* 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.
With lithium hydroxide monohydrate In water at 100℃; for 3 h; Inert atmosphere; Large scale
Under a nitrogen atmosphere, lithium hydroxide monohydrate (17. 8 Kg, 662.4 mol, 1.47 eq), H20 (440.0 OKg) was added to the 2000 L autoclave and stirred to dissolve the lithium hydroxide monohydrate in water. At room temperature, the intermediate 3 (95.5 Å, 449.8111 01, 1.069) was pumped into the reaction mixture, followed by 1 '(379.5 ). Heating to reflux (about 100 ° C) for 3 hours, cooling to 35 to 40 ° C and removing the tetrahydrofuran by rotary evaporation under reduced pressure under a nitrogen atmosphere Water (200 Kg) was added to the reaction vessel Controlled temperature below 20 ° C (74.6 Kg), filtered and the filter cake was washed three times with cold water (20 Kg) and centrifuged until no liquid was obtained, product 4 (146 Kg, yield 100percent)..
83%
Stage #1: With water; lithium hydroxide In tetrahydrofuran; methanolReflux Stage #2: With hydrogenchloride In tetrahydrofuran; methanol; water
According to Scheme 3, first, compound c (27 g, 0.141 mol) was mixed with K2CO3 (82.80 g, 0.60 mol) and DMF (300 mL) in a three neck flask equipped with a condenser and addition funnel. To this mixture ethyl mercaptoacetate (17.5 g, 0.141 mol) was added dropwise at 60-70° C. The mixture was heated at 60-70° C. overnight until no starting materials were detected by GC/MS. The mixture then was poured into water (600 mL) and extracted by diethyl ether (2.x.100 ml). Organic washed by brine (3.x.400 ml), and dried over anhydrous MgSO4. After evaporating the solvent, the brownish crude target was obtained and found to be pure enough for the next reaction (71.0 g, 100percent), leading to compound d with a GC/MS of 212. Compound d (29 g, 0.137 mol) was dissolved into a mixture of THF (200 mL), methanol and LiOH (1M, 200 mL). This mixture was refluxed overnight and poured into concentrated hydrochloric acid (50 mL) The acid mixture was then diluted to 500 mL with water. Solid was filtrated and washed with water (3.x.100 mL). The light yellow solid of Compound 11 was washed with methanol (100 mL) and dried under vacuum overnight (21 g, 83percent). GC-MS 140 [M-COOH].
Reference：
[1] Patent: CN103172646, 2016, B, . Location in patent: Paragraph 0108-0110
[2] Macromolecules, 2013, vol. 46, # 6, p. 2078 - 2091
[3] Advanced Functional Materials, 2012, vol. 22, # 1, p. 48 - 60
[4] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 22, p. 3465 - 3470
[5] New Journal of Chemistry, 2015, vol. 39, # 3, p. 2248 - 2255
[6] Patent: US2012/22116, 2012, A1, . Location in patent: Page/Page column 53-54
[7] Journal of Medicinal Chemistry, 2011, vol. 54, # 20, p. 7385 - 7396
[8] Molecules, 2012, vol. 17, # 10, p. 12163 - 12171
[9] Patent: KR101540066, 2015, B1, . Location in patent: Paragraph 0021; 0022; 0023
[10] Patent: KR101902129, 2018, B1, . Location in patent: Paragraph 0301-0304
[11] Polymer, 2018, vol. 159, p. 150 - 156
2
[ 31486-86-9 ]
[ 1723-27-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 2017, vol. 60, # 7, p. 2697 - 2717
3
[ 930-96-1 ]
[ 1723-27-9 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 22, p. 3465 - 3470
[2] Patent: US2012/22116, 2012, A1,
[3] Advanced Functional Materials, 2012, vol. 22, # 1, p. 48 - 60
[4] Molecules, 2012, vol. 17, # 10, p. 12163 - 12171
[5] Macromolecules, 2013, vol. 46, # 6, p. 2078 - 2091
[6] New Journal of Chemistry, 2015, vol. 39, # 3, p. 2248 - 2255
[7] Patent: KR101540066, 2015, B1,
[8] Patent: CN103172646, 2016, B,
[9] Polymer, 2018, vol. 159, p. 150 - 156
4
[ 98778-43-9 ]
[ 1723-27-9 ]
Reference：
[1] Journal of medicinal chemistry, 1985, vol. 28, # 12, p. 1896 - 1903
5
[ 6319-47-7 ]
[ 1723-27-9 ]
Reference：
[1] Journal of medicinal chemistry, 1985, vol. 28, # 12, p. 1896 - 1903
6
[ 251-41-2 ]
[ 1723-27-9 ]
Reference：
[1] Journal of the Chemical Society, 1940, p. 305,308
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 7, p. 2697 - 2717
7
[ 39131-69-6 ]
[ 1723-27-9 ]
Reference：
[1] Journal of the Chemical Society, 1940, p. 305,308
With sulfuric acid; In water; at 0℃; for 8h;Reflux;
500 mg (2.7 mmol, 1.0 eq) of <strong>[1723-27-9]thieno [3,2-B] thiophene-2-carboxylic acid</strong> (Compound 12-1) was added to methanol 5.0 ml, cooled to 0 C,Concentrated sulfuric acid (265 mg, 2.7 mmol, l.Oeq)After the addition was complete, the reaction was warmed to room temperature and then heated to reflux overnight.TLC raw materials are surplus,The reaction was cooled to 0 C,Supplemented with concentrated sulfuric acid (530 mg, 5.4 mmol, 2.0 eq)Then heated to reflux for 8 hours, TLC reaction completely.The reaction solution was cooled to room temperature, poured into about 50 ml of ice water, stirred for 20 minutes, filtered and the filter cake was rinsed with water and dried to give the product as yellowish solid compound 12-2 (504 mg, yield 94%Directly for the next reaction.
Its synthesis was referenced the four step method according to previous reports by us and Fuller et al.[22,23]. Lithium diisopropylamide (LDA) (27.4 mL 218.9 mmol) was added in the 100 mL of dry THF solution with 3-bromothiophene (7.9 g, 48.5 mmol) and N-formylpiperidine (6.1 mL 54.8 mmol) was added after stirred 30 min at 0 C. After simple purification, the crude product was add to the N,N-dimethylformamide (100 mL) solution containing ethyl 2-sulfanylacetate (4.12g 34.3 mmol) and K2CO3 (8.6 g 62.2 mmol) for stirring 97 h. The crude product was added to the mixture solution of LiOH (1 mol L-1 50 mL) and THF (150 mL) (1/3 v/v) and added 0.1M HCl (15 mL) solution after reflux for 6 h to get the solid powder. The solid powder was added to quinolone (4 mL) solution with Cu powder (0.1 g) stirring at 260 C for 1 h. The crude product was purified by column chromatography (petroleum ether (PE)) and dried in vacuoto give pure TT as white solid. (1.9 g 28%). 1H NMR (400 MHz, CDCl3)delta 7.37 (d, J=4.9 Hz, 2H), 7.26-7.24 (m, 2H). Anal. Calcd for C6H4S2:C, 51.34, H, 2.85 and S, 44.21. Found: C, 51.36, H, 2.56 and S, 44.23.
With bromine; acetic acid; In water; for 4h;Inert atmosphere; Reflux; Large scale;
Under nitrogen protection,Intermediate 4 was added to a 2000 L autoclave(53. 2 Kg, calculated as 100% yield,Only 30Kg,The other for the water,162. 8 mol, 1. Oeq),Ac0H (1500. OKg).Start stirring,The temperature inside the reactor was raised to 50 to 55 C,Draw water (150. OKg),Keep the temperature at 50 ~ 55 C drop bromine(39.lKg, 244.4 mol, 1.5 eq.),After the dropwise addition, the reaction was continued for 1 hour with stirring.Heated to reflux,Close the exhaust valve,Maintain the dropping under refluxBromine(130. 3 Kg, 814.4 mol, 5. Oeq).After the dropwise addition,The reaction was stirred for 3 hours.Sampling monitoring,Until the tribromo intermediate has been less than 10%.Stirring down to 70 C for hot filtration.The filter cake was washed with water (30. OKg) until the filtrate had no color,Dried and dried to give an off-white solid (52. OKg, water content 14%, yield 60.4%). [0114] Step 5:
With lithium hydroxide monohydrate; In water; at 100℃; for 3h;Inert atmosphere; Large scale;
Under a nitrogen atmosphere, lithium hydroxide monohydrate (17. 8 Kg, 662.4 mol, 1.47 eq), H20 (440.0 OKg) was added to the 2000 L autoclave and stirred to dissolve the lithium hydroxide monohydrate in water. At room temperature, the intermediate 3 (95.5 A, 449.8111 01, 1.069) was pumped into the reaction mixture, followed by 1 '(379.5 ). Heating to reflux (about 100 C) for 3 hours, cooling to 35 to 40 C and removing the tetrahydrofuran by rotary evaporation under reduced pressure under a nitrogen atmosphere Water (200 Kg) was added to the reaction vessel Controlled temperature below 20 C (74.6 Kg), filtered and the filter cake was washed three times with cold water (20 Kg) and centrifuged until no liquid was obtained, product 4 (146 Kg, yield 100%)..
83%
According to Scheme 3, first, compound c (27 g, 0.141 mol) was mixed with K2CO3 (82.80 g, 0.60 mol) and DMF (300 mL) in a three neck flask equipped with a condenser and addition funnel. To this mixture ethyl mercaptoacetate (17.5 g, 0.141 mol) was added dropwise at 60-70 C. The mixture was heated at 60-70 C. overnight until no starting materials were detected by GC/MS. The mixture then was poured into water (600 mL) and extracted by diethyl ether (2×100 ml). Organic washed by brine (3×400 ml), and dried over anhydrous MgSO4. After evaporating the solvent, the brownish crude target was obtained and found to be pure enough for the next reaction (71.0 g, 100%), leading to compound d with a GC/MS of 212. Compound d (29 g, 0.137 mol) was dissolved into a mixture of THF (200 mL), methanol and LiOH (1M, 200 mL). This mixture was refluxed overnight and poured into concentrated hydrochloric acid (50 mL) The acid mixture was then diluted to 500 mL with water. Solid was filtrated and washed with water (3×100 mL). The light yellow solid of Compound 11 was washed with methanol (100 mL) and dried under vacuum overnight (21 g, 83%). GC-MS 140 [M-COOH].
With sodium hydroxide; In tetrahydrofuran; water; for 2h;Reflux;
After injecting 21.39 g of ethyl thieno[3,2-b]thiophene-2-carboxylate and 200 mL of tetrahydrofuran into a 500 mL round flask, 8.39 g (1.5 eq) of NaOH was dissolved in 200 mL of distilled water and the temperature was adjusted to 60 C .Thereafter, the reaction mixture was refluxed for 2 hours, and the reaction was terminated via a 1M HCl aqueous solution. The resulting solid was filtered through distilled water to obtain Compound 1A.
With lithium hydroxide; In tetrahydrofuran; water; for 6h;Reflux;
Its synthesis was referenced the four step method according to previous reports by us and Fuller et al.[22,23]. Lithium diisopropylamide (LDA) (27.4 mL 218.9 mmol) was added in the 100 mL of dry THF solution with 3-bromothiophene (7.9 g, 48.5 mmol) and N-formylpiperidine (6.1 mL 54.8 mmol) was added after stirred 30 min at 0 C. After simple purification, the crude product was add to the N,N-dimethylformamide (100 mL) solution containing ethyl 2-sulfanylacetate (4.12g 34.3 mmol) and K2CO3 (8.6 g 62.2 mmol) for stirring 97 h. The crude product was added to the mixture solution of LiOH (1 mol L-1 50 mL) and THF (150 mL) (1/3 v/v) and added 0.1M HCl (15 mL) solution after reflux for 6 h to get the solid powder. The solid powder was added to quinolone (4 mL) solution with Cu powder (0.1 g) stirring at 260 C for 1 h. The crude product was purified by column chromatography (petroleum ether (PE)) and dried in vacuoto give pure TT as white solid. (1.9 g 28%). 1H NMR (400 MHz, CDCl3)delta 7.37 (d, J=4.9 Hz, 2H), 7.26-7.24 (m, 2H). Anal. Calcd for C6H4S2:C, 51.34, H, 2.85 and S, 44.21. Found: C, 51.36, H, 2.56 and S, 44.23.
thieno[3,2-b]thiophene-2-carboxylic acid {(S)-1-[3-oxo-1-(propane-1-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-1-butyl}-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Preparation of Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-1-[3-oxo-1-(propane-1-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-1-butyl}-amide Following the general procedure of Examples 280h-j except substituting <strong>[1723-27-9]thieno[3,2-b]thiophene-2-carboxylic acid</strong> for benzofuran-2-carboxylic acid and 1-propanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 513.2 (M+H)+and diastereomer 2 MS(ES) 513.2 (M+H)+.
thieno[3,2-b]thiophene-2-carboxylic acid{(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(5-trifluoromethyl-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-butyl}-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 33 Preparation of Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-1-(5-trifluoromethyl-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide Following the procedure of Example 12 (a-m), except substituting "5-trifluoromethyl-pyridine-2-sulfonyl chloride" for "pyridine-2-sulfonyl chloride" and "<strong>[1723-27-9]thieno[3,2-b]thiophene-2-carboxylic acid</strong>" for "quinoline-6-carboxylic acid" gave the title compound: 1H NMR: 9.0 (s, 1H), 8.10-8.20 (m, 2H), 7.80 (s, 1H), 7.50 (s, 1H), 7.25 (s, 1H), 7.0 (d, 1H), 6.80 (d, 1H), 5.0-5.10 (m, 1H), 4.60-4.80 (m, 2H), 4.40-4.50 (m, 1H), 3.90 (d, 1H), 2.10-2.20 (m, 2H), 1.50-1.80 (m, 5H), 0.9-1.0 (m, 9H); Electrospray mass spec: M+H+=631.2.
With oxalyl dichloride;dmap; In dichloromethane; at 20℃; for 2h;
Example D Synthesis of 2-(4-Chlorophenyl)-4-(thiopheno[2,3-d]thiophen-2-ylcarbonylamino)thiophene-3-carboxylic acid (20) To a solution of 16 (184 mg, 1 mmol) in CH2Cl2 (2 ml) is added oxalyl chloride (254 mg, 2 mmol) and 4-dimethylaminopyridine (DMAP, 24 mg, 0.2 mmol). The reaction mixture is stirred for 2 h at room temperature. The solvent is removed in vacuo and dried. The residue is dissolved in CH2Cl2 (2 ml) and 7 (124 mg, 0.4 mmol) is added along with Hunig's base, and DMAP in CH2Cl2. The mixture is stirred for 2.5 h at room temperature. The mixture is concentrated under reduced pressure. 10% Pd/C is added to compound 18 in ethanol:ethyl acetate:dichloromethane (2:1:1). The mixture is degassed and placed under H2 (1 atm) and stirred for 30 min. The mixture is filtered through a 0.45 mum syringe filter and concentrated under reduced pressure. LiOH in THF:MeOH:H2O is added and stirred at room temperature for 4 h. The mixture is diluted with DMF and purified by HPLC to provide compound 19.
With thionyl chloride; N,N-dimethyl-formamide; In chloroform; for 1h;Reflux;
After injecting 1.00 g of Compound 1A and 200 mL of chloroform into a 500 mL round flask, 15.76 mL (1.5 eq) of thionyl chloride was slowly injected.Thereafter, dimethyl formamide catalyst was added, and the temperature was adjusted to 65 C and refluxed for 1 hour. The solvent was then removed to give compound 2A.
General procedure: A solution of NHMe(OMe) (0.360 g, 6.0 mmol) and benzoic acid (0.244 g, 2.0 mmol) was stirred in dry toluene (10 mL) at 0 C for 10 min. A solution of PCl3 (0.137 g, 1.0 mmol) in dry toluene (2 mL) was then added dropwise to the mixture. The mixture was warmed to r.t. slowly and then stirred at 60 C for 0.5 h. When the reaction was complete (TLC monitoring), the mixture was cooled to r.t. The mixture was then quenched with sat. NaHCO3 soln (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (anhyd MgSO4). The solvent was removed in vacuo.The product was purified by column chromatography (silica gel, petroleum ether-EtOAc, 3:2) to give pure 3a as a colorless oil; yield: 320 mg (97%).
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