* 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.
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
3
[ 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
4
[ 4651-82-5 ]
[ 124-38-9 ]
[ 18740-38-0 ]
Yield
Reaction Conditions
Operation in experiment
94%
at 90℃; for 48 h;
Compound 1h (1 mmol, 124 mg), [HDBN+][TFE-] (6 mmol, 1.35 g) was added to a 10 ml round bottom flask. In a CO2 environment, the reaction was heated to 90°C for 48 hours, the reaction was stopped, the temperature was cooled to room temperature, and a saturated aqueous solution of NH4Cl was added. Adjust the pH to neutral, extract three times with 20ml CH2Cl2, collect the CH2Cl2 solution and dry it over anhydrous sodium sulfate. After filtration, the solution was removed by evaporation under reduced pressure, and the resulting solid was separated by silica gel column chromatography (eluent: CH2Cl2:CH3OH=15:1).158 mg of a pale yellow solid compound for 2 h, yield 94percent.
Reference：
[1] Patent: CN107698587, 2018, A, . Location in patent: Paragraph 0051; 0052; 0053
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4793 - 4805
7
[ 14080-51-4 ]
[ 57-13-6 ]
[ 18740-38-0 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2010, vol. 31, # 8, p. 2242 - 2246
[2] Bulletin de la Societe Chimique de France, 1975, p. 587 - 591
8
[ 18740-39-1 ]
[ 18740-38-0 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1975, p. 587 - 591
[2] Bulletin de la Societe Chimique de France, 1975, p. 592 - 597
9
[ 56844-43-0 ]
[ 18740-38-0 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1975, p. 592 - 597
10
[ 106666-44-8 ]
[ 57-13-6 ]
[ 18740-38-0 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1975, p. 587 - 591
11
[ 18740-38-0 ]
[ 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,
12
[ 18740-38-0 ]
[ 18740-39-1 ]
Yield
Reaction Conditions
Operation in experiment
56%
With trichlorophosphate In N,N-dimethyl-formamide at 115℃; for 8 h;
Thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (12) (2.5 g, 0.012 mol) and a drop of DMF were added to 20 mL POCl3. Heated to 115 °C for 8 h. After cooling to room temperature, the reactant was added to 500 g ice-water mixture slowly. The product was filtered off and dissolved in CH2Cl2. The insoluble was filtered off and the filtrate was distilled under reduced pressure to afford 1.7g 2,4-dichlorothieno[2,3-d]pyrimidine (13). Yield: 56.0 percent, 1H NMR (400 MHz, DMSO) δ 8.16 (d, J=3.4 Hz, 1H, Ar–H), 7.62 (d, J=3.4 Hz, 1H, Ar–H). ESI-MS m/z: 205.1.
56%
at 115℃; for 5 h;
To 1 g of dry thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione was added 10 g of phosphorus oxychloride,Add 1 drop of DMF catalyst, heating to 115 , the reaction 5h, the reaction is completed, the reaction slowly added to the crushed ice,While stirring vigorously,A brown solid,Filter, filter residue dissolved in 50mL of dichloromethane, to the solution by adding 1g activated carbon and 2g silica gel,Heated to 45 reflux decolorization 1h, while the hot filter, remove the solvent,Pale yellow solid,2,4-dichlorothieno [2,3-d] pyrimidine in a yield of 56.0percent.
56%
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate In acetonitrile at 0 - 85℃; for 24 h;
Thieno[2,3-d] pyrimidine-2,4 (1H, 3H) -dione (IX-2) (5.0 g, 29.7 mmol)And 3 mL of N, N-dimethylaniline were dissolved in 30 mL of acetonitrile,It was cooled to 0 ° C.16 mL of phosphorus oxychloride is kept at the reaction temperature not higher than 25 ° C.I am dripping slowly. The reaction mixture was heated and stirred at 80-85 ° C. for 24 hours.The reaction solution was cooled to 15 ° C.,Was slowly added to 70 mL of ice water.The obtained slurry was collected by filtration,And washed with cold water (20 mL).After drying, column chromatography (elution solvent: hexane: dichloroMethane = 1: 2)3.41 g (yield 56percent) of the dichloro compound (IIa-2) was obtained as gray crystals.
49%
Stage #1: for 0.5 h; Stage #2: for 8 h; Reflux
3 g (0.018 mol) of the intermediate lib was placed in a 100 mL three-necked flask,30 mL (0.329 mol) of phosphorus oxychloride was slowly added dropwise,After 30 min addition, 2 drops of DMF were added to the reaction mixture and the reaction was heated to reflux for 8 h. The reaction was poured into 1000 g of ice water with stirring, and a large amount of orange-colored solid was precipitated. The filter cake was washed with a large amount of water and dried at 45 ° C for 24 hours to obtain 1.8 g of an orange solid in a yield of 49percent.
41%
at 106℃; for 3 h; Inert atmosphere
Under a nitrogen streamThieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (8.4 g, 50.0 mmol) and phosphoryl chlorideL), which was stirred for 3 hours at 106 ° C. After completion of the reaction, the organic layer was separated using ethyl acetateWater was removed using MgSO4. The solvent of the organic layer was removed, and the residue was purified by column chromatography to obtain the target compound2,4-dichlorothieno [2,3-d] pyrimidine (4.2 g, 20.5 mmol, yield 41percent).
40%
at 116℃; for 3 h;
A mixture of thieno[2,3-φyrimidine-2,4(l//,3//)-dione (100 mg, 0.59 mmol) and phosphonyl chloride (2 mL, 21.5 mmol) was heated at 1 16 0C for 3 h. Upon completion of the reaction, the reaction mixture was poured into ice and extract with ethyl acetate 3 times. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by column chromatography, eluting with Hexanes/Ethyl Acetate (9: 1) afforded the product as a white solid (48.1 mg, 40percent): 1H NMR (DMSO, 300 MHz) δ 7.6 (d, J = 6.3 Hz, IH), 8.13(d, J = 5.7 Hz, IH).
35.5%
for 16 h; Reflux
A total of 0.8 mL N,N-dimethylaniline was added to 3.0 g of thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione 6a in 20 mL POCl3. The mixture was then heated under reflux for 16 h. Excess POCl3 was removed in vacuo, and the resulting residue was treated with ice water to yield a precipitate. The solid was collected by filtration, washed with water and dried over a funnel to afford solid 7a (1.3 g, yield 35.5percent). 1H NMR (400 MHz, CDCl3): δ 7.62 (d, J = 6.4 Hz, 1H), 7.43 (d, J = 6.4 Hz, 1H).
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 22, p. 7815 - 7833
[2] Bulletin of the Korean Chemical Society, 2010, vol. 31, # 8, p. 2242 - 2246
[3] European Journal of Medicinal Chemistry, 2015, vol. 93, p. 64 - 73
[4] Patent: CN106831812, 2017, A, . Location in patent: Paragraph 0091; 0092; 0093
[5] Patent: JP6120311, 2017, B2, . Location in patent: Paragraph 0144-0145
[6] Patent: CN103980287, 2016, B, . Location in patent: Paragraph 0148; 0151; 0152
[7] Patent: KR2015/36982, 2015, A, . Location in patent: Paragraph 0100-0103
[8] Patent: WO2008/58285, 2008, A2, . Location in patent: Page/Page column 45
[9] European Journal of Medicinal Chemistry, 2011, vol. 46, # 1, p. 71 - 76
[10] Comptes Rendus des Seances de l'Academie des Sciences, Serie C: Sciences Chimiques, 1968, vol. 266, p. 128 - 130
[11] Patent: WO2006/79916, 2006, A1, . Location in patent: Page/Page column 92
[12] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 11, p. 3325 - 3328
[13] MedChemComm, 2014, vol. 5, # 12, p. 1821 - 1828
With trichlorophosphate; In N,N-dimethyl-formamide; at 115℃; for 8h;
Thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (12) (2.5 g, 0.012 mol) and a drop of DMF were added to 20 mL POCl3. Heated to 115 C for 8 h. After cooling to room temperature, the reactant was added to 500 g ice-water mixture slowly. The product was filtered off and dissolved in CH2Cl2. The insoluble was filtered off and the filtrate was distilled under reduced pressure to afford 1.7g 2,4-dichlorothieno[2,3-d]pyrimidine (13). Yield: 56.0 %, 1H NMR (400 MHz, DMSO) delta 8.16 (d, J=3.4 Hz, 1H, Ar-H), 7.62 (d, J=3.4 Hz, 1H, Ar-H). ESI-MS m/z: 205.1.
56%
With N,N-dimethyl-formamide; trichlorophosphate; at 115℃; for 5h;
To 1 g of dry thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione was added 10 g of phosphorus oxychloride,Add 1 drop of DMF catalyst, heating to 115 , the reaction 5h, the reaction is completed, the reaction slowly added to the crushed ice,While stirring vigorously,A brown solid,Filter, filter residue dissolved in 50mL of dichloromethane, to the solution by adding 1g activated carbon and 2g silica gel,Heated to 45 reflux decolorization 1h, while the hot filter, remove the solvent,Pale yellow solid,2,4-dichlorothieno [2,3-d] pyrimidine in a yield of 56.0%.
56%
With N,N-dimethyl-aniline; trichlorophosphate; In acetonitrile; at 0 - 85℃; for 24h;
Thieno[2,3-d] pyrimidine-2,4 (1H, 3H) -dione (IX-2) (5.0 g, 29.7 mmol)And 3 mL of N, N-dimethylaniline were dissolved in 30 mL of acetonitrile,It was cooled to 0 C.16 mL of phosphorus oxychloride is kept at the reaction temperature not higher than 25 C.I am dripping slowly. The reaction mixture was heated and stirred at 80-85 C. for 24 hours.The reaction solution was cooled to 15 C.,Was slowly added to 70 mL of ice water.The obtained slurry was collected by filtration,And washed with cold water (20 mL).After drying, column chromatography (elution solvent: hexane: dichloroMethane = 1: 2)3.41 g (yield 56%) of the dichloro compound (IIa-2) was obtained as gray crystals.
49%
3 g (0.018 mol) of the intermediate lib was placed in a 100 mL three-necked flask,30 mL (0.329 mol) of phosphorus oxychloride was slowly added dropwise,After 30 min addition, 2 drops of DMF were added to the reaction mixture and the reaction was heated to reflux for 8 h. The reaction was poured into 1000 g of ice water with stirring, and a large amount of orange-colored solid was precipitated. The filter cake was washed with a large amount of water and dried at 45 C for 24 hours to obtain 1.8 g of an orange solid in a yield of 49%.
41%
With trichlorophosphate; at 106℃; for 3h;Inert atmosphere;
Under a nitrogen streamThieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (8.4 g, 50.0 mmol) and phosphoryl chlorideL), which was stirred for 3 hours at 106 C. After completion of the reaction, the organic layer was separated using ethyl acetateWater was removed using MgSO4. The solvent of the organic layer was removed, and the residue was purified by column chromatography to obtain the target compound2,4-dichlorothieno [2,3-d] pyrimidine (4.2 g, 20.5 mmol, yield 41%).
40%
With trichlorophosphate; at 116℃; for 3h;
A mixture of thieno[2,3-phiyrimidine-2,4(l//,3//)-dione (100 mg, 0.59 mmol) and phosphonyl chloride (2 mL, 21.5 mmol) was heated at 1 16 0C for 3 h. Upon completion of the reaction, the reaction mixture was poured into ice and extract with ethyl acetate 3 times. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by column chromatography, eluting with Hexanes/Ethyl Acetate (9: 1) afforded the product as a white solid (48.1 mg, 40%): 1H NMR (DMSO, 300 MHz) delta 7.6 (d, J = 6.3 Hz, IH), 8.13(d, J = 5.7 Hz, IH).
35.5%
With N,N-dimethyl-aniline; trichlorophosphate; for 16h;Reflux;
A total of 0.8 mL N,N-dimethylaniline was added to 3.0 g of <strong>[18740-38-0]thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione</strong> 6a in 20 mL POCl3. The mixture was then heated under reflux for 16 h. Excess POCl3 was removed in vacuo, and the resulting residue was treated with ice water to yield a precipitate. The solid was collected by filtration, washed with water and dried over a funnel to afford solid 7a (1.3 g, yield 35.5%). 1H NMR (400 MHz, CDCl3): delta 7.62 (d, J = 6.4 Hz, 1H), 7.43 (d, J = 6.4 Hz, 1H).
With trichlorophosphate; at 200℃; for 2.3h;
EXAMPLE 402,4-Dichlorothieno[2,3-d]pyrimidine; The dione of Example 39 (2.6 g) was placed into a pressure vessel with phosphorus oxychloride (15 mL). The mixture was heated at 200 0C for 2.3 hours and then cooled to room temperature and concentrated under reduced pressure. Residual phosphorus oxychloride was azeotroped . twice with toluene (30 mL) under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The resulting layers were separated and the organic layer was filtered through anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give 1.06 g of the title compound: MS (ESI+) for C6H2N2CI2S m/z205.0 (M+H)+. 1H NMR (400 MHz, CDCI3) delta 7.42 (d,1 H), 7.61 (d,1 H).
With N,N-dimethyl-aniline; trichlorophosphate; In toluene; at 100℃; for 3h;
To a solution of <strong>[18740-38-0]1H-thieno[2,3-d]pyrimidine-2,4-dione</strong> (62) (92.8 mg, 0.552 mmol) in toluene (1 mL) were added N,N-dimethylaniline (0.140 mL, 1.10 mmol) and phosphoryl chloride (0.280 mL, 3.00 mmol). The reaction mixture was warmed to 100 C and stirred for 3 h. After cooling to room temperature, H2O was added to the reaction mixture and the mixture was extracted with CHCl3. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give 2,4-dichlorothieno[2,3-d]pyrimidine (63). This compound was used for the next reaction without further purification.To a solution of 63 in DMF (4 mL) was added ethyl 2-(4-aminophenyl)acetate (95.2 mg, 0.531 mmol) and the reaction mixture was stirred at 65 C for 2.5 h. After cooling, H2O was added to the reaction mixture and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed (EtOAc/hexane = 0% to 100%) to give the title compound (85.9 mg, 0.247 mmol, 45%) as a colorless solid. 1H NMR (CDCl 3) delta: 1.28 (3H, t, J = 7.4 Hz), 3.64 (2H, s), 4.18 (2H, q, J = 7.4 Hz), 7.03 (1H, d, J = 5.7 Hz), 7.21 (1H, s), 7.29 (1H, d, J = 5.7 Hz), 7.32 (2H, d, J = 8.6 Hz), 7.56 (2H, d, J = 8.6 Hz).
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%
Thieno [2,3- D] pyrimidine-2,4 (1H, 3H) -dione (0.5 g, 2.98 mmol) HMDS (1.2 g, 7.44 mmol), toluene (8 mL) was added to the reaction flask, concentrated sulfuric acid (20 mg) was added with stirring, Stirring and refluxing reaction 12h. The solvent was concentrated to dryness under reduced pressure.
With sulfuric acid; In toluene; for 12h;Reflux;
Thieno[2,3-D]pyrimidine-2,4(1H,3H)-dione(0.5 g, 2.98 mmol), HMDS (1.2 g, 7.44 mmol),Toluene (8 mL) was added to the reaction flask and concentrated sulfuric acid (20 mg) was added with stirring.The reaction was stirred and refluxed for 12 h. The solvent was concentrated under reduced pressure to dryness.
This material (45 g) was suspended in a solution of sodium carbonate (90 g) in water (900 ml), heated for two hours at 100, cooled and acidified with hydrochloric acid to give 1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-2,4-dione (30 g, m.p.>300).
To a stirred solution of methyl-2-aminothiophene-3-carboxyIate (2.03 g, 12.9 mmol) in acetic acid (65 mL) and water (6.5 mL) was added a solution of potassium cyanate (3.14g, 38.7 mmol) dissolved in water (10.4 niL) dropwise via syringe. The reaction was stirred at room temperature for 15 h, upon completion of the reaction; the reaction mixture was concentrated to 75% and filtered off white solid. To the solid was added 6% aqueous sodium hydroxide (16mL) and refluxed for 2 h. After cooling to room temperature, the solution was acidified using 12N HCl to pH = 6. The resultant precipitate was filtered, washed with water and dried in a vacuum oven overnight to give 546 mg (25%) of the title compound as an orange solid which was used without any further purification:1H NMR (DMSO, 300 MHz) 5 7.06 (, J = 5.7 Hz, IH), 7.1 (d, 7= 5.7 Hz, IH), 1 1.1 (broad s, IH), 11.9 (broad s, IH).
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 3 L reaction vial equipped with a mechanical stirrer, internal temperature probe, and a nitrogen bubbler was charged with lH-thieno[3,2,-d]pyrimidine-2,4-dione (80 g). Next, N,iV-dimethylaniline (42 g) and acetonitrile (400 mL) were added to the reaction flask and cooled to 10 C. Phosphorousoxychloride was added to the reaction mixture while maintaining am internal temperature of <25 C. After this addition the reaction mixture was heated to 80 - 85 C and stirred for 16 hours. An aliquot was taken from the reaction mixture and diluted with methanol/ ACN and analyzed by LC/MS to confirm the consumption of starting material. The reaction was then cooled to 15 C and slowly transferred to a 5 L flask containing a mixture of ice and water (1.0 L). A solid was collected by vacuum filtration and the filter cake is washed with cold water (300 mL). The washed solid was dried in a vacuum oven at 40 C for 24 hours to afford 2,4-dicWorothieno[2,3-^pyrimidine as an off white solid (91.43 g., 93.7%). 1H NMR (400 MHz, DMSO-J6) delta 7.619 (d, J= 6.4 Hz, IH), delta 8.155 (d, J = 6.4 Hz, IH) LCMS (ESI pos) m/e 205 (M+l).
To a stirring solution of methyl^-aminothiophene-S-carboxylate (10.0 g, 63.7 mmol) in anhydrous dichloromethane (270 mL) cooled down to -78 C was added dropwise chlorosulfonyl isocyanate (7.6 mL, 87.2 mmol) over 25 minutes. The temperature was warmed to room temperature and stirred for 40 minutes. The reaction mixture was evaporated down. The resulting crude solid was treated with 6M hydrochloric acid (250 mL) and heated at 100 0C for 35 minutes. The cooled reaction mixture was neutralised to pH 3 with solid sodium carbonate. The precipitate was filtered, washed with water and dried to give 3-ureido- thiophene-2-carboxylic acid methyl ester (13.5 g).To a stirring suspension of 3-ureido-thiophene-2-carboxylic acid methyl ester (13.5 g, 67.5 mmol) in 2-propanol (100 mL) was added sodium hydroxide (5.5 g, 137.5 mmol) in water (40 mL). The mixture was stirred at 80 C for 3.5 hours. The cooled reaction mixture was poured onto 2M sodium hydroxide solution (100 mL) and acidified to pH 3 with careful addition of concentrated hydrochloric acid. The precipitate was filtered under vacuum, washed with water and dried to give lH-thieno[2,3-cT]pyrimidine-2,4-dione (8.83 g).
With Lawessons reagent; In 1,4-dioxane; for 0.5h;Reflux;
Thieno [2,3-d] pyrimidine-2,4 (1 H, 3H) -dione(IX-2)(1.0 g, 5.95 mmol)And Lawesson's reagent(2.5 g, 6.18 mmol)Was added to 25 mL of 1,4-dioxane,And heated under reflux for 30 minutes.After the reaction, the solvent was distilled off under reduced pressure,The residue was triturated with ethyl acetate,It was collected by filtration and recrystallized from ethanol.0.72 g (yield 73%) of a pale yellow powder 4-thioxo compound (X-2) was obtained.
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.
1-n-pentylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Compound 24a (231.5 mg, 1.38 mmol) was dissolved in 3 mL of DMF,Potassium carbonate (380.9 mg, 2.76 mmol) was added,Room temperature reaction 1h,Followed by addition of bromo-n-pentane(207.8 mg, 1.38 mmol),Room temperature reaction overnight.After the reaction,Add the right amount of water,Ice bath with 2N HCl adjusted to PH = 3,Extracted three times with ethyl acetate,The combined organic phases were washed with saturated brine,Dried over anhydrous magnesium sulfate,The crude product was distilled under reduced pressure.Separation and purification by column chromatography,To give a pale yellow solid.Yield: 9.7%
With 1,5-diazabicyclo[4.3.0]non-5-ene 2,2,2-trifluoroethanol; at 90℃; for 48h;
Compound 1h (1 mmol, 124 mg), [HDBN+][TFE-] (6 mmol, 1.35 g) was added to a 10 ml round bottom flask. In a CO2 environment, the reaction was heated to 90C for 48 hours, the reaction was stopped, the temperature was cooled to room temperature, and a saturated aqueous solution of NH4Cl was added. Adjust the pH to neutral, extract three times with 20ml CH2Cl2, collect the CH2Cl2 solution and dry it over anhydrous sodium sulfate. After filtration, the solution was removed by evaporation under reduced pressure, and the resulting solid was separated by silica gel column chromatography (eluent: CH2Cl2:CH3OH=15:1).158 mg of a pale yellow solid compound for 2 h, yield 94%.
94%
With 1,5-diazabicyclo[4.3.0]non-5-ene 2,2,2-trifluoroethanol; at 90℃; under 760.051 Torr; for 48h;Green chemistry;
General procedure: Substrate (1.0 mmol), [HDBN+][TFE-] (6.0 mmol) were loaded in a 10 mL glass reaction tube equipped with a magnetic stirrer. The air in the reactor was replaced by CO2. Then, the reactor was stirred at the desired temperature for 3-96 h under CO2 using a balloon. After the reaction, the reaction liquid was cooled to room temperature and quenched by saturated ammonium chloride solution. Then the mixture was filtered to afford the crude product, which was purified by chromatography (silica gel, methanol/dichloromethane=1/20) to give the desired compound. The purified product was characterized by NMR and HR-MS. 1H NMR and 13C NMR studies were carried out with a JEOL NMR 400 (400 MHz, 100 MHz) spectrometer with DMSO-d6 as the solvent. Mass spectra were recorded with an AMD40223(Interambulacra) spectrometer.
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