* 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.
Reference：
[1] Chemical Science, 2018, vol. 9, # 15, p. 3860 - 3865
2
[ 6314-28-9 ]
[ 17890-56-1 ]
Reference：
[1] Journal of the American Chemical Society, 1949, vol. 71, p. 2856,2858
[2] Patent: US2006/111430, 2006, A1, . Location in patent: Page/Page column 21
3
[ 6314-28-9 ]
[ 108-23-6 ]
[ 17890-56-1 ]
Reference：
[1] Patent: EP885869, 1998, A1,
4
[ 6314-28-9 ]
[ 39827-11-7 ]
Yield
Reaction Conditions
Operation in experiment
94.9%
With thionyl chloride In toluene at 20℃; for 8 h; Reflux
Benzo[b]thiophene-2-carbonyl chlorid[0104] Thianaphthene-2-carboxylic acid (356.42 mg, 2 mmol) was suspended in dry toluene (6 mL), thionyl chloride (4.4 mL, 60 mmol) and DMF (0.05 mL) were added at room temperature, and then the mixture was refluxed 8 h.4 The volatiles were removed at reduced pressure gave benzo[b]thiophene-2-carbonyl chloride as a yellow power. Purified by flash chromatography on silica gel, using ethyl acetate/hexane (1 :9) as eluent, give 3 as a white power (393.64 mg, 94.9percent). Spectral data were in accordance with those published.1H-NMR (300 MHz, CDCls): δ 8.31 (s, 1H), 7.04-7.89 (m, 2H), 7.60-7.46 (m, 2H. 13C NMR (300 MHz, CDC13): δ 161.14, 144.07, 138.05, 136.59, 135.89, 128.75, 126.68, 125.66, 122.91.
61%
With pyridine; thionyl chloride In tolueneReflux
Thionyl chloride (0.81 mL, 11.1 mmol) was added to a solution of benzo[b]thiophene-2-carboxylic acid 3 (0.4 g, 2.24 mmol), in pyridine (0.3 mL, 1.8 mmol) and toluene (15 mL, 14.1 mmol) at reflux. The reaction mixture was quenched in ice water and the toluene evaporated in vacuo. The acid chloride was extracted with distilled DCM (2.x.25 mL, 2.x.10 mL) and the combined organic extracts washed with distilled water (2.x.20 mL) and dried. The solvent was evaporated under reduced pressure to give a brown residue, which was purified using flash chromatography with DCM as the eluent to yield 11a17 (0.27 g, 61percent) as a colourless solid. 1H NMR (CDCl3, 300 MHz): δ 7.50 (m, 2H), 7.91 (m, 2H), 8.27 (s, 1H). 13C NMR: δ 123.1 (C3), 125.9 (C7), 126.9 (C4), 128.9 (C5 and C6), 136.1 (C2), 138.3 (C3a), 144.3 (C7) and 161.9 (CO). MS (CI+), m/z 197, 199 [MH+1, 35Cl, 37Cl].
1.1 g
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 1 h;
To a 100-mL round-bottom flask was placed a solution of 1-benzothiophene-2-carboxylic acid (1.0 g,5.61 mmol)in DCM (30 mL) followed by the dropwise addition of oxalyl chloride (1.426 g,11.23 mmol) with stirring at 0°C. To the solution was added DMF (0.01 mL) then the reaction was stirred for 1H at a The solvent was removed under reduced pressure affording 1.1 g of 1-benzothiophene-2-carbonyl chloride as a yellow solid.
Reference：
[1] Journal of the American Chemical Society, 2011, vol. 133, # 11, p. 3764 - 3767
[2] Patent: WO2012/99785, 2012, A2, . Location in patent: Page/Page column 25
[3] Tetrahedron Asymmetry, 2003, vol. 14, # 3, p. 339 - 346
[4] Organometallics, 2015, vol. 34, # 12, p. 3065 - 3071
[5] Journal of the American Chemical Society, 2005, vol. 127, # 43, p. 15010 - 15011
[6] Tetrahedron, 2011, vol. 67, # 36, p. 6895 - 6900
[7] Journal of Medicinal Chemistry, 1984, vol. 27, # 5, p. 570 - 576
[8] European Journal of Medicinal Chemistry, 2004, vol. 39, # 1, p. 85 - 97
[9] Journal of Medicinal Chemistry, 2005, vol. 48, # 3, p. 839 - 848
[10] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 7, p. 2074 - 2079
[11] Journal of Medicinal Chemistry, 2007, vol. 50, # 8, p. 1850 - 1864
[12] Patent: WO2006/91674, 2006, A1, . Location in patent: Page/Page column 87
[13] Patent: US5244893, 1993, A,
[14] Patent: US5304657, 1994, A,
[15] Heterocycles, 2008, vol. 75, # 8, p. 1913 - 1929
[16] Journal of Medicinal Chemistry, 2009, vol. 52, # 15, p. 4883 - 4891
[17] Journal of Medicinal Chemistry, 2009, vol. 52, # 22, p. 7249 - 7257
[18] Chemical Communications, 2010, vol. 46, # 13, p. 2289 - 2291
[19] European Journal of Medicinal Chemistry, 2011, vol. 46, # 1, p. 265 - 274
[20] Journal of Medicinal Chemistry, 2011, vol. 54, # 10, p. 3581 - 3594
[21] Journal of Medicinal Chemistry, 2012, vol. 55, # 9, p. 4189 - 4204
[22] Synthetic Communications, 2013, vol. 43, # 3, p. 337 - 344,8
[23] Synthetic Communications, 2013, vol. 43, # 3, p. 337 - 344
[24] Organic Letters, 2013, vol. 15, # 12, p. 3014 - 3017
[25] European Journal of Medicinal Chemistry, 2013, vol. 66, p. 489 - 498
[26] Organic Letters, 2014, vol. 16, # 18, p. 4718 - 4721
[27] Organic Letters, 2017, vol. 19, # 23, p. 6332 - 6335
[28] European Journal of Organic Chemistry, 2015, vol. 2015, # 17, p. 3727 - 3742
[29] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 19, p. 6418 - 6426
[30] Patent: WO2016/100184, 2016, A1, . Location in patent: Paragraph 00691-00693
[31] Patent: KR2016/21163, 2016, A, . Location in patent: Paragraph 0890; 0892
[32] Patent: KR2015/25531, 2015, A, . Location in patent: Paragraph 0890; 0891; 0892
[33] Patent: CN103961348, 2016, B, . Location in patent: Paragraph 0039; 0051; 0052
[34] Organic Letters, 2017, vol. 19, # 12, p. 3091 - 3094
[35] Molecules, 2017, vol. 22, # 8,
[36] Patent: WO2017/62581, 2017, A1, . Location in patent: Paragraph 0313
[37] Synlett, 2017, vol. 28, # 19, p. 2594 - 2598
[38] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 4, p. 306 - 311
[39] Organic Letters, 2018, vol. 20, # 10, p. 3132 - 3135
[40] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 14, p. 4127 - 4135
[41] Chemical Communications, 2018, vol. 54, # 77, p. 10859 - 10862
[42] Patent: WO2018/231635, 2018, A1, . Location in patent: Paragraph 0045; 0047
Reference：
[1] Chemical Science, 2018, vol. 9, # 15, p. 3860 - 3865
8
[ 67-56-1 ]
[ 6314-28-9 ]
[ 22913-24-2 ]
Yield
Reaction Conditions
Operation in experiment
97.4%
at 60℃; for 16 h;
The compound 2-benzothiophenecarboxylic acid (0901-137) (1.0 g, 5.61 mmol, 1.0 equiv) was added to 20 ml of methanol,Then add concentrated sulfuric acid (0.1 g),The mixture was stirred at 60 °C for 16 hours.After completion of the reaction, 50 ml of a saturated aqueous sodium hydrogencarbonate solution was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the target product 2-benzothiophenecarboxylic acid methyl ester (1.05). g, yield 97.4percent) as a white solid
Reference：
[1] Synlett, 2004, # 6, p. 1113 - 1116
[2] Patent: CN107383024, 2017, A, . Location in patent: Paragraph 0407
9
[ 7342-85-0 ]
[ 201230-82-2 ]
[ 6314-28-9 ]
[ 22913-24-2 ]
Reference：
[1] Journal of Organic Chemistry, 1995, vol. 60, # 26, p. 8336 - 8340
10
[ 67-56-1 ]
[ 7342-85-0 ]
[ 201230-82-2 ]
[ 6314-28-9 ]
[ 22913-24-2 ]
Reference：
[1] Journal of Organic Chemistry, 1995, vol. 60, # 26, p. 8336 - 8340
11
[ 6314-28-9 ]
[ 18107-18-1 ]
[ 22913-24-2 ]
Reference：
[1] Green Chemistry, 2018, vol. 20, # 17, p. 3931 - 3943
12
[ 186581-53-3 ]
[ 6314-28-9 ]
[ 22913-24-2 ]
Reference：
[1] Chemische Berichte, 1933, vol. 66, p. 245,249
13
[ 6314-28-9 ]
[ 75894-07-4 ]
Reference：
[1] Journal of the American Chemical Society, 1949, vol. 71, p. 2856,2858
14
[ 6314-28-9 ]
[ 75-65-0 ]
[ 89673-36-9 ]
Yield
Reaction Conditions
Operation in experiment
94%
for 8 h; Heating / reflux
Benzo[Z>]thiophen-2-yl-carbamic acid tert-butyl ester (1-B).; A solution of compound 1-A (14.4 g, 80.6 mmol), N,N-diisopropylethylamine (15.5 mL, 88.6 mmol) and diphenylphosphoryl azide (20.8 mL, 96.7 mmol) in -butanol (150 mL) was heated at reflux for 8 h. The solvent was evaporated in vacuo, and the residue purified by flash column chromatography on silica gel, eluting with dichloromethane, to afford compound 1-B as a colorless solid (18.9 g, 94percent). 1H-NMR (DMSO-^): δ 1.50 (s, 9H), <n="183"/>6.78 (s, IH), 7.16 (d of d, IH), 7.27 (d of d, IH), 7.58 (d, IH), 7.77 (d, IH), 10.70 (br s, IH); MS: m/z 250.2 (MH+).
94%
for 8 h; Reflux
B. Benzo[b]thiophen-2-yl-carbamic acid tert-butyl ester (1d). A solution of 2-carboxybenzo[b]thiophene (14.4 g, 80.6 mmol), N,N-diisopropylethylamine (15.5 mL, 88.6 mmol) and diphenylphosphoryl azide (20.8 mL, 96.7 mmol) in t-butanol (150 mL) was heated at reflux for 8 hours. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography on silica gel, using dichloromethane as the eluant, to give the product as a colorless solid (18.9 g, 94percent). 1H NMR (DMSO-d6): δ 1.50 (s, 9H), 6.78 (s, 1H), 7.16 (d of d, 1H), 7.27 (d of d, 1H), 7.58 (d, 1H) and 7.77 (d, 1H), 10.70 (br s, 1H); MS: m/z 250.2 (MH+).
94%
for 8 h; Reflux
Example 1 benzo[b]thiophen-2-yl-carbamic acid tert-butyl ester (1-B). A solution of compound 1-A (14.4 g, 80.6 mmol), N,N-diisopropylethylamine (15.5 mL, 88.6 mmol) and diphenylphosphoryl azide (20.8 mL, 96.7 mmol) in t-butanol (150 mL) was heated at reflux for 8 h. The solvent was evaporated in vacuo, and the residue purified by flash column chromatography on silica gel, eluting with dichloromethane, to afford compound 1-B as a colorless solid (18.9 g, 94percent). 1H-NMR (DMSO-d6): δ 1.50 (s, 9H), 6.78 (s, 1H), 7.16 (d of d, 1H), 7.27 (d of d, 1H), 7.58 (d, 1H), 7.77 (d, 1H), 10.70 (br s, 1H); MS: m/z 250.2 (MH+).
64%
for 5 h; Heating / reflux
A solution of benzo[b]thiophene-2 carboxylic acid (1.25 g, 7.03 mmol), diphenylphosphoryl azide (1.94 g, 7.03 mmol) and triethylamine (0.98 mL, 7.03 mmol) in tert-butanol (20 mL) was heated at reflux for 5 hours, at which time thin layer chromatography (DCM/Hexanes) indicates the reaction is complete. The reaction mixture was cooled to room temperature, poured into water and extracted with diethyl ether (3.x.). The combined ether extracts were washed with brine, dried over anhydrous sodium sulfate and then concentrated to afford a beige solid. Purification by column chromatography (SiO2 DCM/Hexanes) afforded compound 235 as a white solid 0.96 g (64percent). HPLC-MS tR=2.7 Min(UV254 nm). Mass calculated for formula C13H15NO2S, M+249.33, observed LC/MS m/z 250.40 (M+H).
64%
for 5 h; Heating / reflux
Example 235; A solution of benzo[b]thiophene-2 carboxylic acid (1.25 g, 7.03 mmol), diphenylphosphoryl azide (1.94 g, 7.03 mmol) and triethylamine (0.98 mL, 7.03 mmol) in tert-butanol (20 mL) was heated at reflux for 5 hours, at which time thin layer chromatography (DCM/Hexanes) indicates the reaction is complete. The reaction mixture was cooled to room temperature, poured into water and extracted with diethyl ether (3.x.). The combined ether extracts were washed with brine, dried over anhydrous sodium sulfate and then concentrated to afford a beige solid. Purification by column chromatography (SiO2 DCM/Hexanes) afforded compound 235 as a white solid 0.96 g (64percent). HPLC-MS tR=2.7 Min (UV254nm). Mass calculated for formula C13H15NO2S, M+ 249.33, observed LC/MS m/z 250.40 (M+H).
62%
for 16 h; Heating / reflux
Example 36; Preparation of 3-(1 -benzothien-2-yl)-6-(3-fluoro-2-hvdroxyphenyl)-2-methyl-5-(2- phenylethyl)-4(3H)-pvrimidinone; [00115] a; 1 ,1-Dimethylethyl 1-benzothien-2-ylcarbamate; EPO <DP n="39"/>[00116] To a solution of i-benzothiophene-2-carboxylic acid (5.0 g, 0.028 mol) in dry NBuOH (70 ml_) was added TEA (4.3 ml_, 0.031 mol). After 5 min. of stirring, DPPA (6.67 ml_, 0.031 mol) was added and the reaction was refluxed for 16 h. The reaction was concentrated and the resulting residue was diluted with ethyl acetate and washed successively with sat. NaHCO3 and brine. The organic phase was dried over Na2SO4, filtered and concentrated before purifying by silica chromatography (0 - 40percent ethyl acetate/hexane) to afford pure product (4.35 g) in 62percent yield. 1H NMR (400 MHz, DMSO-Cf6) .pound. ppm 1.50 (s, 9 H), 6.77 (s, 1 H), 7.15 (t, J=0.85 Hz, 1 H), 7.26 (t, J=0.85 Hz, 1 H), 7.59 (d, J=7.79 Hz, 1 H), 7.76 (d, J=7.78 Hz, 1 H), 10.2 (brs, 1 H).
Lithium aluminum hydride (22.4 mmole, 22.4 ml) was added to a solution of 101 (2.0 g, 11.2 mmole) in THF (100 ml) at 0° C. After 5 minutes, the mixture was warmed to room temperature and stirred for 2 hours. The mixture was then cooled to 0° C., and MeOH (1 ml) was added slowly until no gas was evolved, followed by the addition of 1NHCl. After stirring for 30 min at room temperature, the mixture was concentrated in vacuo, diluted in 1N HCl, and extracted with EtOAc (.x.3). The combined organics were washed with brine, dried (Na2SO4), concentrated in vacuo and dried over pump for 16 hours to give 1.8 g of crude 102.
With thionyl chloride;N,N-dimethyl-formamide; In toluene; at 20℃; for 8h;Reflux;
Benzo[b]thiophene-2-carbonyl chlorid[0104] Thianaphthene-2-carboxylic acid (356.42 mg, 2 mmol) was suspended in dry toluene (6 mL), thionyl chloride (4.4 mL, 60 mmol) and DMF (0.05 mL) were added at room temperature, and then the mixture was refluxed 8 h.4 The volatiles were removed at reduced pressure gave benzo[b]thiophene-2-carbonyl chloride as a yellow power. Purified by flash chromatography on silica gel, using ethyl acetate/hexane (1 :9) as eluent, give 3 as a white power (393.64 mg, 94.9%). Spectral data were in accordance with those published.1H-NMR (300 MHz, CDCls): delta 8.31 (s, 1H), 7.04-7.89 (m, 2H), 7.60-7.46 (m, 2H. 13C NMR (300 MHz, CDC13): delta 161.14, 144.07, 138.05, 136.59, 135.89, 128.75, 126.68, 125.66, 122.91.
61%
With pyridine; thionyl chloride; In toluene;Reflux;
Thionyl chloride (0.81 mL, 11.1 mmol) was added to a solution of <strong>[6314-28-9]benzo[b]thiophene-2-carboxylic acid</strong> 3 (0.4 g, 2.24 mmol), in pyridine (0.3 mL, 1.8 mmol) and toluene (15 mL, 14.1 mmol) at reflux. The reaction mixture was quenched in ice water and the toluene evaporated in vacuo. The acid chloride was extracted with distilled DCM (2×25 mL, 2×10 mL) and the combined organic extracts washed with distilled water (2×20 mL) and dried. The solvent was evaporated under reduced pressure to give a brown residue, which was purified using flash chromatography with DCM as the eluent to yield 11a17 (0.27 g, 61%) as a colourless solid. 1H NMR (CDCl3, 300 MHz): delta 7.50 (m, 2H), 7.91 (m, 2H), 8.27 (s, 1H). 13C NMR: delta 123.1 (C3), 125.9 (C7), 126.9 (C4), 128.9 (C5 and C6), 136.1 (C2), 138.3 (C3a), 144.3 (C7) and 161.9 (CO). MS (CI+), m/z 197, 199 [MH+1, 35Cl, 37Cl].
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane;
(+/-)-fralphan5-l-(Benzo[b]thiophene-2-carbonyl)-2-methyl-l,2,3,4-tetrahydro-quinoline-4- carboxylic acid (4-chloro-phenyl)-ethyl-amide was made following general procedure A, substituting benzo[b]thiophene-2-carbonyl chloride for 4-trifluoromethyl-benzoyl chlorided. Benzo[b]thiophene-2-carbonyl chloride was prepared by reaction of thianaphthene-2-carboxylic acid with oxalyl chloride and dimethylformamide in methylene chloride. The crude l-(benzo[b]thiophene-2-carbonyl)-2- methyl-l,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide was isolated as a mixture of cis and trans isomers. Purification by silica gel chromatography (1% methanol / methylene chloride) followed by purification via HPLC yielded (+/-)-/rans-2-methyl-l-(pyrimidine-5- carbonyl)-l,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide (34%). 1H-NMR (CDCl3) delta: 1.02 - 1.18 (m, 6H), 1.65 - 1.75 (m, IH), 2.55 - 2.65 (m, IH), 3.60 - 3.70 (m, IH),3.80 (q, 2H), 5.05 - 5.15 (m, IH), 6.70 (d, IH), 6.80 - 7.00 (m, 3H), 7.20 -7.40 (m, 4H), 7.45 (s, IH),7.50 (d, 2H), 7.70 (d, IH), 7.80 (d, IH). MS m/z: 489/491 (M+l).
With thionyl chloride; In hexane;
To 57.5 g (0.324 mol) of benzothiophene-2-carboxylic acid in 600 ml of chlorobenzeno there are added dropwise with stirring at reflux temperature 57.8 g (0.468 mol) of thionyl chloride and, when the addition is complete, the mixture is stirred at reflux temperature until the evolution of gas has ceased. For working up, the reaction mixture is allowed to cool to room temperature and then concentrated in vacuo, the residue is stirred with n-hexane, and precipitate which has settled out is filtered off with suction and dried. 57.4 g (90% of theory) of benzothiophene-2-carboxylic acid chloride, which can be reacted further without additional purification, are obtained. STR11
With thionyl chloride;
(1) 1.0 g of <strong>[6314-28-9]benzo[b]thiophene-2-carboxylic acid</strong> was reacted with 2 ml of thionyl chloride under reflux overnight, and then excess thionyl chloride was distilled off under reduced pressure to obtain benzo[b]thiophene-2-carbonyl chloride as a solid product.
With thionyl chloride; for 2h;Reflux;
General procedure: Compounds 1, 2, 3, 4 and 5 were commercially available. Compounds 6, 7, 8, 9 and 10 were prepared from the corresponding carboxylic acid (9.18 mmol) and thionyl chloride (30 mL) with heating under reflux for 2 h. The thionyl chloride was removed in vacuo. The resulting acyl chloride was used without further purification.
With thionyl chloride; for 2h;Reflux;
General procedure: The heteroaryl acyl chlorides used in the synthesis of compounds 1b, 2b, 3b, 4b and 5b were commercially available. For compounds 6b, 7b, 8b, 9b and 10b, the chloride derivatives were prepared from the corresponding carboxylic acid (9.18 mmol) nd thionyl chloride (30 mL) with heating under reflux for 2 h. The thionyl chloride was removed in vacuo. The resulting acyl chloride was used without further purification.
With thionyl chloride;Reflux;
Compound 9a (191 mg, 1 mmol) was refluxed in excess of thionylchloride (3 mL) overnight. Excess of thionyl chloride was evaporatedand the residue was dissolved in CH2Cl2, 3-bromopropylamine hydrobromide (328 mg, 1.5 mmol was addedfollowed by triethylamine (TEA; 0.42 mL, 3 mmol). The reactionmixture was stirred at room temperature. After the reaction wascompleted, the reaction mixture was diluted with CH2Cl2 andsequentially washed with water, 1 N HCl and saturated NaHCO3.The organic layer was dried over MgSO4, filtered and concentrated.The obtained product was purified by column chromatographywith n-hexane/ethyl acetate (EtOAc) = 4:1 to obtain 10a, (236 mg,76%) as white solid.
With thionyl chloride; at 60℃; for 2h;
A mixture of carboxylic acid in thionyl chloride (5 mL/mmol carboxylic acid) was stirred at 60 C for 2 hours. On completion, the solution was concentrated in vacuo to give the acid chloride, which was used directly without further purification. This material (1.1 eq) was added to a mixture of racemic amine (1 eq.) and triethylamine (2 eq.) in dichloromethane (3-5 mL/mmol racemic amine) at room temperature. The mixture was stirred at this temperature for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC to give racemic amide product. Following general procedure A, rac-1 was prepared from benzo[b]thiophene-2 -carboxylic acid and rac-A-104 (0.10 g, 0.65 mmol). The product was purified by prep-HPLC [Instrument: GX-C; Column: Phenomenex Gemini C 18 150x30 mm, particle size: 5 mupiiota; Mobile phase: 35-65% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give rac-1 (0.15 g, 73% yield) as a white solid. LCMS : (ES+) m/z (M+H)+ = 315.1.
With thionyl chloride; In dichloromethane; N,N-dimethyl-formamide; at 50℃; for 0.333333h;
Benzo[b]thiophene-2-carboxylic acid (50 mg, 0.28 mmol)dichloromethane (3 mL) It was dissolved in thionyl chloride (SOCl2, 0.50 mL)and dimethylformamide (2 drops) It was added thereto, and was stirred for 20 minutes at 50C . Thereafter, the reaction mixture was concentrated under reduced pressure, dichloromethane (3 mL)after the diluted, quinolin-3-amine (50.0 mg, 0.347 mmol)and triethyl amine was added and stirred for a (100 mg, 0.988 mmol) and 15 hours at room temperature. Thin film chromatography (TLC) in verifying, new the spot location changes accordingly once created, reaction mixture of decompressing concentrated within, fraction is concentrated tosilica gel thin chromatography (preparative TLC, n/ethyl acetate = 2/1-hexanediol) for purifying the white solid thereby, a desired compound (23.0 mg, 27%) is obtained.
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 50℃; for 0.333333h;
Benzo [b] thiophene-2-carboxylic acid (50 mg, 0.28 mmol) and dichloromethane (3 mL) was dissolved in thionyl chloride (SOCl2, 0.50 mL) and dimethylformamide (2 drops) after the addition, the mixture was stirred for 20 minutes at 50 .Thereafter, the reaction mixture was concentrated under reduced pressure, dichloromethane (3 mL) and then diluted to, quinolin-3-amine (50.0 mg, 0.347 mmol) and triethylamine (100 mg, 0.988 mmol) was added to 15 at room temperature and and it stirred for hours. When the thin film check chromatography (TLC), when a new spot is generated, to give the mixture was concentrated under reduced pressure, and purified by silica gel preparative thin layer chromatography (preparative TLC, ethyl acetate / n- hexane = 2/1), the reaction mixture is object of a white solid to give the compound (23.0 mg, 27%).
With thionyl chloride; In dichloromethane; at 20℃;Inert atmosphere; Reflux;
General procedure: At low temperature conditions,The thionyl chloride was slowly added to the solution of compound 4 in anhydrous dichloromethane,After dripping,The reaction was returned to room temperature and refluxed under nitrogen.After the reaction is complete,Steaming all solvents,Then dissolved in anhydrous tetrahydrofuran or anhydrous dichloromethane,Compounds 3 and pyridine were added at low temperature,The reaction was transferred to room temperature and overnight.To the reaction system by adding water,And extracted three times with ethyl acetate,Combine organic phase,Washed three times with saturated sodium bicarbonate solution and saturated brine,Dried over anhydrous sodium sulfate and subjected to column chromatography to give compound 6.
With thionyl chloride;Reflux;
General procedure: Following a described procedure [24,42,43] with a few modifications, sodium borohydride wasslowly added to a suspension of selenium powder in water at room temperature or in ethanol, N2atmosphere and 0 C, and stirred until the formation of the typical colorless solution of NaHSe. Then,the corresponding aroyl or heteroaroyl chloride was added. Temperature and time of reaction varieddepending on the compounds. Methylation was achieved through the addition of methyl iodide(in excess). Purification was performed by several washings, recrystallization in different solvents orcolumn chromatography. In those cases where the acyl chloride was not available, it was formed bythe reaction of the corresponding carboxylic acid with SOCl2 for 1-8 h at reflux. Solvent was removedunder vacuum by rotatory evaporation, and the product was then washed three times with dry toluene,which was also eliminated by rotatory evaporation.
1.1 g
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 1h;
To a 100-mL round-bottom flask was placed a solution of 1-benzothiophene-2-carboxylic acid (1.0 g,5.61 mmol)in DCM (30 mL) followed by the dropwise addition of oxalyl chloride (1.426 g,11.23 mmol) with stirring at 0C. To the solution was added DMF (0.01 mL) then the reaction was stirred for 1H at a The solvent was removed under reduced pressure affording 1.1 g of 1-benzothiophene-2-carbonyl chloride as a yellow solid.
With thionyl chloride; for 2h;Reflux;
General procedure: Thionyl chloride (9 mL) was added to the carboxylic acid (1.0 equiv, 10.0 mmol) and the mixture wasrefluxed for 2 h. The solution was then concentrated in vacuo. An oven-dried round-bottomed flask(100 mL) equipped with a stir bar was charged with glutarimide (909.4 mg, 0.91 equiv, 8.04 mmol), acyl chloride (1.0 equiv, 8.84 mmol), 4-dimethylaminopyridine (DMAP, 280.4 mg, 0.25 equiv, 2.5mmol) and dichloromethane (50 mL). Triethylamine (typically, 2.0 equiv) was added dropwise to the reaction mixture with vigorous stirring at 0 C, and the reaction mixture was stirred overnight at room temperature. After the indicated time, the reaction mixture was diluted with Et2O (20 mL) and filtered.The organic layer was washed with HCl (1.0 N, 30 mL), brine (30 mL), dried, and concentrated. The residue was purified by recrystallization or chromatography on silica gel to afford the corresponding amide.
With thionyl chloride;Reflux;
General procedure: Compound 28a (191 mg, 1 mmol) was refluxed in excess of thionylchloride (3 mL) overnight. Excess of thionyl chloride was evaporatedand the residue was dissolved in CH2Cl2, 3-bromopropylamine hydrobromide(328 mg, 1.5 mmol was added followed by triethylamine (TEA;0.42 mL, 3 mmol). The reaction mixture was stirred at room temperature.After the reaction was completed, the reaction mixture was dilutedwith CH2Cl2 and sequentially washed with water, 1 N HCl and saturatedNaHCO3. The organic layer was dried over MgSO4, filtered and concentrated.The obtained product was purified by column chromatographywith n-hexane: Ethyl acetate (EtOAc)=4:1 to obtain 29a,(236 mg, 76%) as white solid.
With thionyl chloride; for 3h;Reflux;
To a dry 25mL round bottomed flask was added 44mg (0.25mmol) <strong>[6314-28-9]benzo[b]thiophene-2-carboxylic acid</strong> and excess (5mL) thionyl chloride, and the resulting mixture held at reflux for 3h. The resulting benzo[b]thiophene-2- carbonyl chloride was then evaporated to dryness via rotavap in preparation for the next step.
General procedure: In 0.5 M hexane solvent, 1.25 molar equivalents of Na-TMP was reacted with 0.4 mmol of benzo[b]thiophene (arene) at 25 C. for 30 minutes, 1.5 molar equivalents of heavy water (D2O: electrophilic reagent) was then added thereto and reacted therewith at 0 C. for 1 hour. The product was evaluated through analysis by 1H-NMR, and the yield of isolated deuterated benzo[b]thiophene in which a hydrogen atom located at 2-position of benzo[b]thiophene was substituted by heavy hydrogen was calculated in the same manner as in Experiment Number 1. The isolated yield was 99%.A reaction was performed using benzo[b]thiophene as an arene and carbon dioxide (CO2) as an electrophilic reagent in the same manner as in Experiment Number 2, the product was then evaluated, and the yield of isolated benzo[b]thiophene-2-carboxylic acid in which a carboxy group (-CO2H) was added at 2-position of benzo[b]thiophene was calculated. The isolated yield was 89%.
General procedure: A 20-mL test tube equipped with magnetic stirring bar was charged with 1 mmol substituted cinnamic acid and 5ml DES, heated at 140 C in an oil bath for 4 h. After the mixture was cooled to room temperature, extracted with ethyl acetate (3x15 mL), combined, and evaporated under vacuum. Pure product was obtained by silica gel column chromatography with PE and ethyl acetate.
benzo[<i>b</i>]thiophene-2-carboxylic acid (1-benzyl-pyrrolidin-3-yl)-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
Stage #1: (R)-1-benzyl-3-aminopyrrolidine With 3-formylindol-1-ylmethyltriazol-1-ylCH2styrene DVB copolymer; sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 16h;
Stage #2: benzo[b]thiophene-2-carboxylic acid With N-ethyl-N,N-diisopropylamine; fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 24h;
Stage #3: With trifluoroacetic acid In dichloromethane at 20℃; for 16h;
The compound 2-benzothiophenecarboxylic acid (0901-137) (1.0 g, 5.61 mmol, 1.0 equiv) was added to 20 ml of methanol,Then add concentrated sulfuric acid (0.1 g),The mixture was stirred at 60 C for 16 hours.After completion of the reaction, 50 ml of a saturated aqueous sodium hydrogencarbonate solution was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the target product 2-benzothiophenecarboxylic acid methyl ester (1.05). g, yield 97.4%) as a white solid
benzo[b]thiophene-2-carboxylic acid[2-(3,4-dichloro-phenyl)-ethyl]-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
To a solution of 300 mg (1.68 mmol) of <strong>[6314-28-9]benzo[b]thiophene-2-carboxylic acid</strong> in DMF (8 ml) were added 320 mg (1.68 mmol) of 2-(3,4-dichloro-phenyl)-ethylamine and 595 mg (1.85 mmol) of TBTU. After 10 min 1.47 ml (8.42 mmol) of N,N-diisopropylethyl amine were added and the reaction mixture was stirred over night at RT. Then water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water, brine, sat. NaHCO3 solution, 1N HCl and again with brine. The organic layer was then dried (MgSO4) and concentrated. The remaining residue was purified by column chromatography (silica gel; ethyl acetate/cyclohexane 9:1) to yield 515 mg (87%) of <strong>[6314-28-9]benzo[b]thiophene-2-carboxylic acid</strong>[2-(3,4-dichloro-phenyl)-ethyl]-amide as a white solid. MS (ISP) 350.2 (M+H)+.A solution of 364 mg (1.04 mmol) of <strong>[6314-28-9]benzo[b]thiophene-2-carboxylic acid</strong>[2-(3,4-di-chloro-phenyl)-ethyl]-amide in 10 ml of THF was added dropwise to 5.2 ml of a 1 molar solution of BH3-THF complex in THF at 0 C. The reaction mixture was stirred for 30 min at RT and then heated to reflux over night. Then 2 ml of 6 N HCl were added very carefully at ambient temperature and the mixture was heated again to reflux for 2 hours. After cooling to RT, the pH was adjusted to 8-9 by addition of 1 N sodium hydroxide solution and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried with magnesium sulfate, filtered and concentrated. Final purification of the residue (silica gel; dichloromethane/methanol 95:5) yielded 113 mg (32%) of benzo[b]thiophen-2-ylmethyl-[2-(3,4-dichloro-phenyl)-ethyl]-amine as off-white solid. MS (ISP) 336.2 (M+H)+.
With magnesium(II) nitrate hexahydrate; urea In octane at 120℃; for 24h;
36%
Stage #1: benzo[b]thiophene-2-carboxylic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 25℃; for 0.0833333h;
Stage #2: With ammonium hydroxide In N,N-dimethyl-formamide at 25℃; for 0.5h;
Multi-step reaction with 2 steps
1: thionyl chloride / benzene / 2.5 h / Heating
2: NH3 / dioxane / 2 h / Ambient temperature
Multi-step reaction with 2 steps
1: thionyl chloride / toluene / 2 h / Reflux
2: ammonium hydroxide / water; dichloromethane / 1 h / 0 - 20 °C
4,4-difluoro-3-methyl-3-butenyl benzo[b]thiophene-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With sodium hydrogencarbonate; In DMF (N,N-dimethyl-formamide); at 100℃; for 2h;
Production Example 1; Production of compound (18) by the production method 1; To 5 ml of N,N-dimethylformamide were dissolved 0.40 g (1.8 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate and 0.33 g (1.9 mmol) of benzo[b]thiophene-2-carboxylicacid, followed by the addition of 0.46 g (5.5 mmol) of sodium hydrogencarbonate and stirring at 100 C for 2 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentrating under reduced pressure. The residue was purified with silica gel column chromatography (diisopropyl ether : hexane = 1:7) to obtain 0.48 g (yield: 93 %) of 4,4-difluoro-3-methyl-3-butenyl benzo[b]thiophene-2-carboxylate.1H-NMR (CDCl3, TMS) deltappm: 1.69 (3H, t), 2.42-2.49 (2H, m), 4.41 (2H, t), 7.38-7.49 (2H, m ), 7.85-7.90 (2H, m), 8.05 (1H, s)
6,6-difluoro-5-methyl-5-hexenyl benzo[b]thiophene-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With sodium hydrogencarbonate; In DMF (N,N-dimethyl-formamide); at 100℃; for 3h;
Production Example 2; Production of compound (3) by the production method 1; To 40 ml of N,N-dimethylformamide were dissolved 5.00 g (22 mmol) of 6,6-difluoro-5-methyl-5-hexenyl methanesulfonate and 4.30 g (24 mmol) of benzo[b]thiophene-2-carboxylicacid, followed by the addition of 6.00 g (71 mmol) of sodium hydrogencarbonate and stirring at 100 C for 3 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (diisopropyl ether:hexane=1:7) to obtain 5.50 g (yield: 81 %) of 6,6-difluoro-5-methyl-5-hexenyl benzo[b]thiophene-2-carboxylate.1H-NMR (CDCl3, TMS) deltappm: 1.52-1.62 (5H, m), 1.73-1.83 (2H, m), 2.03-2.09 (2H, m), 4.36 (2H, t), 7.38-7.49 (2H, m), 7.85-7.90 (2H, m), 8.06 (1H, s)
EXAMPLE 7 N-(3-cyano-4-piperidinophenyl)benzo[b]thiophene-2-carboxamide By the reaction and treatment in the same manner as in Example 6 using benzo[b]thiophene-2-carboxylic acid (1.7 g) and <strong>[34595-33-0]5-amino-2-piperidinobenzonitrile</strong> (2.0 g), the title compound (1.0 g) was obtained. melting point: 219-245 C.
EXAMPLE 17 N-[3-cyano-4-(4-methylpiperazin-1-yl)phenyl]benzo[b]thiophene-2-carboxamide By the reaction and treatment in the same manner as in Example 6 using benzo[b]thiophene-2-carboxylic acid (1.3 g) and <strong>[288251-82-1]5-amino-2-(4-methylpiperazin-1-yl)benzonitrile</strong> (1.6 g), the title compound (1.0 g) was obtained. melting point: 263-264° C. 1H-NMR (270 MHz, DMSO-d6)delta:2.24 (3H, s), 3.13-3.14 (4H, m), 3.34-3.35 (4H, m), 7.21 (1H, d, J=9.2 Hz), 7.47-7.51 (2H, m), 7.90-7.93 (1H, m), 8.00-8.08 (2H, m), 8.09 (1H, d, J=2.6 Hz), 8.32 (1H, s), 10.64 (1H, s).
77 Example 77
Example 77 Benzothiophene-2-carboxylic acid was treated with 1.5 equivalents of oxalyl chloride in dichloromethane in the presence of a catalytic amount of DMF to form benzothiophene-2-carbonyl chloride.
In N,N-dimethyl-formamide; benzene
1.A EXAMPLE 1
(A) A mixture of benzothiophene-2-carboxylic acid (2.5 g, 14.0 mmol), oxalyl chloride (2.0 g, 16 mmol), 25 ml of benzene and 0.3 ml of DMF is stirred for about 1.5 hours. The benzene solution is decanted off and solvent removed to give the acid chloride of benzothiophene-2-carboxylic acid.
With potassium hydroxide; In diethyl ether; ethanol; water;
84 g (0.438 mol) of methyl benzothiophene-2-carboxylate (compare, for example, J. Org. Chem. 37. 3224 [1972]) in 218 ml of ethanol and 36.8 g (0.656 mol) of potassium hydroxide in 100 ml of water are combined, and the mixture is stirred for 4 hours at reflux temperature. For working up, the reaction mixture is allowed to cool, the ethanol is then distilled off in vacuo, the aqueous residue is washed once using diethyl ether, and subsequently acidified with dilute hydrochloric acid, and precipitate which has settled out is filtered off with suction, washed once with water and dried. 60.1 g (77% of theory) of benzothiophene-2-carboxylic acid of melting point >220 C. are obtained. The following benzothiophene-2-carboxamide S,S-dioxides of the general formula (I) STR12 are obtained in a corresponding manner and following the general preparation instructions:
With sodium hydroxide; In methanol; water; at 20℃;
General procedure: To a solution of intermediate 2a-c (1 equiv.) in methanol was added 2N sodium hydroxide at ambient temperature. The reaction mixture was stirred for 4 h and the methanol was removed by rotary evaporation. The resultant mixture was adjusted to pH =5-6 with 1N HCl. The precipitated white solid was collected by filtration and dried to give the carboxylic acid intermediate (1a-c).4.7.1. benzo[b]thiophene-2-carboxylic acid (1a) 1H NMR (600 MHz, DMSO-d6) d 13.48 (s, 1H), 8.12 (s, 1H), 8.05(d, J = 8.1 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.53-7.49 (m, 1H), 7.48-7.44 (m, 1H).
With diphenyl phosphoryl azide; N-ethyl-N,N-diisopropylamine; for 8.0h;Heating / reflux;
Benzo[Z>]thiophen-2-yl-carbamic acid tert-butyl ester (1-B).; A solution of compound 1-A (14.4 g, 80.6 mmol), N,N-diisopropylethylamine (15.5 mL, 88.6 mmol) and diphenylphosphoryl azide (20.8 mL, 96.7 mmol) in -butanol (150 mL) was heated at reflux for 8 h. The solvent was evaporated in vacuo, and the residue purified by flash column chromatography on silica gel, eluting with dichloromethane, to afford compound 1-B as a colorless solid (18.9 g, 94%). 1H-NMR (DMSO-^): delta 1.50 (s, 9H), <n="183"/>6.78 (s, IH), 7.16 (d of d, IH), 7.27 (d of d, IH), 7.58 (d, IH), 7.77 (d, IH), 10.70 (br s, IH); MS: m/z 250.2 (MH+).
94%
With diphenylphosphoranyl azide; N-ethyl-N,N-diisopropylamine; for 8.0h;Reflux;
B. Benzo[b]thiophen-2-yl-carbamic acid tert-butyl ester (1d). A solution of 2-carboxybenzo[b]thiophene (14.4 g, 80.6 mmol), N,N-diisopropylethylamine (15.5 mL, 88.6 mmol) and diphenylphosphoryl azide (20.8 mL, 96.7 mmol) in t-butanol (150 mL) was heated at reflux for 8 hours. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography on silica gel, using dichloromethane as the eluant, to give the product as a colorless solid (18.9 g, 94%). 1H NMR (DMSO-d6): delta 1.50 (s, 9H), 6.78 (s, 1H), 7.16 (d of d, 1H), 7.27 (d of d, 1H), 7.58 (d, 1H) and 7.77 (d, 1H), 10.70 (br s, 1H); MS: m/z 250.2 (MH+).
94%
With diphenyl phosphoryl azide; N-ethyl-N,N-diisopropylamine; for 8.0h;Reflux;
Example 1 benzo[b]thiophen-2-yl-carbamic acid tert-butyl ester (1-B). A solution of compound 1-A (14.4 g, 80.6 mmol), N,N-diisopropylethylamine (15.5 mL, 88.6 mmol) and diphenylphosphoryl azide (20.8 mL, 96.7 mmol) in t-butanol (150 mL) was heated at reflux for 8 h. The solvent was evaporated in vacuo, and the residue purified by flash column chromatography on silica gel, eluting with dichloromethane, to afford compound 1-B as a colorless solid (18.9 g, 94%). 1H-NMR (DMSO-d6): delta 1.50 (s, 9H), 6.78 (s, 1H), 7.16 (d of d, 1H), 7.27 (d of d, 1H), 7.58 (d, 1H), 7.77 (d, 1H), 10.70 (br s, 1H); MS: m/z 250.2 (MH+).
64%
With diphenyl phosphoryl azide; triethylamine; for 5.0h;Heating / reflux;
A solution of benzo[b]thiophene-2 carboxylic acid (1.25 g, 7.03 mmol), diphenylphosphoryl azide (1.94 g, 7.03 mmol) and triethylamine (0.98 mL, 7.03 mmol) in tert-butanol (20 mL) was heated at reflux for 5 hours, at which time thin layer chromatography (DCM/Hexanes) indicates the reaction is complete. The reaction mixture was cooled to room temperature, poured into water and extracted with diethyl ether (3×). The combined ether extracts were washed with brine, dried over anhydrous sodium sulfate and then concentrated to afford a beige solid. Purification by column chromatography (SiO2 DCM/Hexanes) afforded compound 235 as a white solid 0.96 g (64%). HPLC-MS tR=2.7 Min(UV254 nm). Mass calculated for formula C13H15NO2S, M+249.33, observed LC/MS m/z 250.40 (M+H).
64%
With diphenyl phosphoryl azide; triethylamine; for 5.0h;Heating / reflux;
Example 235; A solution of benzo[b]thiophene-2 carboxylic acid (1.25 g, 7.03 mmol), diphenylphosphoryl azide (1.94 g, 7.03 mmol) and triethylamine (0.98 mL, 7.03 mmol) in tert-butanol (20 mL) was heated at reflux for 5 hours, at which time thin layer chromatography (DCM/Hexanes) indicates the reaction is complete. The reaction mixture was cooled to room temperature, poured into water and extracted with diethyl ether (3×). The combined ether extracts were washed with brine, dried over anhydrous sodium sulfate and then concentrated to afford a beige solid. Purification by column chromatography (SiO2 DCM/Hexanes) afforded compound 235 as a white solid 0.96 g (64%). HPLC-MS tR=2.7 Min (UV254nm). Mass calculated for formula C13H15NO2S, M+ 249.33, observed LC/MS m/z 250.40 (M+H).
62%
With diphenyl phosphoryl azide; triethylamine; for 16.0h;Heating / reflux;
Example 36; Preparation of 3-(1 -benzothien-2-yl)-6-(3-fluoro-2-hvdroxyphenyl)-2-methyl-5-(2- phenylethyl)-4(3H)-pvrimidinone; [00115] a; 1 ,1-Dimethylethyl 1-benzothien-2-ylcarbamate; EPO <DP n="39"/>[00116] To a solution of i-benzothiophene-2-carboxylic acid (5.0 g, 0.028 mol) in dry NBuOH (70 ml_) was added TEA (4.3 ml_, 0.031 mol). After 5 min. of stirring, DPPA (6.67 ml_, 0.031 mol) was added and the reaction was refluxed for 16 h. The reaction was concentrated and the resulting residue was diluted with ethyl acetate and washed successively with sat. NaHCO3 and brine. The organic phase was dried over Na2SO4, filtered and concentrated before purifying by silica chromatography (0 - 40% ethyl acetate/hexane) to afford pure product (4.35 g) in 62% yield. 1H NMR (400 MHz, DMSO-Cf6) £ ppm 1.50 (s, 9 H), 6.77 (s, 1 H), 7.15 (t, J=0.85 Hz, 1 H), 7.26 (t, J=0.85 Hz, 1 H), 7.59 (d, J=7.79 Hz, 1 H), 7.76 (d, J=7.78 Hz, 1 H), 10.2 (brs, 1 H).
With hydrogenchloride; sodium borohydrid; triethylamine; In tetrahydrofuran; water;
a) (benzo[b]thiophen-2-yl)methanol To a solution of benzo[b]thiophen-2-carboxylic acid (8.925 g) in tetrahydrofuran (50 ml) was added triethylamine (7.7 ml) at 0°C. Then, a solution of isopropyl chloroformate (6.816 g) in tetrahydrofuran (40 ml) was dropwise added, and the mixture was stirred at 0°C for 1 hr. The reaction mixture was filtered through a Celite pad, and the filtrate was poured into a solution of sodium borohydride (3.801 g) in water (50 ml) at 0°C. The mixture was stirred at room temperature for 1.5 hr. 1N Hydrochloric acid was added to the reaction mixture at 0°C to acidify the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over magnesium sulfate and concentrated to give the title compound (7.89 g).
N-((1S)-1-[((3S)-4-[(2-chloro-4-fluorophenyl)sulfonyl]amino}-3-hydroxybutyl)amino]carbonyl}-3-methylbutyl)-1-benzofuran-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;3-hydroxy-3,4-dihydrobenzotriazine-4-one; In dichloromethane; at 0 - 20℃;
To a solution of Lambda/1-((3S)-4-[(2-chloro-4-fluorophenyl)sulfonyl]amino}-3- hydroxybutyl)-L-leucinamide (67 mg, 0.15 mmol) in dichloromethane (2 mL) was added benzothiophene carboxylic acid (29 mg, 0.18 mmol) and HOOBt (2.0 mg, 0.01 mmol) at rt. After cooling the reaction mixture in an ice-bath, NMM (0.45 mmol) and EDCHCI (34 mg, 0.18 mmol) were added. After stirring overnight at rt, the reaction mixture was washed with 10 % (w/w) aqueous citric acid solution (1 mL) and brine. The organic solution was dried over MgSO4, concentrated under reduced pressure, and then purified by silica gel column chromatography (30% - 90% EtOAc/Hex) to give the title compound (0.06Og, 71%, white solid); LCMS: [MH]+= 570.2.
With 4-methyl-morpholine; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide;3-hydroxy-3,4-dihydrobenzotriazine-4-one; In dichloromethane; at 20℃; for 20h;
To a solution of phenylmethyl 4-L-leucyl-1-piperazinecarboxylate (1.0 g, 3.34 mmol) in CH2CI2 (13.5 ml_) was added EDC (571 mg, 2.98 mmol), HOOBt (8.8 mg, 0.054 mmol), i -benzothiophene-2-carboxylic acid (530mg, 2.98 mmol), and 4-methylmorpholine (1.5ml_, 13.5mmol). The reaction mixture was stirred at room temperature for 20 h whereupon the reaction was diluted with CH2CI2 and washed with 10% citric acid and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Column chromatography (10-80% ethyl acetate:hexane) afforded 1.3 g (88% yield) of the title compound as a white solid: LCMS (m/z): 494.2 (M+H).
With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 3-hydroxy-3,4-dihydrobenzotriazine-4-one; In dichloromethane; at 20℃;
To a dichloromethane solution of 1 ,1 -dimethylethyl {3-[(3-cyclohexyl-L- alanyl)amino]propyl}methylcarbamate (3.5 g, 10.26mmol) was added 1 -benzothiophene-2- carboxylic acid (2.192g g, 12.32 mmol), HOOBT (33 mg, 0.205 mmol), and NMM (3.38ml, 30.78mmol). The mixture was stirred several minutes whereupon EDCHCI (2.362 g, 12.32 mmol) was added. The reaction mixture was stirred overnight at RT. The solution was washed with 10% citric acid and brine, dried (MgSO4), filtered and concentrated to a solid. Purification by silica gel column chromatography (30%-90% ethyl acetate/hexane) gave the product as a white solid in 86% yield (4.4g): MS (m/z): 502(M+H).
1,1-dimethylethyl 3-hydroxy-4-[(L-leucylamino)methyl]-1-pyrrolidinecarboxylate[ No CAS ]
1,1-dimethylethyl 3-([N-(1-benzothien-2-ylcarbonyl)-L-leucyl]amino}methyl)-4-hydroxy-1-pyrrolidinecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
To a CH2CI2 (70 ml_, 0.2 M) solution of 1 ,1 -dim ethyl ethyl (3R.4R)- 3-hydroxy-4-[(L-leucylamino)methyl]-1-pyrrolidinecarboxylate (4.6 g, 14.1 mmol) was added i-benzothiophene-2-carboxylic acid (2.76 g, 15.5 mmol ), EDC (3.24 g, 16.9 mmol), HOOBt (0.46 g, 2.82 mmol) and NMM (3.8 ml_, 35.26 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was quenched by the addition of 1 N HCI, and the phases were separated. The organic solution was washed sequentially with saturated NaHCO3 and brine, dried (Na2SO4), filtered and concentrated to give crude product. Purification by silica chromatography (40 - 100% ethyl acetate/hexanes) gave the title compound as a white foam in 87% yield (6.0 g). LCMS (m/z): 490 (M+H)+.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;
General procedure I: Amide coupling:To a 0.1 M stirred solution of a carboxylic acid derivative in CH2Cl2 are added EDC (1.3 eq), HOBt (1.3 eq), Et3N (1.3 eq) and the spiropiperidine derivative (1 eq). The mixture is stirred over night at RT and then poured onto water and extracted with CH2Cl2. The combined organic phases are dried over Na2SO4 and concentrated in vacuo. Flash chromatography or preparative HPLC affords the title compound.; Example 11'-(1-Benzothien-2-ylcarbonyl)-<strong>[38309-60-3]3H-spiro[2-benzofuran-1,4'-piperidine]</strong> Amide coupling according to general procedure I:Amine: 3H-Spiro[2-benzofuran-1,4'-piperidine] (described in J. Org. Chem. 1976, 41, 2628),Acid: Benzo[b]thiophene-2-carboxylic acid,ES-MS m/e (%): 350.2 (M+H+).
1-[(2-benzothienylcarbonyl)amino]cyclohexanecarboxylic acid phenylmethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃;
Reference Example 152 1-[(2-Benzothienylcarbonyl)amino]cyclohexanecarboxylic acid phenylmethyl ester Under ice-cooling, 5.9 g (31 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 5 g (28 mmol) of 2-benzothiophenecarboxylic acid, 6.5 g (28 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and 4.5 g (29 mmol) of 1-hydroxybenzotriazole in methylene chloride. After the mixture was stirred at room temperature overnight, the reaction solvent was distilled off under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate twice. The obtained organic layer was washed with a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and then saturated brine, it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, diethyl ether was added to the obtained residue, and the mixture was stirred overnight. The crystal was collected by filtration and heated and dried under reduced pressure to obtain 10 g (91%) of the title compound. 1H-NMR (CDCl3, delta): 1.25-1.78 (6H, m), 1.93-2.05 (2H, m), 2.12-2.25 (2H, m), 5.18 (2H, s), 6.24 (1H, s), 7.20-7.38 (5H, m), 7.38-7.51 (2H, m), 7.77 (1H, s), 7.80-7.91 (2H, m)
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃;
Under ice-cooling, 5.9 g (31 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 5 g (28 mmol) of 2-benzothiophenecarboxylic acid, 6.5 g (28 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and 4.5 g (29 mmol) of 1-hydroxybenzotriazole in methylene chloride. After the mixture was stirred at room temperature overnight, the reaction solvent was distilled off under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate twice. The obtained organic layer was washed with a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and then saturated brine, and it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, diethyl ether was added to the obtained residue, and the mixture was stirred overnight. The crystal was collected by filtration and heated and dried under reduced pressure to obtain 10 g (91%) of the title compound.1H-NMR (CDCl3, delta): 1.25-1.78 (6H, m), 1.93-2.05 (2H, m), 2.12-2.25 (2H, m), 5.18 (2H, s), 6.24 (1H, s), 7.20-7.38 (5H, m), 7.38-7.51 (2H, m), 7.77 (1H, s), 7.80-7.91 (2H, m)
91%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃;
REFERENCE EXAMPLE 1971-[(2-Benzothienylcarbonyl)amino]cyclohexanecarboxylic acid phenylmethyl ester Under ice-cooling, 5.9 g (31 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 5 g (28 mmol) of 2-benzothiophenecarboxylic acid, 6.5 g (28 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and 4.5 g (29 mmol) of 1-hydroxybenzotriazole in methylene chloride. After the mixture was stirred at room temperature overnight, the reaction solvent was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate twice. The obtained organic layer was washed with a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and then saturated brine, and it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, diethyl ether was added to the obtained residue, and the mixture was stirred overnight. The crystal was collected by filtration and heated/dried under reduced pressure to obtain 10 g (91%) of the title compound.1H-NMR (CDCl3, delta): 1.25-1.78 (6H, m), 1.93-2.05 (2H, m) 2.12-2.25 (2H, m), 5.18 (2H, s), 6.24 (1H, s), 7.20-7.38 (5H, m), 7.38-7.51 (2H, m), 7.77 (1H, s), 7.80-7.91 (2H, m)
91%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃;
Reference example 188; 1-[(2-Benzothienylcarbonyl)amino]cyclohexanecarboxylic acid phenylmethyl ester [Show Image] Under ice-cooling, 5.9 g (31 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 5 g (28 mmol) of 2-benzothiophenecarboxylic acid, 6.5 g (28 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and 4.5 g (29 mmol) of 1-hydroxybenzotriazole in methylenechloride. After the mixture was stirred at room temperature overnight, the reaction solvent was distilled off under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate twice. The obtained organic layer was washed with a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution, and then saturated brine, followed by drying with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and diethyl ether was added to the obtained residue, followed by stirring of the mixture overnight. The cystal was collected by filtration and was heated and dried under reduced pressure to obtain 10 g (91%) of the title compound. 1H-NMR (CDCl3, delta): 1.25-1.78 (6H, m), 1.93-2.05 (2H, m), 2.12-2.25 (2H, m), 5.18 (2H, s), 6.24 (1H, s), 7.20-7.38 (5H, m), 7.38-7.51 (2H, m), 7.77 (1H, s), 7.80-7.91 (2H, m)
Benzo[b]thiophene-2-carboxylic acid 2-[(benzo[b]thiophene-2-carbonyl)-(R)-amino]-3-[4-(3-hydroxycarbamoyl-propyl)-piperidin-1-yl]-3-oxo-propyl ester; A mixture of HOAt (20 mg, 0.15 mmols), <strong>[73724-45-5]<strong>[73724-45-5]Fmoc-D-Ser</strong>-OH</strong> (49 mg, 0.15 mmols) and diisopropylcarbodiimide (0.024 ml, 18 mg, 0.15 mmols) in 3 ml of DMF/DCM, previously maintained at ambient temperature for an hour, is added to the resin obtained in Step C, re-swollen in 2 ml of DCM for 20 minutes. The suspension is agitated for 18 hours at ambient temperature then the resin is filtered off and washed sequentially with DMF (2.x.2 ml) and DCM (2.x.2 ml).The resin is filtered off and suspended in 2 ml of a solution of 20percent piperidine in dichloromethane. After 30 minutes the resin is filtered off and washed sequentially with DMF (2.x.2 ml) and DCM (2.x.2 ml).To the resin obtained in Step E and re-swollen in 2 ml of DCM for 20 minutes are added the mixture of HOAt (68 mg, 0.5 mmols), benzo[b]thiophene-2-carboxylic acid (90 mg, 0.5 mmols) and 0.08 ml of diisopropylcarbodiimide (63 mg, 0.5 mmols) in 3 ml of DMF/DCM previously held at ambient temperature for 1 hour. The suspension is agitated for 18 hours at ambient temperature. The resin is filtered off and washed sequentially with DMF (2.x.2 ml) and DCM (2.x.2 ml).100 mul of trifluoroacetic acid and 100 mul of triethylsilane are added to the thus obtained resin, re-swollen in 2 ml DCM for 20 minutes. It is maintained under agitation for 15 minutes at ambient temperature. The resin is filtered off and washed twice with DCM and MeOH alternately. The filtrates are pooled and evaporated to dryness. Grinding the crude product thus obtained with ethyl ether provides the desired product (41 mg, 75percent yield) with a purity of 95percent (HPLC, 214 nm). MF: C30H31N3O6S2, MW: 593.73.
With Bromotrichloromethane; 4-(diphenylphosphino)-benzyltrimethylammonium bromide; triethylamine; In tetrahydrofuran; dichloromethane; at 60℃; for 6h;Inert atmosphere;
General procedure: IS-PPh3 (746 mg, 1.8 mmol) was dried by a vacuum pump for 2 h at 70 C. To a flask containing IS-PPh3 were added 4-methoxycarboxylic acid (152 mg, 1.0 mmol), BrCCl3 (357 mg, 1.8 mmol), benzylamine (129 mg, 1.2 mmol), triethylamine (0.14 mL, 1.0 mmol), and THF (4 mL). The obtained mixture was stirred for 6 h at 60 C under Ar atmosphere. After the reaction, diethyl ether (10 mL) and aq HCl (1 M, 2 mL) were added at 0 C and the obtained mixture was stirred for 15-30 min at room temperature. Then, the reaction mixture was poured into water (8 mL) and the obtained mixture was extracted with diethyl ether (10 mL×4). The combined organic layer was washed with water (10 mL) and brine (10 mL), and then dried over Na2SO4. After removal of the solvent under reduced pressure, N-benzyl-4-methoxybenzamide was obtained in 93% yield with 99% purity, as estimated by 1H NMR measurement. For cinnamic and aliphatic amides (entries 18-25 in Table 2) and indole-2-carboxamide (entry 16 in Table 2), the reaction mixture was poured into water (8 mL) and the obtained mixture was extracted with chloroform (10 mL×4). The combined organic layer was washed with water (10 mL) and brine (10 mL), and then dried over Na2SO4. After removal of the solvent under reduced pressure, N-benzylamide was obtained. or the recovery of IS-Ph3PO, NaCl (5.0 g) was added to the aqueous layer. The aqueous solution was extracted with CHCl3 (10 mL×5) and the combined organic layer was dried over NaSO4. After removal of the solvent, IS-Ph3PO containing a trace amount of IS-Ph3P was obtained in 95% yield.
With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 15h;
General procedure: A mixture of compound 10 (135 mg, 0.49 mmol) and 4-(thiophen-3-yl)benzoic acid (99.4 mg, 0.49 mmol) in dichloromethane (10 mL) was stirred at 0 C (ice-water bath). Dicyclohexylcarbodiimide(DCC) (121 mg, 0.59 mmol) and hydroxybenzotriazole(HOBt) (80 mg, 0.59 mmol) were added to the above solution.The ice bath was removed, and the reaction mixture was stirred at ambient temperature for 15 h. Dichloromethane (20 mL) was added into the reaction mixture, and the solution was washed with saturated aqueous NaHCO3 solution (3*10 mL). The organic layer was dried over Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography using dichloromethane-methanol (20:1) as the mobile phase to give 11a as a white solid (194 mg, 86%). TLC Rf 0.20 (dichloromethane-methanol 20:1); mp 125.5-126.6 C. 1H NMR(300 MHz, CDCl3) delta 7.75 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H),7.43 (s, 1H), 7.33 (s, 2H), 7.19 (s, 1H), 6.81-6.94 (m, 4H), 3.85 (s,3H), 3.44 (q, J = 5.1 Hz, 2H), 3.25-3.20 (m, 4H), 2.83-2.76 (m,4H), 2.57 (t, J = 5.2 Hz, 2H), 1.93 (t, J = 4.2 Hz, 2H), 1.61-1.69 (m,4H). 13C NMR (CDCl3, 300 MHz): 167.4, 151.4, 142.1, 141.2,138.8, 133.4, 127.5, 126.6, 126.3, 126.1, 121.3, 121.0, 120.7,117.9, 111.6, 57.1, 56.1, 55.3, 54.3, 52.5, 51.8, 39.4, 27.7, 27.3,25.5. HRMS (ESI) Calcd for C27H33N3O2S (M+H)+: 464.2372. Found:464.2379. Anal. (C27H33N3O2S 1.5H2C2O4) C, H, N.
N-(3-(8-nitroquinolin-4-yl)phenyl)benzo[b]thiophene-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃;
General procedure: A mixture of compound 9 or 10 (0.11 mmol), O-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.21mmol), and N,N-diisopropylethylamine (0.54 mmol) in dry DMF (1.5 mL) was stirred at 0 C for 30 min. The appropriate acid (0.16 mmol) was then added. After stirring at room temperature for 1-4 h, the reaction mixture was diluted with saturated aqueous NaHCO3, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with EtOAc-hexane (1:1 to 1:3) to afford the corresponding compounds 11a-o and 12a-c.
With 2,2-diphenyl-1-picrylhydrazyl; tungusten oxide/alumina; oxygen; In acetone; at 80℃; for 4h;
General procedure: A 50 mL three-necked glass flask was charged with a mixture ofDPPH (98.6 mmg, 0.25 mmol),WO3/Al2O3 (0.844 g,W: 3 mmol), alcohol(50 mmol), and 30 mL acetone. One neck was connected with awater condenser to reflux. Besides, there must be a deflated balloonon the top of the condenser to collect the evaporated acetone. And anotherneck was connected with a dropping funnel to add acetone.Then an oxygen steel cylinder was used to slowly provide the oxygenfor the reaction through the third neck with an air duct. The ventilationspeed must be adjusted according to the size of the balloon. Moreover,to maintain the airtightness of the whole reaction, the liquid level inthe dropping funnel should be kept in a certain height. Then themixturewas stirred at 80 °C for 4 h. The reaction mixture was subjected to GCanalysis to supervise the reaction process till the oxidation ended.
3-O-[benzo[b]thiophene-2-carbonyl]caudatin[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86.2%
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃;
General procedure: The DCC (1.2 equiv) was added to the solution of caudatin(0.2 mmol), DMAP (0.2 equiv), and appropriate carboxylic acid (1.2 equiv) in anhydrous CH2Cl2 (8 mL) at 0 C.The resulting mixture was stirred at room temperature until the starting material was not observed by TLC. The reaction mixture was filtered, and the residue was washed with CH2Cl2 (210 mL). Then, the CH2Cl2 solution was washed with 5% HCl (330 mL), saturated NaHCO3 (330 mL) and saturated NaCl (330 mL), respectively. Subsequently, the organic layer was dried by Na2SO4 and concentrated to dryness under reduced pressure. At last, the residue was purified by column chromatography over the silica gel with petroleum ether/acetone (60:40 - 95:5) to yield the pure target compounds.
With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In N,N-dimethyl-formamide; at 20℃; for 12h;
General procedure: In distinct reactors, carboxylic acids (1 equiv) 17-21, 1-hydroxybenzotriazole (1.2 equiv), and suitable amines 22-24(1.2 equiv), were dissolved in dimethylformamide at room temperature. DCC (1.2 equiv) was added, and the mixtures were stirred at room temperature overnight. The precipitate of dicyclohexylurea was filtered off and the filtrate wasadded in cold stirring water and extracted with ethyl acetatex 3. The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. Each crude product was purified by flash chromatography on a short pad of silica gel.
With acetic acid; isopentyl nitrite at 80℃; for 24h; Inert atmosphere;
Benzo[b]thiophene-2-carboxylic acid (15)
Benzo[b]thiophene-2-carboxamide (0.1772 g, 1 mmol)was dissolved in acetic acid (2 mL), and to the stirring solution was added amyl nitrite (0.40 mL, 3mmol). The reaction was placed under N2 atmosphere and heated to 80 °C for 24 hours, whereupon thereaction was complete by consumption of starting material by TLC. The solution was condensed andco-evaporated with toluene (2 x 5 mL), then purified via recrystallization from acetone. The resultingsuspension was filtered to afford off-white powder (0.0846 g, 0.47 mmol)
N-(3-(1H-imidazol-1-yl)propyl)benzo[b]thiophene-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 2h;
N-(3,4-dimethoxyphenethyl)benzo[b]thiophene-2-carboxamide (7)
General procedure: A solution of compound 4b (0.4 g, 2.25 mmol),compound 3 (0.45 g, 2.47 mmol), HBTU (1.01 g, 2.69 mmol) and Et3N (0.48 mL, 3.37 mmol) in DMF (10 mL) was stirred at room temperature for 2 h.Then, the mixture was diluted with water (100 mL), and extracted with EtOAc (50mL × 3). The combined organic layers were dried over MgSO4, concentrated and purified by silica gel column chromatography (CH2Cl2: MeOH = 100:2) to give compound 7 (0.63 g, 73%) as a yellow solid, mp: 93-96 C.
N-(biphenyl-2-one)benzo[b]thiophene-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 14h;
<strong>[6314-28-9]benzo[b]thiophene-2-carboxylic acid</strong> (159 mg, 0.892 mmol), 2-amino-biphenyl (156 mg, 0.922 mmol),DCC (393 mg, 1.90mmol)and DMAP (26 mg, 0.21 mmol)was dissolved in dichloromethane (20 mL) and stirred for 14 hours at room temperature. Thin film chromatography (TLC) in verifying, new the spot location changes accordingly once created, after adding water to the composition, a reaction mixture of a, die chloro methane at extracted times 2. Extracted organic layer are dried, in the form of tetrabutylammonium magnesium, was, concentrating it under reduced pressure. Concentrated reaction mixture column chromatography (silica gel, ethyl acetate/n = 1/9-hexanediol) for purifying the white solid thereby, a desired compound (102 mg, 35%) is obtained.
35%
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 14h;
<strong>[6314-28-9]benzo[b]thiophene-2-carboxylic acid</strong> ( 159 mg , 0.892 mmol ) ,2-amino-biphenyl (156 mg, 0.922 mmol), DCC (393 mg, 1.90mmol) and DMAP ( 26 mg , 0.21 mmol) dissolved in dichloromethane (20 mL) and stirred for 14 hours at room temperature .When confirmation thin layer chromatography (TLC), when a new spot is generated , and then adding water to the reaction mixture , dichloromethane coming And extracted twice with . The extracted organic layer was dried over magnesium sulfate and concentrated under reduced pressure. It was purified by column chromatography (silica gel , ethyl acetate / n- hexane = 1/9 ) to obtain the object compound ( 102 mg , 35 % ) as a white solid
35%
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 14h;
Benzo [b] thiophene-2-carboxylic acid (159 mg, 0.892 mmol), 2-amino-biphenyl (156 mg, 0.922 mmol), DCC (393 mg, 1.90mmol) and DMAP (26 mg, 0.21 mmol) It was dissolved in dichloromethane (20 mL), and stirred for 14 hours at room temperature. when thin layer chromatography (TLC) check when, a new spot is generated, and then adding water to the reaction mixture, dichloromethane comingAnd extracted twice with. The extracted organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Column The concentrated reaction mixture was purified by chromatography (silica gel, ethyl acetate / n- hexane = 1/9) to obtain the object compound (102 mg, 35%) as a white solid.
N-(benzo[b]thiophene-2-carbonyl)-N-(6-phenylpyrimidin-4-yl)benzo[b]thiophene-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; trichlorophosphate; at 80℃; for 1h;
General procedure: Quinoline-4-carboxylic acid (36.4 mg, 0.226 mmol),3-chloro-5 - (methylthio) benzene amine (50.0 mg, 0.205 mmol) and POCl3 (34.6 mg, 0.226 mmol), pyridine (1 mL) was dissolved in, 80 was stirred for 1 hour dongan. When thin layer chromatography (TLC) check when, a new spot is confirmed, water was added to the reaction mixture, and extracted twice with dichloromethane. And the extracted organic layer was dried using magnesium sulfate, vacuum concentrated and, after the water was removed by filtration of the organic extract over MgSO4 and concentrated by silica gel preparative thin layer chromatography (preparative TLC, ethyl acetate / n- hexane = l / l ) to give to give the title compound (11%) of a white solid.
tert-butyl 4-[4-[(4-aminopiperidin-1-yl)methyl]-2-bromophenoxy]piperidine-1-carboxylate[ No CAS ]
tert-butyl 4-[4-[[4-(benzo[b]thiophene-2-amido)piperidin-1-yl]methyl]-2-bromophenoxy]piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;
Benzothiophene-2-carboxylic acid 40 mg (0.22 mmol) and obtained in Preparation Example 2 tert- butyl 4- [4 - [(4-amino-piperidin-1-yl) methyl] -2-bromo- phenoxy] piperidine-1 - carboxylate 109 mg (0.24 mmol) 5 ml of N, N-dimethylformamide was then dissolved and bis(2-oxo-3-oxazolidinyl)phosphinic chloride( BOP-Cl) 84 mg (0.33 mmol) and triethylamine 92 ul (0.66 mmol) was added and the resultant mixture was stirred at room temperature for 16 hours. Water was added to the 30 ml and extracted with ethyl acetate 30 ml. The organic layer was dried and then anhydrous magnesium sulfate (MgSO4), washed with brine, chromatography and the filtrate was purified by silica gel column chromatography (dichloromethane: methanol, 30: 1, v / v) to give the target compound as a yellow 82% of the number to 112mg to give the (0.18mmol).
82%
With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;
To a solution of thieno[3,2-b]pyridine-7-carboxylic acid10(568 mg, 3.18 mmol) and tert-butyl 4-(4-((4-aminopiperidin-1-yl)methyl)-2-bromophenoxy)piperidine-1-carboxylate15(109 mg, 0.24 mmol) in DMF (5 mL) were added bis(2-oxo-3-oxazolidinyl)phosphinic chloride(BOP-Cl, 84 mg, 0.33 mmol) and triethylamine (0.092 ml, 0.66 mmol). After being stirred at room temperature for 16 h, the mixture was diluted with water (30 mL), and extracted with ethyl acetate (30 mL x 2). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo, giving a residue that was subjected to column chromatography on silica gel (3% MeOH/CH2Cl2) to afford 112 mg (82%) of the boc-protected compound11.1H NMR (300 MHz, CDCl3)delta7.79-7.89 (m, 2H), 7.75 (s, 1H), 7.53 (s, 1H), 7.35-7.45 (m, 2H), 7.17 (d,J= 8.4 Hz, 1H), 6.86 (d,J= 8.4 Hz, 1H), 6.02 (d,J= 7.8 Hz, NH), 4.50-4.60 (m, 1H), 3.94-4.08 (m, 1H), 3.58-3.70 (m, 2H), 3.43-3.55 (m, 2H), 3.43 (s, 2H), 2.80-2.90 (m, 2H), 2.11-2.22 (m, 2H), 2.00-2.10 (m, 2H), 1.81-1.91 (m, 4H), 1.51-1.69 (m, 2H), 1.47 (s, 9H).
With tetrabutylammomium bromide; potassium hydroxide; In water; at 135℃; under 7500.75 Torr; for 9h;Autoclave; Inert atmosphere;
A stirred and temperature controlled autoclave was charged with 17.8 g (0.l mol) of 3-mercaptocoumarin, 30% of an aqueous solution of potassium hydroxide, 0.21 ml (about 40 g), 1.0 g (0 · 003m l) of tetrabutylammonium bromide was charged to N2 at about 1Mpa and heated to 135 C for 9 h. The reaction was cooled to room temperature and concentrated hydrochloric acid (36. 5% by weight) was added to the kettle solution to be weakly acidic (i.e., adjusted to pH 3-4). The filter cake was dried (100 C to constant weight) to give a yellow solid 8. 8 g of benzothiophene-2-carboxylic acid was obtained in a yield of 49.4%.
(S)-ethyl (benzothiophene-2-carbonyl)alaninate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
General procedure: Furan-2-carboxylic acid, thiophene-2-carboxylic acid, 5-methylthiophene-2-carboxylic acid, benzofuran-2-carboxylic acid, benzothiophene-2-carboxylic acid, and amino acid ester hydrochlorides were obtained from commercial supplies and were used without further purification. To a two-necked flask, an amino acid ester hydrochloride (1.1 mmol), 1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride (EDC, 0.29 g, 1.5 mmol), HOBt (0.20 g, 1.5 mmol), Et3N (0.42 mL, 3.0 mmol), and CHCl3 or DMF (2.2 mL) were added, and the mixture was stirred at 0 C for 10 min. Furan-2-carboxylic acid or thiophene-2-carboxylic acid dissolved in DMF (2.2 mL) was added, and then stirred for 17 h. The reaction mixture was diluted with water and extracted with EtOAc (3 x 20 mL). The organic phase was then washed with 3 N HCl aq. (3 x 20 mL), saturated NaHCO3 aq. (3 x 20 mL), and brine (20 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/EtOAc = 1/1) to obtain the product. The purity of the product was confirmed by 1H-NMR. Stereochemistry of the final product was measured by high-performance liquid chromatography (HPLC) with a chiral column (Compound 16). The chart is shown in the supporting information.
(R)-ethyl (benzothiophene-2-carbonyl)phenylalaninate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
23%
General procedure: Furan-2-carboxylic acid, thiophene-2-carboxylic acid, 5-methylthiophene-2-carboxylic acid, benzofuran-2-carboxylic acid, benzothiophene-2-carboxylic acid, and amino acid ester hydrochlorides were obtained from commercial supplies and were used without further purification. To a two-necked flask, an amino acid ester hydrochloride (1.1 mmol), 1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride (EDC, 0.29 g, 1.5 mmol), HOBt (0.20 g, 1.5 mmol), Et3N (0.42 mL, 3.0 mmol), and CHCl3 or DMF (2.2 mL) were added, and the mixture was stirred at 0 C for 10 min. Furan-2-carboxylic acid or thiophene-2-carboxylic acid dissolved in DMF (2.2 mL) was added, and then stirred for 17 h. The reaction mixture was diluted with water and extracted with EtOAc (3 x 20 mL). The organic phase was then washed with 3 N HCl aq. (3 x 20 mL), saturated NaHCO3 aq. (3 x 20 mL), and brine (20 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/EtOAc = 1/1) to obtain the product. The purity of the product was confirmed by 1H-NMR. Stereochemistry of the final product was measured by high-performance liquid chromatography (HPLC) with a chiral column (Compound 16). The chart is shown in the supporting information.
Stage #1: benzo[b]thiophene-2-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 1h;
Stage #2: L-serine isopropyl ester hydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 70℃; for 6h;
4.10. General procedure for the synthesis of compounds (12a-t)
General procedure: To a solution of the intermediate acid compound 1a-f (1 equiv.)in anhydrous DMF was added EDCI (1.1 equiv) and HOBt (1.1equiv), respectively. The reaction mixture was stirred for 1 h at ambient temperature, and the L-serine ester (1.1 equiv.) and DIEA(3 equiv.) were added. The solution was heated to 70 C for 6 hand then cooled to room temperature. The reaction mixture was poured into ice water, and the resulting solid was filtered and dried to give the desired compound.
N-(4-tert-butyl-1,3-thiazol-2-yl)-1-benzothiophene-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 80℃; for 3h;
To a solution of benzo[t]thiophene-2-carboxylic acid (274 mg, 1.54 mmol) and 4- (tert-butyl)thiazol-2-amine (200 mg, 1.28 mmol) in DMF (0.84 mL) was added HATU (585 mg, 1.54 mmol) followed by DIEA (791 uL, 4.90 mmol). The mixture was heated to 80 C for 3 h then cooled to ambient temperature, diluted with ethyl acetate (5 mL) and brine (5 mL), and extracted with ethyl acetate (1X5 mL). The organics were combined, washed with brine (2X5 mL), dried with sodium sulfate, filtered, and concentrated. Flash chromatography (0-60% hexanes/ethyl acetate) provided N-(4-tert-butyl-1 ,3-thiazol-2-yl)-1 -benzothiophene-2- carboxamide (397 mg, 98% yield) as an off-white solid. (A145) H NMR (400 MHz, DMSO-d6) delta 12.92 (s, 1 H), 8.63 (s, 1 H), 8.38 - 7.81 (m, 2H), 7.71 - 7.29 (m, 2H), 6.85 (s, 1 H), 3.33 (s, 3H), 1.31 (s, 9H). LCMS for C16H16N202S, found 317 [M+H]+.
With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 12h;
General procedure: To a solution of 3a-3o (1.94 mmol) in anhydrous dichloromethane(20.0 mL) and HATU (2.33 mmol) in the presence of DIEA(3.89 mmol), tert-butylpiperazine-1-carboxylate (2.14 mmol) wasadded and stirred for 12 h. After completion, dilute hydrochloricacid solution was added, extracted with dichloromethane andwashed with saturated sodium carbonate solution three times. Thecombined organic layers were washed with brine and dried with sodium sulfate, filtered, concentrated, and purified by silica gelchromatography with petroleum ether/ethyl acetate as eluent togive pure 4a-4o [34].
N,N′-(decane-1,10-diyl)bis(benzo[b]thiophene-2-carboxamide)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 12h;
In a round bottom flask, 0.400 g of benzothiophene-2-carboxylic acid, 0.176 g of decanediamine, 0.430 g of EDCI, 0.025 g of DMAP, and 10 mL of anhydrous DMF were sequentially added, and the mixture was stirred at room temperature for 12 hours. The pale yellow solid precipitated, suction filtered, washed with dichloromethane (2×2.5 mL) and water (3×5 mL) and dried.Dry to obtain 0.232g of pale yellow solid.The yield was 46% (see Figure 27 for the synthetic route and Figure 28 for the characterization map)
46%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;
General procedure: Compounds 9e-35e were obtained by using one-pot reaction. A mixture of aromatic acid (6.30 mmol), EDCI (7.50 mmol), DMAP (0.60 mmol), and anhydrous dichloromethane (20 mL) was stirred to dissolve, then decane-diamine (3 mmol) was added and stirred at room temperature for 12 h. The mixture solution was filtered under reduced pressure. After that, the residue was washed with little amount of CH2Cl2and water successively, and dried to give the solid. Then, the residue was purified on preparative TLC eluted with chloroform/methanol = 40:1-7:1 to yield compounds 26e, 28e, 30e, and 31e.
With trichloroisocyanuric acid; triphenylphosphine; In dichloromethane; water; at 20℃; for 0.333333h;Sonication;
General procedure: To a cold solution of triphenylphosphine (0.201 g, 0.768 mmol) in dichloromethane (2 mL), trichloroisocyanuric acid (0.0595 g, 0.256 mmol) was added with continuous sonication for 5 minutes. Carboxylic acid (0.64 mmol) was then added, and sonication was continued for 5 minutes. The temperature was raised to room temperature before adding an aqueous solution of sodium cyanamide (0.050 g, 0.768 mmol, 1 mL). After sonication for 10 minutes, the crude product was added with 1 M HCl, then extracted with EtOAc (3x10 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was then purified by short column chromatography using 10% MeOH/EtOAc as the eluent.
phenethyl 1-benzothiophene-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
Stage #1: benzo[b]thiophene-2-carboxylic acid With sodium carbonate In N,N,N,N,N,N-hexamethylphosphoric triamide for 0.5h; Inert atmosphere;
Stage #2: 1-phenyl-2-bromoethane With potassium iodide In N,N,N,N,N,N-hexamethylphosphoric triamide at 0 - 20℃; for 26h; Inert atmosphere; Sealed tube;
3.1.1. General Procedure for the Esterification of Thianaphtene-2-carboxylic Acid
General procedure: Thianaphtene-2-carboxylic acid (3) (1 eq) was added to a vigorously stirred solution of Na2CO3(1.2 eq) in 7 mL of HMPA and the reaction vessel was flushed with argon. After 30 min of stirring, the appropriate bromide (1.2 eq) was added dropwise to the reaction mixture over a period of 10 min. A catalytic amount of KI was added to the reaction vessel, which is then thoroughly flushed with argon gas and sealed under balloon pressure. The reaction mixture was stirred in an ice bath for 2 h and at room temperature for 24 h under argon atmosphere. The resulting solution was quenched with ice/water and stirred for 30 min. The aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic fractions were then washed with brine (3 × 50 mL), decolorized with activated charcoal, dried over MgSO4, and concentrated under vacuum. The resulting crud product was purified by flash chromatography.
Stage #1: Benzo[b]thiophene-2-carboxylic acid; p-chloroaniline hydrochloride With 4-methyl-morpholine; 4-dimethylaminopyridine In dichloromethane at 20℃;
Stage #2: With N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 20℃;
Compound 65
Benzo[b]thiophene-2-carboxylic acid (900 mg, 5.05 mmol), 4-chloroaniline hydrochloride (870 mg, 5.30 mmol) and DMAP (250 mg, 2.02 mmol) were dissolved in CH2CI2 (30 mL). NMM (920 mg, 9.09 mmol) was added and reaction mixture was stirred 10 min at room temperature. 3-(Ethyliminomethyleneamino)-/V,//-dimethylpropan-l-amine hydrochloride (1.45 g, 7.58 mmol) was added in one portion and the resulting solution was stirred at room temperature for 16 h. The resulting suspension was evaporated in vacuo and the residue suspended in a small amount of CH2CI2. The solids were collected by filtration and washed with a minimum of CH2CI2 to give desired product as a white solid (1.23 g, 85%). 1H-NMR (300 MHz, DMSO-dg): 10.63 (s, 1H), 8.38-8.35 (m, 1H), 8.10-7.98 (m, 2H), 7.85-7.77 (m, 2H), 7.54-7.40 (m, 4H). UPLC-ESI (m/z): 288, 290 [M+H]+.
85%
Stage #1: Benzo[b]thiophene-2-carboxylic acid; p-chloroaniline hydrochloride With 4-methyl-morpholine; 4-dimethylaminopyridine In dichloromethane at 20℃;
Stage #2: With N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 20℃;
Compound 65
Benzo[b]thiophene-2-carboxylic acid (900 mg, 5.05 mmol), 4-chloroaniline hydrochloride (870 mg, 5.30 mmol) and DMAP (250 mg, 2.02 mmol) were dissolved in CH2CI2 (30 mL). NMM (920 mg, 9.09 mmol) was added and reaction mixture was stirred 10 min at room temperature. 3-(Ethyliminomethyleneamino)-/V,//-dimethylpropan-l-amine hydrochloride (1.45 g, 7.58 mmol) was added in one portion and the resulting solution was stirred at room temperature for 16 h. The resulting suspension was evaporated in vacuo and the residue suspended in a small amount of CH2CI2. The solids were collected by filtration and washed with a minimum of CH2CI2 to give desired product as a white solid (1.23 g, 85%). 1H-NMR (300 MHz, DMSO-dg): 10.63 (s, 1H), 8.38-8.35 (m, 1H), 8.10-7.98 (m, 2H), 7.85-7.77 (m, 2H), 7.54-7.40 (m, 4H). UPLC-ESI (m/z): 288, 290 [M+H]+.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
