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CAS No. : | 29886-64-4 | MDL No. : | MFCD03783559 |
Formula : | C11H8O2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FISAUHGRILVMDP-UHFFFAOYSA-N |
M.W : | 204.25 | Pubchem ID : | 736862 |
Synonyms : |
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Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P264-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P332+P313-P337+P313-P362-P403+P233-P405-P501 | UN#: | |
Hazard Statements: | H315-H319-H335 | Packing Group: | |
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 |
---|---|---|
Stage #1: 4-iodobenzoic acid chloride; DR9HMPA-CH2OH With dmap; TEA In pyridine at 20℃; for 36h; Stage #2: Thien-3-ylboronic acid With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In water; N,N-dimethyl-formamide at 110℃; Stage #3: With trifluoroacetic acid In dichloromethane at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water at 90℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride at 20℃; for 2h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 4h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 15h; | 7.12. General procedure for preparing the substitutedbenzamide analogues N-(4-(4-(2-methoxyphenyl)-1,4-diazepan-1-yl)butyl)-4-(thiophen-3-yl)benzamide (11a) General procedure: A mixture of compound 10 (135 mg, 0.49 mmol) and 4-(thiophen-3-yl)benzoic acid (99.4 mg, 0.49 mmol) in dichloromethane (10 mL) was stirred at 0 °C (ice-water bath). Dicyclohexylcarbodiimide(DCC) (121 mg, 0.59 mmol) and hydroxybenzotriazole(HOBt) (80 mg, 0.59 mmol) were added to the above solution.The ice bath was removed, and the reaction mixture was stirred at ambient temperature for 15 h. Dichloromethane (20 mL) was added into the reaction mixture, and the solution was washed with saturated aqueous NaHCO3 solution (3*10 mL). The organic layer was dried over Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography using dichloromethane-methanol (20:1) as the mobile phase to give 11a as a white solid (194 mg, 86%). TLC Rf 0.20 (dichloromethane-methanol 20:1); mp 125.5-126.6 °C. 1H NMR(300 MHz, CDCl3) δ 7.75 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H),7.43 (s, 1H), 7.33 (s, 2H), 7.19 (s, 1H), 6.81-6.94 (m, 4H), 3.85 (s,3H), 3.44 (q, J = 5.1 Hz, 2H), 3.25-3.20 (m, 4H), 2.83-2.76 (m,4H), 2.57 (t, J = 5.2 Hz, 2H), 1.93 (t, J = 4.2 Hz, 2H), 1.61-1.69 (m,4H). 13C NMR (CDCl3, 300 MHz): 167.4, 151.4, 142.1, 141.2,138.8, 133.4, 127.5, 126.6, 126.3, 126.1, 121.3, 121.0, 120.7,117.9, 111.6, 57.1, 56.1, 55.3, 54.3, 52.5, 51.8, 39.4, 27.7, 27.3,25.5. HRMS (ESI) Calcd for C27H33N3O2S (M+H)+: 464.2372. Found:464.2379. Anal. (C27H33N3O2S 1.5H2C2O4) C, H, N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 4h; Inert atmosphere; | 45.1 Preparation of [4-(3-thienyl)-phenyl]-methanol Under nitrogen atmosphere, at 0 °C, to a stirring mixture of L1AIH4 (2.0 M THF solution, 3.92 mL, 7.84 mmol) in dry THF (6.0 mL), commercially available 4-(3-thienyl)- benzoic acid (0.4 g, 1.96 mmol) in dry THF (30 mL) was added dropwise. The mixture was left to react at rt for 4 h, then at 0 °C H20 (0.30 mL), 3.0 M KOH solution (0.30 mL) and H20 (1.0 mL) were very slowly added. The mixture was stirred for 1 h at 0 °C, filtered to remove the solid residue, and the organic phase dried over Na2S04. The organic solution was again filtered and concentrated to dryness, affording the title compound (0.222 g, 65%), which was used in the next step without any further purification. 1H NMR (DMSO-d6): δ 4.51 (d, J = 5.75 Hz, 2H), 5.17 (t, J = 5.75 Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.52 - 7.57 (m, 1H), 7.63 (dd, J = 2.9, 5.0 Hz, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.81 - 7.86 (m, 1H). |
65% | With lithium aluminium tetrahydride In diethyl ether at 0 - 20℃; for 4h; Inert atmosphere; | |
65% | With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 4h; Inert atmosphere; | 45.1 Step 1. Step 1. Preparation of [4-(3-thienyl)-phenyl]-methanol Under nitrogen atmosphere, at 0° C., to a stirring mixture of LiAlH4 (2.0 M THF solution, 3.92 mL, 7.84 mmol) in dry THF (6.0 mL), commercially available 4-(3-thienyl)-benzoic acid (0.4 g, 1.96 mmol) in dry THF (30 mL) was added dropwise. The mixture was left to react at rt for 4 h, then at 0° C. H2O (0.30 mL), 3.0 M KOH solution (0.30 mL) and H2O (1.0 mL) were very slowly added. The mixture was stirred for 1 h at 0° C., filtered to remove the solid residue, and the organic phase dried over Na2SO4. The organic solution was again filtered and concentrated to dryness, affording the title compound (0.222 g, 65%), which was used in the next step without any further purification. 1H NMR (DMSO-d6): δ 4.51 (d, J=5.75 Hz, 2H), 5.17 (t, J=5.75 Hz, 1H), 7.35 (d, J=8.1 Hz, 2H), 7.52-7.57 (m, 1H), 7.63 (dd, J=2.9, 5.0 Hz, 1H), 7.67 (d, J=8.1 Hz, 2H), 7.81-7.86 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: lithium aluminium tetrahydride / tetrahydrofuran / 4 h / 0 - 20 °C / Inert atmosphere 2.1: dmap / dichloromethane / 15 h / 20 °C / Inert atmosphere 2.2: 15 h / 20 °C | ||
Multi-step reaction with 2 steps 1.1: lithium aluminium tetrahydride / diethyl ether / 4 h / 0 - 20 °C / Inert atmosphere 2.1: dmap / dichloromethane / 15 h / 20 °C / Inert atmosphere 2.2: 15 h / 20 °C | ||
Multi-step reaction with 2 steps 1.1: lithium aluminium tetrahydride / tetrahydrofuran / 4 h / 0 - 20 °C / Inert atmosphere 2.1: dmap / dichloromethane / 15 h / 20 °C / Inert atmosphere 2.2: 15 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: lithium aluminium tetrahydride / tetrahydrofuran / 4 h / 0 - 20 °C / Inert atmosphere 2.1: dmap / dichloromethane / 15 h / 20 °C / Inert atmosphere 2.2: 15 h / 20 °C 3.1: triethylamine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / dichloromethane / 16 h / 0 - 20 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1.1: lithium aluminium tetrahydride / diethyl ether / 4 h / 0 - 20 °C / Inert atmosphere 2.1: dmap / dichloromethane / 15 h / 20 °C / Inert atmosphere 2.2: 15 h / 20 °C 3.1: triethylamine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / dichloromethane / 16 h / 0 - 20 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1.1: lithium aluminium tetrahydride / tetrahydrofuran / 4 h / 0 - 20 °C / Inert atmosphere 2.1: dmap / dichloromethane / 15 h / 20 °C / Inert atmosphere 2.2: 15 h / 20 °C 3.1: triethylamine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / dichloromethane / 16 h / 0 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With dicyclohexyl-carbodiimide In ethyl acetate at 20℃; for 3h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With palladium diacetate; 2,2-dimethylpropanoic anhydride; triethylamine; 1,4-di(diphenylphosphino)-butane In 1,4-dioxane at 160℃; for 15h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 2h; | |
31% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 2h; | N-( 4-(9-(2-Methoxyphenyl)-3, 9-diazaspirof 5.5 ]undecan-3-yl)butyl)-4-( thiophen-3- yljbenzamide (35). [000275] H (1.0 mmol), 4-(thiophen-3-yl)benzoic acid (1.1 mmol), 1-hydroxybenzotriazole (HOBt) hydrate (1.0 mmol), l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDC) HCl (1.0 mmol) were stirred in 15 mL of CH2CI2 at room temperature for 2 h. The reaction mixture was then washed with a saturated NaHCCb (aq) solution (10 mL). The reaction mixture was extracted with CH2CI2 (3 x 20 mL), and the organic layers were combined, dried, and concentrated to afford a crude white sold. Residue was purified by flash chromatography on silica gel eluding with MeOH/CH2Cl2 (1 : 10) to afford 35 as a white solid. (Yield 31%) NMR (500 MHz, (CD3)2SO) δ 8.66 (m, 1H), 8.00 (bs, 1H), 7.95 (d, J= 7.7 Hz, 2H), 7.82 (d, J= 8.2 Hz, 2H), 7.67- 7.65 (m, 1H), 7.63-7.62 (m, 1H), 6.91-6.88 (m, 3H), 6.85-6.83 (m, 1H), 3.75 (s, 3H), 3.31 (quint, J= 5.9 Hz, 2H), 2.96-2.87 (m, 9H), 1.69 (bs, 6H), 1.57-1.56 (m, 6H); 13C NMR (125 MHz, (CD3)2SO) 5 165.7, 152.0, 141.8, 140.5, 137.5, 132.8, 127.9, 127.3, 126.2, 125.7, 122.3, 122.2, 120.7, 118.1, 111.7, 55.2, 47.5, 45.8, 38.5, 32.6, 28.4, 26.5, 21.5; LC-MS (ESI) m/z: 518.22 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With triethylsilane; palladium diacetate; 2,2-dimethylpropanoic anhydride; 1,4-di(diphenylphosphino)-butane In toluene at 160℃; for 15h; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: formic acid; 4-(thiophen-3-yl)benzoic acid With 4-(4,6-dimethoxy-1,2,5-triazin-2yl)-4-methylmorpholinium chloride In ethanol at 23℃; for 1h; Stage #2: 4-amino-1-(4-(2-chlorophenyl)piperazin-1-yl)butane In ethanol at 23℃; for 16h; | Step 4: General procedure: A solution of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM, 0.44 g, 1.56 mmol, 1.1 eq) and 4-(thiophen-3-yl)benzoic acid (10) (0.32 g, 1.56 mmol, 1.1 eq) in ethanol (10 ml) was stirred at 23 oC. After 1 hour, the 4-(4-arylpiperazin-1-yl)butan-1-amine prepared in step 3 (15a-v) (1.42 mmol) was added, and the reaction was stirred at 23 oC for an additional 16 hours. The reaction was then filtered to remove precipitates and stripped of solvents. The residual material was purified by normal phase chromatography (10% methanol/0.1% ammonium hydroxide in dichloromethane) or reverse phase chromatography (5% acetonitrile/0.1% formic acid in water) as necessary to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: formic acid; 4-(thiophen-3-yl)benzoic acid With 4-(4,6-dimethoxy-1,2,5-triazin-2yl)-4-methylmorpholinium chloride In ethanol at 23℃; for 1h; Stage #2: 4-[4-(2-methyl-phenyl)piperazine]-1-butylamine In ethanol at 23℃; for 16h; | Step 4: General procedure: A solution of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM, 0.44 g, 1.56 mmol, 1.1 eq) and 4-(thiophen-3-yl)benzoic acid (10) (0.32 g, 1.56 mmol, 1.1 eq) in ethanol (10 ml) was stirred at 23 oC. After 1 hour, the 4-(4-arylpiperazin-1-yl)butan-1-amine prepared in step 3 (15a-v) (1.42 mmol) was added, and the reaction was stirred at 23 oC for an additional 16 hours. The reaction was then filtered to remove precipitates and stripped of solvents. The residual material was purified by normal phase chromatography (10% methanol/0.1% ammonium hydroxide in dichloromethane) or reverse phase chromatography (5% acetonitrile/0.1% formic acid in water) as necessary to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: formic acid; 4-(thiophen-3-yl)benzoic acid With 4-(4,6-dimethoxy-1,2,5-triazin-2yl)-4-methylmorpholinium chloride In ethanol at 23℃; for 1h; Stage #2: C15H22N4 In ethanol at 23℃; for 16h; | Step 4: General procedure: A solution of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM, 0.44 g, 1.56 mmol, 1.1 eq) and 4-(thiophen-3-yl)benzoic acid (10) (0.32 g, 1.56 mmol, 1.1 eq) in ethanol (10 ml) was stirred at 23 oC. After 1 hour, the 4-(4-arylpiperazin-1-yl)butan-1-amine prepared in step 3 (15a-v) (1.42 mmol) was added, and the reaction was stirred at 23 oC for an additional 16 hours. The reaction was then filtered to remove precipitates and stripped of solvents. The residual material was purified by normal phase chromatography (10% methanol/0.1% ammonium hydroxide in dichloromethane) or reverse phase chromatography (5% acetonitrile/0.1% formic acid in water) as necessary to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: formic acid; 4-(thiophen-3-yl)benzoic acid With 4-(4,6-dimethoxy-1,2,5-triazin-2yl)-4-methylmorpholinium chloride In ethanol at 23℃; for 1h; Stage #2: 4-[4-(3-cyano-phenyl)-piperazin-1-yl]-butylamine In ethanol at 23℃; for 16h; | Step 4: General procedure: A solution of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM, 0.44 g, 1.56 mmol, 1.1 eq) and 4-(thiophen-3-yl)benzoic acid (10) (0.32 g, 1.56 mmol, 1.1 eq) in ethanol (10 ml) was stirred at 23 oC. After 1 hour, the 4-(4-arylpiperazin-1-yl)butan-1-amine prepared in step 3 (15a-v) (1.42 mmol) was added, and the reaction was stirred at 23 oC for an additional 16 hours. The reaction was then filtered to remove precipitates and stripped of solvents. The residual material was purified by normal phase chromatography (10% methanol/0.1% ammonium hydroxide in dichloromethane) or reverse phase chromatography (5% acetonitrile/0.1% formic acid in water) as necessary to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: formic acid; 4-(thiophen-3-yl)benzoic acid With 4-(4,6-dimethoxy-1,2,5-triazin-2yl)-4-methylmorpholinium chloride In ethanol at 23℃; for 1h; Stage #2: 4-amino-1-(4-(4-cyanophenyl)piperazin-1-yl)butane In ethanol at 23℃; for 16h; | Step 4: General procedure: A solution of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM, 0.44 g, 1.56 mmol, 1.1 eq) and 4-(thiophen-3-yl)benzoic acid (10) (0.32 g, 1.56 mmol, 1.1 eq) in ethanol (10 ml) was stirred at 23 oC. After 1 hour, the 4-(4-arylpiperazin-1-yl)butan-1-amine prepared in step 3 (15a-v) (1.42 mmol) was added, and the reaction was stirred at 23 oC for an additional 16 hours. The reaction was then filtered to remove precipitates and stripped of solvents. The residual material was purified by normal phase chromatography (10% methanol/0.1% ammonium hydroxide in dichloromethane) or reverse phase chromatography (5% acetonitrile/0.1% formic acid in water) as necessary to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: formic acid; 4-(thiophen-3-yl)benzoic acid With 4-(4,6-dimethoxy-1,2,5-triazin-2yl)-4-methylmorpholinium chloride In ethanol at 23℃; for 1h; Stage #2: 4-[4-[2-(trifluoromethyl)phenyl]piperazin-1-yl]butan-1-amine In ethanol at 23℃; for 16h; | Step 4: General procedure: A solution of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM, 0.44 g, 1.56 mmol, 1.1 eq) and 4-(thiophen-3-yl)benzoic acid (10) (0.32 g, 1.56 mmol, 1.1 eq) in ethanol (10 ml) was stirred at 23 oC. After 1 hour, the 4-(4-arylpiperazin-1-yl)butan-1-amine prepared in step 3 (15a-v) (1.42 mmol) was added, and the reaction was stirred at 23 oC for an additional 16 hours. The reaction was then filtered to remove precipitates and stripped of solvents. The residual material was purified by normal phase chromatography (10% methanol/0.1% ammonium hydroxide in dichloromethane) or reverse phase chromatography (5% acetonitrile/0.1% formic acid in water) as necessary to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: formic acid; 4-(thiophen-3-yl)benzoic acid With 4-(4,6-dimethoxy-1,2,5-triazin-2yl)-4-methylmorpholinium chloride In ethanol at 23℃; for 1h; Stage #2: 1-(4-aminobutyl)-4-[3-(trifluoromethyl)phenyl]piperazine In ethanol at 23℃; for 16h; | Step 4: General procedure: A solution of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM, 0.44 g, 1.56 mmol, 1.1 eq) and 4-(thiophen-3-yl)benzoic acid (10) (0.32 g, 1.56 mmol, 1.1 eq) in ethanol (10 ml) was stirred at 23 oC. After 1 hour, the 4-(4-arylpiperazin-1-yl)butan-1-amine prepared in step 3 (15a-v) (1.42 mmol) was added, and the reaction was stirred at 23 oC for an additional 16 hours. The reaction was then filtered to remove precipitates and stripped of solvents. The residual material was purified by normal phase chromatography (10% methanol/0.1% ammonium hydroxide in dichloromethane) or reverse phase chromatography (5% acetonitrile/0.1% formic acid in water) as necessary to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: formic acid; 4-(thiophen-3-yl)benzoic acid With 4-(4,6-dimethoxy-1,2,5-triazin-2yl)-4-methylmorpholinium chloride In ethanol at 23℃; for 1h; Stage #2: C15H22F3N3 In ethanol at 23℃; for 16h; | Step 4: General procedure: A solution of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM, 0.44 g, 1.56 mmol, 1.1 eq) and 4-(thiophen-3-yl)benzoic acid (10) (0.32 g, 1.56 mmol, 1.1 eq) in ethanol (10 ml) was stirred at 23 oC. After 1 hour, the 4-(4-arylpiperazin-1-yl)butan-1-amine prepared in step 3 (15a-v) (1.42 mmol) was added, and the reaction was stirred at 23 oC for an additional 16 hours. The reaction was then filtered to remove precipitates and stripped of solvents. The residual material was purified by normal phase chromatography (10% methanol/0.1% ammonium hydroxide in dichloromethane) or reverse phase chromatography (5% acetonitrile/0.1% formic acid in water) as necessary to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-(thiophen-3-yl)benzoic acid With 4-(4,6-dimethoxy-1,2,5-triazin-2yl)-4-methylmorpholinium chloride In ethanol at 23℃; for 1h; Stage #2: 4-(4-phenylpiperazin-1-yl)butan-1-amine In ethanol at 23℃; for 16h; | Step 4: General procedure: A solution of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM, 0.44 g, 1.56 mmol, 1.1 eq) and 4-(thiophen-3-yl)benzoic acid (10) (0.32 g, 1.56 mmol, 1.1 eq) in ethanol (10 ml) was stirred at 23 oC. After 1 hour, the 4-(4-arylpiperazin-1-yl)butan-1-amine prepared in step 3 (15a-v) (1.42 mmol) was added, and the reaction was stirred at 23 oC for an additional 16 hours. The reaction was then filtered to remove precipitates and stripped of solvents. The residual material was purified by normal phase chromatography (10% methanol/0.1% ammonium hydroxide in dichloromethane) or reverse phase chromatography (5% acetonitrile/0.1% formic acid in water) as necessary to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-(thiophen-3-yl)benzoic acid With 4-(4,6-dimethoxy-1,2,5-triazin-2yl)-4-methylmorpholinium chloride In ethanol at 23℃; for 1h; Stage #2: 4-(4-(3-chlorophenyl)-piperazin-1-yl)-butan-1-amine In ethanol at 23℃; for 16h; | Step 4: General procedure: A solution of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM, 0.44 g, 1.56 mmol, 1.1 eq) and 4-(thiophen-3-yl)benzoic acid (10) (0.32 g, 1.56 mmol, 1.1 eq) in ethanol (10 ml) was stirred at 23 oC. After 1 hour, the 4-(4-arylpiperazin-1-yl)butan-1-amine prepared in step 3 (15a-v) (1.42 mmol) was added, and the reaction was stirred at 23 oC for an additional 16 hours. The reaction was then filtered to remove precipitates and stripped of solvents. The residual material was purified by normal phase chromatography (10% methanol/0.1% ammonium hydroxide in dichloromethane) or reverse phase chromatography (5% acetonitrile/0.1% formic acid in water) as necessary to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-(thiophen-3-yl)benzoic acid With 4-(4,6-dimethoxy-1,2,5-triazin-2yl)-4-methylmorpholinium chloride In ethanol at 23℃; for 1h; Stage #2: 4-(4-chlorophenyl)-1-piperazinebutanamine In ethanol at 23℃; for 16h; | Step 4: General procedure: A solution of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM, 0.44 g, 1.56 mmol, 1.1 eq) and 4-(thiophen-3-yl)benzoic acid (10) (0.32 g, 1.56 mmol, 1.1 eq) in ethanol (10 ml) was stirred at 23 oC. After 1 hour, the 4-(4-arylpiperazin-1-yl)butan-1-amine prepared in step 3 (15a-v) (1.42 mmol) was added, and the reaction was stirred at 23 oC for an additional 16 hours. The reaction was then filtered to remove precipitates and stripped of solvents. The residual material was purified by normal phase chromatography (10% methanol/0.1% ammonium hydroxide in dichloromethane) or reverse phase chromatography (5% acetonitrile/0.1% formic acid in water) as necessary to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-(thiophen-3-yl)benzoic acid With 4-(4,6-dimethoxy-1,2,5-triazin-2yl)-4-methylmorpholinium chloride In ethanol at 23℃; for 1h; Stage #2: 4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butylamine In ethanol at 23℃; for 16h; | Step 4: General procedure: A solution of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM, 0.44 g, 1.56 mmol, 1.1 eq) and 4-(thiophen-3-yl)benzoic acid (10) (0.32 g, 1.56 mmol, 1.1 eq) in ethanol (10 ml) was stirred at 23 oC. After 1 hour, the 4-(4-arylpiperazin-1-yl)butan-1-amine prepared in step 3 (15a-v) (1.42 mmol) was added, and the reaction was stirred at 23 oC for an additional 16 hours. The reaction was then filtered to remove precipitates and stripped of solvents. The residual material was purified by normal phase chromatography (10% methanol/0.1% ammonium hydroxide in dichloromethane) or reverse phase chromatography (5% acetonitrile/0.1% formic acid in water) as necessary to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-(thiophen-3-yl)benzoic acid With 4-(4,6-dimethoxy-1,2,5-triazin-2yl)-4-methylmorpholinium chloride In ethanol at 23℃; for 1h; Stage #2: C14H21Cl2N3 In ethanol at 23℃; for 16h; | Step 4: General procedure: A solution of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM, 0.44 g, 1.56 mmol, 1.1 eq) and 4-(thiophen-3-yl)benzoic acid (10) (0.32 g, 1.56 mmol, 1.1 eq) in ethanol (10 ml) was stirred at 23 oC. After 1 hour, the 4-(4-arylpiperazin-1-yl)butan-1-amine prepared in step 3 (15a-v) (1.42 mmol) was added, and the reaction was stirred at 23 oC for an additional 16 hours. The reaction was then filtered to remove precipitates and stripped of solvents. The residual material was purified by normal phase chromatography (10% methanol/0.1% ammonium hydroxide in dichloromethane) or reverse phase chromatography (5% acetonitrile/0.1% formic acid in water) as necessary to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-(thiophen-3-yl)benzoic acid With 4-(4,6-dimethoxy-1,2,5-triazin-2yl)-4-methylmorpholinium chloride In ethanol at 23℃; for 1h; Stage #2: C14H21Cl2N3 In ethanol at 23℃; for 16h; | Step 4: General procedure: A solution of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM, 0.44 g, 1.56 mmol, 1.1 eq) and 4-(thiophen-3-yl)benzoic acid (10) (0.32 g, 1.56 mmol, 1.1 eq) in ethanol (10 ml) was stirred at 23 oC. After 1 hour, the 4-(4-arylpiperazin-1-yl)butan-1-amine prepared in step 3 (15a-v) (1.42 mmol) was added, and the reaction was stirred at 23 oC for an additional 16 hours. The reaction was then filtered to remove precipitates and stripped of solvents. The residual material was purified by normal phase chromatography (10% methanol/0.1% ammonium hydroxide in dichloromethane) or reverse phase chromatography (5% acetonitrile/0.1% formic acid in water) as necessary to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-(thiophen-3-yl)benzoic acid With 4-(4,6-dimethoxy-1,2,5-triazin-2yl)-4-methylmorpholinium chloride In ethanol at 23℃; for 1h; Stage #2: 4-[4-(2-methoxyphenyl)piperazin-1-yl]butylamine In ethanol at 23℃; for 16h; | Step 4: General procedure: A solution of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM, 0.44 g, 1.56 mmol, 1.1 eq) and 4-(thiophen-3-yl)benzoic acid (10) (0.32 g, 1.56 mmol, 1.1 eq) in ethanol (10 ml) was stirred at 23 oC. After 1 hour, the 4-(4-arylpiperazin-1-yl)butan-1-amine prepared in step 3 (15a-v) (1.42 mmol) was added, and the reaction was stirred at 23 oC for an additional 16 hours. The reaction was then filtered to remove precipitates and stripped of solvents. The residual material was purified by normal phase chromatography (10% methanol/0.1% ammonium hydroxide in dichloromethane) or reverse phase chromatography (5% acetonitrile/0.1% formic acid in water) as necessary to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-(thiophen-3-yl)benzoic acid With 4-(4,6-dimethoxy-1,2,5-triazin-2yl)-4-methylmorpholinium chloride In ethanol at 23℃; for 1h; Stage #2: 4-(4-(3-methoxyphenyl)piperazin-1-yl)butan-1-amine In ethanol at 23℃; for 16h; | Step 4: General procedure: A solution of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM, 0.44 g, 1.56 mmol, 1.1 eq) and 4-(thiophen-3-yl)benzoic acid (10) (0.32 g, 1.56 mmol, 1.1 eq) in ethanol (10 ml) was stirred at 23 oC. After 1 hour, the 4-(4-arylpiperazin-1-yl)butan-1-amine prepared in step 3 (15a-v) (1.42 mmol) was added, and the reaction was stirred at 23 oC for an additional 16 hours. The reaction was then filtered to remove precipitates and stripped of solvents. The residual material was purified by normal phase chromatography (10% methanol/0.1% ammonium hydroxide in dichloromethane) or reverse phase chromatography (5% acetonitrile/0.1% formic acid in water) as necessary to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-(thiophen-3-yl)benzoic acid With 4-(4,6-dimethoxy-1,2,5-triazin-2yl)-4-methylmorpholinium chloride In ethanol at 23℃; for 1h; Stage #2: 4-(4-(4-methoxyphenyl)piperazin-1-yl)butan-1-amine In ethanol at 23℃; for 16h; | Step 4: General procedure: A solution of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM, 0.44 g, 1.56 mmol, 1.1 eq) and 4-(thiophen-3-yl)benzoic acid (10) (0.32 g, 1.56 mmol, 1.1 eq) in ethanol (10 ml) was stirred at 23 oC. After 1 hour, the 4-(4-arylpiperazin-1-yl)butan-1-amine prepared in step 3 (15a-v) (1.42 mmol) was added, and the reaction was stirred at 23 oC for an additional 16 hours. The reaction was then filtered to remove precipitates and stripped of solvents. The residual material was purified by normal phase chromatography (10% methanol/0.1% ammonium hydroxide in dichloromethane) or reverse phase chromatography (5% acetonitrile/0.1% formic acid in water) as necessary to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-(thiophen-3-yl)benzoic acid With 4-(4,6-dimethoxy-1,2,5-triazin-2yl)-4-methylmorpholinium chloride In ethanol at 23℃; for 1h; Stage #2: 2-[4-(4-aminobutyl)-1-piperazinyl]phenol In ethanol at 23℃; for 16h; | Step 4: General procedure: A solution of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM, 0.44 g, 1.56 mmol, 1.1 eq) and 4-(thiophen-3-yl)benzoic acid (10) (0.32 g, 1.56 mmol, 1.1 eq) in ethanol (10 ml) was stirred at 23 oC. After 1 hour, the 4-(4-arylpiperazin-1-yl)butan-1-amine prepared in step 3 (15a-v) (1.42 mmol) was added, and the reaction was stirred at 23 oC for an additional 16 hours. The reaction was then filtered to remove precipitates and stripped of solvents. The residual material was purified by normal phase chromatography (10% methanol/0.1% ammonium hydroxide in dichloromethane) or reverse phase chromatography (5% acetonitrile/0.1% formic acid in water) as necessary to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-(thiophen-3-yl)benzoic acid With 4-(4,6-dimethoxy-1,2,5-triazin-2yl)-4-methylmorpholinium chloride In ethanol at 23℃; for 1h; Stage #2: 3-[4-(4-aminobutyl)-1-piperazinyl]phenol In ethanol at 23℃; for 16h; | Step 4: General procedure: A solution of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM, 0.44 g, 1.56 mmol, 1.1 eq) and 4-(thiophen-3-yl)benzoic acid (10) (0.32 g, 1.56 mmol, 1.1 eq) in ethanol (10 ml) was stirred at 23 oC. After 1 hour, the 4-(4-arylpiperazin-1-yl)butan-1-amine prepared in step 3 (15a-v) (1.42 mmol) was added, and the reaction was stirred at 23 oC for an additional 16 hours. The reaction was then filtered to remove precipitates and stripped of solvents. The residual material was purified by normal phase chromatography (10% methanol/0.1% ammonium hydroxide in dichloromethane) or reverse phase chromatography (5% acetonitrile/0.1% formic acid in water) as necessary to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-(thiophen-3-yl)benzoic acid With 4-(4,6-dimethoxy-1,2,5-triazin-2yl)-4-methylmorpholinium chloride In ethanol at 23℃; for 1h; Stage #2: C14H23N3O In ethanol at 23℃; for 16h; | Step 4: General procedure: A solution of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM, 0.44 g, 1.56 mmol, 1.1 eq) and 4-(thiophen-3-yl)benzoic acid (10) (0.32 g, 1.56 mmol, 1.1 eq) in ethanol (10 ml) was stirred at 23 oC. After 1 hour, the 4-(4-arylpiperazin-1-yl)butan-1-amine prepared in step 3 (15a-v) (1.42 mmol) was added, and the reaction was stirred at 23 oC for an additional 16 hours. The reaction was then filtered to remove precipitates and stripped of solvents. The residual material was purified by normal phase chromatography (10% methanol/0.1% ammonium hydroxide in dichloromethane) or reverse phase chromatography (5% acetonitrile/0.1% formic acid in water) as necessary to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-(thiophen-3-yl)benzoic acid With 4-(4,6-dimethoxy-1,2,5-triazin-2yl)-4-methylmorpholinium chloride In ethanol at 23℃; for 1h; Stage #2: 1-(4-aminobutyl)-4-(3-methylphenyl)piperazine In ethanol at 23℃; for 16h; | Step 4: General procedure: A solution of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM, 0.44 g, 1.56 mmol, 1.1 eq) and 4-(thiophen-3-yl)benzoic acid (10) (0.32 g, 1.56 mmol, 1.1 eq) in ethanol (10 ml) was stirred at 23 oC. After 1 hour, the 4-(4-arylpiperazin-1-yl)butan-1-amine prepared in step 3 (15a-v) (1.42 mmol) was added, and the reaction was stirred at 23 oC for an additional 16 hours. The reaction was then filtered to remove precipitates and stripped of solvents. The residual material was purified by normal phase chromatography (10% methanol/0.1% ammonium hydroxide in dichloromethane) or reverse phase chromatography (5% acetonitrile/0.1% formic acid in water) as necessary to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-(thiophen-3-yl)benzoic acid With 4-(4,6-dimethoxy-1,2,5-triazin-2yl)-4-methylmorpholinium chloride In ethanol at 23℃; for 1h; Stage #2: 1-(4-aminobutyl)-4-(4-methylphenyl)piperazine In ethanol at 23℃; for 16h; | Step 4: General procedure: A solution of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM, 0.44 g, 1.56 mmol, 1.1 eq) and 4-(thiophen-3-yl)benzoic acid (10) (0.32 g, 1.56 mmol, 1.1 eq) in ethanol (10 ml) was stirred at 23 oC. After 1 hour, the 4-(4-arylpiperazin-1-yl)butan-1-amine prepared in step 3 (15a-v) (1.42 mmol) was added, and the reaction was stirred at 23 oC for an additional 16 hours. The reaction was then filtered to remove precipitates and stripped of solvents. The residual material was purified by normal phase chromatography (10% methanol/0.1% ammonium hydroxide in dichloromethane) or reverse phase chromatography (5% acetonitrile/0.1% formic acid in water) as necessary to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-(thiophen-3-yl)benzoic acid With 4-(4,6-dimethoxy-1,2,5-triazin-2yl)-4-methylmorpholinium chloride In ethanol at 23℃; for 1h; Stage #2: 4-Aminobutanol In ethanol at 23℃; for 16h; | Step 1: 4-(4,6-dimethoxy-1,2,5-triazin-2yl)-4-methylmorpholinium chloride (DMT-MM, 120 g, 43.2 mmole, 1.1 eq) and 4-(thiophen-3-yl)benzoic acid (3) (8.0g, 39.2mmol) were dissolved in ethanol (100 ml) and the reaction was stirred at 23 oC. After 1 hour, 4-aminobutan-1-ol (4.0 ml, 42.2 mmol, 1.1 eq) was added and the reaction was stirred at 23 oC for an additional 16 hours. The mixture was filtered to remove insoluble materials, stripped of solvent and the residue was purified by normal phase chromatography to provide N-(4-hydroxybutyl)-4-thiophen-3yl)benzamide. H NMR (400 mHz, MeOD-d4) δ 7.87 (d. J = 856 Hz, 2H), 7.78-7.76 (m,3H), 7.53 (d, J = 2.16 Hz, 2H), 3.63 (d, J = 6.4HZ, 2H), 3.32 (pent, 6H); MS (LC/MS, M+H); 276.10. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With palladium diacetate; 2,2-dimethylpropanoic anhydride; triethylamine; 1,4-di(diphenylphosphino)-butane In 1,4-dioxane at 160℃; for 15h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.9% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 1h; | General procedure for the synthesis of compound 6a-f and 7a-f General procedure: Primary amines 5a-f (1 equiv),4-(thien-3-yl)benzoic acid (0.8 equiv) or 4-(1,3-thiazol-4-yl)benzoic acid (0.8 equiv) weredissolved in CH2Cl2. To the solution, EDC (1.2 equiv) and HOBt hydrate (1.2 equiv) wasadded at 0 and stirred at room temperature for 1 h. The crude mixture was washedwith saturated NaHCO3 solution and brine. The organic layer was dried over Na2SO4 andconcentrated. The product was purified by flash column chromatography on silica gel byelution with a 0-10 % gradient of methanol in CH2Cl2 and converted to the correspondinghydrochloride salt.N-(4-(4-(2-Fluorophenyl)piperazin-1-yl)butyl)-4-(thiophen-3-yl)benzamide (6a). Following thegeneral procedure, 6a (100 mg, 74.9%) was obtained as a white solid: 1H NMR (CDCl3, 500MHz) δ 1.66-1.73 (m, 4H), 2.48 (t, J = 10.0 Hz, 2H), 2.64 (s, 4H), 3.09 (s, 4H), 3.50 (dd, J =10.0, 5.0 Hz, 2H), 6.74 (br, 1H), 6.87-6.94 (m, 2H), 6.98-7.02 (m, 2H), 7.39-7.41 (m, 2H), 7.50-7.51 (m, 1H), 7.63 (d, J = 10.0 Hz, 2H), 7.80 (d, J = 5.0 Hz, 2H); 13C NMR (CDCl3, 125 MHz)δ 167.3, 156.7, 154.7, 141.2, 140.0, 138.6, 133.4, 127.6, 126.6, 126.4, 126.1, 124.4, 122.5, 121.4,118.9, 116.2, 116.0, 58.0, 53.2, 50.3, 50.2, 39.9, 27.4, 24.3; LC-MS (ESI) m/z: 438.23 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.1% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 1h; | General procedure for the synthesis of compound 6a-f and 7a-f General procedure: Primary amines 5a-f (1 equiv),4-(thien-3-yl)benzoic acid (0.8 equiv) or 4-(1,3-thiazol-4-yl)benzoic acid (0.8 equiv) weredissolved in CH2Cl2. To the solution, EDC (1.2 equiv) and HOBt hydrate (1.2 equiv) wasadded at 0 and stirred at room temperature for 1 h. The crude mixture was washedwith saturated NaHCO3 solution and brine. The organic layer was dried over Na2SO4 andconcentrated. The product was purified by flash column chromatography on silica gel byelution with a 0-10 % gradient of methanol in CH2Cl2 and converted to the correspondinghydrochloride salt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 1h; | General procedure for the synthesis of compound 6a-f and 7a-f General procedure: Primary amines 5a-f (1 equiv),4-(thien-3-yl)benzoic acid (0.8 equiv) or 4-(1,3-thiazol-4-yl)benzoic acid (0.8 equiv) weredissolved in CH2Cl2. To the solution, EDC (1.2 equiv) and HOBt hydrate (1.2 equiv) wasadded at 0 and stirred at room temperature for 1 h. The crude mixture was washedwith saturated NaHCO3 solution and brine. The organic layer was dried over Na2SO4 andconcentrated. The product was purified by flash column chromatography on silica gel byelution with a 0-10 % gradient of methanol in CH2Cl2 and converted to the correspondinghydrochloride salt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.3% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 1h; | General procedure for the synthesis of compound 6a-f and 7a-f General procedure: Primary amines 5a-f (1 equiv),4-(thien-3-yl)benzoic acid (0.8 equiv) or 4-(1,3-thiazol-4-yl)benzoic acid (0.8 equiv) weredissolved in CH2Cl2. To the solution, EDC (1.2 equiv) and HOBt hydrate (1.2 equiv) wasadded at 0 and stirred at room temperature for 1 h. The crude mixture was washedwith saturated NaHCO3 solution and brine. The organic layer was dried over Na2SO4 andconcentrated. The product was purified by flash column chromatography on silica gel byelution with a 0-10 % gradient of methanol in CH2Cl2 and converted to the correspondinghydrochloride salt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.1% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 1h; | General procedure for the synthesis of compound 6a-f and 7a-f General procedure: Primary amines 5a-f (1 equiv),4-(thien-3-yl)benzoic acid (0.8 equiv) or 4-(1,3-thiazol-4-yl)benzoic acid (0.8 equiv) weredissolved in CH2Cl2. To the solution, EDC (1.2 equiv) and HOBt hydrate (1.2 equiv) wasadded at 0 and stirred at room temperature for 1 h. The crude mixture was washedwith saturated NaHCO3 solution and brine. The organic layer was dried over Na2SO4 andconcentrated. The product was purified by flash column chromatography on silica gel byelution with a 0-10 % gradient of methanol in CH2Cl2 and converted to the correspondinghydrochloride salt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.2% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 1h; | General procedure for the synthesis of compound 6a-f and 7a-f General procedure: Primary amines 5a-f (1 equiv),4-(thien-3-yl)benzoic acid (0.8 equiv) or 4-(1,3-thiazol-4-yl)benzoic acid (0.8 equiv) weredissolved in CH2Cl2. To the solution, EDC (1.2 equiv) and HOBt hydrate (1.2 equiv) wasadded at 0 and stirred at room temperature for 1 h. The crude mixture was washedwith saturated NaHCO3 solution and brine. The organic layer was dried over Na2SO4 andconcentrated. The product was purified by flash column chromatography on silica gel byelution with a 0-10 % gradient of methanol in CH2Cl2 and converted to the correspondinghydrochloride salt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.2% | Stage #1: 4-(thiophen-3-yl)benzoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: C12H13N3O*ClH With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; | 4.7. General procedure for the synthesis of compounds (14a-j) General procedure: To a solution of acid 13a-j (1.0 equiv.) in DMF, HOBt (1.1 equiv.)and EDCI (1.1 equiv.) were added and the mixturewas stirred for 1 hat room temperature. Then the amino salt 12a (1.1 equiv.) and DIEA(2.2 equiv.) were added. The reaction was stirred and monitoredwith TLC. The mixture was poured into water and extracted withethyl acetate three times. The combined organic layers were driedover Na2SO4 and evaporated in a vacuum [16]. The crude productwas purified by silica gel column chromatography(CH3OH:CH2Cl2 40:1) to afford target compounds 14a-j. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: 4-(thiophen-3-yl)benzoic acid; 2-(2-Aminoethoxy)ethanol With 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride In ethanol at 20℃; for 1h; Stage #2: 2-(2-Aminoethoxy)ethanol In ethanol for 48h; | Preparation of N-(2-(2-hydroxyethoxy)ethyl)-4-(thiophen-3-yl)benzamide A solution of 4-(thiophen-3-yl)benzoic acid (6 g, 29.27 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (8.88 g,32.09 mmol) in ethanol (200 ml) was stirred at room temperature for 1 h. After 1 h, 2-(2-aminoethoxy)-ethanol(3.66 ml, 32.2 mmol) was added into the reaction. The reaction was further stirred for 2 days. After 2 days, the reaction was filtered to give a filtrate. The filtrate waspurified by reverse phase chromatography (50% acetonitrile/0.1% formic acid in water) to provide N-(2-(2-hydroxyethoxy)ethyl)-4-(thiophen-3-yl)benzamide (6.68, 78%yield): 1H NMR (400MHz, MeOD-d4) δ 7.90-7.88 (d, J =8.52 Hz, 2H), 7.79-7.77 (m, 3H), 7.53 (d, J = 2.16 Hz, 2H),3.72-3.67 (quint, J = 4.84, 4.68, 4.28, 1.92, 1.68, 1.4,0.72 Hz, 4H), 3.63-3.59 (quart, 4H); MS (LC/MS, M+H+): 292.75. |
78% | Stage #1: 4-(thiophen-3-yl)benzoic acid; 2-(2-Aminoethoxy)ethanol With 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride In ethanol at 20℃; for 1h; Stage #2: 2-(2-Aminoethoxy)ethanol In ethanol for 48h; | Preparation of N-(2-(2-hydroxyethoxy)ethyl)-4-(thiophen-3-yl)benzamide A solution of 4-(thiophen-3-yl)benzoic acid (6 g, 29.27 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (8.88 g,32.09 mmol) in ethanol (200 ml) was stirred at room temperature for 1 h. After 1 h, 2-(2-aminoethoxy)-ethanol(3.66 ml, 32.2 mmol) was added into the reaction. The reaction was further stirred for 2 days. After 2 days, the reaction was filtered to give a filtrate. The filtrate waspurified by reverse phase chromatography (50% acetonitrile/0.1% formic acid in water) to provide N-(2-(2-hydroxyethoxy)ethyl)-4-(thiophen-3-yl)benzamide (6.68, 78%yield): 1H NMR (400MHz, MeOD-d4) δ 7.90-7.88 (d, J =8.52 Hz, 2H), 7.79-7.77 (m, 3H), 7.53 (d, J = 2.16 Hz, 2H),3.72-3.67 (quint, J = 4.84, 4.68, 4.28, 1.92, 1.68, 1.4,0.72 Hz, 4H), 3.63-3.59 (quart, 4H); MS (LC/MS, M+H+): 292.75. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-(thiophen-3-yl)benzoic acid With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: (l)-serine methyl ester hydrochloride In N,N-dimethyl-formamide | 4.2. General procedure for the synthesis of intermediates 10a-k General procedure: To a solution of different acids (2.45 mmol, 0.50 g) in DMF, HOBt(2.70 mmol, 0.36 g) and EDCI (2.70 mmol, 0.52 g) were added andthe mixture was stirred for 30 min at room temperature. Then, LSerineMethyl Ester Hydrochloride (2.70 mmol, 0.42 g) and DIEA(4.90 mmol, 0.64 g) were added. The reaction was stirred andmonitored with TLC. The mixture was poured into water andextracted with ethyl acetate three times. The combined organiclayers were dried over Na2SO4 and filtered. The filtrate was evaporatedunder reduced pressure to afford intermediates 10a-k, yield73.71% [17]. | |
Stage #1: 4-(thiophen-3-yl)benzoic acid With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: (l)-serine methyl ester hydrochloride In N,N-dimethyl-formamide | 4.2. General procedure for the synthesis of intermediates 10a-k General procedure: To a solution of different acids (2.45 mmol, 0.50 g) in DMF, HOBt(2.70 mmol, 0.36 g) and EDCI (2.70 mmol, 0.52 g) were added andthe mixture was stirred for 30 min at room temperature. Then, LSerineMethyl Ester Hydrochloride (2.70 mmol, 0.42 g) and DIEA(4.90 mmol, 0.64 g) were added. The reaction was stirred andmonitored with TLC. The mixture was poured into water andextracted with ethyl acetate three times. The combined organiclayers were dried over Na2SO4 and filtered. The filtrate was evaporatedunder reduced pressure to afford intermediates 10a-k, yield73.71% [17]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride / N,N-dimethyl-formamide / 0.5 h / 20 °C 1.2: DIEA 2.1: diethylamino-sulfur trifluoride / dichloromethane / 1 h / 78 °C 3.1: lithium dipropan-2-ylazanide / tetrahydrofuran / 0.33 h / -78 °C / Inert atmosphere 3.2: 0.33 h / Inert atmosphere 4.1: sodium tetrahydridoborate / methanol; water monomer / 1 h / 20 °C 5.1: triethylamine; dmap / dichloromethane / 5 h / 20 °C 6.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 6.2: 90 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Stage #1: 4-(thiophen-3-yl)benzoic acid With benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 0.75h; Inert atmosphere; Stage #2: tert-butyl (2-(4-aminophenyl)cyclopropyl)carbamate In N,N-dimethyl-formamide Inert atmosphere; |
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