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Product Details of [ 18791-75-8 ]

CAS No. :18791-75-8 MDL No. :MFCD00005431
Formula : C5H3BrOS Boiling Point : -
Linear Structure Formula :- InChI Key :PDONIKHDXYHTLS-UHFFFAOYSA-N
M.W : 191.05 Pubchem ID :87792
Synonyms :

Calculated chemistry of [ 18791-75-8 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 5
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 1.0
Num. H-bond donors : 0.0
Molar Refractivity : 37.41
TPSA : 45.31 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) : -5.98 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.62
Log Po/w (XLOGP3) : 2.09
Log Po/w (WLOGP) : 2.32
Log Po/w (MLOGP) : 1.19
Log Po/w (SILICOS-IT) : 3.38
Consensus Log Po/w : 2.12

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.74
Solubility : 0.35 mg/ml ; 0.00183 mol/l
Class : Soluble
Log S (Ali) : -2.67
Solubility : 0.407 mg/ml ; 0.00213 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.47
Solubility : 0.647 mg/ml ; 0.00339 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.25

Safety of [ 18791-75-8 ]

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 [ 18791-75-8 ]

* 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 [ 18791-75-8 ]
  • Downstream synthetic route of [ 18791-75-8 ]

[ 18791-75-8 ] Synthesis Path-Upstream   1~24

  • 1
  • [ 68-12-2 ]
  • [ 18791-75-8 ]
YieldReaction ConditionsOperation in experiment
79%
Stage #1: at -40 - 10℃;
Stage #2: With citric acid In water at 10 - 25℃;
Under mechanical agitation,Add (0.42 mol, 100 g) SM and 200 mL of anhydrous THF to a three-neck bottle.Stir until completely dissolved,Replace the nitrogen twice,The solution is cooled to -50~-40 °C,Slowly add (0.71 mol, 545 mL) isopropyl magnesium chloride lithium chloride (1.3 M tetrahydrofuran solution),Control the dropping temperature not to exceed -40 ° C,After the addition is completed, the reaction is carried out at -40 ° C for 7-8 h.To the reaction solution, (0.63 mol, 45.7 g) of N,N-dimethylformamide was slowly added dropwise.Control the dropping temperature not to exceed -40 ° C,Temperature adjustment to -10 ° C,Continue to react at -10 ° C for 16-18 h.The reaction droplets were added to (812 g) of a 16percent by mass aqueous solution of citric acid.Control the dropping temperature not to exceed 10 ° C,Adjust the temperature to 15-25 ° C,Stir at 15-25 ° C for 15-30 min,Let stand layering.The organic layer was concentrated to 100 mL.Add 500mL of toluene,The toluene layer was washed once with 200 mL of water.The organic layer was concentrated to 200 mL.Heat to 50-60 ° C,Stir at 50-60 ° C for 0.5-1 h until completely dissolved.Cooling to 20 ~ 30 , stirred for 20 ~ 30 1 ~ 2h,Add 400 mL of methylcyclomethane dropwise,Continue to cool down to 5 ° C,Stir at 5 ° C for 7 h,filter,The filter cake was rinsed once with 100mL methylcyclohexyl methane,Drying gave the white solid intermediate B (63 g, >98percent EtOAc,Purity ,yield 79percent)Referring to Figure 1, see FIG. 2 NMR.
Reference: [1] Patent: CN108467384, 2018, A, . Location in patent: Paragraph 0011; 0012; 0013; 0014; 0015; 0016
  • 2
  • [ 872-31-1 ]
  • [ 68-12-2 ]
  • [ 18791-75-8 ]
  • [ 930-96-1 ]
YieldReaction ConditionsOperation in experiment
71%
Stage #1: With sodium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.5 h; Inert atmosphere
Stage #2: at 0℃; for 3 h; Inert atmosphere
Stage #3: With ammonium chloride In tetrahydrofuranInert atmosphere
General procedure: To the solution of 1M NaHMDS (8.8 mL, 8.8 mmol) in THF was slowly added the substrate (6.8 mmol) at 0 oC. After stirring for 30 min at 0 oC, the solution of electrophile (8.3 mmol) in anhydrous THF (2 mL) was slowly added into the reaction mixture at 0 oC and stirred for an additional 3h. The reaction was quenched with NH4Cl (sat.) solution (5 mL) and diluted with hexanes (20 mL). The organic layer was separated, washed with 15 wt.percent NaCl aqueous solution (10 mL) and concentrated to give the crude product. The product was isolated by flash chromatography using a Et3N pre-treated silca gel column and 0.1percent Et3N / 4.9percent EtOAc / 95percent hexanes as the eluent.
Reference: [1] Tetrahedron Letters, 2012, vol. 53, # 2, p. 166 - 169
[2] Tetrahedron Letters, 2012, vol. 53, # 2, p. 166 - 169
  • 3
  • [ 98-03-3 ]
  • [ 18791-75-8 ]
Reference: [1] Organic Preparations and Procedures International, 1997, vol. 29, # 4, p. 488 - 494
[2] Organic Letters, 2017, vol. 19, # 18, p. 4854 - 4857
[3] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1167 - 1171
[4] Applied Catalysis A: General, 2019, p. 12 - 24
  • 4
  • [ 38071-22-6 ]
  • [ 98-03-3 ]
  • [ 18791-75-8 ]
Reference: [1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1982, vol. 18, # 2, p. 134 - 138[2] Khimiya Geterotsiklicheskikh Soedinenii, 1982, vol. 18, # 2, p. 176 - 180
  • 5
  • [ 77998-62-0 ]
  • [ 68-12-2 ]
  • [ 18791-75-8 ]
Reference: [1] Tetrahedron Letters, 2012, vol. 53, # 2, p. 166 - 169
  • 6
  • [ 3140-92-9 ]
  • [ 68-12-2 ]
  • [ 18791-75-8 ]
Reference: [1] Arkiv foer Kemi, 1961, vol. 17, p. 165,169
  • 7
  • [ 872-31-1 ]
  • [ 68-12-2 ]
  • [ 18791-75-8 ]
  • [ 930-96-1 ]
YieldReaction ConditionsOperation in experiment
71%
Stage #1: With sodium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.5 h; Inert atmosphere
Stage #2: at 0℃; for 3 h; Inert atmosphere
Stage #3: With ammonium chloride In tetrahydrofuranInert atmosphere
General procedure: To the solution of 1M NaHMDS (8.8 mL, 8.8 mmol) in THF was slowly added the substrate (6.8 mmol) at 0 oC. After stirring for 30 min at 0 oC, the solution of electrophile (8.3 mmol) in anhydrous THF (2 mL) was slowly added into the reaction mixture at 0 oC and stirred for an additional 3h. The reaction was quenched with NH4Cl (sat.) solution (5 mL) and diluted with hexanes (20 mL). The organic layer was separated, washed with 15 wt.percent NaCl aqueous solution (10 mL) and concentrated to give the crude product. The product was isolated by flash chromatography using a Et3N pre-treated silca gel column and 0.1percent Et3N / 4.9percent EtOAc / 95percent hexanes as the eluent.
Reference: [1] Tetrahedron Letters, 2012, vol. 53, # 2, p. 166 - 169
[2] Tetrahedron Letters, 2012, vol. 53, # 2, p. 166 - 169
  • 8
  • [ 18791-75-8 ]
  • [ 624-92-0 ]
  • [ 222554-16-7 ]
  • [ 937-14-4 ]
Reference: [1] Patent: US6096724, 2000, A,
  • 9
  • [ 18791-75-8 ]
  • [ 29064-82-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 1, p. 250 - 254
  • 10
  • [ 18791-75-8 ]
  • [ 62224-16-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 3, p. 491 - 495
[2] Journal of Medicinal Chemistry, 1992, vol. 35, # 6, p. 1109 - 1116
  • 11
  • [ 18791-75-8 ]
  • [ 18791-99-6 ]
YieldReaction ConditionsOperation in experiment
95%
Stage #1: With hydroxylamine hydrochloride In pyridine at 90℃; for 0.166667 h;
Stage #2: With acetic anhydride In pyridine at 80℃; for 1 h;
The 4 - bromo thiophene -2 - formaldehyde (600g, 3.14 µM) and hydroxylamine hydrochloride (438g, 6.30 µM) added to the pyridine (5L) in, heated to 90° C10 minutes after cooling down to room temperature, drop vinegar anhydride (1940g, 19.0 µM) heated to 80 °C, reaction 1 hours, poured into water to (20L) in, stirring 30 minutes, filtered, drying to obtain the product (564g, yield 95percent).
Reference: [1] Patent: CN104230960, 2017, B, . Location in patent: Paragraph 0449; 0450; 0451
[2] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 5, p. 415 - 418
[3] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 11, p. 2870 - 2875
[4] Patent: US2017/151225, 2017, A1, . Location in patent: Paragraph 0926; 0927
  • 12
  • [ 18791-75-8 ]
  • [ 18791-99-6 ]
YieldReaction ConditionsOperation in experiment
51% With sodium hydroxide In water; acetonitrile 4-Bromo-2-cyanothiophene
To a solution of 4-bromo-2-thiophenecarboxaldehyde (1.0 g, 5.2 mmol, Aldrich) in acetonitrile/water (20 mL/2 mL) was added hyroxylamine-O-sulfonic acid (2.4 g, 21.2 mmol, Aldrich).
The dark solution was heated to 65° C. with stirring.
After 8 h, the reaction was quenched with 10percent NaOH (10 mL).
The solution was extracted with EtOAc (30 mL).
The organic layer was washed with water and brine (3*10 mL each), dried (Na2 SO4), and concentrated in vacuo to afford the crude product as a tan solid.
The crude product was purified by silica flash chromatography (5-25percent EtOAc:hexane) to afford 0.50 g (51percent) of 4-bromo-2-cyanothiophene as a white solid.
Reference: [1] Patent: US5688808, 1997, A,
[2] Patent: US5693646, 1997, A,
[3] Patent: US5693647, 1997, A,
[4] Patent: US5696127, 1997, A,
  • 13
  • [ 18791-75-8 ]
  • [ 67-56-1 ]
  • [ 18791-99-6 ]
Reference: [1] Catalysis Science and Technology, 2016, vol. 6, # 20, p. 7429 - 7436
  • 14
  • [ 179898-22-7 ]
  • [ 18791-75-8 ]
  • [ 18791-99-6 ]
YieldReaction ConditionsOperation in experiment
51% With sodium hydroxide In water; acetonitrile 4-Bromo-2-cyanothiophene
To a solution of 4-bromo-2-thiophenecarboxaldehyde (1.0 g, 5.2 mmol, Aldrich) in acetonitrile/water (20 mL/2 mL) was added hyroxylamine-O-sulfonic acid (2.4 g, 21.2 mmol, Aldrich).
The dark solution was heated to 65° C. with stirring.
After 8 h, the reaction was quenched with 10percent NaOH (10 mL).
The solution was extracted with EtOAc (30 mL).
The organic layer was washed with water and brine (3*10 mL each), dried (Na2 SO4), and concentrated in vacuo to afford the crude product as a tan solid.
The crude product was purified by silica flash chromatography (5-25percent EtOAc:hexane) to afford 0.50 g (51percent) of 4-bromo-2-cyanothiophene as a white solid.
51% With sodium hydroxide In water; acetonitrile 4-Bromo-2-cyanothiophene.
To a solution of 4-bromo-2-thiophenecarboxaldehyde (1.0 g, 5.2 mmol, Aldrich) in acetonitrile/water (20 mL/2 mL) was added hyroxylamine-O-sulfonic acid (2.4 g, 21.2 mmol, Aldrich).
The dark solution was heated to 65° C. with stirring.
After 8 h, the reaction was quenched with 10percent NaOH (10 mL).
The solution was extracted with EtOAc (30 mL).
The organic layer was washed with water and brine (3*10 mL each), dried (Na2 SO4), and concentrated in vacuo to afford the crude product as a tan solid.
The crude product was purified by silica flash chromatography (5-25percent EtOAc:hexane) to afford 0.50 g (51percent) of 4-bromo-2-cyanothiophene as a white solid.
Reference: [1] Patent: US5696130, 1997, A,
[2] Patent: US5696133, 1997, A,
  • 15
  • [ 18791-75-8 ]
  • [ 83933-17-9 ]
YieldReaction ConditionsOperation in experiment
98% With hydroxylamine hydrochloride; caesium carbonate In water; dimethyl sulfoxide at 125℃; for 14 h; General procedure: Aldehyde (0.5mmol), NH2OH·HCl (0.6mmol) and Cs2CO3 (0.6mmol) were stirred at 125°C for 48h in a 3:1 mixture of DMSO–H2O (2mL) under air. The progress of the reaction was monitored by TLC using ethyl acetate and hexane as eluent. After completion, the reaction mixture was cooled to room temperature and treated with water (1mL). The resulting mixture was extracted with ethyl acetate (3×5mL). Drying (Na2SO4) and evaporation of the solvent gave a residue that was purified on silica gel column chromatography using ethyl acetate and hexane. The purified products were identified by 1H NMR spectra and the melting points comparison with the literature data.
Reference: [1] Tetrahedron Letters, 2014, vol. 55, # 20, p. 3192 - 3194
[2] RSC Advances, 2016, vol. 6, # 43, p. 37093 - 37098
  • 16
  • [ 18791-75-8 ]
  • [ 2160-62-5 ]
Reference: [1] Journal of Organic Chemistry, 2018,
  • 17
  • [ 18791-75-8 ]
  • [ 79757-77-0 ]
YieldReaction ConditionsOperation in experiment
99% With sodium tetrahydroborate In tetrahydrofuran at 20℃; for 1.5 h; Step l:(4-Bromothiophen-2-yl)methanol (3_26_2): [00212] Sodium borohydride (5.20 g, 0.137 mol) was added to a solution of 4-bromo-thiophene-2-carbaldehyde 3_26_1 (25.0 g, 0.131 mol) in anhydrous tetra- hydrofuran (400 mL) at room temperature and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction was quenched by carefully adding a saturated ammonium chloride solution (100 mL) at room temperature. The mixture was extracted into ethyl acetate and the extract was washed with brine, dried over sodium sulfate, and concentrated to give the product (25.02 g, 99percent yield) which was used in the next step without further purification. [00213] NMR (400 MHz, CDC13): δ = 1.93 (br. s., 1H), 4.79 (s, 2H), 6.93 (s, 1H), 7.18 (d, J = 1.5 Hz, 1H).
98% With sodium tetrahydroborate; ethanol In toluene at 0 - 20℃; Step 1: 4-Bromothiophen-2-yl)methanolSodium borohydride (594 mg, 15.7 mmol) was added to a solution of 2- bromothiophene carboxaldehyde (2.5 g, 13 mmol) in a mixture toluene/ethanol (16 mL, 1 : 1) at 0°C. The reaction mixture was stirred for 2 hours at room temperature then partitioned between water (20 mL) and ethyl acetate (20 mL). The aqueous phase was separated and extracted with ethyl acetate (2 x 30 mL). The combined organic phases were washed with a saturated solution of sodium chloride (2 x 20 mL), dried over sodium sulphate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using petroleum ether/ethyl acetate (7 : 3) as eluent. The title product was obtained as a white solid (2.47 g, 98percent). *H NMR (CDCI3, 400 MHz) : δ (ppm) : 7.21 (d, J = 1.2 Hz, 1 H), 6.88 (d, J = 1.2 Hz, 1H), 4.75 (d, J = 6 Hz, 2H).
97% With hydrogenchloride; sodium borohydrid In methanol; dichloromethane A
4-Bromo-2-(hydroxymethyl)thiophene
4-Bromothiophene-2-carboxaldehyde (4 g, 18.8 mmol) was dissolved in dichloromethane/methanol (9/1, v/v, 100 mL) and the solution was cooled to 0° C.
To this was added sodium borohydride (0.35 g, 9.4 mmol) and the mixture stirred for 3 h at rt.
The reaction mixture was neutralized by addition of 1 N HCl, extracted with dichloromethane, and the extracts dried over magnesium sulfate and concentrated in vacuo.
The residue was purified by column chromatography (EtOAc: n-hexane, 1:4) to give the title compound (3.5 g, 97percent).
1H NMR (CDCl3) δ4.52 (s, 2H), 7.19 (m, 1H), 7.42 (m, 1H). FAB MS: 194 [M+1]+
97% With sodium tetrahydroborate In methanol; dichloromethane at 0 - 20℃; for 3 h; 4-Bromothiophene-2-carboxaldehyde (4 g, 18.8 mmol) was dissolved in dichloromethane/methanol (9/1, v/v, 100 mL) and the solution was cooled to 0C. To this was added sodium borohydride (0.35 g 9.4 mmol) and the mixture stirred for 3 h at rt. The reaction mixture was neutralized by addition of 1N HCl, extracted with dichloromethane, and the extracts dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (EtOAc: n-hexane, 1:4) to give the title compound (3.5 g, 97percent).1H NMR (CDCl3) ? 4.52 (s, 2H), 7.19 (m, 1H), 7.42 (m, 1H).???FAB MS: 194 [M+1]+

Reference: [1] Journal of the American Chemical Society, 2007, vol. 129, # 24, p. 7523 - 7530
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1788 - 1792
[3] Synthesis, 1983, # 1, p. 73 - 75
[4] Patent: WO2013/110643, 2013, A1, . Location in patent: Paragraph 00212; 00213
[5] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 4, p. 1992 - 2010
[6] Patent: WO2011/61214, 2011, A1, . Location in patent: Page/Page column 141-142
[7] Patent: US6492402, 2002, B1,
[8] Patent: EP1140918, 2004, B1, . Location in patent: Page 9; 20
[9] Journal of Medicinal Chemistry, 2001, vol. 44, # 24, p. 4050 - 4061
[10] Heteroatom Chemistry, 2011, vol. 22, # 3-4, p. 531 - 537
[11] Journal of Organic Chemistry, 1999, vol. 64, # 12, p. 4289 - 4297
[12] Journal of Medicinal Chemistry, 1999, vol. 42, # 18, p. 3557 - 3571
[13] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 7, p. 1017 - 1022
[14] Journal of Medicinal Chemistry, 2003, vol. 46, # 17, p. 3612 - 3622
[15] Journal of Medicinal Chemistry, 2002, vol. 45, # 23, p. 5005 - 5022
[16] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 11, p. 2870 - 2875
[17] Patent: US6528510, 2003, B1,
[18] Patent: WO2009/74789, 2009, A1, . Location in patent: Page/Page column 146
[19] Patent: WO2009/77990, 2009, A1, . Location in patent: Page/Page column 100
[20] Patent: US2003/229066, 2003, A1, . Location in patent: Page 39
[21] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 9, p. 3083 - 3088
[22] Journal of Medicinal Chemistry, 2012, vol. 55, # 21, p. 9331 - 9345
[23] Chemical Communications, 2015, vol. 51, # 18, p. 3842 - 3845
[24] Patent: WO2017/96472, 2017, A1, . Location in patent: Paragraph 066
[25] Patent: WO2009/131974, 2009, A1, . Location in patent: Page/Page column 90
  • 18
  • [ 18791-75-8 ]
  • [ 160005-43-6 ]
  • [ 79757-77-0 ]
YieldReaction ConditionsOperation in experiment
96% With sodium borohydrid In ethanol; water Referential Example 5
[Preparation of 4-Bromothiophene-2-Ylacetonitrile]
To a solution of 4-bromothiophene-2-carboxaldehyde (9.55 g, 50 mmol, purchased from Aldrich) in 100 ml of ethanol was added sodium borohydride (3.78 g, 100 mmol purchased from Yoneyama Yakuhin) gradually under cooling in an ice bath.
After the completion of addition, the mixture was stirred further for 1.5 hours at room temperature.
The reaction mixture was acidified with hydrochlorid acid, then was concentrated to dryness under reduced pressure.
To the residue was added water and extracted with ether to give 9.29 g (yield: 96percent) of 4-bromothiophen-2-ylmethanol as an oil.
Reference: [1] Patent: US5589506, 1996, A,
  • 19
  • [ 18791-75-8 ]
  • [ 799293-83-7 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 1, p. 250 - 254
[2] Patent: US2013/116233, 2013, A1,
  • 20
  • [ 18791-75-8 ]
  • [ 799293-85-9 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 1, p. 250 - 254
  • 21
  • [ 18791-75-8 ]
  • [ 41498-07-1 ]
YieldReaction ConditionsOperation in experiment
98.6% With potassium nitrate In dichloromethane; sulfuric acid a
4-Bromo-5-nitro-thiophene-2-carbaldehyde
A solution of potassium nitrate (110 g, 1.09 mol) in H2SO4 (550 mL, conc.) was added to a solution of 4-bromo-thiophene-2-carbaldehyde (207.6 g, 1.08 mol) in H2SO4 (1.1 L, conc.) at CH2Cl2 (5 mL, anhydrous) at 0° C. over a 45 minute period.
The reaction mixture was stirred 0° C. for 2 hrs, then stirred overnight at rt.
The reaction mixture was poured over ice, filtered, and washed with water and hexanes.
The yellow solid was dried overnight to afford the title compound (251.4 g, 98.6percent).
1H-NMR (DMSO-d6): δ 9.90 (s, 1H), 8.56 (s, 1H).
98.6% With sulfuric acid; potassium nitrate In dichloromethane at 0℃; for 2.75 h; A solution of potassium nitrate (110 g, 1.09 mol) in H2SO4 (550 mL, conc.) was added to a solution OF 4-bromo-thiophene-2-carbaldehyde (207.6 g, 1.08 mol) in H2SO4 (1.1 L, conc.) at CH2C12 (5 mL, anhydrous) at 0 oC over a 45 minute period. The reaction mixture was stirred 0 oC for 2 hrs, then stirred overnight at rt. The reaction mixture was poured over ice, filtered, and washed with water and hexanes. The yellow solid was dried overnight to afford the title compound (251.4 g, 98. 6percent). 1H-NMR (DMSO-d6) : δ 9. 90 (S, 1H), 8.56 (s, 1H).
96%
Stage #1: at 0℃;
Stage #2: at 4℃; for 2.5 h;
A 5-L, three-neck, round bottom flask was equipped with a mechanical stirrer and temperature probe and charged with 3-bromothiphenecarboxyaldehyde (360.0 g, 1.884 mol) and H2SO4 (1.5 L). The flask was cooled to 0 0C using an ice/NaCl bath.- In a separate round-bottom flask, KNO3 (209.5 g, 2.076 mol) was dissolved in H2SO4 (1 L). This solution was transferred to an addition funnel and added to the thiophene over a 2 hour period while maintaining the internal temperature below 4 0C. After 30 minutes from the end of the addition, the reaction was complete by TLC analysis (2:1 heptane/EtOAc). A 20 L glass carboy was charged with approximately 10 kg of ice and equipped with a pneumatic stirrer. The reaction mixture was poured slowly into the ice and washed with H2O (3L), then heptane_(3L) and dried in a vacuum oven to yield the title compound as a tan solid (426.2 g, 96percent). 1H-NMR (CDCl3): δ 9.9 (IH, s), 8.8 (s, IH).
6.987 g With sulfuric acid; potassium nitrate In water at 0 - 20℃; A solution of KNO3 (3.38 g, 33.4 mmol) in 96percent aqueous H2SO4 (30 ml) was added to a solution of 4-bromothiophene-2-carbaldehyde (5.8 g, 30.4 mmol) in 96percent aqueous H2SO4 (60 ml) over 45 minutes, maintaining the temperature below 4° C.
The resulting mixture was stirred at 0° C. for 2 hrs and then at RT overnight.
The reaction was poured into ice (300 ml) and the resulting precipitate was filtered and washed with water and hexane to afford 4-bromo-5-nitrothiophene-2-carbaldehyde (Int. 65) (6.987 g, 29.6 mmol).
6.987 g With sulfuric acid; potassium nitrate In water at 0 - 20℃; Step 1: Preparation of 4-bromo-5-nitrothiophene-2-carbaldehyde (Intermediate 65) A solution of KNO3 (3.38 g, 33.4 mmol) in 96percent aqueous H2SO4 (30 ml) was added to a solution of 4-bromothiophene-2-carbaldehyde (5.8 g, 30.4 mmol) in 96percent aqueous H2SO4 (60 ml) over 45 minutes, maintaining the temperature below 4°C. The resulting mixture was stirred at 0°C for 2 hrs and then at T overnight. The reaction was poured into ice (300 ml) and the resulting precipitate was filtered and washed with water and hexane to afford 4-bromo-5-nitrothiophene-2-carbaldehyde (Int. 65) (6.987 g, 29.6 mmol).

Reference: [1] Patent: US2004/9995, 2004, A1,
[2] Patent: WO2003/99805, 2003, A1, . Location in patent: Page 384
[3] Patent: WO2006/101860, 2006, A1, . Location in patent: Page/Page column 91-92
[4] Patent: US2013/324501, 2013, A1, . Location in patent: Paragraph 0327; 0328
[5] Patent: WO2013/182451, 2013, A1, . Location in patent: Page/Page column 85
  • 22
  • [ 18791-75-8 ]
  • [ 73183-34-3 ]
  • [ 881381-12-0 ]
YieldReaction ConditionsOperation in experiment
88% With potassium acetate In 1,2-dimethoxyethane at 150℃; for 0.333333 h; Microwave To 4-bromo-2-thiophenecarbaldehyde (500 mg, 2.61 mmol) in DME (18 mL), bis(pinacolato)diboron (865 mg, 3.403 mmol), potassium acetate (667 mg, 6.81 mmol) and PdCI2(dppf) (96 mg, 0.131 mmol) were added. The reaction mixture was heated by microwave at 1500C for 20 minutes. Then all the solvent was evaporated. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The water layer was extracted with ethyl acetate (2x100 mL). The combined organic phase was washed with brine (100 mL) and dried with Mg2SO4 and concentrated. The crude product was purified by Combiflash (Hexane/ethyl acetate, 1percent -30 percent ethyl acetate, 20 min.) to give title compound (550 mg, 88 percent). LC/MS: m/z, 238.2 (M+H), 1.88 min
57% With potassium acetate In 1,2-dimethoxyethane at 80℃; Inert atmosphere; Heating Intermediate 131 : 4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2-thiophenecarbaldehyde.4-bromo-2-thiophenecarbaldehyde (25 g, 131 mmol), bispinacolatodiboron (30 g, 118 mmol, 0.9 eq), PdCI2(dppf)-CH2CI2 adduct (1.7 g, 2.1 mmol, 0.02 eq), and potassium <n="151"/>acetate (21 g, 214 mmol, 1.6 eq) were diluted in DME (200 ml_). The mixture was degassed by evacuating the flask and back-filling with argon twice, then was heated at 80 0C overnight under argon. The crude reaction mixture was cooled to rt, filtered through a large plastic Buchner funnel pre-filled with celite, washing with ethyl acetate (1.5 L). The solvent was removed in vacuo to afford a brown oil which partially crystallized upon standing. The batch was divided into two portions and each was purified by lsco Combiflash (330 gram column, eluting with 0-30percent ethyl acetate in hexanes). Mixed fractions were repurified by Combiflash as described above. The product fractions were combined and concentrated to give the desired as a fluffy white solid. Over time the color darkened a bit to light tan, even with storage in an amber jar, but the quality did not seem to be affected. 17.9 g (57percent) of the title compound was obtained. LCMS m/z 238.7 (M+H), Rt 0.98 min.
Reference: [1] Patent: WO2006/34317, 2006, A2, . Location in patent: Page/Page column 94
[2] Patent: WO2008/118724, 2008, A1, . Location in patent: Page/Page column 148-149
  • 23
  • [ 18791-75-8 ]
  • [ 73183-34-3 ]
  • [ 881381-12-0 ]
YieldReaction ConditionsOperation in experiment
78% With potassium acetate In 1,2-dimethoxyethane; ethyl acetate Intermediate 23: 5-(5-formyl-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide
The boronate ester used to make the title compound was prepared in 6 separate equal batches according to the following procedure: To a solution of 4-bromo-2-thiophenecarbaldehyde (1.0 g, 4.48 mmol) in DME (20 mL) was added bis(pinacolato)diborane (1.48 g, 5.82 mmol), KOAc (1.14 g, 5.11 mmol) and Pd2Cl2(dppf) (106 mg, 0.448 mmol).
The reactions were run in a Smith microwave at 150° C. for 20 min.
The 6 reactions were pooled and concentrated under reduced pressure.
The residue was taken up in EtOAc (200 mL) and H2O (50 mL).
The layers were separated, the organic layer was washed with saturated NaCl (1*50 mL), dried (Na2SO4), and concentrated under reduced pressure.
The crude product was purified by flash chromatography eluding with hexanes/EtOAc to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarbaldehyde (5 g, 78percent).
Reference: [1] Patent: US2009/143372, 2009, A1,
[2] Patent: US2009/143372, 2009, A1,
  • 24
  • [ 18791-75-8 ]
  • [ 1105187-36-7 ]
Reference: [1] Patent: EP2320906, 2016, B1,
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