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CAS No. : | 18672-03-2 | MDL No. : | MFCD08234602 |
Formula : | C7H5Cl2N3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HAADRTMPUSJNOI-UHFFFAOYSA-N |
M.W : | 202.04 | Pubchem ID : | 466016 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 50.52 |
TPSA : | 54.7 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.75 cm/s |
Log Po/w (iLOGP) : | 1.07 |
Log Po/w (XLOGP3) : | 2.51 |
Log Po/w (WLOGP) : | 2.46 |
Log Po/w (MLOGP) : | 1.96 |
Log Po/w (SILICOS-IT) : | 2.57 |
Consensus Log Po/w : | 2.11 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.23 |
Solubility : | 0.119 mg/ml ; 0.00059 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.3 |
Solubility : | 0.1 mg/ml ; 0.000496 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.79 |
Solubility : | 0.0328 mg/ml ; 0.000163 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.59 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | at 0 - 20℃; for 14 h; | EXAMPLE 138; Synthesis of N4-(5-bromo-2-methylphenyl)-N5-(5,6-dichloro-lH-benzimidazol-2- yl)-lH-imidazole-4,5-dicarboxamide; Synthesis of 5,6-dichloro-lH-benzo[d]imidazol-2-aminc; [00392] 4,5-Dichlorobenzene-l,2-diamine (0.81 g, 0.562 mmol, commercially available from Aldrich) in acetonitrile (10 mL) and water (2 ml) at 0 °C was treated with cyanogen bromide (0.063 g, 0.6 mmol). The reaction mixture was allowed to warm to room temperature, and then stirred for 14 hours. The reaction mixture was then treated with saturated aqueous sodium hydrogen carbonate solution (50 ml) and shaken. The resulting solid was filtered off, washed with water, and dried under reduced pressure to give 0.43 g of 5,6-difluoro-lH-benzo[d]imidazol-2-amine (yield, 50percent). MS (EI): 203 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With hydrogenchloride; dihydrogen peroxide In water | EXAMPLE 5 5,6-Dichloro-2-aminobenzimidazole was prepared by a modification of the method of N. J. Leonard et al., J. Am. Chem. Soc., 69, 2459 (1947) for 2-amino-5-chlorobenzimidazole. To 77.2 g. (0.58 mole) of 2-aminobenzimidazole dissolved in 500 ml. of water and 50 ml. of 12N hydrochloric acid was added an additional 900 ml. of concentrated hydrochloric acid. The solution was stirred during the addition of 120 ml. of 30percent hydrogen peroxide (sp.gr. 1.10) and for 2 hours following the addition. After evaporation to dryness at reduced pressure, the residual solid was taken up in 500 ml. of water and made alkaline by addition of conc. NH4 OH. After the solution had been boiled it was cooled to 20° C., the precipitated solid was collected by filtration and washed with water to afford 104.5 g. (89percent yield) of crude product. Upon recrystallization from ethanol it melted at 252°-254° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.5% | With sodium nitrite In methanol; chloroform; water | Method B A CuCl2 saturated aqueous solution (15 ml) was diluted to 25 ml with water. Sodium nitrite (1.035 g, 5 mmole) was dissolved in 5 ml of water and slowly added to the CuCl2 solution. After two minutes, 2-amino-5,6-dichlorobenzimidazole (0.935 g, 5 mmole) was slowly added in small portions. The mixture was stirred at room temperature for 1 hr. Excess CuCl2 solution was added and the mixture was heated on a steam bath for 1 hr. The aqueous solution was then extracted with ethyl acetate (3*50 ml) and the organic layer was washed with brine, dried with MgSO4, concentrated, and separated on a silica column using 2percent MeOH/CHCl3 to afford 545 mg (49.5percent) of 2,5,6-trichlorobenzimidazole. 1 H NMR, TLC, and MS analysis were identical to the same compound obtained by Method A. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | In water; acetonitrile; at 0 - 20℃; for 14h; | EXAMPLE 138; Synthesis of N4-(5-bromo-2-methylphenyl)-N5-(5,6-dichloro-lH-benzimidazol-2- yl)-lH-imidazole-4,5-dicarboxamide; Synthesis of 5,6-dichloro-lH-benzo[d]imidazol-2-aminc; [00392] 4,5-Dichlorobenzene-l,2-diamine (0.81 g, 0.562 mmol, commercially available from Aldrich) in acetonitrile (10 mL) and water (2 ml) at 0 C was treated with cyanogen bromide (0.063 g, 0.6 mmol). The reaction mixture was allowed to warm to room temperature, and then stirred for 14 hours. The reaction mixture was then treated with saturated aqueous sodium hydrogen carbonate solution (50 ml) and shaken. The resulting solid was filtered off, washed with water, and dried under reduced pressure to give 0.43 g of 5,6-difluoro-lH-benzo[d]imidazol-2-amine (yield, 50%). MS (EI): 203 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.13 g (26%) | With hydrogen bromide; sodium nitrite; In water; | 2-Bromo-5,6-dichlorobenzimidazole 2-Amino-5,6-dichlorobenzimidazole (3 g, 16 mmole) was suspended in 150 ml of water and brought into solution with 2 ml of HBr. Sodium nitrite (3.3 g, 55 mmole) was then added and the mixture was stirred at room temperature for 1 hr. Excess CuBr2 was then added and the mixture was heated on a steam bath for 1 hr. The aqueous solution was extracted with ethyl acetate (3*100 ml), dried with MgSO4, concentrated, and crystallized from ethyl ether to give 1.13 g (26%) of 2-bromo-5,6-dichlorobenzimidazole. 1 H NMR (DMSO-d6) delta7.81 ppm (s, 2H), 13.62 (s, 1H). GC/MS: m/e 266, 185, 158, 150, 133, 124, 107, 97, 88, 73, 62, 52, 37. |
1.13 g (26%) | With hydrogen bromide; sodium nitrite; In water; | Method A(7) 2-Amino-5,6-dichlorobenzimidazole (3 g, 16 mmole) was suspended in 150 ml of water and brought into solution with 2 ml of HBr. Sodium nitrite (3.3 g, 55 mmole) was then added and the mixture was stirred at room temperature for 1 hr. Excess CuBr2 was then added and the mixture was heated on a steam bath for 1 hr. The aqueous solution was extracted with ethyl acetate (3*100 ml), dried with MgSO4, concentrated, and crystallized from ethyl ether to give 1.13 g (26%) of 2-bromo-5,6-dichlorobenzimidazole (7). 1 H NMR (DMSO-d6)delta7.81 ppm (s, 2H), 13.62 (s, 1H). GC/MS: m/e 266, 185, 158, 150, 133, 124, 107, 97, 88, 73, 62, 52, 37. |
1.13 g (26%) | With hydrogen bromide; sodium nitrite; In water; | Method A(7) 2-Amino-5,6-dichlorobenzimidazole (3 g, 16 mmole) was suspended in 150 ml of water and brought into solution with 2 ml of HBr. Sodium nitrite (3.3 g, 55 mmole) was then added and the mixture was stirred at room temperature for 1 hr. Excess CuBr2 was then added and the mixture was heated on a steam bath for 1 hr. The aqueous solution was extracted with ethyl acetate (3*100 ml), dried with MgSO4, concentrated, and crystallized from ethyl ether to give 1.13 g (26%) of 2-bromo-5,6-dichlorobenzimidazole (7). 1 H NMR (DMSO-d6) delta7.81 ppm (s, 2H), 13.62 (s, 1H). GC/MS: m/e 266, 185, 158, 150, 133, 124, 107, 97, 88, 73, 62, 52, 37. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
545 mg (49.5%) | With sodium nitrite; In methanol; chloroform; water; | Method B A CuCl2 saturated aqueous solution (15 ml) was diluted to 25 ml with water. Sodium nitrite (1.035 g, 5 mmole) was dissolved in 5 ml of water and slowly added to the CuCl2 solution. After two minutes, <strong>[18672-03-2]2-amino-5,6-dichlorobenzimidazole</strong> (0.935 g, 5 mmole) was slowly added in small portions. The mixture was stirred at room temperature for 1 hr. Excess CuCl2 solution was added and the mixture was heated on a steam bath for 1 hr. The aqueous solution was then extracted with ethyl acetate (3*50 ml) and the organic layer was washed with brine, dried with MgSO4, concentrated, and separated on a silica column using 2% MeOH/CHCl3 to afford 545 mg (49.5%) of 2,5,6-trichlorobenzimidazole. 1 H NMR, TLC, and MS analysis were identical to the same compound obtained by Method A. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.23 g (85%) | With sodium hydroxide; In methanol; chloroform; acetonitrile; | Method A(182) 2-Amino-5,6-dichlorobenzimidazole (4) (1 g, 4.95 mmole) was dissolved in acetonitrile (200 ml) and NaOH (198 mg, 4.95 mmole) was added. After stirring for 1 hr at room temperature, benzyl bromide (0.589 ml, 4.95 mmole) was added and the mixture was allowed to stir overnight. The mixture was concentrated under reduced pressure and purified on a silica gel column (3.5*5 cm) using 5% MeOH/CHCl3 to give 1.23 g (85%) of 2-amino-1-benzyl-5,6-dichlorobenzimidazole (182). The compound was then recrystallized from EtOH/H2O to give a white powder. 1 H NMR (DMSO-d6): d 5.28 ppm (s, 2H), 6.95 (s, 2H), 7.16 (d, 2H), 7.25 (d, 1H), 7.31 (m, 4H). 13 C NMR (DMSO-d6): D 44.74 ppm, 109.15, 115.37, 119.62, 122.66, 126.82, 127.37, 128.55, 134.10, 136.46, 143.13, 156.91. MS (Electron Impact): m/e 291, 200, 158, 91, 65. MP: 245-246 C. Elemental Analysis: (C14 H11 Cl2 N3): Calculated: C, 57.55; H, 3.79; N, 14.38. Found: C, 57.66; H, 3.83; N, 13.98. UV Imax nm (e*104): (pH 7) 230 (0.761), 260 (0.324), 302 (0.452); (pH 1) 238 (0.306), 294 (0.383), 299 (0.359); (pH 11) 229 (0.869), 257 (0.316), 301 (0.443). |
1.23 g (85%) | With sodium hydroxide; In methanol; chloroform; acetonitrile; | Method A(182) 2-Amino-5,6-dichlorobenzimidazole (4) (1 g, 4.95 mmole) was dissolved in acetonitrile (200 ml) and NaOH (198 mg, 4.95 mmole) was added. After stirring for 1 hr at room temperature, benzyl bromide (0.589 ml, 4.95 mmole) was added and the mixture was allowed to stir overnight. The mixture was concentrated under reduced pressure and purified on a silica gel column (3.5*5 cm) using 5% MeOH/CHCl3 to give 1.23 g (85%) of 2-amino-1-benzyl-5,6-dichlorobenzimidazole (182). The compound was then recrystallized from EtOH/H2O to give a white powder. 1 H NMR (DMSO-d6): d 5.28 ppm (s, 2H), 6.95 (s, 2H), 7.16 (d, 2H), 7.25 (d, 1H), 7.31 (m, 4H). 13 C NMR (DMSO-d6): d 44.74 ppm, 109.15, 115.37, 119.62, 122.66, 126.82, 127.37, 128.55, 134.10, 136.46, 143.13, 156.91. MS (Electron Impact): m/e 291, 200, 158, 91, 65. MP: 245-246 C. Elemental Analysis: (C14 H11 Cl2 N3'): Calculated: C, 57.55; H, 3.79; N, 14.38. Found: C, 57.66; H, 3.83; N, 13.98. UV Imax nm (e*104): (pH 7) 230 (0.761), 260 (0.324), 302 (0.452); (pH 1) 238 (0.306), 294 (0.383), 299 (0.359); (pH 11) 229 (0.869), 257 (0.443). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; water; acetonitrile; | 2-Amino-5,6-dichlorobenzimidazole (4). A modified procedure of the procedure described by Leonard, N.J., et al., J. Am. Chem. Soc. 69:2459 (1947), was followed. Cyanogen bromide (136.6 g, 1.3M, 260 mL of a 5M solution in CH3 CN from) was added to a solution of MeOH (250 mL) in H2 O (1500 mL). 4,5-Dichloro-1,2-phenylenediamine (available commercially from Aldrich Chemical Company) (222.4 g, 1.26M) was then added in five portions, as the initial reaction is exothermic. The reaction mixture was stirred without heating for 80 hr. then treated with activated charcoal (5 g). The 80 hr time period was for convenience alone, since the reaction is probably complete within 24 hr. After stirring for two hrs, the reaction mixture was filtered through Celite. The filter cake was washed with MeOH (250 mL) and H2 O (750 mL) and the filter cake was discarded. The filtrate was diluted with H2 O (1.5 L), adjusted to pH 10 with conc. NH 4 OH (1750 mL) and then allowed to stand overnight at 5 C. The precipitate (yellow leaflets) was collected by filtration, washed with H2 O and then dried under reduced pressure at 50 C. for 60 hr. Crude yield: 265 g. This product was purified by recrystallization from CH3 CN to yield: 205.6 g (80.7%) of 4. MP: 264-266 C. TLC: Rf =0.22 (CHCl3 --MeOH), 10:1; SiO2). See Horner, J. K. et al., J. Med. Chem. 11:946-949 (1968), lit. MP: 260-262 C. As an alternative, the crude material is dissolved in absolute ethanol, treated with activated charcoal, and the solution diluted with an equal volume of H2 O and stored at 5 C. for 18-24 hr. | |
In methanol; water; acetonitrile; | 2-Amino-5,6-dichlorobenzimidazole (4) A modified procedure of the procedure described by Leonard, N. J., et al., J. Am. Chem. Soc. 69:2459 (1947), was followed. Cyanogen bromide (136.6 g, 1.3M, 260 mL of a 5M solution in CH3 CN from) was added to a solution of MeOH (250 mL) in H2 O (1500 mL). 4,5-Dichloro-1,2-phenylenediamine (available commercially from Aldrich Chemical Company) (222.4 g, 1.26M) was then added in five portions, as the initial reaction is exothermic. The reaction mixture was stirred without heating for 80 hr. then treated with activated charcoal (5 g). The 80 hr time period was for convenience alone, since the reaction is probably complete within 24 hr. After stirring for two hrs, the reaction mixture was filtered through Celite. The filter cake was washed with MeOH (250 mL) and H2 O (750 mL) and the filter cake was discarded. The filtrate was diluted with H2 O (1.5 L), adjusted to pH 10 with conc. NH4 OH (1750 mL) and then allowed to stand overnight at 5 C. The precipitate (yellow leaflets) was collected by filtration, washed with H2 O and then dried under reduced pressure at 50 C. for 60 hr. Crude yield: 265 g. This product was purified by recrystallization from CH3 CN to yield: 205.6 g (80.7%) of 4. MP: 264-266 C. TLC: Rf =0.22 (CHCl3 -MeOH), 10:1; SiO2). See Horner, J. K. et al., J. Med. Chem. 11:946-949 (1968), lit. MP: 260-262 C. As an alternative, the crude material is dissolved in absolute ethanol, treated with activated charcoal, and the solution diluted with an equal volume of H2 O and stored at 5 C. for 18-24 hr. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.14 g (15%) | With benzenesulfonamide; In acetonitrile; | 2-Amino-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl) benzimidazole (43) 2-Amino-5,6-dichlorobenzimidazole (4) (3 g, 16 mmole) was dissolved in dry acetonitrile (150 ml) and stirred in an insert atmosphere at 60 C. BSA (4.37 ml, 17 mmole) was added and the mixture was stirred for 10 minutes. 1,2,3,5-tetra-O-acetyl-beta-D-ribofuranose (5.09 g, 16 mmole) and TMSTf (3.29 ml, 17 mmole) were added to the clear solution and the mixture was allowed to stir at 60 C. for 1 hr. The mixture was concentrated under reduced pressure and separated on a silica column to yield 1.14 g (15%) of 2-amino-5,6-dichloro-1-(2,3,5,tri-O-acetyl-beta-d-ribofuranosyl) benzimidazole (43). -- C NMR (CDCl3): d 170.04 ppm, 169.56, 169.11, 154.57, 141.64, 132.53, 125.90, 1123.45, 117.72, 109.49, 85.78, 80.99, 70.95, 69.83, 62.91, 20.74, 20.54, 20.20. 1 H NMR (CDCl3): d 0.96 ppm (s, 3H), 1.09 (s, 3H), 1.13 (s, 3H), 3.75 (m, 2H), 4.08 (dd, 1H), 5.00 (dd, 1H), 5.13 (t, 1H), 5.42 (s, 2H), 5.61 (d, 1H), 7.27 (s, 1H), 7.42 (s, 1H). MS (FAB): m/e 758, 718, 676, 460, 426, 259, 217, 139. |
1.14 g (15%) | With benzenesulfonamide; In acetonitrile; | 2-Amino-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)benzimidazole (43) 2-Amino-5,6-dichlorobenzimidazole (4) (3 g, 16 mmole) was dissolved in dry acetonitrile (150 ml) and stirred in an inert atmosphere at 60 C. BSA (4.37 ml, 17 mmole) was added and the mixture was stirred for 10 minutes. 1,2,3,5-tetra-O-acetyl-beta-D-ribofuranose (5.09 g, 16 mmole) and TMSTf (3.29 ml, 17 mmole) were added to the clear solution and the mixture was allowed to stir at 60 C. for 1 hr. The mixture was concentrated under reduced pressure and separated on a silica column to yield 1.14 g (15%) of 2-amino-5,6-dichloro-1-(2,3,5,tri-O-acetyl-beta-D-ribofuranosyl)benzimidazole (43). 13 C NMR (CDCl3): d 170.04 ppm, 169.56, 169.11, 154.57, 141.64, 132.53, 125.90, 1123.45, 117.72, 109.49, 85.78, 80.99, 70.95, 69.83, 62.91, 20.74, 20.54, 20.20. 1 H NMR (CDCl3): d 0.96 ppm (s, 3H), 1.09 (s, 3H), 1.13 (s, 3H), 3.75 (m, 2H), 4.08 (dd, 1H), 5.00 (dd, 1H), 5.13 (t, 1H), 5.42 (s, 2H), 5.61 (d, 1H), 7.27 (s, 1H), 7.42 (s, 1H). MS (FAB): m/e 758, 718, 676, 460, 426, 259, 217, 139. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetone; | EXAMPLE 25 7,8-Dichloro-1,2-dihydro-2,2,3-trimethyl-1,3,5-triazino[1,2-a]benzimidazol-4(3H)-one Reaction of <strong>[18672-03-2]2-amino-5,6-dichlorobenzimidazole</strong> with acetone and methyl isocyanate according to the procedure of Example 1, first paragraph, provided the title compound. In this case, a 10-N-methylcarbamoyl derivative was not isolated from the reaction mixture. The product was recrystallized from acetone to give a solid, mp 220 C. (dec.). The confirmatory elemental analysis is shown in Table III. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N-methyl-acetamide; | Alkylation of <strong>[18672-03-2]2-amino-5,6-dichlorobenzimidazole</strong> with 4-methyl-1-piperazinyl propyl bromide and sodium hydride in dimethylformamide by the procedure of Example 4 gave 1-[3-(4-methyl-1-piperazinyl)propyl]-<strong>[18672-03-2]2-amino-5,6-dichlorobenzimidazole</strong>, m.p. 226-228 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With hydrogenchloride; dihydrogen peroxide; In water; | EXAMPLE 5 5,6-Dichloro-2-aminobenzimidazole was prepared by a modification of the method of N. J. Leonard et al., J. Am. Chem. Soc., 69, 2459 (1947) for 2-amino-5-chlorobenzimidazole. To 77.2 g. (0.58 mole) of 2-aminobenzimidazole dissolved in 500 ml. of water and 50 ml. of 12N hydrochloric acid was added an additional 900 ml. of concentrated hydrochloric acid. The solution was stirred during the addition of 120 ml. of 30% hydrogen peroxide (sp.gr. 1.10) and for 2 hours following the addition. After evaporation to dryness at reduced pressure, the residual solid was taken up in 500 ml. of water and made alkaline by addition of conc. NH4 OH. After the solution had been boiled it was cooled to 20 C., the precipitated solid was collected by filtration and washed with water to afford 104.5 g. (89% yield) of crude product. Upon recrystallization from ethanol it melted at 252-254 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 46 2-Amino-5,6-dichloro-1,3-bis[(2-bromophenoxy)methyl]-1H-benzimidazol-3-ium chloride Following the procedure of Example 2 and replacing 2-aminobenzimidazole with <strong>[18672-03-2]2-amino-5,6-dichlorobenzimidazole</strong> and replacing 2-bromo-4-chlorophenyl chloromethyl ether with 2-bromophenyl chloromethyl ether, the title compound is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; | (Example 17)--7,8-dichloro-3,4-dihydropyrimido[1,2-a]benzimidazol-2(1H)-one; obtained as a solid, m.p. >345 C.; microanalysis, C10 H7 N3 OCl2 requires: C, 46.9; H, 2.7; N, 16.4%; found: C, 46.9; H, 2.8; N, 16.4%; by heating 5,6-dichloro-2-aminobenzimidazole with MA in ethanol under reflux for 72 hours; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With Thiamine hydrochloride; In ethanol; for 8h;Reflux; | General procedure: A mixture of 2-aminobenzimidazole 1 (3 mmol), aromatic aldehyde2 (6.6 mmol), TMSCN 3 (3.3 mmol) and VB1 (0.09 mmol,3 mol %) in 10 mL EtOH was heated to reflux for 6e12 h (Table 2). After completion of the reaction (TLC), the solid was filtered off andwashed with ethanol to yield the pure products 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | With triethylamine; In N,N-dimethyl-formamide; for 17h; | Intermediate 31 7y-[10,ll-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]dodeca- l(8),6,9,ll-tetraen-3-yl]prop-2-enamide To a stirred solution of prop-2-enamide (170 mg, 2.38 mmol) in DMF (8 mL) were added methyl 3,3,3-trifiuoro-2-oxopropanoate (400 mu., 3.96 mmol) and pyridine (190 mu., 2.38 mmol) at room temperature under nitrogen. The reaction mixture was stirred for 2 h. Thionyl chloride (180 mu, 2.38 mmol) was added dropwise at 0C and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated and the residue filtered through a short pad of silica, eluting with DCM, under nitrogen. The filtrate was concentrated, and the acyl intermediate that remained was dissolved in DMF (6 mL) under nitrogen. The solution of acyl intermediate was added to a solution of 5,6-dichloro-lH-l,3-benzodiazol-2-amine (400 mg, 1.98 mmol) in DMF (8 mL) followed by triethylamine (320 2.38 mmol). The reaction mixture was stirred for 17 h and then concentrated. The residue was dissolved in EtOAc (25 mL) and washed with water (30 mL). The aqueous phase was extracted with EtOAc (20 mL) and the combined organic extracts were washed with 10% citric acid(aq) (2 x 15 mL), brine (25 mL), and then dried (MgSC^), filtered and concentrated. The crude product was triturated in DCM and purified by silica chromatography, using 0-10% MeOH in DCM as eluent, to afford the title compound as a light brown solid (41 mg, 5%); m/z = 378.8, 380.8 (MH)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | Example 62 6-chloro-A'-[10,ll-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]-dodeca- l(12),6,8,10-tetraen-3-yl]pyridine-2-carboxamide (ABR 239356) The general procedure for the preparation of 2-bromo-N-[3-oxo-4-(trifluoromethyl)-2,5,7- triazatricyclo[6.4.0.02'6]dodeca-l (12),6,8,10-tetraen-4-yl]benzamide was used but with the following changes. In the first stage of the reaction, to form the acyl imine intermediate, 6- chloropyridine-2-carboxamide was used instead of 2-bromobenzamide. In the second stage of the reaction, 5,6-dichloro-lH-l ,3-benzodiazol-2-amine was used instead of lH-l ,3-benzodiazol-2- amine and the reaction was stirred for 16 h instead of 4 h. The crude product was purified by silica chromatography, using 2% MeOH in DCM as eluent (14%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
300 mg | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; | Example 2 A^[10,ll-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]dodeca- l(12),6,8,10-tetraen-3-yl]-6-fluoropyridine-2-carboxamide (ABR 239472) To a solution of 6-fluoropyridine-2-carboxamide (700 mg, 4.75 mmol) in DMF (7 mL), under argon, were added ethyl 3,3,3-trifiuoro-2-oxopropanoate (629 mu., 4.75 mmol) and pyridine (383 mu, 4.75 mmol). The reaction mixture was stirred at room temperature for 1 h and then thionyl chloride (344 mu., 4.75 mmol) was added dropwise. Stirring was continued for a further 2.5 h and then the reaction was concentrated to provide the acyl imine intermediate. The resulting acyl imine intermediate was dissolved in DMF (5 mL) and then added to a solution of 5,6-dichloro- lH-l,3-benzodiazol-2-amine (519 mg, 2.57 mmol) in DMF (5 mL). Triethylamine (0.35 ml, 2.56 mmol) was added and the reaction mixture stirred at room temperature for 2 h. The reaction was diluted with brine (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with the water, dried (Na2S04), filtered and concentrated. The crude product was purified by silica chromatography, using 3% MeOH in DCM as eluent, to afford the title compound as an off-white solid (300 mg, 25%); m z = 448.4, 450.4(MH)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere; | Example 37 A-[10,ll-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02,6]dodeca- l(8),6,9,ll-tetraen-3-yl]-3-phenylpropanamide (ABR 239019) To a stirred solution of methyl (2E)-3,3,3-trifiuoro-2-[(3-phenylpropanoyl)imino]-propanoate (100 mg, 0.35 mmol) and 5,6-dichloro-lH-l,3-benzodiazol-2-amine (70 mg, 0.35 mmol) in DMF (5 mL), under nitrogen, was added triethylamine (46 mu, 0.35 mmol). The reaction mixture was stirred at room temperature for 16 h and then concentrated. The residue was purified by silica chromatography, using 0-10% MeOH in DCM as eluent, to afford the title compound as an off white solid (57 mg, 36%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; | Example 54 A^-[10,ll-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]dodeca- l(12),6,8,10-tetraen-3-yl]cyclopentanecarboxamide (ABR 239114) The general procedure for the preparation of 2-bromo-N-[3-oxo-4-(trifluoromethyl)-2,5,7- triazatricyclo[6.4.0.02'6]dodeca-l (12),6,8,10-tetraen-4-yl]benzamide was used but with the following changes. In the first stage of the reaction, to form the acyl imine intermediate, cyclopentanecarboxamide was used instead of 2-bromobenzamide and after the addition of thionyl chloride the reaction mixture was stirred for 2.5 h instead of 16 h. In the second stage of the reaction, 5,6-dichloro-lH-l,3-benzodiazol-2-amine was used instead of lH-l ,3-benzodiazol- 2-amine and the reaction was stirred for 2 h instead of 4 h. The crude product was purified by silica chromatography, using 2% MeOH in DCM as eluent (9%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | Example 55 ^-[10,ll-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]dodeca- l(12),6,8,10-tetraen-3-yl]cyclohexanecarboxamide (ABR 239115) The general procedure for the preparation of 2-bromo-N-[3-oxo-4-(trifluoromethyl)-2,5,7- triazatricyclo[6.4.0.02'6]dodeca-l (12),6,8,10-tetraen-4-yl]benzamide was used but with the following changes. In the first stage of the reaction, to form the acyl imine intermediate, cyclohexanecarboxamide was used instead of 2-bromobenzamide and after the addition of thionyl chloride the reaction mixture was stirred for 2.5 h instead of 16 h. In the second stage of the reaction, 5,6-dichloro-lH-l ,3-benzodiazol-2-amine was used instead of lH-l ,3-benzodiazol-2- amine and the reaction was stirred for 16 h instead of 4 h. The crude product was purified by silica chromatography, using 3% MeOH in DCM as eluent, followed by trituration in DCM/pentane (2%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | Example 56 3-chloro-A-[10,ll-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]-dodeca- l(12),6,8,10-tetraen-3-yl]benzamide (ABR 239414) The general procedure for the preparation of 2-bromo-N-[3-oxo-4-(trifluoromethyl)-2,5,7- triazatricyclo[6.4.0.02'6]dodeca-l (12),6,8,10-tetraen-4-yl]benzamide was used but with the following changes. In the first stage of the reaction, to form the acyl imine intermediate, 3- chlorobenzamide was used instead of 2-bromobenzamide and after the addition of thionyl chloride the reaction mixture was stirred for 18 h instead of 16 h. In the second stage of the reaction, 5,6-dichloro-lH-l ,3-benzodiazol-2-amine was used instead of lH-l ,3-benzodiazol-2- amine and the reaction was stirred for 18 h instead of 4 h. The crude product was purified by silica chromatography, using 2-4% MeOH in DCM as eluent (3%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | Example 57 3 ,5-dichlor o-N-[ 10 ,11 -dichlor o^l -oxo-3 -(trifluoromethyl)-2 ,5 ,7-triazatricy clo- [6.4.0.02'6]dodeca-l(12),6,8,10-tetraen-3-yl]benzamide (ABR 239427) The general procedure for the preparation of 2-bromo-N-[3-oxo-4-(trifluoromethyl)-2,5,7- triazatricyclo[6.4.0.02'6]dodeca-l (12),6,8,10-tetraen-4-yl]benzamide was used but with the following changes. In the first stage of the reaction, to form the acyl imine intermediate, 3,5- dichlorobenzamide was used instead of 2-bromobenzamide and after the addition of thionyl chloride the reaction mixture was stirred for 18 h instead of 16 h. In the second stage of the reaction, 5,6-dichloro-lH-l ,3-benzodiazol-2-amine was used instead of 5,6-dimethyl-lH-l ,3- benzodiazol-2 -amine and the reaction was stirred for 18 h instead of 4 h. The crude product was purified by silica chromatography, using 4% MeOH in DCM as eluent (5%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | Example 58 A^-[10,ll-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]dodeca- l(12),6,8,10-tetraen-3-yl]-4-(pyrrolidin-l-yl)butanamide (ABR 239155) The general procedure for the preparation of 2-bromo-N-[3-oxo-4-(trifluoromethyl)-2,5,7- triazatricyclo[6.4.0.02'6]dodeca-l (12),6,8,10-tetraen-4-yl]benzamide was used but with the following changes. In the first stage of the reaction, to form the acyl imine intermediate, 4- (pyrrolidin-l-yl)butanamide was used instead of 2-bromobenzamide and after the addition of thionyl chloride the reaction mixture was stirred for 72 h instead of 16 h. In the second stage of the reaction, 5,6-dichloro-lH-l,3-benzodiazol-2-amine was used instead of lH-l ,3-benzodiazol- 2-amine and the reaction was stirred for 16 h instead of 4 h. The crude product was purified by automated reverse phase HPLC (low pH Method B) (1%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | Example 59 A^-[10,ll-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]dodeca- l(12),6,8,10-tetraen-3-yl]-4-(morpholin-4-yl)butanamide (ABR 239161) The general procedure for the preparation of 2-bromo-N-[3-oxo-4-(trifluoromethyl)-2,5,7- triazatricyclo[6.4.0.02'6]dodeca-l (12),6,8,10-tetraen-4-yl]benzamide was used but with the following changes. In the first stage of the reaction, to form the acyl imine intermediate, 4- (morpholin-4-yl)butanamide was used instead of 2-bromobenzamide and after the addition of thionyl chloride the reaction mixture was stirred for 2.5 h instead of 16 h. In the second stage of the reaction, 5,6-dichloro-lH-l,3-benzodiazol-2-amine was used instead of lH-l ,3-benzodiazol- 2-amine and the reaction was stirred for 16 h instead of 4 h. The crude product was purified by silica chromatography, using 20% MeOH in DCM as eluent (11%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | Example 60 A^-[10,ll-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]dodeca- l(12),6,8,10-tetraen-3-yl]-2-(morphoKii-4-yl)acetamide (ABR 239358) The general procedure for the preparation of 2-bromo-N-[3-oxo-4-(trifluoromethyl)-2,5,7- triazatricyclo[6.4.0.02'6]dodeca-l (12),6,8,10-tetraen-4-yl]benzamide was used but with the following changes. In the first stage of the reaction, to form the acyl imine intermediate, 2- (morpholin-4-yl)acetamide: prepared according to literature (Chaudhari et al. 2007); was used instead of 2-bromobenzamide and after the addition of thionyl chloride the reaction mixture was stirred for 18 h instead of 16 h. In the second stage of the reaction, 5,6-dichloro-lH-l ,3- benzodiazol-2 -amine was used instead of lH-1 ,3-benzodiazol-2-amine and the reaction was stirred for 16 h instead of 4 h. The crude product was purified by automated reverse phase HPLC (low pH Method B) (4%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
411 mg | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 3h;Inert atmosphere; | Intermediate 11 tert-butyl 6-[10,ll-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]- dodeca-l(12),6,8,10-tetraen-3-yl]carbamoyl}-2-azaspiro[3.3]heptane-2-carboxylate To a stirred solution of tert-bu yl 6-carbamoyl-2-azaspiro[3.3]heptane-2-carboxylate (515 mg, 2.14 mmol) in DMF (20 mL), under nitrogen, was added pyridine (173 mu., 2.14 mmol) and methyl 3,3,3-trifiuoro-2-oxopropanoate (669 mg, 4.29 mmol). The reaction mixture was stirred for 16 h at room temperature and then cooled to 0C. Thionyl chloride (156 mL, 2.14 mmol) added dropwise and the solution was stirred at 0C for 1 h before being concentrated. The residue was filtered through a short pad of silica, eluting with DCM/DMF (10:1), and the filtrate was concentrated. The acyl imine intermediate that remained was dissolved in DMF (20 mL) under nitrogen. 5,6-Dichloro-lH-l,3-benzodiazol-2-amine (325 mg, 1.61 mmol) and triethylamine (285 mu, 2.14 mmol) were added to the solution and the reaction was stirred for 3 h at room temperature before being concentrated. The residue was dissolved in EtOAc (50 mL) and washed with water (3 x 50 mL) and brine (2 x 50 mL). The organic phase was dried (MgSC ), filtered and concentrated. The crude product was purified by silica chromatography, eluting with 0-7% MeOH in DCM, to afford the title compound as an off- white solid (411 mg, 35%); m/z 491.8, 493.8 (MH-tBu)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27 mg | Example 101 A^-[10,ll-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]dodeca- l(8),6,9,ll-tetraen-3-yl]-2-[(2-methoxyethyl)amino]-l,3-thiazole-4-carboxamide (ABR 239601) To a stirred solution of 2-bromo-l ,3-thiazole-4-carboxamide (360 mg, 1.74 mmol) in DMF (15 mL) was added methyl 3,3,3-trifiuoro-2-oxopropanoate (543 mg, 3.48 mmol) followed by pyridine (140 mu, 1.74 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 16 h. Thionyl chloride (126 mu, 1.74 mmol) was added at 0C and the reaction mixture was then stirred for 1 h. The reaction mixture was concentrated and the residue was filtered through a short pad of silica, eluting with DCM, under nitrogen. The filtrate was concentrated, and the acyl intermediate that remained was dissolved in DMF (10 mL) under nitrogen. A solution of 5,6-dichloro-lH-l ,3-benzodiazol-2-amine (293 mg, 1.45 mmol) in DMF (10 mL) and triethylamine (231 mu, 1.74 mmol) were added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated. The residue was diluted with EtOAc (50 mL), washed with washed with 10% citric acid(aq) (2 x 25 mL), water (2 x 25 mL) and brine (2 x 25 mL). The organic phase was dried (MgSC^), filtered and concentrated. The crude product was triturated in DCM to afford a mixture of 2-bromo-N-[10,l 1 -dichloro-4-oxo-3- (trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]dodeca-l(8),6,9,l l -tetraen-3-yi]-l ,3-thiazole-4- carboxamide and 2-chloro-N-[10,l l-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7- triazatricyclo[6.4.0.02'6]dodeca-l (8),6,9,l l-tetraen-3-yl]-l ,3-thiazole-4-carboxamide (746 mg). A microwave tube was charged with a portion of the mixture of 2-bromo-N-[10,l l-dichloro-4- oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]dodeca-l(8),6,9,l l-tetraen-3-yl]-l ,3- thiazole-4-carboxamide and 2-chloro-N-[10,l l-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7- triazatricyclo[6.4.0.02'6]dodeca-l (8),6,9,l l-tetraen-3-yl]-l ,3-thiazole-4-carboxamide (80 mg), K2CO3 (64 mg, 0.47 mmol), 2-methoxyethan-l -amine (40 mu, 0.47 mmol) and dioxane (2 mL). Initially, the reaction was heated in the microwave at 130C for 1 h. Then the reaction was then heated for a further 4 h. During this period, additional 2-methoxyethan-l -amine (160 mu, 1.88 mmol) and K2CO3 (256 mg, 1.88 mmol) were added portionwise with the reaction at room temperature during retreatment. Then the reaction mixture was concentrated. The residue was dissolved in EtOAc (25 mL) and washed with water (25 mL), 10% citric acid(aq) (25 mL) and brine (25 mL). The organic phase was dried (MgSC^), filtered and concentrated. The crude product was purified by automated reverse phase HPLC (low pH Method A) to afford the title compound as a white solid (27 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.2 g | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;Inert atmosphere; | Example 39 3-cyclopentyl-A^-[10 1-dichloro-4-oxo-3-(trifluoromethyl)-2,5 -triazatricyclo[6.4.0.02'6]- dodeca-l(12),6,8,10-tetraen-3-yl]propanamide (ABR 238926) To a stirred solution of 3-cyclopentylpropanamide (3.50 g, 24.8 mmol) in DMF (50 mL) was added methyl 3,3,3-trifiuoro-2-oxopropanoate (3.87 g, 24.8 mmol) followed by pyridine (2.00 mL, 24.8 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 4 h and then cooled to 0C. Thionyl chloride (1.80 mL, 24.8 mmol) was added dropwise to this solution and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and filtered through a short pad of silica, eluting with DCM (100 mL). The filtrate was concentrated, and the acyl imine intermediate that remained was immediately dissolved in DMF (30 mL) under nitrogen. 5,6-Dichloro-lH-l ,3-benzodiazol-2- amine (4.01 g, 19.8 mmol) was added to the solution followed by triethylamine (3.96 mL, 29.7 mmol). The resulting mixture was stirred at room temperature for 2 h and then concentrated. The residue was dissolved in EtOAc (200 mL), washed with water (4 x 100 mL) and brine (2 x 100 mL), dried (MgS04), filtered and concentrated. The crude product was purified by silica chromatography, using 3% MeOH in DCM as eluent, to afford a dark brown foam. This was dissolved in MeOH (100 mL) and decolourised with charcoal. The resulting suspension was filtered through celite and washed with MeOH. The filtrate was concentrated to afford the title compound as a light yellow solid (3.2 g, 29%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20 mg | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;Inert atmosphere; | Example 87 A^-[10,ll-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]dodeca- l(12),6,8,10-tetraen-3-yl]oxane-4-carboxamide (ABR 239441) To a stirred solution of oxane-4-carboxamide (500 mg, 3.87 mmol) in DMF (15 mL) was added pyridine (312 mu, 3.87 mmol) followed by ethyl 3,3,3-trifluoro-2-oxopropanoate (658 mg, 3.87 mmol) at room temperature under argon. The reaction mixture was stirred at room temperature for 1 h and then thionyl chloride (422 mu, 5.81 mmol) was added. The reaction was stirred for a further 16 h and was then concentrated. The acyl intermediate that remained was dissolved in DMF (5 mL) under argon. A solution of 5,6-dichloro-lH-l ,3-benzodiazol-2-amine (587 mg, 2.90 mmol) in DMF (7 mL) and triethylamine (861 mu, 6.19 mmol) were added and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 15 mL). The combined organic extracts were washed with brine, dried (MgSO^, filtered and concentrated. The crude product was purified by silica chromatography. Further purification was carried out by trituration in DCM/MeOH and then pentane to afford the title compound (20 mg, 1%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24 mg | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;Inert atmosphere; | Example 94 A^-[10,ll-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]dodeca- l(8),6,9,ll-tetraen-3-yl]-6-[(2-methoxyethyl)(methyl)amino]pyridine-2-carboxamide (ABR 239537) To a stirred solution of 6-[(2-methoxyethyl)(methyl)amino]pyridine-2-carboxamide (571 mg, 2.73 mmol) in DMF (10 mL) was added methyl 3,3,3-trifiuoro-2-oxopropanoate (852 mg, 5.46 mmol) followed by pyridine (220 mu, 2.73 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 16 h. Thionyl chloride (198 mu, 2.73 mmol) was added at 0C and the reaction mixture was then stirred at room temperature for 1 h. The reaction mixture was concentrated and the residue filtered through a short pad of silica, eluting with DCM, under nitrogen. The filtrate was concentrated, and the acyl intermediate that remained was dissolved in DMF (10 mL) under nitrogen. 5,6-Dichloro-lH-l ,3-benzodiazol-2-amine (441 mg, 2.18 mmol) and triethylamine (381 mu, 2.72 mmol) were added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated. The residue was dissolved in EtOAc (100 mL), washed with water (3 x 50 mL) and then brine (3 x 50 mL). The organic phase was dried (MgSC^), filtered and concentrated. The crude product was purified by silica chromatography, using 0-10% MeOH in DCM as eluent. Further purification was carried out using automated reverse phase HPLC (high pH) to afford the title compound as a yellow solid (24 mg, 2%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35 mg | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 20h;Inert atmosphere; | Example 95 methyl 6-[10,ll-dichloro^l-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]dodeca- l(8),6,9,ll-tetraen-3-yl]carbamoyl}pyridine-2-carboxylate (ABR 239572) To a stirred solution of methyl 6-carbamoylpyridine-2-carboxylate (1.00 g, 5.55 mmol) in DMF (15 mL) was added methyl 3,3,3-trifiuoro-2-oxopropanoate (1.14 mL, 11.11 mmol) followed by pyridine (450 mu, 5.55 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1.5 h. Thionyl chloride (405 mu, 5.55 mmol) was added at 0C and the reaction mixture was then stirred for 1 h. The reaction mixture was concentrated and the residue filtered through a short pad of silica, eluting with DCM, under nitrogen. The filtrate was concentrated, and the acyl intermediate that remained was dissolved in DMF (15 mL) under nitrogen. 5,6-Dichloro-lH-l,3-benzodiazol-2-amine (935 mg, 4.63 mmol) and triethylamine (739 mu, 5.55 mmol) were added and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated. The residue was diluted with EtOAc (50 mL), washed with water (3 x 50 mL) and brine (2 x 50 mL). The organic phase was dried (MgSC ), filtered and concentrated. The crude product was purified by silica chromatography, using 0-3% MeOH in DCM as eluent, to give the title compound as a brown oil (35 mg, 2%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22 mg | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere; | Example 98 A^-[10,ll-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]dodeca- l(12),6,8,10-tetraen-3-yl]-3-fluorobenzamide (ABR 239440) To a stirred solution of 3-fluorobenzamide (500 mg, 3.59 mmol) in DMF (5 mL) was added pyridine (306 mu, 3.59 mmol) followed by ethyl 3,3,3-trifluoro-2-oxopropanoate (476 mu, 3.59 mmol) at room temperature under argon. The reaction mixture was stirred at room temperature for 1 h. Thionyl chloride (231 mu, 3.18 mmol) was added at 0C and the reaction mixture was then stirred at room temperature for 2.5 h. The reaction mixture was concentrated. The acyl intermediate that remained was dissolved in DMF (2 mL) under argon. 5,6-Dichloro-lH-l ,3- benzodiazol-2 -amine (545 mg, 2.70 mmol) and triethylamine (503 mu, 3.59 mmol) were added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried ( a2S04), filtered and concentrated. The crude product was purified by silica chromatography, using 3% MeOH in DCM as eluent. Further purification was carried out by trituration in DCM/MeOH and then pentane to afford the title compound as an off-white solid (22 mg, 1%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20 mg | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;Inert atmosphere; | Example 99 A^-[10,ll-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]dodeca- l(12),6,8,10-tetraen-3-yl]-3,5-difluorobenzamide (ABR 239446) To a stirred solution of 3,5-difluorobenzamide (500 mg, 3.18 mmol) in DMF (5 mL) was added pyridine (271 mu, 3.18 mmol) followed by ethyl 3,3,3-trifluoro-2-oxopropanoate (422 mu, 3.18 mmol) at room temperature under argon. The reaction mixture was stirred at room temperature for 1 h. Thionyl chloride (231 mu, 3.18 mmol) was added at 0C. The reaction mixture was stirred at room temperature for 16 h and then the reaction mixture was concentrated. The acyl intermediate that remained was dissolved in DMF (2 mL) under argon. 5,6-Dichloro-lH-l ,3- benzodiazol-2 -amine (482 mg, 2.39 mmol) and triethylamine (668 mu, 4.77 mmol) were added and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried ( a2S04), filtered and concentrated. The crude product was purified by silica chromatography, using 3% MeOH in DCM as eluent. Further purification was carried out by trituration from DCM/MeOH and then pentane to afford the title compound as an off-white solid (20 mg, 1%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25 mg | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere; | Example 100 3-cyano-A-[10,ll-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]dodeca- l(8),6,9,ll-tetraen-3-yl]benzamide (ABR 239453) To a stirred solution of 3-cyanobenzamide (650 mg, 4.45 mmol) in DMF (7 mL) was added pyridine (378 mu, 4.45 mmol) followed by ethyl 3,3,3-trifluoro-2-oxopropanoate (590 mu, 4.45 mmol) at room temperature under argon. The reaction mixture was stirred at room temperature for 1 h. Thionyl chloride (323 mu, 4.45 mmol) was added at 0C. The reaction mixture was then stirred at room temperature for a further 16 h and before the reaction mixture was concentrated. The acyl intermediate that remained was dissolved in DMF (5 mL) under argon. 5,6-Dichloro- lH-l,3-benzodiazol-2-amine (674 mg, 3.34 mmol) and triethylamine (934 mu, 6.67 mmol) were added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried (Na2SC>4), filtered and concentrated. The crude product was purified by silica chromatography, using 3% MeOH in DCM as eluent. Further purification was carried out by trituration in DCM/MeOH and then pentane to afford the title compound as a white solid (25 mg, 1%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 101 A^-[10,ll-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]dodeca- l(8),6,9,ll-tetraen-3-yl]-2-[(2-methoxyethyl)amino]-l,3-thiazole-4-carboxamide (ABR 239601) To a stirred solution of 2-bromo-l ,3-thiazole-4-carboxamide (360 mg, 1.74 mmol) in DMF (15 mL) was added methyl 3,3,3-trifiuoro-2-oxopropanoate (543 mg, 3.48 mmol) followed by pyridine (140 mu, 1.74 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 16 h. Thionyl chloride (126 mu, 1.74 mmol) was added at 0C and the reaction mixture was then stirred for 1 h. The reaction mixture was concentrated and the residue was filtered through a short pad of silica, eluting with DCM, under nitrogen. The filtrate was concentrated, and the acyl intermediate that remained was dissolved in DMF (10 mL) under nitrogen. A solution of 5,6-dichloro-lH-l ,3-benzodiazol-2-amine (293 mg, 1.45 mmol) in DMF (10 mL) and triethylamine (231 mu, 1.74 mmol) were added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated. The residue was diluted with EtOAc (50 mL), washed with washed with 10% citric acid(aq) (2 x 25 mL), water (2 x 25 mL) and brine (2 x 25 mL). The organic phase was dried (MgSC^), filtered and concentrated. The crude product was triturated in DCM to afford a mixture of 2-bromo-N-[10,l 1 -dichloro-4-oxo-3- (trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]dodeca-l(8),6,9,l l -tetraen-3-yi]-l ,3-thiazole-4- carboxamide and 2-chloro-N-[10,l l-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7- triazatricyclo[6.4.0.02'6]dodeca-l (8),6,9,l l-tetraen-3-yl]-l ,3-thiazole-4-carboxamide (746 mg). A microwave tube was charged with a portion of the mixture of 2-bromo-N-[10,l l-dichloro-4- oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]dodeca-l(8),6,9,l l-tetraen-3-yl]-l ,3- thiazole-4-carboxamide and 2-chloro-N-[10,l l-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7- triazatricyclo[6.4.0.02'6]dodeca-l (8),6,9,l l-tetraen-3-yl]-l ,3-thiazole-4-carboxamide (80 mg), K2CO3 (64 mg, 0.47 mmol), 2-methoxyethan-l -amine (40 mu, 0.47 mmol) and dioxane (2 mL). Initially, the reaction was heated in the microwave at 130C for 1 h. Then the reaction was then heated for a further 4 h. During this period, additional 2-methoxyethan-l -amine (160 mu, 1.88 mmol) and K2CO3 (256 mg, 1.88 mmol) were added portionwise with the reaction at room temperature during retreatment. Then the reaction mixture was concentrated. The residue was dissolved in EtOAc (25 mL) and washed with water (25 mL), 10% citric acid(aq) (25 mL) and brine (25 mL). The organic phase was dried (MgSC^), filtered and concentrated. The crude product was purified by automated reverse phase HPLC (low pH Method A) to afford the title compound as a white solid (27 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | Example 237 A^[10,ll-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]dodeca- l(12),6,8,10-tetraen-3-yl]-2-[(2-methylpropyl)amino]-l,3-thiazole-4-carboxamide (ABR 240019) To a stirred solution of 2-bromo-l ,3-thiazole-4-carboxamide (360 mg, 1.74 mmol) in DMF (15 mL) was added methyl 3,3,3-trifiuoro-2-oxopropanoate (543 mg, 3.48 mmol) followed by pyridine (140 mu, 1.74 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 16 h. Thionyl chloride (126 mu, 1.74 mmol) was added at 0C and the reaction mixture was then stirred for 1 h. The reaction mixture was concentrated and the residue was filtered through a short pad of silica, eluting with DCM, under nitrogen. The filtrate was concentrated, and the acyl intermediate that remained was dissolved in DMF (10 mL) under nitrogen. A solution of 5,6-dichloro-lH-l ,3-benzodiazol-2-amine (293 mg, 1.45 mmol) in DMF (10 mL) and triethylamine (231 1.74 mmol) were added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated. The residue was diluted with EtOAc (50 mL), washed with washed with 10% citric acid(aq) (2 x 25 mL), water (2 x 25 mL) and brine (2 x 25 mL). The organic phase was dried (MgSC^), filtered and concentrated. The crude product was triturated in DCM to afford a mixture of 2-bromo-N-[10,l 1 -dichloro-4-oxo-3- (trifluoromethyl)-2,5,7-triazatricyclo[6.^ carboxamide and 2-chloro-N-[10,l l-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7- triazatricyclo[6.4.0.02'6]dodeca-l (12),6,8,10-tetraen-3-yl]-l ,3-thiazole-4-carboxamide (746 mg). A sealed tube was charged with a portion of the mixture of 2-bromo-N-[10,l 1 -dichloro-4-oxo-3- (trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]dodeca (12),6,8,10-tetraen-3-yl]-l ,3-thr carboxamide and 2-chloro-N-[10,l l-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7- triazatricyclo[6.4.0.02'6]dodeca-l (12),6,8,10-tetraen-3-yl]-l ,3-thiazole-4-carboxamide (190 mg), K2CO3 (255 mg, 1.84 mmol), anhydrous dioxane (3 mL) and 2-methylpropan-l -amine (184 muL·, 1.84 mmol). The tube was sealed and stirred at 130C for 1 h. Additional K2C03 (255 mg, 1.84 mmol) and 2-methylpropan-l -amine (184 1.84 mmol) were added. The reaction was stirred at 130C for a further 18 h and was then concentrated. The residue was diluted with EtOAc (30 mL) and brine (30 mL). The aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine, dried (MgSO^, filtered and concentrated. The crude product was purified by automated reverse phase HPLC (low pH Method A) to afford the title compound as a brown solid (40 mg, 21%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
427 mg | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | Intermediate 18 ethyl 2-[(5,6-dichloro-lH-l,3-benzodiazol-2-yl)amino]-3,3?3-ti"ifluoro-2-[3-(morpholin-4- yl)propanamido]propanoate To a solution of 3-(morpholin-4-yl)propanamide, prepared according to literature (You et. al, 2008); (500 mg, 3.16 mmol), in DMF (5 mL) were added ethyl 3,3,3-trifiuoro-2-oxopropanoate (419 mu, 3.16 mmol) and pyridine (269 muL, 3.16 mmol) were added. The reaction mixture was stirred for 2 h at room temperature under argon and then thionyl chloride (230 mu, 3.16 mmol) was added dropwise to the solution. Stirring was continued for a further 24 h and then the reaction was concentrated. The resulting acyl imine was dissolved in DMF (5 ml) and then added to a solution of 5,6-dichloro-lH-l,3-benzodiazol-2-amine (615 mg, 3.05 mmol) in DMF (5 mL). Triethylamine (422 mu, 3.05 mmol) was added and the reaction mixture stirred at room temperature for 16 h. The reaction was diluted with brine (25 mL) and extracted with EtOAc (2 x 35 mL). The combined organic phases were washed with water, dried (Na2SC>4), filtered and concentrated. The crude product was purified by silica chromatography, using 2% MeOH in DCM as eluent, to afford the title compound as a brown oil (427 mg, 1%); m/z = 512.5 (MH)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65 mg | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 4h; | Example 255 tert-butyl 4-([10,ll-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo- [6.4.0.02'6]dodeca-l(12),6,8,10-tetraen-3-yl]carbamoyl}methyl)piperidine-l-carboxylate (ABR 240055) To a stirred solution of tert-butyl 4-(carbamoylmethyl)piperidine-l -carboxylate (1.00 g, 4.00 mmol) in DMF (8 mL) were added pyridine (316 mu, 4.00 mmol) and ethyl 3,3,3-trifiuoro-2- oxopropanoate (104 uL, 4.00 mmol) under argon. The reaction mixture was stirred at room temperature for 1 h and then thionyl chloride (300 mu., 4.00 mmol) was added dropwise. The reaction mixture was stirred at room temperature for further 16 h and then concentrated to provide the acyl imine intermediate. The acyl imine intermediate was dissolved in DMF (5 mL) and added to a solution of 5,6-dichloro-lH-l ,3-benzodiazol-2-amine (804 mg, 4.00 mmol) in DMF (7 mL), followed by triethylamine (0.56 mL, 4.00 mmol). The reaction mixture was stirred at room temperature for 4 h. The reaction was diluted with brine (25 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with water, dried (Na2SC>4), filtered and concentrated. The crude product was purified by silica chromatography, using 2% MeOH in DCM as eluent, to afford the title compound as a red solid (65 mg, 6%); m/z = 450.4, 452.4 (MH-C02tBu)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59 mg | With triethylamine; In N,N-dimethyl-formamide; for 2h;Inert atmosphere; | Example 257 tert-butyl 3-[10,ll-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]dodeca- l(8),6,9,ll-tetraen-3-yl]carbamoyl}-3-fluoroazetidine-l-carboxylate (ABR 240057) To a stirred solution of tert-butyl 3-carbamoyl-3-fluoroazetidine-l -carboxylate (285 mg, 1.30 mmol) in DMF (25 mL) were added pyridine (105 DL, 1.30 mmol) followed by methyl 3,3,3- trifiuoro-2-oxopropanoate (407 mg, 2.61 mmol) under nitrogen. The reaction was stirred at room temperature for 2 h. Thionyl chloride (95 mu, 1.30 mmol) was added at 0C. The reaction was stirred for 1 h at 0C and then concentrated. The residue was filtered through a short pad of silica, eluting with DCM, under nitrogen. The filtrate was concentrated, and the acyl intermediate that remained was dissolved in DMF (10 mL) under nitrogen. A solution of 5,6-dichloro-lH-l ,3- benzodiazol-2 -amine (220 mg, 1.08 mmol) in DMF (10 mL) and triethylamine (182 mu, 1.30 mmol) were added. The reaction was stirred for 2 h before being concentrated. The residue was dissolved in EtOAc (50 mL) and washed with water (4 x 50 mL) and brine (3 x 50 mL). The organic phase was dried (Na2SC>4), filtered and concentrated. The crude product was purified using automated reverse phase HPLC (low pH Method A) to afford the title compound as a yellow solid (59 mg, 10%); m z = 469.8, 471.8 (MH-lBu)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere; | Example 38 A^-[10,ll-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]dodeca- l(8),6,9,ll-tetraen-3-yl]benzamide (ABR 238949) To a stirred solution of 5,6-dichloro-lH-l,3-benzodiazol-2-amine (100 mg, 0.49 mmol) and methyl (Z)-benzoylimino-3,3,3-trifiuoropropanoate (128 mg, 0.49 mmol) in DMF (2 mL), was added triethylamine (66 mu, 0.49 mmol) under nitrogen. The reaction mixture was stirred for 16 h at room temperature, concentrated and purified by automated reverse phase HPLC (low pH Method A) to afford the title compound as a white solid (24 mg, 11%). |
Tags: 18672-03-2 synthesis path| 18672-03-2 SDS| 18672-03-2 COA| 18672-03-2 purity| 18672-03-2 application| 18672-03-2 NMR| 18672-03-2 COA| 18672-03-2 structure
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