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Structure of 56-04-2 * Storage: {[proInfo.prStorage]}
* 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] Journal of the American Chemical Society, 1937, vol. 59, p. 526,527
[2] Bulletin des Societes Chimiques Belges, 1957, vol. 66, p. 276,289
[3] Journal of the Chemical Society, 1951, p. 1004,1015[4] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, vol. 24, p. 84
[5] Org. Synth. Coll. Vol., 1963, vol. IV, p. 638
[6] European Journal of Medicinal Chemistry, 2008, vol. 43, # 6, p. 1248 - 1260
To methanol (10 mL) was added sodium(30mmol) and then thiourea (10mmol) and acetoaceticacid ethyl ester (10mmol). The mixture was boiled for 7h,methanol was evaporated, and the precipitate was dissolvedin water, neutralized with acetic acid, and filtered off.Yield (1.26 g, 90percent); light yellow crystals; m.p. 275–277∘C.1HNMR: δ = 2.09 (s, 3H, 6-CH3); 5.52 (s, 1H, CH-pyrim.);11.98 [b.s, 2H, (NH)2]. 13C NMR: δ= 17.88; 103.38 151.91;160.32; 175.83. Anal. Calcd for C5H6N2OS: C, 42.24; H, 4.25;N, 19.70; S, 22.55; found: C, 42.24; H, 4.25; N, 19.70; S, 22.55.
59%
With sodium hydroxide In water at 10 - 20℃; for 3 h;
To a solution of sodium hydroxide (8.0 g, 0.30 mol) in H2O (120 mL) was added into thiourea (17.33g, 0.13 mol). When most of the solid dissolve, ethyl acetoacetate (15.22 g, 0.20 mol) was added dropwise under 10-20°C. Then the mixture was stirred for 3h under room temperature, and acidified with hydrochloric acid to pH 4~5. The precipitated solid was filtered, washed with cool water, and dried to get white solid 6c (10.90 g), yield: 59percent, mp > 300°Clit.3 mp > 300°C
Reference:
[1] Organic Process Research and Development, 2010, vol. 14, # 1, p. 205 - 214
[2] Journal of Chemistry, 2017, vol. 2017,
[3] RSC Advances, 2017, vol. 7, # 28, p. 17427 - 17441
[4] Synthetic Communications, 2002, vol. 32, # 6, p. 851 - 855
[5] Journal of the Chemical Society of Pakistan, 2011, vol. 33, # 6, p. 893 - 899
[6] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 23, p. 7093 - 7099
[7] Russian Journal of General Chemistry, 2003, vol. 73, # 3, p. 463 - 466
[8] Russian Journal of General Chemistry, 2004, vol. 74, # 3, p. 423 - 427
[9] Justus Liebigs Annalen der Chemie, 1886, vol. 236, p. 3
[10] Justus Liebigs Annalen der Chemie, 1885, vol. 229, p. 17[11] Justus Liebigs Annalen der Chemie, 1885, vol. 231, p. 249
[12] Justus Liebigs Annalen der Chemie, 1886, vol. 236, p. 3
[13] Journal fuer Praktische Chemie (Leipzig), 1882, vol. <2> 25, p. 74
[14] American Chemical Journal, 1909, vol. 42, p. 108
[15] Justus Liebigs Annalen der Chemie, 1951, vol. 572, p. 217,224
[16] Justus Liebigs Annalen der Chemie, 1951, vol. 572, p. 217,224
[17] European Journal of Medicinal Chemistry, 1988, vol. 23, # 1, p. 53 - 62
[18] Archiv der Pharmazie, 1984, vol. 317, # 5, p. 425 - 430
[19] Collection of Czechoslovak Chemical Communications, 1980, vol. 45, # 3, p. 732 - 739
[20] Collection of Czechoslovak Chemical Communications, 1983, vol. 48, # 7, p. 1872 - 1877
[21] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 3, p. 624 - 631
9
[ 72324-39-1 ]
[ 17356-08-0 ]
[ 56-04-2 ]
Reference:
[1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2011, vol. 50, # 5, p. 745 - 747
Reference:
[1] Journal of Coordination Chemistry, 2010, vol. 63, # 18, p. 3187 - 3197
12
[ 17649-31-9 ]
[ 56-04-2 ]
[ 1380547-50-1 ]
[ 119730-48-2 ]
Reference:
[1] Russian Journal of General Chemistry, 2012, vol. 82, # 4, p. 725 - 728
13
[ 119730-09-5 ]
[ 56-04-2 ]
[ 119730-50-6 ]
Reference:
[1] Russian Journal of General Chemistry, 2012, vol. 82, # 4, p. 725 - 728
14
[ 141-78-6 ]
[ 17356-08-0 ]
[ 56-04-2 ]
Reference:
[1] Chem.Wd. Shanghai, 1959, p. 164[2] Chem.Abstr., 1960, p. 3436
15
[ 1007476-32-5 ]
[ 17356-08-0 ]
[ 56-04-2 ]
Reference:
[1] Meditsinskaya Promyshlennost SSSR, 1958, vol. 12, # 10, p. 36[2] Chem.Abstr., 1959, p. 16 139
16
[ 105-45-3 ]
[ 17356-08-0 ]
[ 56-04-2 ]
Reference:
[1] Synthetic Communications, 2002, vol. 32, # 6, p. 851 - 855
[2] Canadian Journal of Chemistry, 1986, vol. 64, p. 2087 - 2093
[3] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 23, p. 7180 - 7184
17
[ 124-41-4 ]
[ 141-97-9 ]
[ 17356-08-0 ]
[ 56-04-2 ]
Reference:
[1] Org.Synth.Coll.Vol., 1963, vol. IV, p. 638
18
[ 6328-58-1 ]
[ 3524-87-6 ]
[ 626-48-2 ]
[ 56-04-2 ]
Reference:
[1] Polish Journal of Chemistry, 1980, vol. 54, # 2, p. 363 - 365
19
[ 674-82-8 ]
[ 17356-08-0 ]
[ 56-04-2 ]
Reference:
[1] Journal of the Chemical Society, 1954, p. 854,859
[2] Kogyo Kagaku Zasshi, 1954, vol. 57, p. 947[3] Chem.Abstr., 1956, p. 1028
[4] Kogyo Kagaku Zasshi, 1954, vol. 57, p. 947[5] Chem.Abstr., 1956, p. 1028
[6] Journal of the Chemical Society, 1954, p. 854,859
20
[ 56-04-2 ]
[ 17119-73-2 ]
Reference:
[1] Journal of Medicinal Chemistry, 2007, vol. 50, # 6, p. 1146 - 1157
[2] Patent: US5250548, 1993, A,
21
[ 56-04-2 ]
[ 74-88-4 ]
[ 6328-58-1 ]
Yield
Reaction Conditions
Operation in experiment
98%
With sodium hydroxide In water at 20℃; for 4 h;
(EV-AO5743-001) [00128] To water (500 mL) was added NaOH (97percent, 15.7 g, 381 mmol) and the suspension stirred at r.t. for 10 mins. 6-methyl-2-sulfanylidene-l,2,3,4-tetrahydropyrimidin-4-one (98percent, 53.5 g, 369mmol) was added and the mixture stirred until fully dissolved for 10 mins. lodomethane (28.99 mL, 461 mmol) was added dropwise and the mixture stirred at r.t. for 4 h. The colorless solid was filtered, washed with ice cold water (2 x 100 mL) and dried under vacuum at 60 °C to afford the title compound (57 g, 98percent) as a colorless solid. [00129] Method A: LC-MS m/z = 156.9 [M + H]+; RT = 0.61 min.
Reference:
[1] Patent: WO2017/59191, 2017, A1, . Location in patent: Paragraph 00126-00129
[2] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 18, p. 3025 - 3030
[3] Archiv der Pharmazie, 1984, vol. 317, # 5, p. 425 - 430
22
[ 56-04-2 ]
[ 74-88-4 ]
[ 6328-58-1 ]
Yield
Reaction Conditions
Operation in experiment
361.2 g
With potassium carbonate In dimethyl sulfoxide at 25℃; Cooling with acetone-dry ice
To a solution of the pyrimidine (324a; 522.3 g) in DMSO(5 L), potassium carbonate (535.6 g) followed by iodomethane (245 ml) were added while maintaining a reaction temperature of 22-25 C (dry ice/acetone bath). When the addition was complete the reaction was allowed to stir at room temperature overnight. Ice (7 L) and water (13 L) wereadded to the reaction. Afier 0.5 h., the mixture was filtered and the solid washed with cold water, cold acetonitrile and cold ether to give the methyl sulfide (324b; 95.7 g). To the filtrate was added 50percent aq. HC1 (300 ml) while cooled in a dry ice/acetone bath. Afier stirring for 5 mm, thewhite solid was collected, Afier washing with cold water, acetonitrile and ether a thrther portion of the methylsulfide (324b; 361.2 g) was recovered.
With sodium hydroxide; methyloxirane In water at 20℃;
95%
With potassium <i>tert</i>-butylate; iodine In <i>tert</i>-butyl alcohol for 30h; Heating;
85%
Stage #1: 6-methyl-2-thiouracil With chloroacetic acid In water for 9h; Reflux;
Stage #2: With hydrogenchloride In water for 10 - 12h; Reflux;
General Procedure for the Synthesis of 6-methylpyrimidine-2,4(1H,3H)-dione (4)
Chloroacetic acid (34.0 g, 0.36 mol) and compound 3 (12.4 g, 0.09 mol) were suspendedin H20 (160 ml). The reaction mixture was refluxed for 9 h and cooled to room temperature. Thenconc. HCl (0.4 ml) was added carefully, and the reaction mixture was again refluxed for 10-12 h.The reaction was cooled to room temperature, the precipitate formed was collected by filtrationand washed with cold water (4 times) and dried under vaccum to afford pure intermediate 6-methyluracil (4b) as a white solid in 85 % yield.
79%
With potassium superoxide; 18-crown-6 ether In N,N-dimethyl-formamide for 72h; Ambient temperature;
58%
With iodosylbenzene In acetone for 15h; Ambient temperature;
With sodium hydroxide; chloroacetic acid anschliessend mit wss.HCl;
With potassium hydroxide In ethanol at 125℃; for 0.416667h; Microwave irradiation; Inert atmosphere;
91%
With potassium hydroxide In ethanol at 80℃; for 5h;
1 Step 1:
To a vial was added ethyl 3-oxobutanoate (1 g, 8.0 mmol, 1 eq.), thiourea (0.6, 8.0 mmol, 1 eq.) and KOH (0.4 g, 8.0 mmol, 1 eq.) in ethanol (6 ml). The reaction mixture was stirred at 80° C. for 5 h. Ethanol was removed under reduced pressure to one third of its original volume, the reaction mixture was then poured into water and neutralized with 2 N HCl. The resulting mixture was left stirring overnight at rt. A precipitate formed and was filtered by vacuum filtration to provide the desired product 6-methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (1.0 g, 7.033 mmol, 91%) as white solid. ESI-MS: 143.2 [M+H]+.
90%
With anhydrous sodium formate In methanol for 7h; Heating;
3.1. Synthesis of 6-Methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (1)
To methanol (10 mL) was added sodium(30mmol) and then thiourea (10mmol) and acetoaceticacid ethyl ester (10mmol). The mixture was boiled for 7h,methanol was evaporated, and the precipitate was dissolvedin water, neutralized with acetic acid, and filtered off.Yield (1.26 g, 90%); light yellow crystals; m.p. 275-277∘C.1HNMR: δ = 2.09 (s, 3H, 6-CH3); 5.52 (s, 1H, CH-pyrim.);11.98 [b.s, 2H, (NH)2]. 13C NMR: δ= 17.88; 103.38 151.91;160.32; 175.83. Anal. Calcd for C5H6N2OS: C, 42.24; H, 4.25;N, 19.70; S, 22.55; found: C, 42.24; H, 4.25; N, 19.70; S, 22.55.
90%
Reflux;
3.2.1. Synthesis of 6-Substituent-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (1a-1f)
General procedure: All of the thiouracil derivatives (R1 = CH3, C2H5, n-Pr, cyc-Pr, CHF2, CF3) were prepared asfollowed. To a 1000mLthree-neck flask equipped with a magnetic stirrer, a thermometer, and a droppingfunnel, 500 mL of methanol and 59.4 g (1.1 mol) of solid sodium methoxide were added, and the mixturewas then stirred at room temperature. After 0.5 h, 0.5 mol (93.0 g) of ethyl 4,4,4-triuoro-3-oxobutanoateand 0.6 mol of thiourea were added to the flask, and the mixture was heated to reflux for about 4 h.Finally, a 2 M HCl aqueous solution was added to the flask until the reaction mixture was neutralized.The resultant solid was separated by filtration, then washed with water, and finally dried in a desiccatorto produce 88.3 g of intermediate 1b as a white solid at a yield of 90%
84%
With potassium hydroxide In ethanol for 5h; Reflux;
Synthesis of 6-methyl-2-thioxo-2,3-dihydropyrimidin-4(lH)-one (C)
Ethyl 3-oxobutanoate (1.3 mL, 10 mmol) was added to a stirred suspension of thiourea (766 mg, 10 mmol) and KOH (672 mg, 12 mmol) in EtOH (20 mL). The solution was refluxed for 5 h and completion of the reaction was confirmed by LCMS. The solid formed was collected by filtration and then dissolved in H2O. The solution was then acidified with IN HC1 to pH 1 to give white precipitate of 5-ethyl-6-methyl-2-thioxo-2,3-dihydropyrimidin-4(lH)-one that was filtered and dried under vacuum (1.19 g, 84% yield). ESI-MS (m/z): 143.0 [M+H]+.
73%
With potassium etoxide In ethanol at 60 - 85℃; for 3h; Inert atmosphere; Large scale;
A Step A: 6-Methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one
Into a 20 L 4-necked round-bottomed flask, purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 3-oxobutanoate (1500 g, 11.53 mol), ethanol (7500 mL) and EtONa (801 g). This was followed by the addition of thiourea (894 g, 11.74 mol) in portions at 60 °C. The resulting mixture was heated for 3 h at 85 °C. The reaction mixture was then cooled to 25 °C and the solids were collected by filtration. The resulting solid was dissolved in 5 L of H2O. The pH of the solution was adjusted to 2 with hydrogen chloride. The solids were collected by filtration and dried to afford 6-methyl-2-thioxo-2,3-dihydropyrimidin- 4(1H)-one (1200 g, 73%) as a white solid.1H NMR (300 MHz, DMSO-d6) d 12.2- 12.3 (m, 2H), 5.68 (s, 1H), 2.07 (s, 3H).
70%
With potassium hydroxide In ethanol at 80℃; for 5h;
69%
for 0.0666667h; microwave irradiation;
67%
With hydrogenchloride; potassium carbonate In water monomer at 60 - 100℃; for 2h;
General Procedure for the Synthesis 6-methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (3)
Thiourea (9.9 g 0.13 mol) was dissolved in water (18 ml) and was heated at 60 °C. Ethylacetoacetate (26.1 g, 0.2 mol) was added followed by K2CO3 (27.6 g, 0.2 mol). The reactionmixture was heated at 100 °C for 2 h. The reaction mixture was cooled to room temperature, water(70 ml) was added and followed by 60 ml of conc. HCl. The white ppt. formed was collected byfiltration and washed with water and 1N HCl to afforded intermediate 3 as a white solid in 67%)yield.
64%
Stage #1: ethyl acetoacetate; thiourea With potassium hydroxide In ethanol at 50℃; for 12h;
Stage #2: With hydrogenchloride In ethanol; water monomer
59%
With sodium hydroxide In water monomer at 10 - 20℃; for 3h;
2. Preparation of 6-methyl-2-thioxo-2, 3-dihydropyrimidin-4(1H)-one (6c)
To a solution of sodium hydroxide (8.0 g, 0.30 mol) in H2O (120 mL) was added into thiourea (17.33g, 0.13 mol). When most of the solid dissolve, ethyl acetoacetate (15.22 g, 0.20 mol) was added dropwise under 10-20°C. Then the mixture was stirred for 3h under room temperature, and acidified with hydrochloric acid to pH 4~5. The precipitated solid was filtered, washed with cool water, and dried to get white solid 6c (10.90 g), yield: 59%, mp > 300°Clit.3 mp > 300°C
51%
With potassium etoxide In ethanol for 3h; Heating;
51%
With potassium etoxide In ethanol at 60℃; for 3h;
With hydrogenchloride; ethanol Kochen des Reaktionsprodukts mit alkoh. Kalilauge und Ansaeuern mit Salzsaeure;
at 150℃;
With potassium etoxide
With potassium carbonate
With potassium hydroxide
With potassium etoxide In ethanol Heating;
With potassium etoxide In ethanol for 7h; Heating;
With sodium methoxide at 25℃;
With sodium methoxide In methanol at 25℃; other ethyl 2-alkyl-3-oxobutanoates;
With sodium hydroxide In water monomer at 20℃; for 5h;
1.1.1 Step 1: Synthesis of 6-methyl-2-(methylsulfanyl)-3,4-dihydropyrimidin-4-one
(EV-AO5743-001) [00128] To water (500 mL) was added NaOH (97%, 15.7 g, 381 mmol) and the suspension stirred at r.t. for 10 mins. 6-methyl-2-sulfanylidene-l,2,3,4-tetrahydropyrimidin-4-one (98%, 53.5 g, 369mmol) was added and the mixture stirred until fully dissolved for 10 mins. lodomethane (28.99 mL, 461 mmol) was added dropwise and the mixture stirred at r.t. for 4 h. The colorless solid was filtered, washed with ice cold water (2 x 100 mL) and dried under vacuum at 60 °C to afford the title compound (57 g, 98%) as a colorless solid. [00129] Method A: LC-MS m/z = 156.9 [M + H]+; RT = 0.61 min.
86%
With water; sodium hydroxide at 20℃; for 1h; Cooling with ice;
Synthesis of 6-methyl-2-(methylthio)pyrimidin-4(3H)-one (D)
NaOH (176 mg, 4.4 mmol) was added to a suspension of 6-methyl-2-thioxo-2,3- dihydropyrimidin-4(lH)-one (C) (568 mg, 4.0 mmol) in H2O (12 mL) and the resulting mixture was allowed to stir to clarity. Then, the solution was cooled in an ice bath, and iodomethane (0.28 mL, 4.4 mmol) was added dropwise to the solution. The reaction was warmed to room temperature and continued to stir for 1 h, precipitate formed was filtered, washed with H2O and dried under vacuum to yield 6-methyl-2-(methylthio)pyrimidin-4(3H)- one as a white solid (536 mg, 86% yield). 1H NMR (400 MHz, Chloroform-d) δ 6.06 (s, 1H), 2.57 (s, 3H), 2.27 (s, 3H). ESI-MS (m/z): 157.1 [M+H] +.
54%
Stage #1: 6-methyl-2-thiouracil With sodium hydroxide In water for 0.5h;
Stage #2: methyl iodide In water at 10 - 20℃; for 24h;
2 Step 2:
To a vial was added 6-methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (1.5 g, 11 mmol, 1 eq.) and H2O. After that NaOH (0.46 g, 12 mmol, 1.1 eq.) was added portion wise to the vial containing suspension of 6-methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (1.5 g, 11 mmol, 1 eq.) in H2O. The reaction mixture was stirred for 30 min and then it was cooled to 10° C., followed by the addition of methyl iodide (1.8 g, 13 mmol, 1.2 eq). The mixture was stirred for another 24 h at room temperature, followed by again cooling to 10° C. The precipitate formed was filtered by vacuum filtration, washed with H2O and dried to provide desired product 6-methyl-2-(methylthio)pyrimidin-4(3H)-one (0.893 g, 5.72 mmol, 54%) as white solid. APCI-MS: 157.1 [M+H]+.
48%
With potassium carbonate In dimethyl sulfoxide
With potassium hydroxide In methanol for 0.166667h; Ambient temperature;
With sodium hydroxide In water monomer at 10 - 15℃; for 16.3333h;
3. General procedure for preparation of 2-(methylthio)pyrimidin-4(1H)-ones (7a-c)
General procedure: To a solution of 6a-c (0.3 mol), sodium hydroxide (12.40 g, 0.31 mol) in H2O (300 mL) was added dropwise methyl iodide (53.23 g, 0.375 mol) in 20 min under 10-15°C.The mixture was stirred for 16h at room temperature, then cooled to 5-10°C. The precipitated solid was filtered, washed with water, and dried to get white solid 7a-c.
45%
With sodium hydroxide In ethanol at 60℃;
With sodium hydroxide In water monomer at 20℃; for 24h;
Stage #1: 4-methyl-2-thiouracyl With sodium hydroxide In water monomer at 20℃; for 0.5h;
Stage #2: iodomethane In water monomer at 10 - 20℃; for 24h;
4.1.1. General procedure for the synthesis of 12a-c
General procedure: NaOH (6.18 g, 155 mmol) was added portion-wise to a suspension of thiouracils 11a-c (150 mmol) in H2O at room temperature. After the reaction mixture was stirred for 30 min and cooled to 10 °C, iodomethane (25.55 g, 180 mmol) was added. The mixture was stirred for another 24 h at room temperature, followed by cooling to 5-10 °C. The precipitate was filtered off, washed with H2O, and dried to give 2-(methylthio)pyrimidin-4(1H)-ones 12a-c to be used without further purification.
With potassium carbonate In dimethyl sulfoxide
1
To a solution of 6-methyl-2-thiouracil (30 g, 0.210 mole) in dimethylsulfoxide (300 mL) was added anhydrous potassium carbonate (32 g, 0.230 mol) and methyl iodide (14.2 mL, 0.230 mol). The reaction mixture was allowd to stir overnight followed by the addition of of water (740 mL). The precipitate was filtered, washed with water and dried on the air to give 21g of 6-methyl-2-(methylthio)prymidin-4(lH)-one as a white solid, m/z (ESI+)( 163 (MNa+).
With sodium hydroxide In water monomer at 20℃; for 24h;
Stage #1: 4-methyl-2-thiouracyl With sodium hydroxide In water monomer at 20℃;
Stage #2: iodomethane In water monomer at 20℃; for 24h;
23 5.2. General procedure for preparation of target compounds
General procedure: The 2-thiouracil derivatives (0.1 mol) were added into the sodium hydroxide solution (1.05 mol/L, 100 mL) at room temperature. After dissolution, the solution was slowly added with iodomethane (17.74 g, 0.125 mol) as methylating agent. After the reaction mixture was stirred for 24 h at rt, the precipitate was filtered off, washed with H2O, and dried to give 2-(methylthio)pyrimidin-4(1H)-ones 11a-c, which were used without further purification. Compound 11a-c (80 mmol) and 4-cyanoaniline (27.74 g, 240 mmol) were pounded into a fine powder and mixed thoroughly. Then the mixture was slowly heated to 180-200 °C, and reacted in solvent-free condition at this temperature for about 8 h. After cooled to room temperature, the mixture was smashed in acetonitrile with ultrasonic machine. The precipitate was filtered off, washed with acetonitrile (3×10 mL) and then dichloromethane (2×10 mL). The product 12a-c were dried and used without further purification. The common blocks 12a-c (4 mmol) together with t-BuOK (0.45 g, 4 mmol) were then dissolved in DMSO (10 mL) and stirred for 15 min at room temperature. After that, the corresponding 13 (4 mmol) dissolved in DMSO (3 mL) was added slowly into the mixture. Stirring at room temperature for 2-6 h, the reaction was stopped when 13 was not detected by TLC. The mixture was poured into 100 ml H2O and neutralized with 3N HCl. The resulting target compounds 3a-w were collected by filtration and recrystallized from methanol and dichloromethane.
With sodium hydroxide In water monomer at 20℃; Inert atmosphere;
2-[(4-methylpyridin-2-yl)methyl]-thio-6-methyl-4(3H)-pyrimidinone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-benzyl-N,N,N-triethylammonium chloride; triethylamine; In sodium hydroxide; chloroform; ethyl acetate; toluene;
Example 13 Preparation of 2-[(4-methylpyridin-2-yl)methyl]-thio-6-methyl-4(3H)-pyrimidinone A mixture containing 1.23 g (10 mmol) of <strong>[42508-74-7]2-hydroxymethyl-4-methylpyridine</strong> [Bull. Chem. Soc. Jap. 3 , 413 (1955)], 2.1 ml (15 mmol) of triethylamine and 25 ml of chloroform is cooled to 0 C and 0.85 ml (11.7 mmol) of methanesulfonyl chloride is added under stirring. After stirring for 30 minutes 0.2 g of benzyltriethylammonium chloride and 1.42 g (10 mmol) of 6-methyl-2-thiouracil dissolved in 20 ml of 1 N sodium hydroxide solution are added, then the reaction mixture is vigorously stirred at room temperature for 10 hours and worked up in the usual manner. The crude product obtained is crystallized by thoroughly triturating it with diisopropyl ether, m.p.: 157 - 158 C. The product obtained is further purified by recrystallization from the mixture of toluene and ethyl acetate to obtain 1.19 g (48 %) of the title compound, m.p.: 161 - 162 C.
With N-benzyl-N,N,N-triethylammonium chloride; triethylamine; In sodium hydroxide; chloroform; ethyl acetate; toluene;
EXAMPLE 13 Preparation of 2-[(4-methylpyridin-2-yl)methyl]thio- 6-methyl-4(3H)-pyrimidinone A mixture containing 1.23 g (10 mmol) of <strong>[42508-74-7]2-hydroxymethyl-4-methylpyridine</strong> [Bull. Chem. Soc. Jap. 3, 413 (1955)], 2.1 ml (15 mmol) of triethylamine and 25 ml of chloroform is cooled to 0 C. and 0.85 ml (11.7 mmol) of methanesulfonyl chloride is added under stirring. After stirring for 30 minutes 0.2 g of benzyltriethylammonium chloride and 1.42 g (10 mmol) of 6-methyl-2-thiouracil dissolved in 20 ml of 1N sodium hydroxide solution are added, then the reaction mixture is vigorously stirred at room temperature for 10 hours and worked up in the usual manner. The crude product obtained is crystallized by thoroughly triturating it with diisopropyl ether, m.p.: 157-158 C. The product obtained is further purified by recrystallization from the mixture of toluene and ethyl acetate to obtain 1.19 g (48%) of the title compound, m.p.: 161-162 C.
With potassium carbonate In dimethyl sulfoxide at 25℃; Cooling with acetone-dry ice;
324
To a solution of the pyrimidine (324a; 522.3 g) in DMSO(5 L), potassium carbonate (535.6 g) followed by iodomethane (245 ml) were added while maintaining a reaction temperature of 22-25 C (dry ice/acetone bath). When the addition was complete the reaction was allowed to stir at room temperature overnight. Ice (7 L) and water (13 L) wereadded to the reaction. Afier 0.5 h., the mixture was filtered and the solid washed with cold water, cold acetonitrile and cold ether to give the methyl sulfide (324b; 95.7 g). To the filtrate was added 50% aq. HC1 (300 ml) while cooled in a dry ice/acetone bath. Afier stirring for 5 mm, thewhite solid was collected, Afier washing with cold water, acetonitrile and ether a thrther portion of the methylsulfide (324b; 361.2 g) was recovered.
Stage #1: 2-mercapto-6-methylpyrimidin-4(3H)-one; methyl iodide With potassium carbonate In dimethyl sulfoxide at 22 - 25℃; Cooling with acetone-dry ice;
Stage #2: With hydrogenchloride In diethyl ether; water; acetonitrile for 0.0833333h; Cooling with acetone-dry ice;
324
To a solution of the pyrimidine (324a; 522.3g) in DMSO (5L) , potassium carbonate (535.6g) followed by iodomethane (245ml) were added while maintaining a reaction temperature of 22-25C (dry ice/acetone bath). When the addition was complete the reaction was allowed to stir at room temperature overnight. Ice (7L) and water ( 13L) were added to the reaction. After 0.5h., the mixture was filtered and the solid washed with cold water, cold acetonitrile and cold ether to give the methyl sulfide (324b; 95.7g). To the filtrate was added 50% aq. HCl (300ml) while cooled in a dry ice /acetone bath. After stirring for 5 min., the white solid was collected, After washing with cold water, acetonitrile and ether a further portion of the methylsulfide (324b; 361.2g) was recovered.
Stage #1: 2-mercapto-6-methylpyrimidin-4(3H)-one With triethylamine In acetone for 0.25h;
Stage #2: methyl iodide In acetone at 20℃;
4.1.2 6-Methyl-2-methylthio-4-pyrimidinone 2
A mixture of 2-mercapto-6-methylpyrimidin-4-one 1 (0.142g, 1mmol) and triethylamine (0.2mL) in acetone (20mL) was stirred for 15min.; methyl iodide (0.09mL, 1.5mmol) was added on the reaction mixture and continue stirring for 24h at room temperature or by using ultrasonic irradiation at room temperature in 15min. The precipitate formed was filtered off, washed with water and dried, then recrystallized from absolute ethanol, it was obtained as colorless crystals in 83% yield; m. p. 230-231°C (Lit. [76] m. p. 228°C), RF=0.43 (Ethyl acetate/ n-Hexane 2:1).
With sodium hydroxide In ethanol; water at 0 - 20℃; for 0.5h; Reflux;
With copper(l) iodide; tetrabutyl ammonium fluoride; N,N`-dimethylethylenediamine In water; N,N-dimethyl-formamide at 65℃; for 24h; Inert atmosphere; regioselective reaction;
A mixture of <strong>[53967-21-8]6-(bromomethyl)quinoxaline</strong> (900 mg, 4.0 mmol), 6-methyl-2- sulfanylpyrimidin-4-ol (440 mg, 3.1 mmol), and triethylamine (1.1 mL, 7.8 mmol) in absolute ethanol (20 mL) was stirred at room temperature overnight. The reaction mixture was evaporated and then co-evaporated with EtOAc. The solid residue was treated with water (100 mL). The solid product was recovered by filtration, washed with water (2 x 20 mL), diethyl ether (3 x 20 mL), and hexanes (3 x 20 mL), and then dried in vacuo, affording 6-methyl-2-[(quinoxalin-6-ylmethyl)sulfanyl]pyrimidin-4-ol (658 mg, 75% yield). The product was used without further purification.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
A mixture of 2-(chloromethyl)quinoline hydrochloride (1.0 g, 4.67 mmol) and 6- methyl-2-sulfanylpyrimidin-4-ol (0.46 g, 3.26 mmol) and K2CO3 (1.28 g, 9.34 mmol) in DMF (25 mL) was stirred overnight at room temperature. The solvent was filtered and evaporated to provide the crude product. Water was added to the crude reaction mixture to precipitate the product, which was then filtered and washed with water and ether to provide the titled product as a beige solid (0.68 g, 52% yield); 1H NMR (400 MHz, DMSO-J6): delta 2.09(s, 3H), 2.31 (s, 3H), 4.95 (s, 2H), 6.04 (bs, IH), 7.87 (t, J = 7.8, 15.0 Hz, IH), 8.08 (m, 2H), 8.26 (d, J = 8.1 Hz, IH), 8.48 (d, J = 8.2 Hz, IH), 9.00 (d, J = 8.2 Hz, IH); M+ 283.3.
6-methyl-2-sulfanylpyrimidin-4-ol (300 mg, 2.1 mmol) was dissolved in absolute ethanol (10 mL), then triethylamine (650 muL, 4.6 mmol) and 4-(bromomethyl)pyridin- 1-ium bromide (587 mg, 2.3 mmol) were added. The mixture was stirred overnight at room temperature, and the solvent was evaporated. The residue was dissolved in DCM and purified on silica gel using 10% DCM/MeOH to afford, after washing with water, 6-methyl-2-[(pyridin-4-ylmethyl)sulfanyl]pyrimidin-4-ol as white solid (128 mg, 26% yield); 1H NMR (400 MHz, MeOJ4): 62.24 (s, 3H), 4.47 (s, 2H), 6.00 (s, IH), 7.52 (dd, / = 4.5 Hz, J = 1.6 Hz, 2H), 8.45 (dd, J = 4.5 Hz, J = 1.6 Hz, 2H).
A mixture of 4-bromo-2-(bromomethyl)-l-chlorobenzene (4.76 g.16.7 mmol), 6- methyl-2-sulfanylpyrimidin-4-ol (1.83 g, 12.9 mmol), and triethylamine (5 mL, 36.0 mmol) in absolute ethanol (200 mL) was stirred at room temperature overnight. The reaction mixture was evaporated to dryness. The solid residue was treated with water (500 mL). The solid product was recovered by filtration, washed with water (2 x 50 mL), diethyl ether (3 x 50 mL), and hexanes (3 x 50 mL), and then dried in vacuo, affording the title compound (3.23 g, 56% yield); 1H NMR (400 MHz, DMSO-J6): delta 2.21 (s, 3H), 4.39 (s, 2H), 6.00 (s (br), IH), 7. 41 (d, IH, J = 8.4 Hz), 7.53 (dd, IH, / = 2.3 Hz, 8.4 Hz), 7.86 (d, IH, J = 2.0 Hz); M+ 347.
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
92
6-methyl-2-sulfanylpyrimidin-4-ol (772 mg, 5.4 mmol) was dissolved in anhydrous DMF (30 mL), then potassium carbonate (2.25 g, 16.3 mmol) and 4-(chloromethyl)-2- methyl-l,3-thiazole (1.50 g, 8.1 mmol) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 10% DCM in MeOH to afford 6-methyl-2-{ [(2- methyl-l,3-thiazol-4-yl)methyl]sulfanyl}pyrimidin-4-ol (244 mg, 18% yield); 1H NMR (400 MHz, DMSO-J6): δ 2.18 (s, 3H), 2.59 (s, 3H), 4.40 (s, 2H), 5.98 (bs, IH), 7.36 (s, IH); LRMS (ES+) m/z 254 (80%, M+l).
<strong>[30412-42-1]3-(bromomethyl)-2-fluoropyridine</strong>, 6-methyl-2-sulfanylpyrimidin-4-ol (1.42 g, 10 mmol) and triethylamine (1.54 mL, 11 mmol) were mixed in ethanol (50 mL). The mixture was stirred at room temperature for 2 hours. After evaporation, water (100 mL) was added. The suspension was filtered and washed with water and ethyl acetate to provide pure titled product (1.8 g, 72% yield); 1H NMR (400 MHz, DMSO-J6): delta 2.17 (s, 3H), 4.35 (s, 2H), 6.00 (br, IH), 7.28 (m, IH), 8.05 (m, IH), 8.11 (m, IH); M+ 252.
A mixture of <strong>[1256561-65-5]3-(bromomethyl)-5-fluoropyridine hydrobromide</strong> (3.4 mmol), 6-methyl- 2-sulfanylpyrimidin-4-ol (370 mg, 2.6 mmol), and triethylamine (1.7 mL, 12.0 mmol) in absolute ethanol (40 mL) was stirred at room temperature overnight. The solid material was removed by filtration. The filtrate was recovered, evaporated, co- evaporated with EtOAc (20 mL), and then dried in vacuo. The solid residue was treated with water (100 mL). The solid product was recovered by filtration, washed with water (1 x 20 mL) and diethyl ether (2 x 20 mL), and then dried in vacuo, affording the 2-[(5-fluoropyridin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (200 mg, 23% yield); 1H NMR (400 MHz, OMS0-d6): delta 2.21 (s, 3H), 4.41 (s, 2H), 6.02 (s (br), IH), 7. 80 (m, IH), 8.05 (dd, IH, / = 2.0 Hz, 7.6 Hz), 8.46 (d, IH, J = 2.7 Hz), 8.54 (t, IH, J = 1.6 Hz); M+ 252. The product was used without further purification.
To a mixture of crude <strong>[1227602-81-4]3-(bromomethyl)-2-(trifluoromethyl)pyridine</strong> (0.684 g, 2.84 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (0.242 g, 1.70 mmol) in anhydrous ethanol (100 mL) at 00C was added triethylamine (1.14 g, 1.57 mL, 11.36 mmol). The reaction mixture was allowed to stir at room temperature overnight. The solvent was evaporated, and ether was added to the precipitated triethylamine hydrobromide salt. The solid was filtered and washed with ether several times. The solvent was evaporated to provide a crude residue, which was purified by Combiflash using 0- 10% MeOHrdichloromethane. 6-methyl-2-({ [2-(trifluoromethyl)pyridin-3- yl] methyl }sulfanyl)pyrimidin-4-ol was obtained as a white solid (0.438 g, 51% yield); 1H NMR (400 MHz, DMSO-J6): delta 1.14 (t, 3H), 2.21 (s, 3H), 2.61 (q, 2H), 4.35 (s, 2H), 6.00 (bs, IH), 7.69 (s, IH), 8.31 (s, 1H).8.45 (s, IH); M+ 301.5.
100 g (0.70 mol) 4-Hydroxy-2-mercapto-6-methyl pyrimidine and 300 g Raney-Nickel are suspended in water (1000 mL) and the suspension is heated and stirred under reflux over night. Full conversion is detected by TLC (10 % MeOH in DCM). The catalyst is filtered off over celite and the filtrate is evaporated to give crude product as a pale green solid. The product is used without further purification for the next step.
Raney-Nickel; In water;Reflux;
-1a) 6-Methyl-3H-pyrimidin-4-one 100 g (0.70 mol) 4-Hydroxy-2-mercapto-6-methylpyrimidine and 300 g Raney-Nickel are suspended in water (1000 mL) and the suspension is heated and stirred under reflux over night. Full conversion is detected by TLC (10% MeOH in DCM). The catalyst is filtered off over celite and the filtrate is evaporated to give crude product as a pale green solid. The product is used without further purification for the next step.
With hydrogen;Raney-Nickel; In water;Reflux;
100 g (0.70 mol) 4-Hydroxy-2-mercapto-6-methyl-pyrimidine and 300 g Raney-Nickel are suspended in water (1000 mL) and the suspension is heated and stirred under reflux over night. The reaction mixture is filtered over celite and the filtrate is concentrated under reduced pressure to give crude product.
With hydrogen;Raney-Nickel; In water;Reflux;
100 g (0.70 mol) 4-Hydroxy-2-mercapto-6-methyl-pyrimidine and 300 g Raney-Nickel are suspended in water (1000 mL) and the suspension is heated and stirred under reflux over night. The reaction mixture is filtered over celite and the filtrate is concentrated under reduced pressure to give crude product
With Raney-Nickel; In water;Reflux;
100 g (0.70 mol) 4-Hydroxy-2-mercapto-6-methyl-pyrimidine and 300 g Raney-Nickel are suspended in water (1000 mL) and the suspension is heated and stirred under reflux over night. The reaction mixture is filtered over celite and the filtrate is concentrated under reduced pressure to give crude product.
With water;Reflux;
100 g (0.70 mol) 4-Hydroxy-2-mercapto-6-methyl-pyrimidine and 300 g Raney-Nickel are suspended in water (1000 mL) and the suspension is heated and stirred under reflux over night. The reaction mixture is filtered over celite and the filtrate is concentrated under reduced pressure to give crude product.
General procedure
General procedure: To a magnetically stirred solution of thiouracil (2 mmol) and dialkyl acetylenedicarboxylate (2 mmol) in anhydrous 1,4-dioxane (5 mL) was added dropwise a solution of the isocyanide (2 mmol) in 1,4-dioxane (2 mL) over a period of 10 min. The mixture was stirred for 12 h at room temperature. After completion of the reaction as indicated by TLC, the solvent was removed and the residue purified by silica gel column chromatography (hexane-EtOAc, 3:1) to afford products 4a-h and 5a,d,e,g,i. If necessary, the isolated product was further purified by recrystallization from dichloromethane-ether.
General procedure
General procedure: To a magnetically stirred solution of thiouracil (2 mmol) and dialkyl acetylenedicarboxylate (2 mmol) in anhydrous 1,4-dioxane (5 mL) was added dropwise a solution of the isocyanide (2 mmol) in 1,4-dioxane (2 mL) over a period of 10 min. The mixture was stirred for 12 h at room temperature. After completion of the reaction as indicated by TLC, the solvent was removed and the residue purified by silica gel column chromatography (hexane-EtOAc, 3:1) to afford products 4a-h and 5a,d,e,g,i. If necessary, the isolated product was further purified by recrystallization from dichloromethane-ether.
With copper(l) iodide; potassium tert-butylate; L-proline; In N,N-dimethyl-formamide; at 110℃; for 20h;Inert atmosphere;
General procedure: An oven-dried Schlenk tube equipped with a Teflon valve was charged with a magnetic stir bar, 2-mercaptobenzimidazole 1a (125 mg, 0.5 mmol), isothiocyanatobenzene 2a (75 mg, 0.5 mmol), Cs2CO3 (652 mg, 2.0 mmol), CuI (10 mg, 0.05 mmol, 10 mol %), L-Proline (16.5 mg, 0.10 mmol, 20 mol %). The tube was evacuated and backfilled with N2 (this procedure was repeated 3 times). Under a counter flow of N2, DMF (2.0 mL) was added by syringe and the mixture was pre-stirred for several minutes. The tube was sealed and the mixture was allowed to stir at 110 C for 20 h. The reaction was stopped and cooled to room temperature. Then the cooled reaction mixture was dissolved in H2O and extracted with Et2O. The combined organic layer was dried (MgSO4), then concentrated by rotatory evaporation. The crude residue was purified by column chromatography on silica gel using petroleum/ethyl acetate as eluent to give a yellow solid of benzimidazobenzothiazine (3a) (97.7 mg, 82%).
A-2a) 6-Ethyl-3H-pyrimidin-4-one 90 g (0.58 mol) 4-Hydroxy-2-mercapto-6-ethyl pyrimidine and 270 g Raney-Nickel are suspended in water (1000 mL). The suspension is heated and stirred under reflux over night. Full conversion is detected by TLC (10% MeOH in DCM). The catalyst is filtered off over celite and the filtrate is evaporated to give crude product as a pale green solid (70.0 g; 98%). The product is used without further purification for the next step.
With iodine; sodium hydrogencarbonate; potassium iodide In water at 20℃; for 1h;
2.3. Synthesis of trisulfide 12
To a solution of MTU (0.50 g, 3.5 mmol) in aqueous NaHCO3 (0.44 g, 5.2 mmol) solution (5 mL), was added dropwise an aqueous solution of I2 (0.45 g, 1.76 mmol) with KI (0.29 g, 1.76 mmol). The mixture was stirred for 1 h at room temperature. The aqueous solution was extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine solution and dried over anhydrous sodium sulfate. The solvent was removed under reducedpressure to obtain white crude solid. The crude product was purified by pre-loaded silica gel column on Flash chromatography using ethyl acetate and petroleum ether as eluents. The solvents were evaporated to afford the pure trisulfide 12 as white amorphous solid. The pure compound was recrystallized from CHCl3 to obtain colorless crystals suitable for single crystal X-ray diffraction studies. Yield: 3.0 g (27%) 1H NMR (CDCl3) δ (ppm): 2.36 (s, 6H), 6.32 (s, 2H), 13.36 (s, 1H), 14.81 (s, 1H). 13C NMR (CDCl3) δ (ppm): 24.2, 107.9, 163.6, 168.6, 169.2. ESI-MS m/z calcd. for C10H10N4O2S3 [M + H]+ 336.9864; found 336.9785.
With potassium hydroxide; In 1,4-dioxane; water; at 60 - 65℃; for 2h;
Potassium hydroxide (0.685 g, 0.012 mol) was dissolved in 10 mL of water and 6-methyl-2-mercaptopyrimidine (1.415 g, 0.01 mol) was added to the solution, and 2 mL of dioxane was added and the mixture was heated to 60 C The Then, 2-chloromethylenebenzimidazole (0.01 lmol) was ultrasonically dissolved in 8 mL of dioxane at about 60 C, slowly added dropwise to the above reaction system, and the flask was washed with 1.5 mL of dioxane And dropping tube, plus heating 65 C after heating 2 h, and then hot filter, filter cake with a small amount of dioxane washing, and finally vacuum drying 2 benzimidazole substituted 6-methyl-2 thiourea Pyrimidine, yellow solid(2.528 g, 91.93%).
87.9%
With potassium hydroxide; In 1,4-dioxane; water; at 60℃; for 3h;
To a solution of compound 2 (2.844g, 20 mmol) and KOH (1.346 g, 24 mmol) in water (40mL) was slowly added compound 4 (3.332 g, 20 mmol) dissolved in dioxane (20 ml), and the reaction was stirred at 60C for 3 h. The reaction mixture was cooled to room temperature and filtered through a buchner funnel. Then the filter cake was washed with dioxane and dried in a vacuum. 5 (4.784 g, 87.9 %) was obtained as a pale yellow solid.
In aq. phosphate buffer; water; N,N-dimethyl-formamide at 25℃; Electrolysis;
3.1. Electrosynthesis of hydroquinonethioethers (3a-b)
General procedure: In a typical reaction, a 100 mL of phosphate buffer solution (0.2 mol L-1, pH 6) water/DMF (90/10), containing 0.5 mmol of hydroquinone (1a) and 0.5 mmol of 6-methyl-2-thiouracil (3a) or 6-propyl-2-thiouracil (3b), was electrolyzed by five carbon electrodes in an undivided cell at 0.35 V vs. Ag/AgCl. The electrolysis was terminated when the current decayed to 5% of its original value. The process was repeated several times during the electrolysis and the carbon electrodes were washed in acetone repeatedly reactivation. As hydroquinone was soluble in phosphate buffer solution (90 mL) and thiouracile derivatives (3a-3b) were already dissolved in a minimum amount of DMF (10 mL) so the mixture of them was homogeneous. Otherwise the obtained hydroquinonethioethers (6a-6b) would not be soluble under the mentioned conditions; therefore, at the end of the electrolysis, the obtained products (6a-6b) would precipitate out. Finally, each of the formed precipitate was filtered and dried. After drying, purification of the product (6a-6b) was done by using of methanol/acetone (50/50). The resulting product was characterized by melting point, FT-IR, 1H NMR, 13C NMR and elemental analysis.
Stage #1: 6-methyl-2-thiouracil With dihydrogen peroxide at 70℃; for 0.25h;
Stage #2: 2,4,6-Trinitrophenol at 90℃; for 0.25h;
6-Methylpyrimidin-4(3H)-one picrate (XI).
To a3-4% solution of hydrogen peroxide (50 mL) heated to70° 6 g of thiouracil IX was added by portions in thecourse of 30 min with vigorous stirring. After theaddition was completed, the reaction mixture was keptat this temperature for 15 min, then cooled andneutralized with 10% aqueous solution of sodiumhydroxide. The obtained solution was heated to 70°and treated with 9.7 g of picric acid. The mixture wasstirred at 90° for 15 min to homogeneous state. Aftercooling to room temperature the formed suspensionwas kept for no less than 5 h, then filtered. Theobtained precipitate was twice crystallized from waterand dried to a constant mass. Yield 7.3 g (51%), mp147° , Rf 0.81 ( ). Found, %: 38.47; 2.69; N20.12. C5H6N2O·C6H3N3O7. Calculated, %: 38.95;2.67; N 20.65
6-methyl-2-((2-(3-nitrophenyl)-2-oxoethyl)thio)pyrimidin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86.27%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3h;
General procedure for preparation of compounds 2
General procedure: Anhydrous potassium carbonate (1.3821 g, 10 mmol) and substituted phenacyl halides (10 mmol) were added in succession to a suspension of 6-substituted-2-thiouracils(10 mmol) in dry N,N-dimethylformamide (10 mL). After stirring for 3 h at room temperature, the mixture was quenched with water (100 mL) and filtered. The resulting solid was crystallized from a suitable solvent. 6-Methyl-2-((2-(3-nitrophenyl)-2-oxoethyl)thio)pyrimidin-4(3H)-one 2a White solid; yield: 86.27 %; m.p. 252.2-253.7 °C. HRMS(m/z): calcd for C13H12N3O4S (neutral M + H) 306.05485;found 306.057780.
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3h;
General procedure for preparation of compounds 2
General procedure: Anhydrous potassium carbonate (1.3821 g, 10 mmol) and substituted phenacyl halides (10 mmol) were added in succession to a suspension of 6-substituted-2-thiouracils(10 mmol) in dry N,N-dimethylformamide (10 mL). After stirring for 3 h at room temperature, the mixture was quenched with water (100 mL) and filtered. The resulting solid was crystallized from a suitable solvent.
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3h;
General procedure for preparation of compounds 2
General procedure: Anhydrous potassium carbonate (1.3821 g, 10 mmol) and substituted phenacyl halides (10 mmol) were added in succession to a suspension of 6-substituted-2-thiouracils(10 mmol) in dry N,N-dimethylformamide (10 mL). After stirring for 3 h at room temperature, the mixture was quenched with water (100 mL) and filtered. The resulting solid was crystallized from a suitable solvent.
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3h;
General procedure for preparation of compounds 2
General procedure: Anhydrous potassium carbonate (1.3821 g, 10 mmol) and substituted phenacyl halides (10 mmol) were added in succession to a suspension of 6-substituted-2-thiouracils(10 mmol) in dry N,N-dimethylformamide (10 mL). After stirring for 3 h at room temperature, the mixture was quenched with water (100 mL) and filtered. The resulting solid was crystallized from a suitable solvent.
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3h;
General procedure for preparation of compounds 2
General procedure: Anhydrous potassium carbonate (1.3821 g, 10 mmol) and substituted phenacyl halides (10 mmol) were added in succession to a suspension of 6-substituted-2-thiouracils(10 mmol) in dry N,N-dimethylformamide (10 mL). After stirring for 3 h at room temperature, the mixture was quenched with water (100 mL) and filtered. The resulting solid was crystallized from a suitable solvent.
3-((4-hydroxy-6-methylpyrimidin-2-yl)thio)pentane-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
Stage #1: 6-methyl-2-thiouracil With potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 3h;
Stage #2: 3-chloropentane-2,4-dione In N,N-dimethyl-formamide at 25℃; for 24h;
3.2. Synthesis of 3-((4-Hydroxy-6-methylpyrimidin-2-yl)thio)pentane-2,4-dione (2)
The mixture of 6-methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (1) (10mmol) andKOH (10mmol) in dimethylformamide (DMFA) (15 mL) was stirred at room temperature for 3 h; then at cooling3-chloro-pentane-2,4-dione (10mmol) was added. Thereaction mixture was allowed to stand for 24 h at 25∘C; thenDMFA was evaporated at low pressure and the residue wasprocessed with water and filtered off.Yield (1.68 g, 70%); white crystal; m.p. 188-190∘C.1HNMR: δ= 2.18 (s, 3H, 6-CH3); 2.22 [s, 6H, (CH3)2]; 5.92(s, 1H, CH-pyrim.); 12.20 (b.s., 1H,OH-pyrim.); 17.30 (s, 0.9H,OH-enol).Anal.Calcd forC10H12N23S: C, 49.99; H, 5.03;N,11.66; S, 13.34; found: C, 49.81; H, 4.91; N, 11.22; S, 13.00.
Stage #1: 6-methyl-2-thiouracil With potassium hydroxide In N,N-dimethyl-formamide for 3h;
Stage #2: 1,2-dichloro-ethane In N,N-dimethyl-formamide at 0 - 20℃; for 24h;
3.8. Synthesis of 7-Methyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-one (7)
A suspension of compound 3 (10mmol)and KOH (20mmol) in DMFA (10 mL) was stirred for 3 htill salt formation; then at cooling (0∘C) 1,2-dichloroethane(10mmol) was added dropwise and allowed to stand for 24hat roomtemperature.Themixture was filtered off,DMFA wasevaporated at low pressure, and the residue was processedwith CHCl3 and then with ether.Yield (1.2 g, 70%); white crystals; m.p. 118-120∘C. IR(KBr): ] υ= 1660 (C=O). 1HNMR: δ= 2.15 (s, 3H, 7-CH3);3.49 (t, = 7.7, 2H, SCH2); 4.34 (t, = 7.7, 2H, NCH2);5.83 (s, 1H, CH-pyrim.). 13C NMR: δ= 22.76; 25.49; 48.02;106.68; 159.46; 163.22; 163.73. MS: 169 (M + 1). Anal. Calcdfor C7H8N2OS: C, 49.98; H, 4.79; N, 16.65; S, 19.06; found: C,49.81; H, 4.65; N, 16.33; S, 18.80.
4-(2-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-ylthio)acetyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
4.1.18. 4-(2-(4-Methyl-6-oxo-1,6-dihydropyrimidin-2-ylthio)acetyl)benzonitrile (15E)
General procedure: A mixture of compound 14 (300 mg, 2,1 mmol), 2-bromo-1-(4-methoxyphenyl)ethanone (483 mg, 2.1 mmol) and potassiumcarbonate (291 mg, 2.1 mmol) was stirred in anhydrous N,Ndimethylformamide(3 mL) at room temperature for 12 h. Completionof the reaction was monitored by TLC. The reaction contentwas poured on cold water (5 mL) and extracted with ethyl acetate(3 10 mL). The organic layers were combined together, washedwith brine (1 10 mL), dried over anhydrous sodium sulfate andthe solvent was evaporated to dryness. The crude mixture waspurified by column chromatography (hexanes:ethyl acetate gradient)to obtain pure compound 15A as a pale yellow (306 mg, 50%).
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
4.1.14. 2-(2-(4-Methoxyphenyl)-2-oxoethylthio)-6-methylpyrimidin-4(3H)-one (15A)
A mixture of compound 14 (300 mg, 2,1 mmol), 2-bromo-1-(4-methoxyphenyl)ethanone (483 mg, 2.1 mmol) and potassiumcarbonate (291 mg, 2.1 mmol) was stirred in anhydrous N,Ndimethylformamide(3 mL) at room temperature for 12 h. Completionof the reaction was monitored by TLC. The reaction contentwas poured on cold water (5 mL) and extracted with ethyl acetate(3 10 mL). The organic layers were combined together, washedwith brine (1 10 mL), dried over anhydrous sodium sulfate andthe solvent was evaporated to dryness. The crude mixture waspurified by column chromatography (hexanes:ethyl acetate gradient)to obtain pure compound 15A as a pale yellow (306 mg, 50%).1H NMR (DMSO-d6) d 12.659 (s, 1H), 8.0235 (d, J = 9.2 Hz, 2H),7.0745 (d, J = 9.2 Hz, 2H), 5.931 (s, 1H), 4.699 (s, 2H), 3.855 (s,3H), 1.981 (s br., 3H).
2-(2-(4-(diethylamino)phenyl)-2-oxoethylthio)-6-methylpyrimidin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
4.1.15. 2-(2-(4-(Diethylamino)phenyl)-2-oxoethylthio)-6-methylpyrimidin-4(3H)-one (15B)
General procedure: A mixture of compound 14 (300 mg, 2,1 mmol), 2-bromo-1-(4-methoxyphenyl)ethanone (483 mg, 2.1 mmol) and potassiumcarbonate (291 mg, 2.1 mmol) was stirred in anhydrous N,Ndimethylformamide(3 mL) at room temperature for 12 h. Completionof the reaction was monitored by TLC. The reaction contentwas poured on cold water (5 mL) and extracted with ethyl acetate(3 10 mL). The organic layers were combined together, washedwith brine (1 10 mL), dried over anhydrous sodium sulfate andthe solvent was evaporated to dryness. The crude mixture waspurified by column chromatography (hexanes:ethyl acetate gradient)to obtain pure compound 15A as a pale yellow (306 mg, 50%).
6-methyl-2-(2-morpholino-2-oxoethylthio)pyrimidin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
With potassium carbonate; In N,N-dimethyl-formamide;
General procedure: A mixture of compound 14 (300 mg, 2,1 mmol), 2-bromo-1-(4-methoxyphenyl)ethanone (483 mg, 2.1 mmol) and potassiumcarbonate (291 mg, 2.1 mmol) was stirred in anhydrous N,Ndimethylformamide(3 mL) at room temperature for 12 h. Completionof the reaction was monitored by TLC. The reaction contentwas poured on cold water (5 mL) and extracted with ethyl acetate(3 10 mL). The organic layers were combined together, washedwith brine (1 10 mL), dried over anhydrous sodium sulfate andthe solvent was evaporated to dryness. The crude mixture waspurified by column chromatography (hexanes:ethyl acetate gradient)to obtain pure compound 15A as a pale yellow (306 mg, 50%).
With potassium carbonate; In N,N-dimethyl-formamide;
General procedure: A mixture of compound 14 (300 mg, 2,1 mmol), 2-bromo-1-(4-methoxyphenyl)ethanone (483 mg, 2.1 mmol) and potassiumcarbonate (291 mg, 2.1 mmol) was stirred in anhydrous N,Ndimethylformamide(3 mL) at room temperature for 12 h. Completionof the reaction was monitored by TLC. The reaction contentwas poured on cold water (5 mL) and extracted with ethyl acetate(3 10 mL). The organic layers were combined together, washedwith brine (1 10 mL), dried over anhydrous sodium sulfate andthe solvent was evaporated to dryness. The crude mixture waspurified by column chromatography (hexanes:ethyl acetate gradient)to obtain pure compound 15A as a pale yellow (306 mg, 50%).
2-((4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)thio)-N-(3-(anilino)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 6-methyl-2-thiouracil With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 0.5h;
Stage #2: C14H13BrN2O In N,N-dimethyl-formamide at 20℃;
3 Example 3 Synthesis of 2-((4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)thio)-N-(3-(anilino)phenyl)acetamide (Compound 3)
First, 3a was synthesized using 2c intermediate and bromoacetic acid according to the synthesis of 1c,The target compound 3 was synthesized by the synthesis of 3a and the raw material methylthiouracil according to the synthesis method of compound 1. The two stage yields were 45%.;_The compound 4,6-dimethyl-2-mercaptopyrimidine (1.2 mmol, 168.2 mg) was dissolved in DMF (3 ml) and potassium tert-butoxide (2 mmol, 224.4 mg) and the reaction was stirred at room temperature for 30 min. Compound 1c (1 mmol, 302 mg) was dissolved in DMF (1 ml) and slowly added to the reaction. After the reaction was stirred at room temperature for 4-5 h, the reaction was complete by TLC. Ice water (40 ml) was added to the reaction and extracted with ethyl acetate (20 ml x 3). The final organic layer was dried over anhydrous MgSO4. After concentration, Compound 1 (168 mg, 38% overall yield) was obtained by column chromatography.
With 1-ethyl-3-methylimidazolium acetate at 65℃; for 3h; regiospecific reaction;
General procedure: The experimental procedure was very simple, in that, 6-methyl-2-thiouracil was added in excess amount to the ILs, the mixture wasthen stirred under constant agitation (1000 rpm), at room temperaturefor 30min. After reaching the equilibrium(preliminary tests on the timerequired to achieve the equilibriumwere carried out), the alkyl/alkenyl/benzyl bromides (2) were added and stirred at 65 °C for 3 h. Resultsgiven are based on three independent experiments. The products (3)precipitated out when ice water was added to the reaction mixture. No chromatographic separation required, and products were simply purifiedby crystallizing in DMF. All the new products were isolated as white crystalline solids, and were characterized by 1H and 13C NMR as well as IR spectra all of which fully comport with their proposed structures and formulations
Stage #1: 6-methyl-2-thiouracil With triethylamine In N,N-dimethyl-formamide at 20℃; for 0.25h;
Stage #2: C13H10BrFO3 In N,N-dimethyl-formamide at 20℃; for 16h;
(S)-5-(3-Fluoro-4-(((6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)thio)methyl)phenyl)-N-(3-methyl-1-(methylamino)-1-oxobutan-2-yl)furan-2-carboxamide (100).
General procedure: A suspension of 94 (78 mg, 0.399 mmol, 1.0eq) and NEt3 (66 μL, 0.479 mmol, 1.2 eq) in 1.0 mL DMF was stirred for 15 min at room temperature before 954 (150 mg, 0.479 mmol, 1.2 eq) was added and the reaction mixture was stirred for 16 h at room temperature. The solids were filtered, washed with small amounts of water, methanol and diethyl ether,and the product was dried under vacuum to give the corresponding methyl ester (131 mg, 77%) as a whitesolid, which was subsequently hydrolyzed.
N(1')-(3-methylindole)-6'-methyl-2'-thiouracil[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
In N,N-dimethyl-formamide Reflux;
2.2.1. General procedure for the synthesis of compounds 2-8
General procedure: New gramine-uracil conjugates were obtained following a procedurealready reported [16] with some modification. A mixture ofgramine (1 mmol) and appropriate uracil (1.0 mmol) in dry DMF(5 mL) was refluxed for 5-6 h (9 h for compound 5) and the progresswasmonitored by using TLC. On completion of the reaction, themixture was extracted with ethyl acetate (3 20 mL, compounds2-6) or with diethyl ether (3 20 mL, compounds 7, 8). The combinedorganic layer was washed with water (100 mL) and brine(50 mL), dired (Na2SO4) and concentrated under reduced pressureyielding compounds 2-8 in good yields. New compounds wererecrystallized from DMF
With triethylamine In ethanol; dichloromethane for 2h; Schlenk technique; Reflux;
2.2. Synthesis of the complexes
General procedure: [Ru(PPh3)2(2TU)2] (1) and [Ru(PPh3)2(6m2TU)2] (2). In a Schlenk flask, 0.25 mmol of 2TU or 6m2TU ligands were dissolved in ethanol (50 mL) solution containing 20 μL of triethylamine (Et3N). Afterwards, 100 mg (0.12 mmol) of the [RuCl2(PPh3)3)], obtained according to the literature [42], solubilized in 50 mL of dichloromethane, was added to the reaction flask. The mixture was kept under stirring and reflux for 12 h. Then, the volume of the solution was reduced to ca. 4 mL and yellow solids were formed. The solid was collected by filtration, washed with ethanol, diethyl ether and dried under vacuum to yield 76 mg (83%) of complex (1) and 70 mg (74%) of complex (2).
[RuCl2(triphenylphosphine)(1,4-bis(diphenylphosphino)butane)][ No CAS ]
[Ru(1,4-bis(diphenylphosphino)butane)(6-methyl-2-thiouracil)2][ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With triethylamine In methanol; dichloromethane for 12h; Schlenk technique; Reflux;
General procedure: [Ru(dppb)(2TU)2] (3) and [Ru(dppb)(6m2TU)2] (4). In a Schlenk flask, 0.35 mmol of the ligands 2TU or 6m2TU were dissolved in a methanol (50 mL) solution containing 20 μL of triethylamine (Et3N). Afterwards, 50 mL of dichloromethane solution containing 100 mg (0.12 mmol) of the [RuCl2(PPh3)(dppb)] precursor was added to the reaction media. The mixture was maintained under stirring and reflux for 12 h. Then, the volume of the solution was reduced to c.a 4 mL and yellow solids were formed. The solid was collected by filtration, washed with methanol, diethyl ether and dried under vacuum to yield 75 mg (82%) of complex (3) and 69 mg (73%) of complex (4).
4-(4-acetoxybutoxy)-2-(4-acetoxybutylthio)-6-methylpyrimidine[ No CAS ]
3-(4-acetoxybutyl)-2-(4-acetoxybutylthio)-6-methylpyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1: 50%
2: 18%
With potassium carbonate In acetonitrile Reflux; regioselective reaction;
Alkylation of thiouracils 1a-c with 4-bromobutyl acetate
General procedure: A. A mixture of thiouracil 1a-c (0.75 mmol), 4-bromobutyl acetate (0.29 g, 1.5 mmol), and K2CO3 (0.14 g, 1 mmol) in MeCN (10 mL) was refluxed for 4-10 h. The precipitate was filtered off , and the mother liquor was concentrated. The products were purified by column chromatography (products 2c and 3c were isolated using a 1 : 1 CHCl3-ethyl acetate mixture as the eluent; compounds 2a and 3a were isolated using a 5 : 1 CH2Cl2-ethyl acetate mixture; compounds 2b and 4b were isolated with a 5 : 1 CHCl3-ethyl acetate mixture).
3-((4-hydroxy-6-methylpyrimidin-2-yl)thio)piperidine-2,6-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2%
With caesium carbonate; In tetrahydrofuran; at 20℃; for 3h;
To a solution of 2-mercapto-6-methylpyrimidin-4-ol (200 mg, 1.41 mmol) in THF (5 mL) were added <strong>[62595-74-8]3-bromopiperidine-2,6-dione</strong> (324 mg, 1.69 mmol), Cs2CO3 (691 mg, 2.12 mmol). The reaction solution was stirred for 3 h at rt. The reaction mixture was diluted with H2O (50 mL), extracted with EA (50 mL x 2). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated in vacuo. The residue was purified by column to give desired compound (7.2 mg, 2 % yield) as a white solid.1H NMR (400 MHz, DMSO-d6) delta 12.69 (s, 1H), 10.97 (s, 1H), 5.97 (s, 1H), 4.68 (s, 1H), 2.71- 2.61 (m, 1H), 2.56- 2.51 (m, 1H), 2.33- 2.25 (m, 2H), 2.15 (s, 3H); LC/MS (ESI, m/z): [M+1]+ = 254.0.
With potassium carbonate In ethanol; water at 78℃;
11 Preparation of 6-methyl-4-hydroxy-2-paeonol butathiopyrimidine (compound 5i)
Take 1 mmol of 2- (4-bromobutaneoxy) -4-methoxyacetophenone 2 prepared in Example 1 and dissolve it in a round bottom flask containing 10 mmol of absolute ethanol.Add 1 mmol of methylthiouracil 4i, add 1 mmol of anhydrous potassium carbonate, heat the water bath to 78 ° C, and stir the reaction under reflux for about 7-8 hours. During this time, follow the progress of the reaction by TLC (V chloroform: V methanol = 2: 1) After the reaction was completed, anhydrous magnesium sulfate was added to dry overnight, and then filtered. The filtrate was evaporated to dryness under reduced pressure and purified by silica gel column chromatography (V petroleum ether: V ethyl acetate = 1: 1) to obtain white crystal 5i with a yield of 42.30%. ;
2-{2-[(6-methyl-4-oxo-1,4-dihydropyrimidin-2-yl)sulfanyl]ethyl}isoindoline-1,3-dione[ No CAS ]
2-[2-({4-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]-6-methylpyrimidin-2-yl}sulfanyl)ethyl]isoindoline-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1: 70%
2: 7%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 72h;
Preparation of compounds 3-f and 4-d (General method)
General procedure: A mixture of freshly calcined K2CO3 (7.4 mmol), 2-thiouracil 2a-c (7.0 mmol), 2-(bromomethyl)-2-isoindole-1,3-dione (7.7 mmol), and anhydrous DMF (20 ml) was stirred at room temperature for 72 h. The reaction mixture was filtered, and the filtrate was evaporated to dryness. The obtained residue was taken up in 1 aqueous solution, the mixture was filtered, the filtrate was extracted with EtOAc (3×50 ml), dried over MgSO4, filtered, and evaporated at reduced pressure. The solids collected by filtration were air-dried until constant mass, combined with the evaporated organic extract, and the obtained mixture was purified by preparative HPLC. 2-{2-[(6-Methyl-4-oxo-1,4-dihydropyrimidin-2-yl)sulfanyl]ethyl}isoindoline-1,3-dione (3a). Gradient elution: 40→40→60% of eluent B in eluent A over 0-10-50 min, followed by isocratic elution with 100% eluent B. The content of the main component was 100% (ELSD), 100%(UV). Yield 1.54 g (70%), colorless crystals, mp 225.9-226.4°C. Rf 0.27 (hexane-EtOAc, 1:2). IR spectrum, ν, cm-1:3552, 3339, 3021, 2849, 1767, 1712, 1578, 1539, 1471, 1460,1330, 717. 1H NMR spectrum, δ, ppm (J, Hz): 2.05 (3H, s,3); 3.41 (2, t, J = 5.9, SCH2CH2); 3.94 (2, t, J = 6.0,SCH2CH2); 5.87 (1H, s, H pyrimidine); 7.82-7.87 (4, m,H phthalimide); 12.42 (1, s, N). 13C NMR spectrum,δ, ppm (J, Hz): 23.6 (CH3); 28.7 (SCH2); 37.4 (SCH2CH2);103.4 (-5 pyrimidine); 123.5 (-4,7 phthalimide); 132.0(-5,6 phthalimide); 134.9 (-3a,7 phthalimide); 168.1(-2 pyrimidine). Mass spectrum, m/z (Irel, %): 316 [M+H]+(100). Found, %: C 56.98; H 4.21; N 13.09; S 10.22.C15H13N3O3S. Calculated, %: C 57.13; H 4.16; N 13.33;S 10.17.
2-[3-({4-[3-(1,3-dioxoisoindolin-2-yl)propoxy]-6-methylpyrimidin-2-yl}sulfanyl)propyl]isoindoline-1,3-dione[ No CAS ]
2-{3-[(6-methyl-4-oxo-1,4-dihydropyrimidin-2-yl)sulfanyl]propyl}isoindoline-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1: 67%
2: 11%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 72h;
Preparation of compounds 3-f and 4-d (General method)
General procedure: A mixture of freshly calcined K2CO3 (7.4 mmol), 2-thiouracil 2a-c (7.0 mmol), 2-(bromomethyl)-2-isoindole-1,3-dione (7.7 mmol), and anhydrous DMF (20 ml) was stirred at room temperature for 72 h. The reaction mixture was filtered, and the filtrate was evaporated to dryness. The obtained residue was taken up in 1 aqueous solution, the mixture was filtered, the filtrate was extracted with EtOAc (3×50 ml), dried over MgSO4, filtered, and evaporated at reduced pressure. The solids collected by filtration were air-dried until constant mass, combined with the evaporated organic extract, and the obtained mixture was purified by preparative HPLC.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 72h;
A mixture of 1.02 g (7.4 mmol) of freshly calcined K2CO3, 7.0 mmol of the corresponding 2-thiouracil 1-3 and 7.7 mmol of 2-(bromomethyl)-2Hisoindole-1,3-dione in 20 mL of anhydrous DMF was stirred at room temperature for 72 h. The mixture was filtered, the fi ltrate was evaporated to dryness under reduced pressure. The precipitate of mineral salts on the filter was dissolved in 1 M. aqueous H3PO4 and the resulting solution was combined with the bottom residue. The resulting mixture was filtered. The filtercake was washed with water, and then the filtrate was extracted EtOAc (3×50 mL). The filter cake was air dried to constant weight, and the organic extract was dried over anhydrous MgSO4. The dried organic extract was evaporated to dryness under reduced pressure. The residue was mixed with the filter cake and evaporated in a mixture with toluene (3×50 mL) under reduced pressure. A crude product was obtained in the residue, which was subjected to further purification using preparative HPLC. 2-[(6-Methyl-4-oxo-1,2-dihydropyrimidin-2-yl)-sulfanyl]methyl}-2H-isoindole-1,3-dione (4). Yield 63%, mp 251.5252.1C, Rf 0.38 (EtOAc - hexane, 2 : 1). IR spectrum (mineral oil), nu, cm-1: 3006, 1778, 1719,1574, 1540, 1464, 1292, 708. 1H NMR spectrum (400 MHz), delta, ppm: 2.07 s (3H, 3), 5.42 s (2, S2),6.06 s (1, ), 7.86-7.93 m (4Ar), 12.44 s (1, N).Mass spectrum, m/z (I, %): 302.3 (100) [M + H]+. Found,%: C 56.01; H 3.72; N 14.08; S 10.51. C14H11N3O3S.Calculated, %: C 55.80; H 3.68; N 13.95; S 10.64.
dimethyl (7-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)phosphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With potassium carbonate In acetonitrile at 20℃; Inert atmosphere; regioselective reaction;
B. Typical experimental procedure for the synthesis of compounds 3-9
General procedure: A mixture of 0.001 mol of 2-chloroethynylphosphonate 2a-c, 0.001 mol of 2-thiouracil 1a-e, 10 mL of anhydrous acetonitrile, and 0.0012 mol of potassium carbonate was vigorously stirred at room temperature for 3-5 h. After completion of the reaction, the precipitate was filtered off and washed with ethanol. The filtrate was evaporated in vacuum. The title compounds were isolated by column chromatography (eluent ethyl acetate/petroleum ether 40:70), and then recrystallized from ethyl acetate.
diethyl (7-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)phosphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With potassium carbonate In acetonitrile at 20℃; Inert atmosphere; regioselective reaction;
B. Typical experimental procedure for the synthesis of compounds 3-9
General procedure: A mixture of 0.001 mol of 2-chloroethynylphosphonate 2a-c, 0.001 mol of 2-thiouracil 1a-e, 10 mL of anhydrous acetonitrile, and 0.0012 mol of potassium carbonate was vigorously stirred at room temperature for 3-5 h. After completion of the reaction, the precipitate was filtered off and washed with ethanol. The filtrate was evaporated in vacuum. The title compounds were isolated by column chromatography (eluent ethyl acetate/petroleum ether 40:70), and then recrystallized from ethyl acetate.
diisopropyl (7-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)phosphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With potassium carbonate In acetonitrile at 20℃; Inert atmosphere; regioselective reaction;
B. Typical experimental procedure for the synthesis of compounds 3-9
General procedure: A mixture of 0.001 mol of 2-chloroethynylphosphonate 2a-c, 0.001 mol of 2-thiouracil 1a-e, 10 mL of anhydrous acetonitrile, and 0.0012 mol of potassium carbonate was vigorously stirred at room temperature for 3-5 h. After completion of the reaction, the precipitate was filtered off and washed with ethanol. The filtrate was evaporated in vacuum. The title compounds were isolated by column chromatography (eluent ethyl acetate/petroleum ether 40:70), and then recrystallized from ethyl acetate.
7-methyl-3-nitro-9H-pyrido[2′,3′:4,5][1,3]thiazolo[3,2-a]pyrimidin-9-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
With sodium carbonate In N,N-dimethyl-formamide at 80℃;
Compounds 7a-f, and 8c - General Procedure
General procedure: To a solution of compound 1 (1 mmol) and thione 6 (1 mmol) inDMF (10 mL) was added Na2CO3 (106 mg, 1 mmol). The mixturewas stirred at 80 °C until TLC showed no starting materials (3-6h), poured into water (50 mL), acidified with concd HCl to pH 3,and the resulting precipitate was filtered off, washed withwater, and dried in air to give compound 7 or 8.
methyl 7-methyl-9-oxo-9H-pyrido[2′,3′:4,5][1,3]thiazolo[3,2-a]pyrimidine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
18%
With sodium carbonate In N,N-dimethyl-formamide at 80℃;
Compounds 7a-f, and 8c - General Procedure
General procedure: To a solution of compound 1 (1 mmol) and thione 6 (1 mmol) inDMF (10 mL) was added Na2CO3 (106 mg, 1 mmol). The mixturewas stirred at 80 °C until TLC showed no starting materials (3-6h), poured into water (50 mL), acidified with concd HCl to pH 3,and the resulting precipitate was filtered off, washed withwater, and dried in air to give compound 7 or 8.
7-methyl-3-(trifluoromethyl)-9H-pyrido[2′,3′:4,5][1,3]thiazolo[3,2-a]pyrimidin-9-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
With sodium carbonate In N,N-dimethyl-formamide at 80℃;
Compounds 7a-f, and 8c - General Procedure
General procedure: To a solution of compound 1 (1 mmol) and thione 6 (1 mmol) inDMF (10 mL) was added Na2CO3 (106 mg, 1 mmol). The mixturewas stirred at 80 °C until TLC showed no starting materials (3-6h), poured into water (50 mL), acidified with concd HCl to pH 3,and the resulting precipitate was filtered off, washed withwater, and dried in air to give compound 7 or 8.
With sodium hydroxide In water at 110℃; for 3h; Inert atmosphere; Large scale;
B Step B: 6-Methyl-2-(methylthio)pyrimidin-4(1H)-one
Into a 20 L 4-necked round-bottomed flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-methyl-2-sulfanylidene-1,2,3,4-tetrahydropyrimidin-4-one (1200 g, 8.44 mol), water (7200 mL), sodium hydroxide (744 g, 18.60 mol), and Me2SO4(1065 g, 8.45 mol). The resulting mixture was heated for 3 h at 110 °C. The reaction mixture was cooled to 25 °C and the pH of the solution was adjusted to 2 with hydrogen chloride (6 N). The resulting solids were collected by filtration and dried to afford 6-methyl-2- (methylthio)pyrimidin-4(1H)-one (1000 g, 76%) as a white solid.1H NMR (300 MHz, DMSO-d6) d d d12.8 (br s, 1H), 5.97 (br s, 1H), 2.47- 2.65 (m, 3H), 2.27 (s, 3H).
1,1'-((ethane-1,2-diylbis(oxy))bis(4,1-phenylene))bis(2-bromoethanone)[ No CAS ]
2,2'-((ethane-1,2-diylbis(oxy))bis(4,1-phenylene))bis(7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With triethylamine In 1,4-dioxane for 6h; Reflux;
2.13. Synthesis of bis-thiazolopyrimidines 26a,b
General procedure: To a stirred hot solution of pyrimidinethione derivatives 24a or 24b (2 mmol) in dioxane (30 mL), 1,1'-((ethane-1,2-diylbis(oxy))bis(4,1-phenylene))bis(2-bromoethan-1-one) (2) (0.456 g, 1 mmol) and triethylamine (0.7 mL) were added, then the reaction mixture was refluxed for 6 h (monitored byTLC). After cooling, the formed solid product was collected by filtration and washed with aqueous ethanol to dissolve any triethylamine hydrochloride crystals, dried and crystallized from dioxane to give the respectivethiazolopyrimidines 26a,b.
With methyl iso-butyl ketone; sodium hydroxide In methanol at 65℃; for 6h;
4.2.2. 14-O-((4-hydroxythieno[2,3-d]pyrimidin-2-yl)-thioacetyl)-mutilin (3)
General procedure: Intermediate 2 (12.275 g, 23.06 mmol), Intermediate 7 (4.25 g,23.1 mmol) and NaOH (1.22 g, 30.5 mmol) were added to a mixtureof MeOH and MIBK in solvent (1:1) at room temperature andheated to reflux at 65 °C for 6 h. After completion of the reaction,the reaction was concentrated and evaporated dry, water wasadded, and then extracted with DCM (30 mL 3), washed twicewith water, dried with anhydrous Na2SO4, filtered, concentratedand evaporated the organic layer to obtain Intermediate 3 [29,30].Yield: 65.8%.
With methyl iso-butyl ketone; sodium hydroxide In methanol at 65℃; for 6h;
4.2.2. 14-O-((4-hydroxythieno[2,3-d]pyrimidin-2-yl)-thioacetyl)-mutilin (3)
General procedure: Intermediate 2 (12.275 g, 23.06 mmol), Intermediate 7 (4.25 g,23.1 mmol) and NaOH (1.22 g, 30.5 mmol) were added to a mixtureof MeOH and MIBK in solvent (1:1) at room temperature andheated to reflux at 65 °C for 6 h. After completion of the reaction,the reaction was concentrated and evaporated dry, water wasadded, and then extracted with DCM (30 mL 3), washed twicewith water, dried with anhydrous Na2SO4, filtered, concentratedand evaporated the organic layer to obtain Intermediate 3 [29,30].Yield: 65.8%.
With potassium carbonate In N,N-dimethyl-formamide at 80℃;
3.1. Synthesis of Compound 2
General procedure: To a stirred solution of 2-thiouracil, p-methoxy benzyl bromide in DMF was addedpotassium carbonate, and the reaction mixture was heated to 80 °C. The reaction wasmonitored by thin-layer chromatography, quenched with water, and extracted with ethylacetate. The organic layer was washed with brine and dried over sodium sulfate andconcentrated under vacuum. The crude product was purified by column chromatographywith silica-60 to yield the alcohol 2 in 81% yield.
With potassium carbonate In N,N-dimethyl-formamide at 80℃;
3.1. Synthesis of Compound 2
General procedure: To a stirred solution of 2-thiouracil, p-methoxy benzyl bromide in DMF was addedpotassium carbonate, and the reaction mixture was heated to 80 °C. The reaction wasmonitored by thin-layer chromatography, quenched with water, and extracted with ethylacetate. The organic layer was washed with brine and dried over sodium sulfate andconcentrated under vacuum. The crude product was purified by column chromatographywith silica-60 to yield the alcohol 2 in 81% yield.
N-(4-(1H-benzo[d]imidazol-2-yl)phenyl)-2-((4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)thio)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With potassium carbonate In N,N-dimethyl-formamide Reflux;
4.1.4. General procedure III for the synthesis of the benzimidazole-pyrimidineconjugates 12a,b and 13a-d and the benzimidazole-quinazolinone conjugates14a-l
General procedure: A round bottom flask with magnetic stir bar was charged with a solutionof N-(4-(1H-benzo[d]imidazol-2-yl)phenyl)-2-chloroacetamides 4a,b,the 2-thioxopyrimidines 7 and 8a,b or 2-thioxoquinazolinones 11a-f andanhydrous K2CO3 in dry DMF. The reaction mixture was heated underreflux for 15-60 min followed by cooling to room temperature. Themixture was poured on ice-water and the precipitated product was filtered,dried and purified by column chromatography using different eluent systemsto obtain the target compounds 12a,b, 13a-d and 14a-l in ananalytically pure form.
2-chloro-N-(4-(5-nitro-1H-benzo[d]imidazol-2-yl)phenyl)acetamide[ No CAS ]
2-((4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)thio)-N-(4-(5-nitro-1H-benzo[d]imidazol-2-yl)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With potassium carbonate In N,N-dimethyl-formamide Reflux;
4.1.4. General procedure III for the synthesis of the benzimidazole-pyrimidineconjugates 12a,b and 13a-d and the benzimidazole-quinazolinone conjugates14a-l
General procedure: A round bottom flask with magnetic stir bar was charged with a solutionof N-(4-(1H-benzo[d]imidazol-2-yl)phenyl)-2-chloroacetamides 4a,b,the 2-thioxopyrimidines 7 and 8a,b or 2-thioxoquinazolinones 11a-f andanhydrous K2CO3 in dry DMF. The reaction mixture was heated underreflux for 15-60 min followed by cooling to room temperature. Themixture was poured on ice-water and the precipitated product was filtered,dried and purified by column chromatography using different eluent systemsto obtain the target compounds 12a,b, 13a-d and 14a-l in ananalytically pure form.