* 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.
A solution of methyl 2-aminothiophene-3-carboxylate (3.0 g, 19.1 mmol) in formamide (95 ml) was heated at 190° C. for 4 hours. The cooled mixture was poured into water. The precipitate was filtered off, washed with water and dried. The crude product was purified by silica gel chromatography (CH2Cl2/MeOH 50:1) to yield the title compound as a white solid (1.93 g, 66percent).1H NMR (300 MHz, DMSO, 25° C.): δ=12.49 (s, 1H, NH), 8.13 (s, 1H, CH), 7.58 (d, J=5.8 Hz, 1H, CH), 7.39 (d, J=5.8 Hz, 1H, CH) ppm.HRMS: calcd for C6H5N2OS 153.01226, found 153.01155.
66%
at 190℃; for 4 h;
Example 304 Synthesis of thieno[2,3-d]pyrimidin-4(3H)-one A solution of methyl 2-aminothiophene-3-carboxylate (3.0 g, 19.1 mmol) in formamide (95 ml) was heated at 190° C. for 4 hours. The cooled mixture was poured into water. The precipitate was filtered off, washed with water and dried. The crude product was purified by silica gel chromatography (CH2Cl2/MeOH 50:1) to yield the title compound as a white solid (1.93 g, 66percent). 1H NMR (300 MHz, DMSO, 25° C.): δ=12.49 (s, 1H, NH), 8.13 (s, 1H, CH), 7.58 (d, J=5.8 Hz, 1H, CH), 7.39 (d, J=5.8 Hz, 1H, CH) ppm. HRMS: calcd for C6H5N2OS 153.01226, found 153.01155.
66%
at 190℃; for 4 h;
Example 304 Synthesis of thieno[2,3-d]pyrimidin-4(3H)-one A solution of methyl 2-aminothiophene-3-carboxylate (3.0 g, 19.1 mmol) in formamide (95 ml) was heated at 190° C. for 4 hours. The cooled mixture was poured into water. The precipitate was filtered off, washed with water and dried. The crude product was purified by silica gel chromatography (CH2Cl2/MeOH 50:1) to yield the title compound as a white solid (1.93 g, 66percent). 1H NMR (300 MHz, DMSO, 25° C.): δ=12.49 (s, 1H, NH), 8.13 (s, 1H, CH), 7.58 (d, J=5.8 Hz, 1H, CH), 7.39 (d, J=5.8 Hz, 1H, CH) ppm. HRMS: calcd for C6H5N2OS 153.01226. found 153.01155.
58%
at 150℃; for 6 h;
2-aminothiophene-3-carboxylic acid methyl ester (4.7 g, 30 mmol) was added to a 250 mL round bottom flask.Ammonium formate (6.3g, 100mmol) and 25mL formamide,The mixture was heated at 150 °C with stirring for 6 h.After the reaction was completed, it was stored at 0°C for 24 hours and suction filtered to give a brown solid (2.8 g, 58percent).
50%
at 215℃; for 5 h;
The synthesis was carried out according to the procedure of Jang et al.35 Methyl 2-aminothiophene-3-carboxylate (1) (26.0 g, 165 mmol) was mixed with formamide (285 mL) and heated at 215 °C for 5 h. The reaction mixture was then cooled to rt and water (500 mL) was added, followed by extraction with EtOAc (4×500 mL). The combined organic fractions were dried over Na2SO4, and concentrated. Upon storage at −18 °C a solid material precipitated, which was washed with cold EtOAc (4×100 mL). This gave 12.7 g (83.0 mmol, 50percent) of 2 as a yellowish solid, mp. 245 °C (dec), (lit.22 245 °C, dec); 1H NMR (400 MHz, DMSO-d6) δ: 12.45 (s br, 1H), 8.12 (s, 1H), 7.57 (d, J=5.8, 1H), 7.39 (d, J=5.8, 1H); 13C NMR (100 MHz, DMSO-d6) δ: 164.2, 157.5, 145.6, 124.6, 123.8, 121.6; IR (neat, cm−1): 2879, 1647, 1577, 800, 701, 635; HRMS (EI, 70 eV, m/z): 152.0045 (calcd C6H4N2OS, 152.0044, M+). The NMR spectroscopic data corresponds with that reported previously.22
50%
at 215℃; for 5 h;
Thieno[2,3-d]pyrimidin-4(3H)-one (2). Methyl 2-aminothiophene-3-carboxylate (1) (26.0 g, 165 mmol) was mixed with formamide (285 mL) and heated at 215 °C for 5 h. The reaction mixture was then cooled to rt. and water (500 mL) was added, followed by extraction with EtOAc (4 x 500 mL). The combined organic fractions were dried over Na2S04, and concentrated. Upon storage at -18 °C a solid material precipitated which was washed with cold EtOAc (4 x 100 mL). This gave 12.7 g (83.0 mmol, 50percent) of 2 as a yellowish solid, mp. 245 °C (dec); 1H NMR (400 MHz, DMSO-d6) δ: 12.45 (s br, 1H), 8.12 (s, 1H), 7.57 (d, J= 5.8, 1H), 7.39 (d, J= 5.8, 1H); 13C NMR (100 MHz, DMSO-de) δ: 164.2, 157.5, 145.6, 124.6, 123.8, 121.6. IR (neat, cm"1): 2879, 1647, 1577, 800, 701, 635; HRMS (EI, 70 eV, m/z): 152.0045 (calcd C6H4N2OS, 152.0044, M+).
23%
at 190℃; for 3 h;
Methyl 2-aminothiophene-3- carboxylate (10 g, 64 mmol) was charged with formamide (50 mL). The reaction was heated at 190 °C under nitrogen for 3 hours, then cooled to ambient temperature. The resulting slurry was poured into 125 mL of water and extracted with chloroformdsopropyl alcohol mixture (2 times). The solution was concentrated and triturated to afford the title compound (2.25 g, 23percent).
3.45 g
at 200℃; for 4 h; Inert atmosphere
Under an argon atmosphere,118 mL of formamide was added to 7.83 g of methyl 2-aminothiophene-3-carboxylate,The mixture was stirred at 200 ° C. for 4 hours,The temperature was returned to room temperature.Water was added and the mixture was extracted 9 times with ethyl acetate,The organic layer was dried over anhydrous sodium sulfate,After filter paper filtering,The solvent was distilled off under reduced pressure. The solid obtained was subjected to decantation with ethyl acetate 8 times, washed and dried under reduced pressure to give 3.45 g of the title compound as a brown solid.
Reference：
[1] Patent: US2012/46278, 2012, A1, . Location in patent: Page/Page column 81
[2] Patent: US2013/190297, 2013, A1, . Location in patent: Paragraph 1205; 1206; 1207
[3] Patent: US2014/88088, 2014, A1, . Location in patent: Paragraph 1220-1222
[4] Patent: CN107573386, 2018, A, . Location in patent: Paragraph 0048-0050
[5] Tetrahedron, 2012, vol. 68, # 45, p. 9226 - 9233
[6] Patent: WO2015/959, 2015, A1, . Location in patent: Page/Page column 47-48
[7] ChemMedChem, 2015, vol. 10, # 1, p. 69 - 82
[8] MedChemComm, 2015, vol. 6, # 2, p. 339 - 346
[9] Patent: WO2008/118718, 2008, A2, . Location in patent: Page/Page column 61
[10] Bulletin de la Societe Chimique de France, 1975, p. 587 - 591
[11] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 3, p. 844 - 847
[12] Patent: JP2018/154587, 2018, A, . Location in patent: Paragraph 0079
2
[ 4651-81-4 ]
[ 3473-63-0 ]
[ 14080-50-3 ]
Yield
Reaction Conditions
Operation in experiment
77.7%
at 80℃; for 24 h;
250 mL of a three-necked flask,A solution of methyl 2-aminothiophene-3-carboxylate (20 g, 0.127 mol) and formamidine acetate (30 g, 0.29) was dissolved in ethanol at 80 °C for 24 hours and the reaction was complete until the reaction was complete. After the reaction solution was cooled, the mixture was stirred in water,The precipitated solid was filtered and the cake was dried to obtain 15 g of soil yellow powder in a yield of 77.7percent.
Reference：
[1] Patent: CN107253964, 2017, A, . Location in patent: Paragraph 0101; 0102; 0103; 0104
[2] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 1, p. 245 - 256
3
[ 4651-81-4 ]
[ 14080-50-3 ]
Reference：
[1] Patent: US5654307, 1997, A,
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 14, p. 5522 - 5537
Stage #1: at -60 - 20℃; Stage #2: at 75℃; for 1 h;
A 5 L reaction vial equipped with a mechanical stirrer, internal temperature probe, and a nitrogen bubbler was charged with methyl 2-aminothiophene-3 -carboxylate (95 g) and DCM (2.85 L) and cooled to -60 C chlorosulfonyl isocyanate (89.81 g) was added at a rate such that the internal temperature remained at -60 C to -55 C. After completion of addition the reaction was allowed to warm to ambient temperature. The reaction was monitored for complete consumption of starting material by LC/MS. The reaction mixture was concentrated to dryness in vacuo and the solid residue transferred back to the 5 1 reaction vial by water (1.8 L). This mixture was heated at 75 C for one hour, then cooled to 30 C. Next, 1OM aqueous NaOH (200 ML) was added and this mixture was heated at 85 C for 20 minutes before cooling to room temperature. The mixture was then acidified to pH=l by the addition of cone. HCl. The mixture was then stirred for 18 hours at ambient temperature with a ppt forming. This solid material was collected by vacuum filtration and the filter cake washed with water (3 x 30OmL). The solid material was then dried in an vacuum oven at 55 C for 24 hours to afford thieno[2,3-<f]pyrimidine-2,4(lH,3H)-dione as an off white solid (80.05 g, 78.8percent) 1U NMR (400 MHz, DMSO-J6) δ 7.083 (d, J= 5.6 Hz, IH), δ 7.124 (d, J= 5.6 Hz, IH) LCMS (ESI pos) m/e 169 (M+l)
A mixture of methyl 2-aminothiophene-3-carboxylate 5a (20.0 g, 0.13 mol) and urea (60 g, 1.0 mol) was heated at 200 °C for 2 h. The reaction mixture was cooled and poured into a sodium hydroxide solution, and any insoluble material was removed by filtration. The filtrate was then acidified with 2 N HCl to give a white precipitate, which was collected by filtration, washed with water and dried on a funnel to provide the title compound 6a (13.7 g, yield 64percent). MS (ESI): C6H4N2O2S [M - H]- 167.1.
56.1%
at 180℃; for 2 h;
Urea (30 g, 0.5 mol) was added to methyl 2-aminothiophene-3-carboxylate (11, 10 g, 0.06 mol). Heated to 180 °C and stirred for 2 h. After cooling to 140 °C, reactant was dissolved with 1N sodium hydroxide solution. After filtration, 2N hydrochloric acid was added to the filtrate until pH 7. After filtration, the filtrate was refrigerated for 12 h and white solid appeared in the filtrate. The product was filtered off, washed with water and dry to afford 6.0 g thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (12). Yield: 56.1 percent,1H NMR (400 MHz, DMSO) δ 11.94 (s, 1H, CONH), 11.18 (s, 1H, CONH), 7.11 (d, J=16.0, 5.6 Hz, 2H,2 Ar–H) ESI-MS [M−H] m/z: 167.2.
56.1%
at 180℃; for 2 h; Inert atmosphere
Under nitrogen protection,2-Aminothiophene-3-carboxylic acidMethyl ester(10g) and urea (30g) were mixed evenly and mechanically stirredThe temperature was raised to 180 ° C and reacted for 2 h. The reaction was completed and cooled to below 100 ° C. The reaction was poured into 500 mL of 1 mol / LSodium hydroxide solution beaker, stir well, filter; with concentrated hydrochloric acid to adjust the filtrate to pH 6, precipitation of mud-like solid; filter, the filtrate frozen 12h after precipitation of solid,Suction filter yellowish product,Thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione,Yield: 56.1percent.
Reference：
[1] ChemMedChem, 2018,
[2] European Journal of Medicinal Chemistry, 2011, vol. 46, # 1, p. 71 - 76
[3] European Journal of Medicinal Chemistry, 2015, vol. 93, p. 64 - 73
[4] Patent: CN106831812, 2017, A, . Location in patent: Paragraph 0088; 0089; 0090
[5] Comptes Rendus des Seances de l'Academie des Sciences, Serie C: Sciences Chimiques, 1968, vol. 266, p. 128 - 130
[6] Patent: WO2006/79916, 2006, A1, . Location in patent: Page/Page column 92
[7] Patent: CN106167497, 2016, A, . Location in patent: Paragraph 0225; 0226; 0227
7
[ 4651-81-4 ]
[ 18740-38-0 ]
Yield
Reaction Conditions
Operation in experiment
69%
at 170℃; for 2 h;
A solution of 10 g (0.064mol) methyl 2-aminothiophene-3-carboxylate was prepared 30 g (0.5 mol) of urea was placed in a 250 mL three-neck flaskAt 170 ° C for 2 hours. After the reaction was completed, the reaction mixture was poured into 1N sodium hydroxide solution, stirred and filtered. The filtrate was adjusted to pH 5 with 2N hydrochloric acid. A large amount of brown flocculent solid was precipitated, and the filtrate was refrigerated for 12h. A large amount of white solid precipitated, The filter cake was washed with 500 mL of water and dried at 50 ° C for 24 h to obtain 7.4 g of a white solid in 69percent yield.
Reference：
[1] Patent: CN103980287, 2016, B, . Location in patent: Paragraph 0148; 0149; 0150
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 22, p. 7815 - 7833
8
[ 4651-81-4 ]
[ 917-61-3 ]
[ 18740-38-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4793 - 4805
9
[ 4651-81-4 ]
[ 56844-12-3 ]
Reference：
[1] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 4, p. 434 - 438
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 14, p. 5522 - 5537
10
[ 4651-81-4 ]
[ 63894-67-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 22, p. 7815 - 7833
[2] European Journal of Medicinal Chemistry, 2015, vol. 93, p. 64 - 73
[3] Patent: CN103980287, 2016, B,
[4] Patent: CN106831812, 2017, A,
11
[ 4651-81-4 ]
[ 14080-59-2 ]
Reference：
[1] Patent: CN104725398, 2017, B,
[2] Patent: CN107253964, 2017, A,
[3] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 1, p. 245 - 256
12
[ 4651-81-4 ]
[ 18740-39-1 ]
Reference：
[1] Comptes Rendus des Seances de l'Academie des Sciences, Serie C: Sciences Chimiques, 1968, vol. 266, p. 128 - 130
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 22, p. 7815 - 7833
[3] European Journal of Medicinal Chemistry, 2015, vol. 93, p. 64 - 73
[4] Patent: CN103980287, 2016, B,
[5] Patent: CN106831812, 2017, A,
13
[ 40018-26-6 ]
[ 105-34-0 ]
[ 4651-81-4 ]
Yield
Reaction Conditions
Operation in experiment
94%
With triethylamine; N,N-dimethyl-formamide In methanol at 50℃; for 0.05 h; Sealed tube; Microwave irradiation; Inert atmosphere
To two 20 mL microwave pressure vials was each added 1,4-dithiane-2,5-diol (2.0 g, 13.1mmol, 1.0 eq.) and MeOH (10.5 mL), and the vials were sealed. Through the septa was addedmethylcyanoacetate (2.32 mL, 26.3 mmol, 2.0 eq.), Et3N (1.28 mL, 9.20 mmol, 0.7 eq.), andDMF (3 drops), and the reactions were heated via microwave irradiation at 50 °C for 3 min. Atrt, the precipitates were combined and collected by filtration and washed with cold MeOH to provide 16as a white solid (3.88 g, 24.7 mmol, 94percent).
86%
With triethylamine In methanol at 0 - 40℃;
Thienopyrimidine Methyl 2-aminothiophene-3-carboxylate (1). l,4-Dithiane-2,5-diol (312.8 g, 2.05 mol) was mixed with MeOH (1000 mL), and methyl cyanoacetate (304.05 g, 3.06 mol) was added while stirring at 0 °C. Then NEt3 (72.55 g, 0.72 mol) was added drop wise over 2.5 h at 0 °C. The reaction temperature was slowly increased to 40 °C over 1 h. and kept stirring. After cooling to rt, the mixture was filtered and the liquid fraction was concentrated. The concentrated oil was extracted with boiling pet. ether (bp. 60-80 °C) (10χ750 mL). The combined organic fraction was concentrated which gave a solid crystalline product. After drying this gave 408.2 g (86percent) of 1, mp. 78 - 80 °C Rf (CHC13) = 0.33; 1H NMR (400 MHz, DMSO-d6) δ: 7.24 (s br, 2H, NH2), 6.81 (d, J= 5.8, 1H), 6.27 (d, J= 5.8, 1H), 3.69 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ: 164.8, 164.0, 124.9, 106.5, 103.7, 50.5. IR (neat, cm"1): 3421, 3319, 1655, 1316, 1273, 676; HRMS (EI, 70 eV, m/z): 157.0201 (calcd C6H7N02S, 157.0198, M+).
78%
With triethylamine In methanol at 0 - 60℃;
The synthesis was carried out as described by Hallas and Towns.18 1,4-Dithiane-2,5-diol (15.0 g, 99.0 mmol) was mixed with MeOH (30 mL), and methyl cyanoacetate (16.3 g, 164 mmol) was added while stirring. Then NEt3 (5.98 g, 59.1 mmol) was added dropwise over 10 min at 0 °C. The reaction temperature was slowly increased to 60 °C over 1 h, and kept stirring for 1 h. After cooling to rt, the mixture was filtered and the liquid fraction was concentrated and allowed to crystallise at −18 °C for 18 h. The solid formed was isolated, washed with n-heptane (3×50 mL) and dried to yield 20.1 g (128 mmol, 78percent) of 1 as a yellowish solid, mp. 72–73 °C, (lit.15 77–78 °C); Rf (CHCl3)=0.33; 1H NMR (400 MHz, DMSO-d6) δ: 7.24 (s br, 2H, NH2), 6.81 (d, J=5.8, 1H), 6.27 (d, J=5.8, 1H), 3.69 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ: 164.8, 164.0, 124.9, 106.5, 103.7, 50.5; IR (neat, cm−1): 3421, 3319, 1655, 1316, 1273, 676; HRMS (EI, 70 eV, m/z): 157.0201 (calcd C6H7NO2S, 157.0198, M+). The 1H NMR spectrum from CDCl3 corresponded with that reported by Huang et al.39
64%
With triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 3 h;
Add in a 250 mL round bottom flask1,4-Dithio-2,5-diol (7.6 g, 50 mmol),Methyl cyanoacetate (9.9g, 100mmol) and 20mL DMF,The mixture was stirred at 0 °C.Triethylamine (3.6 g, 50 mmol) was gradually added dropwise to the reaction system.Stir at room temperature for 3 h.Quench with water, extract with methylene chloride, and remove the solvent on a rotary evaporator.Purification by column chromatography. White solid (11 g, 64percent) was obtained.
44%
With triethylamine In methanol at 0 - 40℃; for 2.5 h;
To a solution of methanol (35 g, 0.1 mol) in methyl cyanoacetate (10 g, 0.1 mol) and 1,4-dithiane-2,5-diol mL) was adjusted to 0°C and triethylamine (Et3N, 3.8 mL, 0.027 mol) was slowly added over 30 minutes and stirred at 40°C for 2 hours. The resulting solid was filtered and washed with diethyl ether to give compound 16 (7.014 g, 44percent) as a white solid.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 8, p. 1947 - 1953
[2] Patent: WO2015/959, 2015, A1, . Location in patent: Page/Page column 47
[3] Tetrahedron Letters, 2007, vol. 48, # 30, p. 5261 - 5264
[4] Tetrahedron, 2012, vol. 68, # 45, p. 9226 - 9233
[5] Patent: WO2005/63734, 2005, A2, . Location in patent: Page/Page column 60-61
[6] Patent: CN107573386, 2018, A, . Location in patent: Paragraph 0044-0047
[7] MedChemComm, 2015, vol. 6, # 2, p. 339 - 346
[8] Journal of Medicinal Chemistry, 2015, vol. 58, # 14, p. 5522 - 5537
[9] Chemical Biology and Drug Design, 2010, vol. 76, # 2, p. 116 - 129
[10] Patent: KR2017/92126, 2017, A, . Location in patent: Paragraph 0092-0096
[11] Patent: US5654307, 1997, A,
[12] Patent: US2007/99929, 2007, A1,
14
[ 75-07-0 ]
[ 105-34-0 ]
[ 4651-81-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 9, p. 3620 - 3635
[2] European Journal of Medicinal Chemistry, 2019, vol. 161, p. 239 - 251
15
[ 53982-98-2 ]
[ 4651-81-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 12, p. 2655 - 2660
16
[ 4651-81-4 ]
[ 117516-97-9 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 27, p. 6398 - 6402
[2] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 18, p. 4984 - 4995
A mixture of methyl 2-aminothiophene-3-carboxylate 5a (20.0 g, 0.13 mol) and urea (60 g, 1.0 mol) was heated at 200 C for 2 h. The reaction mixture was cooled and poured into a sodium hydroxide solution, and any insoluble material was removed by filtration. The filtrate was then acidified with 2 N HCl to give a white precipitate, which was collected by filtration, washed with water and dried on a funnel to provide the title compound 6a (13.7 g, yield 64%). MS (ESI): C6H4N2O2S [M - H]- 167.1.
56.1%
at 180℃; for 2h;
Urea (30 g, 0.5 mol) was added to methyl 2-aminothiophene-3-carboxylate (11, 10 g, 0.06 mol). Heated to 180 C and stirred for 2 h. After cooling to 140 C, reactant was dissolved with 1N sodium hydroxide solution. After filtration, 2N hydrochloric acid was added to the filtrate until pH 7. After filtration, the filtrate was refrigerated for 12 h and white solid appeared in the filtrate. The product was filtered off, washed with water and dry to afford 6.0 g thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (12). Yield: 56.1 %,1H NMR (400 MHz, DMSO) delta 11.94 (s, 1H, CONH), 11.18 (s, 1H, CONH), 7.11 (d, J=16.0, 5.6 Hz, 2H,2 Ar-H) ESI-MS [M-H] m/z: 167.2.
56.1%
at 180℃; for 2h;Inert atmosphere;
Under nitrogen protection,2-Aminothiophene-3-carboxylic acidMethyl ester(10g) and urea (30g) were mixed evenly and mechanically stirredThe temperature was raised to 180 C and reacted for 2 h. The reaction was completed and cooled to below 100 C. The reaction was poured into 500 mL of 1 mol / LSodium hydroxide solution beaker, stir well, filter; with concentrated hydrochloric acid to adjust the filtrate to pH 6, precipitation of mud-like solid; filter, the filtrate frozen 12h after precipitation of solid,Suction filter yellowish product,Thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione,Yield: 56.1%.
In N,N-dimethyl-formamide; at 200℃; for 3.5h;
EXAMPLE 39Thieno[2,3-d]pyrimidine-2,4(1 H, 3H)-dione; Methyl 2-amino thiophene-3-carboxylate (1.0 g) and urea (2.2 g) were heated in sealed tube for 3.5 hours at 200 0C and then cooled to room temperature. DMF (20 mL) was added and the mixture was refluxed for 1 hour. Ice water (50 ml) was added and the solid thus precipitated was collected and dried to give 0.5 g of the title compound after 1 hour. The compound was used in the next step without further purification. MS (ESI+) for C6H4O2N2S m/z (M+H)+ 169.05.
With sodium hydroxide; In water; at 200℃; for 5h;Reflux;
2-Aminothiophene-3-carboxylic acid methyl ester (200.0 mg, 1.27 mmol)Urea (594.6 mg, 9.90 mmol) in a single-necked flask,200 reaction 2h,After cooling,Add 6 mL of 20% aqueous NaOH solution,Heating reflux 5h,Hot filter,Remove insoluble matter,Ice bath with 2N HCl adjusted to PH = 3,Precipitation of solids,Filter to get brown crude products,Yield: 74.9%
With pyridine In dichloromethane at 0 - 20℃; for 12h;
N
Methyl 2-aminothiophene-3-carboxylate (compound A) (160 mg) was dissolved in anhydrous methylene chloride (5 ml). Pyridine (120 mg: dissolved in 2 ml of anhydrous methylene chloride) and 3,4-dimethoxybenzoyl chloride (compound B) (300 mg) were added to the solution at 0°C, and the mixture was stirred at room temperature for 12 hr. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography using a hexane-acetone system to give 2-(3,4-dimethoxy-benzoylamino)-thiophene-3-carboxylic acid methyl ester (320 mg, yield 100%).
15%
With triethylamine In dichloromethane at 20℃; Cooling with ice;
14 Example 14
Take a 100ml single bottle,Add 10ml of anhydrous methylene chloride,0.19 g of triethylamine and 0.1 g of methyl 2-aminothiophene-3-carboxylate,Stir to dissolveA solution of 0.19 g of 3,4-dimethoxybenzoyl chloride dissolved in dichloromethane was added dropwise on an ice bath.Stir at room temperature overnight. After the reaction is complete, add water to quench.Dichloromethane extraction, drying over anhydrous sodium sulfate, and concentration.Column chromatography gave target compound 3n 0.03 g (15%).
15%
With triethylamine In dichloromethane at 0 - 20℃;
General Procedure for Synthesis of Compounds (3a-3q)
General procedure: To a mixture of Methyl 2-aminothiophene-3-carboxylate (0.1 g, 636.18 umol, 1.0 eq.) and triethylamine (0.19 g, 1.91 mmol, 3.0 eq.) in anhydrous dichloromethane (10 mL), 3,4,5-Trimethoxybenzoyl chloride 2a (0.22 g, 954.28 umol,1.5 eq.) in dichloromethane was slowly added at 0 °C. After stirring at r.t overnight, the reaction mixture was diluted with water (3×10 mL), and the resulting mixture was extracted with dichloromethane. The organic layer was washed with water and brine, then dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography to afford compound 3a.
H
2-Amino-thiophene-3-carboxylic acid methyl ester (compound A) (3.0 g) was dissolved in anhydrous methylene chloride (100 ml). Subsequently, pyridine (2.4 ml) and 3-(chloromethyl)benzoyl chloride (compound B) (2.8 ml) were added to the solution at 0°C, and the mixture was stirred at 0°C for one hr. After the completion of the reaction, distilled water was added thereto, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate and was then concentrated. The residue was purified by column chromatography using a hexane-acetone system to give 2-(3-chloromethyl-benzoylamino)-thiophene-3-carboxylic acid methyl ester as a useful intermediate (4.7 g, yield 100%).
P.1 Methyl 2-Isothiocyanatothiophene-3-Carboxylate
Example P-1 Methyl 2-Isothiocyanatothiophene-3-Carboxylate In a sulfonation flask, 50.2 g (0.32 mol) of methyl 2-aminothiophene-3-carboxylate are added to 480 ml of chloroform and 320 ml of water. Then 40.5 g (0.35 mol and 1000 ml of saturated aqueous sodium bicarbonate solution are added simultaneously in 40 minutes under stirring. The stirring continued for 1 h at room temperature and then the organic phase is separated. The water phase is extracted twice with chloroform and the organic phase dried over sodium sulfate. After removal of the chloroform in the water-jet vacuum 61.3 g of a dark oil is obtained, which is further purified by column chromatography over silica gel (eluant: ethyl acetate/hexane=1:5). 41.5 g of methyl 2-isothiocyanato-thiophene-3-carboxylate are obtained in the form of a brown powder having a melting point of 63-65° C.
With triethylamine In dichloromethane at 20℃; for 3h;
1.1a
To a solution of methyl 2-amino-3-thiophenecarboxylate (2.00 g, 12.7 mmol) and triethyl amine (3.50 mL, 25.2 mmol) in methylene chloride (20.0 mL) was added ethyl 3-chloro-3- oxopropanoate (1.76 mL, 14.0 mmol) dropwise. The reaction was stirred for 3 h at ambient temperature and quenched with ice water. The mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, concentrated in vacuo, and purified via flash chromatography (0- 100% ethyl acetate in hexanes) to afford the title compound as a yellow solid (1.20 g, 34%). 1H NMR (400 MHz, CHLOROFORM-
With pyridine In toluene at -10℃; for 1h;
methyl-2-amino- thiophene-3-carboxylate was reacted with ethylmalonyl chloride to yield intermediate 2- (2-ethoxycarbonyl-acetylamino)-thiophene-3-carboxylic acid methyl ester, depicted by formula (39).
Synthesis of compound 2 (2-aminothienor2,3-dipyrimidin-4-ol)To a solution of cyanamide (1.26 g, 30.0 mmol) in dioxane (10.0 ml_) was added 4N HCI in dioxane (10.0 mL, 40.0 mmol) dropwise. The resulting chloroformamidine (compound 1) precipitated and was stirred for 1 hour, then the solvent was removed under vacuum. The chloroformamidine (compound 1) was partially dissolved in diglyme (20.0 mL) and methyl 2-aminothiophene-3-carboxylate (1.89 g, 12.0 mmol) was added in one portion. This suspension was heated to reflux (2000C oil bath) until all solids dissolved as a pink-brown color solution (-10 minutes). The reaction mixture was then cooled to room temperature, and the precipitate was collected by filtration. The crude material was redisolved in hot (7O0C) 2N NaOH (50 mL), cooled to room temperature, neutralized with concentrated HCI to pH 2.3 and the precipitate collected by filtration to afford 941 mg of 2-aminothieno[2,3-d]pyrimidin-4-o! (compound 2) as a sand color solid (47% yield). 1H NMR (400 MHz, DMSOd6) ? ppm 6.53 (s, 2 H) 6.96 (d, J=5.81 Hz, 1 H) 7.08 (d, J=5.81 Hz, 1 H) 10.90 (s, 1 H).
A 5 L reaction vial equipped with a mechanical stirrer, internal temperature probe, and a nitrogen bubbler was charged with methyl 2-aminothiophene-3 -carboxylate (95 g) and DCM (2.85 L) and cooled to -60 C chlorosulfonyl isocyanate (89.81 g) was added at a rate such that the internal temperature remained at -60 C to -55 C. After completion of addition the reaction was allowed to warm to ambient temperature. The reaction was monitored for complete consumption of starting material by LC/MS. The reaction mixture was concentrated to dryness in vacuo and the solid residue transferred back to the 5 1 reaction vial by water (1.8 L). This mixture was heated at 75 C for one hour, then cooled to 30 C. Next, 1OM aqueous NaOH (200 ML) was added and this mixture was heated at 85 C for 20 minutes before cooling to room temperature. The mixture was then acidified to pH=l by the addition of cone. HCl. The mixture was then stirred for 18 hours at ambient temperature with a ppt forming. This solid material was collected by vacuum filtration and the filter cake washed with water (3 x 30OmL). The solid material was then dried in an vacuum oven at 55 C for 24 hours to afford thieno[2,3-
A solution of 10 g (0.064mol) methyl 2-aminothiophene-3-carboxylate was prepared 30 g (0.5 mol) of urea was placed in a 250 mL three-neck flaskAt 170 C for 2 hours. After the reaction was completed, the reaction mixture was poured into 1N sodium hydroxide solution, stirred and filtered. The filtrate was adjusted to pH 5 with 2N hydrochloric acid. A large amount of brown flocculent solid was precipitated, and the filtrate was refrigerated for 12h. A large amount of white solid precipitated, The filter cake was washed with 500 mL of water and dried at 50 C for 24 h to obtain 7.4 g of a white solid in 69% yield.
methyl 2-(2-ethoxybenzamido)thiophene-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With triethylamine; In dichloromethane; at 0 - 20℃; for 4h;
Example 169 [0581] 2-aminothiophene-3-carboxylate (500 mg, 3.18 mmol) in dichloromethane (25.0 mL) and triethylamine (1.33 mL, 9.54 mmol) was treated at 0 C. with <strong>[42926-52-3]2-ethoxybenzoyl chloride</strong> (587 mg, 3.18 mmol). The reaction mixture was stirred at 0 C. for 2 h and at room temperature for 2 h. The reaction mixture was concentrated and purified via silica gel chromatography using a gradient of 0-100% of EtOAc in hexanes to give 798 mg (82%) of the title product as a white solid which was used directly in the next reaction without further purification.
With copper diacetate; triethylamine In water; toluene at 60℃; for 24h;
General procedure for Chan-Lam cross-coupling reaction methyl 2-aminothiophene-3-carboxylate with aryltrifluoroborates
General procedure: The aryltrifluoroborate (2 equiv), methyl 2-aminothiophene-3-carboxylate (47 mg, 0.3 mmol, 1 equiv), Cu(OAc)2 (81 mg, 0.45 mmol, 1.5equiv), Et3N (83.6 μL, 2 equiv) were added to a glass Biotage vial equipped with a magnetic stirring bar. Toluene (7.5 mL, 0.04 M) and H2O (20 mol %, 0.06 mmol, 1.1 μL) were added,and the reaction was stirred 24 h at 60 °C in the presence of open air (monitored by TLC).The suspension was then filtered through a plug of Celite and purified by Combiflash chromatography using EtOAc and hexanes (0% to 40% EtOAc/hexanes gradient, 24 gcolumn) to obtain the desired product. The product was characterized by spectroscopic techniques.
With copper diacetate; triethylamine In water; toluene at 60℃; for 24h;
General procedure for Chan-Lam cross-coupling reaction methyl 2-aminothiophene-3-carboxylate with aryltrifluoroborates
General procedure: The aryltrifluoroborate (2 equiv), methyl 2-aminothiophene-3-carboxylate (47 mg, 0.3 mmol, 1 equiv), Cu(OAc)2 (81 mg, 0.45 mmol, 1.5equiv), Et3N (83.6 μL, 2 equiv) were added to a glass Biotage vial equipped with a magnetic stirring bar. Toluene (7.5 mL, 0.04 M) and H2O (20 mol %, 0.06 mmol, 1.1 μL) were added,and the reaction was stirred 24 h at 60 °C in the presence of open air (monitored by TLC).The suspension was then filtered through a plug of Celite and purified by Combiflash chromatography using EtOAc and hexanes (0% to 40% EtOAc/hexanes gradient, 24 gcolumn) to obtain the desired product. The product was characterized by spectroscopic techniques.
2-[4-chloro-[1,2,3]dithiazol-(5Z)-ylideneamino]-thiophene-3-carboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6%
With pyridine In dichloromethane at -20℃; Inert atmosphere;
General procedure for the synthesis of imino-1,2,3-dithiazoles 3, 9, 11 and 12 from starting amino ester derivatives.
General procedure: Under an inert atmosphere (argon), dithiazolium salt 1 (0.208 g,1 mmol) was added to a solution of amino ester (1 mmol) in dichloromethane (5 mL). Pyridine (2 mmol) was slowly added. The mixture was stirred until all of the amine had been consumed (tlc control). The mixture was warmed to room temperature and the reaction mixture filtered through acidic alumina and pour into ice water and the organic layer was separated and the aqueous phase extracted with dichloromethane. The crude product was purified by column chromatography using petroleum ether/DCM as the eluent.
Compound 100 (1,202 g, 8,68 mmol, 1.0 eq) was added to the cooled (0 C) solution of sodium methoxide (0,5 16 g, 9,55 mmol, 1.1 eq) in methanol (20 mL). The reaction mixture was stirred at room temperature for 2h to give 101, then cooled to 0 C. Compound 16 (1,364 g, 8,68 mmol, 1.0 eq) and sodium methoxide (0,5 16 g, 9,55 mmol, 1.1 eq) were added to the resulting mixture at 0 C. The reaction mixture was stirred at reflux for 16-18h (monitored by TCL), cooled and concentrated in vacuo. The residue was diluted with water (30 mL), acidified by 5% HC1 to pH = 7 and extracted with CH2C12 (2 x 50 mL). The organic layer was washed with water, saturated sodium chloride, dried over Na2504, filtered and concentrated in vacuo. The solids were triturated with MTBE to give the target compound (1,1 g, 49 % yield).
With isopentyl nitrite; In tetrahydrofuran; at 90℃; for 0.333333h;
A solution of methyl 2-aminothophene-5-carboxylate (152 mg, 1.00 mmol) in the selected solvent (see Table 1, 10 mL) and a solution of isopentyl nitrite (141 mg, 1.20 mmol) in the selected solvent (10 mL) were both pumped at a flow rate of 0.25 mL min&1048576;1 with a Vapourtech ?Easy MedChem V3? system, meeting at a PTFE T-piece and the output flowing through a 6.5 mL coil reactor maintained at 70 C, giving a residence time of 13 min (see Table 2). The pressure of the system was maintained at 7 bar with a variable compression back-pressure regulator. The output mixture was concentrated under reduced pressure (100 mbar) to yield the product as an oil. Three repeat samples were analysed by 1H-NMR spectroscopy with an internal standard (nitrobenzene) and the average used to quantify the conversion to the target thiazole product.
4 Example 4 (0346) Compound 3 : 3 -(2-methyl -4-oxothienor2.3 - midi n-3(4H)-yl )piperidine-2.6-dione
To a solution of methyi-2-aminothiophene-3-carhoxylate (2.00 g, 12.7 mmol) in pyridine (8 mL) at 0°C was added acetyl chloride (1.39 g, 17.8 mmol) dropwise over 5 min. The mixture was stirred at RT for 16 h then concentrated. H2O and EA were added. The organic phase was washed with brine, dried over Na2S04, filtered, and concentrated to give methyl-2- acetamido-3-thiophenecarboxylate as a solid (2.7 grams, 100% yield). MS (ESI) m/z 200.0 [M+H]+.
methyl 2-[(2E)-1-phenylpyrrolidin-2-yldene]amino}thiophene-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31%
Stage #1: 1-phenylpyrrolidin-2-one With trichlorophosphate In dichloromethane at 20℃; for 3h; Inert atmosphere;
Stage #2: Methyl 2-aminothiophene-3-carboxylate In dichloromethane for 16h; Reflux;
2.a Step a) Preparation of methyl 2-{ [(2E)-l-phenylpyrrolidin-2-ylidene]amino} thiophene-3- carboxylate (Compound 2a)
9.23 g (57.26 mmol, 1 eq.) of 1 -phenylpyrrolidin-2-one was dissolved in 70 ml of dry dichloromethane and 8.78 g (5.3 ml, 57.26 mmol, 1 eq.) POCl3 is added under argon. After stirring for three hours at room temperature, a suspension of methyl-2-aminothiophene-3- carboxylate (10 g, 63.61 mmol) in dichloromethane (150 mL) was added via a funnel. The reaction mixture was refluxed for 16 hours, cooled to room temperature, and extracted with 1M hydrochloric acid (5x100 mL). The combined aqueous phases were adjusted to pH 9-10 with saturated Na2C03 solution. The mixture was extracted with dichloromethane (3x200 mL) and the combined organic layers were dried over Na2S04. After filtering off the desiccant, after evaporation, 8.39 g of crude product remained. This was purified on a silica gel column with hexane-ethyl acetate. The appropriate fractions were combined and the residue was recrystallized from heptane:ethyl-acetate 1:1 mixture. Yield: 5.27 g (17.53 mmol, 31%) of methyl 2-{ [(2E)-l- phenylpyrrolidin-2-ylidene]amino} thiophene-3-carboxylate (Compound 2a), pale yellow crystals. NMR (500 MHz, DMSO-d6): d =2,05 (m, 2H), 2,68 (t, J = 7,8 Hz, 2H), 3,70 (s, 3H), 3,92 (t, J = 7,0 Hz, 2H), 6,91 (d, J = 6,0 Hz, 1H), 7,12 (tt, J = 1,1, 7,5 Hz, 1H), 7,13 (d, J = 6,0 Hz, 1H), (0210) 7,37 (dd, J = 7,5, 8,8 Hz, 2H), 7,83 (d, J = 8,8 Hz, 2H). DEPTq (500 MHz, DMSO-d6): d 19,1, 29,3, 50,8, 50,9, 115,3, 115,7, 121,0, 123,7, 127,0, 128,3 140,4, 162,3, 163,0, 163,5.
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