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CAS No. : | 88-13-1 | MDL No. : | MFCD00005467 |
Formula : | C5H4O2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 128.15 | Pubchem ID : | - |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 31.28 |
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) : | -6.02 cm/s |
Log Po/w (iLOGP) : | 1.18 |
Log Po/w (XLOGP3) : | 1.5 |
Log Po/w (WLOGP) : | 1.45 |
Log Po/w (MLOGP) : | 0.52 |
Log Po/w (SILICOS-IT) : | 1.94 |
Consensus Log Po/w : | 1.32 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.98 |
Solubility : | 1.35 mg/ml ; 0.0106 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.48 |
Solubility : | 0.42 mg/ml ; 0.00328 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.0 |
Solubility : | 12.8 mg/ml ; 0.0998 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.94 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | 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 |
---|---|---|
81% | for 24 h; Heating / reflux | To a solution of 3-thiophene carboxylic acid (2.Og, 15.60mmol) in methanol (30ml) was added a catalytic amount of sulphuric acid (0.5ml) and the reaction mixture was heated to reflux for 2 hr. The solvent was removed under reduced pressure and the residue was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with water, concentrated and dried to give 3-thiophene carboxylic acid methyl ester (1.8g, 81percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran for 1 h; Stage #2: for 1 h; |
Compound 9 was synthesized as reported previously [24]. To a solution of diisopropylamine (233g, 2.30mol) in THF (2.3L), a solution of n-BuLi (1.6M in n-hexane, 1.50L, 2.40mol) was added dropwise at 0°C. After stirring at the same temperature for 40min, the reaction mixture was cooled to−60°C, compound 8 (223g, 1.74mol) in THF (500mL) added dropwise, and stirred at the same temperature for 1h. After the addition of MeI (254g, 1.79mol), the reaction mixture was allowed to warm to room temperature and stirred for 1h. Next, the mixture was concentrated under reduced pressure, acidified with 6N aqueous HCl (to pH 1), and extracted with AcOEt. The organic layer was washed with brine and dried over Na2SO4. After filtration, the solvent was concentrated under reduced pressure and the residue was crystallized with H2O/AcOH to give 209g (85percent) of 9 as a pale-yellow solid: 1H NMR (400MHz, CDCl3) δ 7.45 (d, J=5.4Hz, 1H), 7.01 (d, J=5.4Hz, 1H), 2.78 (s, 3H); MS (ESI) m/z: 143 (M+H)+, 141 (M−H)−. |
82.1% | Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere Stage #2: at -78 - 20℃; for 2 h; |
1 (15.00 g, 0.12 mol) was dissolved in THF (50ml). Under argon protection, n-butyl lithium (2.0 M THF solution, 120 ml) wasadded dropwise at -78 °C. The reaction mixture was stirred for 1 h at -78 °C.To this mixture was added CH3I (8.7 ml, 0.14 mol), then the reactionmixture was allowed to warm to room temperature and stirred for 2 hours. Slowlyquenched the reaction with hydrogen chloride (2.0 M ethyl acetate solution), thenstirred the mixture at room temperature for 30 min before concentrating in vacuo. The residue was diluted with H2O(100 ml) and extracted with ethyl acetate (200 ml). The combined organic layerswere washed with H2O (50 ml ×2) and brine (50 ml ×2), dried overanhydrous Na2SO4, and filtrated, then the solvent wasevaporated under reduced pressure to give a yellow crude solid, which waspurified by recrystallization from acetic acid/H2O to afford 2 (14.00 g, 82.1percent ) as a white solid:mp 108-110 °C. 1H NMR (400 MHz, CDCl3)δ 7.45 (d, J = 5.5 Hz, 1H), 7.01 (d, J = 5.5, 1H), 2.73 (s, 3H). MS (EI) m/z: 142 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | at 0 - 20℃; for 48 h; | 13 ml (200 mmol) of thionyl chloride are added dropwise, at 0oC, to a solution of 9 g (70 mmol) of 3-thiophenecarboxylic acid and 86 mg (0.7 mmol) of 4-dimethylaminopyridine in 100 ml of ethanol. The reaction medium is stirred from 0oC to room temperature over 48 hours and then evaporated to dryness. The residue obtained is purified by chromatography on a column of silica eluted with a 1/1 heptane/dichloro- methane mixture. 10 g (91percent) of ethyl thiophene-3- carboxylate are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With bromine In acetic acid | (d) 5-bromo-3-thiophenecarboxylic acid A solution containing 16 g of Br2 (0.1 mol) in glacial acetic acid (200 ml) is added slowly to a solution of 3-thiophenecarboxylic acid (12.8 g; 0.1 mol) in 100 ml of glacial acetic acid. The mixture is stirred for 20' and then poured into water and ice. The white precipitate is filtered, washed and crystallized from water. Yield, 70percent. |
50% | With bromine In acetic acid at 20℃; for 0.25 h; | A. To a stirred solution of 3-thiophenecarboxylic acid (1.00 g, 7.80 mmol) in glacial acetic acid (9 mL) at ambient temperature under nitrogen atmosphere was slowly added bromine (0.39 mL, 7.53 mmol) in glacial acetic acid (6 mL). The reaction mixture was stirred for 15 minutes, then quenched with cold water (50 mL). The precipitate was filtered, washed with water and dried in vacuum oven at 50° C. to afford 5-bromo-3-thiophenecarboxylic acid as a colorless solid (0.78 g, 50percent): mp 133-135° C.; 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J=1.5 Hi, 1H), 7.51 (d, J=1.5 Hz, 1H). |
46% | With bromine In acetic acid at 0 - 20℃; | A solution of bromine (2 mL, 39.06 mmol) in glacial acetic acid (64 mL) was added slowly to a stirred solution of Int-1 (5 g, 39.06 mmol) in glacial acetic acid (37 mL) at 0° C. and stirred at room temperature for 20 minutes. The reaction mixture was then poured into ice water while stirring vigorously. The white precipitated solid was filtered, washed with water and recrystallised from hot water to afford pure Int-2 as white solid (3.68 g, 46percent). 1H NMR (200 MHz, dmso-d6): δ 7.55 (s, 1H), 8.17 (s, 1H). To a stirred solution of Int-2 (3.4 g, 16.42 mmol) in methanol (40 mL) was added H2SO4 (321 mg, 3.28 mmol) and stirred under reflux for 12 hours. Volatiles from the reaction mixture were distilled off under reduced pressure and the resulting residue was extracted with DCM (75 mL). The organic extract was washed with water (40 mL), saturated aqueous NaHCO3 solution (40 mL), brine (40 mL) and dried over Na2SO4, filtered and concentrated under vacuum to afford pure Int-3 as colorless viscous oil (3.3 g, 91percent). 1H NMR (200 MHz, dmso-d6): δ 7.98 (s, 1H), 7.44 (s, 1H), 3.87 (s, 3H). To a stirred solution of Int-3 (0.5 g, 2.26 mmol) in dioxane (25 mL) was added Int-4 (0.51 g, 2.26 mmol) followed by Pd (OAc) 2 (105 mg, 0.45 mmol), xanthpos (265 mg, 0.497 mmol) and CS2CO3 (1.18 g, 3.62 mmol). The reaction mixture was degassed under vacuum, bubbled with N2 for 10 minutes and stirred under reflux for 20 hours. The reaction mixture was concentrated under reduced pressure and was purified by column chromatography to isolate product and a very close spot together eluting with EtOAc. This mixture (140 mg) was further purified with preparative HPLC to obtain pure Int-5 as a yellow solid (80 mg, 10percent). Mass (m/z): 366.0 [M++1]. 1H NMR (200 MHz, dmso-d6): 9.50 (d, J=7 Hz, 1H), 8.51 (d, J=7 Hz, 1H), 8.56 (d, J=5.2 Hz, 1H), 7.74 (brs, 1H), 7.66 (d, J=11.8 Hz, 1H), 7.35 (d, J=7.4 Hz, 1H), 7.11 (s, 1H), 7.02 (d, J=5.6 Hz, 1H), 6.87 (t, J=6.8 Hz, 1H), 3.86 (s, 3H), 2.73 (s, 3H). To a stirred solution of Int-5 (0.7 g, 1.91 mmol) in THF: MeOH: H2O (2:1:2) (50 ml) was added LiOH (0.24 g, 5.74 mmol) at room temperature and stirred while heating at 50° C. for 16 hours. Volatiles from the reaction mixture were distilled off under reduced pressure, the reaction mixture was acidified to about pH 5-6 with 2N HCl. The precipitated solid was filtered and dried under vacuum to afford pure Int-6 (0.51 g, 76percent). Mass (m/z): 352.0 [M++1]. 1H NMR (200 MHz, dmso-d6): δ 12.45 (brs, 1H), 10.87 (s, 1H), 9.70 ((brs, 1H), 8.60 (d, J=4.68 Hz, 1H), 7.67-7.59 (m, 2H), 7.45 (t, J=8.4 Hz, 1H), 7.13 (d, J=5.2 Hz, 1H), 7.04 (s, 2H), 2.65 (s, 3H). |
26% | With bromine In acetic acid for 0.5 h; | To a solution of thiophene-3-carboxylic acid (5.00 g, 39.0 mmol) in acetic acid(140 mL), was added dropwise, a solution of bromine (6.60 g, 40.0 mmol) in acetic acid (40 mL). The reaction mixture was stirred for 30 minutes and then poured into water. The resultant solid was collected by filtration to afford the title compound as a grey solid (2.07g, 26percent). LCMS (Method B): RT = 2.9 min, M+H+ = 208. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h; Stage #2: With bromine In tetrahydrofuran; hexane at -78 - 20℃; |
An oven-dried 100 mL round bottom flask was charged with compound 1 (2.00 g, 15.6 mmol) and tetrahydrofuran (THF; 30 mL). The solution was cooled to -78.0 °C and 2.50 M n-butyllithium in hexane (12.6 mL, 31.5 mmol) was slowly added dropwise. The reaction mixture was stirred for 30 min at -78.0 °C and bromine (0.86 mL, 16.4 mmol) was added dropwise. Stirring was continued for 1 h at -78.0 °C and the mixture was heated to room temperature. After stirring the mixture overnight, a small amount of dilute 1M HCl (50.0 mL) was added to quench the reaction and the solution was then concentrated. After extracting the resultant mixture using ether and water, the organic layer was dried with Na2SO4. The compound was recrystallized twice using a H2O/ether mixture to furnish the compound as faint yellow needles (2.13 g, yield 66.0percent; 1H NMR (500 MHz, DMSO‑d6, d (ppm)): 7.63-7.62 (d,J 5.8 Hz, 1H), 7.32-7.31 (d, J 5.8 Hz, 1H)). |
50% | With carbon tetrabromide; lithium diisopropyl amide In tetrahydrofuran at -78℃; for 2 h; | The reaction temperature was -78 , the reaction time was 2h, the yield was about 50percent. In a 1 L two-necked flask, 24.5 g of 3-methylthiophene (98 g mol-1,24.5 g, 250 mmol) was added and 400 mL of chloroform / glacial acetic acid (V: V = 1: / L,Favoring the inhibition of the bis-brominated product), 44.5 g of NBS (178 g mol-1, 44.5 g, 250 mmol) were added in portions in an ice-water bath.After the addition of NBS to continue stirring for 2-3 hours, TLC monitoring. After treatment: deionized water to quench the reaction, liquid separation, the organic phase was NaOH solution, washed with water, dried, concentrated vacuum pump with fractional distillation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With N-Bromosuccinimide In N,N-dimethyl-formamide at 50℃; for 18 h; Darkness | 3-Thenoic acid (1.49 g, 11.7 mmol) and N-bromosuccinimide (NBS) (4.60 g, 25.8 mmol) were added to degassed DMF (24 mL). The flask was then wrapped with aluminum foil to shield the reaction mixture from light. The mixture was then stirred at 50 °C for 28 h. The mixture was allowed to cool to room temperature, after which it was poured into water (300 mL). The resulting precipitate was collected by filtration and washed with saturated NaCl aq., dried over anhydrous MgSO4, and then filtrated to afford 2,5-dibromo-3-thenoic acid as a white dasolid in 88percent yield. |
80.7% | at 60℃; for 24 h; | Compound 1 (2.00 g, 15.6 mmol) was dissolved in glacial acetic acid (25.0 mL) and Br2 (12.4 g, 78.0 mmol) was added to the above solution dropwise at room temperature. The mixture was heated and stirred at 60 °C for 24 h. After the reaction was completed, the mixture was poured into 200 mL of deionized water to quench the reaction. The precipitate was filtered and dissolved in ethyl acetate(EA). The solution in EA was dried with Na2SO4. After evaporation of the solvent, the crude product was purified by recrystallization from EtOH-H2O to give the product as a white powder (3.60 g, yield 80.7percent; 1H NMR (500 MHz, CDCl3; d (ppm)): 13.29 (s, 1H), 7.44(s, 1H)). |
31% | at 50℃; for 24 h; | To a solution of 3-thiophenecarboxylic acid (25.3 g) in acetic acid (200 mL) was added dropwise bromine (21.3 mL), and the mixture was stirred at 50°C for 1 day. The reaction mixture was concentrated under reduced pressure, and the residue was washed with diisopropyl ether to give the title compound (17.3 g, 31percent) as a white solid. 1H NMR(300MHz, CDCl3) δ ppm 7.40(m,1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0℃; for 2 h; Inert atmosphere Stage #2: at 0 - 20℃; for 16 h; Inert atmosphere |
A 250 mL round bottom flask charged with 3-thiophenecarboxylic acid (10.0 g, 78 mmol) was evacuated andrefilled with N2 gas for three times followed by the addition of150 mL anhydrous CH2Cl2. To this solution, anhydrous dimethylformamide(15 drops) was added and the reaction temperaturewas cooled down to 0 C. Oxalyl chloride (11.1 g, 87 mmol) wasadded to the reaction mixture and the mixturewas stirred for 2 h at0 C. The solvent was removed under reduced pressure and thereaction mixture was re-dissolved in CH2Cl2 (150 mL). To the abovesolution, diethylamine (11.4 g, 156 mmol) was added at 0 C andstirred for 16 h at room temperature. The reaction mixture waspoured into 1M aqueous HCl (200 mL) and extracted with CH2Cl2(200 mL). The organic extract was washed with saturated aqueouspotassium chloride (1 20 mL) and brine (1 20 mL) and driedover anhydrous Na2SO4. The solvent was removed under reducedpressure and crude product obtained was purified on silica gelcolumn chromatography (50percent ethyl acetate and hexane eluent) toobtain the title compound as a pale yellow oil (yield 90percent).1H NMR (500 MHz, CDCl3, d ppm): 1.20 (t, J 8.5 Hz, 6H), 3.45(bs, 4H), 7.19 (dd, J1 2.0 Hz and J2 4.5 Hz, 1H), 7.31e7.33 (m, 1H),7.46e7.48 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: for 3.5 h; Heating / reflux Stage #2: at 0℃; |
Preparation Example U-1. Thiophen-3-yl-carbamic acid tert-butyl ester Thiophene-3-carboxylic acid (2.50g, 19.5mmol), diphenylphosphoryl azide (4.62mL, 21.5mmol), triethylamine (3.26mL,23.4mmol) were dissolved in tert-butanol (50mL), and the solution was stirred for 3.5 hours under reflux. Water was added to the reaction solution at 0°C, which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane: ethyl acetate = 10: 1), and the title compound (3.33g, 16.7mmol,86percent) was obtained as a white solid. 1H-NMR Spectrum (DMSO-d6) δ (ppm):1.46 (9H, s), 6.97 (1H, d, J=5.2Hz), 7.16 (1H, s), 7.38 (1 H, m), 9.61 (1H, s). |
86% | for 3.5 h; Heating / reflux | Thiophene-3-carboxylic acid (2.50g, 19.5mmol), diphenylphosphoryl azide (4.62mL, 21.5mmol), triethylamine (3.26mL, 23.4mmol) were dissolved in tert-butanol (50mL), and the solution was stirred for 3.5 hours under reflux. Water was added to the reaction solution at 0°C, which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane : ethyl acetate = 10 : 1), and the title compound (3.33g, 16.7mmol,86percent) was obtained as a white solid. 1H-NMR Spectrum (DMSO-d6) δ(ppm) :1.46 (9H, s), 6.97 (1H, d, J=5.2Hz), 7.16 (1H, s), 7.38 (1 H, m), 9.61 (1 H, s). |
69% | for 22 h; Heating / reflux | 3-Thiophenecarboxylic acid (31 g, 0.24 mol), Diphenylphosphoryl azide (57 mL, 0.26 mol) and triethylamine (36 mL, 0.26 mol) were combined in dry tert-butanol (450 mL) and the resulting solution was heated to reflux. After 22 h the cooled solution was concentrated in vacuo to remove solvent. The residue was taken up in diethyl ether (1.5 L) and washed with 5percent aqueous citric acid, water and brine (1.5 L each), dried (Na2SO4), and concentrated in vacuo to give the crude product as a tacky tan solid (51 g). Recrystallization from hot ethyl acetate-hexane gave the title compound (33 g, 69percent, m.p. 139-41° C.) as shiny off-white needles. 1H NMR δ 1.45 (s, 9 H, (CH3)3), 6.97 (m, 1 H, ArH), 7.16 (broad s, 1 H, ArH), 7.37 (m, 1 H, ArH), 9.60 (broad s, 1 H, NH). MS (ESI) m/z 198 [M-H]- Analysis calc. for C18H13FO3S: C, 54.25; H, 6.58; N, 7.03 Found: C, 54.26; H, 6.48; N, 6.99 |
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