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CAS No. : | 6160-65-2 | MDL No. : | MFCD00005289 |
Formula : | C7H6N4S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RAFNCPHFRHZCPS-UHFFFAOYSA-N |
M.W : | 178.21 | Pubchem ID : | 80264 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 10 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 47.85 |
TPSA : | 67.73 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.9 cm/s |
Log Po/w (iLOGP) : | 1.17 |
Log Po/w (XLOGP3) : | 0.68 |
Log Po/w (WLOGP) : | 0.76 |
Log Po/w (MLOGP) : | -0.42 |
Log Po/w (SILICOS-IT) : | 0.88 |
Consensus Log Po/w : | 0.61 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.86 |
Solubility : | 2.47 mg/ml ; 0.0139 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.68 |
Solubility : | 3.73 mg/ml ; 0.0209 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.09 |
Solubility : | 14.5 mg/ml ; 0.0815 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.27 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P264-P270-P280-P301+P312+P330-P302+P352-P305+P351+P338-P332+P313-P337+P313-P362+P364-P501 | UN#: | N/A |
Hazard Statements: | H302-H315-H319 | 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 |
---|---|---|
96% | With dmap In dichloromethane at 20℃; for 1 h; Inert atmosphere | To a stirred solution of biphenyl-3-ylamine (338 mg, 2 mmol) in DCM (5 mL), thiocarbonyldiimidazole (TCDI) (535 mg, 3 mmol) and DMAP (48.8 mg, 0.04 mmol) were added and the reaction mixture stirred at r.t under N2 for 1 h (until TLC showed no starting material remaining). The reaction mixture was then purified by a silica plug (DCM). The solvent was then removed in vacuo to leave a colourless oil (407 mg, 96percent). Rf: 0.86 (1:1 DCM/hex). 1H NMR (CDCl3): δ 7.16 (ddd, 1H, J 8, 2, 1 Hz, H6'), 7.34-7.48 (m, 6H, H4'', H5', H4', H3'', H5'', H2'), 7.52 (m, 2H, H2'', H6''). 13C NMR (CDCl3): δ 124.4 (CH), 124.5 (CH), 126.2 (CH), 127.2 (CH), 128.2 (CH), 129.1 (CH), 130.0 (CH), 131.8 (C), 135.7 (NCS), 139.5 (C), 143.0 (C). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: at 20 - 50℃; for 3 h; Stage #2: With ammonia In tetrahydrofuran; methanol at 0 - 60℃; for 20 h; |
To a solution of 1-boc piperazine (5.0 g, 26.88 mmol) in dry THF (50 mL), 1,1-thiocarbonylimidazole (5.48 g, 29.56 mmol) was added at room temperature and stirred for 2 h. The reaction mixture was heated at 50°C for 1 h. It was cooled down to 0 °C and methanolic ammonia solution (50 mL, 7 N) was added. The mixture was stirred at 60°C for 20 h. It was then diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by flash chromatography to give the title compound. Yield: 92percent (4.0 g, white solid). 1H NMR (400 MHz, DMSO-d6): δ 9.2 (m, 2H), 3.16-3.14 (m, 2H), 2.49-2.48 (m, 6H), 1.30 (s, 9H). LCMS: (Method A) 246.2 (M+H), Rt. 2.93 min, 95.3percent (Max). |
92% | Stage #1: at 20 - 50℃; for 2 h; Stage #2: With ammonia In tetrahydrofuran; methanol at 0 - 60℃; for 20 h; |
To a solution of 1-boc piperazine (5.0 g, 26.88 mmol) in dry THE (50 mL), 1,1-thio carbonylimidazole (5.48 g, 29.56 mmol) was added at room temperature and stirred for 2 h. The reaction mixture was heated at 50°C for I h. It was cooled down to 0 °C and methanolic ammonia solution (50 mL, 7 N) was added. The mixture was stirred at 60°C for 20 h. It was then diluted with water and extracted with EtOAc. The organic layerwas dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by flash chromatography to give the title compound. Yield: 92percent (4.0 g, white solid). 1H NMR (400 MHz, DMSO-d6): 6 9.2 (m, 2H), 3.16-3.14 (m, 2H), 2.49-2.48 (m, 6H), 1.30 (s, 9H). LCMS: (Method A) 246.2 (M+H), Rt. 2.93 mm, 95.3percent (Max). |
72% | Stage #1: at 20℃; for 1 h; Stage #2: With ammonia In tetrahydrofuran; water at 20℃; for 12 h; |
The production of compound No. 26 proceeds according to the sequence of reaction steps shown in the following schemes: The first sub-step shown above was performed at 20° C. during 2 hours with a molar excess of CH2N2 (about 2 molar equivalents) in dry ether, then in a second sub-step (shown below) performed at 5° C. HCl gas was bubbled into the reaction mixture for 15 minutes, and the desired intermediate was obtained in 71percent yield. For the conversion from 3 to 4, the first sub-step shown above was performed at 20° C. during 1 hour with a molar excess of thio-carbonyldiimidazole (about 2 molar equivalents) in THF, then in a second sub-step performed at 20° C. for 12 hours a 25percent aqueous NH3 solution was added, and the desired intermediate was obtained in 72percent yield. The conversion from 4 to 5 was performed during 6 hours with 1 molar equivalent NaHCO3 at reflux in methanol, and the desired intermediate was obtained in 92percent yield. The conversion from 5 to 6 was performed during 3 hours at 20° C., and the desired intermediate was obtained in 90percent yield. The conversion from 6 to the final compound was performed during 6 hours at 20° C. in 1,2-dichloroethane (DCE) in the presence of a molar excess of triethylamine (1.2 molar equivalents). |
69% | Stage #1: at 20 - 55℃; for 3 h; Stage #2: With ammonia In tetrahydrofuran; methanol at 20℃; for 72 h; |
To a solution of di(lH-imidazol-l- yl)methanethione 2 (2.14 g, 12 mmol) in anhydrous THF (30 mL) was added tert-butyl piperazine-l-carboxylate 1 (1.86 g, 10 mmol) at ambient temperature. The mixture was allowed to stir at ambient temperature for 2 h, then the mixture was heated at 55 °C for 1 h. The mixture was concentrated under vacuum to about half the volume. To the remaining reaction mixture was added 2 M solution of ammonia in methanol (20 mL) and allowed to stir at ambient temperature for 3 days. The solvent was removed and the residue was purified by chromatography eluting with 50: 1 DCM/MeOH to afford the title compound (1.7 g, 69percent) as white solid. MS (ESI): m/z = 246.1 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | To a solution of 1-boc piperazine (5.0 g, 26.88 mmol) in dry THF (50 mL), 1,1-thiocarbonylimidazole (5.48 g, 29.56 mmol) was added at room temperature and stirred for 2 h. The reaction mixture was heated at 50C for 1 h. It was cooled down to 0 C and methanolic ammonia solution (50 mL, 7 N) was added. The mixture was stirred at 60C for 20 h. It was then diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by flash chromatography to give the title compound. Yield: 92% (4.0 g, white solid). 1H NMR (400 MHz, DMSO-d6): delta 9.2 (m, 2H), 3.16-3.14 (m, 2H), 2.49-2.48 (m, 6H), 1.30 (s, 9H). LCMS: (Method A) 246.2 (M+H), Rt. 2.93 min, 95.3% (Max). | |
92% | To a solution of 1-boc piperazine (5.0 g, 26.88 mmol) in dry THE (50 mL), 1,1-thio carbonylimidazole (5.48 g, 29.56 mmol) was added at room temperature and stirred for 2 h. The reaction mixture was heated at 50C for I h. It was cooled down to 0 C and methanolic ammonia solution (50 mL, 7 N) was added. The mixture was stirred at 60C for 20 h. It was then diluted with water and extracted with EtOAc. The organic layerwas dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by flash chromatography to give the title compound. Yield: 92% (4.0 g, white solid). 1H NMR (400 MHz, DMSO-d6): 6 9.2 (m, 2H), 3.16-3.14 (m, 2H), 2.49-2.48 (m, 6H), 1.30 (s, 9H). LCMS: (Method A) 246.2 (M+H), Rt. 2.93 mm, 95.3% (Max). | |
72% | The production of compound No. 26 proceeds according to the sequence of reaction steps shown in the following schemes: The first sub-step shown above was performed at 20 C. during 2 hours with a molar excess of CH2N2 (about 2 molar equivalents) in dry ether, then in a second sub-step (shown below) performed at 5 C. HCl gas was bubbled into the reaction mixture for 15 minutes, and the desired intermediate was obtained in 71% yield. For the conversion from 3 to 4, the first sub-step shown above was performed at 20 C. during 1 hour with a molar excess of thio-carbonyldiimidazole (about 2 molar equivalents) in THF, then in a second sub-step performed at 20 C. for 12 hours a 25% aqueous NH3 solution was added, and the desired intermediate was obtained in 72% yield. The conversion from 4 to 5 was performed during 6 hours with 1 molar equivalent NaHCO3 at reflux in methanol, and the desired intermediate was obtained in 92% yield. The conversion from 5 to 6 was performed during 3 hours at 20 C., and the desired intermediate was obtained in 90% yield. The conversion from 6 to the final compound was performed during 6 hours at 20 C. in 1,2-dichloroethane (DCE) in the presence of a molar excess of triethylamine (1.2 molar equivalents). |
69% | To a solution of di(lH-imidazol-l- yl)methanethione 2 (2.14 g, 12 mmol) in anhydrous THF (30 mL) was added tert-butyl piperazine-l-carboxylate 1 (1.86 g, 10 mmol) at ambient temperature. The mixture was allowed to stir at ambient temperature for 2 h, then the mixture was heated at 55 C for 1 h. The mixture was concentrated under vacuum to about half the volume. To the remaining reaction mixture was added 2 M solution of ammonia in methanol (20 mL) and allowed to stir at ambient temperature for 3 days. The solvent was removed and the residue was purified by chromatography eluting with 50: 1 DCM/MeOH to afford the title compound (1.7 g, 69%) as white solid. MS (ESI): m/z = 246.1 [M + H]+. | |
With ammonia;Product distribution / selectivity; | b) 4-(5-Trifluoromethyl-thiazol-2-yl)-piperazine-l-carboxylic acid tert-butyl esterTo a solution of 17.5 mmol 2-benzenesulfonyl-3-trifluoromethyl-oxirane in 20 ml N,N-dimethylformamide was added 15.9 mmol 4-thiocarbamoyl-piperazine-l-carboxylic acid tert-butyl ester (prepared from tert-butyl 1-piperazinecarboxylate, 1,1'- thiocarbonyldiimidazole and ammonia according to the procedure of J. Med. Chem. 1998, 41, 5037-5054). The mixture was heated at 90 0C for 10 h. The reaction mixture was then concentrated in vacuo and the residue purified by chromatography (SiO2, ethyl acetate/heptane) to afford the title compound as an orange crystalline solid (yield 26%). MS (m/e): 338.1 (M+H+, 100%).; a) 4-(5-Hydroxymethyl-thiazol-2-yl)-piperazine-l-carboxylic acid tert-butyl esterTo a solution of 179 mmol 30% aqueous hydrogen peroxide in 60 ml water was added 1 N aqueous sodium hydroxide solution until the pH was 9. The reaction mixture was then cooled to 100C and 163 mmol acrolein was added dropwise. Further amounts of 1 N aqueous sodium hydroxide solution were added during the addition in order to maintain the pH of the reaction mixture between pH 8 and 9. The mixture was stirred for 30 min at 0 0C and then 40.8 mmol thiocarbamoyl-piperazine-1-carboxylic acid tert- butyl ester (prepared from tert-butyl 1-piperazinecarboxylate, 1,1'- thiocarbonyldiimidazole and ammonia according to the procedure of J. Med. Chem. 1998, 41, 5037-5054) was added. To the resulting suspension was added 25 ml ethanol and the mixture was heated at 80 0C for 30 min. The resulting solution was diluted with ethyl acetate/tetrahydrofuran (1:1) and the mixture was washed twice with brine. The organic phase was dried over sodium sulphate and concentrated in vacuo to afford the title compound as a yellow oil (yield 99%). MS (m/e): 300.3 (M+H+, 100%).;f) 4-(4-Methyl-5-trifluoromethyl-thiazol-2-yl)-piperazine-l-carboxylic acid tert-butyl esterA mixture of 4.92 mmol rac-2-benzenesulfonyl-2-methyl-3-trifluoromethyl- oxirane and 5.41 mmol 4-thiocarbamoyl-piperazine-l-carboxylic acid tert-butyl ester (prepared from tert-butyl 1-piperazinecarboxylate, l.l'-thiocarbonyldiimidazole and ammonia according to the procedure of J. Med. Chem. 1998, 41, 5037-5054) in 15 ml N,N-dimethylformamide was heated at 100 0C for 4.5 h. The reaction mixture was then concentrated in vacuo and the residue purified by chromatography (SiO2, ethyl acetate/heptane) to afford the title compound as a yellow crystalline solid (yield 30%). MS (m/e): 352.3 (M+H+, 100%).; a) 4-(Dimethylaminomethylene-thiocarbamoyl)-piperazine-l-carboxylic acid tert-butyl esterA mixture of 122 mmol N,N-dirnethylformamide dimethyl acetal and 6.11 mmol 4- thiocarbamoyl-piperazine-1-carboxylic acid tert-butyl ester (prepared from tert-butyl 1- piperazinecarboxylate, lj'-thiocarbonyldiimidazole and ammonia according to the procedure of J. Med. Chem. 1998, 41, 5037-5054) was heated at 110 0C for 3 h. The reaction mixture was then concentrated in vacuo and the residue was resuspended in ethyl acetate/ tetrahydrofuran ( 1:1) and washed with brine. The organic phase was dried over sodium sulphate and concentrated in vacuo to afford the title compound as a light yellow crystalline solid (yield 95%). MS (m/e): 301.4 (M+H+, 100%). | |
To a solution of thiocarbonyldiimidazole (2.1 g, 11.8 mmol) in tetrahydrofuran (30 mL) at room temperature, was added 1,1 -dimethylethyl 1-piperazinecarboxylate (2.0 g, 10.7 mmol). The reaction mixture was stirred at room temperature for 2 h and then heated to 55 C for additional 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure until approximately 20 mL of tetrahydrofuran remained. The residue was then treated with a 2 M solution of ammonia in methanol (10 mL) and stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure, and the residue was triturated with diethyl ether (25 mL) to give a white precipitate. The precipitate was filtered and dried to give 1.5 g of the title compound as a white solid..H NMR (CDCI3) delta 1.39 (s, 9H), 3.32 (m, 4H), 3.73 (m, 4H), 7.49 (br s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In dichloromethane; at 0 - 20℃; for 1.5h; | B. 4-(4-Chloro-phenoxy)-shenylisothiocvanate. To a solution of 1,1'- thiocarbonyldiimidazole (4.99 g, 28 mmol) in CH2CI2 (100 mL) was added a solution of 4- (4-chloro-phenoxy)-phenylamine (2.19 g, 10 mmol) in CH2CI2 (100 mL) dropwise over 1 h at 0 °C. The ice bath was removed, and the reaction mixture was stirred for 30 min at rt. The mixture was then washed with NaHCO3 (50 mL) and brine (50 mL). The organics were dried (Na2SO4), concentrated, passed through a plug of silica gel, and then washed with 20percent EtOAc/hexanes to afford 2.6 g (99percent) of the desired product NMR (400 MHz, CDC13) : 7.25-7. 23 (m, 2H), 7.13-7. 10 (m, 2H), 6.89-6. 84 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | INTERMEDIATE 31; 7-Bromo-2,3-dihydro-benzo[l,4]oxazine-4-carbothioic acid amide; A solution of Intermediate 19 (1.O g, 4.7 mmol) in THF (1OmL) was added to thiocarbonyldiimidazole (1.2 g, 5.8 mmol) and the mixture heated to 12O0C under microwave irradiation for 20 minutes. After cooling to r.t., it was poured into methanolic ammonia (1OmL of a 7M solution, 70 mmol) and stirred at r.t. over the weekend. It was concentrated in vacuo, and the residue triturated with water and Et2O followed by IM hydrochloric acid and Et2O to give the title compound (0.75 g, 58%) as a cream solid. 5H (DMSO-d6) 4.16-4.35 (4H, m), 7.07 (IH, dd, J 8.9, 2.3 Hz), 7.15 (IH, d, J2.3 Hz), 7.39 (IH, d, J 8.9 Hz). LCMS (ES+) 275 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | In dichloromethane; at 0 - 20℃; for 1h; | le 2- (2-tert-Butyl-phenoxy)-3-isothiocyanato-pyridine [00291] To a solution of N, N'-thiocarbonyl-diimidazole (4.4 g, 24.7 mmol) in DCM (20 mL) at 0C was added dropwise a solution of lb (3.0 g, 12. 4 mmol) in DCM (10 mL). The reaction mixture was slowly allowed to warm to rt. After 1 h, the mixture was concentrated. The oily residue was triturated with methanol, and the resulting white solid was filtered and rinsed with methanol. This afforded 1.72 g of the title compound 1c. The mother liquors were concentrated and triturated with methanol to afford another 200 mg of le. Overall yield: 54%. 1H NMR (400 MHz, CDC13) b ppm 1.38 (s, 9 H), 6.94 (m, 2 H), 7.21 (m, 2 H), 7.48 (m, 2 H), 8.01 (dd, J=4. 80,1. 77 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With dmap; In N,N-dimethyl-formamide; at 20 - 60℃; for 18h; | 86 mg (0.2 mmol) of <strong>[721401-53-2]5-chloro-N-((2R)-2-hydroxy-3-[4-(3-oxo-4-morpholinyl)-phenyl]amino}propyl)-2-thiophenecarboxamide</strong> [example 1, stage a)] are dissolved in 5 ml of DMF, and 56.09 mg (0.3 mmol) of N,N'-thiocarbonyldiimidazole and 2.6 mg (0.02 mmol) of 4-N,N-dimethylaminopyridine are added. The solution is stirred at RT for 6 hours and then at 60 C. for 12 hours. The solution is concentrated and the residue is purified by preparative HPLC (column: YMC gel ODS-AQ S-11 mum; mobile phase: water/acetonitrile, gradient 90:10?5:95). Yield: 26 mg (27% of theory) LC-MS (method 5): Rt=2.07 min. MS (ESIpos): m/z=452 [M+H]+ 1 H-NMR (300 MHz, DMSO-d6):delta =8.99 (t, 1H), 7.70 (d, 1H), 7.63 (d, 2H), 7.47 (d, 2H), 7.20 (d, 1H), 5.12-5.02 (m, 1H), 4.42 (t, 1H), 4.41 (s, 2H), 4.16-4.07 (m, 1H), 4.01-3.95 (m, 2H), 3.78-3.72 (m, 2H), 3.65 (t, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.18 g (24%) | In tetrahydrofuran; ethyl acetate; | EXAMPLE 7 1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]thiourea (Compound No. 7-1) A solution of 4-(3-aminopropyl)pyridine (Intermediate No. 2-1) (0.24 g, 1.8 mmol) in anhydrous tetrahydrofuran (10 ml) was added to 1,1'-thiocarbonyldiimidazole (0.31 g, 1.8 mmol) under a nitrogen atmosphere, and the mixture was stirred at room temperature. After one hour, a solution of 2-(1-adamantyl)-N-pentylethylamine hydrochloride (Intermediate No. 1-1) (0.50 g, 1.8 mmol) in anhydrous tetrahydrofuran (10 ml) was added to the mixture, and the whole was refluxed for 2.5 hours. The reaction mixture was allowed to stand, then ethyl acetate (50 ml) and a saturated aqueous sodium hydrogencarbonate solution (50 ml) were added to the reaction mixture, and layers were separated. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution (50 ml) and dried over anhydrous magnesium sulfate. The ethyl acetate layer was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography to give 0.18 g (24%) of the titled compound. IR(neat): 3304, 2902, 2846, 1603, 1530, 1345 cm-1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N-methyl-acetamide; water; ethyl acetate; | Reference Example 5 Synthesis of (-)-3'-5'-O-(1,1.3,3-tetraisopropyl-1,3-disiloxanediyl)-2'-O-imidazolylthiocarbonyl-adenosine from (-)-3',5'-O-(1,1,3,3-tetraisopropyl-1,3-disiloxanediyl) adenosine 0.76 g of (-)-3',5'-O-(1,1,3,3-tetraisopropyl-1,3-disiloxanediyl) adenosine was dissolved in 15 ml dry dimethylformamide, and 0.74 g of 1,1'-thiocarbonyldiimidazole was added thereto. This reaction solution was stirred at room temperature overnight, followed by raising the temperature to 70 C. and stirring for 6 hours. 250 ml ethyl acetate and 50 ml water were added to this reaction solution to stop the reaction. The organic layer was separated, washed twice with 50 ml water, then dried over magnesium sulfate and concentrated. The resulting oily residue was purified by silica gel column chromatography (eluent: methanol/methylene chloride) to give 0.76 g (purity: 81.7%) of the objective compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; | Preparation 124 To a mixture of 1,1'-thiocarbonyldiimidazole (1.87g), imidazole (143mg), acetonitrile (27ml) were added a suspension of <strong>[26177-43-5]3-nitrobenzylamine hydrochloride</strong> (1.32g) in acetonitrile (7ml) and imidazole (477mg) at 2~4C. After stirring for 3 hours at ambient temperature, to the reaction mixture was added 4-fluoro-1,2-benzenediamine (1,77g) under stirring. The reaction mixture was stirred at 50C for 3 hours, and at ambient temperature for 20 hours. The reaction mixture was evaporated under reduced pressure to give a residue which was purified by silica gel chromatography and eluted with ethyl acetate-n-hexane=2/3 to give N-(2-amino-4-fluorophenyl)-N'-(3-nitrobenzyl)thiourea (2.28g). MS:321(M+1) NMR(DMSO, delta):4.80(2H,d,J=5.9Hz), 5.17(2H,br s), 6.2-6.6(2H,m), 6.8-7.1(1H,m), 7.61(1H,t,J=7.9Hz), 7.78(1H,d,J=7.7Hz), 7.8-8.2(3H,m), 9.00(1H,br s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; N,N-dimethyl-formamide; at 65 - 70℃; for 1h; | General Procedure A: Preparation of isothiocyanate 1,1 '-thiocarbonylimidazole (1.1 mmol) was added to a solution of amine (1 mmol) inTHF/DMF (2 mL, 1:1) and the reaction mixture was stirred at 65-70 0C for 1 h. The product thus formed, was used for further transformation without isolation.; Example 1; Synthesis of 2-(Isoquinolin-3-ylamino)-lH-benzimidazole-5-carboxylic acid benzothiazol-6- ylamide3-Isothiocyanatoisoquinoline was prepared from <strong>[25475-67-6]3-aminoisoquinoline</strong> (5 mmol) as described in general procedure A.The isothiocyanate from above was reacted with methyl 3,4-diaminobenzoate (5mmol) followed by cyclization using EDC as described in general procedure B to obtain 2- (Isoquinolin-3-ylamino)-lH-benzimidazole-5-carboxylic acid methyl ester. The ester was hydrolyzed to yield the corresponding carboxylic acid employing general procedure C. Benzothiazol-6-ylamine (0.25 mmol) was coupled with aforementioned carboxylic acid using HBTU employing general procedure D to provide 2-(Isoquinolm-3-ylammo)-lH- benzimidazole-5-carboxylic acid benzothiazol-6-ylamide. MS: m/z 437 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; at 120℃; for 0.333333h;Microwave irradiation; | A mixture of 7-bromo-3,4-dihydro-2H-benzo[l,4]oxazine (7.07 g, 33.00 mmol) and l,l '-thiocarbonyldiimidazole (8.86 g, 49.70 mmol) in TetaF (83 mL) was heated to 1200C under microwave irradiation, in a sealed tube, for 20 minutes, and then cooled to r.t. NH3 (110 mL, 7N solution in MeOH, 770 mmol) was added. The reaction mixture was stirred at r.t. for 16 h, and then concentrated in vacuo. The residue was triturated with IM aqueous HCl, then Et2O, water and again Et2O, and then dried in vacuo to give the title compound (5.31 g, 59%) as a cream solid. deltaH (DMSO-d6) 8.66-7.53 (2H, m), <n="62"/>7.39 (IH, d, J 8.7 Hz), 7.15 (IH, d, J2.3 Hz), 7.07 (IH, dd, J8.9 and 2.3 Hz), 4.30-4.20 (4H, m). LCMS (ES+) 272.9 and 274.9 (M+H)+, RT 3.12 minutes {Method T). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate; at 50℃; for 0.0833333h; | A flask was charged with <strong>[102308-97-4]5-amino-1-methyl-1H-indole</strong> (8.8 g; 60 mmol), thiocarbonyl diimidazole (10.7 g; 60 mmol) and ethyl acetate (200 mL). The reaction was heated at 50 C. for five minutes, and after cooling, the solvent was evaporated. The crude material was dissolved in dichloromethane (100 mL) and filtered through a short plug of silica gel, which was washed with another bolus of dichloromethane (100 mL). The organic eluent was evaporated to give 5-isothiocyanato-1-methyl-1H-indole (8.9 g; 47 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 4 Synthesis [OFN [1 ()- (BENZOXAZOL-2-YLCARBONYL)-PROPYL]-3-PHENYLMETHANESULFONYL-2 (R)-] { [N- (2,2, 2-trifluoroethyl)-morpholin-4-ylcarboximidoyl] amino} propionamide Step 1 To a solution [OF N-TERT-BUTOXYVARBONYL-S-BENZYLCYSTEINE] (7.75 g, 28 mmol, 1.0 equiv. ) (prepared by reacting S-benzylcysteine with boc anhydride via a standard protocol) in methanol (250 mL) was added, with stirring, Oxone (19 g, 31 mmol, 1.1 equiv. ) in H20 (100 mL). The resulting suspension was stirred for 2 h at ambient temperature after which methanol was removed in vacuo. The aqueous layer was extracted with ethyl acetate to give [2-N-TERT-BUTOXYCARBONYL-3-PHENYLMETHANESULFONYLPROPIONIC] acid (7.85 g, 25.5 mmol) which was converted to [{1-] [[1-(BENZOXAZOL-2-YL-HYDROXYMETHYL)-PROPYLCARBAMOYL]-2-] phenylmethanesulfonylethyl)-carbamic acid [TERT-BUTYL] ester as described in Example 1, Step 2 above. Step 2 [L,] [L'-THIOCARBONYLDIIMIDAZOLE] (0.980 g, 5.50 mmol, 1.2 equiv. ) was dissolved in [CH2C12] (200 mL), followed by addition of diisopropylethylamine (3.2 mL), and trifluoroethylamine hydrochloride (0.620 g, 4.58 mmol, 1.0 equiv. ). The solution was stirred for 1 h at ambient temp, then 2-amino-N-[l-(benzoxazol-2-ylhydroxymethyl)-propyl]-3- phenylmethanesulfonylpropionamide was added in one portion. After stirring overnight, the reaction mixture was diluted with EtOAc (150 mL), washed with saturated bicarb, brine, dried over [MGS04.] Purification with flash chromatography (50% ETOAc/hexanes as eluent) afforded [N [L- (BENZOXAZOL-2-YLHYDROXYMETHYL)-PROPYL]-3-PHENYLMETHANESULFONYL-2- [3-] (2, 2, 2-trifluoroethyl) thioureido] propionamide (0.720 g) as a mixture of diasteomers. Step 3 Copper [SULFATE-5H20] (0.75 g) was added to flash silica gel (2.25 g) and the mixture placed in an oven and heated at [240 C] for 2 h, then cooled in a dessicator. In a dry microwave tube was placed THF (4 mL), [N [L- (BENZOXAZOL-2-YLHYDROXYMETHYL)-PROPYL]-3-] [PHENYLMETHANESULFONYL-2- [3- (2,] 2,2-trifluoroethyl) thioureido] propionamide (0.20 g, 0.350 mmol, 1.0 equiv), morpholine (0.122 g, 1.40 mmol, 4.0 equiv), [CUSO4/SIO2] (0.525 g, 1.5 equiv. ), and Et3N (0.035 g, 1.0 equiv. ). The mixture was heated via microwave to [80 C] for 30 min. The suspension was filtered and the solid washed with 10% [MEOH/CH2CL2.] The filtrate was concentrated and the resulting residue was purified by reverse phase chromatography to afford [N [L- (BENZOXAZOL-2-YL-HYDROXYMETHYL)-PROPYL]-3-] phenylmethanesulfonyl-2- { [[N-(2,] 2, [2-TRIFLUOROETHYL)-MORPHOLIN-4-YLCARBOXIMIDOYL]-] amino} propionamide (0.090 g) as a mixture of diastereomers. Step 4 [ TO N- [L- (BENZOXAZOL-2-YL-HYDROXYMETHYL)-PROPYL]-3-PHENYLMETHANESULFONYL-2- { [N-] (2,2, [2-TRIFLUOROETHYL)-MORPHOLIN-4-YLCARBOXIMIDOYL]-AMINO}] propionamide (40 mg, 0.064 mmol) in [CH2C12] (0.5 mL) was added Dess-Martin Periodinane (110 mg, 0.256 mmol) and the solution stirred for 2 h at ambient temperature. The reaction mixture was quenched with 0.26 M Na2S204 in sat'd [NAHCO3] and diluted with EtOAc. The organic layer was washed with water, brine, and dried over MgS04 and concentrated to give the title compound as a white solid. MS = 624.5 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
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Example 1-43; (2-Chloro-pyridin-4-yl)-{5-[2-(2,6-dichloro-phenyl)-3H-benzoimidazol-5-yl]- [1 ,3,4]oxadiazol-2-yl}-amine.; Combine 4-amino-3-chloro-pyridine (78 mg, 0.606 mmol) and di-imidazol-1-yl- methanethione (108 mg, 0.606 mmol) in DMF (1.5 mL) and stir overnight. Add 2-(2,6- dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (150 mg, 0.466 mmol) and DMF (1.5 mL). Heat to 80 C for 1 hr. Add EDCI (179 mg, 0.932 mmol) and heat to 80 C for 1 hr. Upon cooling, dilute the reaction with EtOAc (75 mL) and extract with water (15 mL). Dry the organic phase over Na2SO4 and concentrate. Purify the concentrate by reverse-phase HPLC (25 - 40 % ACN / H2O + 5 mM NH4OH) to afford the title compound as a yellow solid: 1 H NMR (400 MHz, DMSO-d6) delta ppm 7.51 (d, J=4.17 Hz, 1 H) 7.62 - 7.68 (m, 1 H) 7.70 (s, 1 H) 7.73 (dd, J=7.39, 1.96 Hz, 2 H) 7.75 - 7.87 (m, 1 H) 7.87 - 7.95 (m, 1 H) 8.07 (tautomer, br. s., 1 H) 8.19 (tautomer, br. s., 1 H) 8.29 (d, J=5.68 Hz, 1 H) 11.58 (br. s., 1 H) 13.32 (br. s., 1 H); MS m/z = 456.9 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 1-42; {5-[2-(2,6-Dichloro-phenyl)-3H-benzoimidazol-5-yl]-[1,3,4]oxadiazol-2-yl}-(2-methyl- pyridin-4-yl)-amine.; Combine 4-amino-3-methyl-pyridine (66 mg, 0.606 mmol) and di-imidazol-1-yl- methanethione (108 mg, 0.606 mmol) in DMF (1.5 mL) and stir overnight. Add 2-(2,6- dichloro-phenyO-SH-benzoimidazole-delta-carboxylic acid hydrazide (150 mg, 0.466 mmol) <n="90"/>and DMF (1.5 ml_). Heat to 80 C for 1hr. Add EDCI (179 mg, 0.932 mmol) and heat to 80 C for 1 hr. Upon cooling, dilute the reaction with EtOAc (75 mL) and extract with water (15 mL). Dry the organic phase over Na2SO4 and concentrate. Take the concentrate up in boiling toluene / EtOAc and cool to 4 C. Collect the resulting precipitate and purify by reverse-phase HPLC (20 - 45 % ACN / H2O + 5 mM NH4OH) to afford the title compound as a light yellow solid: 1 H NMR (400 MHz, DMS0-cf6, 100 C) delta ppm 2.46 (s, 3 H) 7.36 (dd, J=5.75, 2.14 Hz, 1 H) 7.42 (s, 1 H) 7.59 - 7.67 (m, 3 H) 7.81 (d, J=8.68 Hz, 1 H) 7.87 (dd, J=8.44, 1.47 Hz, 1 H) 8.16 (s, 1 H) 8.27 (d, J=5.69 Hz, 1 H); MS m/z = 437.0 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
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84% | In tetrahydrofuran; at 0 - 20℃; | Reference Example 95 5-Isothiocyanato-2,4-dimethoxypyrimidine To a solution of <strong>[14048-15-8]2,4-dimethoxypyrimidin-5-amine</strong> (prepared by the method described in U.S. Pat. No. 6,342,503B1) (4.68 g, 30.0 mmol) in tetrahydrofuran (60 mL) was added 1,1-thiocarbonyldiimidazole (6.41 g, 36.0 mmol) portionwise at 0 C. The mixture was warmed to room temperature and stirred for 20 hr. The mixture was concentrated in vacuo to give a residue which was passed through a pad of silica gel eluding with n-hexane/ethyl acetate. The filtrate was concentrated in vacuo to give the title compound (5.0 g, 84%) as a colorless solid. 1H NMR (CDCl3) delta 3.99 (s, 3H), 4.09 (s, 3H), 8.06 (s, 1H). MS Calcd.: 197; Found: 198 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In acetonitrile; at 50℃; for 4h; | Step A: N-(4,5,6,7-Tetrahydrobenzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide To 4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (0.5 g, 3.24 mmol) in acetonitrile (20 mL) was added di(1H-imidazol-1-yl)methanethione (0.58 g, 3.24 mmol). The reaction was stirred at 50 C. for 4 hours. The reaction was cooled and concentrated to yield crude product. The crude material was purified via flash chromatography (50-100% ethyl acetate-hexane) to yield N-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide (0.60 g, 2.27 mmol, 70.0% yield) as a white powder. |
70% | In acetonitrile; at 50℃; for 4h; | Step A: N-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide To 4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (0.5 g, 3.24 mmol) in acetonitrile (20 mL) was added di(lH-imidazol-l-yl)methanethione (0.58 g, 3.24 mmol). The reaction was stirred at 50 C for 4 hours. The reaction was cooled and concentrated to yield crude product. The crude material was purified via flash chromatography (50-100% ethyl acetate-hexane) to yield N-(4,5,6,7- tetrahydrobenzo[d]thiazol-2-yl)-lH-imidazole-l-carbothioamide (0.60 g, 2.27 mmol, 70.0 % yield) as a white powder. |
70% | In acetonitrile; at 50℃; for 4h; | To 4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (0.5g, 3.24 mmol) in acetonitrile (20 mL) was added di(1Himidazol-I-yl)methanethione (0.58 g, 3.24 mmol). The reactionwas stirred at 50 C. for 4 hours. The reaction was cooledand concentrated to yield crude product. The crude materialwas purified via flash chromatography (50-100% ethylacetate-hexane) to yield N-( 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-IH-imidazole-I-carbothioamide (0.60 g, 2.27mmol, 70.0% yield) as a white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; at 65℃; for 2h; | Step A: (3-Hydroxy-3-((3-(5-phenylthiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate To <strong>[39136-63-5]5-phenylthiazol-2-amine</strong> (0.52 g, 2.9 mmol) in acetonitrile (6 mL) was added 1,1'-thiocarbonyldiimidazole (0.68 g, 3.8 mmol). The reaction mixture was stirred at 65 C. for 2 hours. The precipitate was filtered and washed with acetonitrile (2×20 mL) to yield intermediate N-(5-phenylthiazol-2-yl)-1H-imidazole-1-carbothioamide. The intermediate was taken up in N,N-dimethylformamide (30 mL) and treated with (3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate (0.5 g, 2.9 mmol). The reaction mixture was stirred for 5 hours at 65 C. The reaction was concentrated in vacuo and purified via silica gel chromatography (30-100% ethyl acetate/hexane). The product fractions were combined and concentrated in vacuo to yield (3-hydroxy-3-((3-(5-phenylthiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate (0.85 g, 2.19 mmol, 74.4% yield) as a white powder. LC/MS confirmed product with loss of BH3 in the LC/MS conditions: retention time 3.26 (M+1-BH3=375.33). | |
In acetonitrile; at 65℃; for 2h; | Step A: (3-hydroxy-3-((3-(5-phenylthiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate To <strong>[39136-63-5]5-phenylthiazol-2-amine</strong> (0.52 g, 2.9 mmol) in acetonitrile (6 mL) was added Iota, Gamma-thiocarbonyldiimidazole (0.68 g, 3.8 mmol). The reaction mixture was stirred at 65 C for 2 hours. The precipitate was filtered and washed with acetonitrile (2 x 20 mL) to yield intermediate N-(5-phenylthiazol-2-yl)- ^-imidazole-l- carbothioamide. The intermediate was taken up in N,N-dimethylformamide (30 mL) and treated with (3-(aminomethyl)-3-hydroxy-l-ammoniobicyclo[2.2.2]octan-l- yl)trihydroborate (0.5 g, 2.9 mmol). The reaction mixture was stirred for 5 hours at 65 C. The reaction was concentrated in vacuo and purified via silica gel chromatography (30-100% ethyl acetate/hexane). The product fractions were combined and concentrated in vacuo to yield (3-hydroxy-3-((3-(5-phenylthiazol-2- yl)thioureido)methyl)-l-ammoniobicyclo[2.2.2]octan-l-yl)trihydroborate (.85 g, 2.19 mmol, 74.4 % yield) as a white powder. LC/MS confirmed product with loss of BH3 in the LC/MS conditions: retention time 3.26 (M+1-BH3= 375.33). | |
In acetonitrile; at 65℃; for 2h; | To <strong>[39136-63-5]5-phenylthiazol-2-amine</strong> (0.52 g, 2.9 mmol) inacetonitrile (6 mL) was added 1,1'-thiocarbonyldiimidazole(0.68 g, 3.8 mmol). The reaction mixture was stirred at 65 C.for 2 hours. The precipitate was filtered and washed withacetonitrile (2x20 mL) to yield intermediate N-(5-phenylthiazol-2-yl)_1H-imidazole-I-carbothioamide. The intermediatewas taken up in N,N-dimethylformamide (30 mL) andtreated with (3-(aminomethyl)-3-hydroxy-I-ammoniobicyclo[2.2.2]octan-I-yl)trihydroborate (0.5 g, 2.9 mmol). Thereaction mixture was stirred for 5 hours at 65 C. The reactionwas concentrated in vacuo and purified via silica gel chromatography(30-100% ethyl acetate/hexane). The product fractionswere combined and concentrated in vacuo to yield(3-hydroxy-3-((3-(5-phenylthiazol-2-yI)thioureido)methy1)l-ammoniobicyclo[2.2.2]octan-I-yl)trihydroborate (0.85 g,2.19 mmol, 74.4% yield) as a white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | 0.618 g (3.47 mmol) N,N'-thiocarbonyldiimidazole was dissolved in 20 mL acetonitrile, and 0.500 g (3.47 mmol) isoquinoline-3-amine in the form of a suspension in 15 mL acetonitrile was added dropwise in portions. The clear orange solution which formed was stirred for 12 hr, whereupon a reddish precipitate formed. The intermediate product was directly reacted, without workup, with 0.535 g (6.940 mmol) ammonium acetate for 25 min at 85° C. in a CEM microwave (100 watts). The solvent was removed under vacuum. The residue was stirred in water, and the resulting precipitate was suctioned off and washed with water. For further purification the solid was taken up in 5 mL acetonitrile and combined with 50 mL diisopropyl ether. The precipitate was filtered again and dried in a vacuum drying oven at 40° C., resulting in the isolation of 0.540 g (2.647 mmol, 76percent) purified N-isoquinolin-3-yl-thiourea.ESI-MS [M+H+]=204.15 Calculated for C10H9N3S=203.27 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1. 6-methyl[1,3]oxazolo[5,4-b]pyridine-2(1H)-thione<strong>[52334-51-7]3-Amino-5-methylpyridin-2-ol</strong> (0.21 g, 1.7 mmol) was dissolved in THF (5 mL), and 1,1'-thiocarbonyldiimidazole (0.48 g, 2.7 mmol) was added. The mixture was stirred at RT for 20 min. The reaction was diluted with water, treated with 1N HCl to adjust the pH to the range of 4-5. The product was then extracted with ethyl acetate, the extracts were washed with brine, and dried over sodium sulfate, filtered and concentrated to afford the product, used without further purification in the following step. LCMS (M+H)+: m/z=167.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 20℃; for 24h; | General procedure: A solution of CDI or TCDI (0.19 mmol) and 8-aminoquinoline (1, 3, or 4, 0.39 mmol) in dry CH2Cl2 (5 mL) was stirred at ambient temperature for 24 h. The solvent was distilled off. The reaction mixture was dissolved in CH2Cl2 (20 mL) and washed with water (3 × 5 mL) followed by brine solution (5 mL). The organic layer was dried (Na2SO4) and concentrated to afford crude product, which was purified by column chromatography on silica gel (100-200 mesh) using 1.5% CH3OH in CH2Cl2 to provide product as viscous oil. Treatment with HCl solution (2 N in ether) provided their HCl salts. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | In dichloromethane; at 50℃; for 3h; | Step B: 6-fluoro-3-isothiocyanato-1H-indazole To 6-fluoro-lH-indazol-3 -amine (0.32 g, 2.1 mmol) in dichloromethane (15 mL) was added l,l'-thiocarbonyldipyridin-2(lH)-one (0.53 g, 2.30 mmol). The reaction was stirred at 50 C for 3 hours. The reaction was cooled to room temperature and the crude product was purified by column chromatography (25% ethyl acetate/hexanes) to afford 6-fluoro-3-isothiocyanato-lH-indazole (0.30 g, 1.53 mmol, 73.0 % yield) as a light yellow powder. XH NMR (500 MHz, DMSO-D6) delta ppm 13.39 (s, 1 H), 7.78 (dd, J=8.85, 4.88 Hz, 1 H), 7.41 (dd, J=9.31, 1.68 Hz, 1 H), 7.14 (td, J=9.16, 1.83 Hz, 1 H). MS (LC/MS) R.T. = 3.69; [M+H]+ = 194.07. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester may be prepared from <strong>[66315-16-0]3-amino-4-methylamino-benzoic acid methyl ester</strong>, 2-amino-6-(trifluoromethoxy)benzothiazole, 1,1?-thiocarbonyl-diimidazole, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC). 1,1?-Thiocarbonylimidazole may be added to a solution of 2-amino-6-(trifluoromethoxy)benzothiazole in DMF, and the reaction mixture stirred at 90-100 C. for a day. To this reaction mixture at room temperature is added EDC and stirred at 60 C. for 5 min. To this reaction mixture at room temperature is added <strong>[66315-16-0]3-amino-4-methylamino-benzoic acid methyl ester</strong> and stirred at 90 C. The reaction mixture may then be cooled to room temperature, poured into ice-cold water and the solid collected by filtration. The crude product thus obtained may be purified by trituration with dichloromethan-methanol (9:1). LC/MS: m/z 423.8 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With dmap; In dichloromethane; at 20.0℃; for 1.0h;Inert atmosphere; | To a stirred solution of biphenyl-3-ylamine (338 mg, 2 mmol) in DCM (5 mL), thiocarbonyldiimidazole (TCDI) (535 mg, 3 mmol) and DMAP (48.8 mg, 0.04 mmol) were added and the reaction mixture stirred at r.t under N2 for 1 h (until TLC showed no starting material remaining). The reaction mixture was then purified by a silica plug (DCM). The solvent was then removed in vacuo to leave a colourless oil (407 mg, 96%). Rf: 0.86 (1:1 DCM/hex). 1H NMR (CDCl3): delta 7.16 (ddd, 1H, J 8, 2, 1 Hz, H6'), 7.34-7.48 (m, 6H, H4'', H5', H4', H3'', H5'', H2'), 7.52 (m, 2H, H2'', H6''). 13C NMR (CDCl3): delta 124.4 (CH), 124.5 (CH), 126.2 (CH), 127.2 (CH), 128.2 (CH), 129.1 (CH), 130.0 (CH), 131.8 (C), 135.7 (NCS), 139.5 (C), 143.0 (C). |
Yield | Reaction Conditions | Operation in experiment |
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44% | 500 mg (3.6 mmoles) (S)-1-(2-fluorophenyl) ethylamine and 700 mg (3.95 mmoles) 1,1-thiocarbonyldiimidazole are dissolved in 10 ml dichlormethane and stirred at room temperature for 1,5 hour. Thereafter, 240 mg (3.95 mmoles) 2-aminoethanol dissolved in 3 ml dichlormethane are added dropwise and the resulting mixture is stirred at ambient temperature for 18 hours. The reaction mixture is diluted with water; the organic phase is separated off, dried over Na2SO4, filtered and the solvent is evaporated under reduced pressure. The residue is purified by chromatography (silica gel; dichlormethan/methanol = v/v 9: 1). Yield: 400 mg (44 % of therory). logP (HCOOH) = 1.5 1H-NMR (DMSO-d6): delta, 5.65 m (examplified signals). |
Yield | Reaction Conditions | Operation in experiment |
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In N,N-dimethyl-formamide; at 20℃; for 1.5h; | Example 252A [001025] 7-isothiocyanato-3,4-dihydroquinolin-2(lH)-one [001026] A solution of 7-amino-3,4-dihydroquinolin-2(lH)-one (0.20 g, 1.2 mmol) in DMF (5.2 mL) was added dropwise to a solution of Iota,Gamma-thiocarbonyldiimidazole (0.22 g, 1.2 mmol) in DMF (2.1 mL) at room temperature over 1 hour. The mixture was stirred for 30 minutes and then water was slowly added. The resulting precipitate was collected by filtration (rinsed with water) and dried under vacuum to afford the title compound (0.21 g, 83% yield), which was used without purification. |
Yield | Reaction Conditions | Operation in experiment |
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89% | Triethylamine (55.8 muL, 0.4 mmol) and thiocarbonyldiimidazole (46.3 mg, 0.26 mmol) were added to a methylene chloride solution (0.4 mL) of <strong>[610-36-6]4-amino-2-nitrobenzoic acid</strong> (36.4 mg, 0.2 mmol) at room temperature , followed by stirring at room temperature for 10 minutes. The reaction mixture was dissolved in ethyl acetate and washed with 1 M hydrochloric acid, the organic layer was separated, and then the organic layer was dried over magnesium sulfate. Thereafter, filtration and concentration under reduced pressure to dryness were carried out to obtain 4-isothiocyanato-2-nitrobenzoic acid as a colorless solid (40 mg, yield: 89%, HPLC purity: 96.4%)1H-NMR (DMSO-d6) delta: 7.80 (dd, J=2.1, 8.1 Hz, 1H), 7.93 (d, J=8.1 Hz, 1H), 8.12 (d, J=2.1 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In dichloromethane; at 20℃; for 1h; | a) 4-(4-Isothiocvanatobenzoyl)morpholine (1-112) l-(lH-imidazole-l-carbothioyl)-lH-imidazole (172.8 mg; 0.97 mmol; 1 eq) was added to a solution of 4-(morpholine-4-carbonyl)aniline (200 mg; 0.97 mmol; 1 eq) in dichloromethane (5 ml). The reaction mixture was stirred at room temperature for 1 hour, and then concentrated to dryness. The crude was purified on silica gel using dichloromethane as an eluent. The title compound 4-(4-isothiocyanatobenzoyl) morpholine was obtained in 89% yield (215 mg) as a yellow gum. 1H NMR (CDC13): delta (ppm) 3.62 (brs, 8Eta), 7.26 (s, 1Eta), 7.28 (s, 1Eta), 7.42 (m, 2H); MS (ESI+): m/z = 249.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
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72% | In dichloromethane; at 20℃; for 2h; | a) Methyl 2-chloro-5-isothiocyanatobenzoate (1- 115) l-(lH-imidazole- l-carbothioyl)-lH-imidazole (200 mg; 1.12 mmol; 1 eq) was added to a solution of <strong>[42122-75-8]methyl 5-amino-2-chlorobenzoate</strong> (208.3 mg; 1.12 mmol; 1 eq) in dichloromethane (5 ml). The reaction mixture was stirred at room temperature for 2 hours, and then concentrated to dryness. The crude was purified on silica gel using cyclohexane/ethyl acetate (100/0 to 95/5) as an eluent. The title compound methyl 2- chloro-5-isothiocyanatobenzoate was obtained in 72% yield (185 mg) as white solid. 1H NMR (CDC13): delta (ppm) 3.94 (s, 3Eta), 7.26 (m, 1Eta), 7.42 (d, 1Eta), 7.7 (d, 1Eta). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | In dichloromethane; at 0 - 20℃; under 760.051 Torr;Inert atmosphere; | In a 100 mL round-bottomed flask, di(lH-imidazol-l-yl)methanethione (1.25 g, 7.02 mmol, Eq: 1.5) was combined with CH2CI2 (30 mL) to give a colorless solution. 3-chloro-4- fluoro-5-(trifluoromethyl)aniline (lg, 4.68 mmol, Eq: 1.00) in CH2CI2 (20 mL) was added dropwise at 0C. The reaction was allowed to warm to room temperature, and allowed to stir overnight. Concentrate the solution, the compound was isolated by column chromatography (CH2C12/Hexanes = 80/20) to give the product 0.8 g (67%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In dichloromethane; at 0 - 20℃; under 760.051 Torr;Inert atmosphere; | In a 100 mL round-bottomed flask, di(lH-imidazol-l-yl)methanethione (1.84 g, 10.3 mmol, Eq: 1.5) was combined with CH2CI2 (30 mL) to give a colorless solution. 3-chloro-5- fluoroaniline (1 g, 6.87 mmol, Eq: 1.00) in CH2CI2 (20 mL) was added dropwise at 0C. The reaction was allowed to warm to room temperature, and allowed to stir overnight. Concentrate the solution, the compound was isolated by column chromatography (Hexanes/EtOAc = 80/20) to give the product 1.2 g (93%). |
Yield | Reaction Conditions | Operation in experiment |
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Example 1. N-(4-methoxybenzo[d]thiazol-2-yl)-5-(4-methoxyphenyl)-l,3,4- oxadiazol-2-amine 4-Methoxybenzhydrazide (0.332 mg, 2.0 mmol) was dissolved in acetonitrile (10 mL) and to this mixture was added 1 , l'-thiocarbonyldiimidazole (445 mg, 2.5 mmol). After stirring at rt for 3 hours, <strong>[5464-79-9]2-amino-4-methoxy-benzothiazole</strong> (450 mg, 2.5 mmol) was added and the temperature raised to 85 C with stirring continued for 20 hours. After cooling, the acetonitrile was removed by rotary evaporator. Water was added (100 mL) and this mixture was extracted with 3 volumes of ethyl acetate (50 mL). The organic layers were collected and solvent removed en vacuo. To this thiosemicarbazide intermediate was added tosyl chloride (393 mg, 2.1 mmol) and pyridine (0.29 mL, 3.6 mmol) in THF (20 mL). The solution was heated to 70 C, bringing the mixture to reflux for 20 h, then cooled. Ethyl acetate (10 mL) and HC1 (1.0 M, 10 mL) were added and the mixture was vigorously stirred for 10 minutes. The aqueous layer was removed and extracted with EtOAc (20 mL), and the combined organic layers were flushed with concentrated to a slurry. After purification via reverse-phase HPLC (water/acetonitrile, 10-95%), the product fractions were collected, concentrated and lyophilized to furnish a white solid. ESI-MS m/z 355 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In dichloromethane; at 0 - 20℃;Inert atmosphere; | In a 100 mL round-bottomed flask, di(lH-imidazol-1-yl)methanethione (718 mg, 4.03 mmol, Eq:1.5) was combined with CH2Ch (30 mL) to give a colorless solution. 1-(4- Aminophenyl)pyridin-2(1H)-one (500 mg, 2.69 mmol, Eq: 1.00) in CH 2Ch (20 mL) was added dropwise at ooc. The reaction was allowed to warm to room temperature, and allowed to stirovernight. Concentrate the solution, the compound was isolated by column chromatography(Hexanes/EtOAc = 80/20) to give the product 580 mg (95% ). MH+228.9 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With triethylamine; In dichloromethane; at 0 - 20℃; for 2h; | Step 1 : TEA(1.1 g, 10.87 mmol, 3.00 equiv) was added into a solution of l ,l'-thiocarbonyldiimidazole (1.28 g, 7.18 mmol, 2.00 equiv) and 4-aminotetrahydropyran hydrochloride (500 mg, 3.63 mmol, 1.00 equiv) in DCM (5 mL) at 0 °C. The reaction mixture was warmed to RT and stirred for 2 h at this temperature. The resulting solution was then diluted with 20 mL of water and extracted with 3x100 mL of DCM. The combined organic layers were dried (Na2S04) and concentrated under vacuum. The residue was purified on an Si02 column with ethyl acetate/petroleum ether (1 :3) to give 200 mg (38percent) of 48 as colorless oil. 'H-NMR (300MHz, CDC13) 83.98-3.87 (m, 3H), 3.60-3.53 (m, 2H), 2.06-1.97 (m, 2H), 1.89-1.79 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54.5% | In dichloromethane; acetonitrile; for 5h;Reflux; | A solution of 17-(lH-benzimidazol-l-yl)androsta-5,16-dien-3 -ol (VN/124-1) (0.2 g, 0.515 mmol), l,l'-thiocarbonyldiimidazole (0.18 g, 1.03 mmol) in anhydrous acetonitrile (2 mL) and DCM (1 mL) was refluxed for 5 h . The solvent evaporated, residue treated with water, and filtered. The crude brown solids obtained was purified by FCC using 1.7 percent ethanol in DCM in presence of traces of TEA (0.06percent) to give V PP397 (0.14 g, 54.5percent): mp 187-88 °C; IR (Neat) 1487, 1456, 1386, 1324, 1291, 1243, 1222, 1110, 986, 827, 743 cm"nH NMR (400 MHz, CDC13)? 1.03 (s, 3 H, 18-CH3), 1.14 (s, 3 H, I9-CH3), 5.31 - 5.42 (m, 1 H, 3a-H), 5.48 - 5.57 (m, 1 H, 6-H), 6.00 (br. s., 1 H, 16-H), 7.03 (s, 1 H, Ar-42 H), 7.28 - 7.35 (m, 2 H, Ar-51 and 61 Hs), 7.49 (d, J=5.14 Hz, 1 H, Ar-52 H), 7.64 (s, 1 H, Ar-41 H), 7.82 (d, J=7.58 Hz, 1 H, Ar-71 H), 7.96 (s, 1 H, Ar-21), 8.35 (s, 1 H, Ar-22 H); 13C NMR (400 MHz CDC13)? 183.3, 147.1, 143.3, 141.6, 139.0, 136.7, 130.7, 124.1, 123.4, 123.2, 122.5, 120.2, 117.9, 111.1, 83.3, 55.7, 50.3, 47.2, 37.2, 36.8, 36.6, 34.8, 31.1, 30.3, 30.2, 27.0, 20.6, 19.2, 16.0 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In tetrahydrofuran; at 25℃; for 6h;Inert atmosphere; | A mixture of <strong>[211172-52-0]2-amino-3-hydroxybenzonitrile</strong> (200 mg, 1.22 mmol), TCDI (260 mg, 1.46 mmol) and in THF (10 mL) was stirred at RT for 6 h under N2 atmosphere. The mixture was diluted with iN HC1, extracted with EtOAc, dried over Na2SO4 and concentrated in vacuum to givethe product 2-mercaptobenzo[d]oxazole-4-carbonitrile (200 mg, yield: 80%), which was used for the next step without further purification. ?H-NMR (CDC13, 400 MHz) oe 7.45 (t, J 8.0 Hz, 2H), 7.25 (t, J= 8.0 Hz, 1H). MS (M+H): 177. |
In tetrahydrofuran; at 20℃; for 6h;Inert atmosphere; | A mixture of <strong>[211172-52-0]2-amino-3-hydroxybenzonitrile</strong> (200 mg, 1.22 mmol), TCDI (260 mg, 1.46 mmol) and in THF (10 mL) was stirred at RT for 6 h under N2 atmosphere. The mixture was diluted with iN HC1, extracted with EtOAc, dried over Na2504 and concentrated in vacuum to give the product 2-mercaptobenzo[d]oxazole-4-carbonitrile (200 mg, yield: 80%), which was used for the next step without further purification. ?H-NMR (CDC13, 400 MHz) oe7.45 (t, J= 8.0 Hz, 2H), 7.25 (t, J= 8.0 Hz, 1H). MS (M+H): 177. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37.5% | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;Inert atmosphere; | General procedure: Triethylamine (3 or 6.25 equiv.) was added to a solution of the amine (1 equiv. in dimethylformamide at RT under N2). To the resultant solution, 1,1?-thiocarbonyldiimidazole (2 equiv. in DMF at RT under N2) was added in a dropwise fashion over 15min, with continued stirring at RT for 18h. The solution was quenched with water and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried (magnesium sulfate) and concentrated. The crude material was purified using silica gel chromatography (ethyl acetate-hexanes) to afford the desired isothiocyanate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | To a suspension of thiocarbonyldiimidazoe (206 mg, 1.10 mmol) in DCM (3 mL) at 0C, a solution of tertbutyl 4(3aminophenyl)piperidine1carboxylate (160 mg, 0.58 mmo) in DCM (2 mL) was added dropwise and the mixture was stirred at rt for 3 h. The reaction mixture was cooled again to 0 00 and a solution of ammonia in MeOH 7N (2 mL) was added dropwise. The reaction mixture was stirred at rt for 16 h. Water was added andextracted with DCM. Purification by flash chromatography, silica gel, gradient hexane to 50% acetone afforded the desired product (180 mg, 93% yield) as white foam, 1H NMR (400MHz, ODd3) 6 ppm: 8,16 (bs, 1H), 7.39 (t, J=7.6Hz, 1H), 7.18 (d, J7.6Hz, 1H), 7.12 (d, J=76Hz, 1H), 7.09 (m, 1H), 6.17 (bs, 2H), 4.26 (m, 2H), 2.81 (m, 2H),2.68 (m, IH), 1.83 (m, 2H(, 1.62 (m, 2H), 1.50 (m, 9H). | |
93% | At 0C, a solution of 1,1'-thiocarbonyldiimidazole (206 mg, 1.10 mmol) in DCM (3 mL) was added dropwise <strong>[387827-19-2]4-(3-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester</strong> (160 mg, 0.58 mmol) in DCM (2 mL) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled again to 0C and a solution of ammonia in MeOH 7N (2 mL) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. Water was added and extracted with DCM. Purification by flash chromatography (silica gel, gradient to hexanes to 50% acetone). The desired product was obtained as a white foam (180 mg, 93% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 100℃; for 1h;Microwave irradiation; Sealed tube; | A stirred mixture of <strong>[89182-17-2]6-chloropyridine-3,4-diamine</strong> (500 mg, 3.48 mmol), 1,1?-thiocarbonyldiimidazole (1.24 g, 6.97 mmol), and triethylamine (0.49 mL, 3.48 mmol) in anhydrous DMF (15.0 mL) was microwaved in a Biotage Initiator at 100 C. at normal power for 1 h. Then the reaction mixture was evaporated at reduced pressure, and the resulting residue extracted with DCM (200 mL) and allowed to stand at 10 C. overnight. The mixture filtered and the solids washed with cold DCM (2×20 mL), and air dried to afford the title compound as a solid. LC-MS: calculated for C6H4ClN3S 184.98 observed m/e: 186.07 (M+H)+ (Rt 0.62/2.0 min) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With triethylamine; In dichloromethane; at 20℃;Inert atmosphere; | Under the protection of argon, the cross spore alkali (1.86 g, 4.0 mmol) for 100 ml dichloromethane dissolved, at room temperature by adding 10 ml triethylamine andN,N' - Sulfur carbonyl diimidazole (1.3 g, 8.0 mmol), the reaction overnight at room temperature. The reaction solution is poured into 100 ml ice water, dichloromethane extraction, anhydrous sodium sulfate after drying the organic phase concentration, silica gel column chromatography separation, dichloromethane: methanol=20:1 (v/v) elute and get the 3' -N- (1 - Imidazole sulfur on behalf of the carboxamido) cross spore alkali 1.9 g, yield 82%, |
78% | With triethylamine; In dichloromethane; at 20℃; | Et3N (1.0mL) and N,N?-thiocarbonyldiimidazole (214mg, 1.2mmol) were added sequentially to a solution of <strong>[62996-74-1]staurosporine</strong> (186mg, 0.4mmol) in CH2Cl2 (10mL) at rt. After stirring overnight, the reaction flask contents were poured into cold water (20mL) and extracted with CH2Cl2 (3×30mL). The combined organic layers were then washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by FCC eluting with CH2Cl2-MeOH (20:1) to provide 3?-N-(1H-imidazole-1-carbamothioyl)<strong>[62996-74-1]staurosporine</strong> (11, 180mg, 0.312mmol, 78% yield) as a light yellow solid; Rf 0.62 (20:1 CH2Cl2-MeOH); [alpha]D18 +362 (c 0.07, CHCl3); IR (KBr): 3723, 1673, 1584, 1456, 1398, 1344, 1315, 1226, 1119, 749, 615cm-1; 1H NMR (500MHz, DMSO-d6) delta 9.32 (d, J=7.9Hz, 1H), 8.63 (s, 1H), 8.12 (s, 1H), 8.07 (d, J=7.7Hz, 1H), 8.03 (d, J=8.5Hz, 1H), 7.64 (d, J=7.2Hz, 1H), 7.59 (br s, 1H), 7.51 (t, J=7.4Hz, 1H), 7.50 (t, J=7.7, 1H),7.37 (t, J=7.4Hz, 1H), 7.32 (t, J=7.5Hz, 1H), 7.13 (br s, 1H), 7.06 (m, 1H), 5.47 (m, 1H), 5.01 (s, 2H), 4.79 (br s, 1H), 3.06 (s, 3H), 3.05 (m, 1H), 2.73 (s, 3H), 2.44 (s, 3H), 2.43 (m, 1H); 13C NMR (125MHz, DMSO-d6) delta 179.3, 171.9, 138.8, 137.7, 136.2, 132.7, 129.3, 129.0, 125.8, 125.4, 125.2 (2×C), 123.9, 122.7, 121.6, 120.5, 119.9, 119.6, 119.6, 115.3, 114.3, 113.5, 108.9, 94.8, 81.9 (2×C), 60.4, 58.1, 45.5, 38.2, 29.4, 27.1; HRESI-MS m/z 577.2031 [M+H]+ (calcd for C32H29N6O3S, 577.2022). Compound 11 (80mg, 0.14mmol) was dissolved in 10mL of CH3CN and treated with MeI (86muL, 1.39mmol) at room temperature. The mixture was stirred at rt for 24h. The solvent was removed under vacuum and the residue was washed with 50mL of PE-CH2Cl2 (1:1) to provide the thiocarbamoylimidazolium salt 12 (75mg, 0.105mmol, 76% yield) as a light yellow powder; [alpha]D18 +267 (c 0.07, MeOH); IR (KBr): 1680, 1549, 1531, 1515, 1460, 1347, 1312, 747cm-1; 1H NMR (500MHz, DMSO-d6) delta 9.71 (s, 1H), 9.31 (d, J=8.0Hz, 1H), 8.65 (s, 1H), 8.16 (br s, 1H), 8.09 (d, J=7.7Hz, 1H), 8.05 (d, J=8.3Hz, 1H), 7.87 (br s, 1H), 7.64 (d, J=7.7Hz, 1H), 7.53 (t, J=7.3Hz, 1H), 7.51 (t, J=7.7Hz, 1H), 7.39 (t, J=7.4Hz, 1H), 7.32 (t, J=7.5Hz, 1H), 7.18 (t, J=7.1Hz, 1H), 5.40m, 1H), 5.01 (s, 2H), 4.77 (br s, 1H), 3.92 (s, 3H), 3.09 (s, 3H), 3.12 (m, 1H), 2.75 (s, 3H), 2.46 (s, 3H), 2.46 (m, 1H); 13C NMR (125MHz, DMSO-d6) delta 174.3, 171.8, 138.8, 138.1, 136.2, 132.7, 129.2, 127.0, 127.0, 125.8, 125.4, 125.3, 123.9, 123.8, 122.8, 121.6, 120.6, 119.7, 119.6, 115.4, 114.4, 113.5, 108.9, 94.7, 81.8, 81.2, 60.5, 59.3, 45.5, 38.6, 36.5, 29.4, 26.8; HRESI-MS m/z 591.2164 [M-I]+ (calcd for C33H31N6O3S, 591.2173). |
78% | With triethylamine; In dichloromethane; at 20℃; | A solution of <strong>[62996-74-1]staurosporine</strong> (186 mg, 0.4 mmol)Dissolved in 10 mL of methylene chloride,1 mL of triethylamine and N, N'-thiocarbonyldiimidazole (214 mg, 1.2 mmol) were added at room temperature,Overnight at room temperature.The reaction solution was poured into 20 mL of ice water,Dichloromethane extraction,The organic phase was dried over anhydrous sodium sulfate and concentrated,Silica gel column chromatography,Dichloromethane: methanol = 20: 1 (v / v)3'-N- (1-imidazolylthio)<strong>[62996-74-1]Staurosporine</strong>(168) 180mg,Yield 78%. |
78% | With triethylamine; In dichloromethane; at 20℃; | The <strong>[62996-74-1]staurosporine</strong> (186 mg, 0.4 mmol) was dissolved in 10 mL of dichloromethane,1 mL of triethylamine and N, N'-thiocarbonyldiimidazole (214 mg, 1.2 mmol) were added at room temperature,Room temperature overnight reaction.The reaction solution was poured into 20 mL of ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate and then concentrated. The column was separated by silica gel column chromatography,Dichloromethane: methanol = 20: 1 (v / v)Eluted to give 180 mg of 3'-N- (1-imidazolylthioformyl) <strong>[62996-74-1]staurosporine</strong> (168) in a yield of 78%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | In dichloromethane; for 16h;Inert atmosphere; Reflux; | A solution of compound 6 (122 mg, 0.672 mmol) and 1,1'-(thiocarbonyl)diimidazole (60.4 mg,0.339 mmol) in dichloromethane (5 mL) was heated at reflux for 16 h. The mixture was cooled andconcentrated under a stream of nitrogen. The residue was diluted with ethyl acetate (25 mL) andwashed with brine (2 × 25 mL) and water (2 × 25 mL). The organic layer was dried over MgSO4and concentrated in vacuo. The crude product was purified by flash chromatography using 1:12ethyl acetate / dichloromethane as eluent to give the title compound as a white solid (82 mg, 66%);m.p. 244-246 C; IR (neat) numax (cm-1) 3208, 2952, 2365, 1724, 1659, 1612, 1529, 1435; 1H NMR(300 MHz, DMSO-d6) delta 13.0 (s, 1H, NH), 7.52 (dd, J = 2.1, 1.2 Hz, 1H), 7.43 (m, 2H), 7.36 (t, J =1.7 Hz, 1H), 7.32-7.31 (m, 2H), 3.87 (s, 3H, OMe), 3.83 (s, 3H, OMe), 3.64 (s, 3H, OMe);13C {1H} NMR (75 MHz, DMSO-d6) delta 174.6, 164.0, 159.9, 158.7, 156.0, 134.0, 132.3, 132.2,128.0, 124,8, 119.0, 117,6, 116.8, 115.5, 107.9, 55.69, 55.66, 52.2; HRMS (ESI, +ve)C18H16N2O5SNa+ [MNa+] requires m/z = 395.0672, found 395.0665. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3%Chromat.; 0.02%Chromat.; 110 g | With triethylamine; In dichloromethane; at 10 - 30℃; | To a 250 ml round bottom flask fitted with a mechanical stirrer, thermometer socket was charged methylene chloride (200 ml), 4-Amino-2-trifluoromethyl benzonitrile of Formula 2 (100 gms) and l,i-Thiocarbonyldiimidazole (105.3 gms) at room temperature. The reaction mass temperature was cooled to 10C to 15C, was added triethylamine (108.7 gms) slowly at 10C to 15C. After addition of the triethylamine reaction mass becomes homogeneous solution. The reaction mass was stirred for 2 to 2.5 hours at 25C to 30C. After completion of the reaction charged methylene chloride (300 ml) and cooled to -10C to about 0C, was charged precooled aqueous hydrochloric acid (dissolved 260 ml cone. HC1 and 740 ml water) and stirred for 15-20 min. Separated the organic and aqueous layers. The organic layer washed with 7% aq. sodium bicarbonate solution (dissolved 35 gms sodium bicarbonate in 500 ml water and stir well) followed by brine solution (1 x500 ml). The organic layer was distilled under vacuum and was recrystallized from n-heptane to obtain the title compound as a solid and dried under vacuum at a temperature about 25-30C. Yield: l lO.Ogms; Purity by HPLC: 95.0%; Formula 3A by HPLC: 0.02%; Formula 3B by HPLC: Not detected; Formula 3C by HPLC: 3% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In dichloromethane; at 0 - 20℃;Inert atmosphere; | To a 1 L 3-neck round bottom flask equipped with a magnetic stirrer, condenser, thermocouple and nitrogen inlet was charged N-methyl-L-alanine (compound 1, 1.0 g; 9.70 mmol) and DCM (600 mL) followed by DIEA (3.7 mL; 21.4 mmol; 2.2 eq). This solution was chilled to 0 oC via an ice bath. The 1,1?-thiocarbonyldiimidazole (TDI, 1.82 g; 10.2 mmol, 1.05 eq) was added to the reaction mixture in portions over 4 hours. The reaction was stirred in an ice bath and slowly warmed to room temperature overnight. The reaction was filtered through a plug of silica gel with DCM then eluted with ethyl acetate/hexanes. The filtrate was concentrated to dryness giving the title compound as an orange oil (1.29 g, 91% yield). MS (ESI, pos.): calc?d for C5H7NO2S, 145.18; found 146.00 (M+H), 168.2 (M+Na). 1H-NMR (300 MHz, CDCl3): ^ 4.02- 4.14 (q, 1H), 3.05 (s, 3H), 1.52- 1.50 (d, 3H). 13C-NMR (300 MHz, CDCl3): ^ 198.1, 164.2, 67.7, 29.5, 16.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | In a 250 mL flask, 1,1?-Thiocarbonyldiimidazole (2.67 g, 14.96 mmol) was added in 36 mL of dioxane. [2-(3,4-dimethoxy-N-methyl-anilino)-2-oxo- ethyl]ammonium;2,2,2-trifluoroacetate (4.60 g, 13.6 mmol) was dissolved in 100mL of dioxane. The acidic solution was then neutralized by addition of triethylamine, and then added dropwise in the flask. The solution was then stirred at room temperature for 1.5 hour. Then <strong>[64465-53-8]4-fluoro-3-methoxy-aniline</strong> (1.92 g, 13.6 mmol) and triethylamine (5.70 mL, 40.79 mmol) were added to the solution. Reaction mixture was stirred at 60C overnight. The solvent was removed.Residue was dissolved in ethyl acetate, and washed with water, aqueous 0.1 N HC1 solution, brine, and dried over MgSO4. After evaporation, precipitation of the crude in ethanol gave 3.78 g of N-(3,4-dimethoxyphenyl)-2-[(4-fluoro-3-methoxy- phenyl)carbamothioylamino]-N-methyl-acetamide as a yellow powder, leading to a 68% yield.MS: [M+H] mlz = 408.?H NMR (DMSO-d6): oe (ppm) 3.17 (s, 3H) ; 3.77 (s, 3H) ; 3.79 (s, 3H) ; 3.81 (s, 3H) ; 4.01 (d, J = 4.0 Hz, 2H) ; 6.87-6.92 (m, 2H) ; 7.03 (d, J = 8.5 Hz, 1H)7.12-7.19 (dd, J= 11.3, 8.5 Hz, 1H) ; 7.36-7.40 (dd, J= 8.5, 2.3 Hz, 1H) ; 7.78 (t, J = 4.0 Hz, 1H) ; 9.92 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.4% | A reaction flask was charged with compound IV-1 (750 mg, 4.0 mmol), compound III-1 (1.32 g, 4.7 mmol), N,N'-thiocarbonyldiimidazole (0.80 g, 4.5 mmol) and Toluene (15 mL) was stirred and heated to 100-105 C for 20 hours. The mixture was cooled and concentrated under reduced pressure. N,N-Dimethylacetamide (DMA) (20 mL) was added to the residue and ethanol (200 mL) was added. The mixture was stirred, heated to 70 C., and added with hydrochloric acid (2M, 10 mL). Stir for 2 hours. Cool to 0C and stir for 2 hours. It was filtered and the filter cake was stirred with ethanol/water (ratio by volume 1:1), filtered off and dried in vacuo to afford compound WX-101 (1.33 g, 65.4%) as an off-white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With triethylamine; In N,N-dimethyl-formamide; at 50℃; for 4h; | General procedure: 1, 1-thiocarbonyldiimidazole 82 (1.2 equiv) was dissolved in dry DMF at 50C. To this mixture, a solution of the appropriate amines 81a-j (1 equiv) and dry Et3N (1 equiv) in dry DMF was slowly added dropwise. The mixture was stirred at 50C, and the progress monitored by TLC or UPLC/MS. Then the reaction was cooled down, water was added, and the aqueous phase was extracted with EtOAc (3×10mL). Organic phases were washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash column chromatography was performed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 3h; | General procedure: 1, 1-thiocarbonyldiimidazole 82 (1.2 equiv) was dissolved in dry DMF at 50C. To this mixture, a solution of the appropriate amines 81a-j (1 equiv) and dry Et3N (1 equiv) in dry DMF was slowly added dropwise. The mixture was stirred at 50C, and the progress monitored by TLC or UPLC/MS. Then the reaction was cooled down, water was added, and the aqueous phase was extracted with EtOAc (3×10mL). Organic phases were washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash column chromatography was performed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | In tetrahydrofuran; at 20℃; | The reaction mixture of <strong>[89182-17-2]6-chloropyridine-3,4-diamine</strong> (100 mg, 0.697 mmol), di(1H-imidazol-1-yl)methanethione (124 mg, 0.697 mmol) in tetrahydrofuran (4 mL, 0.697 mmol) was stirred at RT overnight. The precipitate was filtrated and 6-chloro-3H-imidazo[4,5-c]pyridine-2-thiol (100 mg, 0.539 mmol, 77% yield) was obtained. 1HNMR (400 MHz, CD3OD) delta 7.76 (s, 1H), 7.07 (s, 1H), ESI-MS: m/z 185.82 (M+H)30 |
77% | Experimental Chemistry Synthesis Schemes, Methods and Procedures: 6-Chloro-3H-imidazo[4,5-c]pyridine-2-thiol (Compound 2) The reaction mixture of <strong>[89182-17-2]6-chloropyridine-3,4-diamine</strong> (100 mg, 0.697 mmol), di(1H-imidazol-1-yl)methanethione (124 mg, 0.697 mmol) in tetrahydrofuran (4 mL, 0.697 mmol) was stirred at RT overnight. The precipitate was filtrated and 6-chloro-3H-imidazo[4,5-c]pyridine-2-thiol (100 mg, 0.539 mmol, 77% yield) was obtained. 1HNMR (400 MHz, CD3OD) delta 7.76 (s, 1H), 7.07 (s, 1H), ESI-MS: m/z 185.82 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With dmap; In acetonitrile; at 20℃; for 4.0h; | 7-Methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-thione (Compound 8): To a solution of <strong>[13958-86-6]5-methylpyridine-3,4-diamine</strong> (100 mg, 0.812 mmol) and N,N-dimethylpyridin-4-amine (109 mg, 0.893 mmol) in MeCN was added di(1H-imidazol-1-yl)methanethione (217 mg, 1.218 mmol) portionwise. The mixture was stirred at room temperature for 4 h. The precipitate formed was filtered, washed with water, Et2O, DCM and dried to give 7-methyl-1H-imidazo[4,5-c]pyridine-2 (3H)-thione (100 mg, 75% yield) as a pale red solid. 1H-NMR (400 MHz, DMSO-d6) delta ppm 12.73 (brs, 2H), 8.20 (s, 1H), 8.06 (s, 1H), 2.33 (s, 3H); ESI-MS: m/z 165.84 (M+H)+. |
75% | With dmap; In acetonitrile; at 20℃; for 4.0h; | To a solution of <strong>[13958-86-6]5-methylpyridine-3,4-diamine</strong> (100 mg, 0.81.2 mmol) and N,N dimethylpyridin-4-amine (109 mg, 0.893 mmol) in MeCN was added di(l H-imidazol-1-yl)methanethione (217 mg, 1.218 mmol) portionwise. The mixture was stirred at room temperature for 4 h. The precipitate formed was filtered, washed with water, Et2O, DCM and dried to give 7-methyl-1H-imidazo[4,5-c]pyridine-2(3H)-thione (100 mg, 75% yield) as a pale red solid. 1H-NMR (400 MHz, DMSO-d6) delta ppm 12.73 (brs, 2H), 8.20 (s, 1H), 8.06 (s, 1H), 2.33 (s, 3H); ESI-MS: m/z 165.84 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; at 20℃; for 2.0h; | A compound 37 (500 mg, 4.06 mmol) was suspended in acetonitrile (15 mL). To the suspension was added 1,1?-thiocarbonyldiimidazole (868 mg, 4.87 mmol). The mixture was stirred at room temperature for 2 hours. To the reaction mixture, water was added. A solid was obtained by filtration, washed by water and dried to give a compound 38 (619 mg) as a crude product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.06 g | With triethylamine; In tetrahydrofuran; at 20℃; for 4h; | 1.81 g <strong>[23687-26-5]isoquinolin-6-amine</strong>, 2.46 g TCDI and 2 eq Et3N in 8 ml THF were stirred at room temperature for 4 hours. After removing THF by vacuum, the residue was purified by a column (EA/Hexane=1:1) to give 1.06 g of product. The NMR spectral data of the compound is listed below:1H NMR (500 MHz DMSO d-6): delta 7.67 (d, 1H), 7.81 (d, 1H), 8.04 (s, 1H), 8.21 (d, 1H), 8.54 (d, 1H), 9.33 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.2% | In ethanol;Reflux; | A mixture of N1-(tert-butyl)benzene-1,2-diamine (316 mg, 1.93 mmol), di(1H- imidazol-1-yl)methanethione (1.03 g, 5.78 mmol) in EtOH(5 mL) was refluxed overnight. The mixture was cooled to room temperature, concentrated in vacuo. The residue was purified by CC on silica gel eluting with PE : EA =4:1 to give 1-(tert-butyl)-1,3-dihydro-2H-benzo[d]imidazole- 2-thione (65 mg, yield 16.2%) as a yellow solid. LC/MS (ESI, m/z): [M+1]+ = 207.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 20℃; for 16.0h;Inert atmosphere; | Methyl 5-amino-l-methyl-pyrazole-3-carboxylate [92406-53-6] (500 mg, 3.22 mmol,) was dissolved in DCM (10 mL) under nitrogen. I, -Thiocarbonyldiimidazole (702 mg, 3.55 mmol) was added and the reaction was stirred at r.t. for 16 h. The crude reaction mixture was then concentrated in vacuo to give a yellow solid which was purified by flash column chromatography on silica (gradient elution with 20% to 100% EtOAc in isohexane) to afford the title compound (177 mg, 0.900 mmol, 28% Yield) as a white solid. LCMS [M+H]+ 198.0, RT 0.49 minutes, purity 91% (Method 7). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With hydrogenchloride; In 1,4-dioxane; dichloromethane; at 20℃; for 24.5h; | l,l'-Thiocarbonyldiimidazole (368 mg, 1.96 mmol, 95 mass%) and then hydrochloric acid in dioxane (0.89 mL, 3.6 mmol, 4 mol/L) were added to a solution of <strong>[1079054-78-6]5-amino-6-methylpicolinonitrile</strong> (250 mg, 1.78 mmol, 95 mass%) in DCM (8.9 mL) under air. The reaction was stirred at r.t. for 24.5 hours before being concentrated in vacuo and purified by flash column chromatography on silica (gradient elution with 0% to 100% EtOAc in isohexanes) to give the title compound (176 mg, 56 % Yield). LCMS [M+H]+ 176, RT 0.93 minutes (Method 7). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With hydrogenchloride; In 1,4-dioxane; dichloromethane; at 20℃; for 5h; | l,T-Thiocarbonyldiimidazole (516 mg, 2.75 mmol, 95 mass%) and then hydrochloric acid in dioxane (1.25 mL, 5.00 mmol, 4 mol/L) were added to a solution of <strong>[164666-68-6]3-amino-6-chloro-2-picoline</strong> (368 mg, 2.50 mmol, 97 mass%) in DCM (7.5 mL) under air. The reaction was stirred at r.t. for 5 hours, concentrated in vacuo and purified by flash column chromatography on silica (gradient elution with 0% to 50% EtOAc in isohexanes) to give the title compound (326 mg, 71 % Yield). A few drops of isobutylamine were added to the LCMS sample of the product before analysis, LCMS [M+H]+ 258, RT 1.24 minutes [M = l-(6-chloro-2-methyl-3-pyridyl)-3-isobutyl-thiourea] (Method 4). |
Tags: 6160-65-2 synthesis path| 6160-65-2 SDS| 6160-65-2 COA| 6160-65-2 purity| 6160-65-2 application| 6160-65-2 NMR| 6160-65-2 COA| 6160-65-2 structure
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Code | Phrase |
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P378 | |
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P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
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P402 | Store in a dry place. |
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Physical hazards | |
Code | Phrase |
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H242 | Heating may cause a fire |
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H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
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Health hazards | |
Code | Phrase |
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H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
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H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
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H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
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H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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