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CAS No. : | 95201-93-7 | MDL No. : | MFCD00052081 |
Formula : | C6H5BrO3S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | UFTXASQYKJFRKI-UHFFFAOYSA-N |
M.W : | 237.07 | Pubchem ID : | 2777611 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.17 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 45.32 |
TPSA : | 74.77 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.84 cm/s |
Log Po/w (iLOGP) : | 2.07 |
Log Po/w (XLOGP3) : | 2.68 |
Log Po/w (WLOGP) : | 2.0 |
Log Po/w (MLOGP) : | 1.08 |
Log Po/w (SILICOS-IT) : | 2.6 |
Consensus Log Po/w : | 2.09 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.2 |
Solubility : | 0.149 mg/ml ; 0.000627 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.9 |
Solubility : | 0.0297 mg/ml ; 0.000125 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.03 |
Solubility : | 2.23 mg/ml ; 0.0094 mol/l |
Class : | Soluble |
PAINS : | 1.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.52 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With bromine In acetic acid at 20℃; for 24 h; | To a solution of 10g of 1 (63.2 mmol) in 22 mL of acetic acid was added 3.24 mL of bromine (63.2 mmol) then the mixture was stirred at room temperature for 24h. The solution was poured on 50 mL of water and extracted with 50 mL of CH2Cl2. The organic phase was washed twice with 50 ml of water then dried over MgSO4 and the solvent was removed at reduced pressure. The crude product was purified by flash chromatography on silica gel (CH2Cl2 - EP : 1/2) to afford 11.3 g of 2 (76 percent). m.p. = 86 °C 1H NMR (CDCl3): 3.92 (s, 3H), 7.38 (s, 1H), 9.74 (s, 1H) 13C NMR (CDCl3): 52.2, 102.6, 103.8, 128.1, 160.4, 165.8. MS (EI) : m/z = 236 (M+.) |
10% | With N-Bromosuccinimide In tetrahydrofuran; methanol at 0 - 20℃; for 6 h; | General procedure: NBS (63 mg,0.35 mmol) was added to a solution of 1 (100 mg, 0.70 mmol) in 10 mL of THF – CH3OH (1:1, v/v) at 0 C and the mixture was stirred at roomtemperature. After 2 h, NBS (50.4 mg, 0.28 mmol) was added again to the mixture at 0 C, and it was stirred at room temperature for 2 h. The solvent wasremoved in vacuo, and water (15 mL) was added to the residue. The aqueouslayer was extracted three times with EtOAc (30 mL). The organic layers weregathered together, washed with water and brine, dried over MgSO4, filtered,and concentrated in vacuo. Et2O (10 mL) was added to the dry residue todiscard succinimide. The filtrate was concentrated in vacuo, and heptane(10 mL) was added to the dry residue to afford 4 as an orange powder (68.6 mg,44percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With bromine; In acetic acid; at 20℃; for 24h; | To a solution of 10g of 1 (63.2 mmol) in 22 mL of acetic acid was added 3.24 mL of bromine (63.2 mmol) then the mixture was stirred at room temperature for 24h. The solution was poured on 50 mL of water and extracted with 50 mL of CH2Cl2. The organic phase was washed twice with 50 ml of water then dried over MgSO4 and the solvent was removed at reduced pressure. The crude product was purified by flash chromatography on silica gel (CH2Cl2 - EP : 1/2) to afford 11.3 g of 2 (76 %). m.p. = 86 C 1H NMR (CDCl3): 3.92 (s, 3H), 7.38 (s, 1H), 9.74 (s, 1H) 13C NMR (CDCl3): 52.2, 102.6, 103.8, 128.1, 160.4, 165.8. MS (EI) : m/z = 236 (M+.) |
40% | With bromine; acetic acid; at 20℃;Inert atmosphere; | <strong>[5118-06-9]Methyl 3-hydroxythiophene-2-carboxylate</strong> (60A) (5g, 31.6mmol) under N2Dissolved in acetic acid (30 mL), then bromine (10.1 g, 63.2 mmol)It was added dropwise to the reaction and added to the reaction at room temperature overnight.A saturated sodium hydrogen sulfite solution (50 mL) was added to the reaction mixture.The aqueous phase was extracted with methyl tert-butyl ether (30 mL×3).The combined organic phases were saturated with sodium bicarbonate (30 mL×2)Washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate and filtered.After the filtrate was concentrated under reduced pressure, the crude material was crystallized from methanol to give white solid.Methyl 4-bromo-3-hydroxythiophene-2-carboxylate (60B) (3.0 g, yield: 40%). |
10% | With N-Bromosuccinimide; In tetrahydrofuran; methanol; at 0 - 20℃; for 6h; | General procedure: NBS (63 mg,0.35 mmol) was added to a solution of 1 (100 mg, 0.70 mmol) in 10 mL of THF - CH3OH (1:1, v/v) at 0 C and the mixture was stirred at roomtemperature. After 2 h, NBS (50.4 mg, 0.28 mmol) was added again to the mixture at 0 C, and it was stirred at room temperature for 2 h. The solvent wasremoved in vacuo, and water (15 mL) was added to the residue. The aqueouslayer was extracted three times with EtOAc (30 mL). The organic layers weregathered together, washed with water and brine, dried over MgSO4, filtered,and concentrated in vacuo. Et2O (10 mL) was added to the dry residue todiscard succinimide. The filtrate was concentrated in vacuo, and heptane(10 mL) was added to the dry residue to afford 4 as an orange powder (68.6 mg,44% yield). |
With bromine; | EXAMPLE 7 Methyl 3-hydroxy-4-bromo-2-thiophenecarboxylate Prepared by the method described in Example 4 from <strong>[5118-06-9]methyl 3-hydroxy-2-thiophenecarboxylate</strong> (12.0 g, 76 mmoles) and bromine (12.1 g, 76 mmoles). Recrystallization from methanol gave the product (9.4 g); mp 79-81 C. | |
With bromine; | EXAMPLE 7 Methyl 3-hydroxy-4-bromo-2-thiophenecarboxylate. Prepared by the method described in Example 4 from <strong>[5118-06-9]methyl 3-hydroxy-2-thiophenecarboxylate</strong> (12.0 g, 76 mmoles) and bromine (12.1 g, 76 mmoles). Recrystallization from methanol gave the product (9.4 g); mp 79-81C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuryl dichloride; In methanol; chloroform; | EXAMPLE 14 Methyl 3-hydroxy-4-bromo-5-methoxy-2-thiophenecarboxylate Sulfuryl chloride (3.1 mL, 37 mmoles) is added dropwise at room temperature to a stirred solution of <strong>[95201-93-7]methyl 3-hydroxy-4-bromo-2-thiophenecarboxylate</strong> (8.2 g, 35 mmoles) in chloroform (40 mL) under argon. After 24 hours the mixture is evaporated under reduced pressure and the residue is stirred in methanol (25 mL). After another 24 hours the precipitate is filtered off, rinsed with methanol and dried to give the product (4.2 g); mp 107-109 C. | |
With sulfuryl dichloride; In methanol; chloroform; | EXAMPLE 14 Methyl 3-hydroxy-4-bromo-5-methoxy-2-thiophenecarboxylate. Sulfuryl chloride (3.1 mL, 37 mmoles) is added dropwise at room temperature to a stirred solution of <strong>[95201-93-7]methyl 3-hydroxy-4-bromo-2-thiophenecarboxylate</strong> (8.2 g, 35 mmoles) in chloroform (40 mL) under argon. After 24 hours the mixture is evaporated under reduced pressure and the residue is stirred in methanol (25 mL). After another 24 hours the precipitate is filtered off, rinsed with methanol and dried to give the product (4.2 g); mp 107-109C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; In acetone; for 6h;Heating / reflux; | METHYL-3-HYDROXY-4-BROMO-2-THIOPHENECARBOXYLATE (10.0 g, 42.2 mmol) was dissolved in 250 mL of acetone. Potassium carbonate (30.0 g, 217.4 MMOL) was added followed by a solution of iodomethane (14.5 mL, 233.0 MMOL). The mixture was heated to reflux and continued for 6 h. After cooled to room temperature, the mixture was filtered, the solid material was rinsed with acetone (-200 mL). The filtrate and rinsing were concentrated under reduced pressure to a solid, further dried on high vacuum, yielding 13.7 g (100%) of METHYL-3-METHOXY-4-BROMO-2-THIOPHENECARBOXYLATE (MH+ = 251.0). |
100% | With potassium carbonate; In acetone; for 6h;Heating / reflux; | Methyl-3-hydroxy-4-bromo-2-thiophenecarboxylate (10.0 g, 42.2 mmol) was dissolved in 250 ML of acetone.Potassium carbonate (30.0 g, 217.4 mmol) was added followed by a solution of iodomethane (14.5 ML, 233.0 mmol).The mixture was heated to reflux and continued for 6 h.After cooled to room temperature, the mixture was filtered, the solid material was rinsed with acetone (~200 ML).The filtrate and rinsing were concentrated under reduced pressure to a solid, further dried on high vacuum, yielding 13.7 g (100%) of methyl-3-methoxy-4-bromo-2-thiophenecarboxylate (MH+=251.0). |
100% | With potassium carbonate; In acetone; at 20℃; for 6h;Heating / reflux; | Methyl-3-hydroxy-4-bromo-2-thiophenecarboxylate (10.0 g, 42.2 mmol) was dissolved in 250 mL of acetone. Potassium carbonate (30.0 g, 217.4 mmol) was added followed by a solution of iodomethane (14.5 mL, 233.0 mmol). The mixture was heated to reflux and continued for 6 h. After cooled to room temperature, the mixture was filtered, the solid material was rinsed with acetone (200 mL). The filtrate and rinsing were concentrated under reduced pressure to a solid, further dried on high vacuum, yielding 13.7 g (100%) of methyl-3-methoxy-4-bromo-2-thiophenecarboxylate (MH+=251.0). |
100% | With potassium carbonate; In acetone; for 6h;Heating / reflux; | PREPARATIVE EXAMPLE 13.19; Step A; Methyl-3-hydroxy-4-bromo-2-thiophenecarboxylate (10.0 g, 42.2 mmol) was dissolved in 250 mL of acetone. Potassium carbonate (30.0 g, 217.4 mmol) was added followed by a solution of iodomethane (14.5 mL, 233.0 mmol). The mixture was heated to reflux and continued for 6 h. After cooled to room temperature, the mixture was filtered, the solid material was rinsed with acetone (-200 mL). The filtrate and rinsing were concentrated under reduced pressure to a solid, further dried on high vacuum, yielding 13.7 g (100%) of methyl-3-methoxy-4-bromo-2-thiophenecarboxylate (MH+ = 251.0). |
100% | With potassium carbonate; In acetone; for 4.5 - 6h;Heating / reflux;Product distribution / selectivity; | Methyl-3-hydroxy-4-bromo-2-thiophenecarboxylate (10.0 g, 42.2 mmol) was dissolved in 250 mL of acetone. Potassium carbonate (30.0 g, 217.4 mmol) was added followed by a solution of iodomethane (14.5 mL, 233.0 mmol). The mixture was heated to reflux and continued for 6 h. After cooled to room temperature, the mixture was filtered, the solid material was rinsed with acetone (-200 mL). The filtrate and rinsing were concentrated under reduced pressure to a solid, further dried on high vacuum, yielding 13.7 g (100%) of methyl-3-methoxy-4-bromo-2-thiophenecarboxylate (MH+ = 251.0). Methyl-4-bromo-3-hydroxy-2-thiophenecarboxylate (20g, 84.36 mmol) was dissolved in 400 mL of acetone. Potassium carbonate (58g, 420.3 mmol) was added followed by iodomethane (45 mL, 424 mmol). The resulting mixture was heated at reflux for 4.5 h. After cooling, the mixture was filtered through a thin Celite pad, rinsing with methylene chloride. The filtrate was concentrated in vacuo to give 22.5 g of methyl-4-bromo-3-methoxy-2-thiophenecarboxylate (crude, 100%, MH+ = 251.0) as a dark green solid. |
100% | With potassium carbonate; In acetone; for 4.5h;Heating / reflux; | PREPARATIVE EXAMPLE 16; Step A; Methyl-4-bromo-3-hydroxy-2-thiophenecarboxylate (20g, 84.36 mmol) was dissolved in 400 mL of acetone. Potassium carbonate (58g, 420.3 mmol) was added followed by iodomethane (45 mL, 424 mmol). The resulting mixture was heated at reflux for 4.5 h. After cooling, the mixture was filtered through a thin Celite pad, rinsing with methylene chloride. The filtrate was concentrated in vacuo to give 22.5 g of methyl-4-bromo-3-methoxy-2-thiophenecarboxylate (crude, 100%, MH(at) = 251.0) as a dark green solid. |
95% | To a suspension of NaH (60% in mineral oil, 242 mg, 6.05 mmol) in DMF ( 20 ml.) at 0 0C was added <strong>[95201-93-7]methyl 4-bromo-3-hydroxy-2-thiophenecarboxylate</strong> (1.15 g, 4.85 mmol) in DMF (5 ml_) dropwise and the resulting suspension was stirred for 30 min. To the above mixture was added MeI (1.7 g, 9.7 mmol). After 30 min, the mixture was poured onto water, and extracted with diethyl ether (10 ml_ x 3). The organic fractions were dried, concentrated under vacuum and purified on silica gel (hexanes/EtOAc, 10%) to give the title compound (1.2 g, 95% ) as a white solid: LC-MS (ES) m/z = 252 (M+H)+. | |
89.7% | With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h; | Methyl 4-bromo-3-hydroxythiophene-2-carboxylate (60B) (3.0 g, 12.7 mmol)Soluble in N,N-dimethylformamide(30mL), add potassium carbonate (3.55g, 25.3mmol)And methyl iodide (2.69g, 19.0mmol), added at 60 C It should be 2 hours. After cooling, water (60 mL) was added to the reaction solution.Solid product washed out, filtered,The filter cake was washed with water (20 mL x 3). White solid after dryingMethyl 4-bromo-3-methoxythiophene-2-carboxylate(60C) (2.85 g, yield: 89.7%). |
80% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 20h; | General procedure: To a solution of 2.4 g of 2 (10 mmol) in 40 ml of DMF was added 13 g of K2CO3 then 1.5 equivalents of the halogenated compound (methyl iodide, 1-bromohexane or 1-bromo-2-ethylhexane). The mixture was stirred at room temperature for 20h then was acidified with HCl 2M. For compound 3a (R = Me), the precipitate obtained after acidification was washed with water and dried into a desiccators to give 2.0 g of 3a (80%). m.p. = 77 - 78 C 1H NMR (CDCl3): 3.88 (s, 3H), 3.96 (s, 3H), 7.39 (s, 1H). MS (EI) : m/z = 236 (M+.) |
66% | To a suspension of NaH (1.20 g, 50.63 mmol) in THF (20 mL), a solution of methyl 4-bromo-3 hydroxythiophene-2-carboxylate 1 (10.0 g, 42.1 mmol) in THF (100 mL) was added it. The reaction mixture was stirred at 0 C for 30 min and to the reaction mixture MeI (18.0 g, 126.9 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with cold water and extracted with ethyl acetate (3×100 mL). The organic layer was washed with H2O (100 mL), brine solution (100 mL), dried over Na2SO4 and concentrated under reduced pressure to afford the Methyl 4-bromo-3-methoxythiophene-2-carboxylate (2) as an off white solid (6.98 g, 66%). M.P: 74-78 C; 1H NMR (400 MHz, CDCl3) delta 3.12 (s, 3H), 3.22 (s, 3H), 7.32 (s, 1H); 13C NMR (100 MHz, DMSO-d6) delta 165.1, 163.1, 133.9, 121.2, 112.7, 67.3, 57.3; MS m/z: 252 [M+H] +; Anal. Calcd. C7H7BrO3S: C, 33.48; H, 2.81; Found: C, 33.58; H, 2.92. | |
64% | To a suspension of 60% NaH (1.00 g, 25 mmol) in THF (15 mL), a solution of methyl 4-bromo-3-hydroxy-thiophene-2-carboxylate 1 (5.00 g, 21 mmol) in THF (60 mL) was added. The reaction mixture was stirred at 0C for 30 min, and then MeI (9.00 g, 63.4 mmol) was added. The reaction mixture was stirred at room temperature for 16 h, quenched with cold water and extracted with ethyl acetate (3× 60 mL). The organic layer was washed with H 2 O (60 mL), brine solution (50 mL), dried over Na 2 SO 4 , and concentrated under reduced pressure to a ord the product 2 as an o white solid. Yield 64%, mp 74-78C. 1 H NMR spectrum (CDCl 3 ), delta, ppm: 3.12 s (3H), 3.22 s (3H), 7.32 s (1H). 13 C NMR spectrum, delta, ppm: 165.1, 163.1, 133.9, 121.2, 112.7, 67.3, 57.3. MS: m/z: 252 [M + H] + . Found, %: C 33.58; H 2.92. C 7 H 7 BrO 3 S. Calculated, %: C 33.48; H 2.81. | |
13.7 g (100%) | With potassium carbonate; In acetone; | Step A Methyl-3-hydroxy-4-bromo-2-thiophenecarboxylate (10.0 g, 42.2 mmol) was dissolved in 250 mL of acetone. Potassium carbonate (30.0 g, 217.4 mmol) was added followed by a solution of iodomethane (14.5 mL, 233.0 mmol). The mixture was heated to reflux and continued for 6 h. After cooled to room temperature, the mixture was filtered, the solid material was rinsed with acetone (~200 mL). The filtrate and rinsing were concentrated under reduced pressure to a solid, further dried on high vacuum, yielding 13.7 g (100%) of methyl-3-methoxy-4-bromo-2-thiophenecarboxylate. (MH+=251.0). |
13.7 g (100%) | With potassium carbonate; In acetone; | Step A Methyl-3-hydroxy-4-bromo-2-thiophenecarboxylate (10.0 g, 42.2 mmol) was dissolved in 250 mL of acetone. Potassium carbonate (30.0 g, 217.4 mmol) was added followed by a solution of iodomethane (14.5 mL, 233.0 mmol). The mixture was heated to reflux and continued for 6 h. After cooled to room temperature, the mixture was filtered, the solid material was rinsed with acetone (~200 mL). The filtrate and rinsing were concentrated under reduced pressure to a near colorless solid, further dried on high vacuum, yielding 13.7 g (100%) of methyl-3-methoxy-4-bromo-2-thiophenecarboxylate (MH+=251.0). |
13.7 g (100%) | With potassium carbonate; In acetone; | Step A Methyl-3-hydroxy-4-bromo-2-thiophenecarboxylate (10.0 g, 42.2 mmol) was dissolved in 250 mL of acetone. Potassium carbonate (30.0 g, 217.4 mmol) was added followed by a solution of iodomethane (14.5 mL, 233.0 mmol). The mixture was heated to reflux and continued for 6 h. After cooled to room temperature, the mixture was filtered, the solid material was rinsed with acetone (-200 mL). The filtrate and rinsing were concentrated under reduced pressure to a solid, further dried on high vacuum, yielding 13.7 g (100%) of methyl-3-methoxy4-bromo-2-thiophenecarboxylate. (MH+=251.0). |
With potassium carbonate; In dimethyl sulfoxide; | 2. Preparation of Methyl 4-bromo-3-methoxy-2-thiophenecarboxylate To a solution of 36 g (0.15 mole) of <strong>[95201-93-7]methyl 4-bromo-3-hydroxy-2-thiophenecarboxylate</strong> in 300 mL of dimethyl sulfoxide (DMSO) was added 32 g (0.23 mole) of methyl iodide and then 32 g of powdered K2CO3. After 2 hr, the reaction mixture was poured into water and extracted with ether. The organic phase was washed with water (4*200 mL), dried over MgSO4, filtered and concentrated to give 36 g of a colorless solid. 1H NMR (300 MHz, CDCl3): delta 7.4 (s, 1H); 4.0 (s, 3H); 3.9 (s, 3H). Anal. Calc'd for C7H7BrO3S: C, 33.48; H, 2.81; S, 12.77. Found: C, 33.18; H, 2.70; S, 12.49. | |
13.7 g (100%) | With potassium carbonate; In acetone; | Step A Methyl-3-hydroxy-4-bromo-2-thiophenecarboxylate (10.0 g, 42.2 mmol) was dissolved in 250 mL of acetone. Potassium carbonate (30.0 g, 217.4 mmol) was added followed by a solution of iodomethane (14.5 mL, 233.0 mmol). The mixture was heated to reflux and continued for 6 h. After cooled to room temperature, the mixture was filtered, the solid material was rinsed with acetone (~200 mL). The filtrate and rinsing were concentrated under reduced pressure to a solid, further dried on high vacuum, yielding 13.7 g (100%) of methyl-3-methoxy-4-bromo-2-thiophenecarboxylate (MH+=251.0). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.4% | A solution of 4-bromothiophene-2-carboxylic acid methyl ester(500mg, 2.1mmol), sodium hydroxide(261mg, 6.3mmol) in a mixed solvent of methanol/water(2.5mL+2.5mL) was refluxed for 2 hours. After the reaction mixture was cooled to room temperature, 2N hydrochloric acid was added to adjust pH to 1, and it was diluted with ethyl acetate. The ethyl acetate layer was washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound(326mg, 69.4%) as a red brown powder.1H-NMR(CDCl3): delta 4.05(1H, brs), 7.40(1H, s). | |
69.4% | A solution of 4-bromothiophene-2-carboxylic acid methyl ester(500mg, 2.1mmol), sodium hydroxide(261mg, 6.3mmol) in a mixed solvent of methanol/water(2.5mL+2.5mL) was refluxed for 2 hours. After the reaction mixture was cooled to room temperature, 2N hydrochloric acid was added to adjust pH to 1, and it was diluted with ethyl acetate. The ethyl acetate layer was washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound(326mg, 69.4%) as a red brown powder.1H-NMR(CDCl3): delta 4.05(1H, brs), 7.40(1H, s). | |
69.4% | A mixture of 4-bromothiophene-2-carboxylic acid methyl ester(500mg, 2.1mmol), sodium hydroxide(261mg, 6.3mmol) in a mixed solvent of methanol/water(2.5mL+2.5mL) was refluxed for 2 hours. After the reaction mixture was cooled to room temperature, 2N hydrochloric acid was added to adjust pH to 1, and it was diluted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give the title compound(326mg, 69.4%) as a red brown powder.1H-NMR(CDCl3): delta 4.05(1H, brs), 7.40(1H, s). |
69.4% | (1) 4-Bromo-3-hydroxythiophene-2-carboxylic acid. A mixture of 4-bromothiophene-2-carboxylic acid methyl ester(500mg, 2.1mmol), sodium hydroxide(261mg, 6.3mmol) in a mixed solvent of methanol/water(2.5mL+2.5mL) was refluxed for 2 hours. After the reaction mixture was cooled to room temperature, 2N hydrochloric acid was added to adjust pH to 1, and it was diluted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give the title compound(326mg, 69.4%) as a red brown powder. 1H-NMR(CDCl3): delta 4.05(1H, brs), 7.40(1H, s). | |
69.4% | A mixture of 4-bromothiophene-2-carboxylic acid methyl ester(500mg, 2.1mmol), sodium hydroxide(261mg, 6.3mmol) in a mixed solvent of methanol/water(2.5mL+2.5mL) was refluxed for 2 hours. After the reaction mixture was cooled to room temperature, 2N hydrochloric acid was added to adjust pH to 1, and it was diluted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give the title compound(326mg, 69.4%) as a red brown powder.1H-NMR(CDCl3): delta 4.05(1H, brs), 7.40(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine;dmap; In dichloromethane; at 0 - 20℃; for 2h; | The first step of Scheme 30: To a solution of <strong>[95201-93-7]4-bromo-3-hydroxy-thiophene-2-carboxylic acid methyl ester</strong> (2.37 g, 10 mmol) in DCM (20 mL) was added TEA (2.09 mL, 15 mmol), DMAP (61 mg, 0.5 mmol) and Tf2O (2.02 mL, 12 mmol) at 0 C. The reaction mixture was stirred at room temperature for 2 hours, washed with aq. NaHCO3, and dried over MgSO4. The crude product was purified on a CombiFlash column eluted with hexanes/EtOAc to give the desired product, 4-bromo-3-trifluoromethanesulfonyloxy-thiophene-2-carboxylic acid methyl ester (3.69 g, 100%). 1H NMR (400 MHz, CHLOROFORM-D) 8 ppm 3.95 (s, 3H) 7.55 (s, 1H). |
90% | With pyridine; In dichloromethane; at 0 - 20℃; for 1h; | At 0 oC to a solution of methyl 4-bromo-3-[(trifluoromethyl)sulfonyl]oxy}-2-thiophenecarboxylate (2.0 g, 8.44 mmol) in CH2Cl2 (20 mL) and pyridine (1.5 mL, 18.55 mmol) was added Tf2O (1.6 mL, 9.47mmol). The mixture was stirred for 1 h, and poured to ice water (10 mL), and extracted with CH2Cl2 (5 mL x 3). The collected organic layers were dried (Na2SO4), and concentrated to give a red syrup (2.8 g, 90%), which was used directly to next step with out further purification. LC-MS (ES) m/z = 369 (M)+; 1HNMR: (400 MHz, CDCl3) delta ppm 7.57(s, 1H), and 3.57 (s, 3H); 13C NMR (101 MHz, CDCl3) delta ppm 52.3 (s, 1C), 105.9 (s, 1C), 118.0 (q, J = 322.2 Hz, 1C), 142.7 (s, 1C), and 158.9 (s, 1C). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | The first step of Scheme 1: To a solution of <strong>[95201-93-7]4-bromo-3-hydroxy-thiophene-2-carboxylic acid methyl ester</strong> (2.37 g, 10 mmol) in DMF (20 mL) was added tert-butyl bromoacetate (1.77 mL, 12 mmol) and K2CO3 (2.76 g, 20 mmol). The resultant reaction mixture was stirred at room temperature overnight, diluted with EtOAc and washed with aq. NH4Cl. The aqueous layer was extracted with EtOAc. The combined organic layer was dried over MgSO4, and the crude product was purified on SiO2 gel column eluted with EtOAc/Hexanes (1/10 to 1/8) to give 4-bromo-3-tert-butoxycarbonylmethoxy-thiophene-2-carboxylic acid methyl ester as a colorless crystalline (2.97 g, 85%). 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 1.49 (s, 9H) 3.86 (s, 3H) 4.80 (s, 2H) 7.39 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In diethyl ether; ethanol; water; | 16. Preparation of 2-Amino-5,8-dimethoxy[1,2,4]-triazolo[1,5-a]pyridine A mixture of 58.4 g (0.21 mole) of ethyl [(3,6-dimethoxypyridin-2-yl)amino]carbono-thioylcarbamate, 70 g (1 mole) of hydroxylamine hydrochloride and 105 mL (0.6 mole) of diisopropylethylamine in 1 liter of ethanol was heated to reflux for 12 hr. After cooling, the resulting solution was evaporated to dryness under vacuum. Water (250 ml) and diethyl ether (100 ml) were added to the residue and the mixture was stirred for 15 min. The product was collected by filtration and dried under a vacuum at room temperature to give 25.2 g of 2-amino-5,8-dimethoxy[1,2,4]triazolo[1,5-a]pyridine. mp 223-234 C. 1H NMR (DMSO-d6): delta 6.9 (d, 1H, j=8.7); 6.2 (d, 1H, j=8.4); 5.9 (s, 2H); 4.0 (s, 3H); 3.8 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 20h; | General procedure: To a solution of 2.4 g of 2 (10 mmol) in 40 ml of DMF was added 13 g of K2CO3 then 1.5 equivalents of the halogenated compound (methyl iodide, 1-bromohexane or 1-bromo-2-ethylhexane). The mixture was stirred at room temperature for 20h then was acidified with HCl 2M. For compound 3a (R = Me), the precipitate obtained after acidification was washed with water and dried into a desiccators to give 2.0 g of 3a (80%). m.p. = 77 - 78 C 1H NMR (CDCl3): 3.88 (s, 3H), 3.96 (s, 3H), 7.39 (s, 1H). MS (EI) : m/z = 236 (M+.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 20h; | General procedure: To a solution of 2.4 g of 2 (10 mmol) in 40 ml of DMF was added 13 g of K2CO3 then 1.5 equivalents of the halogenated compound (methyl iodide, 1-bromohexane or 1-bromo-2-ethylhexane). The mixture was stirred at room temperature for 20h then was acidified with HCl 2M. For compound 3a (R = Me), the precipitate obtained after acidification was washed with water and dried into a desiccators to give 2.0 g of 3a (80%). m.p. = 77 - 78 C 1H NMR (CDCl3): 3.88 (s, 3H), 3.96 (s, 3H), 7.39 (s, 1H). MS (EI) : m/z = 236 (M+.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 2h; | Example 6 8-(3-methoxyphenyl)-2-methyl-2,3,4,5-tetrahydrothieno[2,3-f][1,4]oxazepine 1 hydrochloride [Show Image](step 1) methyl 4-bromo-3-(2-tert-butoxy-1-methyl-2-oxoethoxy)thiophene-2-carboxylate A solution of methyl 4-bromo-3-hydroxythiophene-2-carboxylate (1.42 g), tert-butyl 2-bromopropanoate (1.2 mL), potassium carbonate (2.45 g) and DMF (30 mL) was stirred at 50°C for 2 hr. The reaction mixture was cooled to room temperature, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to give the title compound (2.16 g, 99percent) as colorless crystals.1H-NMR(CDCl3): delta1.43 (9H, s), 1.58 (3H, d, J=6.8 Hz), 3.85 (3H, s), 5.16 (1H, q, J=6.8 Hz), 7.38 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h; | Example 1 8-(furan-3-yl)-2,3,4,5-tetrahydrothieno[2,3-f][1,4]oxazepine 1 hydrochloride [Show Image](step 1) 3-(2-amino-2-oxoethoxy)-4-bromothiophene-2-carboxylic acid A solution of <strong>[95201-93-7]methyl 4-bromo-3-hydroxythiophene-2-carboxylate</strong> (53.0 g), potassium carbonate (46.2 g), 2-bromoacetamide (37.0 g) and DMF (500 mL) was stirred at 60C for 2 hr, and the solvent was evaporated under reduced pressure. Water (300 mL) was added to the residue, and the solid was collected by filtration. To the obtained solid were added potassium carbonate (61.6 g), water (20 mL) and MeOH (500 mL), and the mixture was stirred at 85C for 1 hr. After cooling to room temperature, the solid were collected by filtration. The obtained solid was dissolved in water (300 mL), and the mixture was adjusted with 6 N hydrochloric acid to pH 3. The obtained solid was collected by filtration, and washed with water to give the title compound (50.5 g, 80.8%) as a solid.1H-NMR(DMSO-d6): delta4.90 (2H, s), 7.82 (1H, brs), 7.92 (1H, s), 8.00 (1H, brs), 13.46 (1H, brs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With tributylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 10 - 30℃; for 2h; | (step 2) methyl 4-bromo-3-{(1S)-2-[(tert-butoxycarbonyl)amino]-1-methylethoxy}thiophene-2-carboxylate To a solution of <strong>[95201-93-7]methyl 4-bromo-3-hydroxythiophene-2-carboxylate</strong> (237 mg), tert-butyl [(2R)-2-hydroxypropyl]carbamate (175 mg), tri-n-butylphosphine (0.75 mL) and THF (10 mL) was added dropwise diethyl azodicarboxylate (40% toluene solution, 1.4 mL) at room temperature, and the mixture was stirred for 2 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent gradient; 0?15% ethyl acetate/hexane) to give the title compound (239 mg, 65%) as a colorless oil.1H-NMR(CDCl3): delta1.33 (3H, d, J=6.4 Hz), 1.45 (9H, s), 3.35-3.42 (2H, m), 3.88 (3H, s), 4.67-4.79 (1H, m), 5.51-5.62 (1H, m), 7.41 (1H, s). ESI-MS: m/z 296(M-Boc+H)+. |
Tags: 95201-93-7 synthesis path| 95201-93-7 SDS| 95201-93-7 COA| 95201-93-7 purity| 95201-93-7 application| 95201-93-7 NMR| 95201-93-7 COA| 95201-93-7 structure
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