parkinson's disease, huntington's disease or amyotrophic lateral sclerosis.
17. A process for the preparation of a compound of formula I according to claim 1, which process comprises:
a) reacting a compound of the formula
With a compound of the formula
To give a compound of the formula
Wherein
A is phenyl or pyridin-2 or 3-yl, R1-R7Has the meaning given in claim 1, hal is Br or Cl, or
b) Cleavage of the N-protecting group from a compound of the formula
To give a compound of the formula
Wherein, A and R1-R6Has the meaning given in claim 1, P is an N-protecting group.
18. The use of a compound of formula I as claimed in any one of claims 1 to 13 for the manufacture of a medicament for the treatment of a disease for which a therapeutic indication based on an NMDA receptor subtype specific blocker is indicated, said disease being selected from the group consisting of acute neurodegenerative diseases caused by stroke and brain trauma, chronic neurodegenerative diseases and neurodegenerative diseases associated with bacterial or viral infections, and depression and chronic or acute pain.
19. The use of claim 18, wherein the chronic neurodegenerative disease is alzheimer's disease, parkinson's disease, huntington's disease, or amyotrophic lateral sclerosis.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP01101947.8 | 2001-01-29 | ||
| EP01101947 | 2001-01-29 | ||
| PCT/EP2002/000552 WO2002060877A1 (en) | 2001-01-29 | 2002-01-21 | Imidazole derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1063794A1 HK1063794A1 (en) | 2005-01-14 |
| HK1063794B true HK1063794B (en) | 2011-01-14 |
Family
ID=
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1489580B (en) | Imidazole derivatives | |
| DE69736642T2 (en) | Heterocyclic compounds, their preparation and use | |
| TWI452035B (en) | 5-membered heterocycle-based p38 kinase inhibitors | |
| EP1194144B1 (en) | Antibacterial compounds | |
| US5332831A (en) | Benzofuran derivatives | |
| IE74202B1 (en) | 4,5,6-substituted-2-pyrimidinamines | |
| CZ303101B6 (en) | Neurotrophin production/secretion promoting agent | |
| CZ305099B6 (en) | Pyrazole derivative, process and intermediates to the preparation thereof, pharmaceutical composition containing the derivative and medicinal application thereof particularly for treating HIV infection | |
| CA2129146A1 (en) | Imidazole, triazole and tetrazole derivatives | |
| BG60429B2 (en) | (1h-azol-1-ilmethyl) substituted benzotriazol derivatives | |
| IL121299A (en) | 4-hydroxy-piperidine derivatives, a process for their preparation and pharmaceutical compositions containing them | |
| US5922718A (en) | Triazolones as apolipoprotein-B synthesis inhibitors | |
| JP2003277379A (en) | Nitrogen-containing heterocyclic compound, method for producing the same and use thereof | |
| HK1063794B (en) | Imidazole derivatives | |
| HK1146646B (en) | Imidazole derivatives | |
| AU2002246043B2 (en) | Imidazole derivatives | |
| AU2002246043A1 (en) | Imidazole derivatives | |
| TWI328584B (en) | Imidazole derivatives | |
| AU2016366443A1 (en) | Aminoazole derivative |