* 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.
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[1] Polish Journal of Chemistry, 1980, vol. 54, # 2, p. 363 - 365
7
[ 626-48-2 ]
[ 31462-59-6 ]
Reference：
[1] Chemische Berichte, 1899, vol. 32, p. 1533,2930, 2934
8
[ 626-48-2 ]
[ 5424-21-5 ]
Yield
Reaction Conditions
Operation in experiment
84%
at 100℃; for 3 h;
Step 1. The titled compound 166-01 was prepared in a yield of 84 (540 mg) as a white soild from 6-methylpyrimidine-2, 4-diol (500 mg, 3.97 mmol) and phosphorus oxychloride (4 ml) according to the procedure for 49-01. Mass (m/z) : 164.7 [M+H] +.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 10, p. 1755 - 1757
[2] Molecules, 2012, vol. 17, # 4, p. 4533 - 4544
[3] Patent: WO2018/14802, 2018, A1, . Location in patent: Paragraph 0472; 0473
[4] Organic and Biomolecular Chemistry, 2003, vol. 1, # 19, p. 3353 - 3361
[5] Journal of Heterocyclic Chemistry, 1987, vol. 24, # 1, p. 205 - 209
9
[ 626-48-2 ]
[ 5424-21-5 ]
Yield
Reaction Conditions
Operation in experiment
91%
for 6 h; Reflux
In a 500 mL round-bottomed flask,6-methyluracil (158.59 mmol) taken in phosphorus oxychloride (1180.12 mmol) to give a brown suspension. The reaction mixture was refluxed for 6 h. Phosphorus oxychloride was distilled out under reduce pressure and remaining oil was diluted with THF (250mL) and ice (400 g). The reaction mixture was basified at pH 8 under cold condition. Reaction mass was extracted with ethylacetate (250 mL x 3). Organic layers were dried over sodium sulphate and solvent was removed under vacuum. The residue was purified by flash column chromatography using 15 percent ethyl acetate in hexane to give 2,4-dichloro-6-methylpyrimidine (91 percent). 1H NMR (300 MHz, DMS0 ) δ ppm 2.51 (s, 3 H) 7.75 (s, 1 H), MS (ES+), (M+H)+ = 163.27 for C5H4CI2N2.
69.7%
at 105℃; for 3 h;
Mixture of 6-methyl uracil (10 g, 1 eq) in POCl3 (150 mL, 20 eq.) was heated to 105° C. for three hours when TLC (Mobile phase 30percent ethyl acetate in n-hexane) indicated absence of starting material (Rf 0.5) and formation of product (Rf-0.8). Excess POCl3 was then distilled in vacuum. The residue was quenched with ice and extracted with chloroform. Chloroform extract was washed with brine till pH was neutral, dried over anhydrous sodium sulfate, and concentrated to yield 9 g 2,4-dichloro-6-methylpyrimidine as light yellow solid. This was characterized by LCMS NMR.Analytical DataMol. Wt: -163.00MH+ observed in LCMS: -163 (M+) 164 (MH+)HPLC Purity: -99.86percent1H NMR DMSO-d6: -2.54 (s, 3H), 7.18 (s, 1H)
58%
for 3 h; Reflux
6-Methyluracyl (5 g, 39.65 mmol) was added to phosphorylchloride (7 eq, 25 ml) and the mixture was heated at reflux for 3 h. The mixturewas poured onto ice and the organic layer was extracted by chloroform (3 times,20 ml) and dried over anhydrous MgSO4. The solvents were evaporated to givethe dichioride as yellow crystals (3.77 g, 58percent). 1H NMR (400 MHz, CDCI3) o7.19 (s, 1H), 2.55 (s, 3H); 13C NMR (100 MHz, CDCI3) 6 171.8, 162.4, 160.4,119.5, 23.8. The 1H NMR spectrum was in accordance with literature: Wang, H., K. Wen, L. Wang, Y. Xiang, X. Xu, Y. Shen and Z. Sun (2012). Molecules. 2012, 17(4), 4533-4544.
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[1] Patent: WO2015/181799, 2015, A1, . Location in patent: Page/Page column 16
[2] Journal of Heterocyclic Chemistry, 1984, vol. 21, # 3, p. 741 - 744
[3] Patent: US2012/295874, 2012, A1, . Location in patent: Page/Page column 197
[4] Patent: WO2018/151681, 2018, A1, . Location in patent: Paragraph 0098
[5] Chemische Berichte, 1899, vol. 32, p. 1533,2930, 2934
[6] Chemical and Pharmaceutical Bulletin, 1988, vol. 36, # 6, p. 2042 - 2049
[7] Journal of Molecular Structure, 2009, vol. 923, # 1-3, p. 19 - 23
[8] Patent: US2015/80570, 2015, A1, . Location in patent: Paragraph 0300
[9] New Journal of Chemistry, 2018, vol. 42, # 4, p. 2790 - 2803
10
[ 102-82-9 ]
[ 626-48-2 ]
[ 5424-21-5 ]
[ 111697-13-3 ]
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[1] Journal of Heterocyclic Chemistry, 1987, vol. 24, # 1, p. 205 - 209
11
[ 121-44-8 ]
[ 626-48-2 ]
[ 5424-21-5 ]
[ 42487-73-0 ]
[ 23448-78-4 ]
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[1] Journal of Heterocyclic Chemistry, 1987, vol. 24, # 1, p. 205 - 209
12
[ 121-69-7 ]
[ 626-48-2 ]
[ 5424-21-5 ]
[ 93669-49-9 ]
[ 93669-68-2 ]
[ 4871-62-9 ]
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13
[ 626-48-2 ]
[ 10025-87-3 ]
[ 5424-21-5 ]
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[1] Chemische Berichte, 1899, vol. 32, p. 1533,2930, 2934
14
[ 626-48-2 ]
[ 5541-07-1 ]
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[1] Yakugaku Zasshi, 1942, vol. 62, p. 315,333; dtsch. Ref. S. 95, 106[2] Chem.Abstr., 1951, p. 5150
15
[ 6328-58-1 ]
[ 3524-87-6 ]
[ 626-48-2 ]
[ 56-04-2 ]
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[1] Polish Journal of Chemistry, 1980, vol. 54, # 2, p. 363 - 365
16
[ 626-48-2 ]
[ 20090-69-1 ]
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[1] Patent: CN105906621, 2016, A,
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[ 18592-13-7 ]
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[1] Nucleosides, Nucleotides and Nucleic Acids, 2005, vol. 24, # 5-7, p. 367 - 373
[2] European Journal of Medicinal Chemistry, 2013, vol. 70, p. 400 - 410
[3] Patent: CN105906573, 2016, A,
[4] Patent: CN106892902, 2017, A,
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[1] Chemistry of Heterocyclic Compounds, 2012, vol. 48, # 7, p. 1018 - 1027[2] Khim. Geterotsikl. Soedin., 2012, vol. 48, # 7, p. 1095 - 1106,12
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[ 626-48-2 ]
[ 16018-87-4 ]
[ 50610-49-6 ]
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[1] Chemistry of Heterocyclic Compounds, 2012, vol. 48, # 7, p. 1018 - 1027[2] Khim. Geterotsikl. Soedin., 2012, vol. 48, # 7, p. 1095 - 1106,12
20
[ 626-48-2 ]
[ 15018-56-1 ]
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[1] Journal of Chemical Research - Part S, 2002, # 12, p. 624 - 625
[2] Chemistry of Heterocyclic Compounds, 2012, vol. 48, # 7, p. 1018 - 1027[3] Khim. Geterotsikl. Soedin., 2012, vol. 48, # 7, p. 1095 - 1106,12
[4] Journal of Heterocyclic Chemistry, 2006, vol. 43, # 5, p. 1327 - 1329
[5] Synlett, 2009, # 14, p. 2309 - 2311
[6] Justus Liebigs Annalen der Chemie, 1885, vol. 229, p. 17[7] Justus Liebigs Annalen der Chemie, 1885, vol. 231, p. 249
[8] Izv.chim.Inst.Bulgarska Akad., 1951, vol. 1, p. 277,285[9] Chem.Abstr., 1953, p. 1607
[10] Izv.chim.Inst.Bulgarska Akad., 1951, vol. 1, p. 277,285[11] Chem.Abstr., 1953, p. 1607
[12] Yakugaku Zasshi, 1942, vol. 62, p. 315,333; dtsch. Ref. S. 95, 106[13] Chem.Abstr., 1951, p. 5150
[14] Patent: US4532240, 1985, A,
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[16] Chemistry of Heterocyclic Compounds, 2012, vol. 48, # 7, p. 1018 - 1027[17] Khim. Geterotsikl. Soedin., 2012, vol. 48, # 7, p. 1095 - 1106,12
21
[ 626-48-2 ]
[ 15018-56-1 ]
[ 62459-19-2 ]
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[1] Chemistry of Heterocyclic Compounds, 2012, vol. 48, # 7, p. 1018 - 1027[2] Khim. Geterotsikl. Soedin., 2012, vol. 48, # 7, p. 1095 - 1106,12
[3] Chemistry of Heterocyclic Compounds, 2012, vol. 48, # 7, p. 1018 - 1027[4] Khim. Geterotsikl. Soedin., 2012, vol. 48, # 7, p. 1095 - 1106,12
22
[ 626-48-2 ]
[ 50-00-0 ]
[ 147-61-5 ]
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[1] Synthetic Communications, 2006, vol. 36, # 19, p. 2913 - 2920
[2] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 23, p. 7399 - 7407
[3] Journal of Organic Chemistry, 1985, vol. 50, # 8, p. 1264 - 1271
[4] Heterocycles, 2004, vol. 63, # 11, p. 2523 - 2536
[5] Journal of Organic Chemistry, 1981, vol. 46, # 16, p. 3273 - 3283
[6] Justus Liebigs Annalen der Chemie, 1911, vol. 385, p. 295
[7] Journal of Chemical Research, 2015, vol. 39, # 9, p. 531 - 534
[8] Journal of Chemical Research, 2017, vol. 41, # 12, p. 730 - 733
[9] Journal of Sulfur Chemistry, 2017, vol. 38, # 5, p. 488 - 495
[10] Phosphorus, Sulfur and Silicon and the Related Elements, 2018, vol. 193, # 9, p. 545 - 551
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[ 626-48-2 ]
[ 147-61-5 ]
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[1] Journal of the American Chemical Society, 1941, vol. 63, p. 2063
24
[ 626-48-2 ]
[ 13162-27-1 ]
Reference：
[1] Patent: CN105906621, 2016, A,
25
[ 626-48-2 ]
[ 6554-69-4 ]
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[1] Justus Liebigs Annalen der Chemie, 1885, vol. 229, p. 17[2] Justus Liebigs Annalen der Chemie, 1885, vol. 231, p. 249
26
[ 626-48-2 ]
[ 10026-13-8 ]
[ 10025-87-3 ]
[ 6554-69-4 ]
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[1] Justus Liebigs Annalen der Chemie, 1885, vol. 229, p. 17[2] Justus Liebigs Annalen der Chemie, 1885, vol. 231, p. 249
27
[ 626-48-2 ]
[ 56745-01-8 ]
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[1] Journal of Heterocyclic Chemistry, 2006, vol. 43, # 5, p. 1327 - 1329
[2] Yakugaku Zasshi, 1942, vol. 62, p. 315,333; dtsch. Ref. S. 95, 106[3] Chem.Abstr., 1951, p. 5150
28
[ 626-48-2 ]
[ 16632-21-6 ]
Yield
Reaction Conditions
Operation in experiment
83%
Stage #1: at 0 - 40℃; Stage #2: at 15 - 20℃; for 0.5 h;
The procedure was adapted from that reported in J. Med. Chem. 1976, 19, 1072. 6-Methylpyrimidine-2,4(lH,3H)-dione (7.Og, 55.56mmol) was added to concentrated sulfuric acid (26 mL) cooled in ice at such a rate that the internal <n="99"/>temperature did not exceed 40°. To this mixture fuming nitric acid (5.2 mL) was added dropwise whilst maintaining the temperature below 15°. The cooling bath was removed and the mixture was stirred at room temperature for 30 min then dumped into 100ml of crushed ice. After stirring for 10 min the solid was collected and washed with cold water then dried in vacuo over phosphorus pentoxide. A yellow-green solid of 6- rnethyl-5-nitropyrimidine-2,4(lH,3H)-dione was obtained (7.92 g, 83percent).
65.2%
at -2 - 35℃; for 12 h;
The raw material 11 (6.3g) was dissolved in 30ml concentrated sulfuric acid and slowly mixed with low acid (concentrated sulfuric acid / concentrated nitric acid = 10ml / 12ml) at -2 . Finally, the reaction was carried out at 35 for 12h.The reaction solution was poured into ice water and precipitated with a large amount of a pale yellow solid. After filtration under reduced pressure, a pale yellow solid 12 (4 g) was obtained in a yield of 65.2percent.
2.7 g
at 50℃; for 10 h; Inert atmosphere
To a stirred mixture of 96percent H2S04(15 mL) and of 70percent HN03(15 mL) was added 6- methyl pyrimidine-2,4-(lH,3H)-dione (2.5 g,19.8 mmol). The solution was kept at 50 °C for lOh. The mixture was cooled to room temperature and poured into a large volume of ice water. The solid was collected and dried in vacuo. Recrystallization with MeOH gave the final compound (2.7g,16.2 mmol) as yellows solid.1H NMR (200 MHz,DMSO) δ 2.31 (s,3H), 11.82 (s,1H), 11.85 (s,1H).
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[1] Journal of Chemical Research, Miniprint, 1989, # 9, p. 2086 - 2097
[2] Patent: WO2009/62258, 2009, A1, . Location in patent: Page/Page column 97-98
[3] Synthetic Communications, 2007, vol. 37, # 14, p. 2421 - 2431
[4] ChemMedChem, 2018, vol. 13, # 2, p. 178 - 185
[5] Patent: CN105906621, 2016, A, . Location in patent: Paragraph 0030
[6] Chemische Berichte, 1901, vol. 34, p. 1242
[7] Justus Liebigs Annalen der Chemie, 1887, vol. 240, p. 11
[8] Justus Liebigs Annalen der Chemie, 1905, vol. 343, p. 138
[9] Patent: US6002004, 1999, A,
[10] European Journal of Medicinal Chemistry, 2012, vol. 52, p. 205 - 212
[11] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 7, p. 1749 - 1755
[12] Chemical Biology and Drug Design, 2015, vol. 85, # 3, p. 296 - 299
[13] Patent: CN106866678, 2017, A, . Location in patent: Paragraph 0114; 0116; 0117; 0118; 0119; 0120
[14] Patent: WO2018/69532, 2018, A1, . Location in patent: Paragraph 0547; 0549
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[ 13162-26-0 ]
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[1] Patent: CN105906621, 2016, A,
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[ 13162-26-0 ]
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[1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 15, p. 2497 - 2500
[2] Journal of Heterocyclic Chemistry, 2013, vol. 50, # 6, p. 1395 - 1399
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[ 7164-43-4 ]
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[1] Patent: CN106946887, 2017, A,
[2] Patent: CN108069972, 2018, A,
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[ 7139-02-8 ]
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[1] Patent: CN106946887, 2017, A,
[2] Patent: CN108069972, 2018, A,
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[ 626-48-2 ]
[ 65996-50-1 ]
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[1] European Journal of Medicinal Chemistry, 2012, vol. 52, p. 205 - 212
[2] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 7, p. 1749 - 1755
[3] Patent: CN106866678, 2017, A,
[4] ChemMedChem, 2018, vol. 13, # 2, p. 178 - 185
34
[ 626-48-2 ]
[ 63200-54-4 ]
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[1] European Journal of Medicinal Chemistry, 2012, vol. 52, p. 205 - 212
[2] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 7, p. 1749 - 1755
[3] Patent: CN106866678, 2017, A,
[4] ChemMedChem, 2018, vol. 13, # 2, p. 178 - 185
2,4-dichloro-6-methylpyrimidine
In a 500 mL round-bottomed flask,6-methyluracil (158.59 mmol) taken in phosphorus oxychloride (1180.12 mmol) to give a brown suspension. The reaction mixture was refluxed for 6 h. Phosphorus oxychloride was distilled out under reduce pressure and remaining oil was diluted with THF (250mL) and ice (400 g). The reaction mixture was basified at pH 8 under cold condition. Reaction mass was extracted with ethylacetate (250 mL x 3). Organic layers were dried over sodium sulphate and solvent was removed under vacuum. The residue was purified by flash column chromatography using 15 % ethyl acetate in hexane to give 2,4-dichloro-6-methylpyrimidine (91 %). 1H NMR (300 MHz, DMS0 ) δ ppm 2.51 (s, 3 H) 7.75 (s, 1 H), MS (ES+), (M+H)+ = 163.27 for C5H4CI2N2.
83%
With trichlorophosphate for 3h; Heating;
69.7%
With trichlorophosphate at 105℃; for 3h;
13.1
Mixture of 6-methyl uracil (10 g, 1 eq) in POCl3 (150 mL, 20 eq.) was heated to 105° C. for three hours when TLC (Mobile phase 30% ethyl acetate in n-hexane) indicated absence of starting material (Rf 0.5) and formation of product (Rf-0.8). Excess POCl3 was then distilled in vacuum. The residue was quenched with ice and extracted with chloroform. Chloroform extract was washed with brine till pH was neutral, dried over anhydrous sodium sulfate, and concentrated to yield 9 g 2,4-dichloro-6-methylpyrimidine as light yellow solid. This was characterized by LCMS & NMR.Analytical DataMol. Wt: -163.00MH+ observed in LCMS: -163 (M+) & 164 (MH+)HPLC Purity: -99.86%1H NMR DMSO-d6: -2.54 (s, 3H), 7.18 (s, 1H)
58%
With trichlorophosphate for 3h; Reflux;
2,4-dichloro-6-methylpyrimidine (PYI)
6-Methyluracyl (5 g, 39.65 mmol) was added to phosphorylchloride (7 eq, 25 ml) and the mixture was heated at reflux for 3 h. The mixturewas poured onto ice and the organic layer was extracted by chloroform (3 times,20 ml) and dried over anhydrous MgSO4. The solvents were evaporated to givethe dichioride as yellow crystals (3.77 g, 58%). 1H NMR (400 MHz, CDCI3) o7.19 (s, 1H), 2.55 (s, 3H); 13C NMR (100 MHz, CDCI3) 6 171.8, 162.4, 160.4,119.5, 23.8. The 1H NMR spectrum was in accordance with literature: Wang, H., K. Wen, L. Wang, Y. Xiang, X. Xu, Y. Shen and Z. Sun (2012). Molecules. 2012, 17(4), 4533-4544.
With trichlorophosphate
With trichlorophosphate
With trichlorophosphate
With trichlorophosphate Heating;
With trichlorophosphate Reflux;
With trichlorophosphate at 105℃;
General Procedure for the Synthesis of 2,4-dichloro-6-substitutedpyrimidine 5(a and b)
General procedure: Commercially available uracil 4a (5.6 g, 0.05 mol) and 6-methyluracil 4b (7.1 g, 50.05mol) were refluxed in phosphorus oxychloride (35 ml) at 105 oC for 4-5 h. The resulting mixturewas cooled to room temperature and excess phosphorus oxychloride was reduced under reducedpressure. The reaction mixture was poured into crushed ice, extracted with ethyl acetate (3x60mL). The organic phases were washed with water, brine, dried over anhydrous sodium sulfate andevaporated under reduced pressure. Crude products were purified by column chromatography using Ethyl acetate/petroleum ether as the mobile phase to obtain pure 2,4-dichloro-6-substitutedpyrimidine 5(a and b) in 70-80% yield.
5-Bromo-6-methyl-2,4(1H,3H)pyrimidinedione Bromine (39.97 g, 0.25 mole) was added dropwise to a cooled mixture of 31.5 g (0.25 mole) of 6-methyl-2,4(1H,3H)pyrimidinedione in 200 ml of glacial acetic acid. The resulting mixture was stirred at ambient temperature for 16 hours and then filtered. The solid which was collected was washed with water and dried in vacuo overnight at 69 C. to give 39.9 g of the product as a white solid, mp 254 C. (dec.).
The procedure was adapted from that reported in J. Med. Chem. 1976, 19, 1072. 6-Methylpyrimidine-2,4(lH,3H)-dione (7.Og, 55.56mmol) was added to concentrated sulfuric acid (26 mL) cooled in ice at such a rate that the internal <n="99"/>temperature did not exceed 40. To this mixture fuming nitric acid (5.2 mL) was added dropwise whilst maintaining the temperature below 15. The cooling bath was removed and the mixture was stirred at room temperature for 30 min then dumped into 100ml of crushed ice. After stirring for 10 min the solid was collected and washed with cold water then dried in vacuo over phosphorus pentoxide. A yellow-green solid of 6- rnethyl-5-nitropyrimidine-2,4(lH,3H)-dione was obtained (7.92 g, 83%).
80%
With sulfuric acid; nitric acid; at 20℃; for 2.0h;
Parent compound 5 was synthesized starting from commercially available 6-methyluracil (1),shown in Scheme 1. Nitration at C5 was accomplished by adding 6-methyluracil to a solution ofconcentrated sulfuric and nitric acids at 0 C, followed by quenching in ice water to give 2 as apale yellow solid [24]. This was followed by a modified Batcho-Leimgruber indole synthesis tofirst prepare enamine 3 [52,53]. Ring cyclization is accomplished by reduction of the nitro moietyto an amino group, with subsequent nucleophilic attack at C8 by the amino lone pair with loss of dimethylamine. The reduction of the nitro group is accomplished by stirring 3 in acetic acid and zincdust overnight at 80 C, followed by filtration, formation of the N5 sodium salt via NaOH dissolution,then re-acidification and collection of solid 4 [23,24]
65.2%
With sulfuric acid; nitric acid; at -2 - 35℃; for 12.0h;
The raw material 11 (6.3g) was dissolved in 30ml concentrated sulfuric acid and slowly mixed with low acid (concentrated sulfuric acid / concentrated nitric acid = 10ml / 12ml) at -2 . Finally, the reaction was carried out at 35 for 12h.The reaction solution was poured into ice water and precipitated with a large amount of a pale yellow solid. After filtration under reduced pressure, a pale yellow solid 12 (4 g) was obtained in a yield of 65.2%.
With phosphorus pentaoxide; nitric acid; In ice-water;
a) 50.5 g (0.40 mol) of 6-methyluracil (Merck) are introduced in portions over the course of one hour with stirring at 0 to +5 C. into a solution of 200 ml of 100% nitric acid (fuming) and 50 g of phosphorus pentoxide. When the exothermic reaction is complete, the mixture is stirred at +5 C. for a further 5 hours. The reaction mixture is subsequently poured into 1 kg of ice-water. The resultant precipitate is filtered, washed with water and then dried to constant weight, giving 37 g (54%) of 5-nitro-6-methyluracil, pale-yellow powder, m.p. 281 C. with decomposition.
With sulfuric acid; nitric acid; at 20℃; for 0.5h;
In a 100 mL eggplant flask was added 520 ml of concentrated sulfuric acid,Under ice bath, 140 g of 6-methyluracil was added in portions,Keep the temperature no more than 40 C. After all dissolved,Slowly dropping 104ml fuming nitric acid, keep the temperature does not exceed 15 .Drop finished,After stirring at room temperature for 30 min,The reaction solution was poured into crushed ice,Have a solid wash out. Filter, filter cake by water,Acetone was washed and dried to give the title compound 1-1.
2.7 g
With sulfuric acid; nitric acid; at 50℃; for 10.0h;Inert atmosphere;
To a stirred mixture of 96% H2S04(15 mL) and of 70% HN03(15 mL) was added 6- methyl pyrimidine-2,4-(lH,3H)-dione (2.5 g,19.8 mmol). The solution was kept at 50 C for lOh. The mixture was cooled to room temperature and poured into a large volume of ice water. The solid was collected and dried in vacuo. Recrystallization with MeOH gave the final compound (2.7g,16.2 mmol) as yellows solid.1H NMR (200 MHz,DMSO) delta 2.31 (s,3H), 11.82 (s,1H), 11.85 (s,1H).
With 2,2'-azobis(isobutyronitrile); oxygen; cobalt(II) acetate; acetic acid; at 80℃; for 15h;
To a 500 ml three-necked flask, 6-methylpyrimidine-2,4 (1H, 3H) -dione (10.0 g,(0.28 g, l.6 mmol), glacial acetic acid (250 mL), oxygen (flow rate: 6-10 m / s), tube diameter (flow rate: 6-10 m / s), AIBN (azobisisobutyronitrile, 0.26 g, l.6 mmol) (T6m2), heated to 80 C reaction for 15 hours, after the end of the reaction, into the saturated salt water, vacuum pumping, drying, recrystallization (good solvent chloroform,Poor solvent methanol) gave a white solid, 11.48, in a yield of 92.0%.
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;
1,3-Dibenzoyl-6-methyluracil (3). To a suspension of 6-methyluracil (5.0 g, 0.040 mol) in anhydrous MeCN (100 mL) and anhydrous pyridine (20 mL) benzoyl chloride (12.5 mL, 0.108 mol) was added in one portion and stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo at a bath temperature not exceeding 60 °C, cooled and the residue partitioned between CHCl3(200 mL) and ice water (100 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo at a bath temperature not exceeding 60 °C. The residue was crystallized from Et2O (25 mL) to give 10.0 g (76%) of compound 3 as a yellow crystalline solid with mp 80-82 . 1H NMR (400 MHz, DMSO-d6), δ ppm 2.59 (3, s, 3), 7.55 (1, s, 5), 7.58-7.65 (4, m, aryl), 7.74-7.81 (2, m, aryl), 8.10-8.16 (4, m, aryl). 13C NMR (100 MHz, DMSO-d6), δ ppm 26.97, 114.88, 130.87, 130.93, 132.59, 132.61, 133.37, 133.51, 138.21, 138.30, 163.42, 166.30, 167.03, 170.17, 177.57.
2,4-Di-(trimethylsilyloxy)-(6-methylpyrimidine) (5).
A suspension of 6-methyluracil (1 g, 7.93 mmol) andwell-grinded ammonium sulphate (80 mg, 0.60 mmol 0.076 eq) in HMDS (8.4 mL, 39.7 mmol, 5 eq)was heated to 120 C under anhydrous conditions until full dissolution occurred. Upon completion,the excess of HMDS was removed through distillation, toluene was added twice (5 mL) followed bydistillation to remove all traces of excess HMDS to yield 2.1 g (7.8 mmol, 97%) of the title compoundwhich was characterized without further purification. 1H-NMR (200 MHz, CDCl3): = 0.34 (s, 18H),1.95 (3H, s), 5.81 ppm (1H, s). 13C-NMR (50 MHz, CDCl3): = 0.00 (3C), 0.03 (3C), 23.4, 102.6, 162.6,169.8, 170.0 ppm.
With ammonium sulfate for 12h; Heating;
With ammonium sulfate for 18h; Heating;
With chloro-trimethyl-silane Heating;
for 8h; Heating;
With ammonium sulfate at 130℃; for 16h;
3
EXAMPLE 3; Preparation of a Compound of Formula (1 c),; 6-Methyl-3-propyl-1, 3-dihydropyrimidine-2,4-dione; i 0 S, o 0 1 H'' 'reflux S 1' heat 0 N H H [0116] A suspension of 2, 4-dihydroxy-6-methyluracil (20g, 0. 16mol) and ammonium sulfate (1g, 0. 007mol, 0. 05eq.) was stirred in HMDS (200ml) at 130 °C for 16h, during which time the reaction mixture becomes homogeneous. Excess HMDS was distilled off, and the reaction mixture was cooled to 100 °C. To the above residual solution, iodopropane (62ml, 0. 64mol) was added and the mixture was stirred at 100 °C for 48 h. The reaction mixture was cooled and poured into water. The product was extracted with dichloromethane (3x100 mL). The organic layer was washed with water, brine, and dried over Na2S04. Removal of solvent gave the product as a solid material, which was washed with ether to get a clean 6-methyl-3-propyl-1, 3- dihydropyrimidine-2,4-dione (12 g) and used as such for the next step. The material was characterized by proton and mass spectroscopy.
With ammonium sulfate at 135℃; for 6h;
With ammonium sulfate Reflux; chemoselective reaction;
4 Experimental 4.1 RRN 5,7,9,11,13,15,17,19,21,23,...General procedure for the preparation of O-alkylated uracils 4(a-r)
General procedure: To a mixture of 5-substituted uracils 1(a-c) (1mmol) and ammonium sulfate (0.06mmol, 0.008g), HMDS (4mL) was added and refluxed until the precipitate was dissolved. Then, the solvent was removed under reduced pressure and the resulting oily liquid was dissolved in dry DMF (4mL) and NaH (2mmol, 0.048g) was added at -10°C. After stirring of the reaction mixture for 1h, various alkyl halides (1mmol) were added. The progress of the reaction was monitored by TLC using chloroform/methanol as eluent (20:1). After the completion of the reaction, the mixture was neutralized by 2N HCl and extracted by CH2Cl2 (2×30mL). The combined organic phase was dried over Na2SO4 and removed under reduced pressure. The resulting solid was recrystallized in EtOAc and n-hexane.
With diphosphorus pentasulfide; sodium hydrogencarbonate In diethylene glycol dimethyl ether at 110℃; for 1h;
82%
With Lawessons reagent In 1,4-dioxane at 100℃; for 2h;
2 Intermediate 7: Synthesis of 6-methyl-4-sulfanylidene-l,2,3,4- tetrahydropyrimidin-2-one
[00181] To a solution of 6-methyl-l,2,3,4-tetrahydropyrimidine-2,4-dione (2.0 g, 15.86 mmol) in dioxane (30 ml) was added 2,4-bis(4-methoxyphenyl)-l,3,2,4-dithiadiphosphetane 2,4-disulfide (6.41 g, 15.86 mmol) and stirred at 100 °C for 2 h. The reaction mixture was cooled to r.t. and the white precipitate filtered under vacuum, washing with dioxane (20 ml), to afford the title compound (1.85 g, 82%) as an off white powder. [00182] Method B: LC-MS: m/z = 142.85 (M+H)+; RT = 0.36.
76%
With pyridine; diphosphorus pentasulfide for 20h; Heating;
With diphosphorus pentasulfide
With pyridine; tetraphosphorus decasulfide at 120℃; for 16h;
291.1 Step 1: 6-Methyl-4-thioxo-3, 4-dihydropyrimidin-2 (1H) -one
Step 1: 6-Methyl-4-thioxo-3, 4-dihydropyrimidin-2 (1H) -one[0973][0974]To a solution of phosphorus pentasulfide (3.59 g, 16.2 mmol) in pyridine (60 mL) was added 6-methylpyrimidine-2, 4 (1H, 3H) -dione (3.40 g, 27.0 mmol) at 25 . The reaction mixture was stirred at120 for 16h. The resulting mixture was cooled to 25 and solventwas evaporated under reduced pressure. The resulting mixture was quenched with water (200 mL) . The mixture was filtered, washed with water (30 mL) . The filter cake wasre-crystallized from ethanol (50 mL) . The title compound was obtained as a solidwhichwas used in the next step without further purification. MS (+ESI) m/z 143.0.
With selenium(IV) oxide; acetic acid for 24h; Heating;
68%
With selenium(IV) oxide; acetic acid at 20 - 115℃; for 5h;
1 Example 1
At room temperature,1000mL of glacial acetic acid and 150g of selenium dioxide were added into three-necked flask,125 g of compound VII was added to a three neck flask with stirring,After the temperature control to 115 ° C reflux reaction 5h.After the reaction,The filter cake was added to 400 mL of purified water,Refluxing at 95 beating 1h,After filtration and concentration to dryness,To this was added again 400 mL of purified water,After 1h beating at room temperature,The filter cake was washed successively with purified water and absolute ethanol,After air drying, 90 g of a light yellow solid (Compound VI) was obtained,Yield 68%.
65%
With selenium(IV) oxide; acetic acid at 20℃; for 7h; Reflux;
1 Example 1
At room temperature, glacial acetic acid (1500 ml),Selenium dioxide (200 g) was added to a three-necked flask, and 6-methyluracil (189 g) was added to the above reaction mixture with stirring. After the addition, the reaction was refluxed for 7 h.After the reaction is completed, suction filtration, adding the filter cake and an appropriate amount of purified water to the three-necked bottle.Stir under temperature and reflow for at least half an hour, suction filtration,The combined filter cake was concentrated to dryness. The fraction was added with water and beaten at room temperature. Filtering,The filter cake was washed successively with an appropriate amount of water and absolute ethanol. The obtained filter cake is blown dry,A yellow-white solid 130 g, Compound 1, was obtained in a yield of 65%.
62.5%
With selenious acid; acetic acid for 5h; Reflux;
37%
With acetic acid; copper(II) oxide at 110℃; for 5h; Large scale;
1 Example 1Synthesis of 6-formyl uracil by copper oxide oxidation
In a 500 L reactor,6-methyluracil (20.0 kg, 158.59 mol) was added to 150 L of acetic acid,200g of copper oxide was added under stirring and air was introduced into the system at atmospheric pressure.Heated to 110 ° C,The color of the reaction solution changed from white turbid to green turbid solution, and the reaction was continued for 5 hours. The point reaction disappeared by TLC (dichloromethane: methanol = 5: 1) and the reaction was completed.After completion of the reaction, the solvent was evaporated to dryness under reduced pressure (55 ° C, 0.09 MPa), acetic acid was filtered through celite and the filtrate was cooled to room temperature. The mixture was adjusted to pH≈1 with concentrated hydrochloric acid, left to stand for 8 hours, filtered with suction, washed with 10L ethanol, Dried at 60 ° C for 7 hours to give compound 1 as a pale yellow solid (8.2 kg, 37% yield).
35%
With selenium(IV) oxide; acetic acid Reflux;
With selenium(IV) oxide; acetic acid for 6h; Reflux;
Preparation of model compound
The synthesis of 6-HOMU includes two steps (Fig. 2): synthe-sis of orotaldehyde and reduction of orotaldehyde to 6-HOMU. Theorotaldehyde was prepared by Kwang-Yuen’s method [23]. Briefly,6-methyl uracil (2.54 g) was refluxed in acetic acid (60 mL) withselenium dioxide (2.66 g) for 6 h. The hot reaction mixture was fil-tered and the yellow filtrate collected and solvent evaporated. Thecrude orotaldehyde was then dissolved in hot water (24 mL) and5% sodium bisulfite was added dropwise into the stirred mixture.The solution was boiled with active carbon for 10 min and thengravity filtered to remove the carbon. The filtrate was acidified to pH 1 using concentrated HCl. Upon cooling, pure orotaldehyde wasobtained as a precipitate from the solution. A mixture of pure oro-taldehyde (0.14 g) and sodium borohydride (0.076 g) was refluxedin 95% methanol for 4 h. The resulting solution was filtered and thesolvent was evaporated yielding the pure 6-HOMU with the purityof 98%.
Stage #1: 6-Methyluracil With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20℃; for 0.5h; Inert atmosphere;
Stage #2: chloromethyl methyl ether In acetonitrile at 0℃; for 72h; Inert atmosphere;
67%
Stage #1: 6-Methyluracil With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20℃; for 0.5h;
Stage #2: chloromethyl methyl ether In acetonitrile at 0 - 20℃;
65%
Stage #1: 6-Methyluracil With sodium hydride In N,N-dimethyl-formamide at 20℃; for 4h;
Stage #2: chloromethyl methyl ether In N,N-dimethyl-formamide at 20℃; for 96h; Further stages.;
With dihydrogen peroxide; acetic acid; potassium iodide at 20 - 25℃;
94%
With iodine; lead(IV) dioxide; acetic acid at 50℃; for 3h;
93%
With [bis(acetoxy)iodo]benzene; iodine In dichloromethane at 20℃; for 0.75h;
80%
With iodine; orthoperiodic acid In ethanol for 0.75h; Heating;
70%
With iodine In water monomer
35%
With [bis(acetoxy)iodo]benzene; iodine In dichloromethane
2.1 (Step 1) 5-Iodine-6-methyl-1H-pyrimidine-2,4-dione
(Step 1) 5-Iodine-6-methyl-1H-pyrimidine-2,4-dione (0132) (0133) Iodobenzene diacetate (38.0 g, 119 mmol) was dissolved in dichloromethane (100 ml), iodine (5.00 g, 19.8 mmol) was added thereto, and the resulting mixture was stirred for 30 minutes. 6-Methyl-1H-pyrimidine-2,4-dione (5.01 g, 39.7 mmol) was added to the reaction solution, and the resulting mixture was stirred. The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1 to 1:3) to obtain the title compound (3.50 g, 35%). (0134) 1H NMR (DMSO-d6, 300 MHz): δ 11.3 (s, 2H), 2.27 (s, 3H).
7.32 g
With ammonium cerium (IV) nitrate; iodine In acetonitrile at 90℃; for 6h;
Multi-step reaction with 2 steps
1: copper(II) oxide; acetic acid / 5 h / 110 °C / 760.05 Torr / Large scale
2: sodium tetrahydroborate / tetrahydrofuran; water / 3.33 h / 20 °C / Large scale
Stage #1: 6-Methyluracil With sodium hydroxide In water at 20℃; for 0.166667h;
Stage #2: formaldehyd In water for 3h;
2.1
To a flask containing 6-methyl-lH-pyrimidine-2,4-diope (lOg, 79.3mmol) is added NaOH (1.25 N, 95 mL) and the solution is allowed to stir for 10 min at room temperature. Formaldehyde (37%, 19.60 mL) is added dropwise over 30 min. After 30 min, a thick white precipitate forms and the reaction is allowed to proceed for 150 min. The suspension is then filtered and the filter cake is transferred to an Erlenmeyer flask to which EtOH (absolute, 200 mL) is. added. The resulting suspension of white solid is stirred for 30 min. The white solid is collected by filtration, washed with EtOH (50 mL), Et2O (100 mL) and vacuum dried to provide the title compound as a white solid. [MS mass expected (156.14) ; mass found (156.02)].
Synthesis of [6mu]2[pydcH2] (1)
A well-ground mixture of 6mu (200 mg, 1.6 mmol), pydcH2(140 mg, 0.8 mmol) in distilled water (30 mL) was placed in aTeflon-lined stainless steel autoclave, heated to 180 °C for 72 h (seeScheme 1). The mixture was extracted with the mixed solvent ofDMF (20 mL) and CH3OH (15 mL), and then filtered. The filtrate wasremained in the atmosphere of laboratory. By slow evaporation ofsolution, the colorless solid obtained after 16 days, was filteredoff, washed with acetone and dried at 60 .C (yield: 30% based onpydcH2).
Stage #1: 6-Methyluracil With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 1h;
Stage #2: C17H16BrClO2 In N,N-dimethyl-formamide at 70℃; for 16h;
4.2.2. Synthesis of 1-[2-[4-chloro-2-(3,5-dimethylbenzoyl)phenoxy]ethyl]-6-methyluracil (25)
A suspension of 6-methyluracil (5.0 g, 39.65 mmol) and K2CO3 (1.7 g, 12.30 mmol) in 50 mL DMF was stirred at ∼70 °C for 1 h and then treated with a solution of 1-bromo-2-[4-chloro-2-(3,5-dimethylbenzoyl)phenoxy]ethane 5 (2.9 g, 7.89 mmol) in DMF (10 mL). The mixture was stirred at ∼70 °C for 16 h, then was kept at room temperature overnight and filtered. The inorganic precipitate was washed with DMF, and the filtrate was evaporated in vacuum. The residue was dissolved in water (80 mL), extracted with chloroform (50 mL × 3), and the combined organic phases were dried on CaCl2 and evaporated. The target compound 25 was obtained by double recrystallization from a isopropanol:DMF (1:1) mixture. Yield: 64%, mp: 192-194 °C, Rf 0.59 (elution with ethyl acetate); 1H NMR (DMSO-d6): δ 1.78 (d, 3H, J = 0.6 Hz, CH3), 2.27 (s, 6H, CH3), 3.85 (t, 2H, J = 5 Hz, N-CH2), 4.19 (t, 2H, J = 5 Hz, O-CH2), 5.01 (s, 1H, H-5), 7.21 (m, 1H, H-5'), 7.24-7.26 (m, 3H, H-3', H-2, H-6), 7.55 (d, 1H, J = 2.6 Hz, H-4), 7.55 (dd, 1H, J = 8.9 and 2.8 Hz, H-6'), 11.04 (s, 1H, NH); 13 NMR (DMSO-d6): δ 19.4, 20.6, 43.0, 66.2, 100.9, 114.7, 125.0, 126.9, 127.7, 130.6, 131.2, 135.5, 135.9, 137.9, 151.3, 153.7, 153.9, 162.1, 194.0; HRMS calcd for C22H21ClN2O4, [M+H]+ 413.1263; found (FAB) m/z ([M+H]+): 413.1265 (35Cl), 415.1250 (37Cl).
With tetrabutylammomium bromide; potassium carbonate In N,N-dimethyl-formamide at 20℃; for 48h;
With sodium hydroxide In water at 0 - 60℃; for 72h;
1
6-Methylpyrimidine-2,4(1H,3H)-dione (5.5 g, 43.6 mmol) was suspended in water (80 ml) and cooled to 0° C. NaOH (17.44 g, 436 mmol) was added slowly, forming a solution. Ethyl iodide (14.10 ml, 174 mmol) was added and the mixture heated at 60° C. for 3 days. The reaction mixture was cooled to RT and diluted with water. The mixture was extracted with chloroform (3×). The basic extracts were evaporated under vacuum. The residue was dissolved in DCM and evaporated onto silica. The silica was deposited onto a 25 g silica cartridge and the system eluted progressively with 10% EtOAc/isohexane, 20% EtOAc/isohexane, 40% EtOAc/isohexane, 75% EtOAc/isohexane and EtOAc to yield the title compound as a colourless oil; [1805] 1H NMR (400 MHz, CDCl3) δ 5.59 (1H, s), 4.01 (2H, q), 3.92 (2H, q), 2.26 (3H, s), 1.30 (3H, t), 1.24 (3H, t). [1806] LC-MS Rt 0.72 mins; MS 183.5 m/z [M+H](Method 2minLowpHv01)
With Selectfluor In water at 80℃; for 4h; Green chemistry;
37%
With Selectfluor In water at 80℃; for 4h;
General procedure: Fluorination of 6-methyl- and 1,3,6-trimethyluracils1 and 2 (general procedure). A solution ofuracil 1 or 2 and F-TEDA-BF4 in water was stirredunder the conditions indicated in table, the solvent waspurged off with a stream of air, the residue was dissolvedin DMSO-d6, and 1H and 19F NMR spectra wererecorded. In some cases (see table), excess F-TEDABF4was removed by adding KI and Na2S2O3 to thereaction mixture before purging with air.
With water; Selectfluor at 80℃; for 3h; Green chemistry;
92%
With Selectfluor In water at 80℃; for 3h;
General procedure: Fluorination of 6-methyl- and 1,3,6-trimethyluracils1 and 2 (general procedure). A solution ofuracil 1 or 2 and F-TEDA-BF4 in water was stirredunder the conditions indicated in table, the solvent waspurged off with a stream of air, the residue was dissolvedin DMSO-d6, and 1H and 19F NMR spectra wererecorded. In some cases (see table), excess F-TEDABF4was removed by adding KI and Na2S2O3 to thereaction mixture before purging with air.
1-(2',3',5'-tri-O-benzoyl-2'-methyl-β-D-ribofuranosyl)-6-methyluracil[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88.5%
To a solution of 6-methyluracil (302.0 mg, 2.40 mmol) in dry CH3CN (5 mL), was added N,O-bistrimethylsilylacetamide (1.18 mL, 7.00 mmol) and the mixture was stirred for 20 min at room temperature. To this mixture, a solution of 1,2,3,5-tetra-O-benzoyl-2'-methyl-beta-d-ribofuranose (1.16 g, 2.00 mmol) in dry CH3CN (10 mL) was added, followed by dropwise addition of TMSOTf (1.4 mL) at -20 C. The reaction mixture was then allowed to warm slowly to 10-15 C and stirred for 6 h. The mixture was then poured into CH2Cl2 and washed with saturated aq NaHCO3. The organic layer was combined, dried over Na2SO4 and filtered. After removal of all the volatiles, the residue was purified by column chromatography (hexane/ethyl acetate 3:1?3:2), to give product 2 (1.08 g) as an oil in 88.5% yield. The undesired N1,N3-bis-riboside (66.0 mg) was obtained as an oil in 5.7% yield. 1H NMR (300 MHz, DMSO-d6): delta 11.56 (s, 1H, 3-NH), 8.07-7.35 (m, 15H, aromatic), 6.34 (s, 1H, H-1'), 6.31 (d, 1H, J = 8.7 Hz, 3'- H), 5.66 (s, 1H, H-5), 4.73-4.66 (m, 1H, H-4'), 4.61-4.59 (m, 2H, H-5'), 2.39 (s, 3H, 6-CH3), 1.76 (s, 3H, 2'-CH3); 13C NMR (75 MHz, DMSO-d6): delta 165.6 (5"-C=O), 165.1 (2"-C=O), 164.9 (3"-C=O), 162.4 (4-C), 154.1 (2-C), 150.9 (6-C), 134.0-128.7 (15* C-aromatic), 102.9 (5-CH), 91.3 (1'-CH), 88.0 (4'-CH), 77.4 (2'-CH), 77.1 (3'-CH), 64.5 (5'-CH2), 19.7 (7-CH3), 18.1 (6'-CH3); HRMS for C32H28N2O9 [M+H]+ calcd: 585.1867; found: 585.1897.
1,3-bis(cyclopropylmethyl)-6-methyl-1H-pyrimidine-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51.81%
Stage #1: 6-Methyluracil With potassium carbonate In N,N-dimethyl-formamide at 10 - 35℃; for 0.5h;
Stage #2: cyclopropylcarbinyl bromide In N,N-dimethyl-formamide at 20℃; for 16h;
112.1 (Step 1)
(Step 1) (0984) To a solution of 6-methyluracil (8.0 g, 63.43 mmol) in DMF (290 mL) was added potassium carbonate (43.77 g, 317.16 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added bromocyclopropylmethane (25.69 g, 18.45 mL, 190.29 mmol), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 0.5% methanol/dichloromethane) to give 1,3-bis(cyclopropylmethyl)-6-methyl-1H-pyrimidine-2,4-dione (7.70 g, 51.81%) as a grayish white solid. MS (API) :235 (M+H)
N-hexyl-6-methyl-2,4-dioxopyrimidine-1-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; dmap; triethylamine In toluene at 90℃; for 3h;
4.2. General Procedure for the Synthesis of Uracil Derivatives 1-15
General procedure: Compounds 1-15 were synthesized according to Scheme 1. The appropriately substitutedcarboxylic acid (0.5 mmol) was dissolved in dry CH2Cl2 (5 mL). Oxalyl chloride (0.6 mmol, 0.05 mL)and DMF (0.01 mL) were added, and the reaction mixture was stirred at 0 °C for 1 h. The solventwas evaporated under reduced pressure, keeping the temperature below 30 °C. The crude residuewas redissolved with anhydrous acetone (5 mL) and then dropwise added into a stirred and ice-coldsolution of NaN3 (1.0 mmol, 33 mg) in H2O (1 mL). The resulting mixture was stirred at 0 °C for30 min, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrousNa2SO4, and concentrated under reduced pressure. The residue was then dissolved in toluene (15 mL),and refluxed for 2 h. The reaction solution was cooled to room temperature, and dropwise added toa solution of the corresponding uracil derivatives (0.5 mmol) in dry pyridine (0.5 mL). After beingstirred at 90 °C for 3 h, the mixture was cooled and evaporated. The crude was purified by flashchromatography on silica gel to afford compounds 1-15.
To an EtOH-distilled water solution (v/v = 1: 1, 10 mL) containing 2,4-dihydroxy-6-methyl pyrimidine (DHMPI, 12.6 mg, 0.10 mmol) was added H2tfBDC (23.8 mg, 0.10 mmol) with constant stirring for 30 min. The clear and homogeneous solution was slowly evaporated at room temperature, and block colorless crystals were obtained three weeks later. The crystals were picked up from the mother liquor and washed with EtOH-distilled water solution (v/v = 1: 1), and dried under vacuum. Yield: 31.7 mg (64.65% based on H2tfBDC), m.p.: 212 C. Elemental Anal. Calcd (%) for C18H14F4N4O8: C, 44.05; H, 2.86; N, 11.42. Found: C, 44.42; H, 2.78; N, 11.36. IR data (KBr disc, cm-1): 3436m, 3108m, 2952m, 2856m, 2711w, 2645w, 2589w, 2536w, 2431w, 2011w, 1733s, 1639s, 1608s, 1510w, 1482s, 1463m, 1390m, 1359m, 1306m, 1266w, 1239w, 1200m, 1074w, 1043w, 1000m, 968w, 909w, 860m, 770w, 695m, 653w, 622w, 546m, 515m.
ethyl 2,2-difluoro-2-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With tris[2-phenylpyridinato-C2,N]iridium(III); dipotassium hydrogenphosphate In dimethyl sulfoxide for 12h; Inert atmosphere;
9 Embodiment 9
To 25 ml in the reaction tube, adding 2.6 mg (1mol %) Ir (PPy)3, k2HPO4(0.8mmol), compound A-2 (0.4mmol, 1 equivalent), after nitrogen replacement three times by adding 2 ml of dimethyl sulfoxide (DMSO), injection 100 μ L (0.80mmol) compound B-3, under irradiation in blue light stirring 12 hours, to obtain compound C-3, the yield is 94%.
94%
With dipotassium hydrogenphosphate; fac-tris[2-phenylpyridinato-C2,N]iridium(III) In dimethyl sulfoxide at 20℃; for 24h; Schlenk technique; Irradiation; Inert atmosphere;
1-(5-O-benzoyl-4-C-methyl-2,3-O-acetyl-β-D-ribofuranosyl)-6-methyluracil[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 6-Methyluracil With ammonium sulfate; 1,1,1,3,3,3-hexamethyl-disilazane for 17h; Reflux;
Stage #2: 5-O-benzoyl-4-C-methyl-1,2,3-O-acetyl-D-ribofuranose With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 20℃; for 2.5h; Inert atmosphere;
15 preparation of 1- (5-O- benzoyl-4-C-methyl-2,3-O-acetyl- β -D-ribofuranosyl) -6-methyl uracil - (8)
A suspension of 6-methyl uracil was treated withhexamethyldisilazane (HMDS, 21 mL) while refluxing for 17 hours and a catalyticamount of ammonium sulfate. After cooling to room temperature, the mixture wasdistilled off under reduced pressure, the residue obtained as a colorless oilwas diluted in dehydrated 1,2-dichloroethane (7.5 mL). To the resultingsolution, dehydrated 1,2-dichloroethane (14 mL) of 7 (0.99g, 2.51mmol) wasadded, and then trimethylsilyl trifluoromethanesulfonate (TMSTf, 0.97mL,5.02mmol) was added. The solution was stirred for 2.5 hours at room temperatureunder an argon atmosphere, and diluted with chloroform (150 mL), and washedwith same amount of saturated aqueous sodium hydrogen carbonate solution andfinally with water (2 × with 100 mL). The organic phase was dried overanhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude material was purified bysilica gel column chromatography [eluent: methanol (0% to 2%) / step gradientof chloroform] to give pure 8.
6-methyl-5-(perfluorohexyl)pyrimidine-2,4(1H,3H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With caesium carbonate In dimethyl sulfoxide at 20℃; for 24h; Schlenk technique; Inert atmosphere; Irradiation;
49%
With tris(2,2'-bipyridyl)ruthenium dichloride; caesium carbonate In dimethyl sulfoxide at 20℃; for 24h; Irradiation; Inert atmosphere; Schlenk technique; Green chemistry;
General procedure for the direct perfluoroalkylation of uracilsand uracil nucleosides
General procedure: To a 25 mL of Schlenk tube equipped with a Teflon septum were added Ru(bpy)3Cl2 (1.5 mg, 0.5 mol%), Cs2CO3 (130 mg, 1.0 equiv) and 1 (0.4 mmol, 1.0 equiv) followed by DMSO 3.0 mL) with stirring. Perfluoroalkyl iodine (2.0 equiv.) was then added subsequently under Ar. The Schlenk tube was screw capped and the reaction was then under irradiated with a 12 W blue LEDs (460 nm-470 nm). After stirring for 24 h, the reaction mixture was diluted with ethyl acetate, washed with brine, the organic phases were collected and dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified with silica gel chromatography to provide pure product.
1,3-bis[(2,2-dichlorocyclopropyl)methyl]-6-methylpyrimidine-2,4(1H,3H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
Stage #1: 6-Methyluracil With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate In N,N-dimethyl-formamide at 20℃; for 10h;
Stage #2: 2-(chloromethyl)-1,1-dichlorocyclopropane In N,N-dimethyl-formamide at 90℃;
Synthesis of compounds 3 and 4.
General procedure: A mixture of 0.05 mol of 6-methyluracil 1, 0.065 mol of K2CO3, 0.15 g of triethylbenzylammonium chloride, and 18 mL of DMF was stirred at room temperature for 2 h and allowed to stand at that temperature for 8 h. Alkylating agent 2 (or 2b), 0.055 mol, was then added, the mixture was vigorously stirred for 4 (2) or 8 h (2b) at 90°, cooled down, and allowed to stand for 8 h. The precipitate was filtered off, and the filtrate was evaporated. The residue was treated with 15 mL of 10% KOH, treated with chloroform (310 mL), and the combined extract was dried over MgSO4. The solvent was distilled off, and the residue was chromatographed on KSKG silica (63-200 µm), eluent benzene-ethanol (19 : 1). The target compounds were isolated as isomer mixtures 3/4 and 3b/4b.
1,3-bis(1,3-dioxolan-4-ylmethyl)-6-methylpyrimidine-2,4(1H,3H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
Stage #1: 6-Methyluracil With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate In N,N-dimethyl-formamide at 20℃; for 10h;
Stage #2: 4-chloromethyl-[1,3]dioxolane In N,N-dimethyl-formamide at 90℃;
Synthesis of compounds 3 and 4.
General procedure: A mixture of 0.05 mol of 6-methyluracil 1, 0.065 mol of K2CO3, 0.15 g of triethylbenzylammonium chloride, and 18 mL of DMF was stirred at room temperature for 2 h and allowed to stand at that temperature for 8 h. Alkylating agent 2 (or 2b), 0.055 mol, was then added, the mixture was vigorously stirred for 4 (2) or 8 h (2b) at 90°, cooled down, and allowed to stand for 8 h. The precipitate was filtered off, and the filtrate was evaporated. The residue was treated with 15 mL of 10% KOH, treated with chloroform (310 mL), and the combined extract was dried over MgSO4. The solvent was distilled off, and the residue was chromatographed on KSKG silica (63-200 µm), eluent benzene-ethanol (19 : 1). The target compounds were isolated as isomer mixtures 3/4 and 3b/4b.
(Z)-1-((phenyl)(hydroxyimino)methyl)-6-methylpyrimidine-2,4-(1H,3H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide In methanol; N,N-dimethyl-formamide at 20℃;
1.3
(3) 2.4 mmol of o-chloro-aromatic aldoxime, 2 mmol of substituted urotropine and 2.4 mmol of sodium hydroxide were dissolved in 10 mLN, N-dimethylformamide and 10mL methanol mixed solvent, stirred at room temperature for 2-4h, until the reaction is complete, extracted, washed,3-Carboxybenzaldehyde was added and the mixture was stirred at room temperature for 6h, a white solid was precipitated, which was filtered, washed, dried over anhydrous sodium sulfate, and separated or recrystallized by column chromatography to obtain 1-aryl-aldoxime-uracil.
With sodium hydroxide In methanol at 20℃;
1 General procedure for the synthesis of 1-(aryl aldehyde oxime) uracil derivatives (8a-t)
General procedure: Compounds 5a-i (6mmol), compound 6 (5mmol) and NaOH (6mmol) were added to 15mL methanol. After stirring for 2-4hat room temperature, completion of the reaction was monitored by TLC. The reaction mixture was evaporated by a rotary evaporator, extracted with ethyl acetate, concentrated and purified by flash column chromatography (PE/EA=4:1) to yield compounds 8a-m. (57-81% yield).
(Z)-1-((2-fluorophenyl)(hydroxyimino)methyl)-6-methylpyrimidine-2,4-(1H,3H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide In methanol at 20℃;
2 General procedure for the synthesis of 1-(aryl aldehyde oxime) uracil derivatives (8a-t)
General procedure: Compounds 5a-i (6mmol), compound 6 (5mmol) and NaOH (6mmol) were added to 15mL methanol. After stirring for 2-4hat room temperature, completion of the reaction was monitored by TLC. The reaction mixture was evaporated by a rotary evaporator, extracted with ethyl acetate, concentrated and purified by flash column chromatography (PE/EA=4:1) to yield compounds 8a-m. (57-81% yield).
6-methyl-5-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With caesium carbonate In dimethyl sulfoxide for 24h; Inert atmosphere; Irradiation;
11 Example 11
In a 25 mL reaction tube,Add Cs2CO3 (0.8 mmol),Compound A-3 (0.4 mmol, 1 equivalent),After replacing argon three times, add 3 mL of dimethyl sulfoxide (DMSO).100 μL (1.20 mmol) of Compound B in DMSO was injected.After stirring for 24 hours under blue light,Compound C-3,The yield was 68%.
64%
With caesium carbonate In dimethyl sulfoxide at 20℃; for 24h; Schlenk technique; Inert atmosphere; Irradiation;
3-(5-bromopyridin-2-yl)-6-methylpyrimidine-2,4(1H,3H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26%
With copper(l) iodide; 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 70℃; for 18h;
35.1 Synthesis of 3-(5-bromopyridin-2-yl)-6-methylpyrimidine-2,4(1H,3H)-dione
5-bromo 2-iodopyridine (1.1 g, 3.7 mmol), copper iodide (0.30 g, 1.6 mmol), and DBU (0.93 ml, 6.4 mmol) were sequentially added to an acetonitrile solution (10 ml) of 6-methyluracil (0.40 g, 3.2 mmol), and the mixture was stirred at 70°C for 18 hours. The reaction solution was cooled to room temperature, and was filtered through celite, followed by concentration under reduced pressure. The residue was subjected to reverse phase HPLC using ODS as a packing material for elution with a mixed solution of water and acetonitrile containing 0.1% (v/v) of trifluoroacetic acid, and the targeted fraction was freeze-dried to give the title compound (0.23 g, 26%). MS (ESI) m/z 282 [M+H]+
With tetra-(n-butyl)ammonium iodide; potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 18h;
In the reactor, 1.0 g, 1.0 equiv. as shown in Formula IV2-(Bromomethyl)-1-fluoro-3-(trifluoromethyl)benzene was dissolved in 10 mL of DMF.To this was added 1.2 equiv. 6-methyluracil as shown in Formula V, 1.8 equiv. potassium carbonate,0.1equiv. of TBAI, the system is heated to 70 ° C for 18h;After the reaction was completed, the reaction mixture was concentrated to dryness, and the concentrate was washed with a mixture of dichloromethane and 1N aqueous hydrochloric acid.The organic phase is separated, and the organic phase is washed successively with a saturated aqueous solution of sodium hydrogencarbonate and brine.Subsequently, it is dried over sodium sulfate and spin-dried to obtain 0.89 equiv. of the polysubstituted pyrimidine derivative as shown in Formula I.The yield was 89percent.
6-methyl-5-(phenylselanyl)pyrimidine-2,4(1H,3H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With dihydrogen peroxide; sodium iodide In dimethyl sulfoxide at 50℃; for 3h; Schlenk technique;
30 Example 30
Add 0.2 mmol of 6-methyluracil, 0.1 mmol of NaI and 0.3 mmol to a clean Schlenk reaction tube.Diphenyl diselenide and a stir bar,Then add 3 mL of DMSO solvent with a syringe.Finally add with a micro syringe0.6 mmol H2O2, reacted at 50 ° C for 3 hours, TLC spot plate detection;After the reaction was completed, the reaction solution was added with water and extracted with ethyl acetate three times.The organic layer is concentrated and separated by column chromatography to obtain pure5-phenylseleno-(6-methyl)-uracil, white solid,The yield was 93%.
85%
With dihydrogen peroxide; sodium iodide In dimethyl sulfoxide at 50℃;
77%
With potassium iodide In dimethyl sulfoxide at 20℃; for 15h; Electrolysis; Green chemistry;
2.1 General experimental procedures for Compound 3
General procedure: In an undivided three-necked flask (25 mL) equipped with a stir bar, uracils (0.5 mmol), various dialkyldiselenides (diaryldiselenides) (0.25 mmol), KI (0.125 mmol) and DMSO (8 mL) were added. The flask was equipped with platinum electrodes (15 mm x 15 mm x 0.3 mm) as cathode, graphite rod (Φ 6 mm) as the anode. The reaction mixture was stirred and electrolyzed at a constant current of 10 mA under room temperature for 15 h. Method A: The reaction mixture was diluted with water, and the products were extracted with ethyl acetate (3 × 40 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The pure products 3 were obtained by flash chromatography on silica gel by using dichloromethane/ethyl acetate as elute. Method B: After completion, water (10 mL) was added dropwise into the mixture. The precipitates were formed and collected by filtration and wash with ethyl acetate to give the pure products 3.
6-methyl-5-(p-tolylthio)pyrimidine-2,4(1H,3H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With dihydrogen peroxide; sodium iodide In dimethyl sulfoxide at 100℃; for 18h; Schlenk technique;
14 Example 14
Add 0.2 mmol of 6-methyluracil, 0.1 mmol of NaI and 0.3 mmol to a clean Schlenk reaction tube.P-toluene thiophenol and a stir bar,Then add 3 mL of DMSO solvent with a syringe.Finally add 1.8mmol with a micro syringeH2O2 (3 hours apart, added in three portions), reacted at 100 ° C for 15 hours,TLC dot plate detection; after the reaction is over,The reaction solution was added with water and extracted with ethyl acetate three times.The organic layer is concentrated and separated by column chromatography to obtain pure5-(4-methylphenyl)thio-6-methyluracil, white solid,The yield was 93%.
85%
With dihydrogen peroxide; sodium iodide In dimethyl sulfoxide at 100℃; for 15h;
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 5h;
Operation step: in a reactor, 1.0 g, 1.0 equiv. of (2-fluoro-6-(trifluoromethyl)phenyl)methanol as shown in Formula V, 1.2 equiv. as shown in Formula VI 6-methyluracil was dissolved in 10 mL of THF, and 1.5 equiv. of triphenylphosphine was added sequentially at room temperature. 1.5 equiv. DIAD, followed by reaction at room temperature for 5 h;After the reaction is completed, a mixture of ethyl acetate and 1N aqueous hydrochloric acid is used as a detergent washing reaction mixture, and the organic phase is separated, and then the organic phase is washed with a saturated aqueous solution of sodium hydrogencarbonate and brine.Then dry with sodium sulfate and spin dry the solvent.Finally, by column chromatography, a polysubstituted pyrimidine derivative of the formula I was obtained in a yield of 89%. The detection was performed by high resolution mass spectrometry (ESI+) with a detection value of 303.0758; the high resolution mass spectrum of M+H+ was calculated to be 303.0751, and the product structure was confirmed by comparison.
6-methyl-1,3-bis(prop-2-yn-1-yl)-2,4(1H,3H)-pyrimidinedione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With tetrabutylammomium bromide; potassium carbonate In N,N-dimethyl-formamide at 20℃;
5.1.2. Procedure for the synthesis of 6-methyl-1,3-di(prop-2-ynyl)pyrimidine-2,4(1H,3H)-dione (6)
To a stirred solution of 1 g of 6-methyl uracil 5 (7.9 mM), 2.32 g ofpotassium carbonate (16.2 mM) and 0.53 g of tetra-n-butyl ammoniumbromide (1.05 mM) in 40 mL of DMF was added 1.42 mL of propargylbromide (16.2 mM) drop wise. Reaction mixture was stirred at roomtemperature for about 12-14 h till the completion of reaction as indicated by TLC. Then the reaction mixture quenched in ice cold waterand extracted using ethyl acetate (15 mL×3). 1.2 g of light yellowcompound 6 was obtained after evaporation of ethyl acetate underreduced pressure. White; Yield 84%; m.p: 124-126 °C; IR (KBr): cm-11652 and 1702 (C]O), 2218 (C^C); 1H NMR (CDCl3, 400 MHz): δ ppm5.68 (s, 1H, alkene-CH), 4.71 and 4.69 (d, 2H, J=2 Hz, -alkyne-CH2),2.39 (s, 3H, eCH3) 2.36 and 2.17 (t, 1H, J=2 Hz, alkyne-CH); 13CNMR (CDCl3, 100 MHz): δ ppm 160.86, 151.31, 151.06, 102.14, 78.01,77.20, 73.40, 70.70, 34.18, 30.58, 19.51; EI-MS: MS (EI) m/z: Calcd. forC11H10N2O2-202.0742; Found: 202 [M+%-100%].
78%
Stage #1: 6-Methyluracil With sodium hydride In hexane; N,N-dimethyl-formamide for 8h; Heating;
Stage #2: propargyl bromide In hexane; N,N-dimethyl-formamide at 115 - 120℃; for 16h;
2. General procedure for the synthesis of 1,3-bis(alkynyl)-2,4(1H,3H)-pyrimidine-, quinazoline-, and benzo[g]pteridinediones
General procedure: Sodium hydride (30 mmol) preliminarily treated with hexane was added to a solution of 15 mmol of uracil 1, 6-methyluracil 2, thymine 3, quinazoline-2,4-dione 4, and allox-azine 5 in DMF (150 mL). The reaction mixture was stirred for 8 h at 65-70 °C, cooled to room temperature and 60 mmol of the corresponding alkyne (propargyl bromide, 5-iodo-1-pentyne or 6-iodo-1-hexyne) was added to the sodium salt thus obtained. The mixture was stirred at 115-120 °C until the pH achieved 7.0-7.3 (12-16 h). The solvent was distilled off, 100 mL of chloroform was added to the residue and filtered. The filtrate was concen-trated to 10-15 mL and purified by column chromatography on silica gel. The column was eluted first with petroleum ether and then by the mixture of petroleum ether-ethyl acetate (1.5:1). The target compounds 1a-c, 2a-c, 3a-c, 4a-c, 5a-c were isolated from the second fraction.
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 70℃; for 3h;
General Procedure for the Preparation of N-Alkylated Uracil Substrates
General procedure: NaH (60% dispersion in mineral oil, 2.4 equiv) and corresponding alkyl halide (2.4 equiv) was added to a suspension of NH-uracil (10 mmol) in DMF (2 mL). The reaction mixture was stirred and heated at 70 °C for 3 h. Upon completion, distilled deionized H2O (10 mL) was added, and the mixture was extracted with ethyl acetate (EtOAc) (2 x 20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting organic residue was purified by flash chromatography column over silica gel (SiO2) to afford the N-alkylated uracil.
4.1. General Procedure for the Synthesis of Uracil-Iodonium(III) Triflates
General procedure: To a stirred solution of 1,3-dimethyluracil 1a (0.50 mmol) and 4-chloroiodobenzene diacetate 2e (0.55 mmol) in dichloromethane or acetonitrile (2 mL), a solution of trifluoromethanesulfonic acid (ca. 150 mg, 1.0 mmol, 2 equiv) in acetonitrile (1 mL) was added dropwise at room temperature, and the resulting slightly colored solution was stirred for 3 h. After addition of methanol (~2 mL), the solvents were removed under reduced pressure. The residue was then treated with diethyl ether with stirring for precipitation of the iodonium(III) salt. The precipitate was filtered and dried in vacuo to give a pure iodonium(III) salt in powder form.
With 3-chloro-benzenecarboperoxoic acid In acetonitrile at 20℃;
4.1. General Procedure for the Synthesis of Uracil-Iodonium(III) Triflates
General procedure: To a stirred solution of 1,3-dimethyluracil 1a (0.50 mmol) and 4-chloroiodobenzene diacetate 2e (0.55 mmol) in dichloromethane or acetonitrile (2 mL), a solution of trifluoromethanesulfonic acid (ca. 150 mg, 1.0 mmol, 2 equiv) in acetonitrile (1 mL) was added dropwise at room temperature, and the resulting slightly colored solution was stirred for 3 h. After addition of methanol (~2 mL), the solvents were removed under reduced pressure. The residue was then treated with diethyl ether with stirring for precipitation of the iodonium(III) salt. The precipitate was filtered and dried in vacuo to give a pure iodonium(III) salt in powder form.
11 Synthesis of (9H-fluoren-9-yl)methyl 4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-carboxylic acid tert-butyl ester
2,4-dihydroxy-6-methylpyrimidine (1.0g), pyridine (6ml) was added to a 25mL flask and stirred, and the temperature was slowly lowered from 0 °C to 10 °C.9-mercaptomethyl chloroformate (2.05g), after completion, the reaction was incubated for 4h, the reaction system was filtered, the filtrate was concentrated, and concentrated column chromatography (PE/EA=3:1) gave 2.29g of product. 83%
4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-carboxylic acid 1-chloroethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With pyridine at 0 - 10℃; for 4h;
12 Synthesis of 4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-carboxylic acid 1-chloroethyl ester
Add 2,4-dihydroxy-6-methylpyrimidine (1.0g) and pyridine (5ml) to a 25mL flask and stir. Slowly add 1-chloroethyl chloroformate (1.1g) at 0°C10°C. After the dropwise addition, the reaction was incubated for 4 h, the reaction system was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (PE/EA=6:1) to yield product 1.58 g, yield 86%.
2-(bromomethyl)-4-fluoro-1-(trifluoromethyl)benzene[ No CAS ]
[ 626-48-2 ]
[ 830346-47-9 ]
Yield
Reaction Conditions
Operation in experiment
95%
With potassium carbonate; In dimethyl sulfoxide; at 0 - 10℃; for 4h;
2-Fluoro-6-(trifluoromethyl)bromobenzyl (2.0 g), tert-butyl 4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1 (6H)-carboxylic acid tert-butyl ester (1.81 g), A 100 mL flask of dimethyl sulfoxide (40 ml), and potassium carbonate (2.34 g) was stirred at 0 C to 10 C for 4 h. Ethyl acetate and a water layer were added to the reaction system, the upper organic layer was left, the organic layer was washed with brine, and the organic layer was concentrated. 30 ml of dichloromethane was added to the concentrate, and the mixture was heated to 30 C to 40 C by adding trifluoroacetic acid (2.0 g). Reaction 4h, systemThe organic layer was extracted with a saturated aqueous solution of sodium bicarbonate, and the aqueous layer was extracted with 20 ml of dichloromethane. The organic layer was washed with brine, and the organic layer was washed with methyl t-butyl ether and dried to give the product 2.23 g. The product content of formula IV is 97.6%, the IV-imp content is 1.0%, and the yield is 95.0%.
10 Synthesis of tert-butyl 4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-carboxylic acid tert-butyl ester
Add 2,4-dihydroxy-6-methylpyrimidine (1.0g) and pyridine (5ml) to a 25mL flask and stir. Slowly add BOC anhydride (1.9g) at 0°C10°C, drip, and keep the reaction for 6h. ,Filter the reaction system,The filtrate was concentrated and concentrated by column chromatography (PE/EA = 6:1) to give the product (yield: 85%), yield: 85%.
1-(prop-2-yn-1-yl)-3H-6-methyl-2,4-pyrimidinedione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34%
Stage #1: 6-Methyluracil With potassium hydroxide In water at 65 - 70℃; for 3h;
Stage #2: propargyl bromide In N,N-dimethyl-formamide; toluene for 15h; Reflux; regioselective reaction;
1-(Prop-2’-yn-1’-yl)-3H-6-methyl-2,4-pyrimidinedione (4a)
6-Methyluracil 4 (4.7 g, 37.0 mmol) was added to a solution of KOH (2.1 g, 37.50 mmol) in water (150 mL), the mixture was stirred for 3 h at 65-70 °C and then evaporated. The traces of water was removed azeotropically with toluene. Then absolute toluene (250 mL) and propargyl bromide (4.5 g, 38.0 mmol) were added to the dry potassium salt, the mixture was refluxed for 15 h. The solvent was evaporated in a vacuum, and the residue was treated with CHCl3 (200 mL) and filtered. The filtrate was concentrated to 30 mL and purified by column chromatography on silicagel (eluent petroleum ether-ethyl acetate = 1.5:1, then ethyl acetate). The target compound 4a was obtained by the evaporation of the ethyl acetate fraction as a cream colored powder (2.06 g, 34 %). M.p. 183 °C. 1H NMR (400 MHz, CDCl3): δ 8.86 (s, 1H, NH), 5.59 (s, 1H, C5H), 4.64 (d, 2H, J =2.4 Hz, C7H2), 2.39 (s, 3H, C6CH3), 2.34 (t, 1H, J = 2.5 Hz, C9H). 13C NMR (100 MHz, DMSO-d6): δ 162.10 (C4=O), 153.33 (C2=O), 150.89 (C6), 101.34 (C5), 78.60 (C8), 74.73 (C9), 32.45 (C7),18.61 (C6CH3). MALDI-MS: calcd. for C8H8N2O2 [M+H]+ 165.1, [M+Na]+ 187.0, [M+K]+ 203.0; found [M+H]+ 165.1, [M+Na]+ 187.1, [M+Na]+ 203.1. Anal.,%: C 58.46; H 5.00, N 16.98. C8H8N2O2. Calcd., %: C 58.53; H 4.91; N 17.06. M 164.06.
34%
Stage #1: 6-Methyluracil With sodium hydride In N,N-dimethyl-formamide
Stage #2: propargyl bromide In N,N-dimethyl-formamide
6-methyl-1,3-di(pent-4-yn-1-yl)pyrimidine-2,4(1H,3H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
Stage #1: 6-Methyluracil With sodium hydride In N,N-dimethyl-formamide at 70℃; for 8h;
Stage #2: 1-bromo-4-pentyne In N,N-dimethyl-formamide at 120℃; for 24h;
6-Methyl-1,3-di(pent-4-yn-1-yl)pyrimidine-2,4(1H,3H)-dione (2).
Sodium hydride, 2.20 g(0.092 mol), was added to a solution of 5 g (0.04 mol)of 6-methyluracil (1) in 200 mL of anhydrous DMF,and the mixture was stirred at 70°C for 8 h. The mixture was cooled to room temperature, 33.10 g(0.32 mol) of 5-bromopent-1-yne was added, and themixture was stirred at 120°C for 24 h. The solvent was evaporated, the residue was treated with 150 mL ofchloroform, the precipitate was filtered off, and thefiltrate was concentrated to a volume of 20 mL and passed through a column charged with silica gel(60 mesh). The column was eluted in succession with light petroleum ether and petroleum ether-ethyl acetate(1.5 : 1 by volume). Yield 6.49 g (63%), mp 61°C.1H NMR spectrum (600 MHz, CDCl3), δ, ppm: 1.84-1.87 m (4H, 8-H, 13-H), 1.93 t (1H, 11-H, 4J = 2.8 Hz),2.00 t (1H, 16-H, 4J = 2.7 Hz), 2.21-2.23 m (2H, 9-H),2.24 s (6-CH3), 2.25-2.27 m (2H, 14-H), 3.90-3.93 t(2H, 7-H, 3J = 7.7 Hz), 3.98-4.00 t (2H, 12-H, 3J =7.0 Hz), 5.55 s (1H, 5-H). 13C NMR spectrum (CDCl3),δC, ppm: 15.85 (C8), 16.29 (C13), 20.51 (6-CH3), 40.46(C7), 44.14 (C12), 68.51 (C10), 69.51 (C15), 82.58 (C11),83.39 (C16), 101.73 (C5), 151.14 (C6), 152.00 (C2),162.12 (C4). Mass spectrum, m/z: 259.1 [M + H]+,281.1 [M + Na]+, 297.2 [M + K]+. Found, %: C 69.68;H 7.10; N 10.93. C15H18N2O2. Calculated, %: C 69.74;H 7.02; N 10.84. M 258.14.
Stage #1: 6-Methyluracil With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20℃; for 0.5h; Inert atmosphere;
Stage #2: 2-Methoxyethoxymethyl chloride In acetonitrile at 0℃; for 24h; Inert atmosphere;
Stage #1: 6-Methyluracil With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20℃; for 0.5h; Inert atmosphere;
Stage #2: Benzyloxymethyl chloride In acetonitrile at 0℃; for 24h; Inert atmosphere;
6-methyl-1,3-bis(hex-5-yn-1-yl)-2,4(1H,3H)-pyrimidinedione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
Stage #1: 6-Methyluracil With sodium hydride In hexane; N,N-dimethyl-formamide for 8h; Heating;
Stage #2: 1-iodo-5-hexyne In hexane; N,N-dimethyl-formamide at 115 - 120℃; for 16h;
2. General procedure for the synthesis of 1,3-bis(alkynyl)-2,4(1H,3H)-pyrimidine-, quinazoline-, and benzo[g]pteridinediones
General procedure: Sodium hydride (30 mmol) preliminarily treated with hexane was added to a solution of 15 mmol of uracil 1, 6-methyluracil 2, thymine 3, quinazoline-2,4-dione 4, and allox-azine 5 in DMF (150 mL). The reaction mixture was stirred for 8 h at 65-70 °C, cooled to room temperature and 60 mmol of the corresponding alkyne (propargyl bromide, 5-iodo-1-pentyne or 6-iodo-1-hexyne) was added to the sodium salt thus obtained. The mixture was stirred at 115-120 °C until the pH achieved 7.0-7.3 (12-16 h). The solvent was distilled off, 100 mL of chloroform was added to the residue and filtered. The filtrate was concen-trated to 10-15 mL and purified by column chromatography on silica gel. The column was eluted first with petroleum ether and then by the mixture of petroleum ether-ethyl acetate (1.5:1). The target compounds 1a-c, 2a-c, 3a-c, 4a-c, 5a-c were isolated from the second fraction.
Stage #1: 6-Methyluracil With N,O-bis-(trimethylsilyl)-acetamide In acetonitrile at 20℃; for 0.333333h; Inert atmosphere;
Stage #2: 1,2,3,5-tetraacetylribose With trimethylsilyl trifluoromethanesulfonate In acetonitrile at -20 - 20℃; for 6h; Inert atmosphere;
2’,3’,5’-Tri-O-acetyl-6-methyluridine (1)
To a solution of 6-methyluracil (1 g, 7.90 mmol) in dry CH3CN (20 mL), was added N,O-bistrimethylsilylacetamide (3.9 mL, 23.2 mmol) and the mixture was stirred for 20 min at room temperature. To this mixture, a solution of 1,2,3,5-tetra-O-acetylβ-D-ribofuranose (1.90 g, 6.60 mmol) in dry CH3CN (20 mL) was then added. After cooling to -20 °C, TMSOTf (3.9 mL, 7.3 mmol) was added and the reaction mixture was allowed to warm slowly to 15-20 °C and stirred for 6h. The mixture was then poured into CH2Cl2 and washed with saturated aq. NaHCO3 . The water layer was extracted with CH2Cl2. The organic extracts were combined and dried over Na2SO4, filtered and evaporated in vacuo. The crude residue was purified by column chromatography (CH2Cl2/MeOH 50:1) on silica gel to give product 1 (2.50 g) as an anomeric mixture. 1H NMR (600MHz, DMSO-d6): δ 11.39 (s, 1H, NH), 5.57 (d, 1H, J = 2.2 Hz, H-2’), 5.57-5.55 (m, 2H, H-5 and H-1’), 5.42 (dd, 1H, J = 2.2 Hz and J = 6.6 Hz, H-3’), 4.32 (m, 1H, H-5’), 4.15-4.12 (m, 1H, H-4’), 4.03 (m, 1H, H-5’’), 2.25 (s, 3H, 6-CH3), 2.11 (s, 3H, CH3), 2.10 (s, 3H, CH3), 2.09 (s, 3H, CH3); 13C NMR (150MHz, DMSO-d6): δ 170.2 (2xCO), 169.5 (CO), 162.4 (4-C), 153.0 (2-C), 150.6 (6-C), 102.5 (5-CH), 90.1 (1’-CH), 78.2 (4’-CH), 73.0 (2’-CH), 69.7 (3’-CH), 62.9 (5’-CH2), 20.6 (CH3), 20.5 (CH3), 20.3 (CH3), 19.5 (6-CH3); HRMS for C16H20N2O9 [M-H]- Calc.: 383.1095, found: 383.1103. Anal. (C16H20N2O9) Calc.: C, 50.00, H, 5.25, N, 7.29., found: C, 50.12, H, 5.31, N, 7.34.
With sulfuric acid; potassium chloride In water monomer at 80℃; for 5h;
Deiodination of compound 1 in acidic media in the presenceof 6-methyluracil (3) (general procedure)
General procedure: To a mixture of compound1 (0.15 g, 0.50 mmol), 6-methyluracil (3) (0.06 g,0.50 mmol), and KCl or KBr (2.50 mmol) in water (1.90 mL)heated to 80 C, 98% H2SO4 (0.05 mL) was added dropwise. Themixture was stirred at 80 C for 5 h, cooled to room temperature,treated with 10% aqueous Na2S2O3•5H2O, and extracted withCHCl3. The combined organic layers were washed with distilledwater, dried with Na2SO4, and concentrated in vacuo. In the caseof KCl, 0.09 g of a mixture of compounds 1 and 2 in a 1 : 10ratio and 0.10 g (83%) of 5-iodo-6-methyluracil (4) were obtained.In the case of KBr, 0.08 g of a mixture of compounds 1and 2 in a 1 : 15 ratio and 0.11 g of a mixture of compounds 4and 5 in a 1 : 2 ratio were obtained.5-Iodo-6-methyluracil (4). 1H NMR (500.13 MHz, CDCl3),: 2.25 (s, 3 H, C(6)CH3), 11.25 (br.s, 2 H, N(1)H, N(3)H)
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