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Chemical Structure| 3141-26-2
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Product Details of [ 3141-26-2 ]

CAS No. :3141-26-2 MDL No. :MFCD00005465
Formula : C4H2Br2S Boiling Point : -
Linear Structure Formula :- InChI Key :VGKLVWTVCUDISO-UHFFFAOYSA-N
M.W : 241.93 Pubchem ID :18452
Synonyms :

Calculated chemistry of [ 3141-26-2 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 7
Num. arom. heavy atoms : 5
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 0.0
Num. H-bond donors : 0.0
Molar Refractivity : 39.72
TPSA : 28.24 Ų

Pharmacokinetics

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) : -5.66 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.28
Log Po/w (XLOGP3) : 2.98
Log Po/w (WLOGP) : 3.27
Log Po/w (MLOGP) : 2.8
Log Po/w (SILICOS-IT) : 4.02
Consensus Log Po/w : 3.07

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.75
Solubility : 0.0434 mg/ml ; 0.000179 mol/l
Class : Soluble
Log S (Ali) : -3.24
Solubility : 0.14 mg/ml ; 0.00058 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.38
Solubility : 0.102 mg/ml ; 0.00042 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.6

Safety of [ 3141-26-2 ]

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:

Application In Synthesis of [ 3141-26-2 ]

* 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.

  • Upstream synthesis route of [ 3141-26-2 ]
  • Downstream synthetic route of [ 3141-26-2 ]

[ 3141-26-2 ] Synthesis Path-Upstream   1~42

  • 1
  • [ 3141-27-3 ]
  • [ 188290-36-0 ]
  • [ 1003-09-4 ]
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  • [ 3141-26-2 ]
Reference: [1] Journal of Organic Chemistry, 1996, vol. 61, # 23, p. 8074 - 8078
  • 2
  • [ 3141-26-2 ]
  • [ 30318-99-1 ]
Reference: [1] Patent: US4398939, 1983, A,
  • 3
  • [ 3141-26-2 ]
  • [ 632-15-5 ]
  • [ 30318-99-1 ]
Reference: [1] Journal of Organic Chemistry, 1997, vol. 62, # 25, p. 8681 - 8686
  • 4
  • [ 3958-03-0 ]
  • [ 3141-26-2 ]
YieldReaction ConditionsOperation in experiment
77%
Stage #1: With n-butyllithium In diethyl ether; hexane at 0℃; for 1.66667 - 1.83333 h; Argon atmosphere
Stage #2: at 0℃;
A stirred and cooled solution of thiophene (185 mL, 2.3 mol) at 0 °C in chloroform was treated dropwise with bromine (500 mL, 1560 g, 9.75 mol) for 5 h. During the last hour bromine was added without cooling the reaction mixture. Then the mixture was stirred and heated at reflux for 5 h, cooled to room temperature, quenched with 3 M aqueous NAOH, and stirred vigerously to consume excess bromine. The aqueous layer was separated, the organic phase was washed with water, and then with acetone (150 mL) to remove remaining water. The organic residue was dried and then dissolved at reflux in chloroform (1 L). When cooling, the target tetrabromo- thiophene was precipitated as colorless crystals (693 g, 75percent). A solution of this tetrabromo- thiophene (47 g, 0.12 mol) in dry diethyl ether (300 mL) was cooled to 0 °C and treated dropwise with butyllithium in hexane (150 ML, 0.24 mol, 1.6 M) for 80-90 min under argon. Then the mixture was stirred for an additional 20 min, and ice water (250 mL) was added carefully with stirring. The organic phase was separated, the aqueous phase extracted twice with ether, and the organic extracts all combined, dried over anhydrous calcium chloride, and concentrated in vacuo. The residue was distilled at 15 MMHG to give 22 g (77percent) of 3,4-dibromothiophene. A solution of this 3,4-dibromothiophene (72 g, 33 ML, 0.3 mol) in dry ether (120 ML) was cooled TO-78 °C, added to a solution of nBuLi (206 mL, 0.33 mol, 1.6 M) AT-78 °C, and stirred for 5 min. A cold - 78 °C solution OF DMF (35 ML, 33 g, 0.45 mol) in dry ether (120 ML) was slowly added to the reaction mixture AT-78 °C. After 10 min, the cold bath was removed and an aqueous HC1 (150 mL, 6N) solution was added carefully, the mixture warmed to 23 °C and the aqueous phase separated and washed further with ether. The organic extracts were then combined, washed with saturated aqueous sodium bicarbonate, and the organic partition evaporated. The residue was distilled twice under vacuum to provide pure title compound (40 g, 69percent).
Reference: [1] Patent: WO2004/58763, 2004, A1, . Location in patent: Page 41-42
  • 5
  • [ 3958-03-0 ]
  • [ 3141-26-2 ]
YieldReaction ConditionsOperation in experiment
77% With n-butyllithium In diethyl ether; hexane at 0℃; for 1.66667 - 1.83333 h; A stirred and cooled solution of thiophene (185 mL, 2.3 mol) at 0 °C in chloroform was treated dropwise with bromine (500 ML, 1560 g, 9.75 mol) for 5 h. During the last hour bromine was added without cooling the reaction mixture. Then the mixture was stirred and heated at reflux for 5 h, cooled to room temperature, quenched with 3 M aqueous NAOH, and stirred vigerously to consume excess bromine. The aqueous layer was separated, the organic phase was washed with water, and then with acetone (150 mL) to remove remaining water. The organic residue was dried and then dissolved at reflux in chloroform (1 L). When cooling, the target tetrabromo- thiophene was precipitated as colorless crystals (693 g, 75percent). A solution of this tetrabromo- thiophene (47 g, 0.12 mol) in dry diethyl ether (300 ML) was cooled to 0 °C and treated dropwise with butyllithium in hexane (150 ML, 0.24 mol, 1.6 M) for 80-90 min under argon. Then the mixture was stirred for an additional 20 min, and ice water (250 mL) was added carefully with stirring. The organic phase was separated, the aqueous phase extracted twice with ether, and the organic extracts all combined, dried over anhydrous calcium chloride, and concentrated in vacuo. The residue was distilled at 15 MMHG to give 22 g (77percent) of 3,4-dibromothiophene. A solution of this 3,4-dibromothiophene (72 g, 33 mL, 0.3 mol) in dry ether (120 mL) was cooled TO-78 °C, added to a solution of nBuLi (206 mL, 0.33 mol, 1.6 M) AT-78 °C, and stirred for 5 min. A cold - 78 °C solution OF DMF (35 mL, 33 g, 0.45 mol) in dry ether (120 mL) was slowly added to the reaction mixture AT-78 °C. After 10 min, the cold bath was removed and an aqueous HCI (150 mL, 6N) solution was added carefully, the mixture warmed to 23 °C and the aqueous phase separated and washed further with ether. The organic extracts were then combined, washed with saturated aqueous sodium bicarbonate, and the organic partition evaporated. The residue was distilled twice under vacuum to provide pure title compound (40 g, 69percent).
73% With acetic acid; zinc In water at 20℃; for 12 h; Step 2:
Tetrabromothiophene (20 g, 50 mmol) is added to a mixed solution of acetic acid (60 ml) and water (20 ml), to which zinc powder (19.6 g, 300 mmol) is added in portions.
The mixture is stirred at room temperature for 12 hrs.
Excess zinc powder is filleted out, and excess acetic and water are removed by rotary evaporation.
The crude is passed through a chromatographic column, to give a colorless liquid, 3,4-dibromothiophene (compound 2), yield 73percent, purity 95percent.
Reference: [1] Journal of Organic Chemistry, 2008, vol. 73, # 1, p. 323 - 326
[2] Synthesis, 1990, # 5, p. 403 - 405
[3] Synthesis, 1990, # 5, p. 403 - 405
[4] Chemistry - A European Journal, 2004, vol. 10, # 13, p. 3331 - 3340
[5] Tetrahedron Letters, 2004, vol. 45, # 17, p. 3405 - 3407
[6] Patent: WO2004/58702, 2004, A2, . Location in patent: Page 32; 24
[7] Canadian Journal of Chemistry, 1985, vol. 63, p. 2669 - 2672
[8] Patent: US2016/264595, 2016, A1, . Location in patent: Paragraph 0058; 0060
[9] Journal of the American Chemical Society, 2007, vol. 129, # 26, p. 8310 - 8319
[10] Journal of Materials Chemistry, 1999, vol. 9, # 8, p. 1719 - 1725
[11] Journal of Materials Chemistry, 2012, vol. 22, # 1, p. 100 - 108
[12] Journal of Molecular Structure, 2000, vol. 521, # 1-3, p. 285 - 301
[13] Journal of Organic Chemistry, 1997, vol. 62, # 7, p. 1940 - 1954
[14] Electrochimica Acta, 2010, vol. 56, # 1, p. 326 - 332
[15] Acta Chemica Scandinavica (1947-1973), 1959, vol. 13, p. 1045
[16] Arkiv foer Kemi, 1957, vol. 11, p. 317,322
[17] Justus Liebigs Annalen der Chemie, 1934, vol. 512, p. 136,156
[18] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1993, vol. 29, # 8, p. 889 - 891[19] Khimiya Geterotsiklicheskikh Soedinenii, 1993, # 8, p. 1046 - 1048
[20] Chemistry Letters, 2003, vol. 32, # 8, p. 744 - 745
[21] Journal of Materials Chemistry, 2012, vol. 22, # 11, p. 4944 - 4952
[22] Organic Letters, 2012, vol. 14, # 19, p. 5058 - 5061
[23] Journal of Polymer Science, Part A: Polymer Chemistry, 2017, vol. 55, # 16, p. 2629 - 2638
  • 6
  • [ 188290-36-0 ]
  • [ 872-31-1 ]
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Reference: [1] Organic Letters, 2004, vol. 6, # 19, p. 3381 - 3384
  • 7
  • [ 1003-09-4 ]
  • [ 872-31-1 ]
  • [ 3141-26-2 ]
Reference: [1] Synthetic Communications, 1990, vol. 20, # 11, p. 1697 - 1700
  • 8
  • [ 1003-09-4 ]
  • [ 3141-26-2 ]
  • [ 3141-24-0 ]
  • [ 3141-25-1 ]
  • [ 3958-03-0 ]
Reference: [1] Synthetic Communications, 1990, vol. 20, # 14, p. 2119 - 2122
  • 9
  • [ 3141-25-1 ]
  • [ 3141-26-2 ]
Reference: [1] Canadian Journal of Chemistry, 1985, vol. 63, p. 2669 - 2672
[2] Justus Liebigs Annalen der Chemie, 1934, vol. 512, p. 136,156
  • 10
  • [ 188290-36-0 ]
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Reference: [1] Journal of the American Chemical Society, 1998, vol. 120, # 22, p. 5355 - 5360
  • 11
  • [ 39129-54-9 ]
  • [ 3141-26-2 ]
  • [ 70061-39-1 ]
  • [ 508170-24-9 ]
  • [ 301677-76-9 ]
Reference: [1] Russian Journal of Physical Chemistry A, 2009, vol. 83, # 11, p. 1873 - 1878
[2] Russian Journal of Physical Chemistry A, 2009, vol. 83, # 13, p. 2371 - 2375
  • 12
  • [ 3141-25-1 ]
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Reference: [1] Canadian Journal of Chemistry, 1985, vol. 63, p. 2669 - 2672
  • 13
  • [ 3958-03-0 ]
  • [ 3141-26-2 ]
  • [ 3141-25-1 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1934, vol. 512, p. 136,156
[2] Arkiv foer Kemi, 1957, vol. 11, p. 317,322
  • 14
  • [ 3141-27-3 ]
  • [ 188290-36-0 ]
  • [ 1003-09-4 ]
  • [ 872-31-1 ]
  • [ 3141-26-2 ]
Reference: [1] Journal of Organic Chemistry, 1996, vol. 61, # 23, p. 8074 - 8078
  • 15
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  • [ 124-41-4 ]
  • [ 51792-34-8 ]
YieldReaction ConditionsOperation in experiment
81.5% With copper(I) bromide In methanol at 70 - 97℃; Inert atmosphere 21 g of sodium methoxide and 72 g of methanol were added to a 100 ml four-necked flask (the concentration of sodium methoxide relative to the methanol solvent was 22.6percent by weight based on the total amount of sodium methoxide before the reaction) and dissolved at 70 under an argon atmosphere.After addition of 0.83 g of cuprous bromide, 15 g of 3,4-dibromothiophene was added dropwise, and the reaction solution became colorless transparent to black. After completion of the dropwise addition, 50 g of methanol was distilled off (sodium methoxide to methanol solvent The concentration was 48.8 wtpercent based on the total amount of sodium methoxide before the reaction)The reaction was heated to reflux at 97 .When the reaction was traced by gas chromatography, 3,4-dibromothiophene and 3-bromo-4-methoxythiophene were found to be below the detection limit at the reflux starting time of 5 hours.After water was added to the reaction mixture and the mixture was filtered, the crude product was extracted from toluene, and the toluene layer was washed with water, and then the toluene layer was dried with magnesium sulfate.After the magnesium sulfate was removed by filtration, the toluene layer was concentrated by a rotary evaporator and then subjected to vacuum distillation to obtain 7.28 g (yield: 81.5percent) of 3,4-dimethoxythiophene. The purity of its 3,4-dimethoxythiophene was 98.01percent by gas chromatography.The purity (concentration) by gas chromatography in the present invention was indicated by the area ratio of the peak area obtained by the detection device by FID using Agilent 6890N network GC manufactured by Aglient Technologies.
60% With copper(l) iodide In methanol at 80℃; for 72 h; Step 3:
3,4-dibromothiophene (10 g, 41.2 mmol) is added to 30 g of a methanol-sodium methoxide solution with a mass percent of 30percent and stirred.
Then CuI (1.96 g, 10.3 mmol) is added quickly, and refluxed at 80° C. for 72 hrs.
The mixture is cooled to room temperature, to which a saturated NaCl solution is added.
The mixture is extracted with ethyl acetate several times, and dried over anhydrous sodium sulfate to remove solvents.
The crude is passed through a separation column, to give a oily liquid, 3,4-dimethoxythiophene (compound 3), yield 60percent, purity 95percent.
Reference: [1] Chinese Chemical Letters, 2014, vol. 25, # 4, p. 517 - 522
[2] Journal of Polymer Science, Part A: Polymer Chemistry, 2014, vol. 52, # 14, p. 1989 - 1999
[3] Patent: KR101558628, 2015, B1, . Location in patent: Paragraph 0184-0190
[4] Tetrahedron, 1992, vol. 48, # 17, p. 3633 - 3652
[5] Langmuir, 2014, vol. 30, # 51, p. 15581 - 15589
[6] Patent: US2016/264595, 2016, A1, . Location in patent: Paragraph 0058; 0061
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YieldReaction ConditionsOperation in experiment
88%
Stage #1: at 0℃;
Stage #2: With potassium iodide; copper(II) oxide In methanol for 72 h; Heating / reflux
EXAMPLE 1: Synthesis of Chloromethyl-3,4-ethylenedioxythiophene for conversion to EDOT-MEOH:; 1) 3,4-dimethoxythiophene synthesis from 3,4-dibromothiophene for the improved EDOT-MeOH synthesis:; [0084] Sodium methoxide was prepared by slow addition of small cubes of sodium metal (25 g, 1.05 mol) to ice bath cooled anhydrous methanol (600 mL) in a 1 L 3-necked flask equipped with a reflux condenser under a nitrogen blanket. Between additions of the sodium it was covered in kerosene to exclude moisture. After complete dissolution of the sodium, 50 g (0.207 mol) of 3,4- dibromothiophene, 16.5 g (0.207 mol) copper (II) oxide, and 1.37 g (0.00827 mol) potassium iodide was added to the reaction mixture. The reaction was refluxed for three days. The reaction was then cooled to room temperature and filtered through a sintered glass fritted funnel. The resulting solid was rinsed with ether and the filtrate was poured into 500 mL water. The solution was then extracted with ether. The organic fractions were combined and dried with magnesium sulfate. Solvent removal gave a light yellow oil. Vacuum distillation gave 26.2 g of a clear, colorless oil whose structure and purity were confirmed by ^H and ^C NMR and GC-MS. Yield was 88percent of theoretical.
Reference: [1] Patent: WO2006/73968, 2006, A2, . Location in patent: Page/Page column 24
  • 17
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  • [ 67-56-1 ]
  • [ 51792-34-8 ]
Reference: [1] Synthetic Communications, 1998, vol. 28, # 12, p. 2237 - 2244
[2] Journal of Molecular Structure, 2000, vol. 521, # 1-3, p. 285 - 301
[3] Electrochimica Acta, 2010, vol. 56, # 1, p. 326 - 332
[4] Journal of Organic Chemistry, 2008, vol. 73, # 1, p. 323 - 326
[5] Journal of Materials Chemistry, 2012, vol. 22, # 1, p. 100 - 108
[6] Journal of Materials Chemistry, 2012, vol. 22, # 11, p. 4944 - 4952
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  • [ 51792-34-8 ]
  • [ 110545-69-2 ]
YieldReaction ConditionsOperation in experiment
23.2% With potassium iodide; copper(II) oxide In methanol for 72 h; Reflux A mixture of 21.78 g 1 (0.09 mol), 150 cm3 methanol, 15 g sodium methylate, 3.6 g KI, and 3.6 g CuO was refluxed for 72 h. After removing methanol via vacuum distillation, the residue was dissolved in ethyl acetate. The mixture was filtered and the filtrate was washed by 100 cm3 x 3 saturated brine and dried over anhydrous sodium sulfate. Ethyl acetate was then removed and the residue was purified on silica column chromatography and 4.02 g (23.2 percent) 3-bromo-4-methoxythiophene (3) and 1.44 g (11 percent) 3,4-dimethoxythiophene (2) was obtained. 3-bromo-4-methoxythiophene: 1H NMR (CDCl3, 400 MHz) ppm: d = 7.18 (d, J = 3.5 Hz, 1H), 6.23 (d, J = 3.5 Hz, 1H), 3.86 (s, CH3O); MS (70 eV): m/z = 192.0 (M+). 3,4-dimethoxythiophene: 1H NMR (CDCl3, 400 MHz) ppm: d = 6.20 (s, 2H), 3.86 (s, 2CH3O); MS (70 eV): m/z = 144.0 (M+).
Reference: [1] Research on Chemical Intermediates, 2015, vol. 41, # 9, p. 6385 - 6391
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  • [ 67-56-1 ]
  • [ 51792-34-8 ]
  • [ 110545-69-2 ]
Reference: [1] Journal of Polymer Science, Part A: Polymer Chemistry, 2012, vol. 50, # 10, p. 1967 - 1978
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  • [ 1003-09-4 ]
  • [ 3141-26-2 ]
  • [ 3141-24-0 ]
  • [ 3141-25-1 ]
  • [ 3958-03-0 ]
Reference: [1] Synthetic Communications, 1990, vol. 20, # 14, p. 2119 - 2122
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  • [ 16694-17-0 ]
YieldReaction ConditionsOperation in experiment
68%
Stage #1: With n-butyllithium In diethyl ether at -78℃; for 0.333333 h;
Stage #2: at -78℃; for 1 h;
Ether (100 ml) was cooled to -78 °C under nitrogen. A 1.6 M solution ofn-butyllithium (28.4 ml) was added. A solution of3,4-dibromothiophene (10 g, 41 .3 mmol) in 50 ml ether was added over 10 min. The solutionwas stirred at -78 °C for 1 0 min, the excess (>50 g) freshly powdered CQ was added. Afterstirring at -78 °C for 1 h, 1 M NaOH (30 ml) diluted with 100 ml water was added (note: CQ>evolution). The solution was allowed to warm until the ice melts. The phases were separated,and the ether phase was extracted with 25 ml 1 N NaOH. The aq, phases were pooled andacidified with 1 N HCI (1 00 ml). The precipitate was filtered off and washed with water, anddried in a vacuum oven to yield white solid (5.8 g, 68percent yield).
56%
Stage #1: With iodine; magnesium; isopropyl bromide In tetrahydrofuran at 0℃; for 2 h; Inert atmosphere
Stage #2: at -30 - 20℃;
1.1
4-Bromothiophene-3-carboxylic acid
To a mixture of Mg (1.4 g, 60 mmol) and I2(0.1 g) in anhydrous THF (2 mL) was added dropwise a solution of 2-bromo-propane (7.4 g, 60 mmol) in anhydrous THF (60 mL) at room temperature under nitrogen during a period of 30 min.
After the addition, the mixture was refluxed until the most of magnesium was consumed.
The resulting Grignard reagent was added dropwise to a solution of 3,4-dibromo-thiophene (12.1 g, 50 mmol) in anhydrous THF (60 mL) at 0° C. under nitrogen within about 30 min.
The mixture was allowed to stir at 0° C. for 1.5 h.
Excessive CO2 was purged into the mixture at -30° C. and the reaction mixture was stirred until the temperature rose to room temperature.
Then the reaction was quenched with water (30 mL) and basified with 8percent aq. NaOH solution to pH 11 and was washed with ethyl acetate (3*60 mL).
The aqueous layer was acidified with 5percent aq. HCl to pH 1-2, the precipitate was filtered and was dried to give the title compound as off-white solid (5.8 g, yield 56percent).
LC-MS (ESI+): m/e 209 (M+H)+, Rt: 0.69 min.
50%
Stage #1: With iodine; magnesium; isopropyl bromide In tetrahydrofuran at 0℃; for 2 h; Inert atmosphere
Stage #2: at -30 - 20℃;
1.1.1 4-Bromothiophene-3-carboxylic acid To a mixture of Mg (1.4 g, 60 mmol) and I2 (0.1 g) in anhydrous THF (2 mL) was added dropwise a solution of 2-bromo-propane (7.4 g, 60 mmol) in anhydrous THF (60 mL) at room temperature under nitrogen during a period of 30 min. After the addition, the mixture was refluxed until the most of magnesium was consumed. The resulting Grignard reagent was added dropwise to a solution of 3,4-dibromo-thiophene (12.1 g, 50 mmol) in anhydrous THF (60 mL) at 0°C under nitrogen within about 30 min. The mixture was allowed to stir at 0°C for 1.5 h. Then an excess C02 was purged into the mixture at -30°C and the reaction mixture was stirred until the temperature rose to room temperature. The reaction was quenched with water (30 mL) and basified with 8percent aq. NaOH solution to pH 11 and was washed with ethyl acetate (3><60 mL). The aqueous layer was acidified with 5percent aq. HC1 to pH 1-2, the precipitate was filtered and was dried to give the desired compound as off-white solid (5.2 g, 50percent yield). LC-MS (Method A): m/z 209 (M+H)+, Rt: 0.69 min.
Reference: [1] Pharmazie, 2006, vol. 61, # 11, p. 901 - 907
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1994, # 19, p. 2735 - 2744
[3] Patent: WO2006/3096, 2006, A1, . Location in patent: Page/Page column 71-72
[4] Patent: US2013/116233, 2013, A1, . Location in patent: Paragraph 1018; 1019
[5] Patent: WO2014/140086, 2014, A1, . Location in patent: Page/Page column 68-69
[6] Macromolecules, 2011, vol. 44, # 23, p. 9146 - 9154
[7] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1993, # 9, p. 1589 - 1596
[8] Archiv der Pharmazie, 1998, vol. 331, # 12, p. 405 - 411
[9] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 2, p. 297 - 308
[10] Journal of Heterocyclic Chemistry, 1999, vol. 36, # 3, p. 761 - 765
[11] Patent: WO2017/27310, 2017, A1, . Location in patent: Page/Page column 94
[12] Patent: WO2017/27309, 2017, A1, . Location in patent: Page/Page column 109
[13] Patent: WO2017/27312, 2017, A1, . Location in patent: Page/Page column 105
  • 22
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YieldReaction ConditionsOperation in experiment
70.3% With tert.-butyl lithium In pentane a)
To a solution of 3,4-dibromothiophene (15 g, 62 mmol) in 80 mL ether under a positive nitrogen atmosphere was added dropwise 75 mL 1.7M t-BuLi in pentane at below -73° C. and the resulting reaction solution was stirred at -78° C. for 0.5 h.
After that, the ether solution was poured into dry ice and extracted with water.
The aq solution was washed with ether and then acidified with concentrated HCl.
The solid was filtered and air-dried to give 9 g of 4-bromo-3-thiophenecarboxylic acid, yield 70.3percent.
Reference: [1] Patent: US5498630, 1996, A,
[2] Arkiv foer Kemi, 1957, vol. 11, p. 317,322
[3] Justus Liebigs Annalen der Chemie, 1934, vol. 512, p. 136,156
[4] Arkiv foer Kemi, 1957, vol. 11, p. 317,322
[5] Patent: US4737184, 1988, A,
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Reference: [1] Macromolecules, 2011, vol. 44, # 23, p. 9146 - 9154
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  • [ 109-72-8 ]
  • [ 60-29-7 ]
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Reference: [1] Arkiv foer Kemi, 1957, vol. 11, p. 317,322
[2] Arkiv foer Kemi, 1957, vol. 11, p. 317,322
  • 25
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  • [ 7342-82-7 ]
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Reference: [1] Asian Journal of Chemistry, 2015, vol. 27, # 4, p. 1547 - 1548
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Reference: [1] Macromolecules, 2011, vol. 44, # 23, p. 9146 - 9154
  • 28
  • [ 3141-26-2 ]
  • [ 68-12-2 ]
  • [ 18791-78-1 ]
YieldReaction ConditionsOperation in experiment
69%
Stage #1: With n-butyllithium In diethyl ether at -78℃; for 0.0833333 h;
Stage #2: at -78℃; for 0.166667 h;
A stirred and cooled solution of thiophene (185 mL, 2.3 mol) at 0 °C in chloroform was treated dropwise with bromine (500 ML, 1560 g, 9.75 mol) for 5 h. During the last hour bromine was added without cooling the reaction mixture. Then the mixture was stirred and heated at reflux for 5 h, cooled to room temperature, quenched with 3 M aqueous NAOH, and stirred vigerously to consume excess bromine. The aqueous layer was separated, the organic phase was washed with water, and then with acetone (150 mL) to remove remaining water. The organic residue was dried and then dissolved at reflux in chloroform (1 L). When cooling, the target tetrabromo- thiophene was precipitated as colorless crystals (693 g, 75percent). A solution of this tetrabromo- thiophene (47 g, 0.12 mol) in dry diethyl ether (300 ML) was cooled to 0 °C and treated dropwise with butyllithium in hexane (150 ML, 0.24 mol, 1.6 M) for 80-90 min under argon. Then the mixture was stirred for an additional 20 min, and ice water (250 mL) was added carefully with stirring. The organic phase was separated, the aqueous phase extracted twice with ether, and the organic extracts all combined, dried over anhydrous calcium chloride, and concentrated in vacuo. The residue was distilled at 15 MMHG to give 22 g (77percent) of 3,4-dibromothiophene. A solution of this 3,4-dibromothiophene (72 g, 33 mL, 0.3 mol) in dry ether (120 mL) was cooled TO-78 °C, added to a solution of nBuLi (206 mL, 0.33 mol, 1.6 M) AT-78 °C, and stirred for 5 min. A cold - 78 °C solution OF DMF (35 mL, 33 g, 0.45 mol) in dry ether (120 mL) was slowly added to the reaction mixture AT-78 °C. After 10 min, the cold bath was removed and an aqueous HCI (150 mL, 6N) solution was added carefully, the mixture warmed to 23 °C and the aqueous phase separated and washed further with ether. The organic extracts were then combined, washed with saturated aqueous sodium bicarbonate, and the organic partition evaporated. The residue was distilled twice under vacuum to provide pure title compound (40 g, 69percent).
Reference: [1] Organic and Biomolecular Chemistry, 2011, vol. 9, # 23, p. 8016 - 8029
[2] RSC Advances, 2015, vol. 5, # 77, p. 62336 - 62342
[3] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 6, p. 3682 - 3688
[4] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1994, # 19, p. 2735 - 2744
[5] Chemistry - A European Journal, 2016, vol. 22, # 2, p. 694 - 703
[6] Patent: WO2004/58702, 2004, A2, . Location in patent: Page 32; 24
[7] Patent: US6340759, 2002, B1, . Location in patent: Example 278
[8] Journal of Photochemistry and Photobiology A: Chemistry, 2010, vol. 212, # 2-3, p. 81 - 87
[9] Journal of the American Chemical Society, 2017, vol. 139, # 24, p. 8194 - 8199
[10] Bulletin de la Societe Chimique de France, 1967, p. 4115 - 4120
[11] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 15, p. 2011 - 2014
[12] Patent: WO2016/144848, 2016, A1, . Location in patent: Page/Page column 43; 44
[13] Patent: WO2016/144846, 2016, A1, . Location in patent: Page/Page column 65
[14] Patent: WO2016/144849, 2016, A1, . Location in patent: Page/Page column 38
[15] Patent: WO2016/144847, 2016, A1, . Location in patent: Page/Page column 42
  • 29
  • [ 3141-26-2 ]
  • [ 18791-78-1 ]
YieldReaction ConditionsOperation in experiment
74% With n-butyllithium In diethyl ether; water; ethyl acetate; N,N-dimethyl-formamide Production Example 102
4-Bromothiophene-3-carboxaldehyde
After dissolving 25.2 g of 3,4-dibromothiophene in 300 ml of diethyl ether, the solution was cooled to -78° C. Next, 44.1 ml of n-butyllithium (2.6 M, n-hexane solution) was added dropwise while stirring at below -60° C.
After 1 hour, 9.66 ml of N,N-dimethylformamide was added dropwqise at below -60° C.
After an additional 45 minutes, water was added to the reaction solution, the temperature was returned to room temperature, and extraction was performed with ethyl acetate.
The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (14.78 g, 74percent yield).
1H-NMR (400 MHz, CDCl3); δ (ppm) 7.36 (1H, d, J=3.6 Hz), 8.15 (1H, d J=3.6 Hz), 9.34 (1H, s).
29% With n-butyllithium In tetrahydrofuran; N,N-dimethyl-formamide EXAMPLE 74
Preparation of N-hydroxy-N-[(4-bromo-thien-3-yl)methyl]urea
To a -78° C. stirred solution of 3,4-dibromothiophene (10 g, 41.33 mmole) in THF (25 mL) was added n-BuLi (45.5 mmole, 2.5M in hexanes).
The reaction was stirred 5 min. and cannulated into a cold (-78° C.) stirred solution of DMF (4.35 g, 62 mmole) in THF (20 mL).
The reaction was allowed to stir overnight at room temperature, poured into dilute HCl and extracted with ethyl acetate.
The combined organic layers were washed with water, dried (MgSO4) and concentrated to give a brown oil.
Distillation yielded 2.31 g (29percent) of 4-bromothien-3-yl carboxaldehyde as a liquid (bp: 65°, 0.5 mm Hg).
Reference: [1] Patent: US2004/167224, 2004, A1,
[2] Patent: US5185363, 1993, A,
[3] Patent: US4332952, 1982, A,
  • 30
  • [ 3141-26-2 ]
  • [ 79-22-1 ]
  • [ 78071-37-1 ]
Reference: [1] Patent: US2011/230495, 2011, A1, . Location in patent: Page/Page column 35-36
[2] Advanced Synthesis and Catalysis, 2016, vol. 358, # 24, p. 4129 - 4135
  • 31
  • [ 3141-26-2 ]
  • [ 79-22-1 ]
  • [ 78071-37-1 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 2, p. 297 - 308
  • 32
  • [ 3141-26-2 ]
  • [ 18853-32-2 ]
YieldReaction ConditionsOperation in experiment
72%
Stage #1: for 4 h; Reflux
Stage #2: With hydrogenchloride; iron(III) chloride In N,N-dimethyl-formamide at 70℃; for 0.75 h;
Stage #3: With sodium hydrogencarbonate In water; N,N-dimethyl-formamide
[0156] Detailed synthesis of 3, 4-dicyanothiophene .[0157] A mixture of 3, 4-dibromothiophene (2.00 g, 8.3 mmol) and copper (I) cyanide (CuCN) (2.24 g, 25 mmol) in dry DMF (5 mL) was stirred under reflux for 4 hours. After cooling, the dark solution thereby formed was added to a solution of FeC13 (8.50 g) in HCl 2M (15 mL) and maintained at 700C for 45 minutes. After cooling at room temperature, this mixture was extracted three times with CH2Cl2. The organic layers were combined and washed successively with HCl 6M (2 times) , water, saturated NaHCO3 solution and again water. The organic layer was dried over magnesium sulfate and then evapored to dryness. The crude solid produced was then purified by chromatography on silica gel (CH2Cl2) or sublimated (3.10-3 mbar, 1400C) to afford 800 mg of a white solid (72percent yield) .1H-NMR (CDCl3): 8.07 (s, 2H).13C-NMR (CDC13) : 137.0, 113.0, 111.7.
Reference: [1] Tetrahedron, 2010, vol. 66, # 49, p. 9560 - 9572
[2] Patent: WO2011/20712, 2011, A2, . Location in patent: Page/Page column 57
[3] Journal of the American Chemical Society, 2012, vol. 134, # 46, p. 19035 - 19042
[4] European Journal of Inorganic Chemistry, 2011, # 6, p. 888 - 894
[5] Dalton Transactions, 2016, vol. 45, # 36, p. 14071 - 14079
[6] Patent: EP2093228, 2009, A1, . Location in patent: Page/Page column 11
[7] Patent: EP2431371, 2012, A1, . Location in patent: Page/Page column 25
[8] Patent: EP1964842, 2008, A1, . Location in patent: Page/Page column 26
  • 33
  • [ 3141-26-2 ]
  • [ 544-92-3 ]
  • [ 18853-32-2 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1993, # 9, p. 1589 - 1596
[2] Journal of the American Chemical Society, 1998, vol. 120, # 22, p. 5355 - 5360
[3] Organic Letters, 2004, vol. 6, # 19, p. 3381 - 3384
[4] Patent: WO2008/127029, 2008, A1, . Location in patent: Page/Page column 18
[5] Phosphorus and Sulfur and the Related Elements, 1983, vol. 14, p. 211 - 224
[6] Journal of the American Chemical Society, 2002, vol. 124, # 43, p. 12742 - 12751
[7] Patent: EP2083011, 2009, A1, . Location in patent: Page/Page column 10
[8] Patent: US2008/176900, 2008, A1, . Location in patent: Page/Page column 12
  • 34
  • [ 3141-26-2 ]
  • [ 18853-32-2 ]
Reference: [1] Patent: US2003/45540, 2003, A1,
[2] Patent: US2003/105089, 2003, A1,
  • 35
  • [ 3141-26-2 ]
  • [ 557-21-1 ]
  • [ 18895-10-8 ]
  • [ 18853-32-2 ]
Reference: [1] Synthesis, 2004, # 1, p. 23 - 25
  • 36
  • [ 3141-26-2 ]
  • [ 73882-41-4 ]
YieldReaction ConditionsOperation in experiment
78%
Stage #1: With n-butyllithium In diethyl ether at -78℃; for 1 h; Inert atmosphere
Stage #2: With iodine In diethyl ether at -78 - 25℃; for 1 h;
1) Prepared according to the flow chart in Figure 1 1)3,4-dibromothiophene (24.2 g, 100 mmol) was dissolved in anhydrous diethyl ether,N2 protection,Cooling to -78 ,N-BuLi (66 ml, 105 mmol, 1.6 M) was slowly added dropwise,After reaction for 1 h at -78 & lt; 0 & gt; C, I2 (26.67 g, 105 mmol)Continue stirring for 1 h and warm to room temperature (25 ° C).The reaction solution was quenched with NaHSO3, extracted with ether, dried over Mg2SO4, dried and distilled under reduced pressure to give 3-bromo-4-iodothiophene (22.55 g, 78percent)Color liquid 2.
Reference: [1] Patent: CN106317070, 2017, A, . Location in patent: Paragraph 0104; 0105; 0106
[2] Journal of Heterocyclic Chemistry, 1980, vol. 17, # 1, p. 171 - 174
[3] Journal of Organic Chemistry, 1982, vol. 47, # 16, p. 3177 - 3180
  • 37
  • [ 3141-26-2 ]
  • [ 111-83-1 ]
  • [ 65016-62-8 ]
  • [ 161746-06-1 ]
Reference: [1] Chemistry - A European Journal, 2008, vol. 14, # 34, p. 10735 - 10744
  • 38
  • [ 3141-26-2 ]
  • [ 2050-77-3 ]
  • [ 65016-55-9 ]
Reference: [1] European Journal of Organic Chemistry, 2015, vol. 2015, # 24, p. 5448 - 5452
  • 39
  • [ 3141-26-2 ]
  • [ 107-21-1 ]
  • [ 126213-50-1 ]
YieldReaction ConditionsOperation in experiment
15% With potassium phosphate; copper(l) iodide; 8-quinolinol In N,N-dimethyl-formamide at 120℃; for 24 h; To 30cc reaction tube that has been replaced with nitrogen, 3,4-dibromothiophene 0.48g (2.0mmol), ethylene glycol 0.14g (2.2mmol), 19mg copper iodide (0.10mmol), 8-hydroxyquinoline 58mg (0.20mmol), potassium phosphate anhydride 1.7g (8.0mmol), N,N-dimethylformamide 9.6 g, was reacted for 24 hours at 120 °C. The reaction mixture was allowed to cool, after dissolving the residual base is added to water and diluted with toluene. Subsequently, subjected to filtration to give a brown transparent organic layer. Analysis of the present organic layer by gas chromatography quantitative analysis cyclododecane as an internal standard, 3,4-ethylenedioxythiophene (EDOT) is 15percent yield of (3,4-dibromo-thiophene basis) generated by the percentage, of the intermediate 3-bromo-4-(1-hydroxy-alkyloxy)thiophene is at the same time, was produced at a rate of 43percent yield (3,4 dibromothiophene criteria).
Reference: [1] Patent: JP5663871, 2015, B2, . Location in patent: Paragraph 0049; 0052
  • 40
  • [ 3141-26-2 ]
  • [ 544-92-3 ]
  • [ 190723-12-7 ]
Reference: [1] Journal of the American Chemical Society, 1997, vol. 119, # 21, p. 5065 - 5066
  • 41
  • [ 3141-26-2 ]
  • [ 111-86-4 ]
  • [ 201230-82-2 ]
  • [ 773881-43-9 ]
Reference: [1] European Journal of Organic Chemistry, 2015, vol. 2015, # 16, p. 3430 - 3434
  • 42
  • [ 3141-26-2 ]
  • [ 111-86-4 ]
  • [ 201230-82-2 ]
  • [ 773881-43-9 ]
Reference: [1] European Journal of Organic Chemistry, 2015, vol. 2015, # 16, p. 3430 - 3434
[2] European Journal of Organic Chemistry, 2015, vol. 2015, # 16, p. 3430 - 3434
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