5-Nitrouracil(CAS:611-08-5) is a piperazine derivative that inhibits the growth of cells by binding to detoxification enzymes and blocking their activity. It also inhibits the synthesis of proteins, which are necessary for cell division. 5-Nitrouracil is effective against cancerous cells in culture, as well as inhibiting the growth of tumor cells in mice.
Application In Synthesis of [ 611-08-5 ]
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With trichlorophosphate In <i>N</i>,<i>N</i>-dimethyl-aniline at 110℃; for 8 h;
5-nitro-uracil (6.28 g, 0.040 mol) was mixed with phosphorus oxychloride (26 ml) and slowly added with stirringN, N-dimethylaniline (8 ml) and then heated to 110 ° C for 8 h. After the reaction, the excess phosphorus oxychloride was distilled off,And the mixture was triturated and chromatographed on silica gel and concentrated to give 6.2 g of a yellow oily liquid. (Yield: 94percent)
68%
Reflux
Example 1; Compounds Made by Route 1Example 1.1 7-Methoxy-3-phenyl-pyrimido[5,4-e][l,2,4]triazineStep A: 2,4-Dichloro-5-nitropyrimidineFollowing the procedure in Route 1, a mixture of 5-nitrouracil (5.0 g, 31.8 mmol), phosphoryl chloride (25.0 ml, 274 mmol) and dimethylaniline (6 ml, 47.8 mmol) was heated with occasional shaking, until the reaction commenced. When this had subsided the mixture was refluxed for 2 h, then cooled, and most of the phosphoryl chloride evaporated off under reduced pressure. The residue was poured on ice with vigorous stirring and, after 5 minutes, extracted with ether, the extract was washed with water and dried with Na2SO4. Removal of the ether and distillation of the residue gave the title compound as a pale yellow oil (4.2 g, 68percent). 1H NMR (CDCl3, 300 MHz): δ 9.16 (s, IH).
51%
at 150℃; for 1.25 h;
N,N-dimethylaniline (12.1 mL, 95.5 mmol) is combined with 5-nitrouracil (10.0 g, 63.7 mmol) and stirred under a N2 atmosphere. Phosphorous oxychloride (23.7 mL, 254.6 mmol) is slowly added to the stirring mixture. Upon completion of addition, the mixture is heated to 150° C. for 75 min. The reaction mixture was then poured over ice and extracted with Et2O (3.x.250 mL). The combined organics are washed with brine, dried over MgSO4 and concentrated to afford the crude product as a brown oil (6.3 g, 51percent) which was further used without purification. 1H NMR (300 MHz, CDCl3) δ 9.19 (s, 1H).
41%
for 3 h; Reflux; Inert atmosphere
5-nitropyrimidine-2,4(1H,3H)-dione 5 (8.66 g, 55.1 mmol) was dissolved in freshly distilled phosphorus oxytrichloride (25.7 mL, 275.5 mmol) at room temperature. N,N-Dimethylaniline (17.4 mL, 137.8 mmol) was added dropwise to the stirred solution and the reaction was refluxed for 3 hours, or until complete. The black solution was cooled and concentrated under reduced pressure to remove excess phosphorus oxytrichloride, then poured into ice-water (82 mL). The aqueous solution was extracted with diethyl ether (3 x 110 mL), and the combined organic layers were washed with brine (160 mL), dried over anhydrous magnesium sulfate and the solvent evaporated to yield a brown oil. The crude product was purified by silica gel chromatography using ethyl acetate/hexane (1/10 v/v) as an eluent. The product was obtained as a yellow oil 5 (4.3 g, 22.5 mmol, 41percent). m.p. 29-30 °C; Rf 0.42 (1/10 v/v ethyl acetate/hexane); IR (ZnSe cell, solid) vmax: 1541 (s, NO2), 1342 (s, NO2/C-N=C), 1305 (s, NO2/C-N=C), 1203 (s, C-Cl), 1178 (s, C-Cl), 871 (s, C=C-H), 678 (s, C=C-H); 1H NMR (500 MHz, CDCl3): δ 9.16 (1H, s) ppm; 13C NMR (125 MHz, CDCl3): δ 162.74 (4-CCl), 156.62 (6-CH), 155.69 (2-CCl), 141.67 (5-CNO2) ppm; LRMS (+ GC/MS, 3.14 min) m/z: 197, 195, 193 ([M]+, 7, 39, 59percent), 160, 158 ([M - Cl]+, 25, 70percent), 137, 135 ([M - (CH2ClN)2 + H]+, 34, 53percent), 124, 122, 120 ([M – (C2HClN)3 + H]+, 11, 65, 100percent), 93 (63percent), 65, 63 (32, 78percent).
16.8 g
at 130℃; for 3 h;
25 gm of 5-nitro uracil is suspended in 490 ml of phosphorous oxychloride for 10 minutes and diisopropyl ethylamine is slowly added to the suspension at room temp. The reaction suspension is refluxed at 130 oC for 3h. The solution is concentrated under reduced pressure to be a volume of 100 ml. Then the solution is added dropwise to 500 ml of ice water and stirred for 1h, and extracted with diethyl ether. The organic layer is washed with 500 ml of saturated ammonium chloride and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (ethyl acetate: Hexane=1:5) affords 16.8 gm of the title compound. White solid; mp:30-32 oC; IR (KBr): 1670, 1620, 1350, 785 cm-1; 1H NMR (400 MHz, CDCl3): δ 9.25 (s, 1H, H6) ppm; m/z=195(M+).
Reference：
[1] Patent: CN106432239, 2017, A, . Location in patent: Paragraph 0066; 0071; 0072
[2] Journal of Heterocyclic Chemistry, 2012, vol. 49, # 2, p. 321 - 328
[3] Tetrahedron Letters, 2006, vol. 47, # 50, p. 8897 - 8900
[4] Patent: WO2010/83645, 2010, A1, . Location in patent: Page/Page column 27
[5] Patent: US7256196, 2007, B1, . Location in patent: Page/Page column 8; 9-10
[6] European Journal of Medicinal Chemistry, 2015, vol. 95, p. 29 - 34
[7] Chemische Berichte, 1906, vol. 39, p. 252
[8] Journal of the Chemical Society, 1951, p. 1565,1568[9] Journal of the Chemical Society, 1953, p. 1646
[10] Journal of the Chemical Society, 1951, p. 474,478[11] Journal of the Chemical Society, 1952, p. 4219,4224
[12] Journal of Medicinal Chemistry, 2004, vol. 47, # 1, p. 240 - 253
[13] Patent: US2002/52375, 2002, A1,
[14] Patent: WO2003/99809, 2003, A1, . Location in patent: Page 32
[15] Patent: WO2003/99231, 2003, A2, . Location in patent: Page 32
[16] Patent: WO2005/3099, 2005, A2, . Location in patent: Page 136-137
[17] Patent: WO2005/97162, 2005, A2, . Location in patent: Page/Page column 541; 549; 552-553
[18] Tetrahedron Letters, 2011, vol. 52, # 42, p. 5521 - 5524
[19] Patent: US2015/266828, 2015, A1, . Location in patent: Paragraph 0313
2
[ 611-08-5 ]
[ 49845-33-2 ]
Reference：
[1] Journal of Organic Chemistry, 2015, vol. 80, # 5, p. 2676 - 2699
[2] Journal of Chemical Research, Miniprint, 1992, # 2, p. 514 - 539
[3] Patent: WO2009/155156, 2009, A1, . Location in patent: Page/Page column 77-78
3
[ 611-08-5 ]
[ 10025-87-3 ]
[ 49845-33-2 ]
Reference：
[1] Patent: US6342503, 2002, B1, . Location in patent: Example 105
Reference：
[1] Chemische Berichte, 1906, vol. 39, p. 252
6
[ 66-22-8 ]
[ 611-08-5 ]
Yield
Reaction Conditions
Operation in experiment
92%
at 50 - 55℃; for 3 h; Inert atmosphere
Nitric acid solution (5.34 mL, 120 mmol, 70percent solution) was added drop-wise to a concentrated sulfuric acid (19.7 mL, 360 mmol, 98percent solution) during which time the temperature did not exceed 50 °C. Pyrimidine-2,4(1H,3H)-dione 5 (7.204 g, 60 mmol) was added in several portions to the stirred solution ensuring the temperature did not exceed 50 °C. The reaction was heated to 55 °C for 3 hours, and then cooled below room temperature and quenched with ice-water (38 mL). The resulting white precipitate was collected by filtration, washed with a small amount of ice water and dried under reduced pressure at 55 °C to yield a white solid 6 (8.658 g, 55.11 mmol, 92percent).m.p. >288 oC decomposition; Rf 0.00 (1/10, ethyl acetate/hexane); IR (ZnSe cell , solid) vmax: 3142-2811 (m, br, O-H/N-H/C-H), 1732 (s, C=O), 1677, 1624 (s, NO2), 1417 (m, C-H), 1356 (m, NO2), 1318 (s, aromatic R2NH/R3N), 1234 (s, -OH), 975, 832 (w, aromatic ring bending); 1H NMR (500 MHz, d6-DMSO): δ 8.84 (1H, s, 6-CH) ppm; 13C NMR (125 MHz, d6-DMSO): δ 155.5 (4-C=O), 149.8 (6-CH), 147.9 (2-C=O), 125.1 (5-CNO2) ppm.
Reference：
[1] European Journal of Medicinal Chemistry, 2015, vol. 95, p. 29 - 34
[2] American Chemical Journal, 1905, vol. 33, p. 443
[3] American Chemical Journal, 1908, vol. 40, p. 31[4] Journal of Biological Chemistry, 1908, vol. 4, p. 410
[5] Journal of the American Chemical Society, 1919, vol. 41, p. 786
[6] Journal of the Chemical Society, 1951, p. 1565,1568[7] Journal of the Chemical Society, 1953, p. 1646
[8] Journal of Applied Chemistry, 1952, vol. 2, p. 239
[9] Tetrahedron Letters, 2011, vol. 52, # 42, p. 5521 - 5524
7
[ 626-48-2 ]
[ 611-08-5 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1886, vol. 236, p. 50
8
[ 98198-74-4 ]
[ 611-08-5 ]
Reference：
[1] American Chemical Journal, 1905, vol. 33, p. 443
9
[ 6965-19-1 ]
[ 611-08-5 ]
Reference：
[1] American Chemical Journal, 1905, vol. 33, p. 443
10
[ 141-90-2 ]
[ 611-08-5 ]
Reference：
[1] American Chemical Journal, 1905, vol. 33, p. 443
Reference：
[1] Justus Liebigs Annalen der Chemie, 1886, vol. 236, p. 34
[2] Justus Liebigs Annalen der Chemie, 1885, vol. 229, p. 17[3] Justus Liebigs Annalen der Chemie, 1885, vol. 231, p. 249
15
[ 3106-01-2 ]
[ 611-08-5 ]
[ 17039-17-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 5, p. 1648 - 1651
16
[ 7254-29-7 ]
[ 7664-93-9 ]
[ 611-08-5 ]
Reference：
[1] American Chemical Journal, 1905, vol. 34, p. 564
17
[ 69099-99-6 ]
[ 7664-93-9 ]
[ 611-08-5 ]
Reference：
[1] American Chemical Journal, 1906, vol. 36, p. 176
18
[ 100-25-4 ]
[ 58431-12-2 ]
[ 611-08-5 ]
[ 100-25-4 ]
Reference：
[1] Journal of Physical Chemistry, 1986, vol. 90, # 19, p. 4648 - 4650
19
[ 100-19-6 ]
[ 58431-12-2 ]
[ 611-08-5 ]
[ 100-19-6 ]
Reference：
[1] Journal of Physical Chemistry, 1986, vol. 90, # 19, p. 4648 - 4650
20
[ 17687-24-0 ]
[ 7732-18-5 ]
[ 611-08-5 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1889, vol. 251, p. 238
[2] Justus Liebigs Annalen der Chemie, 1886, vol. 236, p. 34
21
[ 141-90-2 ]
[ 7697-37-2 ]
[ 611-08-5 ]
Reference：
[1] American Chemical Journal, 1905, vol. 33, p. 443
22
[ 611-08-5 ]
[ 932-52-5 ]
Yield
Reaction Conditions
Operation in experiment
81%
at 75℃; for 3 h; Inert atmosphere
Example 15-aminopyrimidine-2,4(1H,3H)-dione 1 Into a 5-L 4-necked round-bottom flask were placed water (2.871 L), ammonia (116.1 mL) and 5-nitropyrimidine-2,4(1H,3H)-dione (180 g, 1.15 mol, 1.00 equiv). This was followed by the addition of Na2S2O2 (860 g, 6.06 mol, 4.30 equiv) in several batches. The pH value of the solution was adjusted to 8 with ammonia (25percent). The resulting solution was stirred for 3 h (hours) at 75° C. The reaction mixture was cooled to 15° C. with an ice/water bath. The solid was collected by filtration. This resulted in 118 g (81percent) of 5-aminopyrimidine-2,4(1H,3H)-dione 1 as a yellow solid (see Scheme 1).
Reference：
[1] Patent: US2011/207713, 2011, A1, . Location in patent: Page/Page column 58
[2] American Chemical Journal, 1905, vol. 33, p. 443
[3] Justus Liebigs Annalen der Chemie, 1899, vol. 309, p. 255,256
[4] Justus Liebigs Annalen der Chemie, 1889, vol. 251, p. 238
[5] Justus Liebigs Annalen der Chemie, 1885, vol. 229, p. 17[6] Justus Liebigs Annalen der Chemie, 1885, vol. 231, p. 249
[7] Justus Liebigs Annalen der Chemie, 1887, vol. 240, p. 11
[8] Chemische Berichte, 1896, vol. 29, p. 1951
[9] American Chemical Journal, 1905, vol. 33, p. 443
[10] Justus Liebigs Annalen der Chemie, 1899, vol. 309, p. 255,256
[11] Journal of the American Chemical Society, 1919, vol. 41, p. 786
[12] Journal of the American Chemical Society, 1924, vol. 46, p. 704
[13] Journal of the Chemical Society, 1957, p. 4997,5000
[14] Journal of the American Chemical Society, 1933, vol. 55, p. 1667
23
[ 611-08-5 ]
[ 20636-41-3 ]
[ 932-52-5 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1889, vol. 251, p. 238
[2] Justus Liebigs Annalen der Chemie, 1885, vol. 229, p. 17[3] Justus Liebigs Annalen der Chemie, 1885, vol. 231, p. 249
With ammonia; at 75℃; for 3h;pH 8;Inert atmosphere;
Example 15-aminopyrimidine-2,4(1H,3H)-dione 1 Into a 5-L 4-necked round-bottom flask were placed water (2.871 L), ammonia (116.1 mL) and 5-nitropyrimidine-2,4(1H,3H)-dione (180 g, 1.15 mol, 1.00 equiv). This was followed by the addition of Na2S2O2 (860 g, 6.06 mol, 4.30 equiv) in several batches. The pH value of the solution was adjusted to 8 with ammonia (25%). The resulting solution was stirred for 3 h (hours) at 75 C. The reaction mixture was cooled to 15 C. with an ice/water bath. The solid was collected by filtration. This resulted in 118 g (81%) of 5-aminopyrimidine-2,4(1H,3H)-dione 1 as a yellow solid (see Scheme 1).
With trichlorophosphate; In N,N-dimethyl-aniline; at 110℃; for 8h;
<strong>[611-08-5]5-nitro-uracil</strong> (6.28 g, 0.040 mol) was mixed with phosphorus oxychloride (26 ml) and slowly added with stirringN, N-dimethylaniline (8 ml) and then heated to 110 C for 8 h. After the reaction, the excess phosphorus oxychloride was distilled off,And the mixture was triturated and chromatographed on silica gel and concentrated to give 6.2 g of a yellow oily liquid. (Yield: 94%)
68%
With N,N-dimethyl-aniline; trichlorophosphate;Reflux;
Example 1; Compounds Made by Route 1Example 1.1 7-Methoxy-3-phenyl-pyrimido[5,4-e][l,2,4]triazineStep A: 2,4-Dichloro-5-nitropyrimidineFollowing the procedure in Route 1, a mixture of 5-nitrouracil (5.0 g, 31.8 mmol), phosphoryl chloride (25.0 ml, 274 mmol) and dimethylaniline (6 ml, 47.8 mmol) was heated with occasional shaking, until the reaction commenced. When this had subsided the mixture was refluxed for 2 h, then cooled, and most of the phosphoryl chloride evaporated off under reduced pressure. The residue was poured on ice with vigorous stirring and, after 5 minutes, extracted with ether, the extract was washed with water and dried with Na2SO4. Removal of the ether and distillation of the residue gave the title compound as a pale yellow oil (4.2 g, 68%). 1H NMR (CDCl3, 300 MHz): delta 9.16 (s, IH).
51%
With N,N-dimethyl-aniline; trichlorophosphate; at 150℃; for 1.25h;
N,N-dimethylaniline (12.1 mL, 95.5 mmol) is combined with 5-nitrouracil (10.0 g, 63.7 mmol) and stirred under a N2 atmosphere. Phosphorous oxychloride (23.7 mL, 254.6 mmol) is slowly added to the stirring mixture. Upon completion of addition, the mixture is heated to 150 C. for 75 min. The reaction mixture was then poured over ice and extracted with Et2O (3×250 mL). The combined organics are washed with brine, dried over MgSO4 and concentrated to afford the crude product as a brown oil (6.3 g, 51%) which was further used without purification. 1H NMR (300 MHz, CDCl3) delta 9.19 (s, 1H).
41%
With N,N-dimethyl-aniline; trichlorophosphate; for 3h;Reflux; Inert atmosphere;
5-nitropyrimidine-2,4(1H,3H)-dione 5 (8.66 g, 55.1 mmol) was dissolved in freshly distilled phosphorus oxytrichloride (25.7 mL, 275.5 mmol) at room temperature. N,N-Dimethylaniline (17.4 mL, 137.8 mmol) was added dropwise to the stirred solution and the reaction was refluxed for 3 hours, or until complete. The black solution was cooled and concentrated under reduced pressure to remove excess phosphorus oxytrichloride, then poured into ice-water (82 mL). The aqueous solution was extracted with diethyl ether (3 x 110 mL), and the combined organic layers were washed with brine (160 mL), dried over anhydrous magnesium sulfate and the solvent evaporated to yield a brown oil. The crude product was purified by silica gel chromatography using ethyl acetate/hexane (1/10 v/v) as an eluent. The product was obtained as a yellow oil 5 (4.3 g, 22.5 mmol, 41%). m.p. 29-30 C; Rf 0.42 (1/10 v/v ethyl acetate/hexane); IR (ZnSe cell, solid) vmax: 1541 (s, NO2), 1342 (s, NO2/C-N=C), 1305 (s, NO2/C-N=C), 1203 (s, C-Cl), 1178 (s, C-Cl), 871 (s, C=C-H), 678 (s, C=C-H); 1H NMR (500 MHz, CDCl3): delta 9.16 (1H, s) ppm; 13C NMR (125 MHz, CDCl3): delta 162.74 (4-CCl), 156.62 (6-CH), 155.69 (2-CCl), 141.67 (5-CNO2) ppm; LRMS (+ GC/MS, 3.14 min) m/z: 197, 195, 193 ([M]+, 7, 39, 59%), 160, 158 ([M - Cl]+, 25, 70%), 137, 135 ([M - (CH2ClN)2 + H]+, 34, 53%), 124, 122, 120 ([M - (C2HClN)3 + H]+, 11, 65, 100%), 93 (63%), 65, 63 (32, 78%).
With trichlorophosphate; In N,N-dimethyl-aniline;
Preparation of 2.4-Dichloro-5-nitropyrimidine <strong>[611-08-5]5-Nitrouracil</strong> was treated with phosphorus oxychloride and N,N-dimethylaniline, according to the procedure of Whittaker (J. Chem. Soc. 1951, 1565), to give 2,4-dichloro-5-nitropyrimidine as an orange oil, which was used without distillation immediately in the next step.
With N,N-dimethyl-aniline; trichlorophosphate;
5- Nitrouracil, (1), was treated with phosphorous [OXYCHLORIDE] [(POC13)] and N, N- dimethylaniline [(PHNME2),] according to the procedure of Whittaker (J. Chem. Soc. 1951,1565), to give compound 2. Compound 2 is also available from City Chemical (West Haven, CT).
With N,N-dimethyl-aniline; trichlorophosphate;
Preparation of 2,4-dichloro-5-nitropyrimidine. <strong>[611-08-5]5-Nitrouracil</strong>, was treated with phosphorous oxychloride and N, N- [DIMETHYLANILINE,] according to the procedure of Whittaker (J. Chem. Soc. 1951,1565), to give the title compound, which is also available from City Chemical (West Haven, CT).
With N,N-dimethyl-aniline; trichlorophosphate; at 80℃; for 0.333333h;
A stirring solution of 34 (10.0 g, 63.6 mmol), phosphorus oxychloride (25.0 mL), and N, N-dimethylaniline (17.0 g, 140 mmol) in a 200 mL three-necked round-bottomed flask equipped with a magnetic stirrer was heated at 80 C for a period of 20 minutes. The solution was concentrated under reduced pressure. The residue was residue was poured into ice-water (300 g) and the mixture was basified with saturated aqueous NaHC03 solution. The mixture was partitioned between CH2C12 and water. The organic portion was dried (MGS04) and cooled to- 78 C. To this solution was added Et3N (8.70 mL, 63.0 mmol) followed by the dropwise addition of dimethylarnine (31.8 mL, 63.6 mmol, 2.0 M in THF) at-78 C over a period of 10 minutes. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using (30% EtOAc, 70% Hexane) to obtain 35 (3.9 g, 19.2 mmol, 30% yield) as a yellow solid NMR (CDC13) 6 3.01 (s, 6H), 8. 62 (s, 1H).
With N,N-dimethyl-aniline; trichlorophosphate;
<strong>[611-08-5]5-Nitrouracil</strong> (Aldrich Chemical Company) was treated with phosphorous oxychloride and NN-dimethylaniline according to the procedure described in Whittaker, J. Chem. Soc. 1951,1565, to give 2,4-dichloro-5-nitropyrimidine as an orange oil which was used without distillation immediately in the next step.
16.8 g
With N-ethyl-N,N-diisopropylamine; trichlorophosphate; at 130℃; for 3h;
25 gm of 5-nitro uracil is suspended in 490 ml of phosphorous oxychloride for 10 minutes and diisopropyl ethylamine is slowly added to the suspension at room temp. The reaction suspension is refluxed at 130 oC for 3h. The solution is concentrated under reduced pressure to be a volume of 100 ml. Then the solution is added dropwise to 500 ml of ice water and stirred for 1h, and extracted with diethyl ether. The organic layer is washed with 500 ml of saturated ammonium chloride and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (ethyl acetate: Hexane=1:5) affords 16.8 gm of the title compound. White solid; mp:30-32 oC; IR (KBr): 1670, 1620, 1350, 785 cm-1; 1H NMR (400 MHz, CDCl3): delta 9.25 (s, 1H, H6) ppm; m/z=195(M+).
With N,N-dimethyl-aniline; trichlorophosphate; for 5h;Reflux;
A suspension of 5-nitrouracil (10 g, 63 mmol) in POCl3 (100 mL) was refluxed for 5 h in the presence of N,N-dimethylaniline (10 mL), cooled to room temperature and poured on to crushed ice with vigorous stirring. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and the solvent was evaporated under reduce pressure. The residue was purified by chromatography on silica gel (hexane/ethyl acetate; 1/1; v/v) to give the desired 2,4-dichloro-5-nitropyrimidine. LCMS: ret. time: 23.26 min.; purity: 95%; 1H NMR (CDCl3): delta 9.16 (1H, s).
With sulfuric acid; nitric acid; at 50 - 55℃; for 3h;Inert atmosphere;
Nitric acid solution (5.34 mL, 120 mmol, 70% solution) was added drop-wise to a concentrated sulfuric acid (19.7 mL, 360 mmol, 98% solution) during which time the temperature did not exceed 50 C. Pyrimidine-2,4(1H,3H)-dione 5 (7.204 g, 60 mmol) was added in several portions to the stirred solution ensuring the temperature did not exceed 50 C. The reaction was heated to 55 C for 3 hours, and then cooled below room temperature and quenched with ice-water (38 mL). The resulting white precipitate was collected by filtration, washed with a small amount of ice water and dried under reduced pressure at 55 C to yield a white solid 6 (8.658 g, 55.11 mmol, 92%).m.p. >288 oC decomposition; Rf 0.00 (1/10, ethyl acetate/hexane); IR (ZnSe cell , solid) vmax: 3142-2811 (m, br, O-H/N-H/C-H), 1732 (s, C=O), 1677, 1624 (s, NO2), 1417 (m, C-H), 1356 (m, NO2), 1318 (s, aromatic R2NH/R3N), 1234 (s, -OH), 975, 832 (w, aromatic ring bending); 1H NMR (500 MHz, d6-DMSO): delta 8.84 (1H, s, 6-CH) ppm; 13C NMR (125 MHz, d6-DMSO): delta 155.5 (4-C=O), 149.8 (6-CH), 147.9 (2-C=O), 125.1 (5-CNO2) ppm.
With pyridine; for 1h;Reflux; Schlenk technique; Inert atmosphere;
General procedure: 2',3',5'-tri-O-Benzoyl-5-fluorouridine (3a)S1 (Table 2, entry 1). A mixture of5-fluorouracil (51.1 mg, 0.39 mmol), pyridine (0.6 mL), and hexamethyldisilazane(HMDS) (1.2 mL) was refluxed for ca. 40 min to give a clear solution of 2a. All thevolatiles were then removed under reduced pressure (ca. 1 mmHg) to give a clear syrup,which was dissolved in acetone (3.0 mL). To this were added1-O-acetyl-2,3,5-tri-O-benzoyl--D-ribofuranose (1) (151.8 mg, 0.30 mmol) and 7b (4.5mg, 0.015 mmol, 5 mol%) and the mixture was stirred under reflux for 6 h. After themixture was cooled to rt, it was diluted with EtOAc (2 mL), followed by the addition ofa saturated NaHCO3 aq (2 mL) at 0 C. After the mixture was stirred at 0 oC for 15min, EtOAc (30 mL) and a saturated NaHCO3 aq (20 mL) were added. The organicphase was separated and the aqueous phase was back-extracted with EtOAc (30 mL x 3).The combined organic layers were dried with Na2SO4 and evaporated to afford a crudematerial, which was purified by recrystallization from EtOAc (5 mL) and hexane (7mL) to afford 2',3',5'-tri-O-benzoyl-5-fluorouridine (3a) (152 mg, 88%) as a whitepowder.
With pyridine; for 1h;Schlenk technique; Inert atmosphere; Reflux;
The reaction withsilylated 5-nitrouridine was conducted on a 0.30 mmol scale as follows. Silylation: 5-nitrouracil (61.3 mg, 0.39 mmol), HMDS (1.2 mL), pyridine (0.6 mL), reflux, 1 h.
100%Chromat.
With chitosan-silica sulfate nanohybrid; at 90℃; for 0.366667h;Green chemistry;
General procedure: To a round-bottom flask (50 mL) was added a mixture of the desired nucleobases or other N-heterocycles (1 mmol), CSSNH (0.05 g), and HMDS (10 mL). The reaction mixture was heated at 90 C until a clear liquid was attained (Table 3). Subsequently, the catalyst was filtered and the filtrate was then evaporated using vacuum to separate the crude silylated product from HMDS. The crude product was pure enough to be applied in the next step without further purification.
With sodium hydroxide; potassium carbonate; In N-methyl-acetamide; water;
EXAMPLE 109 Preparation of 5-nitro-1-methyl-uracil STR148 5-nitrouracil (10.00 g, 64 mmole) and potassium carbonate were stirred in dimethylformamide (50 mL) for 15 min. A solid formed. Iodomethane (5.3 mL, 85 mmol) was added and the flask was shaken until the solid dissolved. After the reaction mixture was stirred for 30 min., 2% NaOH (w/v) (200 mL) was added, followed by water (100 mL). The solution was washed with ethyl acetate (100 mL), and the aqueous layer was acidified to pH 3 with 1.0N HCl. A precipitate formed as the pH was lowered. After allowing the heterogeneous solution to stand for 16 hours, the product was filtered, washed with water, and air dried. The title compound was isolated in 77% yield as a yellow powder; m.p. 249 to 250 C.
77%
With sodium hydroxide; potassium carbonate; In N-methyl-acetamide; water;
Example 109 Preparation of 5-nitro-1-methyl-uracil STR150 5-nitrouracil (10.00 g, 64 mmole) and potassium carbonate were stirred in dimethylformamide (50 mL) for 15 min. A solid formed. Iodomethane (5.3 mL, 85 mmol) was added and the flask was shaken until the solid dissolved. After the reaction mixture was stirred for 30 min., 2% NaOH (w/v) (200 mL) was added, followed by water (100 mL). The solution was washed with ethyl acetate (100 mL), and the aqueous layer was acidified to pH 3 with 1.0N HCl. A precipitate formed as the pH was lowered. After allowing the heterogeneous solution to stand for 16 hours, the product was filtered, washed with water, and air dried. The title compound was isolated in 77% yield as a yellow powder; m.p. 249 to 250 C.
77%
With sodium hydroxide; potassium carbonate; In N-methyl-acetamide; water;
Example 109 Preparation of 5-nitro-1-methyl-uracil STR131 5-nitrouracil (10.00 g, 64 mmole) and potassium carbonate were stirred in dimethylformamide (50 mL) for 15 min. A solid formed. Iodomethane (5.3 mL, 85 mmol) was added and the flask was shaken until the solid dissolved. After the reaction mixture was stirred for 30 min., 2% NaOH (w/v) (200 mL) was added, followed by water (100 mL). The solution was washed with ethyl acetate (100 mL), and the aqueous layer was acidified to pH 3 with 1.0N HCl. A precipitate formed as the pH was lowered. After allowing the heterogeneous solution to stand for 16 hours, the product was filtered, washing with water, and air dried. The title compound was isolated in 77% yield as a yellow powder. m.p. 249-250 C.
77%
With sodium hydroxide; potassium carbonate; In N-methyl-acetamide; water;
Example 109 Preparation of 5-Nitro-1-methyl-uracil STR129 5-nitrouracil (10.00 g, 64 mmole) and potassium carbonate were stirred in dimethylformamide (50 mL) for 15 min. A solid formed. Iodomethane (5.3 mL, 85 mmol) was added and the flask was shaken until the solid dissolved. After the reaction mixture was stirred for 30 min., 2% NaOH (w/v) (200 mL) was added, followed by water (100 mL). The solution was washed with ethyl acetate (100 mL), and the aqueous layer was acidified to pH 3 with 1.0N HCl. A precipitate formed as the pH was lowered. After allowing the heterogeneous solution to stand for 16 hours, the product was filtered, washing with water, and air dried. The title compound was isolated in 77% yield as a yellow powder. m.p. 249-250 C.
77%
5-nitrouracil (10.00 g, 64 mmole) and potassium carbonate were stirred in dimethylformamide (50 ML) for 15 min.. A solid formed.. iodomethane (5.3 ML, 85 mmol) was added and the flask was shaken until the solid dissolved.. After the reaction mixture was stirred for 30 min., 2% NaOH (w/v) (200 ML) was added, followed by water (100 ML).. The solution was washed with ethyl acetate (100 ML), and the aqueous layer was acidified to PH 3 with 1.0N HCl. A precipitate formed as the PH was lowered.. After allowing the heterogeneous solution to stand for 16 hours, the product was filtered, washed with water, and air dried.. The title compound was isolated in 77% yield as a yellow powder; m.p. 249 to 250 C.
(EX-4A) A solution of 5-nitro-2,4(1H,3H) pyrimidinedione in dimethylsulfoxide (0.2 M) is added 1.1 equivalents potassium carbonate in one portion with stirring. After approximately 10 minutes, a solution of 1 equivalent 2-(trimethylsilyl)ethoxy-methyl chloride in dimethylsulfoxide is added drop wise. The reaction mixture is then heated to 40 C. and allowed to stir for 18 hours. Typical aqueous work up followed by chromatographic purification provides pure product EX-4A.
With chloro-trimethyl-silane; for 24h;Heating / reflux;
5-nitrouracil (10.00 g, 64 mmole), 1,1,1-3,3,3-hexamethyldisilazane (40 ML, 190 mmole) and chlorotrimethylsilane (4.0 ML, 32 mmole) are heated to reflux for 24 hours.. The solution is concentrated under reduced pressure to afford 5-nitrouracil bis(trimethylsilyl) ether.
With iodine; potassium carbonate; triethylamine; triphenylphosphine; In N,N-dimethyl-formamide; for 10h;Reflux;
General procedure: In a double-necked round bottom flask (100 mL) equipped with a condenser was added a mixture, consisting of alcohol (1 mmol),TPP (1 mmol), I2 (1 mmol) Et3N (1 mmol), K2CO3 (1 mmol), and thedesire nucleo base (1 mmol) in anhydrous DMF (5 mL).33 The mixture was heated at reflux. Heating was continued until TLC indicated no further improvement in the conversion (Table 5). The solvent was evaporated under vacuum and the remaining foam was dissolved in CHCl3 (100 mL) and subsequently washed with water (2100 mL). The organic layer was dried (Na2SO4) and evaporated. The crude product was purified by short column chromatography on silica gel eluting with proper solvents.
71%
With potassium carbonate; 1-n-butyl-3-methylimidazolim bromide; triethylamine; p-toluenesulfonyl chloride; at 80℃; for 11h;Green chemistry;
General procedure: In a double-necked round-bottom flask (100 mL) wasadded a mixture consisting of nucleobase (0.01 mol),alcohol (0.012 mol), TsCl (2.86 g, 0.015), TEA (1.01 g,0.01 mol) and K2CO3 (1.38 g, 0.010 mol) in bmim[Br](10 mL). The flask was immersed in an oil bath, kept at80 C and stirred for the time when TLC indicated no furtherprogress in the conversion (Tables 4, 5, 6). The mixturewas then diluted with water (200 mL) and extracted withEtOAc (3 × 50 mL). The organic layer was dried (Na2SO4)and evaporated to afford the crude product which was purifiedby traditional column chromatography on silica geleluting with proper solvents.
To a solution of <strong>[611-08-5]5-nitro-1H-pyrimidine-2,4-dione</strong> (1.0 g, 6.4 mmol) in 1,2-dicholoroethane (15 mL) was added bis(trimethylsilyl)acetamide (3.1 mL, 12.8 mmol), followed by stirring at 80C for 30 min in a nitrogen atmosphere. The solution was chilled to 0C, mixed with 2,6-difluorobenzyl bromide (1.45 g, 7.0 mmol) and stirred at 85C for 12 hrs. The addition of methanol (7 mL) to the solution cooled to room temperature resulted in the formation of white solids. This suspension was neutralized with an aqueous saturated ammonium chloride and mixed with dichloromethane to separate an organic layer. This organic layer was concentrated and the residue was purified using silica gel chromatography (eluent: dichloromethane/methanol, 50/1) and dried in a vacuum to afford 230 mg of the compound as a pale yellowish foam (yield 30%). 1H NMR (300MHz, DMSO-d6) delta 5.17(2H, s), 7.13(2H, m), 7.47(1H, m), 9.44 (1H, s), 12.0 (1H, s)
30%
Step A. 1-(2,6-difluoro-benzyl)-<strong>[611-08-5]5-nitro-1H-pyrimidine-2,4-dione</strong> To a solution of <strong>[611-08-5]5-nitro-1H-pyrimidine-2,4-dione</strong> (1.0 g, 6.4 mmol) in 1,2-dicholoroethane (15 mL) was added bis(trimethylsilyl)acetamide (3.1 mL, 12.8 mmol), followed by stirring at 80 C. for 30 min in a nitrogen atmosphere. The solution was chilled to 0 C., mixed with 2,6-difluorobenzyl bromide (1.45 g, 7.0 mmol) and stirred at 85 C. for 12 hrs. The addition of methanol (7 mL) to the solution cooled to room temperature resulted in the formation of white solids. This suspension was neutralized with an aqueous saturated ammonium chloride and mixed with dichloromethane to separate an organic layer. This organic layer was concentrated and the residue was purified using silica gel chromatography (eluent: dichloromethane/methanol, 50/1) and dried in a vacuum to afford 230 mg of the compound as a pale yellowish foam (yield 30%). 1H NMR (300 MHz, DMSO-d6) delta 5.17 (2H, s), 7.13 (2H, m), 7.47 (1H, m), 9.44 (1H, s), 12.0 (1H, s)
Step 178.5: 1 ,3-Dimethyl-5-nitro-1 H-pyrimidine-2,4-dione The title compound was prepared in analogy to the procedure described for step 100.5 but using 5- nitrouracil. The reaction was performed at rt for 20 h. The reaction mixture was concentrated and triturated in CH2CI2. The resulting suspension was filtered and the solid was purified by flash chromatography (CH2CI2/MeOH, 94:6). tR: 0.41 min (LC-MS 2); ESI-MS: 186.1 [M+H]+ (LC-MS 2); Rf = 0.55 (CH2CI2/MeOH, 9:1 ).
General procedure: A solution of 8AQ (1 mmol) dissolved in 70C methanol(30 mL) was added a solution of metal salts (1 mmol in 2mL methanol), and then heated for 45 min. Subsequently, asolution of 5Iu or 5Nu (1 mmol in 2 mL methanol) wasadded to the reaction mixture and heated for another 1 h.The formed solid product was collected by filtration, washed3-4 times with cold MeOH and dried under reduced preesureat room temperature
General procedure: A solution of 8AQ (1 mmol) dissolved in 70C methanol(30 mL) was added a solution of metal salts (1 mmol in 2mL methanol), and then heated for 45 min. Subsequently, asolution of 5Iu or 5Nu (1 mmol in 2 mL methanol) wasadded to the reaction mixture and heated for another 1 h.The formed solid product was collected by filtration, washed3-4 times with cold MeOH and dried under reduced preesureat room temperature
General procedure: A solution of 8AQ (1 mmol) dissolved in 70C methanol(30 mL) was added a solution of metal salts (1 mmol in 2mL methanol), and then heated for 45 min. Subsequently, asolution of 5Iu or 5Nu (1 mmol in 2 mL methanol) wasadded to the reaction mixture and heated for another 1 h.The formed solid product was collected by filtration, washed3-4 times with cold MeOH and dried under reduced preesureat room temperature
We have used L-histidine (99% (TLC), Sigma-Aldrich) and 5-nitrouracil (98%, Aldrich), as initial reagents. The needle-like crystalsof the title compound (I) have been obtained by slow evaporationat ambient temperature of an aqueous solution containing Lhistidineand 5-nitrouracil with 1:2M ratio. The known monoclinic(II) form has been obtained also from an aqueous solution but withstoichiometric 1:1M ratio.
Stage #1: 5-nitrobarbituric acid; 5-bromo-2’,3’,5’-tri-O-acetyluridine With N,O-bis-(trimethylsilyl)-acetamide In acetonitrile at 20℃; for 1h; Microwave irradiation;
Stage #2: With trimethylsilyl trifluoromethanesulfonate In acetonitrile at 80℃; for 1h; Microwave irradiation; Sealed tube;
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