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CAS No. : | 6964-21-2 | MDL No. : | MFCD00005473 |
Formula : | C6H6O2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RCNOGGGBSSVMAS-UHFFFAOYSA-N |
M.W : | 142.18 | Pubchem ID : | 23404 |
Synonyms : |
3-Thienylacetic acid
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.17 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 35.86 |
TPSA : | 65.54 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) : | -6.66 cm/s |
Log Po/w (iLOGP) : | 1.23 |
Log Po/w (XLOGP3) : | 0.72 |
Log Po/w (WLOGP) : | 1.38 |
Log Po/w (MLOGP) : | 0.63 |
Log Po/w (SILICOS-IT) : | 2.21 |
Consensus Log Po/w : | 1.23 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.45 |
Solubility : | 5.0 mg/ml ; 0.0351 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.67 |
Solubility : | 3.01 mg/ml ; 0.0212 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.42 |
Solubility : | 5.42 mg/ml ; 0.0381 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.86 |
Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P305+P351+P338 | 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 |
---|---|---|
99% | Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 2 h; Stage #2: With water In tetrahydrofuran; ethyl acetate |
Step 2: 2-(thiophen-3-yl)ethanol Tetrahydrofuran (200 mL) was added to LiAlH4 (4.56 g, 0.12 mol) and the mixture was stirred at 0° C. 2-(thiophen-3-yl)acetic acid (14.2 g, 0.1 mol) in THF (100 mL) was added dropwise at this temperature. After the addition, the reaction mixture was stirred at 0° C. for further 2 hours. To the reaction mixture was added EtOAc (200 mL) slowly and then 5 mL of water. The suspension was filtered though ceilite, the filtrate was dried over anhydrous sodium sulfate and concentrated to dryness to afford 2-(thiophen-3-yl)ethanol (12.44 g, yield: 99percent). 1H NMR (MeOD, 400 MHz): δ5.92-5.87 (m, 1H), 5.69-5.66 (m, 1H), 5.57 (s, 1H) 2.90 (d, J=14.0 Hz, 1H), 2.38 (d, J=14 Hz, 1H), 1.55-1.42 (m, 2H). |
98% | With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 3 h; Schlenk technique; Inert atmosphere | In a flame-dried Schlenk flask, equipped with a magnetic stirring bar, an argon inlet, and a septum, LiAlH4 (5.7 g, 150 mmol, 1.5 equiv) was dissolved in THF (100 mL) at 0 °C. A solution of 3-thienylacetic acid (3, 14.2 g, 100 mmol, 1.0 equiv) in THF (50 mL) at 0 °C was added dropwise. The mixture was stirred for 3 h at 0 °C and then it was carefully quenched with EtOAc and EtOH. Subsequently, 1–2percent NaOH (20 mL) was added and the mixture was stirred for 1 h, allowing aluminum hydroxide to precipitate as a granular solid. Finally, the mixture was filtered over Celite. The collected organic layers were dried (MgSO4), and the solvent was evaporated in vacuo to give the pure alcohol 4 (12.5 g, 98percent) as a pale yellow oil. |
78% | With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 7 h; | To a 0 C cooled stirred suspension of lithium aluminiumhydride (8.0 g, 0.21 mol) in THF (100 mL) was added 3-Thiopheneaceticacid 01 (20 g, 0.14 mol) in THF (100 mL) drop wise over1 h. Reaction mixture was warmed to room temperature and stirredfor 6 h. Reaction progress was checked by TLC for completionand then quenched with 10percent NaOH solution. The mixture was filteredover Celite, washed with ethylacetate. Aqueous layer wasextracted with ethylacetate and the combined organic layer waswashed with brine. Dried over sodium sulfate and concentratedto yield 2 as a yellow liquid (14.2 g, 78percent) 1H NMR (MeOD, 400MHz): d 5.92–5.87 (m, 1H), 5.69–5.66 (m, 1H), 5.57 (s, 1H) 2.90(d, J = 14.0 Hz, 1H), 2.38 (d, J = 14 Hz, 1H), 1.55–1.42 (m, 2H). 13CNMR (DMSO d6, 100 MHz): 145.53, 129.13, 126.54, 121.45,64.46, 38.85; ESI-MS m/z: (Calcd for C6H8OS: 128.03); Found:128.9 [M+H]+. |
3.59 g | With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 1.25 h; | Step 1: 2-(3-Thienyl)ethanol [00367] A solution of thiophene-3-acetic acid (4.982 g, 35.04 mmol) in THF ( 120 mL, 1500 mmol) was cooled to 0 °C, and lithium tetrahydroaluminate ( 1 .596 g, 42.05 mmol) was added slowly over 15 min. The reaction was allowed to warm to rt and stirred for 2hrs. The reaction was quenched via addition of water (5 mL) and EtOAc ( 10ml). The mixture was filtered, and the filter cake was washed with 30ml EtOAc. The filtrate was concentrated in vacuo to afford the title compound (3.59 g). NMR (400 MHz, Chloroform-d) δ 7.31 (dd, J = 4.9, 3.0 Hz, 1 H), 7.1 1 - 7.05 (m, 1 H), 7.05 - 6.97 (m, 1 H), 3.87 (t, J = 6.4 Hz, 2H), 2.92 (t, J = 6.4 Hz, 2H), 1.71 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With acetyl chloride; at 0 - 20℃; | Acetyl chloride (7.50 ml, 106 mmol) was added dropwise to a solution of <strong>[6964-21-2]3-thiopheneacetic acid</strong> (5.00 g, 35.3 mmol) in dry MeOH (150 ml) at 0 C. The mixture was left to slowly reach room temperature and stirred overnight. Solvents were evaporated and residue filtered through a short plug of silica gel (DCM) to give a quantitative yield of the title compound as an oil. 1H NMR (400 MHz, CDCl3): δ 3.64 (s, 2H), 3.70 (s, 3H), 7.03-7.05 (m, 1H), 7.14-7.15 (m, 1H), 7.27-7.29 (m, 1H). |
100% | With acetyl chloride; at 0 - 20℃; | Acteyl chloride (7.50 ml, 106 mmol) was added dropwise to a solution of <strong>[6964-21-2]3-thiopheneacetic acid</strong> (5.00 g, 35.3 mmol) in dry MeOH (150 ml) at 0 C. The mixture was left to slowly reach room temperature and stirred overnight. Solvents were evaporated and residue filtered through a short plug of silica gel (DCM) to give a quantitative yield of the title compound an oil. 1H MR (400 MHz, CDC13): 3.64 (s, 2H), 3.70 (s, 3H), 7.03-7.05 (m, 1H), 7.14 7.15 (m, 1H), 7.27-7.29 (m, 1H). |
80% | With sulfuric acid; at 0℃; for 14h;Reflux; | To a stirred solution of 2-(thiophen3-yflacetic acid (5 g, 35.2 mmoi) in methanol (60 ml) at 0 cc was added drop wise solution of H2S04 (6.92 ml, 130 mmofl, The reaction mixture was refluxed for 1 4h, After completion of reaction, methanol was evaporated and residue was further diluted with dichioromethane, An organic layer was washed with saturated sodium bicarbonate solution and evaporated under reduced pressure to afford methyl 2-(thiophen-3-yl)acetate (4.4 g, 80%) as oil. |
With sulfuric acid; for 24h;Reflux; | [00165] Methyl thiophene-3-acetate LXXXIV (M3) was synthesized following the method reported by Kim, L. Chen, Gong, Y. Osada, Macromolecules 1999, 32, 3964- 3969, the disclosure of which is incorporated herein by reference in its entirety. Briefly, 3-Thiopheneacetic acid (8.52 g, 60 mmol) was dissolved in 50 mL of methanol with 2 drops of concentrated H2504. The mixture was heated in an oil bath and refluxed for 24 hours. After the removal of methanol, the crude product was redissolved in diethylether, washed with DI water and dried with anhydrous magnesium sulfate. Pure product was obtained after filtration and evaporation of solvent. The structure was analyzed and confirmed with ‘H NMR spectroscopy. | |
With thionyl chloride; at 0 - 68℃; for 12h; | To a solution of 2-(3-thienyl)acetic acid (12.1, 5.40 g, 37.9 mmol, 1 equivalent) in MeOH (50 mL) was added thionyl chloride (6.78 g, 56.9 mmol, 4.13 mL, 1.5 equivalent) at 0 C. The mixture was heated to 68 C. for 12 hours. After this time, the reaction solution was evaporated and to this residue was added saturated sodium bicarbonate solution (80 mL). The suspension was extracted with ethyl acetate (35 mL*3), then dried over sodium sulfate and the solvent was removed to afford methyl 2-(thiophen-3-yl)acetate (12.2, 5.8 g, yield=93%) as a yellow oil without further purification. | |
With thionyl chloride; at 0 - 25℃; for 1h; | To a solution of 2-(thiophen-3-yl)acetic (500 mg, 3.52 mmol) in MeOH (5 ml) at 0 C was added SOCl2 (1.02 ml, 14.07 mmol) and stirred at 25 C for 1 h. The RM was concentrated in vacuo to give methyl 2-(thiophen-3-yl)acetate as a yellow oil.1H NMR (400 MHz, MeOD) d 7.35 (dd, J = 5, 3 Hz, 1H), 7.21 (dd, J = 3, 1 Hz, 1H), 7.03 (dd, J = 5, 1 Hz, 1H), 3.69 (s, 3H), 3.63 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With oxalyl dichloride;N,N-dimethyl-formamide; In tetrahydrofuran; | The procedure described above for the synthesis of 1-chloro-3-[2-(3-methylbenzo[b]thiophen-2-yl)propan-2-one was followed, reacting thiophene-3-acetic acid (5.32 g, 37.4 mmol) with oxalyl chloride (3.6 mL, 5.2 g, 41 mmol, then ethereal diazomethane, then dry HCl gas. Work-up gave pure product, a brown oil which solidified upon refrigeration to a golden-brown, waxy solid (6.52 g, 100% yield): 1H NMR (400 MHz, CDCl3) δ 3.94 (s, 2H) 4.13 (s, 2H) 6.99 (d, J=5.1 Hz, 1H) 7.16 (dd, J=1.5, 0.8 Hz, 1H) 7.33 (dd, J=4.9, 2.9 Hz, 1H). | |
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 3h; | General method 2: preparation of ethyl-5-substituted-1 ,2,4-oxadiazole-3carboxylateStep I A mixture of a 2-aryl acetic acid (3.78 mmol; 1 equivalent) and oxalyl chloride (4.16 mmol,1.1 equivalents) in dichloromethane (12 ml_) with few drops of DMF was stirred at room temperature for 3 h.Step IlThe resulting solution from step I was added to a mixture of ethyl 2-amino-2- (hydroxyimino)acetate (3.78 mmol 1 equivalent) and N1N diisopropylethylamine (6.06 mmol, 1.60 equivalents) in dichloromethane (6 ml.) at -15C. The reaction mixture was then stirred at room temperature for 12 to 36 h and poured into a mixture of ice and water. The formed precipitate was filtered off. When a precipitate was not formed, the organic layer was separated, dried over magnesium sulphate, filtered and evaporated to dryness. Step III The precipitate or the residue from step Il was refluxed in a sealed tube with pyridine (18 ml.) for 20 h and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica to yield the desired compound.; INTERMEDIATE 105 - PREPARATION OF ethyl 5-(thiophen-3-ylmethyl)-1 ,2,4- oxadiazole-3-carboxylate; This compound was prepared according to general method 2 with (step I) 2-(thiophen-3- yl)acetic acid (0.568 g; 3.78 mmol), oxalyl chloride (0.352 ml 4.16 mmol) in dichloromethane (12 ml.) with few drops of DMF; (step II) ethyl 2-amino-2- (hydroxyimino)acetate (0.5 g; 3.78 mmol); N, N diisopropylethylamine (1.05 ml 6.06 mmol) in dichloromethane (6 mL) and (step III) pyridine (18 ml_).The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.343 g (38%) of ethyl 5-(thiophen-3-ylmethyl)-1 ,2,4-oxadiazole-3-carboxylate as a yellow solid. ESI/APCI(+): 239(M+H). | |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 18h;Inert atmosphere; | General procedure: Carboxylic acid (0.735 mmol, 1.0 eq.) was added to a flame dried microwave vial under Argon. DCM (3 mL) was added, followed by oxalyl chloride (0.075mL, 0.885 mmol, 1.2 eq) and DMF (1 drop). The reaction mixture was stirred at room temperature under Argon for 18 hours. The solvent was removed under reduced pressure to afford the crude product. The resulting crude material was used directly for the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Step 2: 2-(thiophen-3-yl)ethanol Tetrahydrofuran (200 mL) was added to LiAlH4 (4.56 g, 0.12 mol) and the mixture was stirred at 0 C. 2-(thiophen-3-yl)acetic acid (14.2 g, 0.1 mol) in THF (100 mL) was added dropwise at this temperature. After the addition, the reaction mixture was stirred at 0 C. for further 2 hours. To the reaction mixture was added EtOAc (200 mL) slowly and then 5 mL of water. The suspension was filtered though ceilite, the filtrate was dried over anhydrous sodium sulfate and concentrated to dryness to afford 2-(thiophen-3-yl)ethanol (12.44 g, yield: 99%). 1H NMR (MeOD, 400 MHz): δ5.92-5.87 (m, 1H), 5.69-5.66 (m, 1H), 5.57 (s, 1H) 2.90 (d, J=14.0 Hz, 1H), 2.38 (d, J=14 Hz, 1H), 1.55-1.42 (m, 2H). | |
98% | With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 3h;Schlenk technique; Inert atmosphere; | In a flame-dried Schlenk flask, equipped with a magnetic stirring bar, an argon inlet, and a septum, LiAlH4 (5.7 g, 150 mmol, 1.5 equiv) was dissolved in THF (100 mL) at 0 C. A solution of 3-thienylacetic acid (3, 14.2 g, 100 mmol, 1.0 equiv) in THF (50 mL) at 0 C was added dropwise. The mixture was stirred for 3 h at 0 C and then it was carefully quenched with EtOAc and EtOH. Subsequently, 1-2% NaOH (20 mL) was added and the mixture was stirred for 1 h, allowing aluminum hydroxide to precipitate as a granular solid. Finally, the mixture was filtered over Celite. The collected organic layers were dried (MgSO4), and the solvent was evaporated in vacuo to give the pure alcohol 4 (12.5 g, 98%) as a pale yellow oil. |
78% | With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 7h; | To a 0 C cooled stirred suspension of lithium aluminiumhydride (8.0 g, 0.21 mol) in THF (100 mL) was added 3-Thiopheneaceticacid 01 (20 g, 0.14 mol) in THF (100 mL) drop wise over1 h. Reaction mixture was warmed to room temperature and stirredfor 6 h. Reaction progress was checked by TLC for completionand then quenched with 10% NaOH solution. The mixture was filteredover Celite, washed with ethylacetate. Aqueous layer wasextracted with ethylacetate and the combined organic layer waswashed with brine. Dried over sodium sulfate and concentratedto yield 2 as a yellow liquid (14.2 g, 78%) 1H NMR (MeOD, 400MHz): d 5.92-5.87 (m, 1H), 5.69-5.66 (m, 1H), 5.57 (s, 1H) 2.90(d, J = 14.0 Hz, 1H), 2.38 (d, J = 14 Hz, 1H), 1.55-1.42 (m, 2H). 13CNMR (DMSO d6, 100 MHz): 145.53, 129.13, 126.54, 121.45,64.46, 38.85; ESI-MS m/z: (Calcd for C6H8OS: 128.03); Found:128.9 [M+H]+. |
With lithium aluminium tetrahydride;Inert atmosphere; | General procedure: The majority of alcohols were commercially available. Alcohols 9c,26 9i,27 9j28 and 9k29 were prepared by LiAlH4 reduction of the corresponding carboxylic acids and gave spectral data consistent with those in the literature. | |
3.59 g | With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 1.25h; | Step 1: 2-(3-Thienyl)ethanol [00367] A solution of thiophene-3-acetic acid (4.982 g, 35.04 mmol) in THF ( 120 mL, 1500 mmol) was cooled to 0 C, and lithium tetrahydroaluminate ( 1 .596 g, 42.05 mmol) was added slowly over 15 min. The reaction was allowed to warm to rt and stirred for 2hrs. The reaction was quenched via addition of water (5 mL) and EtOAc ( 10ml). The mixture was filtered, and the filter cake was washed with 30ml EtOAc. The filtrate was concentrated in vacuo to afford the title compound (3.59 g). NMR (400 MHz, Chloroform-d) δ 7.31 (dd, J = 4.9, 3.0 Hz, 1 H), 7.1 1 - 7.05 (m, 1 H), 7.05 - 6.97 (m, 1 H), 3.87 (t, J = 6.4 Hz, 2H), 2.92 (t, J = 6.4 Hz, 2H), 1.71 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With sulfuric acid; for 24h;Reflux; | Step 1: Preparation of ethyl 2-(thiophen-3-yl)acetate 10.75 g (74.1 mmol) of 2-(thiophen-3-yl)acetic acid were solubilized in 100 ml of ethanol, 6 ml (72 mmol) of sulfuric acid were added to this solution. The mixture was heated with magnetic stirring with reflux for 24 h. After returning to r.t., the mixture was concentrated in vacuo, the crude residue was treated with 100 ml of a mixture consisting of water and ice. The aqueous phase was extracted with 2*100 ml of ethyl acetate. The combined organic phases were washed with 100 ml of water, 100 ml of a saturated NaHCO3 aqueous solution and 100 ml of a saturated NaCl aqueous solution and then dried on MgSO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo in order to obtain 12.27 g (yield=97%) of ethyl 2-(thiophen-3-yl)acetate as a colorless oil. LC-MS: m/z=non-ionized. 1H NMR (300 MHz, CDCl3) δ 7.24 (dd, J=6.0, 3.0 Hz, 1H), 7.16-7.07 (m, 1H), 7.02 (dd, J=4.9, 1.1 Hz, 1H), 4.13 (q, J=7.1 Hz, 2H), 3.62 (s, 2H), 1.23 (t, J=7.1 Hz, 3H). |
97% | With sulfuric acid; for 24h;Reflux; | 10.75 g (74.1 mmol) of 2-(thiophen-3-yl)acetic acid were solubilized in 100 ml of ethanol, 6 ml (72 mmol) of sulfuric acid were added to this solution. The mixture was heated with magnetic stirring with reflux for 24 h. After returning to r.t., the mixture was concentrated in vacuo, the crude residue was treated with 100 ml of a mixture consisting of water and ice. The aqueous phase was extracted with 2*100 ml of ethyl acetate. The combined organic phases were washed with 100 ml of water, 100 ml of a saturated NaHCO3 aqueous solution and 100 ml of a saturated NaCl aqueous solution and then dried on MgSO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo in order to obtain 12.27 g (yield=97%) of ethyl 2-(thiophen-3-yl)acetate as a colorless oil. LC-MS: m/z=non-ionized. 1H NMR (300 MHz, CDCl3) δ 7.24 (dd, J=6.0, 3.0 Hz, 1H), 7.16-7.07 (m, 1H), 7.02 (dd, J=4.9, 1.1 Hz, 1H), 4.13 (q, J=7.1 Hz, 2H), 3.62 (s, 2H), 1.23 (t, J=7.1 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; | Take a 100mL round bottom flask,DCC (1.0320g, 5mmol)And DMAP (0.1222 g, 1 mmol) was added to 10 mL of dry dichloromethane.Stir until all dissolved.3-Thiopheneacetic acid (0.7109 g, 5 mmol) was dissolved in 20 mL of dry dichloromethane, and then slowly added dropwise to the above solution using a constant pressure dropping funnel.Stir for 24-72h.It was dried to dryness and then subjected to column chromatography (eluent: ethyl acetate: petroleum ether: = 1:5) to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 2 This Example illustrates the preparation of (E)-methyl 3-methoxy-2-(3-thienyl)propenoate (compound number 1 of Table II). Methyl 3-thienylacetate was prepared by heating 3-thienylacetic acid in acidic methanol. It is an oil, 1H nmr: delta 3.71 (2H,s), 3.76 (3H,s) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With N-chloro-succinimide; In acetic acid; at 20℃; for 12h; | A solution of 3-thiophene acetic acid (1.42 g, 10.0 mmol) in acetic acid (10 mL) was treated with N-chlorosuccinimide (3. 1 g, 23 mmol, 2.3 equivalents), and the solution was stirred for 12 h at room temperature then concentrated in vacuo. The residue was diluted with water and stirred for 1 h whereupon the resulting solid was collected by filtration. The solid was dried in a vacuum oven at room temperature for 10 hours providing 1.51 g (72%) of (2, 5-dichlorothien-3-vl) acetic acid as a brown solid, which was used as such in the next step. MS (ESI) m/z 209/211/213 ( [M-H]-). |
72% | With N-chloro-succinimide; In acetic acid; at 20℃; for 12h; | A solution of 3-thiophene acetic acid (1.42 g, 10.0 mmol} in acetic acid (10 mL) was treated with N-chlorosuccinimide (3. 1g, 23 mmol, 2.3 equivalents), and the solution was stirred for 12 h at room temperature then concentrated in vacuo. The residue was diluted with water and stirred for 1 h whereupon the resulting solid was collected by filtration. The solid was dried in a vacuum oven at room temperature for 10 hours providing 1.51 g (72%) of (2. 5-dichlorothien-3-yl) acetic acid as a brown solid, which was used as such in the next step. MS (ESI) m/z 209/211/213 ( [M-H]-). |
72% | With N-chloro-succinimide; In acetic acid; at 20℃; for 12h; | Step 1: A solution of 3-thiophene acetic acid (1.42 g, 10.0 mmol) in acetic acid (10 mL) was treated with N-chlorosuccinimide (3. 1g, 23 mmol, 2.3 equivalents), and the solution was stirred for 12 h at room temperature then concentrated in vacuo. The residue was diluted with water and stirred for 1 h whereupon the resulting solid was collected by filtration. The solid was dried in a vacuum oven at room temperature for 10 hours providing 1.51 g (72%) of (2, 5-dichlorothien-3-yl) acetic acid as a brown solid, which was used as such in the next step. MS (ESI) m/z 209/211/213 ( [M-H]-). |
72% | With N-chloro-succinimide; In acetic acid; at 20℃; for 12h; | Example 141: 1-(2, 5-dichlorothien-3-vl)-2-piperazine-1-ylethyllcyclohexanol dihvdrochloride [0391] Step 1: A solution of 3-thiophene acetic acid (1.42 g, 10.0 mmol) in acetic acid (10 mL) was treated with N-chlorosuccinimide (3. 1g, 23 mmol, 2.3 equivalents), and the solution was stirred for 12 h at room temperature then concentrated in vacuo. The residue was diluted with water and stirred for 1 h whereupon the resulting solid was collected by filtration. The solid was dried in a vacuum oven at room temperature for 10 hours providing 1.51 g (72%) of (2. 5-dichlorothien-3-yl) acetic acid as a brown solid, which was used as such in the next step. MS (ESI) m/z 209/211/213 ( [M-H]-). |
72% | With N-chloro-succinimide; In acetic acid; at 20℃; for 12h; | A solution of 3-thiophene acetic acid (1.42 g, 10.0 mmol) in acetic acid (10 mL) was treated with N-chlorosuccinimide (3. 1g, 23 mmol, 2.3 equivalents), and the solution was stirred for 12 h at room temperature then concentrated in vacuo. The residue was diluted with water and stirred for 1 h whereupon the resulting solid was collected by filtration. The solid was dried in a vacuum oven at room temperature for 10 hours providing 1.51 g (72%) of (2. 5-dichlorothien-3-yl) acetic acid as a brown solid, which was used as such in the next step. MS (ESI) m/z 209/211/213 ( [M-H]-). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example B60 Synthesis of N-[(3-thienyl)acetyl]alanine Iso-butyl Ester Following General Procedure BI above, and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): δ=7.33 (m, 1H), 7.14 (m, 1H), 7.01 (m, 1H), 6.09 (m, 1H), 4.58 (m, 1H), 3.88 (m, 2H), 3.60 (s, 2H), 1.91 (m, 1H), 1.37 (d, 3H) 0.92 (d, 6H). | ||
Example B60 Synthesis of N-[(3-Thienyl)acetyl]alanine iso-Butyl Ester Following General Procedure BI above, and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. | ||
Example 60 Synthesis of N-[(3-thienyl)acetyl]alanine iso-butyl ester Following General Procedure I above, and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and alanine iso-butyl ester (prepared following General Procedure J above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1 H-nmr (CDCl3): δ=7.33 (m, 1H), 7.14 (m, 1H), 7.01 (m, 1H), 6.09 (m, 1H), 4.58 (m, 1H), 3.88 (m, 2H), 3.60 (s, 2H), 1.91 (m, 1H), 1.37 (d, 3H) 0.92 (d, 6H). |
EXAMPLE A60 Synthesis of N-[(3-thienyl)acetyl]alanine iso-butyl ester Following General Procedure I' above, and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and alanine iso-butyl ester (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): δ=7.33 (m, 1H), 7.14 (m, 1H), 7.01 (m, 1H), 6.09 (m, 1H), 4.58 (m, 1H), 3.88 (m, 2H), 3.60 (s, 2H), 1.91 (m, 1H), 1.37 (d, 3H) 0.92 (d, 6H). | ||
EXAMPLE A60 Synthesis of N-[(3-thienyl)acetyl]alanine Iso-butyl Ester Following General Procedure I' above, and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and alanine iso-butyl ester (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): δ=7.33 (m, 1H), 7.14 (m, 1H), 7.01 (m, 1H), 6.09 (m, 1H), 4.58 (m, 1H), 3.88 (m, 2H), 3.60 (s, 2H), 1.91 (m, 1H), 1.37 (d, 3H) 0.92 (d, 6H). | ||
Example A60 Synthesis of N-[(3-thienyl)acetyl]alanine iso-butyl ester Following General Procedure I' above, and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and alanine iso-butyl ester (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): δ=7.33 (m, 1H), 7.14 (m, 1H), 7.01 (m, 1H), 6.09 (m, 1H), 4.58 (m, 1H), 3.88 (m, 2H), 3.60 (s, 2H), 1.91 (m, 1H), 1.37 (d, 3H) 0.92 (d, 6H). | ||
With 1-(3-(1-pyrrolidinyl)-propyl)-3-ethylcarbodiimide; In chloroform; at 23℃; for 96h; | Example 60 Synthesis of N-[(3-thienyl)acetyl]alanine iso-butyl ester Following General Procedure I above, and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and alanine iso-butyl ester (prepared following General Procedure J above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): δ = 7.33 (m, 1H), 7.14 (m, 1H), 7.01 (m, 1H), 6.09 (m, 1H), 4.58 (m, 1H), 3.88 (m, 2H), 3.60 (s, 2H), 1.91 (m, 1H), 1.37 (d, 3H) 0.92 (d, 6H). Optical Rotation: [α]23-52 (c 1 MeOH) ã 589 nm. C13H19NO3S (MW = 269, Mass Spectroscopy (MH+ 269)). GENERAL PROCEDURE IP-EPC coupling P-EPC coupling employs an amino acid ester and a substituted acetic acid compound. The acetic acid derivative is well known in the art and is typically commercially available. The amino acid ester is prepared by conventional methods from the known and typically commercially available N-BOC amino acid as described in GENERAL PROCEDURE J below. Specifically, the appropriate amino ester free base (0.0346 mmols) and substituted phenylacetic acid (0.069 mmols) were dissolved in 2.0 mL CHCl3 (EtOH free), treated with 150 mg of P-EPC (0.87 meq./g) and the reaction was mixed for 4 days at 23C. The reaction was filtered through a plug of cotton, rinsed with 2.0 mL of CHCl3 and the filtrate evaporated under a stream of nitrogen. The purity of each sample was determined by 1H NMR and ranged from 50% to >95%. Between 8.0 and 15.0 mg of final product was obtained from each reaction and was tested without additional purification |
Yield | Reaction Conditions | Operation in experiment |
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Example B18 Synthesis of 2-[(thien-3-yl)acetamido]butyric Acid Iso-butyl Ester Following General Procedure BI above and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): δ=7.37 (m, 1H), 7.16 (m, 1H), 7.04 (m, 1H), 6.05 (bd, 1H), 4.57 (m, 1H), 3.66 (s, 2H), 1.93 (m, 2H), 1.67 (m, 1H), 0.91 (d, 6H), 0.86 (t, 3H). | ||
Example B18 Synthesis of 2-[(Thien-3-yl)acetamido]butyric Acid iso-Butyl Ester Following General Procedure BI above and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): δ=7.37 (m, 1H), 7.16 (m, 1H), 7.04 (m, 1H), 6.05 (bd, 1H), 4.57 (m, 1H), 3.66 (s, 2H), 1.93 (m, 2H), 1.67 (m, 1H), 0.91 (d, 6H), 0.86 (t, 3H). | ||
Example 18 Synthesis of 2-[(thien-3-yl)acetamido]butyric acid iso-butyl ester Following General Procedure I above and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1 H-nmr (CDCl3): δ=7.37 (m, 1H), 7.16 (m, 1i), 7.04 (m, 1H), 6.05 (bd, 1H), 4.57 (m, 1H), 3.66 (s, 2H), 1.93 (m, 2H), 1.67 (m, 1H), 0.91 (d, 6H), 0.86 (t, 3H). |
EXAMPLE A18 Synthesis of 2-[(thien-3-yl)acetamido]butyric acid iso-butyl ester Following General Procedure I' above and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): δ=7.37 (m, 1H), 7.16 (m, 1H), 7.04 (m, 1H), 6.05 (bd, 1H), 4.57 (m, 1H), 3.66 (s, 2H), 1.93 (m, 2H), 1.67 (m, 1H), 0.91 (d, 6H), 0.86 (t, 3H). | ||
Example A18 Synthesis of 2-[(thien-3-yl)acetamido]butyric Acid Iso-butyl Ester Following General Procedure I' above and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tIc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): δ=7.37 (m, 1H), 7.16 (m, 1H), 7.04 (m, 1H), 6.05 (bd, 1H), 4.57 (m, 1H), 3.66 (s, 2H), 1.93 (m, 2H), 1.67 (m, H), 0.91 (d, 61), 0.86 (t, 3H). | ||
EXAMPLE A18 Synthesis of 2-[(thien-3-yl)acetamido]butyric Acid Iso-butyl Ester Following General Procedure I' above and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): δ=7.37 (m, 1H), 7.16 (m, 1H), 7.04 (m, 1H), 6.05 (bd, 1H), 4.57 (m, 1H), 3.66 (s, 2H), 1.93 (m, 2H), 1.67 (m, 1H), 0.91 (d, 6H), 0.86 (t, 3H). | ||
With 1-(3-(1-pyrrolidinyl)-propyl)-3-ethylcarbodiimide; In chloroform; at 23℃; for 96h; | Example 18 Synthesis of 2-[(thien-3-yl)acetamido]butyric acid iso-butyl ester Following General Procedure I above and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): δ = 7.37 (m, 1H), 7.16 (m, 1H), 7.04 (m, 1H), 6.05 (bd, 1H), 4.57 (m, 1H), 3.66 (s, 2H), 1.93 (m, 2H), 1.67 (m, 1H), 0.91 (d, 6H), 0.86 (t, 3H). GENERAL PROCEDURE IP-EPC coupling P-EPC coupling employs an amino acid ester and a substituted acetic acid compound. The acetic acid derivative is well known in the art and is typically commercially available. The amino acid ester is prepared by conventional methods from the known and typically commercially available N-BOC amino acid as described in GENERAL PROCEDURE J below.Specifically, the appropriate amino ester free base (0.0346 mmols) and substituted phenylacetic acid (0.069 mmols) were dissolved in 2.0 mL CHCl3 (EtOH free), treated with 150 mg of P-EPC (0.87 meq./g) and the reaction was mixed for 4 days at 23C. The reaction was filtered through a plug of cotton, rinsed with 2.0 mL of CHCl3 and the filtrate evaporated under a stream of nitrogen. The purity of each sample was determined by 1H NMR and ranged from 50% to >95%. Between 8.0 and 15.0 mg of final product was obtained from each reaction and was tested without additional purification |
Yield | Reaction Conditions | Operation in experiment |
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With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | EXAMPLE 13; 3-[4-(5-Methoxy-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl)-phenyl]-2-[3-methyl-2-(2-thiophen-3-yl-acetylamino)-butyrylamino]-propionic acid, Cpd 107; A solution of Compound 12a (17 mg, 0.027 mmol), Compound 13a (4 mg, 0.03 mmol), EDC (8 mg, 0.04 mmol), HOBt (7 mg, 0.054 mmol), and DIEA (16 μL, 0.09 mmol) in 5 mL of CH2Cl2 was allowed to stir at rt overnight. The mixture was washed with 10% citric acid (aq) followed by saturated NaHCO3 (aq) solution. The organic layer was dried (MgSO4), filtered, and concentrated to yield Compound 13b (12 mg). |
Yield | Reaction Conditions | Operation in experiment |
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72% | In acetic acid; at 20℃; for 12h; | A solution of 3-thiophene acetic acid (1.42 g, 10.0 mmol) in acetic acid (10 mL) was treated with N-chlorosuccinimide (3.1 g, 23 mmol, 2.3 equivalents), and the solution was stirred for 12 h at room temperature then concentrated in vacuo. The residue was diluted with water and stirred for 1 h whereupon the resulting solid was collected by filtration. The solid was dried in a vacuum oven at room temperature for 10 hours providing 1.51 g (72%) of (2,5-dichlorothien-3-yl)acetic acid as a brown solid, which was used as such in the next step. MS (ESI) m/z 209/211/213 ([M-H]-). |
Yield | Reaction Conditions | Operation in experiment |
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With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 16h; | A stirred solution of 711 mg (5.0 mmol) of 3-thienylacetic acid, 720 mg (5.0 mmol) of Meldrum's acid, and 610 mg (5. 0 mmol) of 4-dimethylaminopyridine in 10 mL of DCM was treated with a solution of 1. 03 g (5.0 mmol) of DCC in 10 mL of DCM. The resulting solution was stirred at room temperature for 16 h, during which time a white precipitate appeared in the reaction mixture. The reaction mixture was filtered through a pad of Celite to remove the precipitated dicyclohexylurea and the filtrate was washed successively with 1 N HCl (1 x 15 mL), H2O (1 x 15 mL), brine (1 x 15 mL). The filtrate was dried (MgS04) and solvents were removed in vacuo. The resulting crude oil was dissolved in 8 mL of absolute ethanol and heated to 80 C for 4 h. The reaction mixture was cooled to room temperature and ethanol was removed in vacuo. Purification of the resulting oil by silica gel flash column chromatography eluting with hexanes/EtOAc 2: 1 afforded 1.02 g (97%) of the title compound as a yellow oil :'H NMR (CDC13, 400 MHz) 8 7.27 (m, 1 H), 7.06 (s, 1 H), 6.92 (m, 1 H), 4.09 (q, 2 H, J= 6. 8), 3.83 (s, 2 H), 3.41 (s, 2 H), 1.22 (t, 3 H, J= 6. 8). |
Yield | Reaction Conditions | Operation in experiment |
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68% | With selenium(IV) oxide; acetic acid; In tetrahydrofuran; 1,4-dioxane; water; ethyl acetate; | (1) A mixture of thiophen-3-acetic acid (56.9 g), selenium dioxide (66.6 g), dioxane (500 ml), acetic acid (35 ml) and water (10 ml) is refluxed with stirring for 24 hours and filtered. The filtrate is concentrated and to the residue is added ethyl acetate (700 ml). The insoluble materials are filtered off and the filtrate is dried and then the solvent is distilled off. The residue is dissolved in tetrahydrofuran (1 l) and thereto is added diphenyldiazomethane (103 g) under ice cooling over a period of 30 minutes. The mixture is stirred at room temperature for 1 hour and then filtered. The filtrate is concentrated and purified by silica gel column chromatography (solvent: hexane/ethyl acetate) to give (3-thienyl)glyoxylic acid diphenylmethyl ester (88.1 g). Yield: 68 % M.p.: 63 - 64C |
Yield | Reaction Conditions | Operation in experiment |
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55% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl-formamide; at 70℃; | A solution of 3,4-dihydro-2H-<strong>[5735-53-5]1,4-benzoxazine</strong> (0.52 g, 3.8 mmol) and thiophene-3-acetic acid (0.82 g, 5.7 mmol) in 1:1 CH2Cl2:DMF (20 mL) was treated with DIPEA (2.6 ml, 15 mmol), HOBt (1.29 g, 9.5 mmol), and EDCI (1.83 g, 9.5 mmol) and stirred at 70 C. overnight. The reaction was then diluted with CH2Cl2, washed with saturated aqueous NaHCO3, dried over Na2SO4, and concentrated. Chromatography (0-10% 1 N NH3-MeOH/EtOAc) provided 2A as a red solid (0.54 g, 55%) |
Yield | Reaction Conditions | Operation in experiment |
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Reference Production Example 9 [Show Image] To a mixture of 3.08 g of 2-bromo-4'-chloropropiophenone, 1.79 g of <strong>[6964-21-2]3-thiopheneacetic acid</strong>, acetonitrile and 10 ml of DMF was added 1.53 g of triethylamine, and the mixture was stirred for 2 hours at room temperature. The resultant mixture was cooled to 0C, and 4.60 g of 1,8-diazabicyclo[5.4.0]undec-7-ene was added dropwise into this, and the mixture was stirred for 3 hours at room temperature. Then, the reaction mixture was stirred for 11 hours at room temperature while blowing air into the reaction mixture. To the reaction mixture was added 200 ml of 1 mol/L hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and saturated brine sequentially, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure to obtain 3.98 g of 4-(4-chlorophenyl)-5-hydroxy-5-methyl-3-(3-thienyl)-2(5H)-fu ranone. |
Yield | Reaction Conditions | Operation in experiment |
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69% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 20h; | Step A: N-{3-[3-(2-Chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(3-thienyl)acetamide To solution of {3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}amine (125 mg, 0.4 mmol) (see Example 2, step A) in THF (5 mL) were added 3-thienylacetic acid (67 mg, 0.47 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (90 mg, 0.47 mmol), N-hydroxybenzotriazole (63 mg, 0.47 mmol), and diisopropylethylamine (200 μL, 1.2 mmol). After 20 h at rt, the reaction mixture was diluted with DCM, washed with water, dried over Na2SO4, filtered, and adsorbed onto silica gel. The crude product was purified by column chromatography to generate the title compound in 69% yield. ES-LC/MS m/z=446 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
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47% | Step C. Preparation of N-{3-[3-(2-[3-(1,3-oxazol-5-yl)phenyl]amino}-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(3-thienyl)acetamide (title compound) To a solution of 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[3-(1,3-oxazol-5-yl)phenyl]-2-pyrimidinamine (50 mg, 0.112 mmol) in 5:1 THF:DMA (2 mL) was added HOBT (46 mg, 0.34 mmol), 0.28 g polystyrene-bound carbodiimide resin (280 mg, 0.34 mmol), and 3-thienylacetic acid (48 mg, 0.34 mmol). After stirring at rt for 48 h, excess Dowex 550A OH anion-exchange resin was added and the resulting mixture was allowed to stir overnight. The solids were then removed by vacuum filtration and rinsed with THF (25 mL) and MeOH (25 mL). The filtrate was concentrated under reduced pressure and purified by mass-guided prep LC (C18, 15% H20 (with 0.1% formic acid)/CH3OH to 100% CH3OH gradient) to afford the title compound (30 mg, 47%). 1H NMR (400 MHz, DMSO-d6) δ 3.65 (s, 2H), 6.51 (d, 1H, J=5.37 Hz), 7.07-7.12 (m, 2H), 7.23-7.48 (m, 7H), 7.55 (s, 1H), 7.68-7.76 (m, 2H), 7.89 (s, 1H), 8.20 (s, 1H), 8.27 (d, 1H, J=5.37 Hz), 8.38 (s, 1H), 8.50-8.51 (m, 1H), 8.81 (d, 1H, J=6.84 Hz), 9.73 (s, 1H), 10.28 (s, 1H). ES-LC/MS m/z=570 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
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50% | Step B. N-(3-{3-[2-({3-[(Dimethylamino)methyl]phenyl}amino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)-2-(3-thienyl)acetamide (title compound)To a solution of 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-{3-[(dimethylamino)methyl]phenyl}-2-pyrimidinamine (50 mg, 0.115 mmol) in 5:1 THF:DMA (2 mL) was added HOBT (46 mg, 0.34 mmol), 0.28 g polystyrene-bound carbodiimide resin (280 mg, 0.34 mmol), and 3-thienylacetic acid (48 mg, 0.34 mmol). After stirring at rt for 48 h, excess Dowex 550A OH anion-exchange resin was added and the resulting mixture was allowed to stir overnight. The solids were then removed by vacuum filtration and rinsed with THF (25 mL) and MeOH (25 mL). The filtrate was concentrated under reduced pressure and purified by column chromatography (0-100% 9:1:0.1 DCM:MeOH: NH4OH) to afford the title compound (32 mg, 50%). 1H NMR (400 MHz, CDCl3) δ 2.27 (s, 6H), 3.46 (s, 2H), 3.78 (s, 2H), 6.54 (d, 1H, J=5.31 Hz), 6.90 (dd, 1H, J=1.47, 6.96 Hz), 6.99-7.00 (m, 1H), 7.06 (dd, 1H, J=1.28, 4.94 Hz), 7.22-7.38 (m, 8H), 7.53-7.56 (m, 2H), 7.61-7.63 (m, 1H), 7.77-7.80 (m, 1H), 8.16 (d, 1H, J=5.31 Hz), 8.32-8.35 (m, 1H), 8.46-8.48 (m, 1H). ES-LC/MS m/z=560 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
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72% | With triethylamine; HATU; In tetrahydrofuran; at 20℃; | Step C: N-[3-(3-{2-[(3-[2-(dimethylamino)ethyl]oxy}phenyl)amino]-4-pyrimidinyl}pyrazolo[1,5-a]pyridin-2-yl)phenyl]-2-(3-thienyl)acetamide (title compound) To a solution of 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-[2-(dimethylamino)ethyl]oxy}phenyl)-2-pyrimidinamine (140 mg, 0.3 mmol) in THF were added 3-thienylacetic acid (51 mg, 0.36 mmol), TEA (125 μL, 0.9 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (136 mg, 0.36 mmol). The reaction was stirred overnight at rt, after which the reaction mixture was diluted with DCM, washed with 5% aqueous Na2CO3, dried over Na2SO4, and adsorbed onto silica gel. The crude product was purified by column chromatography and lyophilized to generate the title compound in 72% yield. 1H NMR (400 MHz, d6-DMSO) δ 10.27 (s, 1H), 9.55 (s, 1H), 8.83 (d, J=6.7 Hz, 1H), 8.51 (d, J=8.8 Hz, 1H), 8.26 (d, J=5.1 Hz, 1H), 7.89 (s, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.40-7.53 (m, 4H), 7.26-7.31 (m, 3H), 7.08-7.18 (m, 3H), 6.53 (d, J=8.2 Hz, 1H), 6.48 (d, J=5.3 Hz, 1H), 3.99 (t, J=5.7 Hz, 2H), 3.66 (s, 2H), 2.58 (t, J=5.9 Hz, 2H), 2.18 (s, 6H). ES-LC/MS m/z=588 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
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27% | A solution of 3-thienylacetic acid (2.544 g, 17.89 mmol) in dry tetrahydrofuran (100 mL) was cooled with an ICE/SALT bath TO-10 C and the solution of lithium HEXAMETHYLSILAZANE (40 ML, 1M, in THF) was added drop-wise, over a period of 30 minutes. After additional stirring at cold for 30 minutes, the neat 2, 2-DIMETHOXY-1-BROMOETHANE was added via syringe. The cooling bath was removed and the stirring at room temperature was continued for another 3 hrs. The reaction mixture was poured onto water (100 mL), the non-acidic components were extracted with diethyl ether (2 x 50 mL). The pH of the aqueous solution was set to 3, (HCI, 2 N) and the crude acid was extracted into diethyl ether (3 x 50 mL). The combined organic extracts were dried with anhydrous sodium sulfate, and the solvent was evaporated to dryness to leave 1.12 g (27 %) of the crude acid, used in the next step without additional purification. This racemic acid could be resolved into its respective enantiomers using (R)-AND/OR (S) -a- PHENYLETHYLAMINE salts via crystallization from ethyl acetate. The acid, which ultimately led to the more active enantiomer of the racemate shown under Example 30, was obtained by crystallizations using the salts derived form the (S)-AMINE |
Yield | Reaction Conditions | Operation in experiment |
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Example 41 Preparation of methyl 2-(thiophen-3-yl)acetate (E41) To 2-(thiophen-3-yl)acetic acid in MeOH at 0 C. was added TMS-CH2N2. The solution was stirred for 3 hours then quenched with a few drops of AcOH. The solvents were evaporated. Column chromatography (SiO2, 3-15% EtOAc/Hex) gave pure methyl 2-(thiophen-3-yl)acetate (E41). | ||
In methanol; at 0℃; for 3h; | To 2-(thiophen-3-yl)acetic acid in MeOH at 0C was added TMS-CH2N2. The solution was stirred for 3 hours then quenched with a few drops of AcOH. The solvents were evaporated. Column chromatography (Si02, 3-15% EtO Ac/Hex) gave pure methyl 2- (thiophen-3-yl)acetate (E41). |
Yield | Reaction Conditions | Operation in experiment |
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4% | 5. 3,3-Dimethyl-6-(3-thienylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1 -one3-Hydroxy-2-(1 H-indol-3-yl)-5,5-dinnethylcyclohex-2-en-1-one (example A1 ) (1.0 g) is dissolved in dry dichloroethane (15 ml) and the solution is cooled to O0C (ice bath). Zinc chloride (1 M in diethyl ether, 8.2 ml) is added drop by drop and the mixture is stirred at O0C for 30 min. In parallel, 3- thiopheneacetic acid (1.17 g) is dissolved in trifluoroacetic acid anhydride (1.17 ml) and the mixture is stirred for 20 min at room temperature. The formed mixed anhydride is diluted with dichloroethane (5 ml) and added to the zinc chloride mixture, prepared above, within 5 min at O0C. The mixture is stirred for 5 h at room temperature. After that, ammonia (7M in methanol, 5.6 ml) and ammonium acetate (3.02 g) are added and the mixture is refluxed for 18 h. After cooling, 2M am- monia solution (30 ml) is added and the aqueous phase is extracted with dichloromethane (2 x 30 ml). The combined organic extracts are washed with 2M ammonia solution (2 x 50 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with gradient dichloromethane / ethyl acetate 98:2 to 90:10 (v/v)) to yield 57 mg (4%) of the title compound. 1H-NMR (300 MHz, d6-DMSO + CD3OD); δ = 1.10 (s, 6H), 2.68 (s, 2H), 3.16 (s, 2H), 4.52 (s, 2H), 7.10 (dd, J = 1.5 Hz, 4.9 Hz, 1 H), 7.23 (ddd, J = 1.5 Hz, 6.4 Hz, 8.1 Hz, 1 H), 7.26-7.29 (m, 1 H), 7.39-7.44 (m, 1 H), 7.55-7.66 (m, 1 H), 9.24 (d, J = 8.1 Hz, 1 H). MS (MH+ found) = 361.3 |
Yield | Reaction Conditions | Operation in experiment |
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Method B 1-{4-[4-(2-Phenylethyl)-1,3-thiazol-2-yl]piperidin-1-yl}-2-(thiophen-3-yl)ethanone (I-63) Thiophen-3-ylacetic acid (156 mg) and Hünig base (323 mg) are dissolved in dichloromethane (10 ml) and stirred for 30 min. 4-[4-(2-Phenylethyl)-1,3-thiazol-2-yl]piperidine hydrochloride (II-1, 309 mg), prepared according to Process 1.2, is added, and the mixture is stirred for a further 5 min before bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (599 mg) is added. The reaction mixture is stirred at room temperature overnight. After removal of the solvent under reduced pressure, the residue is purified chromatographically. This gives 1-{4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidin-1-yl}-2-(thiophen-3-yl)ethanone (99 mg). 1H NMR (DMSO-d6): δ 7.44-7.43 (m, 1H), 7.28-7.12 (m, 6H), 7.05 (s, 1H), 6.99 (d, 1H), 4.38 (bs, 1H), 3.99 (bs, 1H), 3.72 (s, 2H), 3.22-3.15 (m, 2H), 2.96 (s, 4H), 2.81 (bs, 1H), 2.00 (d, 2H), 1.52 (m, 2H) ppm MS (ESI): 397 ([M+H]+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-chloro-succinimide; acetic acid; In benzene; at 80℃; for 1h;Inert atmosphere; | 2-(thiophen-3-yl)acetic acid (150 mg, 1.06 mmol) was dissolved in acetic acid/benzene (1:1, 2 mL) and stirred under nitrogene atmosphere. N-chlorosuccinimide (141.0 mg, 1.06 mmol, 1 eq) was added and the reaction mixture was heated to 80C. After 1 h the solution was poured into ice water and extracted with DCM (3x20 mL). The combined organic layers were dried (MgSO4), the solvent evaporated in vacuo and purified by column chromatography (1% MeOH, 1% acetic acid in DCM) to yield 188 mg (1.06 mmol, quant.) of the title compound. TLC: Rf (1 % MeOH, 1 % AcOH in DCM): 0.25 |
Yield | Reaction Conditions | Operation in experiment |
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80% | 5.169 N-[2-(2,6-DIOXO-PIPERIDIN-3-YL)-1,3-DIOXO-2,3-DIHYDRO-1H-ISOINDOL-4-YLMETHYL]-2-THIOPHEN-3-YL-ACETAMIDE To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and <strong>[6964-21-2]3-thiopheneacetic acid</strong> (0.3 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight then was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (3×40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc:CH2Cl2 3:7) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-thiophen-3-yl-acetamide (0.7 g, 80%) as a white solid: mp 163-165 C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=2.39 min. (99%); 1H NMR (DMSO-d6) δ 2.02-2.09 (m, 1H), 2.52-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.55 (s, 2H), 4.71 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 7.04-7.06 (m, 1H), 7.28-7.29 (m, 1H), 7.45-7.48 (m, 1H), 7.61-7.67 (m, 1H), 7.76-7.83 (m, 2H), 8.60 (t, J=5.9 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 21.95, 30.90, 36.88, 37.83, 48.83, 121.87, 122.35, 125.76, 127.11, 128.67, 131.51, 133.18, 134.67, 135.82. 139.17, 166.91, 167.44, 169.78, 170.23, 172.73; Anal. Calcd. for C20H17N3O5S: C, 58.39; H, 4.16; N, 10.21; S, 7.79. Found: C, 58.37; H, 3.98; N, 10.05; S, 7.83. ; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dicyclohexyl-carbodiimide; In dimethyl sulfoxide; at 110℃; | General procedure: A solution of ortho-hydroxybenzaldehyde (1-4, 8 mmol), substituted acetic acid (a-c, 10 mmol) and DCC (12 mmol) in dimethylsulfoxide (DMSO, 10 mL), was heated (oil bath) at 110 C for 24-48 h. On completion of the reaction, cold water (100 mL) and acetic acid (15 mL) were added. The reaction mixture was stirred at room temperature for 4 h and extracted with diethyl ether (4 × 100 mL). The precipitated dicyclohexylurea was filtered off. The filtrate was extracted with 5% aqueous NaHCO3 (200 mL). The organic phase was stirred for 1 h with 5% aqueous sodium metabisulfite in order to remove the unreacted hydroxybenzaldehyde. The organic phase was washed with water, dried (Na2SO4) and the solvent removed under reduced pressure. The residue was purified by column chromatography (Hexane/EtOAc, 9:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dicyclohexyl-carbodiimide; In dimethyl sulfoxide; at 110℃; | General procedure: A solution of ortho-hydroxybenzaldehyde (1-4, 8 mmol), substituted acetic acid (a-c, 10 mmol) and DCC (12 mmol) in dimethylsulfoxide (DMSO, 10 mL), was heated (oil bath) at 110 C for 24-48 h. On completion of the reaction, cold water (100 mL) and acetic acid (15 mL) were added. The reaction mixture was stirred at room temperature for 4 h and extracted with diethyl ether (4 × 100 mL). The precipitated dicyclohexylurea was filtered off. The filtrate was extracted with 5% aqueous NaHCO3 (200 mL). The organic phase was stirred for 1 h with 5% aqueous sodium metabisulfite in order to remove the unreacted hydroxybenzaldehyde. The organic phase was washed with water, dried (Na2SO4) and the solvent removed under reduced pressure. The residue was purified by column chromatography (Hexane/EtOAc, 9:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dicyclohexyl-carbodiimide; In dimethyl sulfoxide; at 110℃; | General procedure: A solution of ortho-hydroxybenzaldehyde (1-4, 8 mmol), substituted acetic acid (a-c, 10 mmol) and DCC (12 mmol) in dimethylsulfoxide (DMSO, 10 mL), was heated (oil bath) at 110 C for 24-48 h. On completion of the reaction, cold water (100 mL) and acetic acid (15 mL) were added. The reaction mixture was stirred at room temperature for 4 h and extracted with diethyl ether (4 × 100 mL). The precipitated dicyclohexylurea was filtered off. The filtrate was extracted with 5% aqueous NaHCO3 (200 mL). The organic phase was stirred for 1 h with 5% aqueous sodium metabisulfite in order to remove the unreacted hydroxybenzaldehyde. The organic phase was washed with water, dried (Na2SO4) and the solvent removed under reduced pressure. The residue was purified by column chromatography (Hexane/EtOAc, 9:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dicyclohexyl-carbodiimide; In dimethyl sulfoxide; at 110℃; | General procedure: A solution of ortho-hydroxybenzaldehyde (1-4, 8 mmol), substituted acetic acid (a-c, 10 mmol) and DCC (12 mmol) in dimethylsulfoxide (DMSO, 10 mL), was heated (oil bath) at 110 C for 24-48 h. On completion of the reaction, cold water (100 mL) and acetic acid (15 mL) were added. The reaction mixture was stirred at room temperature for 4 h and extracted with diethyl ether (4 × 100 mL). The precipitated dicyclohexylurea was filtered off. The filtrate was extracted with 5% aqueous NaHCO3 (200 mL). The organic phase was stirred for 1 h with 5% aqueous sodium metabisulfite in order to remove the unreacted hydroxybenzaldehyde. The organic phase was washed with water, dried (Na2SO4) and the solvent removed under reduced pressure. The residue was purified by column chromatography (Hexane/EtOAc, 9:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19.2% | General procedure: The appropriate acetic acid (15 mmol) was refluxed for 30 min with triphosgene [bis(trichloromethyl) carbonate] (5 mmol) in dry CH2Cl2 (50 mL). A solution of the appropriately substituted imine (10 mmol) in dry CH2Cl2 (10 mL) was added dropwise to the refluxing solution. Triethylamine (30 mmol) was added. The reaction mixture was heated at reflux for 5 h and stirred at room temperature overnight. The mixture was washed firstly with distilled water (twice) (50 mL) and then with saturated aqueous sodium bicarbonate solution (50 mL). The organic layer was dried over anhydrous sodium sulphate. The pure product was isolated by flash column chromatography over silica gel (hexane/ethyl acetate gradient). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With pyridine; HATU; at 80℃; for 12h; | Example 20Production of N-(5-{4-fluoro-3-[(thiophen-3-ylacetyl)amino]phenoxy}[1,3]thiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide N-[5-(3-Amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (55 mg, 0.16 mmol) produced in Example 16(vi) was dissolved in pyridine (2.0 mL), thiophen-3-ylacetic acid (45 mg, 0.32 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (120 mg, 0.32 mmol) were added, and the mixture was stirred at 80 C. for 12 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), and washed successively with 5% aqueous ammonium chloride solution (5 mL), saturated aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate/heptane to give the title compound (51 mg, 68%) as a colorless powder.1H-NMR (DMSO-d6, 300 MHz) δ 0.88-1.04 (4H, m), 1.92-2.08 (1H, m), 3.75 (2H, s), 6.80-7.02 (1H, m), 7.03-7.19 (2H, m), 7.24-7.41 (2H, m), 7.47 (1H, dd, J=4.9, 3.0 Hz), 7.82 (1H, dd, J=6.6, 2.8 Hz), 8.15 (1H, d, J=8.7 Hz), 10.04 (1H, s), 12.69 (1H, br s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium acetate; In toluene; at 210 - 245℃;Inert atmosphere; | General procedure: 2.2 mmol of phthalic anhydride, 2.7 mmol of the corresponding phenylacetic acid and 0.26 mmol of sodium acetate with 5 mL of toluene were adapted in a round bottom flask to a Dean-Stark apparatus. The mixtures were maintained under Nitrogen at 210-245 C, with magnetic stirring, for 9-33 h. After cooling the reaction mixture was treated with ethyl acetate and washed with (sat.) Na2CO3, brine and water, dried over Na2SO4 and concentrated under reduced pressure to give the crude products. Solid products were purified by crystallization and oils by flash chromatography on silica gel. All phthalides were obtained as Z-isomers, configuration confirmed through NOE or ROESY experiments, and yields ranged 40-95%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With dicyclohexyl-carbodiimide; In dichloromethane; at 50℃; for 24h; | General procedure: 2-F-alkylethyl 4-hydroxythiobenzoate was synthesized in three steps following a synthesis procedure previously reported [20], [21] and [22]. Dicyclohexylcarbodiimide (DCC) (1.07 g, 5.2 mmol) was added to a solution of <strong>[6964-21-2]3-thiopheneacetic acid</strong> (0.74 g, 5.2 mmol) in dichloromethane. After stirring during 30 min at 50 C, 2-F-alkylethyl 4-hydroxythiobenzoate (5.2 mmol) was added. After a day, the solvent was removed and the crude was purified by column chromatography (silica gel; eluent: dichloromethane) to yield the products as white solids. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With dicyclohexyl-carbodiimide; In dichloromethane; at 50℃; for 24h; | General procedure: 2-F-alkylethyl 4-hydroxythiobenzoate was synthesized in three steps following a synthesis procedure previously reported [20], [21] and [22]. Dicyclohexylcarbodiimide (DCC) (1.07 g, 5.2 mmol) was added to a solution of <strong>[6964-21-2]3-thiopheneacetic acid</strong> (0.74 g, 5.2 mmol) in dichloromethane. After stirring during 30 min at 50 C, 2-F-alkylethyl 4-hydroxythiobenzoate (5.2 mmol) was added. After a day, the solvent was removed and the crude was purified by column chromatography (silica gel; eluent: dichloromethane) to yield the products as white solids. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With dicyclohexyl-carbodiimide; In dichloromethane; at 50℃; for 24h; | General procedure: 2-F-alkylethyl 4-hydroxythiobenzoate was synthesized in three steps following a synthesis procedure previously reported [20], [21] and [22]. Dicyclohexylcarbodiimide (DCC) (1.07 g, 5.2 mmol) was added to a solution of <strong>[6964-21-2]3-thiopheneacetic acid</strong> (0.74 g, 5.2 mmol) in dichloromethane. After stirring during 30 min at 50 C, 2-F-alkylethyl 4-hydroxythiobenzoate (5.2 mmol) was added. After a day, the solvent was removed and the crude was purified by column chromatography (silica gel; eluent: dichloromethane) to yield the products as white solids. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 2h;Inert atmosphere; | [00201] Step 1: Synthesis of N-methoxy-N-methyl-2-(thiophen-3-yl)acetamide:[00202] A mixture of 2-(thiophen-3-yl)acetic acid (2.0g, 14.1 mmol), 0,N-dimethyl- hydroxylamine (1.68 g, 16.9 mmol), EDCI (2.95 g, 15.5 mmol), HOBT (2.15 g, 15.5 mmol), and TEA (3.7 mL, 31 mmol) in anhydrous DCM (50 mL) was stirred at room temperature under nitrogen for two hours. The reaction mixture was diluted with CH2CI2, and the organic layer was washed with aqueous HC1 solution (0.5 mol/L, 30 mLx2), saturated NaHC03 (30 mLx2) and brine(30 mL), dried over Na2S04, filtered, and concentrated to give the crude N- methoxy-N-methyl-2-(thiophen-3-yl)acetamide (2.0 g, yield 76.6%). | |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 2h;Inert atmosphere; | [00341] A mixture of 2-(thiophen-3-yl)acetic acid (2.0g, 14.1 mmol), 0,/V-dimethyl- hydroxylamine(1.68 g, 16.9 mmol), EDCI (2.95 g, 15.5 mmol), HOBT (2.15 g, 15.5 mmol), and TEA (3.7 mL, 31 mmol) in anhydrous DCM (50 mL) was stirred at room temperature under nitrogen for two hours. The reaction mixture was diluted with CH2CI2, and the organic layer was washed with aqueous HC1 solution (0.5 mol/L1, 30 mLx2), saturated NaHC03 (30 mLx2) and brine(30 mL), dried over Na2S04, filtered, and concentrated to give the crude N- methoxy-N-methyl-2-(thiophen-3-yl)acetamide (2.0 g, yield 76.6%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41.8% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 25℃; for 23.25h;Inert atmosphere; Cooling with ice; | A solution of 8.24 mmol of DCC in 1 mL dry dichloromethane was added dropwise to a solution of 16.49 mmol HEMA and 8.24 mmol 3-thiophene acetic acid in 4 mL dry dichloromethane containing 0.41 mmol DMAP, with stirring and under cooling with ice. The esterification reaction was performed under nitrogen atmosphere. The reaction was allowed to stand on the ice bath for another 15 min more after adding DCC and then stood at 25 C (RT) for 23 h with continuous stirring. Then, the reaction mixture diluted with 250 mL dichloromethane and transferred to a separatory funnel. The mixture was extracted with 0.5 N HCl (100 mL), 0.5 N NaHCO3 (100 mL) and NaCl solution (100 mL) then dried over MgSO4. The solvent was evaporated out with a rotaevaporator and a yellowish oily residue was obtained. 1H NMR, FT-IR spectra of HEMAT are given in Figs. 1 and 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47.5% | Example 46-Chloro-2-oxo-8-[(2 hiophen-3-yl-acetylamino)-methyl]-1 ,2-dihydroquinoline-3- carboxylic acid a) 6-Chloro-8-[2 hiophen-3-yl)-acetylamino]-methyl}-2-methoxy-quinoline-3- carboxylic acid methyl ester[00155] To a mixture of <strong>[6964-21-2]thiophen-3-yl-acetic acid</strong> (0.0399 g, 0.28 mmol) in abs. CH2CI2 (5 ml_) is added EDC (54 mg, 0.281 mmol), DMAP (3 mg, 0.026 mmol) and Et3N (62 mg, 0.613 mmol). After 5 min methyl 8-aminomethyl-6-chloro-2-methoxy-quinoline- 3-carboxylate hydrochloride (10a) is added. The reaction mixture is stirred at rt for 27 h (LC/MS control), then it is washed with NaHCO3, and water. The organic phase is separated and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (EtOAc:Hexane, 2:1 ) to give the title compound (49 mg, 47.5%) as white solid after drying over P2O5 in vacuo. 1H-NMR (400 MHz, CDCI3), δ (ppm): 3.63 (s, 2H); 3.87 (s, 3H); 3.97 (s, 3H); 4.84 (d, 6.4 Hz, 2H); 6.47 (t, 6.4 Hz, 1 H) 6.89 (d, 4 Hz, 1 H); 7.09 (s, 1 H); 7.29 (dd, 4 and 2 Hz, 1 H); 7.61 (d, 2 Hz, 1 H); 7.69 (d, 2 Hz, 1 H); and 8.51 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With cesium fluoride; In tetrahydrofuran; at 125℃; for 24h; | General procedure: The aryne precursor (1.5 equiv) was added to a mixture of carboxylic acid (0.25 mmol) and CsF (4.0 equiv) in 15 mL of freshly distilled THF, and the reaction mixture was then stirred in a closed vial at 125 C for 18 h. After the reaction mixture was allowed to cool to room temperature, it was eluted through a plug of silica gel with ethyl acetate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel using hexanes/EtOAc as the eluent to afford the desired o-hydroxyaryl ketone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.3% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at -10 - 20℃;Inert atmosphere; | The monomer TATEMPO was synthesized according to the procedures shown in Scheme 1. A round-bottom flask was filled with 2-(thiophene-3-yl)acetic acid (1.79 g), 4-amino-TEMPO (2.15 g), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDCl) (2.40 g) and 4-dimethylaminopyridine (DMAP)(1.53 g).Dichloromethane (50mL) was then added. Subsequently, the content of the flask was stirred at-10C under nitrogen atmosphere. Then triethylamine (Et3N) (1.26g) was added dropwise to the above mixture. After addition, the mixture was warmed to room temperature and stirred overnight. The reaction product was washed with dilute hydrochloric acid and saturated sodium carbonate respectively three times and the organic layer dried over sodium sulfate. The resulting product TATEMPO was obtained by column chromatography on silica gel in 73.3% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.92% | With boric acid; In toluene; for 24h;Reflux; | Thiophene amide was synthesized according to a published procedure.2,6 3-Thiophene acetic acid (0.711 g, 5.0 mmol) and boric acid (0.031 g, 0.5 mmol) were dissolved in toluene (100 mL), respectively. These two solutions were thoroughly mixed in a 250 mL round-bottom flask, after which N,N-dimethylethylenediamine (0.443 g, 5.0 mmol) was added in one portion. The resulting mixture was heated under reflux for 24 h, and the reaction was monitored by using TLC. The water was collected azeotropically in a Dean-Stark apparatus. After the reaction time, the mixture was cooled to 40-45 C, and excess boric acid was removed using filtration followed by further cooling to 25-35 C. After stirring for 1 h at 25-35 C, the toluene was decanted, and the resulting crude material was dissolved in methanol (50 mL). Distillation afforded (1.01 g, yield 94.92%) as a syrup. 1H nuclear magnetic resonance (1H NMR) (D2O, 400 MHz; Supporting Information Figure S1): δ 7.98 (t, 1H, N-H), 7.46 (s, 1H, thiophene moiety), 7.22 (d, 1H, thiophene moiety), 7.02 (d, 1H, thiophene moiety), 3.45 (s, 2H, -CH2), 3.19 (m, 2H, -CH2), 2.28 (m, 2H, -CH2), 2.106 (s, 6H, -CH3). Fourier transform infrared (FTIR) (KBr, Supporting Information Figure S2), υ 3280 cm-1 (N-H), 3070 cm-1(=C-H), 2910 cm-1 (C-H), 1640 cm-1 (C=O amide), 1520 cm-1 (N-H bond), 1450 cm-1 (C=C), 1125 cm-1 (C-N), and 750 cm-1 (C-S). High resolution mass spectrometry (HRMS) (electrospray ionization-mass spectrometry (ESI-MS), Supporting Information Figure S3) m/z calc. for C10H16Br2N2OS [M+ H]+, 213.31; found, 213.33. |
67% | 3-Thiopheneacetic acid (4.26 g, 30 mmol) was dissolved in 100 mL of anhydrous THF in a three-necked round bottom flask, followed by the addition of 5.88 g (36 mmol) of 1,1-Carbonyldiimidazole (CDI). The mixture was cooled in an ice-bath (0 C) and kept stirring for 20 minutes under a positive nitrogen flow. 3.28 mL of N,N’-dimethylethylenediamine (30 mmol) diluted in 10 mL of anhydrous THF was added dropwise with a dropping funnel. After the complete of addition, the mixture was warmed up to room temperature and kept stirring overnight. THF was removed with a rotary evaporator, and the product was purified with silica gel column chromatography (MeOH/CH2C12/ethyl acetate, 1/10/10 (v/v/v)). Pure product was obtained as a light yellowish liquid at 67 % yield. ‘H NMR (300 MHz, CDC13) ö7.31 (m, 1H), 7.15 (s, 1H), 7.02 (d, 1H, J= 4.8 Hz), 6.14 (s, 1H), 3.58 (s, 2H), 3.30 (m, 2H), 2.37 (t, 2H, J= 6.0 Hz), 2.18 (s, 6H) (FIG. 13). ‘3C NMR (300 MHz, CDC13) ö170.72, 135.26, 128.62, 126.38, 123.15, 57.89, 45.23, 38.29, 37.18 (FIG. 14). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58%; 19% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; chloroform; at 70℃; for 20h; | General procedure: The appropriate imine (0.762 mmol) and carboxylic acid (0.915 mmol, 1.2 eq.) were stirred in theappropriate solvent. NEt(i-Pr)2 (182 mg, 246 μL, 1.410 mmol, 1.85 eq.) and [T3P (364 mg, 1.14 mmol,1.5 eq. (728 mg of 50% wt. solution in THF)] were added by syringe and the reaction mixture stirred at70 C for 20 h. The reaction was poured into sat. NaHCO3 (10 mL) and extracted with CH2Cl2 (3 × 10mL). The combined organic phases were dried (MgSO4), filtered, and concentrated to give the crudematerial. At this stage the diastereoselectivity was determined using 1H NMR. The material was purifiedby column chromatography (see individual entries for eluting solvent systems). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-iodo-succinimide; acetic acid; In dichloromethane; at 20℃; for 10h; | 1, into a 25mL round bottom flask add 450 mg (3.2mmol) of 2-thiopheneacetic acid, 1650 mg (7.4mmol) of iodo-succinimide, 5mL of dichloromethane and 2mL of acetic acid, the reaction is stirred at room temperature for 10 hours, the reaction mixture is subjected to extraction, drying and concentration, and then separated by column chromatography, obtained intermediate product a-1. 400 mg of intermediate product a-1 is first dissolved into 100mL of methanol and then added into 2.2mL of concentrated sulfuric acid, the reaction has been terminated after refluxing for 4 hours, and the reaction mixture is subjected to extraction, drying and concentration, and then separated by column chromatography, after that obtained compound b-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 60℃; for 9h;Inert atmosphere; | [Reaction 1] As shown in Reaction 1, 2-(thiophene-3-yl) acetic acid) (1 g, 7.03 mmol), propane-1,3-dithiol (0.753 g, 7.03 mmol), and 4-dimethylaminopyridine (4-DMAP) (2.014 g, 1.75 mmol) were dissolved in 80 ml of methylene chloride in a three-neck round bottom flask, after which stirring was performed at 60 C. in a nitrogen atmosphere. The stirred mixture solution was slowly added with N,N'-dicyclohexylcarbodiimide (DCC) (2.89 g, 14.06 mmol) dissolved in 20 ml of methylene chloride, and was then allowed to react for 9 hours. The reaction solution was washed using saturated aqueous Na2CO3, dried over MgSO4, and filtered. The remaining solvent was removed by rotary evaporation to obtain a yellowish solution. This solution was diluted with acetone, and cooled to 0 C., to obtain residual 1,3-dicyclohexylurea ("DCU") as a precipitate. This precipitate was removed by filtration through a paper filter, and addition of acetone and removal of the DCU precipitate were repeated until DCU precipitate was no longer evident in the solution. Finally, the remaining solvent was removed by rotary evaporation, and the crude purified using a silica column eluted with a solution of methylene chloride and methanol (60:1 v/v), thereby producing after collection of the fractions and removal of the solvent, S-3-mercaptopropyl-2-(thiophene-3-yl)ethanethioate ("MTE") (the monomer) as a pure yellow compound. The characteristic H1-NMR spectrum (in acetone-d6) of the product is shown in . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetic anhydride; at 30℃; for 2h; | General procedure: General procedure A Step-a: Synthesis of 2-(4-fluorophenyl)-3-(4-((E)-3-methoxy-3-oxoprop-1-en-1-yl) phenyl) acrylic acid (C). A mixture of 4-fluorophenylacetic acid (2.5 g, 13.2 mmol) and methyl (E)-3-(4-formylphenyl)acrylate (2.03 g, 13.2 mmol) were dissolved under stirring with acetic anhydride (8 ml). To this mixture diisopropylethylamine (DIPEA) (3.4 ml, 19.7 mmol) was added and stirred at 30 C for 2 h. Upon completion (as monitored by TLC using 100% ethyl acetate as eluent), the reaction mixture was poured into water and the pH was adjusted to 1 using dil. HClaq (1:1). The aqueous layer was extracted with ethyl acetate (2 * 150 ml). The combined ethyl acetate layer was washed with water till the washings were neutral and dried over anhydrous Na2SO4. The ethyl acetate layer was evaporated to dryness to obtain a sticky compound, which was triturated with cold dichloromethane (DCM) to furnish a white solid. It was filtered and dried under vacuum to afford the title compound (2 g, 47%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | (5)-tert-Butyl S -((5)-2-(((2H-tetrazol-S -yl)methyl)carbamoyl)-2,3 -dihydro- iHpyrrolo [2,3-bj pyridin- i -yl)-4-((tert-butoxycarbonyl)amino)-S -oxopentanoate (49.7 mg, 0.0880 mmol) was dissolved in 4M HC1 in dioxane (iO mL) and the reaction was heated to 50C for 3 hours. Both tert-butyl ester and Boc group were removed. The solvent wasevaporated to give a residue as a colorless glass. In a separated flask were dissolved2-(thiophen-3-yl)acetic acid (i25,i mg, 0.880 mmol, iO eq.), HOBt (i6.i mg, 0.i06 mmol, i.2 eq.) and EDC (30.2 mg, 0.i06 mmol, i.2 eq.) in DMF (S mL). DIPEA was then added (0.230 mL, i.320 mmol, iS eq.) and the mixture was stirred at RT for iO minutes. A solution in DMF (2 mL) of the residue obtained previously was slowlyadded to the mixture containing the 2-(thiophen-3-yl)acetic acid and the reaction was left at RT for iO minutes. The solvent was then evaporated and the product was purified by first a preparative reverse phase HPLC purification using a iO minutes gradient from 40% to S2% methanol in water. The excess 2-(thiophen-3-yl)acetic acid and the desired product co-eluted on this column. The product was then repurified by normal phasechromatography using S% methanol in DCM as the eluent to remove the excess acid and then iO% methanol, i% HCOOH and 89% DCMto elute desired the title compound (45)- S -oxo-S- [(25)-2- [(2H- i ,2,3,4-tetrazol-S -ylmethyl)carbamoylj - iH,2H,3H-pyrrolo [2,3-bjpyridin- l-ylj -4-[2-(thiophen-3 -yl)acetamidojpentanoic acid (C37) that was obtained as a white solid (12.5 mg, 27%). ‘H NMR (400 MHz, DMSO-d6) ö 1.82 (1H, m), 2.03 (1H, m), 2.30-2.45 (2H, m), 2.48-2.53 (2H, m), 2.96 (1H, d, J18Hz), 3.43 (1H, dd, J=11, 18Hz), 4.47 (1H, dd, J=5, 16 Hz), 4.67 (1H, dd, J=6, 16Hz), 5.00 (1H, dd, J4, 11Hz),5.88 (1H, m), 6.98-7.04 (2H, m), 7.23 (1H, s), 7.43 (1H, m), 7.65 (1H, d, J=7Hz), 8.14 (1H, d, J=5Hz), 8.35 (1H, d, J=8Hz), 8.92 (1H, m), MS (LC/MS) m/z observed 498.96, expected 499.15 [M+Hj. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With potassium carbonate; sulfur; at 120℃; for 24h; | General procedure: Elemental sulfur powder (S8, Mol. wt 32, 4 mmol) and K2CO3 (2 equiv) were added to a vial (10 mL) containing phenylacetic acid 1 or cinnamic acid 4 (1 mmol) and DMF (1 mL). The reaction mixture was heated at 120/100 C in an oil bath for 24 h. After completion of the reaction as determined by TLC, reaction mixture was allowed to cool to room temperature, diluted with water and then extracted with ethyl acetate (3*10 mL). The combined organic phase was evaporated under reduced pressure, and the resulting crude was separated through column chromatography using hexane-ethyl acetate as an eluent to afford the pure product 3/5. The formation of the products 7, however, required the use of DMSO for smooth reaction. 4.1.9. N,N-Dimethylthiophene-3-carbothioamide (3i). 11a Yellow oil; yield (66%, 112 mg); 1H NMR (CDCl3, 300 MHz): δ 7.35 (s, 1H), 7.25-7.28 (m, 1H), 7.13 (d, J=5.1 Hz, 1H), 3.55 (s, 3H), 3.26 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 195.0, 142.9, 126.9, 125.3, 123.6, 43.9, 43.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 12.5h;Inert atmosphere; | General procedure: General SynthesisThe appropriate thiophene alcohol (0.82 mmol), the selected carboxylic acid (1.23 mmol), DCC(2.46 mmol) and DMAP (2.05 mmol) were dissolved in CH2Cl2 (15 mL) at 0 C for 30 min. The resultingmixture was stirred at room temperature for 12 h under inert atmosphere. The suspension was filteredin order to remove DCU formed during the reaction, and the filtrates were concentrated under reducedpressure at 45 C. The crude product was purified by column chromatography in silica gel, usingn-hexane/CH2Cl2 (2:5) and then pure CH2Cl2 as eluent to give the desired product TPM1 (Figure 1).All monomers were characterized by 1H- and 13C-NMR spectroscopy and the spectra are included inthe Supplementary Materials. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 12.5h;Inert atmosphere; | General procedure: General SynthesisThe appropriate thiophene alcohol (0.82 mmol), the selected carboxylic acid (1.23 mmol), DCC(2.46 mmol) and DMAP (2.05 mmol) were dissolved in CH2Cl2 (15 mL) at 0 C for 30 min. The resultingmixture was stirred at room temperature for 12 h under inert atmosphere. The suspension was filteredin order to remove DCU formed during the reaction, and the filtrates were concentrated under reducedpressure at 45 C. The crude product was purified by column chromatography in silica gel, usingn-hexane/CH2Cl2 (2:5) and then pure CH2Cl2 as eluent to give the desired product TPM1 (Figure 1).All monomers were characterized by 1H- and 13C-NMR spectroscopy and the spectra are included inthe Supplementary Materials. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With potassium acetate; for 16h;Reflux; Inert atmosphere; | General procedure: Compounds were synthesized under anhydrous conditions, using a material previously dried at 60 C for at least 12 h and at 300 C for a few minutes immediately before use. A solution containing anhydrous CH3CO2K (2.94 mmol), the corresponding thiophenylacetic acid (1.67 mmol) and the corresponding hydroxysalicylaldehyde (1.67 mmol), in Ac2O (1.2 mL), was refluxed for 16 h. The reaction mixture was cooled, neutralized with 10% aqueous NaHCO3, and extracted with EtOAc (3 × 30 mL). The organic layers were combined, washed with water, dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The product was purified by recrystallization in EtOH and dried in vacuum to afford the desired compound [26,27]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium acetate; for 16h;Reflux; Inert atmosphere; | General procedure: Compounds were synthesized under anhydrous conditions, using a material previously dried at 60 C for at least 12 h and at 300 C for a few minutes immediately before use. A solution containing anhydrous CH3CO2K (2.94 mmol), the corresponding thiophenylacetic acid (1.67 mmol) and the corresponding hydroxysalicylaldehyde (1.67 mmol), in Ac2O (1.2 mL), was refluxed for 16 h. The reaction mixture was cooled, neutralized with 10% aqueous NaHCO3, and extracted with EtOAc (3 × 30 mL). The organic layers were combined, washed with water, dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The product was purified by recrystallization in EtOH and dried in vacuum to afford the desired compound [26,27]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 48h;Inert atmosphere; | General procedure: Each reaction tube of a 24-position Bohdan Miniblock XT was flushed with argon, then a solution of the amine scaffold 6b-d (70 mg) in anhydrous dichloromethane (2 mL) was added, followed by the appropriate acid (1.2 equiv), EDC (1.2 equiv) and DMAP (1.2 equiv). The reactions were shaken at 500 rpm at rt for 48 h, then water (2 mL) added. The reactions were passed through Isolute hydrophobic phase separator tubes, which allowed the halogenated solvent layer to pass through. The aqueous layers were extracted with dichloromethane (2×2 mL). The combined organics were evaporated in a Genevac EZ-2 Plus parallel evaporator and subjected to mass-directed preparative HPLC purification to afford pure amides 11b-d{1-13} |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 48h;Inert atmosphere; | General procedure: Each reaction tube of a 24-position Bohdan Miniblock XT was flushed with argon, then a solution of the amine scaffold 6b-d (70 mg) in anhydrous dichloromethane (2 mL) was added, followed by the appropriate acid (1.2 equiv), EDC (1.2 equiv) and DMAP (1.2 equiv). The reactions were shaken at 500 rpm at rt for 48 h, then water (2 mL) added. The reactions were passed through Isolute hydrophobic phase separator tubes, which allowed the halogenated solvent layer to pass through. The aqueous layers were extracted with dichloromethane (2×2 mL). The combined organics were evaporated in a Genevac EZ-2 Plus parallel evaporator and subjected to mass-directed preparative HPLC purification to afford pure amides 11b-d{1-13} |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 48h;Inert atmosphere; | General procedure: Each reaction tube of a 24-position Bohdan Miniblock XT was flushed with argon, then a solution of the amine scaffold 6b-d (70 mg) in anhydrous dichloromethane (2 mL) was added, followed by the appropriate acid (1.2 equiv), EDC (1.2 equiv) and DMAP (1.2 equiv). The reactions were shaken at 500 rpm at rt for 48 h, then water (2 mL) added. The reactions were passed through Isolute hydrophobic phase separator tubes, which allowed the halogenated solvent layer to pass through. The aqueous layers were extracted with dichloromethane (2×2 mL). The combined organics were evaporated in a Genevac EZ-2 Plus parallel evaporator and subjected to mass-directed preparative HPLC purification to afford pure amides 11b-d{1-13} |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In neat (no solvent); at 20℃; for 3h;Green chemistry; | General procedure: To octanoic acid 1a (4.32 g, 30 mmol) HMDS (3.63 g, 22.5 mmol) was added, and the mixture was stirred at room temperature until the complete consumption 1a. The initial heterogeneous reaction mixture became homogeneous, and 1H NMR analysis confirmed full conversion. The excess of HMDS was distilled off under reduced pressure, and distillation of the crude product furnished trimethylsilyl octanoate 2a (5.91 g, 91%) as a transparent oil. The distilled excess of HMDS could be reused. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | (135.7 mg, 0.500 mmol) was dissolved in dichloromethane (CH2Cl2, 7.1 mL, 0.07 M) and then trifluoroacetic acid (0.77 mL, 10.0 mmol) was added dropwise. The temperature is slowly raised to room temperature and then stirred for 2 hours. 10 mL of water was added to terminate the reaction, and 6N NaOH was added to neutralize the reaction product. Transfer the solution to a separatory funnel and separate the organic and aqueous layers. The aqueous layer was extracted with diethyl ether (3 x 10 mL), and the combined organic layers were washed with Na2SO4, filtered, and concentrated under reduced pressure.The concentrated solution was dissolved in dichloromethane (CH2Cl2, 10.0 mL, 0.05 M) without further purification and then EDC.HCl (143.8 mg, 0.75 mmol), triethylamine (94 μL, 0.135 mmol), thiophene 3-acetic acid (Thiophene 3-acetic acid, 71 mg, 0.500 mmol) at 0 C. The reaction mixture was stirred at room temperature for 24 hours, then sat. NH4Cl (10 mL) was added to terminate the reaction, followed by extraction with diethyl ether (3 x 10 mL). The combined organic layers were washed with Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography on silica gel (3 cm x 13 cm, eluent hexane: ethyl acetate = 40:60) afforded compound 35 (93.1 mg, 0.315 mmol, 63% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Preparation 1 1-(3-Thienyl)propan-2-one Suspend 2-(3-thienyl)acetic acid (26.5 g, 146.5 mmol) in acetic anhydride (87.9 mL, 913 mmol,) and add 1-methylimidazole (7.57 g, 91.3 mmol). Stir the reaction mixture for 4 hours at room temperature under nitrogen. Cool the reaction mixture to 0 C., add water (150 mL), and stir for 1 hour. Dilute the solution with EtOAc (300 mL) and wash successively with 2 M NaOH (2*200 ml), water (200 mL) and brine (200 mL). Separate the organic extracts phase, dry over sodium sulfate, filter, and concentrate to dryness to obtain the title compound (28.16 g, 77%) as a yellow oil. 1H NMR (400.13 MHz, CDCl3) δ 2.14 (s 3H), 3.7 (s, 2H), 6.94 (d, J=5.1 Hz, 1H), 7.08 (bs, 1H), 7.29-7.26 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | General procedure: Acetamides (1a-1x, 1ab, 1ac and 1ba-1bc). To a solution of 2-phenylacetic acid (7.0mmol), <strong>[1535-75-7]2-(trifluoromethoxy)aniline</strong> (7.7mmol) in anhydrous CH2Cl2 (25mL) were added EDCI (1.745g, 9.1mmol) and DMAP (256.6mg, 2.1mmol). The reaction mixture was stirred at room temperature overnight, diluted with HCl (1M) aqueous solution, and extracted with CH2Cl2 (3×25mL). The combined organic phase was washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated under vacuum. Purification by flash chromatography (Silica gel, petroleum ether: ethyl acetate=50: 1 as eluent) gave the corresponding 2-phenyl-N-[2-(trifluoromethoxy)phenyl]acetamide compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With acetic anhydride; In diethyl ether; at 20℃; for 61.2h; | (A) To an ice-cooled solution of 1091 <strong>[6964-21-2]3-thiopheneacetic acid</strong> (2.0 g, 14.1 mmol) and 1092 acetic anhydride (5.19 mL, 54.9 mmol) in 1093 ethyl ether (8 mL) was added 1094 boron trifluoride diethyl etherate (2.65 mL, 21.1 mmol) in drop-wise fashion over 15 min. The reaction mixture was then warmed to rt over 1 h, and was stirred at rt for 2.5 d. The reaction was quenched with 12 water, and the mixture was extracted with EtOAc. The combined organic extracts were washed successively with satd. aq NaHCO3, water and brine, and then dried (MgSO4) filtered and concentrated under reduced pressure. The resultant residue was purified by silica gel chromatography (20-80% EtOAc/heptanes) to afford 1095 7-methyl-5H-thieno[2,3-c]pyran-5-one (2.34 g, 51%). LC/MS: mass calcd. for C8H6O2S: 166.01, found: 167.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With acetic anhydride; potassium carbonate; at 130℃; for 4h; | General procedure: A mixture of 100.0 mg (0.58 mmol, 1.00 mol eq) 1,4-dihydro-4-oxoquinoline-3-carbaldehyde 1a together with 87.0 mg (0.639 mmol, 1.10 mol eq) of phenylacetic acid(2a) and 8.00 mg (0.639 mmol, 0.10 mol eq) of K2CO3 (abs) was stirred in 3 mL of freshly distilled Ac2O at 130 C for 4 h. After cooling the reaction mixture to rt, the solid product 3a was filtered off, washed with H2O (2 9 5 mL), Et2O (1 9 5 mL) and dried under vacuum to yield 129 mg (0.46 mmol, 80%) of 3a (Scheme 2). Here we are showing physico-chemical characteristics for the compound 3a. The characteristics for all sixteen novel compounds 3 together with their spectral figures are published in the Supporting Information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With acetic anhydride; sodium hydroxide; at 20℃; for 4h;Inert atmosphere; | Suspend 2-(3-thienyl)acetic acid (26.5 g, 146.5 mmol) in acetic anhydride (87.9 mL, 913 mmol,) and add 1-methylimidazole (7.57 g, 91.3 mmol). Stir the reaction mixture for 4 hours at room temperature under nitrogen. Cool the reaction mixture to 0 C, add water (150 mL), and stir for 1 hour. Dilute the solution with EtOAc (300 mL) and wash successively with 2 M NaOH (2200 ml), water (200 mL) and brine (200 mL). Dry the organic extract over sodium sulfate, filter, and concentrate to dryness to obtain the title compound (28.16 g, 77%) as a yellow oil. 1H NMR (400.13 MHz, CDCl3) δ 2.14 (s 3H), 3.7 (s, 2H), 6.94 (d, J= 5.1Hz, 1H), 7.08 (bs, 1H), 7.29-7.26 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | 2-Bromo-3-thiophenecarboxaldehyde (1.91 g, 10 mmol) was added to a solution of 3-thiopheneacetic acid (1.42 g, 10 mmol), Pd(OAc)2 (224 mg, 0.1 mmol), PPh3 (524 mg, 0.2 mmol), and K2CO3 (2.76 g, 20 mmol) in anhyd DMF (50 mL) and the mixture was stirred to 110 °C for 24 h. The reaction suspension was then cooled to 50 °C and then 2-octyldodecyl bromide (3.61 g, 10 mmol) was added in one portion together with a catalytic amount of Bu4NI (184 mg, 0.5 mmol). The mixture was stirred for a further 24 h. After removal of solvent under reduced pressure, the crude mixture was purified by flash chromatography (SiO2; n-hexanes/EtOAc/CH2Cl2 (10:0.5:0.5). The pure product 6 was obtained as a colorless oil (61percent), together with a small amount of 2-octyldodecyl-3-thiophene acetate (11percent).6 Yield: 3.14 g (61percent); Rf = 0.34 (99:0.5:0.5 hexanes/EtOAc/CH2Cl2). 1H NMR (CDCl3, 300 MHz): delta = 8.56 (s, 1H), 8.36 (d, J = 5.6 Hz, 1H), 7.53 (d, J = 5.6 Hz, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.44 (d, J = 5.4 Hz, 1H), 4.36 (d, J = 5.7 Hz, 2 H), 1.88 (m, 1H), 1.55-1.20 (m, 34 H), 0.87 (t, J = 7.0 Hz, 6 H). 13C NMR (CDCl3, 75 MHz): delta = 166.9, 137.8, 136.0, 135.6, 134.7, 125.7, 125.4, 125.2, 125.0, 124.2, 122.3, 67.8, 37.4, 31.8, 31.4, 29.9, 29.6, 29.5, 29.4, 29.2, 26.7, 22.6, 14.0. FIA-MS: m/z = 515 [M + 1]+, 1029 [2 M + 1]+. Anal. Calcd for C31H46O2S2: C, 72.32; H, 9.01. Found: C, 72.0; H, 8.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | 2-Bromobenzaldehyde (1.16 mL, 10 mmol) was added to a solution of <strong>[6964-21-2]3-thiopheneacetic acid</strong> (1.42 g, 10 mmol), Pd(OAc)2 (224 mg, 0.1 mmol), PPh3 (524 mg, 0.2 mmol), K2CO3 (2.76 g, 20 mmol) in anhyd DMF (50 mL) and then stirred to 110 C for 24 h. The reaction suspension was then cooled to 50 C and then 2-octyldodecyl bromide (3.61 g, 10 mmol) was added in one portion together with catalytic amount of Bu4NI (184 mg, 0.5 mmol). The reaction mixture was kept stirring under the same conditions for a further 24 h. After removal of solvent under reduced pressure, the crude reaction mixture was purified by flash chromatography (SiO2; n-hexanes/EtOAc 10:1). Pure product was obtained as a colorless oil; yield: 4.63 g (91%). 1H NMR (CDCl3, 300 MHz): δ = 8.56 (s, 1H), 8.36 (d, J = 5.5 Hz, 1H), 8.17 (d, J = 8.1Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.61 (d, J = 5.5 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 4.37 (d, J = 5.7 Hz, 2 H), 1.89 (m, 1H), 1.38-1.18 (m, 32 H), 0.88 (t, J = 6.2 Hz, 6 H). 13H NMR (CDCl3, 75 MHz): δ = 166.78, 138.99, 135.10, 130.81, 130.24, 130.06, 129.40, 128.82, 126.04, 125.87, 125.60, 123.71, 123.48, 67.94, 37.43, 31.80, 31.46, 29.88, 29.55, 29.52, 29.48, 29.23, 26.71, 22.57, 14.00. ESI-MS: m/z = 509 [M + 1]+, 1017 [2 M + 1]+. Anal. Calcd for C33H48O2S: C, 77.9; H, 9.5. Found: C, 77.4; H, 9.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane;Inert atmosphere; | Prop-2-yn-1-yl 2-(thiophen-3-yl)acetate was synthesized similarly to that described by Ks kan et al. [21]. To 50 mL DCM solution of a 3-thiophene acetic acid (1.0 g, 7.03 mmol), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride(1.35 g, 7.03 mmol), and DMAP (0.29 g, 0.58 mmol) was dropped propargyl alcohol (0.83 mL, 14.06 mmol) under argon atmosphere.End of the certain reaction time, DCM (50 mL) and water (50 mL)were poured. Aqueous layerwas separated and extracted with DCM(50 mL) twice more. After combination, organic phases were washed with 100mL of saturated NaCl solution, dried over MgSO4,and volatiles evaporated by rotary evaporation. The product was purified by silica column chromatography with DCM as eluent.(Yield: 91%). FT-IR (cm-1): 3285 (νC-H), 2130 (νC≡C), 1734(νC=O), 1H NMR (500 MHz, CDCl3, δ): 7.29-7.05 (m, 3H, C4H3S),4.72 (m, 2H, C≡CCH2), 3.71 (d, 2H, CH2-C4H3S), and 2.48 (s, 1H,HC≡C); EI-MS: m/e 180 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | In a 100 ml flask, with a magnetic stirrer, thermometer and coolant, in an inert atmosphere, 2,5-dibromobenzene-1 ,4-dicarbaldehyde having formula (IV) obtained as described in Example 2 (0.292 g; 1.0 mmol) and potassium carbonate (K2CO3) (Aldrich) (0.691 g; 5.0 mmol) were added to a mixture of 3-thiopheneacetic acid [heteroaryl compound having general formula (V) wherein Y = oxygen and Z = sulfur] (Aldrich) (0.312 g; 2.2 mmol), triphenylphosphine (Aldrich) (0.026 g; 0.1 mmol), palladium(ll)acetate (0233) [Pd(OAc)2] (0.112 g; 0.5 mmol) in L/,/V-dimethylformamide anhydrous (DMF) (Aldrich) (5 ml): the resulting reaction mixture was heated to 80C and maintained under stirring, at said temperature, for 24 hours. Subsequently, 1 -bromo-2-octyldodecane (Aldrich) [alkyl halide having general formula (VI) wherein R1 = 2-octyldodecyl and X - bromine] (0.672 g; 2.2 mmol) was added in a single portion: the reaction mixture obtained was left, under stirring, at 80C, for 24 hours. Subsequently, after cooling to room temperature (25C), the reaction mixture was placed in a 500 ml separator funnel: a solution of ammonium chloride (NH4CI) 0.1 M (Aldrich) (3 x 100 ml) was added to said reaction mixture and everything was extracted with ethyl acetate (Aldrich) (3 x 100 ml) obtaining an aqueous phase and an organic phase. The entire organic phase (obtained by joining the organic phases deriving from the three extractions) was separated and subsequently anhydrified on sodium sulfate (Aldrich) and evaporated. The residue obtained is purified through elution on a silica gel chromatography column [(eluent: n-heptane/ethylacetate 98/2) (Carlo Erba)], obtaining 0.083 g of bis(2-hexyldecyl)anthra[1 ,2-b:5,6-b?]dithiophene-4, 10- dicarboxylate having formula (la) as a white solid (yield 10%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | A suspension of thiophene-3-yl acetic acid (2.22 g, 15.6 mmol) and N-bromosuccinimide (2.78 g, 15.6 mmol) in DCM (140 mL) was kept in an ultrasound bath for 30 minutes. The solvent was evaporated under reduced pressure, and methanol (140 mL) and conc. sulfuric acid (0.5 mL) were added. The solution was stirred at 70 C for 16 hours. After cooling to room temperature, the solution was neutralized by the addition of saturated aqueous Na2CO3 (saturated), extracted with DCM (3 × 80 mL), and the combined organic solutions were dried over Na2SO4. After evaporation of the solvent, the crude product was purified by column chromatography (ca. 300 g SiO2, hexane/EA 1:0 9:1) to give 10 (2.30 g, 15.6 mmol, 63%) as colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | General procedure: The requisite aryl/alkenyl/alkyl acetic acid (2.0 equiv.) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, EDCIHCl (1.5 equiv.) were dissolved in CH2Cl2 andallowed to stir at rt for 5 min before the addition of the requisite phenol (1.0 equiv.). Thereaction mixture was stirred at rt for 21 h before being diluted with CH2Cl2 (× 1) and washedwith saturated, aqueous NaHCO3 (× 2). The organic layer was extracted, dried over MgSO4and the filtrate concentrated in vacuo. The crude material was purified by flash silica columnchromatography to give the desired activated aryl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | 3-Thiopheneacetic acid (0.03 g, 0.4 mmol) and HOBt (0.068 g, 0.5 mmol) were dissolved in anhydrous dichloromethane (CH2Cl2; 20 mL) under an ice bath followed by the addition of EDCI (0.096 g, 0.5 mmol). The mixture was stirred at room temperature for 30 min. Compound 8 (0.20 g, 0.5 mmol) and triethylamine (0.07 mL) in CH2Cl2 (30 mL) were added directly. The reaction was stirred at room temperature for 3 h. Then, CH2Cl2 solution was washed with 1 N HCl, saturated NaHCO3, and brine for thrice, dried over anhydrous Na2SO4, and evaporated under vacuum. The crude product was purified by chromatography using EtOAc/hexane (1:1) as the mobile phase to obtain 1 as a white solid (yield: 57%). 1H NMR (400 MHz DMSO-d6): δ 2.79-2.89 (m, 2H), 3.02-3.04 (m, 1H), 3.47 (t, J = 7.56 Hz, 1H), 3.59 (t, J = 7.40 Hz, 1H), 3.64-3.69 (m, 4H), 3.81 (s, 3H), 4.46 (d, J = 4.68 Hz, 2H), 6.93-7.07 (m, 3H), 7.25-7.29 (m, 3H), 7.44-7.50 (m, 2H), 7.70 (d, J = 8.32 Hz, 1H), 7.75 (d, J = 8.32 Hz, 1H), 8.05-8.10 (m, 1H). 13C NMR (101 MHz, DMSO-d6): δ 170.3, 155.7, 144.1, 138.5, 135.5, 129.6, 129.2, 128.6, 128.2, 127.7, 127.2, 127.0, 126.8, 125.9, 124.3, 122.4, 112.7, 79.3, 74.6, 55.8, 48.9, 46.7, 34.6, 34.3, 31.9. HRMS (AP-ESI) m/z: calcd for C25H25ClN2O4S2 [M + Na]+, 539.0842; found, 539.0866. |
[ 4282-29-5 ]
Thiophene-3,4-dicarboxylic acid
Similarity: 0.83
[ 78071-30-4 ]
4-Methylthiophene-3-carboxylic acid
Similarity: 0.83
[ 16188-55-9 ]
4-(Methylthio)phenylacetic acid
Similarity: 0.64
[ 19156-54-8 ]
4,5,6,7-Tetrahydrobenzo[b]thiophene-3-carboxylic acid
Similarity: 0.63
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P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
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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