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CAS No. : | 20503-40-6 | MDL No. : | MFCD00173800 |
Formula : | C8H7NO2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KRUCRVZSHWOMHC-UHFFFAOYSA-N |
M.W : | 181.21 | Pubchem ID : | 2779855 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 47.11 |
TPSA : | 68.54 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.26 cm/s |
Log Po/w (iLOGP) : | 0.98 |
Log Po/w (XLOGP3) : | 0.2 |
Log Po/w (WLOGP) : | 2.01 |
Log Po/w (MLOGP) : | 0.76 |
Log Po/w (SILICOS-IT) : | 0.62 |
Consensus Log Po/w : | 0.91 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.46 |
Solubility : | 6.29 mg/ml ; 0.0347 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.2 |
Solubility : | 11.5 mg/ml ; 0.0634 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.04 |
Solubility : | 1.63 mg/ml ; 0.00902 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.91 |
Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | |
Hazard Statements: | H302-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 |
---|---|---|
With pyridine hydrochloride; sodium carbonate; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; hexane; 2-methoxy-ethanol; acetone; | EXAMPLE 112 4-(1,1-Dioxo-1H-benzo[b]thiophen-6-ylamino)-6,7-diethoxy-quinoline-3-carbonitrile A solution of 400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile, 230 mg (1.54 mM) of <strong>[20503-40-6]6-Amino-1,1-dioxobenzo[b]thiophene</strong> and 161 mg of pyridine hydrochloride in 12 ml of 2-methoxyethanol was refluxed for 6 hours. To the warm solution was added 1 ml of 1M sodium carbonate and the sample was heated for 5 minutes at 100 C., then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80 C. The solid was dissolved in acetone and dried onto silica gel under high vacuum. Purification of the compound was obtained by chromatography using a gradient of 30% to 50% acetone in hexane. The first of the three components of the mixture isolated from the column was the desired product. Removal of the solvent by evaporation yielded 69 mg of 4-(1,1-Dioxo-1H-benzo[b]thiophen-6-ylamino)-6,7-diethoxy-quinoline-3-carbonitrile as a yellow solid: mass spectrum (electrospray, m/e): M+H 421.9, mp=155-160 C. | |
A solution of 400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile, 230 mg (1.54 mM) of <strong>[20503-40-6]6-Amino-1,1-dioxobenzo[b]thiophene</strong> and 161 mg of pyridine hydrochloride in 12 ml of 2-methoxyethanol was refluxed for 6 hours. To the warm solution was added 1 ml of 1M sodium carbonate and the sample was heated for 5 minutes at 100C, then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80C. The solid was dissolved in acetone and dried onto silica gel under high vacuum. Purification of the compound was obtained by chromatography using a gradient of 30% to 50% acetone in hexane. The first of the three components of the mixture isolated from the column was the desired product. Removal of the solvent by evaporation yielded 69 mg of 4-(1,1-Dioxo-1H-benzo[b]thioghen-6-ylamino)-6,7-diethoxy-quinoline-3-carbonitrile as a yellow solid: mass spectrum (electrospray, m/e): M+H 421.9, mp = 155-160C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In water; acetone; at 20℃; for 1 - 24h; | Carboxylic acid 71 (0.091 g, 0.24 mmol), methylene chloride (3 mL), DMF (4 drops), oxalyl chloride (0.057 mL, 0.65 mmol) were used as in general procedure V and added to a solution of 6-amino-1,1-dioxobenao(b)thiophene (Maybridge, 0.044 g, 0.24 mmol), acetone (1.0 mL), sodium bicarbonate (0.184 g, 2.2 mmol), and water (1 mL) as used in general procedure VI. The product was purified by filtering through a silica pad eluted with methylene chloride. The organics were washed with saturated sodium bicarbonate, dried over MgSO4, and concentrated in vacuo. The product was further purified by flash chromatography using 9:1 methylene chloride:methanol as elutant to afford 461 as a yellow solid (0.013 g, 10%). 1H NMR (DMSO-d6, 400 MHz) delta4.75 (s, 2H), 7.2 (d, 1H), 7.25 (d, 1H), 7.5 (d, 1H), 7.54-7.58 (m, 2H), 7.59-7.64 (m, 2H), 7.85 (d, 2H), 7.9 (d, 1H), 8 (s, 1H), 10.4 (s, 1H); MS (ES-) m/z 538 (M-H)-.; General procedure VI: Coupling of acid chlorides to aromatic amines using sodium bicarbonate Into a round-bottom flask were placed the appropriate aromatic amine, acetone (1-10 mL/mmol amine), sodium bicarbonate (2-10 mmol/mmol amine), and water (0.25-10 mL). The acid chloride was added as a solution in acetone (1-10 mL/mmol of acid chloride) in a dropwise manner and the reaction mixture was allowed to stir at rt for 1-24 h. When judged to be complete, the mixture was poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected and was washed with water, brine, dried over MgSO4, filtered and the solvents were removed under reduced pressure. See specific examples for details regarding further purification of the products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | 12. 238 mg of 4-[(1,1-dioxo-1H-benzo[b]thiophen-6-yl)hydrazono]-4H-pyrazole-3,5-diamine was prepared in two steps starting with 179.0 mg (0.99 mmol) of 1,1-dioxo-1H-1lambda6-benzo[b]thiophen-6-ylamine. MS (m/z, ES+): 291 (M+1). Yield 83%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With hydrogenchloride; copper(II) sulfate; In dichloromethane; | a 1,1-Dioxobenzo[b]thiophene-6-sulfonyl chloride A mixture of 6-amino-1,1-dioxobenzo[b]thiophene (253 mg, 1.39 mmol) and 30% aqueous HCl (1.53 mL) was cooled to 0 C. in an open flask, and then 40% aqueous sodium nitrite (754 muL) was added dropwise over 2.25 minutes. The mixture was stirred at 0 C. for 15 minutes, and then 30% aqueous HCl (768 muL) and solid CuSO4 (20.4 mg, 0.128 mmol) were added. To this mixture was added 40% aqueous NaHSO3 (2.39 mL) dropwise over 6 minutes, and the reaction was stirred at 0 C. for 2.5 hours. The reaction was diluted with water (50 mL) and extracted with dichloromethane (2*50 mL). The combined organic layers were washed with brine (75 mL), dried over Na2SO4, filtered and evaporated. The product was purified by flash column chromatography through 20 g of silica gel using CH2Cl2 to give the title compound (171 mg, 46%) as a pale yellow solid. 1H-NMR (300 MHz, CDCl3) delta8.35 (m, 1H), 8.26 (dd, 1H, J=8.0, 1.8 Hz), 7.65 (d, 1H, J=8.0 Hz), 7.34 (dd, 1H, J=7.0, 1.0 Hz), 7.02 (d, 1H, J=7.0 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.1% | With pyridine; In tetrahydrofuran; at 0 - 20℃; for 1.5h; | Example 121; N-(1,1-Dioxido-1-benzothien-6-yl)-4-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine-1-carboxamide; (1) 2,2,2-Trichloroethyl (1,1-dioxido-1-benzothien-6-yl)carbamate; To a solution of 1-benzothiophen-6-amine 1,1-dioxide (1.00 g, 5.52 mmol) and pyridine (0.525 ml, 6.62 mmol) in tetrahydrofuran (18 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (0.916 ml, 6.62 mmol), and the mixture was stirred at room temperature for 1 hour and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 1.71 g (87.1%) of the desired product as a solid was separated by filtration. 1H-NMR (CDCl3) delta; 4.85 (2H, s), 6.67 (1H, d, J = 6.9 Hz), 7.18 - 7.21 (1H, m), 7.31 - 7.34 (2H, m), 7.62 - 7.66 (1H, m), 7.87 - 7.88 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 48h;Inert atmosphere; | To a solution of 2-phenylquinoline-4-carboxylic acid (249 mg, 1.0 mmol) and 1,1-dioxo-1H-1lambda6-benzo[b]thiophen-6-ylamine (181 mg, 1.0 mmol) in 10 mL of CH2Cl2 was added DIPEA (387 mg, 3.0 mmol). HBTU (759 mg, 2.0 mmol) was added at 0 C. The resulting mixture was stirred at r.t. for 48 h. The reaction mixture was diluted with EtOAc (300 mL) and washed with water (50 mL). The organic layer was separated and dried with anhydrous Na2SO4. The solution was concentrated to give a crude product, which was further purified with short silica gel column (EtOAc/hexane = 1/1 to 4/1) to obtain the desired product (160 mg, 39%) as a pale yellow solid (mp 277-278 C). HPLC purity 99.2% (tR = 32.39 min). 1H NMR (600 MHz, DMSO-d6) delta 11.29 (s, 1H), 8.44 (s, 1H), 8.38 (d, 2H, J = 7.2 Hz), 8.34 (s, 1H), 8.20 (dd, 2H, J = 5.4 Hz, 13.8 Hz), 7.98 (d, 1H, J = 7.8 Hz), 7.88 (t, 1H, J = 7.2 Hz), 7.54-7.70 (m, 6H), 7.34 (d, 1H, J = 6.6 Hz). 13C NMR (150 MHz, DMSO-d6) delta 165.8, 155.8, 147.9, 142.2, 141.2, 138.0, 137.2, 132.9, 130.5, 130.4, 130.0, 129.7, 129.0, 127.6, 127.3, 126.6, 126.3, 125.1, 124.2, 123.0, 117.1, 117.1, 112.3, 112.3. HRMS (ESI) calcd for C24H17N2O3S 413.0954 (M + H)+, found 413.0959. |
39% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 52h; | [00137] To a solution of 2-phenyl-quinoline-4-carboxylic acid (249 mg, 1.0mmol) and 1,1-dioxo-1H-IA6-benzo[b]thiophen-6-ylamine (181 mg, 1.0 mmol) in 10 mL ofDCM was added DIPEA (388 mg, 3.0 mmol). HBTU (569 mg, 1.5 mmol) was added at 0 C.The resulting mixture was stirred at r.t. for 28 h. An additional amount of HBTU (190 mg,0.5 mmol) was added to the solution at 0 C, and the resulting mixture was stirred at r.t. for24 h. A white suspension formed during the reaction. The precipitate was dissolved in DMF(10 mL). The solution was added to the stirring water dropwise. A yellow solid was formed.The solid was filtered and washed with H20. 160 mg of the desired product was obtained as ayellow solid (39% yield). 1H NMR (600 MHz, DMSO-d6) o 11.29 (s, 1H), 8.44 (s, 1H), 8.38(d, 2H, J= 7.2 Hz), 8.34 (s, 1H), 8.20 (dd, 2H, J= 5.4 Hz, 13.8 Hz), 7.98 (d, 1H, J= 7.8 Hz),7.88 (t, 1H, J= 7.2 Hz), 7.54-7.70 (m, 6H), 7.34 (d, 1H, J= 6.6 Hz). 13C NMR (150 MHz,DMSO-d6) o 165.8, 155.8, 147.9, 142.2, 141.2, 138.0, 137.2, 132.9, 130.5, 130.4, 130.0,129.7, 129.0, 127.6, 127.3, 126.6, 126.3, 125.1, 124.2, 123.0, 117.1, 117.1, 112.3, 112.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | A solution of 5-chloro-2-hydroxybenzoic acid (2.0 g, 11 mmol) and 4 mL of SOCl2 in 4 mL of toluene was stirred at 110 C overnight. The mixture was concentrated to give a crude product as a pale yellow oil. To the solution of pyridine (869 mg, 11 mmol) and 1,1-dioxo-1H-1lambda6-benzo[b]thiophen-6-ylamine (200 mg, 1.1 mmol) was added the solution of the acid chloride (500 mg, 2.6 mmol) in DMF (15 mL) dropwise at 0 C. The mixture was stirred at r.t. for 24 h. The mixture was added to the water solution dropwise. The yellow solid was formed and filtrated. To the mixture of the crude product in THF (8 mL) was added 1 N LiOH (2.2 mL, 2.2 mmol) at 0 C. The mixture was stirred at 0 C for 30 min. The mixture was diluted with EtOAc (50 mL) and washed with 2 N HCl (10 mL). The organic layer was separated and dried with anhydrous Na2SO4. The solution was concentrated to afford the crude product, which was washed with CH2Cl2 (20 mL) to give the desired product (150 mg, 39%) as a yellow solid (mp 268-269 C). HPLC purity 98.3% (tR = 17.24 min). 1H NMR (600 MHz, DMSO-d6) delta 11.50 (s, 1H), 10.74 (s, 1H), 8.25 (s, 1H), 7.92 (d, 1H, J = 8.4 Hz), 7.86 (d, 1H, J = 2.4 Hz), 7.59-7.62 (m, 2 H), 7.48 (d, 1H, J = 9.0 Hz), 7.31 (d, 1H, J = 6.6 Hz), 7.04 (d, 1H, J = 8.4 Hz). 13C NMR (150 MHz, DMSO-d6) delta 165.1, 156.2, 140.7, 137.1, 133.1, 132.8, 130.3, 128.6, 126.5, 126.2, 124.6, 122.8, 120.4, 119.0, 112.7. HRMS (ESI) calcd for C15H11ClNO4S 336.0092 (M + H)+, found 336.0098. | |
39% | A solution of 5-chloro-2-hydroxybenzoic acid (2.0 g, 11 mmol)and 4 mL of SOCh in 4 mL of toluene was stirred at 110 C overnight. The mixture wasconcentrated to give a crude product as a pale yellow oil. To the solution of pyridine (869 mg,11 mmol) and 1,1-dioxo-1H-1e6-benzo[b]thiophen-6-ylamine (200 mg, 1.1 mmol) was added20 the solution of the acid chloride (500 mg, 2.6 mmol) in DMF (15 mL) dropwise at 0 C. Themixture was stirred at r.t. for 24 h. The mixture was added to the water solution dropwise.The yellow solid was formed and filtrated. To the mixture of the crude product in THF (8 mL)was added 1 N LiOH (2.2 mL, 2.2 mmol) at 0 C. The mixture was stirred at 0 C for 30 min.The mixture was diluted with EtOAc (50 mL) and washed with 2 N HCl (10 mL). The25 organic layer was separated and dried with anhydrous Na2S04. The solution was concentratedto afford the crude product, which was washed with CH2Ch (20 mL) to give the desiredproduct (150 mg, 39%) as a yellow solid (mp 268-269 C). HPLC purity 98.3% (tR = 17.24min). 1H NMR (600 MHz, DMSO-d6) J 11.50 (s, 1H), 10.74 (s, 1H), 8.25 (s, 1H), 7.92 (d, 1H,J= 8.4 Hz), 7.86 (d, 1H, J= 2.4 Hz), 7.59-7.62 (m, 2 H), 7.48 (d, 1H, J= 9.0 Hz), 7.31 (d,30 1H, J= 6.6 Hz), 7.04 (d, 1H, J= 8.4 Hz). 13C NMR (150 MHz, DMSO-d6) J 165.1, 156.2,140.7, 137.1, 133.1, 132.8, 130.3, 128.6, 126.5, 126.2, 124.6, 122.8, 120.4, 119.0, 112.7.HRMS (ESI) calcd for C1sHuClN04S 336.0092 (M + Ht, found 336.0098. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 28h;Inert atmosphere; | General procedure: To a solution of cyanoacetic acid (340 mg, 4.0 mmol) and 1,1-dioxo-1H-1lambda6-benzo[b]thiophen-6-ylamine (362 mg, 2.0 mmol) in 10 mL of CH2Cl2 was added DIPEA (774 mg, 6.0 mmol). HBTU (1.14 g, 3.0 mmol) was added at 0 C. The resulting mixture was stirred at r.t. for 28 h. The reaction mixture was diluted with CH2Cl2 (80 mL) and washed with water (20 mL). The organic layer was separated and dried with anhydrous Na2SO4. The solution was concentrated to give a crude product, which was purified with silica gel column (EtOAc/hexane = 1/1) to obtain the desired product (400 mg, 81%) as a yellow solid (mp 207-208 C). HPLC purity 98.6% (tR = 10.93 min). 1H NMR (600 MHz, DMSO-d6) delta 10.79 (s, 1H), 8.04 (s, 1H), 7.67-7.69 (m, 1H), 7.60 (d, 1H, J = 7.2 Hz), 7.57 (d, 1H, J = 7.8 Hz), 7.30 (d, 1H, J = 7.2 Hz), 3.98 (s, 2H). 13C NMR (150 MHz, DMSO-d6) delta 162.0, 140.7, 137.3, 132.8, 130.3, 126.7, 126.1, 123.4, 115.6, 111.4, 27.0. HRMS (ESI) calcd for C11H19N2O3S 249.0328 (M + H)+, found 249.0330. |
50% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 52h; | [00141] To a solution of 2,6-diphenylisonicotinic acid (150 mg, 0.6 mmol) and1,1-dioxo-1H-IA6-benzo[b]thiophen-6-ylamine (119 mg, 0.7 mmol) in 10 mL of DCM wasadded DIPEA (211 mg, 1.6 mmol). HBTU (330 mg, 0.9 mmol) was added at 0 C. Theresulting mixture was stirred at r.t. for 28 h. An additional amount of HBTU (190 mg, 0.5mmol) was added to the solution at 0 C, and the resulting mixture was stirred at r.t. for 24 h.The mixture was diluted with DCM (50 mL) and washed with water (20 mL ). The organiclayer was separated and dried with anhydrous Na2S04. The solution was concentrated to givea crude product. This residue was purified with silica gel column (EtOAc/hexane = 1/2) toprovide HJC-1-36 (120 mg, 50%) as a pale yellow solid. 1H NMR (600 MHz, CDCh) o 8.76(s, 1H), 8.34 (d, 1H, J= 6.6 Hz), 8.23 (d, 4H, J= 7.2 Hz), 8.14 (s, 2H) 7.93 (s, 1H), 7.41-7.55(m, 6H), 7.40 (d, 1H, J = 8.4 Hz), 7.13-7.15 (m, 1H), 6.26-6.28 (m, 1H). 13C NMR (150MHz, DMSO-d6) o 164.7, 156.6, 143.9, 141.1, 138.1, 137.1, 132.8, 130.4, 129.7, 129.0,126.9, 126.6, 126.3, 124.6, 116.7, 112.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 28h;Inert atmosphere; | General procedure: To a solution of cyanoacetic acid (340 mg, 4.0 mmol) and 1,1-dioxo-1H-1lambda6-benzo[b]thiophen-6-ylamine (362 mg, 2.0 mmol) in 10 mL of CH2Cl2 was added DIPEA (774 mg, 6.0 mmol). HBTU (1.14 g, 3.0 mmol) was added at 0 C. The resulting mixture was stirred at r.t. for 28 h. The reaction mixture was diluted with CH2Cl2 (80 mL) and washed with water (20 mL). The organic layer was separated and dried with anhydrous Na2SO4. The solution was concentrated to give a crude product, which was purified with silica gel column (EtOAc/hexane = 1/1) to obtain the desired product (400 mg, 81%) as a yellow solid (mp 207-208 C). HPLC purity 98.6% (tR = 10.93 min). 1H NMR (600 MHz, DMSO-d6) delta 10.79 (s, 1H), 8.04 (s, 1H), 7.67-7.69 (m, 1H), 7.60 (d, 1H, J = 7.2 Hz), 7.57 (d, 1H, J = 7.8 Hz), 7.30 (d, 1H, J = 7.2 Hz), 3.98 (s, 2H). 13C NMR (150 MHz, DMSO-d6) delta 162.0, 140.7, 137.3, 132.8, 130.3, 126.7, 126.1, 123.4, 115.6, 111.4, 27.0. HRMS (ESI) calcd for C11H19N2O3S 249.0328 (M + H)+, found 249.0330. |
39% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 48h; | [00145] To a solution of acridine-9-carboxylic acid (150 mg, 0.67 mmol) and1,1-dioxo-1H-IA6-benzo[b]thiophen-6-ylamine (146 mg, 0.81 mmol) in 10 mL of DCM was added DIPEA (434 mg, 3.36 mmol). HBTU (637 mg, 1.68 mmol) was added at 0 C. Theresulting mixture was stirred at r.t. for 2 days. A yellow suspension formed during thereaction. The mixture was filtered. The precipitate was dissolved in DMF (10 mL). Thesolution was added to the stirring water dropwise. A yellow solid was formed. The solid wasfiltered and washed with H20 (100 mL). 100 mg of the desired product was obtained as ayellow solid (39% yield). 1H NMR (600 MHz, DMSO-d6) o 8.71 (d, 1H, J= 8.4 Hz), 8.32 (d,2H, J = 8.4 Hz), 8.08-8.13 (m, 5 H), 7.97 (t, 2H, J = 7.8 Hz), 7.82 (t, 1H, J = 8.4 Hz), 7.68 (t,2H, J= 7.8 Hz). 13C NMR (150 MHz, DMSO-d6) o 163.4, 147.9, 136.1, 133.9, 132.9, 131.1,129.5, 128.0, 128.0, 125.2, 121.7, 116.5, 115.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 28h;Inert atmosphere; | General procedure: To a solution of cyanoacetic acid (340 mg, 4.0 mmol) and 1,1-dioxo-1H-1lambda6-benzo[b]thiophen-6-ylamine (362 mg, 2.0 mmol) in 10 mL of CH2Cl2 was added DIPEA (774 mg, 6.0 mmol). HBTU (1.14 g, 3.0 mmol) was added at 0 C. The resulting mixture was stirred at r.t. for 28 h. The reaction mixture was diluted with CH2Cl2 (80 mL) and washed with water (20 mL). The organic layer was separated and dried with anhydrous Na2SO4. The solution was concentrated to give a crude product, which was purified with silica gel column (EtOAc/hexane = 1/1) to obtain the desired product (400 mg, 81%) as a yellow solid (mp 207-208 C). HPLC purity 98.6% (tR = 10.93 min). 1H NMR (600 MHz, DMSO-d6) delta 10.79 (s, 1H), 8.04 (s, 1H), 7.67-7.69 (m, 1H), 7.60 (d, 1H, J = 7.2 Hz), 7.57 (d, 1H, J = 7.8 Hz), 7.30 (d, 1H, J = 7.2 Hz), 3.98 (s, 2H). 13C NMR (150 MHz, DMSO-d6) delta 162.0, 140.7, 137.3, 132.8, 130.3, 126.7, 126.1, 123.4, 115.6, 111.4, 27.0. HRMS (ESI) calcd for C11H19N2O3S 249.0328 (M + H)+, found 249.0330. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 28h;Inert atmosphere; | General procedure: To a solution of cyanoacetic acid (340 mg, 4.0 mmol) and 1,1-dioxo-1H-1lambda6-benzo[b]thiophen-6-ylamine (362 mg, 2.0 mmol) in 10 mL of CH2Cl2 was added DIPEA (774 mg, 6.0 mmol). HBTU (1.14 g, 3.0 mmol) was added at 0 C. The resulting mixture was stirred at r.t. for 28 h. The reaction mixture was diluted with CH2Cl2 (80 mL) and washed with water (20 mL). The organic layer was separated and dried with anhydrous Na2SO4. The solution was concentrated to give a crude product, which was purified with silica gel column (EtOAc/hexane = 1/1) to obtain the desired product (400 mg, 81%) as a yellow solid (mp 207-208 C). HPLC purity 98.6% (tR = 10.93 min). 1H NMR (600 MHz, DMSO-d6) delta 10.79 (s, 1H), 8.04 (s, 1H), 7.67-7.69 (m, 1H), 7.60 (d, 1H, J = 7.2 Hz), 7.57 (d, 1H, J = 7.8 Hz), 7.30 (d, 1H, J = 7.2 Hz), 3.98 (s, 2H). 13C NMR (150 MHz, DMSO-d6) delta 162.0, 140.7, 137.3, 132.8, 130.3, 126.7, 126.1, 123.4, 115.6, 111.4, 27.0. HRMS (ESI) calcd for C11H19N2O3S 249.0328 (M + H)+, found 249.0330. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 28h;Inert atmosphere; | General procedure: To a solution of cyanoacetic acid (340 mg, 4.0 mmol) and 1,1-dioxo-1H-1lambda6-benzo[b]thiophen-6-ylamine (362 mg, 2.0 mmol) in 10 mL of CH2Cl2 was added DIPEA (774 mg, 6.0 mmol). HBTU (1.14 g, 3.0 mmol) was added at 0 °C. The resulting mixture was stirred at r.t. for 28 h. The reaction mixture was diluted with CH2Cl2 (80 mL) and washed with water (20 mL). The organic layer was separated and dried with anhydrous Na2SO4. The solution was concentrated to give a crude product, which was purified with silica gel column (EtOAc/hexane = 1/1) to obtain the desired product (400 mg, 81percent) as a yellow solid (mp 207-208 °C). HPLC purity 98.6percent (tR = 10.93 min). 1H NMR (600 MHz, DMSO-d6) delta 10.79 (s, 1H), 8.04 (s, 1H), 7.67-7.69 (m, 1H), 7.60 (d, 1H, J = 7.2 Hz), 7.57 (d, 1H, J = 7.8 Hz), 7.30 (d, 1H, J = 7.2 Hz), 3.98 (s, 2H). 13C NMR (150 MHz, DMSO-d6) delta 162.0, 140.7, 137.3, 132.8, 130.3, 126.7, 126.1, 123.4, 115.6, 111.4, 27.0. HRMS (ESI) calcd for C11H19N2O3S 249.0328 (M + H)+, found 249.0330. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 28h;Inert atmosphere; | General procedure: To a solution of cyanoacetic acid (340 mg, 4.0 mmol) and 1,1-dioxo-1H-1lambda6-benzo[b]thiophen-6-ylamine (362 mg, 2.0 mmol) in 10 mL of CH2Cl2 was added DIPEA (774 mg, 6.0 mmol). HBTU (1.14 g, 3.0 mmol) was added at 0 C. The resulting mixture was stirred at r.t. for 28 h. The reaction mixture was diluted with CH2Cl2 (80 mL) and washed with water (20 mL). The organic layer was separated and dried with anhydrous Na2SO4. The solution was concentrated to give a crude product, which was purified with silica gel column (EtOAc/hexane = 1/1) to obtain the desired product (400 mg, 81%) as a yellow solid (mp 207-208 C). HPLC purity 98.6% (tR = 10.93 min). 1H NMR (600 MHz, DMSO-d6) delta 10.79 (s, 1H), 8.04 (s, 1H), 7.67-7.69 (m, 1H), 7.60 (d, 1H, J = 7.2 Hz), 7.57 (d, 1H, J = 7.8 Hz), 7.30 (d, 1H, J = 7.2 Hz), 3.98 (s, 2H). 13C NMR (150 MHz, DMSO-d6) delta 162.0, 140.7, 137.3, 132.8, 130.3, 126.7, 126.1, 123.4, 115.6, 111.4, 27.0. HRMS (ESI) calcd for C11H19N2O3S 249.0328 (M + H)+, found 249.0330. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 96h; | General procedure: [00160] To a solution of pyridine-2-carboxylic acid (148 mg, 1.2 mmol) and1,1-dioxo-1H-IA6-benzo[b]thiophen-6-ylamine (181 mg, 1.0 mmol) in 10 mL of DCM wasadded DIPEA (388 mg, 3.0 mmol). HBTU (570 mg, 1.5 mmol) was added at 0 C. Theresulting mixture was stirred at r. t. for 24 h and then was concentrated. The residue wasdissolved in DMF (10 mL). The solution was added to the stirring water (50 mL) dropwise. Ayellow solid was formed. The solid was filtered and washed with H20 (50 mL). 130 mg ofthe desired product was obtained as a yellow solid (45% yield). [00165] The general procedure was the same as HJC-3-20 by using 2-bromoisonicotinicacid as reactant. Obtained as a pale yellow solid (82% yield); 1H NMR (600MHz, DMSO-d6) o 10.96 (s, 1H), 8.63 (d, 1H, J = 4.8 Hz), 8.23 (s, 1H), 8.15 (s, 1H), 7.97-7.99 (m, 1H), 7.91 (d, 1H, J= 4.8 Hz), 7.61-7.63 (m, 2H), 6.33 (d, 1H, J = 7.2 Hz). 13C NMR(150 MHz, DMSO-d6) o 162.9, 151.3, 144.4, 141.8, 140.8, 137.1, 132.8, 130.5, 126.5, 126.5,125.9, 124.6, 121.6, 112.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 96h; | General procedure: [00160] To a solution of pyridine-2-carboxylic acid (148 mg, 1.2 mmol) and1,1-dioxo-1H-IA6-benzo[b]thiophen-6-ylamine (181 mg, 1.0 mmol) in 10 mL of DCM wasadded DIPEA (388 mg, 3.0 mmol). HBTU (570 mg, 1.5 mmol) was added at 0 C. Theresulting mixture was stirred at r. t. for 24 h and then was concentrated. The residue wasdissolved in DMF (10 mL). The solution was added to the stirring water (50 mL) dropwise. Ayellow solid was formed. The solid was filtered and washed with H20 (50 mL). 130 mg ofthe desired product was obtained as a yellow solid (45% yield). The general procedure was the same as HJC-3-20 by using quinoline-3-carboxylic acid as reactant. Obtained as a pale yellow solid (48% yield); 1H NMR (600MHz, DMSO-d6) o 11.25 (s, 1H), 9.08 (d, 1H, J= 4.2 Hz), 8.31 (s, 1H), 8.18 (d, 1H, J= 8.4Hz), 8.14 (d, 1H, J= 7.2 Hz), 7.93-7.95 (m, 1H), 7.85-7.88 (m, 1H), 7.79 (d, 1H, J= 4.2 Hz),7.70-7.72 (m, 1H), 7.63-7.65 (m, 2H), 7.34 (d, 1H, J= 6.6 Hz). 13C NMR (150 MHz, DMSOd6)0 166.7, 151.0, 149.7, 142.4, 139.1, 133.1, 131.6, 130.7, 128.5, 127.7, 127.2, 126.3,125.1, 124.8, 124.7, 120.0, 113.3, 113.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With triethylamine; In dichloromethane; at 0 - 20℃; for 0.166667h; | General procedure: [00152] To the solution ofDIPEA (713 mg, 5.5 mmol) and 1,1-dioxo-1H-IA6-benzo[b]thiophen-6-ylamine (500 mg, 2.8 mmol) in 10 mL of DCM was added the solutionof AcCl (260 mg, 3.3 mmol) in DCM (15 mL) dropwise at 0 C. The mixture was stirred atr.t. for 10 min. The mixture was diluted with DCM (50 mL) and washed with H20 (10 mL).The organic layer was separated and dried with anhydrous Na2S04. The solution wasconcentrated to afford the crude product, which was purified with silica gel column(EtOAc/hexane = Ill) to afford the desired product (400 mg, 65%) as a pale yellow solid. [0100] The general procedure was the same as HJC-1-62. Obtained as a yellow solid(46% yield); 1H NMR (600 MHz, DMSO-d6) o 7.74 (d, 2H, J = 9.0 Hz), 7.69 (d, 1H, J = 7.2Hz), 7.66 (d, 1H, J= 7.8 Hz), 7.53 (d, 1H, J= 7.2 Hz), 7.42 (d, 1H, J= 1.2 Hz), 7.26-7.28(m, 1H), 7.18 (d, 2H, J = 9.0 Hz), 3.90 (s, 3H). Be NMR (150 MHz, DMSO-d6) o 164.0,137.2, 137.1, 135.6, 133.1, 132.8, 132.0, 130.7, 129.1, 126.9, 123.8, 114.8, 56.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With triethylamine; In dichloromethane; at 0 - 20℃; for 0.166667h; | General procedure: [00152] To the solution ofDIPEA (713 mg, 5.5 mmol) and 1,1-dioxo-1H-IA6-benzo[b]thiophen-6-ylamine (500 mg, 2.8 mmol) in 10 mL of DCM was added the solutionof AcCl (260 mg, 3.3 mmol) in DCM (15 mL) dropwise at 0 C. The mixture was stirred atr.t. for 10 min. The mixture was diluted with DCM (50 mL) and washed with H20 (10 mL).The organic layer was separated and dried with anhydrous Na2S04. The solution wasconcentrated to afford the crude product, which was purified with silica gel column(EtOAc/hexane = Ill) to afford the desired product (400 mg, 65%) as a pale yellow solid. The general procedure was the same as HJC-1-62. Obtained as ayellow solid (30% yield); 1H NMR (600 MHz, DMSO-d6) o 7.65-7.72 (m, 5H), 7.54 (d, 1H,J = 6.6 Hz), 7.49 (d, 2H, J = 7.8 Hz), 7.26-7.28 (m, 1H), 2.46 (s, 3H). Be NMR (150 MHz,DMSO-d6) o 145.9, 137.2, 135.3, 135.0, 133.2, 133.0, 132.0, 130.1, 128.2, 127.0, 123.8,21.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 0.166667h; | [00152] To the solution ofDIPEA (713 mg, 5.5 mmol) and 1,1-dioxo-1H-IA6-benzo[b]thiophen-6-ylamine (500 mg, 2.8 mmol) in 10 mL of DCM was added the solutionof AcCl (260 mg, 3.3 mmol) in DCM (15 mL) dropwise at 0 C. The mixture was stirred atr.t. for 10 min. The mixture was diluted with DCM (50 mL) and washed with H20 (10 mL).The organic layer was separated and dried with anhydrous Na2S04. The solution wasconcentrated to afford the crude product, which was purified with silica gel column(EtOAc/hexane = Ill) to afford the desired product (400 mg, 65%) as a pale yellow solid. 1HNMR (600 MHz, DMSO-d6) o 10.44 (s, IH), 8.12 (s, IH), 7.68 (d, IH, J= 7.8 Hz), 7.56 (d,IH, J= 6.6 Hz), 7.51 (d, IH, J= 7.8 Hz), 7.25 (d, IH, J= 6.6 Hz), 2.10 (s, 3H). 13C NMR(150 MHz, DMSO-d6) o 169.1, 141.7, 137.2, 132.9, 129.8, 126.5, 125.2, 122.9, 111.0, 24.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With pyridine; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h; | [00154] To a solution of pyridine (395 mg, 5.0 mmol) and 1,1-dioxo-1H-IA6-benzo[b]-thiophen-6-ylamine (181 mg, 1.0 mmol) in 5 mL ofDMF was added the solution of4-methoxy-benzoyl chloride (170 mg, 1.0 mmol) in DMF (5 mL) dropwise at 0 C. Themixture was stirred at r.t. for 16 h. The mixture was diluted with EtOAc (100 mL) andwashed with H20 (10 mL). The organic layer was separated and dried with anhydrousNa2S04. The solution was concentrated to afford the crude product, which was washed withDCM (30 mL) to give the desired product (120 mg, 38%) as a yellow solid. 1H NMR (600MHz, DMSO-d6) o 10.52 (s, IH), 8.28 (s, IH), 7.98-8.01 (m, 3H), 7.56-7.61 (m, 2H), 7.28(d, IH, J= 6.0 Hz), 7.09 (d, 2H, J= 8.4 Hz), 3.85 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 24h; | [00160] To a solution of pyridine-2-carboxylic acid (148 mg, 1.2 mmol) and1,1-dioxo-1H-IA6-benzo[b]thiophen-6-ylamine (181 mg, 1.0 mmol) in 10 mL of DCM wasadded DIPEA (388 mg, 3.0 mmol). HBTU (570 mg, 1.5 mmol) was added at 0 C. Theresulting mixture was stirred at r. t. for 24 h and then was concentrated. The residue wasdissolved in DMF (10 mL). The solution was added to the stirring water (50 mL) dropwise. Ayellow solid was formed. The solid was filtered and washed with H20 (50 mL). 130 mg ofthe desired product was obtained as a yellow solid (45% yield). 1H NMR (600 MHz, DMSOd6)o 11.17 (s, 1H), 8.77 (d, 1H, J= 4.2 Hz), 8.46 (s, 1H), 8.20 (d, 1H, J= 2.4 Hz), 8.19 (d,1H, J= 1.8 Hz), 8.08-8.11 (m, 1H), 7.70-7.72 (m, 1H), 7.58-7.61 (m, 2H), 7.31 (d, 1H, J=6.6 Hz). 13C NMR (150 MHz, DMSO-d6) o 163.3, 149.3, 148.6, 141.0, 138.3, 137.1, 132.8,130.3, 127.3, 126.4, 126.0, 124.6, 122.8, 112.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | 0-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (217 mg, 0.57 mmol, 2.0 equiv) and diisopropylethylamine (DIPEA) (0.15 mL, 0.85 mmol, 3.0 equiv) were added to a solution of 5-[(3,5-Dichloro-4-pyridinyl)sulfanyl]-4-nitrothiophene-2-carboxylic acid (100 mg, 0.285 mmol) in 1 mL DMF while stirring at 0 C and held at this temperature for twenty minutes. Benzo[b]thiophen-6-amine, 1,1-dioxide (56 mg, 0.314 mmol, 1.1 equiv) was added and the reaction was allowed to slowly warm to RT. After 4 h, the reaction mixture was diluted with EtOAc (100 mL) and washed with 1M HCl solution (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative reverse phase HPLC using a linear gradient of 10-95% CH3CN over 15 min with a flow rate of 20 mL/min. After lyophilization, pure product (58 mg, 40%) was obtained as a light yellow solid. Rf=0.55 (Hexane/ethyl acetate 1 : 1); HRMS (ESI) (m/z) [MH]+ calcd for C18H9Cl2N3O5S3, 513.9160, found 513.9179. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 6h;Inert atmosphere; | A mixture of 2-((3,5-dichloropyridin-4-yl)thio)-4-(trifluoromethyl)thiazole-5-carboxylic acid (1 9 mg, 0.051 mmol) and 6-aminobenzo[£>]thiophene 1 ,1 -dioxide (14 mg, 0.076 mmol) in DMF (2 mL) was treated with HATU (35 mg, 0.092 mmol) followed by DIPEA (13 mg, 0.1 0 mmol). The reaction mixture was stirred at room temperature for 6 h, quenched with H2O, and extracted with EA. The combined organic extracts were washed with H2O. The separated organic layer was concentrated and residue was purified by preparative reverse phase HPLC using a linear gradient of 1 0-95% CH3CN over 24 min with a flow rate of 20 imL/min. After lyophilization, pure product (8 mg, 29%) was obtained as a white solid. 0.55 (Hex:EA = 1 :1 ); HRMS (ESI) (m/z) [MH]+calcd for C18H9CI2F3N3O3S3, 537.9135, found 537.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With trimethylaluminum; In toluene; at 20 - 90℃; for 3h;Inert atmosphere; | A mixture of methyl 2-((3,5-dichloropyridin-4-yl)thio)oxazole-5-carboxylate (21 mg, 0.069 mmol) and 6-aminobenzo[b]thiophene 1 ,1 -dioxide (15 mg, 0.083 mmol) in toluene (1 imL) was treated with a solution of AIMe3 (2.0 N in toluene, 0.17 imL, 0.34 mmol) at room temperature under N2. The reaction mixture was stirred at 90QC for 3 hours. The reaction was quenched with three drops of H2O and stirred for an additional 10 minutes. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative reverse phase HPLC using a linear gradient of 10-90% CH3CN over 16 min with a flow rate of 20 imL/min. After lyophilization, pure product (5 mg, 16%) was obtained as a white solid. 0.15 (Hex:EA = 1 :1 ); HRMS (ESI) (m/z) [MH]+calcd for C17H10CI2N3O4S2, 453.9490, found 453.9670. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With trimethylaluminum; In dichloromethane; toluene; at 0 - 20℃; for 14.16h;Reflux; Inert atmosphere; | A mixture of ethyl 5-((3,5-dichloropyridin-4-yl)thio)-1 ,3,4-thiadiazole-2-carboxylate (1 01 mg, 0.30 mmol) and 6-aminobenzo[£>]thiophene 1 ,1 -dioxide (63 mg, 0.35 mmol) in anhydrous CH2CI2 (1 0 mL) was treated with a solution of AIMe3 (2.0 M solution in toluene, 0.30 mL, 0.60 mmol) dropwise at 0QC. After addition, the reaction was stirred at room temperature for 1 0 minute, and then refluxed for 14 hours. H2O (0.2 mL) was added and stirred for 1 5 minutes. The reaction was filtered and concentrated. The residue was purified by preparative reverse phase HPLC using a linear gradient of 1 0- 90% CH3CN over 1 8 min with a flow rate of 20 mL/min. After lyophilization, pure product (38 mg, 27%) was obtained as a light yellow solid. 0.50 (Hex:EA = 1 :1 ); HRMS (ESI) (m/z) [MH]+calcd for C16H9CI2N4O3S3, 470.9214, found 470.9031 . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | In 2-methyltetrahydrofuran; at 20℃; for 1h; | 163 mg of 2-toluenesulfonyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole was dissolved in 2-methyltetrahydrofuran,Add 60 mg of tert-butyl hypochlorite, and stir at room temperature for 2 minutes, then add 6-aminobenzo [b] thiophene 1,1-dioxide (0.6 mmol, 109 mg), and stir for 1 hour at room temperature. After monitoring the reaction of the raw materials by TLC at a wavelength of nm, the reaction solution was concentrated by distillation under reduced pressure. The sample was loaded by dry method and purified by silica gel chromatography (petroleum ether / CH2Cl2 = 1:10, v / v) to obtain 134 mg of compound 29 with a reaction yield of 53%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With 1-hydroxy-7-azobenzotriazole; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;Cooling with ice; | Weighing _ mg (1 equivalent) of 2- (2-phenylimid [l, 2-a] pyridin-3-yl) acetic acid and 80 mg (1 equivalent of M) of 6-aminobenzothoxyphene-U -Dioxane in the flask,Using N, N-dimethylformamide as a solvent,Under ice bath conditions,Add 228 mg of 1-hydroxy-7-azobenzotriazole (HOAt), And 156 mg of N, N-diisopropylethylamine (DIPEA),Stir at room temperature for 4 hours,The reaction is complete,After extraction with ethyl acetate and water,The organic phase is dried over anhydrous sodium sulfate,After spin-drying the solvent, column chromatography (dichloromethane: methanol = 20: 1, V / V)82 mg of light yellow solid was obtained,The yield is: 49%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With pyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 12h; | 4.1.54. (S)-2-Amino-N-(1,1-dioxidobenzo[b]thiophen-6-yl)-3-methylbutanamide (25f) To a solution of 6-aminobenzo[b]thiophene 1,1-dioxide (550 mg,3.0 mmol) and Boc-L-Val-OH (989 mg, 4.6 mmol) in 50 mL of 30%Py/DCM was added EDCI (1.2 g, 6.1 mmol) at 0 C. The resultingmixture was stirred at RT for 12 h, and then concentrated. Theresidue was purified by column chromatography (DCM/MeOH 50:1) to afford the Boc-protected intermediate as a yellowsolid. (850 mg, 73%). 1H NMR (300 MHz, CDCl3) d 9.34 (s, 1H), 8.31(s, 1H), 7.13e6.91 (m, 3H), 6.49 (d, J 6.6 Hz, 1H), 5.23 (d, J 7.5 Hz,1H), 4.11 (t, J 7.5 Hz, 1H), 2.19e2.05 (m, 1H), 1.47 (s, 9H), 1.08e1.00(m, 6H). The intermediate (500 mg, 1.3 mmol) was dissvoled in10 mL of DCM, and 2 mL of TFAwas added at 0 C. The mixture wasstirred at RT for 12 h. Then the mixture was concentrated, and10 mL of MeOH and 1 mL of ammonium hydroxide was addedsuccessively. The resulting mixturewas stirred at RT for 10 min, andthen concentrated. The residue was purified by column chromatography(DCM/MeOH 20:1 to 10:1) to afford compound 25f as ayellow solid (350 mg, 95%). |
73% | With pyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 12h; | 4.1.54. (S)-2-Amino-N-(1,1-dioxidobenzo[b]thiophen-6-yl)-3-methylbutanamide (25f) To a solution of 6-aminobenzo[b]thiophene 1,1-dioxide (550 mg,3.0 mmol) and Boc-L-Val-OH (989 mg, 4.6 mmol) in 50 mL of 30%Py/DCM was added EDCI (1.2 g, 6.1 mmol) at 0 C. The resultingmixture was stirred at RT for 12 h, and then concentrated. Theresidue was purified by column chromatography (DCM/MeOH 50:1) to afford the Boc-protected intermediate as a yellowsolid. (850 mg, 73%). 1H NMR (300 MHz, CDCl3) d 9.34 (s, 1H), 8.31(s, 1H), 7.13e6.91 (m, 3H), 6.49 (d, J 6.6 Hz, 1H), 5.23 (d, J 7.5 Hz,1H), 4.11 (t, J 7.5 Hz, 1H), 2.19e2.05 (m, 1H), 1.47 (s, 9H), 1.08e1.00(m, 6H). The intermediate (500 mg, 1.3 mmol) was dissvoled in10 mL of DCM, and 2 mL of TFAwas added at 0 C. The mixture wasstirred at RT for 12 h. Then the mixture was concentrated, and10 mL of MeOH and 1 mL of ammonium hydroxide was addedsuccessively. The resulting mixturewas stirred at RT for 10 min, andthen concentrated. The residue was purified by column chromatography(DCM/MeOH 20:1 to 10:1) to afford compound 25f as ayellow solid (350 mg, 95%). |
Tags: 20503-40-6 synthesis path| 20503-40-6 SDS| 20503-40-6 COA| 20503-40-6 purity| 20503-40-6 application| 20503-40-6 NMR| 20503-40-6 COA| 20503-40-6 structure
[ 1263378-01-3 ]
N-Methyl-4-(methylsulfonyl)aniline hydrochloride
Similarity: 0.72
[ 1263378-01-3 ]
N-Methyl-4-(methylsulfonyl)aniline hydrochloride
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[ 931114-41-9 ]
2-(Hydroxymethyl)naphtho[1,2-b]thiophene 1,1-dioxide
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[ 913614-18-3 ]
1-(Benzo[b]thiophen-4-yl)piperazine hydrochloride
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P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
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 |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
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 |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
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 |
Sorry,this product has been discontinued.
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