* 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] Synthetic Communications, 1991, vol. 21, # 7, p. 959 - 964
[2] Justus Liebigs Annalen der Chemie, 1937, vol. 527, p. 83,101
2
[ 6345-55-7 ]
[ 19301-35-0 ]
Reference：
[1] Synthetic Communications, 1991, vol. 21, # 7, p. 959 - 964
[2] Justus Liebigs Annalen der Chemie, 1937, vol. 527, p. 83,101
[3] Journal of the American Chemical Society, 1956, vol. 78, p. 5351,5354
[4] Journal of the American Chemical Society, 1956, vol. 78, p. 5351,5354
3
[ 6345-55-7 ]
[ 4965-26-8 ]
Yield
Reaction Conditions
Operation in experiment
95%
With copper In quinoline; ethyl acetate at 190℃; Inert atmosphere
To a solution of 5-nitrobenzothiophene-2-carboxylic acid (50) (40 g, 179 mmol) in quinoline (350 mL) was added copper powder (11.3 g, 179 mmol) with good mechanical stirring. The reaction mixture was heated to 190 °C until gas evolution was complete, then cooled to RT, poured into crushed ice and acidified with conc. hydrochloric acid. The resulting suspension was warmed with ethyl acetate, layers separated, and the organic layer washed with 2 N hydrochloric acid, water, brine solution, dried with anhydrous sodium sulfate, and concentrated to obtain 30.5 g 5-nitrobenzothiophene (51) (95percent). 1H NMR (DMSO, 400 MHz): 8.85 (d, 1H), 8.31 (d, 1H), 8.18 (dd, 1H), 8.06 (d, 1H), 7.73 (d, 1H). LC-MS: (electrospray): m/z = 180 [M+1].
68%
With copper In 2,3-diethynylquinoxaline at 170 - 190℃; for 0.666667 h;
Copper (8.18 g, 0.129 mol) was added to a mechanically stirred slurry of 5- nitrobenzo[b]thiophene-2-carboxylic acid (28.73 g, 0.129 mol) and quinoxaline (160 mL). The thick mixture was heated to 190 °C. Upon heating, stirring became easier, and at around 170 °C gas evolution was observed. Gas evolution ceased after 40 min and the reaction mixture was allowed to cool to r.t. overnight. The mixture was then poured over crushed ice and acidified with concentrated hydrochloric acid. The resulting brown suspension was warmed with diethyl ether (4 x 400 mL). The ether layers were combined, washed with 2 N aqueous hydrochloric acid (300 mL), water (300 mL) and brine (300 mL), and then separated, dried over sodium sulfate, filtered, and the solvent evaporated in vacuo. The crude yellow solid (26 g) was recrystallized from hot acetone (175 mL) to yield 5-nitrobenzo[b]thiophene (15.58 g, 68percent) as pale yellow crystals. 1H NMR δ (dβ- DMSO, 400 MHz) 7.63 (d, / = 5.5 Hz, 1 H), 7.95 (d, / = 5.5 Hz, 1 H), 8.08 (dd, /=9, 2 Hz, 1 H), 8.20 (d, /=9 Hz, 1 H), 8.75 (d, /=2 Hz, 1 H).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 3, p. 403 - 427
[2] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 8, p. 735 - 740
[3] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 3, p. 338 - 343
[4] Patent: WO2006/66172, 2006, A1, . Location in patent: Page/Page column 27
[5] Synthetic Communications, 1991, vol. 21, # 7, p. 959 - 964
[6] Journal of the American Chemical Society, 1948, vol. 70, p. 1955,1957
[7] Journal of the Chemical Society, 1957, p. 826,830
[8] Journal of the American Chemical Society, 1935, vol. 57, p. 1611,1614
[9] Journal of Medicinal Chemistry, 1990, vol. 33, # 9, p. 2621 - 2629
[10] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 5, p. 963 - 968
With potassium hydroxide; In water; for 3.0h;Reflux;
General procedure: The solution of compound 2a-2n (1.1 mmol) in water (10 mL)was stirred and then potassium hydroxide pellets (5.4 mmol) wereadded, which was refluxed for 3 h. The aqueous layer was thenacidified to pH 1 with 1M hydrochloric acid solution. The aqueouslayer was extracted with dichloromethane (3 x 15 mL). The combinedorganic layers were dried with sodium sulfate, filtered, andthe solvents were removed under reduced pressure to afford thetitle compound 3a-3n [31,34].
360 mg
With lithium hydroxide monohydrate; In methanol; water; at 75℃; for 1.0h;
A mixture of 400 mg of methyl 5-nitrobenzo[b]thiophene-2-carboxylate, 85 mg of lithium hydroxide monohydrate,5 ml of water, and 15 ml of methanol was stirred for 1 hour at 75C. After being cooled to room temperature, the reactionmixture was concentrated under reduced pressure. Water was added to the residues, and the residue was washed threetimes with tert-butyl methyl ether. Concentrated hydrochloric acid water added to the aqueous layer, and then extractionwas performed three times by using tert-butyl methyl ether. The collected organic layer was washed with saturatedsaline, dried over magnesium sulfate, and then concentrated under reduced pressure, thereby obtaining 360 mg of 5-nitrobenzo[b]thiophene-2-carboxylic acid (hereinafter, described as a "compound 18 of the present invention").1H-NMR (DMSO-D6) delta: 13.88 (br s, 1H), 8.99 (d, 1H, J = 2.2 Hz), 8.36 (s, 1H), 8.35 (d, 1H, J = 9.3 Hz), 8.30 (dd, 1H, J= 2.2, 9.3 Hz).
880 mg
With water; sodium hydroxide; at 0℃; for 2.0h;Reflux; Inert atmosphere;
To a solution of methyl thioglycolate (530 mg, 5 mmol) in absolutemethanol (20 mL) at 40 C was added a solution of sodiummethoxide (320 mg, 6 mmol) in methanol (5 mL). The reactionmixture was heated to 50 C and treated drop wise a solution of2-chloro-5-nitro benzaldehyde (49) (1 g, 5 mmol) in methanol(10 mL) was added drop wise. A precipitate was formed duringthe addition. The resulting suspension was heated at 60 C for1.5 h and cooled to RT. A solution of sodium hydroxide (2 mL,2.5 N solution) was added and the reaction mixture was refluxedfor 2 h, cooled to 0 C and acidified with conc. hydrochloric acid(pH 4). The resulting solid was isolated by filtration, redissolvedin hot sodium hydroxide solution, and acidified with drop wiseaddition of conc. hydrochloric acid. The solid obtained was isolatedby filtration, washed with water, co-evaporated with toluene, anddried to get 880 mg 5-nitrobenzothiophene-2-carboxylic acid (50)(74%).1H NMR (DMSO, 400 MHz): 8.90 (d, 1H), 8.75 (d, 1H), 8.32 (t,1H), 8.05 (d, 1H), 3.33 (s, 3H). MS (electrospray): m/z = 222 [M-1].
3-[1-methyl-4-[1-methyl-4-[5-[4-N,N-bis(2-chlroethyl)aminocinnamoyl]aminobenzothiophene-2-carboxamido]-pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine hydrochloride[ No CAS ]
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