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Structure of 51-21-8 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With trichlorophosphate In <i>N</i>,<i>N</i>-dimethyl-aniline at 100℃; for 13 h; Inert atmosphere; Large scale
5-fluoropyrimidine-2,4-diol (525 kg, 1.00 mol eq) is mixed with phosphorous oxychloride (1545 kg, 2.50 mol eq) and heated to about 100° C. with stirring under a nitrogen atmosphere. N,N-dimethylaniline (980 kg, 2.00 mol eq) is then added over a period of about 9 hours and the resulting mixture stirred at about 100° C. for up to 4 hours. This is then cooled to about 20° C. over about 2 hours and then quenched into a mixture of water (3150 kg) and dichloromethane (1915 kg), maintaining the temperature below 40° C. The contents are then stirred at about 20° C. for at least 3 hours and then the layers separated. The aqueous phase is washed with dichloromethane (1915 kg) and the layers again separated. The combined organics are then washed with concentrated aqueous hydrochloric acid (525 kg) at least once, sometimes more than once, then with 5percent w/w aqueous sodium hydrogen carbonate solution (2625 kg). The resulting organic solution is then distilled at atmospheric pressure down to about 1310 kg to give a solution of 2,4-dichloro-5-fluoro-pyrimidine in dichloromethane, with typical solution strength of about 50percent w/w and yield of about 95percent. This solution is then used directly in the next process.
92%
at 95 - 120℃; for 4 h;
After the input of 5-fluoropyrimidine-2,4-diol (formula 11) 11.2g (86.1m) and phosphorus oxychloride (POCl3) 38.9g (253.8m) to the reactor and heated to 95 °C, 20.7g N,N-dimethylamine (DMA) was added dropwise for 1 hour and the temperature was raised to 120 °C, this mixture was stirred for 3 hours. Cooling the temperature to 0 °C, and the dropwise addition of 3N HCl solution in 1500ml below 10 °C. After the addition was complete, filtered and stirred for 3 hours at 10 °C and dried to give 2,4-dichloro-5-fluoropyrimidine (chemical formula 9) 13.2g (79.1mmol) (yield: 92percent).
Reference：
[1] Patent: US2015/175639, 2015, A1, . Location in patent: Paragraph 0145
[2] Journal of Organic Chemistry, 2011, vol. 76, # 10, p. 4149 - 4153
[3] Patent: KR2016/69892, 2016, A, . Location in patent: Paragraph 0090-0093
[4] Chemical and Pharmaceutical Bulletin, 1991, vol. 39, # 9, p. 2288 - 2300
[5] Patent: US2005/234046, 2005, A1, . Location in patent: Page/Page column 64
6
[ 51-21-8 ]
[ 2927-71-1 ]
Yield
Reaction Conditions
Operation in experiment
94%
at 95 - 120℃; for 4 h;
11.1 g (85.3 mmol) of 5-fluorouracil (Formula 10) and 39.4 g (257.0 mmol) of phosphorus oxychloride (POCl3) were added to the reactor, and the temperature was raised to 95 °C. N,N-Dimethylamine was added dropwise for 1 hour, the temperature was raised to 120 °C, and the mixture was stirred for 3 hours. The temperature was cooled to 0 °C and 1500 ml of 3N HCl aqueous solution was added dropwise at 10 °C or lower. After completion of the dropwise addition, the mixture was stirred at 10 °C for 3 hours, filtered and dried to obtain 13.4 g (80.3 mmol) of 2,4-dichloro-5-fluoropyrimidine (formula 9) (yield: 94percent)
87%
Stage #1: at 95℃; for 3.5 h; Stage #2: With hydrogenchloride In water at 0 - 20℃;
Example 30A was also prepared as follows. Dimethylaniline (195 mL, 1.54 mol) was added to a slurry of 5-fluorouracil (99.73 g, 0.77 mol) in phosphorus oxychloride (215 mL, 2.31 mol) at 95 °C under a nitrogen atmosphere. The reaction mixture was stirred at this temperature for 3.5 h, cooled to room temperature and then slowly added to a stirred mixture of ice (200 g) and 6 M HCl (200 mL). The resulting slurry was extracted with dichloromethane (2 x 400 mL) and the combined organic extracts were washed with DI water (4 x 275 mL), dried over MgSO4 and concentrated under reduced pressure to afford 111.77 g (87percent, 98.1percent AUC by HPLC) of 5-fluoro-2,4-dichloro-pyrimidine as an amber oil. A molar solution of sodium hydroxide (1.34 L) was slowly added to a solution of the 5-fluoro-2,4-dichloro-pyrimidine (111.77 g, 0.67 mol) in THF (377 mL) at 0 °C. After the reaction mixture was stirred for about 30 min at room temperature, the pH was adjusted to 6 by a slow addition of 1.0 M HCl. The aqueous solution was extracted with ethyl acetate (440 mL) to remove impurities following which the pH was adjusted to 1 with 1.0 M HCl. The acidic aqueous solution was extracted with ethyl acetate (4 x 555 mL) and the combined organic extracts were washed with brine (111 mL), dried over MgSO4 and concentrated under reduced pressure to produce 88.35 g (89percent, 99.2percent AUC by HPLC) of 2-chloro-5-fluoro-3H-pyrimidin-4-one as an off-white powder.
87%
at 95℃; for 3.5 h;
Example 1a 2-Chloro-5-fluoro-3H-pyrimidin-4-one The title compound was prepared in 56percent yield from 2,4-dichloro-5-fluoro-pyrimidine as described in U.S. patent application Ser. No. 10/918,317. Specifically, 5-Fluoro-2,4-dichloro-pyrimidine was stirred in THF (10 mL) with 1N NaOH at r.t. for 3 h. The solution was made slightly acidic with 1N HCl and was extracted with CHCl3. Organics were dried (MgSO4) and concentrated in vacuo. Precipitation from 20percent CHCl3/hexanes and collection by filtration gave the title compound. 1H NMR (400 MHz, DMSO-d6): δ 13.98 (br s, 1H), 8.14 (d, 1H, J=3.2 Hz). The title compound of Example 1a was also prepared as follows. Dimethylaniline (195 mL, 1.54 mol) was added to a slurry of 5-fluorouracil (99.73 g, 0.77 mol) in phosphorus oxychloride (215 mL, 2.31 mol) at 95° C. under a nitrogen atmosphere. The reaction mixture was stirred at this temperature for 3.5 h, cooled to room temperature and then slowly added to a stirred mixture of ice (200 g) and 6 M HCl (200 mL). The resulting slurry was extracted with dichloromethane (2.x.400 mL) and the combined organic extracts were washed with DI water (4.x.275 mL), dried over MgSO4 and concentrated under reduced pressure to afford 111.77 g (87percent, 98.1percent AUC by HPLC) of 5-fluoro-2,4-dichloro-pyrimidine as an amber oil. A molar solution of sodium hydroxide (1.34 L) was slowly added to a solution of the 5-fluoro-2,4-dichloro-pyrimidine (111.77 g, 0.67 mol) in THF (377 mL) at 0° C. After the reaction mixture was stirred for about 30 min at room temperature, the pH was adjusted to 6 by a slow addition of 1.0 M HCl. The aqueous solution was extracted with ethyl acetate (440 mL) to remove impurities following which the pH was adjusted to 1 with 1.0 M HCl. The acidic aqueous solution was extracted with ethyl acetate (4.x.555 mL) and the combined organic extracts were washed with brine (111 mL), dried over MgSO4 and concentrated under reduced pressure to produce 88.35 g (89percent, 99.2percent AUC by HPLC) of 2-chloro-5-fluoro-3H-pyrimidin-4-one as an off-white powder.
85%
for 1.66667 h; Reflux; Inert atmosphere
Intermediate Example 3 Preparation of 2, 4-Dichloro-5-fluoropyrimidine. To 5-fluorouracil (5.0 g, 0.04 mol) was added phosphorus oxychloride (25 mL, 0.27 mol) and N,N-diethylaniline (6 mL, 0.06 mol) while stirring at room temperature. After being heated under reflux for 100 min, the mixture was concentrated under reduced pressure. The residue was poured into ice water (100 mL) and extracted with ether. The organic layer was dried with sodium sulfate and evaporated at 0 °C under reduced pressure to give 5.35 g of the desired product (85percent). Mp 37-38 °C. HNMR: δ 8.95 (s, 1H).
84%
at 20℃; Reflux
To a stirred mixture of 5-fluoropyrimidine-2,4(1 H,3H)-dione (3.0 g, 23 mmol) and phosphorous pentachloride (14.41 g, 69 mmol) was added phosphorous oxychloride (12.6 mL, 130 mmol). The reaction mixture was heated to reflux, stirred 5 hours and then cooled to ambient temperature and stirred overnight. The mixture was carefully poured onto ice/water (600 mL) and stirred for 1 hour. Sodium chloride was added and the product was extracted into dichloromethane. The combined organic layer was dried (MgS0 ), filtered and evaporated to give the title compound (84percent) as a yellow solid.LRMS (m/z): 167 (M+1)+.1H-NMR δ (CDCI3): 8.49 (s, H)
84%
for 5 h; Reflux
5-fluoropyrimidine-2,4(1H,3H)-dione (3.0 g, 23 mmol) and phosphorous pentachloride (14.41 g, 69 mmol) was added phosphorous oxychloride (12.6 mL, 130 mmol). The reaction mixture was heated to reflux, stirred 5 hours and then cooled to ambient temperature and stirred overnight. The mixture was carefully poured onto ice/ water (600 mL) and stirred for 1 hour. Sodium chloride was added and the product was extracted into dichloromethane. The combined organic layer was dried (MgSO4), filtered and evaporated to give the title compound (84percent) as a yellow solid.LRMS (m/z): 167 (M+1)+.1H-NMR δ (CDCl3): 8.49 (s, 1 H)
84%
at 20℃; Reflux
PREPARATION 212,4-Dichloro-5-fluoropyrimidineTo a stirred mixture of 5-fluoropyrimidine-2,4(1 /-/,3/-/)-dione (3.0 g, 23 mmol) and phosphorous pentachloride (14.41 g, 69 mmol) was added phosphorous oxychloride (12.6 mL, 130 mmol). The reaction mixture was stirred and heated to reflux for 5 hours and then cooled to ambient temperature and stirred overnight. The mixture was carefully poured onto ice/water (600 mL) and then stirred for 1 hour. Sodium chloride was added and the product was extracted into dichloromethane. The combined organic layer was dried (MgS04), filtered and evaporated to give the title compound (84percent) as a yellow solid.LRMS (m/z): 167 (M+1 )+.1H-NMR δ (CDCIs): 8.49 (s, 1 H).
84%
for 5 h; Reflux
To a stirred mixture of 5-fluoropyrimidine-2,4(1H,3H)-dione (3.0 g, 23 mmol) and phosphorous pentachloride (14.41 g, 69 mmol) was added phosphorous oxychloride (12.6 mL, 130 mmol). The reaction mixture was heated to reflux, stirred 5 hours and then cooled to ambient temperature and stirred overnight. The mixture was carefully poured onto ice/water (600 mL) and stirred for 1 hour. Sodium chloride was added and the product was extracted into dichloromethane. The combined organic layer was dried (MgSO4), filtered and evaporated to give the title compound (84percent) as a yellow solid. LRMS(m/z): 167(M+1)+. 1H-NMR δ (CDCl3): 8.49 (s, 1H).
50%
for 3 h; Reflux
A mixture of 15.6 g of 5-FU [1] in 80 mL of POCl3 was stirred in a three neck-flask equipped with condenser, thermometer and dropping funnel at 40° C. After addition of 25 mL of N,N-dimethylaniline drop wise, the resulting mixture was heated to reflux for 3 hours. The excess of POCl3 was evaporated under reduced pressure. The mixture was cooled to room temperature and poured into 75 g of crushed ice. It was then extracted with chloroform (50 mL three times). The combined extracts were washed with water, dried with MgSO4, and concentrated to give a yellowish solid of compound [7] in about 50percent yield.
Reference：
[1] Patent: KR2016/69892, 2016, A, . Location in patent: Paragraph 0067-0070
[2] J. Gen. Chem. USSR (Engl. Transl.), 1992, vol. 62, # 6.2, p. 1122 - 1125[3] Zhurnal Obshchei Khimii, 1992, vol. 62, # 6, p. 1363 - 1366
[4] Patent: EP1506967, 2005, A1, . Location in patent: Page/Page column 67
[5] Patent: US2007/66636, 2007, A1, . Location in patent: Page/Page column 19; 20
[6] Patent: EP2311825, 2015, B1, . Location in patent: Paragraph 0162; 0163
[7] Patent: WO2011/76419, 2011, A1, . Location in patent: Page/Page column 112
[8] Patent: EP2338888, 2011, A1, . Location in patent: Paragraph 0144; 0145
[9] Patent: WO2013/17461, 2013, A1, . Location in patent: Page/Page column 82
[10] Patent: EP2554544, 2013, A1, . Location in patent: Paragraph 0153
[11] Patent: US9551724, 2017, B2, . Location in patent: Page/Page column 15; 16; 19
[12] Tetrahedron Letters, 1997, vol. 38, # 7, p. 1111 - 1114
[13] Nucleosides and Nucleotides, 1999, vol. 18, # 4-5, p. 635 - 636
[14] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 18, p. 2961 - 2966
[15] Patent: US2006/58525, 2006, A1, . Location in patent: Page/Page column 17-18
[16] Patent: US2002/165241, 2002, A1,
[17] Patent: US2002/165241, 2002, A1,
[18] Patent: US6586594, 2003, B1,
[19] Patent: US5998436, 1999, A,
[20] Patent: US5278175, 1994, A,
[21] Patent: WO2008/91681, 2008, A2, . Location in patent: Page/Page column 199; 235
[22] Patent: US2009/238808, 2009, A1,
[23] Patent: US2010/16298, 2010, A1, . Location in patent: Page/Page column 168
[24] Journal of Medicinal Chemistry, 2011, vol. 54, # 2, p. 510 - 524
[25] Bulletin of the Korean Chemical Society, 2013, vol. 34, # 5, p. 1349 - 1354
[26] Organic Process Research and Development, 2001, vol. 5, # 1, p. 28 - 36
[27] Patent: US2015/266828, 2015, A1, . Location in patent: Paragraph 0312
[28] Patent: CN106349169, 2017, A, . Location in patent: Paragraph 0013
7
[ 51-21-8 ]
[ 79-11-8 ]
[ 56059-30-4 ]
Yield
Reaction Conditions
Operation in experiment
60%
Stage #1: With potassium hydroxide In water at 100℃; for 1.33333 h; Stage #2: at 60℃; for 6 h;
FUAC was prepared as published in the literature [21], with some modifications. An aqueoussolution of KOH (0.60 g, 10.6 mmol, 10 mL) was added to 5-FU (1 g, 5.2 mmol). The reaction mixturewas stirred at 100 °C for 80 min. Then a solution of chloroacetic acid (84 mL, 0.5 g, 5.2 mmol) wasadded gradually in an oil bath at 60 °C and stirred for 6 h. The result was acidified by adding dilutedHCl to reach pH = 2 and cooled to 4 °C for 12 h. The precipitate formed was collected by filtration andredissolved in a saturated solution of KHCO3. Again, the solution was acidifying by diluted HCl toreach pH = 2 to get the needle-like crystals of FUAC (0.82 g, 60percent yield).
57%
Stage #1: With potassium hydroxide In water at 100℃; for 1.16667 h; Stage #2: at 60℃; for 6 h;
5-FUAC was synthesized according to previously described method (Sun et al., 2012) with some modification. 5-FU (0.5 g, 2.6 mmol) was dissolved completely in 5 ml aqueous solution of KOH (0.3 g, 5.3 mmol), and the reaction mixture was stirred at 100°C for 70 min. After that 4 ml of chloroacetic acid (0.25 g, 2.6 mmol) solution was added slowly and stirred in an oil bath under 60°C for 6 h. The product was acidified to pH 2 with HCl, followed by cooling 4°C for 12 h. Then, the precipitate was filtered and re-dissolved in a saturated KHCO3 solution, again acidified to pH 2 with HCl to obtain the needle-like crystals of 5-FUAC (Yield = 0.41 g, 57percent).
52.5%
With potassium hydroxide In water at 70℃; for 2 h;
A mixture of 5-fluorouracil (3) (5 g, 38.4 mmol), potassium hydroxide (9.07 g, 161.6 mmol) and chloroacetic acid (3.63 g, 38.4 mmol) in 100 mL of water was refluxed for 2h at 70°C. After cooling to room temperature, the pH of the solution was adjusted to 5.5 by the addition of concentrated hydrochloric acid. The reaction mixture was then kept in a refrigerator (5°C) for 18h and the resulting white crystals isolated by filtration and washed with cold water to produce 4 in 52.5percent yield. mp>200°C. H1 NMR (500 MHz, D2O) 7.76 (d, 1H, J=6 Hz, CH), 4.29 (s, 2H, CH2); C13 NMR (D2O): 173.58 (C=O), 159.97 (C=O), 150.80 (C=O), 141.20 (C), 131.74 (CH), 51.48 (CH2). ESMS (M-H+): Found 187.10, calculated for C6H5O4N2F=188.11.
40%
Stage #1: With sodium hydroxide In water for 2 h; Heating / reflux Stage #2: With hydrogenchloride In water
Dissolve 3.92 g of 5-FU and 3.65 g of sodium hydroxide (NaOH) in 22 ml of water, add 12 ml of aqueous solution of 3.30 g of chloroacetic acid, maintain at pH 10, reflux for 2 hr, acidify solution using concentrated HCl to obtain a light brown precipitate. Recrystallize it to obtain 2.26 g of white solid with a yield of 40percent.
40%
Stage #1: With sodium hydroxide In water for 2 h; Heating / reflux
Example 2 Dissolve 3.92 g of 5-FU and 3.65 g of sodium hydroxide (NaOH) in 22 ml of water, add 12 ml of aqueous solution of 3.30 g of chloroacetic acid, maintain at pH 10, reflux for 2 hr, and acidify the solution using concentrated HCl to obtain a light brown precipitate. Recrystallize it to obtain 2.26 g of white solid with a yield of 40percent. Dissolve 0.5 g of carob bean gum in 20 ml of DMSO, add 0.25 g of N,N'-dicyclohexylcarbodiimide (DCC) and 15 mg of 4-dimethylaminopyridine (DMAP), and then add 0.5 g of 5-Fu-1-acetic acid, stirring for 24 hr at 40° C. At completion, pour the reaction mixture into ethanol forming a jelly-like substance. Filter off the jelly-like substance, rinse it with methanol, and then dry under vacuum to obtain final product.
Reference：
[1] Chemical Communications, 2011, vol. 47, # 38, p. 10713 - 10715
[2] Medicinal Chemistry Research, 2007, vol. 16, # 7-9, p. 370 - 379
[3] Nucleosides, Nucleotides and Nucleic Acids, 2011, vol. 30, # 4, p. 280 - 292
[4] Chemical Communications, 2016, vol. 52, # 30, p. 5254 - 5257
[5] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 11, p. 2584 - 2588
[6] Chemistry - A European Journal, 2013, vol. 19, # 38, p. 12806 - 12814
[7] Molecules, 2017, vol. 22, # 11,
[8] Carbohydrate Polymers, 2017, vol. 157, p. 1442 - 1450
[9] Patent: WO2017/89800, 2017, A1, . Location in patent: Page/Page column 37; 39
[10] Patent: US2008/4237, 2008, A1, . Location in patent: Page/Page column 5; 9
[11] Patent: US2008/85871, 2008, A1, . Location in patent: Page/Page column 6-7
[12] Chemistry of Natural Compounds, 1994, vol. 30, # 5, p. 607 - 612[13] Khimiya Prirodnykh Soedinenii, 1994, # 5, p. 655 - 662
[14] Bulletin des Societes Chimiques Belges, 1995, vol. 104, # 3, p. 129 - 136
[15] Pharmazie, 2006, vol. 61, # 5, p. 489 - 490
[16] Molecules, 2010, vol. 15, # 4, p. 2114 - 2123
[17] Journal of the Brazilian Chemical Society, 2011, vol. 22, # 2, p. 308 - 318
[18] Natural Product Research, 2011, vol. 25, # 19, p. 1817 - 1826
[19] International Journal of Pharmaceutics, 2010, vol. 388, # 1-2, p. 95 - 100
[20] European Journal of Medicinal Chemistry, 2012, vol. 49, p. 48 - 54
[21] Chinese Chemical Letters, 2012, vol. 23, # 6, p. 677 - 680
[22] Carbohydrate Polymers, 2012, vol. 87, # 4, p. 2642 - 2647,6
[23] Patent: US2014/155577, 2014, A1, . Location in patent: Paragraph 0189
[24] Synthesis and Reactivity in Inorganic, Metal-Organic and Nano-Metal Chemistry, 2016, vol. 46, # 5, p. 653 - 658
[25] Patent: CN107892686, 2018, A, . Location in patent: Paragraph 0031-0034
8
[ 51-21-8 ]
[ 79-08-3 ]
[ 56059-30-4 ]
Yield
Reaction Conditions
Operation in experiment
85%
Stage #1: With potassium hydroxide In water at 40 - 60℃; for 5 h; Stage #2: With hydrogenchloride In waterCooling with ice
KOH (2.56 g, 45 mmol) and 5-fluorouracil (1.34 g, 10 mmol) dissolved in a clean flask, then 5 ml aqueous solution of bromoacetic acid (1.7 g, 18 mmol) was added under the temperature of 40 °C while stirred smoothly. The reaction mixture was stirred at 60 °C for 5 h and then cooled by ice-bath, adjusted to pH 5.5 with hydrochloric acid, after filtration through a membrane, the crude product was recrystallized by water, and compound 2 was obtained as white solid 1.53 g. Yield 85percent, mp 255-257 °C. 1H NMR (400 MHz, D2O): 4.41 (s, 2H, N-CH2), 7.54 (d, 1H, J = 5.2 Hz, 5-FU-H), ESI MS (m/z): calcd for 188.11. obsd 189.01 ([M+H]+)
72%
at 50℃;
5-FU (5-fluorouracil) and bromoacetic acid solution with a molar ratio of 1: 1.5 were added to the KOH solution, and after the reaction was completed at 50 ° C.,Cooled to room temperature, adjusted to pH 5.5 with concentrated hydrochloric acid, placed in the refrigerator for 2h, the precipitate was filtered off, plus concentrated hydrochloric acid to adjust the pH value of the solution to 2, placed in the freezer 6h,Filtered to obtain a solid material,That is, 5-fluorouracil-1-yl acetic acid, and the obtained yield was 72percent.
70%
With potassium hydroxide In water at 40℃; for 4 h;
5-FU (3.9 g, 30 mmol)was dissolved in KOH solution (9 ml, 5.7 mol/L), thenan aqueous solution of 2-bromoacetic acid (8 ml, 45 mmol) was added dropwiseat the temperature of 40 C. The mixture was stirred for approximately 4 h, until no free 5-FU was detectable by thin-layer chromatography. Thesolution was then transferred to anice-bath, and the pH was adjusted to 1.0with hydrochloric acid (10 mol/L) to obtain the crude product. Compound Iwas collected by filtration, washed with water for 3 times and then dried in 40 C as 3.95 g white solid with a yield of 70 percent (Ouyang et al. 2011). Compound I: 1H-NMR (400 MHz, D2O): 8.10–8.08 (d, 1H, J = 6.8 Hz),4.37 (s, 2H). ESI-MS (m/z): calcd for 188.11. obsd 187.01 ([M-H]+)
64.4%
With potassium hydroxide In water at 80℃; for 4 h;
Potassium hydroxide (19.2 g, 0.34 mol), water (80 mL) and 5-fluorouracil were sequentially added to a 250 mL jar.(13.0 g, 0.1 mol), stirring to dissolve it, then raising the temperature to 80° C., slowly adding dropwise bromoacetic acid (18.1 g, 0.13 mol).After completion of stirring for 4 hours, TLC showed that the reaction was complete, cooled to room temperature, adjusted to pH 2 with concentrated hydrochloric acid, and cooled on ice.However, solids precipitated and were filtered. The residue was recrystallized from hot water to give the product IIIa
Reference：
[1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 12, p. 3750 - 3756
[2] MedChemComm, 2016, vol. 7, # 10, p. 2016 - 2019
[3] Research on Chemical Intermediates, 2012, vol. 38, # 7, p. 1421 - 1429
[4] Patent: CN104672294, 2017, B, . Location in patent: Paragraph 0033; 0034; 0035; 0037; 0038
[5] Pharmazie, 2014, vol. 69, # 4, p. 271 - 276
[6] Chemical Communications, 2011, vol. 47, # 5, p. 1482 - 1484
[7] Patent: CN107698521, 2018, A, . Location in patent: Paragraph 0063; 0064; 0065
[8] Journal of Chemical Crystallography, 2008, vol. 38, # 11, p. 807 - 813
[9] Journal of Chemical Research, 2009, # 4, p. 261 - 264
[10] Letters in Organic Chemistry, 2013, vol. 10, # 8, p. 594 - 601
[11] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 1235 - 1246
[12] MedChemComm, 2017, vol. 8, # 2, p. 385 - 389
9
[ 51-21-8 ]
[ 105-36-2 ]
[ 56059-30-4 ]
Yield
Reaction Conditions
Operation in experiment
38.7%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1 h; Cooling with ice Stage #2: for 2 h; Stage #3: With sodium hydroxide In water at 20℃; for 1 h;
Add 5 mL of anhydrous solvent N,N-dimethylformamide (DMF) to a 25 mL eggplant-shaped flask, and slowly add 5-fluorouracil(1.05 g, 8.0 mmol, Beijing Coupling Technology Co., Ltd.) under stirring, and mix well. After being placed in an ice bath, sodium hydride (0.23 g, 9.6 mmol) was slowly added portion wise, and the mixture was transferred to room temperature for 1 hour, andethyl bromoacetate (1.60 g, 9.6 mmol) was slowly added dropwise, and the reaction was continued for 2 h. Filtration, washed three times with water (5×3 mL), the filtrate was combined, 0.96 g of sodium hydroxide (24.0 mmol) was added, and the mixturewas stirred at room temperature for 1 h, placed in an ice bath, adjusted to pH 3.0 with 4M HCl, and stirred for 30 min. Themixture was allowed to stand, suction filtered, and the filter cake was washed with water and dried to give the object product white powder solid, intermediate 6 (0.58 g, 38.7percent). LC-MS (ESI, M-H ) m/z 187.4.
Reference：
[1] Patent: CN108558883, 2018, A, . Location in patent: Paragraph 0070; 0183; 0184
10
[ 51-21-8 ]
[ 3926-62-3 ]
[ 84568-51-4 ]
[ 56059-30-4 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1982, vol. 47, # 10, p. 2806 - 2813
Example 16 N4-[(trans-4-aminocyclohexyl)methyl]-5-fluoro-N2-[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine Phosphorous pentachloride (8.0 g, 38.4 mmol) was added to a mixture of 5-fluorouracil (10.0 g, 76.9 mmol) and phosphorous oxychloride (30 mL). The reaction mixture was heated at reflux, for 14 h, under N2. The reaction mixture was cooled to room temperature and then poured into ice. The remaining residue from the flask was dissolved in saturated Na2CO3 and poured into the ice mixture. The mixture was extracted with EtOAc (*3) and the organic phase was dried over anhydrous Na2SO4. The solution was concentrated in vacuo to yield 9.1 g (71percent) of 5-fluoro-2,4-dichloropyridine as a pale yellow oil.
With pyridine; phosphorus pentaoxide; In chloroform;
EXAMPLE 10 In a sealed tube, 780 mg (6 m mole) of 5-fluorouracil, 5 ml of pyridine, 100 mg (0.70 m mole) of phosphorus pentoxide and 1.26 g (18 m mole) of 2,3-dihydrofuran were heated at 100 C for 17 hours. After the reaction, pyridine was distilled off from the reaction mixture under a reduced pressure. The residue was dissolved in chloroform and the insoluble unreacted 5-fluorouracil was separated by a filtration and the residue was purified by a column chromatography using a silica gel column (mixture of benzene; ethyl acetate and acetone = 2: 1: 1 (V/V) as a developing medium) to obtained 200 mg of N1,N3 -bis(2-tetrahydrofuryl)-5-fluorouracil (yield: 12.3%) and 757.6 mg of N1 -(2-tetrahydrofuryl)-5-fluorouracil (yield: 63.0%). The former product was recrystallized from ether to obtain a purified product having a melting point of 99 to 101 C.
With potassium carbonate; sodium iodide In dimethyl sulfoxide at 80 - 85℃;
Synthesis of 1,3-dipropargyl-5-fluorouracil (9):
To astirred mixture of 5-fluorouracil (5) (1.3 g, 10 mmol) in DMSO (25 mL), was added potassium carbonate (1.38 g, 10mmol), sodium iodide (0,3 g, 2 mmol) and propargyl bromide(2.38 g, 20 mmol). The reaction mixture was stirred ina bath at 80 - 85 °C for 2 h. The mixture was cooled, diluted with water (150 mL) and then extracted with dichloromethane (3 20 mL). The organic layer was washed with water (30 mL) and brine (30 mL), and then dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure to give crude of 1,3-dipropargyl-5-fluorouracil (9),that was purified by flash chromatography (5% MeOH inCHCl3). 1,3-Dipropargyl-5-fluorouracil (9): Yield 53% (whitepowder); mp: 94-96 °C; ESI-MS [M+H]+: 207.85; IR (KBr, (cm-1)): 3279 (C-Halkyne), 2997 (C-H), 1715-1655 (C=O),2110 (CC). 1H-NMR (DMSO-d6, 500 MHz, ppm) 8.25 (d,J = 6.0 Hz, 1H, H-6), 4.56 (t, J = 2.5 Hz, 4H, 1-CH2-, 3-CH2-), 3.43 (t, J = 2.5 Hz, 1H, 1-CH2-CCH), 3.13 (t, J = 2.5 Hz,1H, 3-CH2-CCH). 13C-NMR (DMSO-d6, 125 MHz, ppm) 155.8 (C-4), 148.4 (C-2), 139.1 (C-5), 128.2 (C-6), 78.3 (3-CH2-CCH), 77.8 (1-CH2-CCH), 76.5 (1-CH2-CCH),73.4 (3-CH2-CCH), 30.7 (1-CH2-, 3-CH2-).
51%
Stage #1: 5-fluorouracil With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h;
Stage #2: propargyl bromide In N,N-dimethyl-formamide at 20℃; for 1.5h;
Synthesis of dipropargyl substituted 5-FU 11
To a stirred solution of 5-FU (100mg, 0.77mmol, 1.0eq) in DMF (10mL) was added K2CO3 (106mg, 0.77mmol, 1.0eq) at room temperature. 30min later, propargyl bromide (184μL, 2.31mmol, 3.0eq) was added to the above solution. The mixture was stirred at room temperature for 1.5h. Upon completion, EtOAc and H2O were added, the aqueous layer was extracted with EtOAc, the combined organic layers were washed with H2O for several times to remove the DMF, and the organic layers were washed with brine, dried over MgSO4 and evaporated to give the residue, which was recrystallized from EtOH (2mL) to give the product, white solid, yield: 51%, m. p.: 96.3-97.8°C, Rf=0.33 (petroleum ether/acetone=2/1). 1H NMR (400MHz, CDCl3) δ 7.63 (d, JC-F=5.3Hz, 1H), 4.76 (d, J=2.3Hz, 2H), 4.64 (d, J=2.5Hz, 2H), 2.59 (t, J=2.6Hz, 1H), 2.23 (t, J=2.4Hz, 1H).13C NMR (100MHz, CDCl3) δ 156.08 (d, JC-F=26.1Hz), 148.83, 140.18 (d, JC-F=237.4Hz), 125.16 (d, JC-F=33.6Hz), 77.13, 76.69, 75.33, 71.41, 38.07, 31.17
Stage #1: 5-fluorouracil With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.25h;
Stage #2: propargyl bromide In N,N-dimethyl-formamide at 20℃; for 6h;
Typical procedure for the synthesis of 1,3-dipropargylated uracils
General procedure: To a well stirred suspension of potassium carbonate (4 mmol) in dry DMF was added substituted uracil (1 mmol). The resulting suspension was stirred for 15 min at room temperature followed by the addition of (2.2 mmol) propargyl bromide. The reaction was stirred at room temperature for 6e7 h and the progress was monitored using TLC. The reaction mixture on completion was treated with brine solution and extracted with (2 50 mL) ethyl acetate. The organic layers were combined, dried over anhyd. sodium sulfate and concentrated under reduced pressure. The crude product was purified with column chromatography using a (65:35) mixture of hexane: ethyl acetate to yield the desired precursor 2.
With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 4 - 20℃; Inert atmosphere;
Synthesis of 1,3-dipropargy-5-fluorouracil (7)
5-Fuoruouracil (100 mg, 0.8 mmol) and DBU (345 p1, 2,3 mmol) were dissolved in dry DMF (2 ml) under a nitrogen atmosphere, and the mixture was cooled down to 4 “C in an ice bath. Propargyl bromide (170 p1, 1.6 mmol) was added dropwise and the reaction mixture allowed to warm up to room temperature. The mixture was stirred overnight, the solvents removed in vacuo and the resulting crude purified via flash chromatography (eluent: 1.5% MeCH in DCM), to yield compounds 7 as a colourless soNd (136 mg, 86 %). ‘H NMR (500 MHz, CDCI3) 6 7.60 (d, J = 5.3, IH), 4.72 (d, J = 2,4, 2H), 4.61 (d, J =2.6, 21-fl, 2.56(t, J= 2,6, 1H), 2.20 (t, J= 2.5, IH). 13C NMR (126 MHz, CDC13) 6156.19 (d, J = 26.0, C), 148.92, 140.26 (d, J = 237.3, C), 125.33 (d, J = 33.7, CH), 77.24, 76.74 (CH), 75.47, 71.51 (CH), 38.18 (CH2), 31 .27 (CH2). MS(ES1)m/z 435.2 [2M÷Na].
In N,N-dimethyl-formamide at 0 - 20℃; Alkaline conditions;
With glucose-6-phosphate dehydrogenase; glucose-6-phosphate; CYP2A6.1, wild-type; NADP; magnesium chloride; In aq. buffer; at 37℃;pH 7.4;Enzymatic reaction;Kinetics;
General procedure: For determining kinetic parameters, FT, coumarin, andnicotine concentrations varied in ranges between 0.03 and 10 mM, 0.1 and 30,and 3 and 500 mM, respectively. All reactions were performed in a linear rangeof the metabolite formation with respect to enzyme amount and incubationtime. Kinetic parameters were estimated by fitting the data to eq. 1 (monophasickinetics) or eq. 2 (biphasic kinetics):V Vmax S=Km S 1V Vmax1 S=Km1 S Vmax2 S=Km2 S 2where V is metabolite formation rate; S is substrate concentration in theincubation mixture; Km1 and Km2 are Michaelis-Menten constants for high- andlow-affinity phases, respectively; and Vmax1 and Vmax2 are maximum velocitiesfor high- and low-affinity phases, respectively
With C19XeF6 In dichloromethane for 24h; Ambient temperature;
89.4%
With fluorine; trifluoroacetic acid at -10℃; Inert atmosphere;
1
(Figure 1) corning straight channel module 1 (as premix preheat module), corning "heart" microchannel reaction module 6, corning straight channel module 1 (as quenching module) and heat transfer module 8 , And the continuous flow microchannel reaction system is composed according to the reaction flow shown in Fig. The reaction heat transfer medium is made of heat transfer oil. According to the principle of forced heat transfer of microchannel reactor, only two temperature measurement points are set in the inlet and outlet of the reactor. Before the reaction, the microchannel reaction system and the connecting pipeline were treated by dewatering and degreasing respectively. The system and the connecting line were passivated with 5mol% fluorine and nitrogen gas mixture to carry out the airtightness check of 1.0MPa. The uracil solution (i.e., a mixture of uracil and anhydrous hydrofluoric acid, and the concentration of uracil 7%) was continuously added to the microchannel reaction system by the 1-liquid chestnut (Fig. 3). With the gas mass flow meter of Fig. 3, A 20 mol% fluorine-nitrogen mixed gas was continuously added to the microchannel reaction system.Set the heat exchanger temperature 0 ° C, ie the reaction temperature. Set the reaction pressure 0. IMPa. The molar ratio of fluorine gas to uracil was 1.2: 1, and the molar ratio of fluorine gas to uracil was 1.2: 1. The reaction mixture was heated into the "heart-shaped" microchannel reaction module 4 by the microchannel pre-heating module 3 and the fluorine-nitrogen mixed gas was directly introduced into the "heart-shaped" microchannel reaction module 4 through the gas mass flow meter. Heart-shaped "microchannel reaction module 4-9, the fluorine-nitrogen mixture reacts with uracil. The crude reaction product is separated by a gas-liquid separator after quenching the module 10 and then treated by a system and dried to obtain a 5-fluorouracil product. The reaction product was analyzed by liquid chromatography. The results showed that the purity of 5-fluorouracil reached 98.6% and the product yield was 86.7%. The same Corning microchannel reactor was used as in Example 1, and the same connection method and control method were used. This example changes the reaction conditions.Set the heat exchanger temperature -10 ° C, ie the reaction temperature. Set the reaction pressure 0. 3MPa. The reaction material 2 is a uracil solution, i.e., a mixture of uracil and trifluoroacetic acid, with a mass concentration of uracil of 7% and a feed rate of 50 g / min. The raw material 1 is 20 mol% of the fluorine-nitrogen mixed gas, and the feed rate is 4. 2 L / min. The molar ratio of fluorine to uracil is 1. 2: 1. Reaction of raw materials 2 uracil solution through the micro-channel pre-mixed preheating module 3 into the "heart-shaped" micro-channel reaction module 4, fluorine nitrogen mixture through the gas mass flow meter directly into the micro-channel reaction module 4, in the "heart" micro In the channel reaction module 4-9, the fluorine-nitrogen mixture reacts with uracil. The crude reaction product is separated by a gas-liquid separator after quenching the module 10 and then treated by a system and dried to obtain a 5-fluorouracil product. The reaction product was analyzed by liquid chromatography, the purity of 5-fluorouracil reached 99. 2%, the product yield 89. 4%.
81.4%
7 EXAMPLE 7
EXAMPLE 7 This example is the same as Example 2 except that 1.001 grams of uracil were used, the reaction temperature was maintained at 5° C., and heating was effected for 4 hours to yield 0.946 gram of 5-fluorouracil with a yield of 81.4%.
81.3%
9 EXAMPLE 9
EXAMPLE 9 This example was carried out as in Example 2 except that 1.000 gram of uracil were used, the reaction temperature was 5° C., and the heat treatment was at 60° C. for 2.5 hours. 0.943 gram of 5-fluorouracil, were obtained with a yield of 81.3%.
75.6%
In water
2 EXAMPLE 2
The Teflon beaker containing the slurry of uracil was placed in a 1 l separable flash (1.4 l of total inner volume) equipped with a gas introducing inlet. The separable flask was evacuated using a vacuum pump, while it was cooled with ice water. After the evacuation, the fluorination of uracil was carried out by introducing elemental fluorine diluted to 20% concentration with helium into the separable flask until the pressure within the flask reached 0 kg/cm2 gauge and by maintaining the temperature of the flask at 15° C. and stirring the slurry with a magnetic stirrer for 8 hours. After completion of fluorination, the Teflon beaker was removed from the separable flask and it was heat-treated at 100° C. for 1 hour. Thereafter, the beaker was allowed to cool to room temperature and precipitated crystals were filtered off. The crystals thus obtained were recrystallized using water as the solvent to obtain 0.879 gram of 5-fluorouracil with a yield of 75.6%.
71.8%
4 EXAMPLE 4
EXAMPLE 4 This example was carried out as in Example 2 except that 1.003 grams of uracil were used, the reaction temperature was maintained at 0° C., and the reaction was carried out for 24 hours, to yield 0.836 gram of 5-fluorouracil. The yield was 71.8%.
71.9%
With phosphoric acid
6 EXAMPLE 6
EXAMPLE 6 This example is the same as Example 5, except that 0.999 gram of uracil were used, to which were added 4.5 ml of 90% aqueous phosphoric acid, the reaction temperature was kept to 5° C., and the reaction continued for 8 hours to yield 0.834 gram of 5-fluorouracil with a yield of 71.9%.
67.5%
5 EXAMPLE 5
EXAMPLE 5 This example is the same as Example 4 except that 0.998 gram of uracil were used, the reaction temperature was maintained at 20° C., and the reaction continued for 4 hours to yield 0.782 gram of 5-fluorouracil with a yield of 67.5%.
1 EXAMPLE 1
EXAMPLE 1 Into a 500 -ml., 3-neck flask, equipped with a magnetic stirrer, a monel bubbler, and a gas outlet tube leading to a 5% KI indicator solution, was placed 7.34 g. (65mM) of uracil and 250 ml. of distilled water. A tared cylinder of fluorine and a cylinder of nitrogen were connected to the inlet tube. At room temperature, while stirring the uracil dispersion, a mixture of fluorine and notrogen, about equal volumes, was added at a rate of 6.7 g. of fluorine/hr. During addition the temperature of the reaction mixture rose to about 50° and after 5 g. (131 mM) of fluorine was added no dispersed solids remained. Evaporation of the reaction mixture gave 7 g. of crude product which on sublimation at 190°/0. 1mm pressure gave 3 g. (23 mM), 35.7% yield, of 5-fluorouracil, m.p. 280°-282°(Lit. value 281°-282°).
With purine nucleoside phosphorylase; uridine phosphorylase; In aq. phosphate buffer; dimethyl sulfoxide; at 80℃; for 3h;Enzymatic reaction;
5-Fluoruracil nucleosides were prepared as previously described above. One ml catalyst (cell lysate) withtransglycosylation activity of about 12 units/ml cell lysate was added to 150 ml of a solution kept thermostatically at 80C and having the following composition:- 7.5mM uridine/2?-Deoxyuridine,- 2.5mM 5-fluorouracil, and- 30 mM potassium phosphate buffer, pH 7.[0091] After 3 hour at 80 C, the reaction mixture was filtered by centrifugation at 2000 3g for 30 min, at 4C, throughTable 4. Production yields of 2,6-Diaminopurine nucleosides at different temperatures without use organic co-solvents.Temperature (C) 80 90 100Biotransformation (%) 79.3 79.6 81.1Amicon ultra-4 Centrifugal Filter Devices (Millipore, Bedford, MA) with a 3000-Da cut-off, and the filtrate was recovered.The bioconversion yield of the reaction was higher than 50%. The resulting 5-fluoruracil nucleosides (5-fluorouridineand 5-fluoro-2?-deoxyuridine) were analyzed by HPLC.
Weigh 10.07 g of 5-fluorouracil (77.41 mmol) in a 250 ml round bottom bottle.Then add 13.03g KOH (0.23mol) and add a small amount of water.After the reaction at 100 C for half an hour, the temperature dropped to 60 C.Weigh 10.97 g of chloroacetic acid (0.12 mol), dissolve it with a small amount of water, slowly drop it into the original bottom bottle in a dropping funnel, and react for 6 hours. After the reaction is finished, adjust the pH to 5.0 with hydrochloric acid and cool at 4 C for 4 hours. Filter with a sand core funnel, remove the precipitate, adjust the pH to 2.0 with hydrochloric acid, cool in the refrigerator overnight, collect the precipitate, adjust the pH to 5.0 with saturated NaHCO3, cool for 4 hours, filter, adjust the pH to 2.0 with hydrochloric acid. The mixture was placed in a refrigerator, and the precipitate was collected and dried in a vacuum oven to obtain 14.3 g of a white solid product in a yield of 85.1%. The white solid was examined by 1H NMR and 13C NMR, and the spectrum is shown in Fig. 1,
82%
With potassium hydroxide; In water; at 100℃; for 2h;
An aqueous solution of chloroacetic acid (1.1 eq in 4ml of water)was added dropwise to a solution of 5-fluorouracil 1 (1.0 g, 1.0 eq)and KOH (3.0 eq) in water (4 ml) at 100 C. The reaction mixturewas stirred for 2h at the same temperature, then cooled to r.t. andacidified to pH 2. The formed precipitate was collected by filtrationandwashed withwater and Et2O. The crude solidwas recrystallizedfrom the minimum amount of water to obtain the titled compoundas a white powder. 82% yield; m.p. 280e282 C; silica gel TLC Rf 0.05(MeOH/CHCl3 10% v/v); dH (400 MHz, DMSO-d6): 13.29 (s, 1H, exchangewith D2O, COOH), 11.96 (s, 1H, exchange with D2O, CONHCO),8.12 (d, J 6.7 Hz, 1H, AreH), 4.40 (s, 2H, CH2); dC (100 MHz,DMSO-d6): 170.32, 158.51 (d, J2 CF 25.8 Hz), 150.72, 140.38 (d, J2CF 228.9 Hz), 131.56 (d, J2 CF 33.9 Hz), 49.70; dF (376 MHz,DMSO-d6): 170.04 (s); m/z (ESI negative) calcd for C6H4FN2O4[M H]- 187.0, found 186.9.
60%
FUAC was prepared as published in the literature [21], with some modifications. An aqueoussolution of KOH (0.60 g, 10.6 mmol, 10 mL) was added to 5-FU (1 g, 5.2 mmol). The reaction mixturewas stirred at 100 C for 80 min. Then a solution of chloroacetic acid (84 mL, 0.5 g, 5.2 mmol) wasadded gradually in an oil bath at 60 C and stirred for 6 h. The result was acidified by adding dilutedHCl to reach pH = 2 and cooled to 4 C for 12 h. The precipitate formed was collected by filtration andredissolved in a saturated solution of KHCO3. Again, the solution was acidifying by diluted HCl toreach pH = 2 to get the needle-like crystals of FUAC (0.82 g, 60% yield).
57%
5-FUAC was synthesized according to previously described method (Sun et al., 2012) with some modification. 5-FU (0.5 g, 2.6 mmol) was dissolved completely in 5 ml aqueous solution of KOH (0.3 g, 5.3 mmol), and the reaction mixture was stirred at 100C for 70 min. After that 4 ml of chloroacetic acid (0.25 g, 2.6 mmol) solution was added slowly and stirred in an oil bath under 60C for 6 h. The product was acidified to pH 2 with HCl, followed by cooling 4C for 12 h. Then, the precipitate was filtered and re-dissolved in a saturated KHCO3 solution, again acidified to pH 2 with HCl to obtain the needle-like crystals of 5-FUAC (Yield = 0.41 g, 57%).
52.5%
With potassium hydroxide; In water; at 70℃; for 2h;
A mixture of 5-fluorouracil (3) (5 g, 38.4 mmol), potassium hydroxide (9.07 g, 161.6 mmol) and chloroacetic acid (3.63 g, 38.4 mmol) in 100 mL of water was refluxed for 2h at 70C. After cooling to room temperature, the pH of the solution was adjusted to 5.5 by the addition of concentrated hydrochloric acid. The reaction mixture was then kept in a refrigerator (5C) for 18h and the resulting white crystals isolated by filtration and washed with cold water to produce 4 in 52.5% yield. mp>200C. H1 NMR (500 MHz, D2O) 7.76 (d, 1H, J=6 Hz, CH), 4.29 (s, 2H, CH2); C13 NMR (D2O): 173.58 (C=O), 159.97 (C=O), 150.80 (C=O), 141.20 (C), 131.74 (CH), 51.48 (CH2). ESMS (M-H+): Found 187.10, calculated for C6H5O4N2F=188.11.
~ 40%
Dissolve 3.92 g of 5-FU and 3.65 g of sodium hydroxide (NaOH) in 22 ml of water, add 12 ml of aqueous solution of 3.30 g of chloroacetic acid, maintain at pH 10, reflux for 2 hr, acidify solution using concentrated HCl to obtain a light brown precipitate. Recrystallize it to obtain 2.26 g of white solid with a yield of 40%.
~ 40%
Example 2 Dissolve 3.92 g of 5-FU and 3.65 g of sodium hydroxide (NaOH) in 22 ml of water, add 12 ml of aqueous solution of 3.30 g of chloroacetic acid, maintain at pH 10, reflux for 2 hr, and acidify the solution using concentrated HCl to obtain a light brown precipitate. Recrystallize it to obtain 2.26 g of white solid with a yield of 40%. Dissolve 0.5 g of carob bean gum in 20 ml of DMSO, add 0.25 g of N,N'-dicyclohexylcarbodiimide (DCC) and 15 mg of 4-dimethylaminopyridine (DMAP), and then add 0.5 g of 5-Fu-1-acetic acid, stirring for 24 hr at 40 C. At completion, pour the reaction mixture into ethanol forming a jelly-like substance. Filter off the jelly-like substance, rinse it with methanol, and then dry under vacuum to obtain final product.
Into a solution of 5-fluorouracil (6.5 g, 50 mmol) and potassium hydroxide (5.6 g, 100 mmol) in water (40 mL) was added the solution of chloroacetic acid (4.75 g, 50 mmol) in water (20 mL) and stirred for 30 min at room temperature. The pH value of the reaction mixture was adjusted to, and kept at 10 by the drop-by-drop addition of a 10% potassium hydroxide aqueous solution. The mixture was then refluxed for 2 h, cooled, and acidified to pH 2 by the addition of concentrated hydrochloric acid and the crystals of 10 were isolated by suction. Recrystallization was completed by dissolving the product in the saturated aqueous sodium bicarbonate and reprecipitated with concentrated hydrochloric acid to result in white needles.
Unlike the previously reported method (Tada, 1975), we developed an improved synthetic approach in which 5-fluorouracil (1.54 g) was dissolved in KOH (2.564 g) aqueous solution (8.0 ml) at 50 C for 30 min. Chloroacetic acid (1.7 g) was then added to the solution slowly over 30 min, and the mixture was stirred at 60 C. The reaction was monitored by fluorescence thin-layer chromatography. After 5 h, the reaction solution was cooled to room temperature, and then hydrochloric acid was added to adjust pH to 5.5, followed by cooling to 4 C for 2 h. Unreacted 5-fluorouracil was removed by filtration. More hydrochloric acid was added to adjust the pH to 2, followed by cooling for 12 h. Then, the formed precipitate was filtered, and washed with distilled water three times. After crystallization, needle-like crystals were obtained after drying. The melting point was determined using an X-2 micromelting point apparatus.
With potassium hydroxide;
Two 5-Fluorouracil (5-Fu) peptide conjugates were synthesized using two different linkages, amide and ester, to connect 5-Fu with dipeptide. For amide linkage, a 5-Fu acetic acid linker was synthesized by reacting 5-Fu with chloroacetic acid in KOH solution. For the ester linkage, 5-Fu succinic acid was synthesized by reacting 1,3-dimethylol-5-fluorouracil with benzyl succinate. The benzyl protecting group was removed later with 10% Pd/C and H2. Both 5-Fu derivatives were reacted with lysine amine side chain to form amide or ester bond using the standard amide formation method (HBTU, DIPEA). The peptide synthesis achieved manually with Fmoc/t-Bu solid-phase peptide synthesis on rink amide resin and was purified by RP-HPLC. The synthesis scheme is shown below:
With potassium hydroxide; In water; at 60℃; for 5h;
5-Fluorouracil (1.56 g) was dissolved in a solution of KOH(2.56 g) in water (8 mL), then a solution of chloroacetic acid(1.7 g) in water (4 mL) was added dropwise at 60C. The reaction mixture was stirred at 60C for 5 h. After that, an excessof concentrated hydrochloric acid was added to make thesolution acidic and a white precipitate appeared at the sametime, then cooled in the refrigerator for 2 h to get more whiteprecipitate. The white precipitate was collected and dissolvedin excessive ethanol. A few drops of concentrated sulfuric acidwas added as a catalyst and the mixture was refluxed for 10 h.the solvent was evaporated and the residue was taken up in amixture of ethyl acetate/water (1:1; 300 mL). The organiclayer was isolated, and washed with several portions of water.Evaporation of the organic layer gave the product as a whitesolid. Yield: 53.6%. m.p. 162C.1H NMR (200 MHzCD3COCD3): 1.25-1.32 (t, JD7.2Hz, 3H,CH3), 4.19-4.29(q, J D 7.0 Hz, 2H, CH2), 4.58 (s, 2H,COCH2N), 7.90-7.93 (d, JD6.0 Hz, 1H, FluH).
With potassium hydroxide; In water; at 60℃; for 5h;
First, 1.6 g of 5-fluorouracil and 10% by weight aqueous alkali solution were added to a three-necked flask equipped with a reflux condenser and magnetic stirring.Then add 4ml of 0.525g/mL chloroacetic acid solution slowly to the three-necked flask. After the addition is complete, heat and stir in a water bath at 60C for 5h. After the reaction is complete, the reaction solution is cooled to room temperature and the pH is adjusted to 2 and then Placed in a refrigerator at 4C overnight, suction filtration, drying to obtain needle-like crystal 5-fluorouracil-1-acetic acid
With potassium hydroxide; at 100℃; for 2h;pH 10;
Compound c was synthesized according to a published procedure (Liu, et al., 2006). Briefly, alpha-chloroacetic acid was added to a solution of 5-FU in potassium hydroxide at pH 10 and stirred for 2 hours at 100 C. After cooling to room temperature, the reaction was acidified to pH 2 with HCl to form a precipitate. The precipitate was filtered, dissolved in saturated potassium hydrogen carbonate, and again acidified to pH with HCl. The precipitate was filtered and dried to produce the expected product with good yield.
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile for 1.5h; Inert atmosphere; Reflux;
4.1.5. Synthesis of 5-fluoro-1-(prop-2-yn-1-yl)pyrimidine-2,4(1H,3H)-dione 7
Propargyl bromide (1.0 eq) was added dropwise to a solution of5-fluorouracil 1 (0.5 g, 1.0 eq) and DBU (1.0 eq) in dry CH3CN (7 ml)at 0 C under a nitrogen atmosphere. The reaction mixture wasrefluxed for 1.5h, then quenched with HCl(aq) 1M (15 ml) andextracted with EtOAc (25 ml). The organic layer was dried overNa2SO4, filtered-off and concentrated under vacuo to give a residuethat was purified by silica gel coloumn chromatography elutingwith 40% EtOAc in n-hexane to afford the title compound 7 as whitesolid. 63% yield; m.p. 140e142 C; silica gel TLC Rf 0.20 (EtOAc/nhexane40% v/v); dH (400 MHz, DMSO-d6): 11.92 (s, 1H, exchangewith D2O, CONHCO), 8.17 (d, J 6.6 Hz, 1H, AreH), 4.49 (d,J 2.3 Hz, 2H, CH2), 3.48 (t, J 2.3 Hz, 1H, CH); dC (100 MHz,DMSO-d6): 158.40 (d, J2 CF 25.9 Hz), 150.12, 140.87 (d, J2CF 230.5 Hz), 129.96 (d, J2 CF 33.9 Hz), 79.18, 77.18, 38.05; dF(376 MHz, DMSO-d6): 168.41; m/z (ESI negative) calcd forC7H4FN2O2 [M H]- 167.0, found 167.1.
52%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h;
52%
With potassium carbonate In acetonitrile for 3.5h; Reflux; regioselective reaction;
40%
Stage #1: 5-fluorouracil With potassium carbonate In N,N-dimethyl-formamide for 0.5h;
Stage #2: propargyl bromide In N,N-dimethyl-formamide at 50℃;
General procedure for the syntheses of propargylated nucleobases
General procedure: To a stirred suspension of nucleobase (uracil, thymine, 5-fluorouracil and adenine,1.0 eq.) in anhydrous DMF, K2CO3 (1.0 eq.) was added and stirred for 30 min. Thenpropargyl bromide (1.1 eq.) was added to this mixture and allowed to stir at 50°Cfor 8-12 hours with the assistance of TLC (CH2Cl2:MeOH, 9:0.4) control. After theremoval of the solvent by evaporating under reduced pressure, the residue was puri-ed by silica gel column chromatography and aorded the pure monopropynylatedproducts (a-d).[44]
40%
With potassium carbonate In N,N-dimethyl-formamide; toluene at 50℃;
39%
Stage #1: 5-fluorouracil With potassium carbonate In N,N-dimethyl-formamide for 0.5h;
Stage #2: propargyl bromide In N,N-dimethyl-formamide at 50℃; for 12h;
31%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 6h; Inert atmosphere;
27%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide; toluene at 20℃; for 20h; Inert atmosphere;
With potassium carbonate In N,N-dimethyl-formamide Ambient temperature;
With potassium carbonate In N,N-dimethyl-formamide
Stage #1: 5-fluorouracil With sodium hydride In N,N-dimethyl-formamide for 0.25h;
Stage #2: propargyl bromide In N,N-dimethyl-formamide at 20℃;
With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 4 - 20℃; Inert atmosphere;
1 General method for synthesis of 5-FU prodrugs from 5-FU
General procedure: DBU (276 p1, 1.85 mmol, 1.2 equiv.) and 5-FU (200 mg, 1.54 mmol, I equiv.) were dissolved in dry DMF (2 ml) under N2 atmosphere and cooled to 4 Cc. Either allyl, propargyl or benzyl bromide (1.54 mmol, I equiv.) were dissolved in dry DMF (0.5 ml). The solution was added dropwise to the mixture and the resulting mixture stirred at room temperature overnight. Solvents were then removed under reduced pressure and the crude purified via flash chromatography (3 % MeOH in DCM).
Stage #1: 5-fluorouracil With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 20℃; for 0.5h;
Stage #2: propargyl bromide at 20℃;
With potassium carbonate In N,N-dimethyl-formamide
With dmap In acetonitrile at 20℃; for 19h; Inert atmosphere;
92%
With dmap In acetonitrile at 20℃; for 3h;
78%
With dmap
68%
With dmap In acetonitrile at 20℃; for 4h;
40%
With dmap In N,N-dimethyl-formamide; acetonitrile at 20℃;
5-Fluoruouracil (100 mg, 0.77 mmol) was dissolved in a 2:1 mixture of acetonitrile and DMF (3 ml). Boc2O (252 mg, 1.16 mmol) and DMAP (19 mg, 0.15 mmd) were subsequently added to the mixture and stirred overnight at room temperature. the solvents removed in vacuo and the resulting crude purified via flash chromatography (eluent: hexanel EtOAc 3:1), to yield compound 4 as a white solid (70 mg, 40 %). ‘H
With triethylamine In N,N-dimethyl-formamide at 60℃;
91%
With tetrabutylammomium bromide; zinc(II) oxide at 100℃; for 0.416667h; microwave irradiation;
90%
With tetrabutylammomium bromide at 100℃; for 0.35h; Microwave irradiation; Neat (no solvent);
81%
With 1,4-diaza-bicyclo[2.2.2]octane; tetrabutylammomium bromide for 0.1h; microwave irradiation;
75%
With triethylamine In N,N-dimethyl-formamide for 36h;
20.1
[00592] STEP-1: To a solution of 5-fluorouracil 1 (650mg, 5mmol) in anhydrous DMF (8mL), triethylamine (ioomg, immol) was added while stirring. After 5mm, methyl acrylate 2 (ig, i0mmol) was added dropwise. Stirring was continued for 36h. The solvent was evaporated under reduced pressure, and the residue was purified on chromatographic column (95:5 CH2C12/ MeOH) to give compound 3 (860mg, 75%).
75%
With triethylamine In N,N-dimethyl-formamide for 36h;
20.1 STEP-1:
To a solution of 5-fluorouracil 1 (650mg, 5mmol) in anhydrous DMF (8mL), triethylamine (lOOmg, lmmol) was added while stirring. After 5min, methyl acrylate 2 (lg, lOmmol) was added dropwise. Stirring was continued for 36h. The solvent was evaporated under reduced pressure, and the residue was purified on chromatographic column (95:5 CH2C12/ MeOH) to give compound 3 (860mg, 75%).
75%
Stage #1: 5-fluorouracil With triethylamine In N,N-dimethyl-formamide for 0.0833333h;
Stage #2: ethyl acrylate In N,N-dimethyl-formamide for 36h;
20.1
STEP-i: To a solution of 5-fluorouracil 1 (650mg, 5mmol) in anhydrous DMF (8mL), triethylamine (100mg, lmmol) was added while stirring. After 5mm, methyl acrylate 2 (ig, lOmmol) was added dropwise. Stirring was continued for 36h. The solvent was evaporated under reduced pressure, and the residue was purified on chromatographic column (95:5 CH2C12/ MeOH) to give compound 3 (860mg, 75%).
84.0 % Chromat.
With Bacillus subtilis alkaline protease EC 3.4.21.14 In dimethyl sulfoxide at 50℃; for 24h;
With ammonium sulfate; 1,1,1,3,3,3-hexamethyl-disilazane; potassium iodide In acetonitrile at 120℃; for 1h; Microwave irradiation; Autoclave; regioselective reaction;
General experimental procedure for the synthesis of N1-alkylpyrimidine 3 using Microwave irradiation: method B
General procedure: Pyrimidine (0.5 mmol), ammonium sulfate (5 mg), potassium iodide (0.25 mmol, 41mg), acetonitrile (2ml), hexamethyldisilazane (0.5ml) and the appropriate amount of alkyl bromide were mixed into a pressure-resistant closed vessel and heated at 120 °C (400W) for 30-60 minutes in a professional microwave. Then the mixture cooled, treated with methanol and evaporated under reduced pressure. The residue was purified by flash chromatography using a mixture of methanol/dichloromethane as eluting to obtain the corresponding N1 alkylated pyrimidines 3a, m.
40%
Stage #1: 5-fluorouracil With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere;
Stage #2: ethyl bromoacetate In N,N-dimethyl-formamide Inert atmosphere;
General procedure: 4.1.4. Ethyl 2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetate(3e)To a dry flask was added uracil (1e, 0.56 g, 5.0 mmol), K2CO3(1.38 g, 10.0 mmol) and anhydrous DMF (6 mL). The mixture wasstirred vigorously under an argon atmosphere at room temperaturefor 1 h, and then ethyl bromoacetate (0.67 mL, 6.0 mmol) wasadded dropwise via syringe and stirred overnight. Water (10 mL)was added to the residue and extracted with ethyl acetate(3 10 mL). The combined organic phases were dried over Na2SO4,and removed under reduced pressure. Silica gel column chromatography(hexanes/ethyl acetate, 2: 1, v: v) afforded the product aswhite acicular crystal: yield 0.38 g (38%);
21%
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 24h;
With phosphorus pentachloride; trichlorophosphate; for 14.0h;Heating / reflux;
Example 16 N4-[(trans-4-aminocyclohexyl)methyl]-5-fluoro-N2-[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine Phosphorous pentachloride (8.0 g, 38.4 mmol) was added to a mixture of 5-fluorouracil (10.0 g, 76.9 mmol) and phosphorous oxychloride (30 mL). The reaction mixture was heated at reflux, for 14 h, under N2. The reaction mixture was cooled to room temperature and then poured into ice. The remaining residue from the flask was dissolved in saturated Na2CO3 and poured into the ice mixture. The mixture was extracted with EtOAc (*3) and the organic phase was dried over anhydrous Na2SO4. The solution was concentrated in vacuo to yield 9.1 g (71%) of 5-fluoro-2,4-dichloropyridine as a pale yellow oil.
EXAMPLE 25 In 10 ml of pyridine were dissolved 0.34 g of 5-fluorouracil and 0.42 g of 2,3-dihydrofuran. To the solution was added 0.3 g of active carbon and the mixture was then reacted at 130 C. for 8 hours. After the reaction, the active carbon was separated and the solvent was distilled off under reduced pressure. Chloroform and a small amount of water were added to the residue and the mixture was stirred and separated. The chloroform layer was dried and the chloroform was distilled off whereby 0.43 g of 1-(2-tetrahydrofuryl)-5-fluorouracil was obtained. The yield was 72%.
EXAMPLE 16 In 30 ml of dimethylformamide were dissolved 2.6 g of 5-fluorouracil and 0.246 g of nicotinic acid. 2.8 Grams of 2,3-dihydrofuran in several portions were added in 4 hours to the solution while heating it at 140 C. The mixture was then reacted for 4 hours at the same temperature. After completion of the reaction, dimethylformamide was distilled off from the reaction liquid and 50 ml of chloroform were added to the residue. After stirring, the solution was filtered to remove insoluble matters and the filrate was washed with water and dried over anhydrous sodium sulfate. Then, chloroform was distilled off from the dried filtrate to obtain 1.85 g of 1-(2-tetrahydrofuryl)-5-fluorouracil which had a melting point of 165-168 C. The chloroform insoluble matters were 5-fluorouracil containing 0.24 g of nicotinic acid.
With hydrogenchloride; N2; In pyridine; chloroform;
EXAMPLE 5 5-Fluoro-3,4-dihydro-2,4-dioxo-N-(3-indolylmethyl)-1(2H-pyrimidinecarboxamide: STR16 5-Fluorouracil (2.00 g, 15.4 mmol) was suspended into pyridine (60 ml). A little excess dichlorocarbonyl was blown into the suspension and stirred well at 0°~5° C. After raising to 10° C., N2 was blown into the reaction mixture, and nonreacted excess dichlorocarbonyl was removed. After recooling to 0° C., <strong>[22259-53-6]3-aminomethylindole</strong> (2.30 g, 15.7 mmol) in pyridine (20 ml) was dropped into the reactant. After stirring the reactant and raising the temperature for one hour to room temperature, the solvent was distilled under reduced pressure. Chloroform (20 ml) and 1N hydrochloric acid (50 ml) were added into the residue. The obtained solids were washed with water and then methanol, and vacuum-dried. 5-Fluoro-3,4-dihydro-2,4-dioxo-N-(3-indolylmethyl)-1(2H-pyrimidinecarboxamide (1.63 g, 5.39 mmol) was obtained. Yield: 35percent, Melting point: 176°~178° C. IRmax (KBr disk): 3440, 3300, 3200(NH), 3120 (=CH--), 1740, 1690~1720(>=0), 1235(=CF--) [cm-1 ]. Element analysis: Found C 55.68 H 3.50, N 18.25 [percent]; Calculated [for C14 H11 FN4 O3 ]: C 55.59, H 3.67, N 18.60 [percent].
With calcium chloride; trifluoroacetic acid; In chloroform; N,N-dimethyl-formamide; toluene;
EXAMPLE 18 In a sealed tube, 780 mg (6 m mole) of 5-fluorouracil, 100 mg (0.90 m mole) of calcium chloride, 5 ml of N,N-dimethylformamide and 1.26 g (18 m mole) of 2,3-dihydrofuran were heated at 100 C for 3 hours. The reaction mixture was further admixed with 800 mg (11.5 m mole) of 2,3-dihydrofuran and the mixture was heated for 17 hours. After the reaction, N,N-dimethylformamide was distilled off from the reaction mixture under a reduced pressure. The residue was dissolved in chloroform and the insoluble matters (small amount) were separated. Chloroform was distilled off from the filtrate and the residue was admixed with 5 ml of toluene and 0.9 ml of trifluoroacetic acid and the mixture was stirred at the room temperature for one night and toluene and trifluoroacetic acid was distilled off under a reduced pressure and the residue was washed with ether to obtain 1.0223 g of white crystals of N1 -(2-tetrahydrofuryl)-5-fluorouracil (yield: 85.2%; melting point: 155.5 to 158.5 C). The product was recrystallized from ethanol to obtain 0.915 g of a pure compound having a melting point of 166 to 168 C.
85%
With dimethylmonochlorosilane; triethylamine; In acetonitrile; at 16℃;
To the flask was added 100 g (0.769 mol) of 5-fluoro-uracil, 83.5 g (1.192 mol) of 2,3-dihydrofuran, 800 ml of acetonitrile, 8.7 g of triethylamine,148.5 g (1.586 mol) of dimethylchlorosilane was added dropwise and reacted at 16 C for 2-3 hours,After completion of the reaction, the reaction solution was poured into 1000 ml of ice water, and the pH of the solution was adjusted to 9 with sodium hydroxide,Stirred at room temperature for 30 minutes, 300 ml of petroleum ether extracted twice, discarded organic phase,The aqueous phase was adjusted to pH 4.5 with hydrochloric acid and extracted three times with 400 ml of dichloromethane,The organic phase was dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give a pale yellow solid.The resulting pale yellow solid was added to the flask, and 860 ml of acetone was added and dissolved by heating at 50 C. The crystals were crystallized at -20 C for 4 hours to obtain 130.8 g of product, 85% yield and 99.97% purity. Product melting point of 169 C.
69%
titanium tetrachloride; In pyridine; chloroform;
EXAMPLE 13 In 40 ml of pyridine were dissolved 5.2 g of 5-fluorouracil. The solution was ice cooled and 0.8 g of titanium tetrachloride was added thereto. Then, 6 ml of 2,3-dihydrofuran in 20 ml of pyridine were added to the mixture in 1.5 hours while stirring it at 80 C. The reaction was continued for 4 hours. After completion of the reaction, pyridine was removed from the reaction liquid by distillation and 500 ml of chloroform and 5 g of silica gel were added to the residue. The mixture was decolored and filtered and the filtrate was concentrated to obtain 5.5 g of 1-(2-tetrahydrofuryl)-5-fluorouracil in a yield of 69%.
36.4%
With chloro-trimethyl-silane; triethylamine; In acetonitrile;
EXAMPLE 7 Into a mixture of 5.0 g of 5-fluorouracil, 4.1 g of 2,3-dihydrofuran and 0.45 g of triethylamine in 40 ml of acetonitrile kept at 15 C. was added 9.2 g of trimethylchlorosilane as a portion to have the reaction take place followed by the same procedure for the treatment of the reaction mixture after the reaction as in Example 1 to give 2.8 g of a crystalline product of N1 -(2-tetrahydrofuryl)-5-fluorouracil having a melting point of 167.6 C. The yield was 36.4% of the theoretical.
27%
With pyridine; antimony(III) chloride; In chloroform; acetone;
EXAMPLE 5 In a sealed tube, 780 mg (6 m mole) of 5-fluorouracil, 5 ml of pyridine, 100 mg (0.44 m mole) of antimony trichloride and 1.26 g (18 m mole) of 2,3-dihydrofuran were heated at 100 C for 3 hours. The reaction mixture was further admixed with 800 mg (11.5 m mole) of 2,3-dihydrofuran and the mixture was heated for 17 hours. After the reaction, pyridine was distilled off under a reduced pressure and the residue was dissolved in chloroform and the insoluble matters were separated by a filtration. Chloroform was distilled off from the filtrate and the residue was purified by a column chromatography using a silica gel column (mixture of chloroform and acetone = 8: 1 (V/V) as a developing medium) to obtain 1.10 g of N1,N3 -bis(2-tetrahydrofuryl)-5-fluorouracil (yield: 68.0%) and 325 mg of N1 -(2-tetrahydrofuryl)-5-fluorouracil (yield: 27%). The former product was recrystallized from ether to obtain a purified product having a melting point of 99 to 101 C.
With pyridine; In water ethanol;
EXAMPLE 6 In an autoclave, 520 g of 5-fluorouracil, 1400 g of 2,3-dihydrofuran and 1.56 l of pyridine were heated together at 185 C. for 3 hours. After cooling, the reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in 6 l of ethanol-water(1:1). The solution was heated at 70 C. for 2 hours, after which it was treated with activated charcoal. After filtration, the solution was concentrated under reduced pressure to about one-half of its original volume. After cooling, the resultant crystals were recovered by filtration and dried. By the above procedure was obtained 780 g of 1-(tetrahydro-2-furyl)-5-fluorouracil. If necessary, this product may be recrystallized from ethanol. Recrystallization yielded 600 g of colorless needles, melting point: 167.5 C. Elemental analysis: Calcd. for C8 H9 FN2 O3: C, 48.00; H, 4.53; N, 13.99. Found: C, 47.93; H, 4.52; N, 13.85.
In pyridine; chloroform;
EXAMPLE 21 In 100 ml of pyridine were dissolved 13.0 g of 5-fluorouracil and 10.5 g of 2,3-dihydrofuran. To the solution were added 7.5 g of alumina and the mixture was reacted at 130 C. for 24 hours. After completion of the reaction, the reaction liquid was filtered to remove the catalyst and the solvent was distilled off. The residue was dissolved in chloroform to recover 3.04 g of insoluble unreacted 5-fluorouracil. The chloroform was distilled off from the chloroform layer and the residue was recrystallized from ethanol to give 13.52 g of 1-(2-tetrahydrofuryl)-5-fluorouracil. The yield of the end product was 88.9% based on the consumed 5-fluorouracil.
EXAMPLE 19 In 10 ml of pyridine were dissolved 0.39 g of 5-fluorouracil and 0.42 g of 2,3-dihydrofuran. To the solution were added 72 mg of dimethylphenylsulfonium perchlorate and the mixture was reacted for 5 hours at 130 C. After the reaction, pyridine was distilled off under reduced pressure and 20 ml of water were added to the residue. The aqueous solution was treated with caustic soda to have a pH value of 10-11 and then washed with 20 ml of chloroform. The aqueous alkaline solution was treated while cold with diluted hydrochloric acid to adjust the pH value of the solution to 3.5 and then extracted three times with 20 ml of chloroform. The chloroform extract was dried and then the chloroform was distilled off. The residue was recrystallized from ethanol to obtain 0.35 g of 1-(2-tetrahydrofuryl)-5-fluorouracil. The yield was 58.3%.
With tetramethlyammonium chloride; In N-methyl-acetamide;
EXAMPLE 9 In 20 ml of dimethylformamide were dissolved 1.3 g of 5-fluorouracil and 0.6 g of tetramethylammonium chloride. To this solution were added 2.25 ml of 2,3-tetrahydrofuran and the mixture was reacted in an autoclave for 9 hours at 150 C. After the reaction, dimethylformamide was removed from the reaction liquid and the residue was stirred together with chloroform and a small amount of water and filtered to separate insoluble matters. The chloroform layer of the filtrate was dried and concentrated and the precipitated crystals were collected by filtration. The crystals were washed with ether and dried to obtain 0.85 g of 1-(2-tetrahydrofuryl)-5-fluorouracil, which had a melting point of 165-168 C. From the chloroform insoluble matters previously separated 0.5 g of the starting 5-fluorouracil were recovered. The yield of the end product was 69% based on the consumed 5-fluorouracil.
EXAMPLE 1 In a 300 cc 4-necked flask equipped with a stirrer, a thermometer and a dropping funnel were placed 80 ml of dimethylformamide. Then, 10.41 g (0.08 mol) of 5-fluorouracil was dissolved in the dimethylformamide and 24.29 g (0.24 mol) of triethylamine was added to this solution. To the mixture was added dropwise over 15 minutes 10.93 g (0.08 mol) of butyryloxymethyl chloride. The mixture was reacted together for 5 hours at room temperature and the reaction liquid was filtered to remove the precipitated triethylamine hydrochloride. The solvent was then distilled from the filtrate and the residue was subjected to a treatment using a column packed with silica gel and a mixture (1:1 in mixing ratio) of benzene and ethyl acetate whereby crude 1-butyryloxymethyl-5-fluorouracil was isolated. This crude product was recrystallized from benzene whereby 16.0 g of pure white crystals having a melting point of 96~98 C. were obtained in a yield of 86.9%.
EXAMPLE 2 Using a reactor similar to that used in Example 1, 3.90 g (0.03 mol) of 5-fluorouracil was dissolved in 50 ml of dimethylformamide. Then, 3.0 g of triethylamine was added to this solution. To the mixture was added dropwise 4.73 g (0.0287 mol) of caproyloxymethyl chloride. The mixture was reacted for 3 hours at 50 C. After completion of the reaction, the reaction liquid was filtered to remove the precipitated triethylamine hydrochloride and then the dimethylformamide was removed by distillation from the filtrate. Next, 50 ml of chloroform was added to the residue and the mixture was stirred and filtered to remove insoluble unreacted 5-fluorouracil. The chloroform phase was washed with water and then dried. By removing the chloroform by distillation, 3.0 g of 1-caproyloxymethyl-5-fluorouracil was obtained as white crystals having a melting point of 95~96 C. in a yield of 38.7%.
With sodium hydroxide; triethylamine; In chloroform; acetonitrile;
EXAMPLE 1 Into a mixture of 60 g of 5-fluorouracil and 50 g of 2,3-dihydrofuran in 480 ml of acetonitrile was slowly added 5.2 g. of triethylamine and then 127.7 g of dimethyldichlorosilane was added as a portion at 15 C. followed by the reaction at 30-35 C. for 2 hours. After the end of the above reaction time, the reaction mixture was cooled to room temperature and admixed with 480 ml of chloroform. The reaction mixture was poured into a chilled aqueous solution of sodium hydroxide in another vessel under agitation and then acidified with 6 N hydrochloric acid to a pH value of 4.4-4.5. The aqueous solution in the upper layer separated by standing was taken and twice extracted with small portions of chloroform. Thus obtained organic solution was, after dehydration with anhydrous magnesium sulfate, subjected to distillation under reduced pressure to leave light brown solid as a residue. This residue was treated with a small amount of chilled isopropyl alcohol with agitation and the insoluble crystals were taken by filtration. This crystalline material was washed with cold isopropyl alcohol repeatedly, air-dried and further dried by heating to give 78.9 g of white crystalline material which was identified as the objective N1 -(2-tetrahydrofuryl)-5-fluorouracil having a melting point of 168-169 C. and giving a single spot by thin-layer chromatography. The yield was 85.5% of the theoretical.
75.4%
With pyridine; In acetonitrile;
EXAMPLE 2 Into a mixture of 5.0 g of 5-fluorouracil, 4.1 g of 2,3-dihydrofuran and 0.3 g of pyridine in 40 ml of acetonitrile kept at 15 C. was added 10.4 g dimethyldichlorosilane as a portion and the reaction took place for about 30 minutes at 20-26 C. The procedure for the treatment of the reaction mixture after the above reaction time was analogous to that in Example 1 to give 5.8 g of crystalline product of N1 -(2-tetrahydrofuryl)-5-fluorouracil having a melting point of 168.9 C. The yield was 75.4% of the theoretical.
Elementary analysis: (C8 H9 FN2 O3) EXAMPLE 19 In a sealed tube, 780 mg (6 m mole) of 5-fluorouracil, 100 mg (0.42 m mole) of calcium bromide(CaBr2.2H2 O), 5 ml of N,N-dimethylformamide and 1.26 g (18 m mole) of 2,3-dihydrofuran were heated at 100 C for 3 hours. The reaction mixture was further admixed with 800 mg (11.5 m mole) of 2,3-dihydrofuran and the mixture was heated for 17 hours. After the reaction, N,N-dimethylformamide was distilled off from the reaction mixture under a reduced pressure. The residue was dissolved in chloroform and the insoluble matter (small amount) were separated by a filtration. Chloroform was distilled off from the filtrate and the residue was purified by a column chromatography using a silica gel column (mixture of chloroform and acetone = 8:1 (V/V) as a developing medium) to obtain 440 mg of N1,N3 -bis(2-tetrahdrofuryl)-5-fluorouracil (yield: 27.1%) and 750 mg of N1 -(2-tetrahydrofuryl)-5-fluorouracil (yield: 62.5%). The former was recrystallized from ether to obtain a pure compound having a melting point of 99 to 101 C.
tin(IV) chloride; In 1,4-dioxane; isopropyl alcohol; acetone;
EXAMPLE 1 2,3-dihydrofuran (16.80 g, 0.240 mole) was slowly added while stirring to a pH=2.0 buffered aqueous solution (1.8 ml, 0.100 mole) while the temperature was kept at 60-65. After the addition was completed the reaction mixture was further stirred at 65 for half an hour, cooled to room temperature and the volatile materials were removed by heating to 50 under reduced pressure. 16.50 g of colourless residue were thus obtained. 1.900 g of the crude addition product was added while stirring to a mixture of stannic chloride (0.65 ml; 5.5 m.mole) and anhydrous dioxane (20 ml) followed by silylated 5-fluorouracil (2.740 g; 10.0 m.mole). The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. Thereafter isopropanol (20 ml) was added and the reaction mixture was stirred at room temperature for 10 minutes. After removal of the isopropanol by distillation the resulting crude product was taken up in acetone/petrol-ether and filtered through a silica-gel bed. Ftorafur (1.840 g; m.p. 158-160) and unreacted 5-fluorouracil (0.100 g) were thus obtained.
With sodium iodide; In isopropyl alcohol; acetonitrile;
EXAMPLE 5 1.600 g of crude addition product of water to 2,3-dihydrofuran (prepared as described in Example 1) were added to a solution of 1.880 g (12.5 m.mole) of sodium iodide in anhydrous acetonitrile (20 ml) and immediately afterwards 2.740 g (10.0 m.mole) of silylated-5-fluorouracil was added. The reaction mixture was brought to reflux and stirred for 4 hours. The volatile materials were removed under reduced pressure (45-50/30 mm Hg). Isopropanol (20 ml) was added to the residual oil and the resulting mixture was stirred for 10 minutes at room temperature after which it was concentrated in vaccuo. The resulting crude product was filtered through silica-gel bed. 0.169 g of unreacted 5-fluorouracil and 1.700 g of Ftorafur were obtained.
Stage #1: 5-fluorouracil; methyl-1-tert-butyl-(2S,4R)-4,5-bis(acetyloxy)-pyrrolidine-1,2-dicarboxylate With N,O-bis-(trimethylsilyl)-acetamide In dichloromethane at 20℃; Inert atmosphere;
Stage #2: With tin(IV) chloride In dichloromethane at 0 - 20℃;
Stage #3: With sodium hydrogencarbonate In dichloromethane; chloroform; water Cooling;
80%
Stage #1: 5-fluorouracil; methyl-1-tert-butyl-(2S,4R)-4,5-bis(acetyloxy)-pyrrolidine-1,2-dicarboxylate With N,O-bis-(trimethylsilyl)-acetamide In dichloromethane at 20℃; for 2h;
Stage #2: With tin(IV) chloride In dichloromethane at 0 - 20℃; for 16h;
8.a; 8.b
To the solution of l-ter-butyl-2-methyl (2S,4R)-4,5-bis(acetyloxy)pyrrolidine-l,2- dicarboxylate (8), (0,06 g, 0,185 mmol) in 5 ml of anhydrous CH2Cl2, at r.t. N,O- bis trimethylsilylacetamide (0,09 g, 0,43 mmol) and then 5-FU (0,02 g, 0,19 mmol) are dropped and reacted until nucleobase id completely solubilised (2 hours). Then tin tetrachloride (0,05 g, 0,19 mmol) is added at 00C and reacted at r.t. for 16 hours. The reaction mixture is treated with 5% NaHCO3 (5 ml) at 00C and the filtered on celite. The organic phase is separated and extracted with H2O, dried over sodium sulfate, evaporated to dryness and purified by flash chromatography.b) Purification of l-ter-butyl-2-methyl (2S,4R,5R)-4-(acetyloxy)-5-(5-fluoro-2,4- dioxo-3 ,4-dihydropyrimidine- 1 -(2H)-yl)pyrrolidine- 1 ,2-dicarboxylate (9d) Eluting mixture: Ethyl acetate/Cyclohexane 30%. Rf = 0,2. HPLC purification: Isopropanol/n-Hexane 8%, λ = 270 nm, Rt = 7,91 min. Yield = 80%. White solid: m.p. = 94-98 0C; [α]D25 = -21,86 (c = 0,53, CHCl3).1H NMR (CDCl3, 500 MHz, 27°C): δ 1,41 (s, 9H), 1,46 (s, 9H), 2,13 (s, 6H), 2,21 (m, 2H), 2,44 (m, 2H), 3,85 (s, 6H), 4,44-4,56 (m, IH), 5,29 (m, 2H), 6,01(m, 2H), 8,47-8,62 (m, 2H), 9,57 (2H, NH).13C NMR (CDC13, 50 MHz, 27°C): δ 20,8, 28,0, 32,7, 53,0, 58,0, 74,0, 75,8, 94,0, 124,3, 139,7, 141,6, 149,3, 152,5, 156,8, 162,0, 169,5, 172,9.Elemental analysis. Calculated for Ci7H22FN3O8: C, 49,16; H, 5,34; F, 4,57; N, 10,12. Found: C, 49,14; H, 5,32; F, 4,58; N, 10,09. Theoretical mass for CnH22FN3O8: 415,14. Found: 415,11.
Dissolve 31.2g of 5-fluorouracil51.28g of sodium hydroxide solid160 mL aqueous solution;The temperature was raised to 40 C, and 80 mL of 50 g of bromoacetic acid solution was slowly added dropwise.Adding time for 120min,And stirring the reaction for 12 h to obtain a first reaction product;The first reaction product was cooled to room temperature, and the pH was adjusted to 5.5 with concentrated hydrochloric acid.The mixture is allowed to stand at a temperature of 3 C for 2 h; if a precipitate is precipitated, the precipitate is filtered off to obtain a first clear solution;Adding concentrated hydrochloric acid to the first clear solution to adjust the pH of the solution to 2,The mixture was allowed to stand at a temperature of -5 C for 6 h.Filtered and the precipitate was washed 3 times with cold water.The compound 5-fluorouracil-1-ylacetic acid was obtained.
85%
KOH (2.56 g, 45 mmol) and 5-fluorouracil (1.34 g, 10 mmol) dissolved in a clean flask, then 5 ml aqueous solution of bromoacetic acid (1.7 g, 18 mmol) was added under the temperature of 40 C while stirred smoothly. The reaction mixture was stirred at 60 C for 5 h and then cooled by ice-bath, adjusted to pH 5.5 with hydrochloric acid, after filtration through a membrane, the crude product was recrystallized by water, and compound 2 was obtained as white solid 1.53 g. Yield 85%, mp 255-257 C. 1H NMR (400 MHz, D2O): 4.41 (s, 2H, N-CH2), 7.54 (d, 1H, J = 5.2 Hz, 5-FU-H), ESI MS (m/z): calcd for 188.11. obsd 189.01 ([M+H]+)
72%
With potassium hydroxide; at 50℃;
5-FU (5-fluorouracil) and bromoacetic acid solution with a molar ratio of 1: 1.5 were added to the KOH solution, and after the reaction was completed at 50 C.,Cooled to room temperature, adjusted to pH 5.5 with concentrated hydrochloric acid, placed in the refrigerator for 2h, the precipitate was filtered off, plus concentrated hydrochloric acid to adjust the pH value of the solution to 2, placed in the freezer 6h,Filtered to obtain a solid material,That is, 5-fluorouracil-1-yl acetic acid, and the obtained yield was 72%.
70%
With potassium hydroxide; In water; at 40℃; for 4h;
5-FU (3.9 g, 30 mmol)was dissolved in KOH solution (9 ml, 5.7 mol/L), thenan aqueous solution of 2-bromoacetic acid (8 ml, 45 mmol) was added dropwiseat the temperature of 40 C. The mixture was stirred for approximately 4 h, until no free 5-FU was detectable by thin-layer chromatography. Thesolution was then transferred to anice-bath, and the pH was adjusted to 1.0with hydrochloric acid (10 mol/L) to obtain the crude product. Compound Iwas collected by filtration, washed with water for 3 times and then dried in 40 C as 3.95 g white solid with a yield of 70 % (Ouyang et al. 2011). Compound I: 1H-NMR (400 MHz, D2O): 8.10-8.08 (d, 1H, J = 6.8 Hz),4.37 (s, 2H). ESI-MS (m/z): calcd for 188.11. obsd 187.01 ([M-H]+)
64.4%
With potassium hydroxide; In water; at 80℃; for 4h;
Potassium hydroxide (19.2 g, 0.34 mol), water (80 mL) and 5-fluorouracil were sequentially added to a 250 mL jar.(13.0 g, 0.1 mol), stirring to dissolve it, then raising the temperature to 80 C., slowly adding dropwise bromoacetic acid (18.1 g, 0.13 mol).After completion of stirring for 4 hours, TLC showed that the reaction was complete, cooled to room temperature, adjusted to pH 2 with concentrated hydrochloric acid, and cooled on ice.However, solids precipitated and were filtered. The residue was recrystallized from hot water to give the product IIIa
General procedure: Potassium hydroxide (40.0 mmol) was stirred to be dissolved in distilled water (10 mL) at r.t. and the appropriate uracil or 5'-substituted uracil (10.0 mmol) was added portionwise with vigorous stirring until the mixture was well-distributed, and then the mixturewas heated at 60 C for 0.5-1 h to be a clear solution. To this solution, the solution of bromoacetic acid (12.1e14.5 mmol) in distilled water (8 mL) was added dropwise over 30 min. The reaction mixture was heated at 60 C for another 5 h and was allowed to cool to r.t. The mixture was acidified to pH 2 with concentrated HCl aqueous solution and stirred overnight. The resulting precipitate was collected by filtration to yield a white or pale yellow solid, which was recrystallized from the minimal amount of distilled water to afford the title compound, an N-acetic acid derivative of the uracils 5a-e in 60-90% yield.
Stage #1: C11H22NO6P; C11H22NO6P; 5-fluorouracil With N,O-bis-(trimethylsilyl)-acetamide In acetonitrile
Stage #2: trimethylsilyl trifluoroacetate In acetonitrile at 50℃; for 6h;
4
EXAMPLE 4; Preparation of the compound of formula (I) wherein R2 is Et. Ri is Me and B is fluorouracil ; N, O-bis (trimethylsilyl) acetamide (2.54 mmol) was added to a suspension of fluorouracil (0.618 mmol) in anhydrous acetonitrile (3 ml). A solution in anhydrous acetonitrile (3 mi) of the epimeric mixture of isoxazolidine of formula (V) and (VI) (0.517 mmol), prepared as described above in Example 3, was added to the clarified solution; subsequently trimethylsilyl triflate (0.18 mmol) was added. The reaction mixture was then left under stirring at 50C for 6h and after cooling, the solution was neutralised using a solution of sodium bicarbonate 5% and vacuum concentrated. Dichloromethane (8 ml) was then added to the crude product and, after extraction, the organic phase was washed with water (2 x 10 ml), dried on sodium sulfate, and vacuum concentrated, to obtain the product of the title in the form of epimeric mixture. The mixture was then subjected to flash chromatography using as eluent the mixture cyclohexane/ethyl acetate 3: 7, from which the product of the title with a ratio o/? 1.0 : 99.0 was obtained.
Stage #1: 5-fluorouracil With 1,1,1,3,3,3-hexamethyl-disilazane In acetonitrile at 110 - 120℃; for 5 - 6h;
Stage #2: 2<SUP>1</SUP>-deoxy-2<SUP>1</SUP>,2<SUP>1</SUP>-difluoro-3,5-bis-O-benzoyl-D-ribose trichloroacetimidate With trimethylsilyl trifluoromethanesulfonate In acetonitrile at 90℃; for 10h;
Stage #3: With water In dichloromethane; acetonitrile
10
Example-10Preparation of2-Deoxy-2,2-difluoro-3,5-dbenzoate-5-fluoro uridine hydrochloride salt. 5-Fluorouracil (5 gm; 0.038 mol was heated with hexamethyldisilazane(13.77gm; 0.085mol) and catalytic amount (0.50 ml) of methanesulfonic acid in acetonitrile (15ml) at 110-120° C for 5-6 hrs to get a clear solution. The reaction mixture was concentrated under reduced pressure to give a gummy mass which was heated to 60° C and mixed with a solution of 21-Deoxy-21,21-difluoro-3,5- bisbenzoyloxy-D-ribose trichloroacetimidate (Ia; 6.70 gm; 0.013mol) in acetonitrile (5 ml), followed by addition of trimethylsilyl trifluoromethane sulphonate (7.12 gm; 0.03 mol). The reaction mixture was heated under agitation at 900C for lOhrs. The reaction mixture was poured in to a mixture dichloromethane and water(100 ml; 1:1). The organic phase was separated and washed with 5% sodium bicarbonate solution, water and then evaporated to give 6.28 g (100%) of a white solid.Chromatography of the solid over silica gel using a mixture of ethyl acetate and hexane (1:1) gave 3.25 gm (51.7%) of the free base (Ha)1H NMR (CDCl3, δ) : 4.59 (q, IH, H-4'), 4.68, 4.91 (dd, dd, 2H, H-5'), 5.79 (dd, IH,H-3'), 6.52 (q, IH, H-I'), 8.06 (d, IH, H-6)Mass Spectrum (M+): 489
One mmol of Fmoc-Asp-OtBu is dissolved in 20 ml DCM. The mixture is cooled to 0 C. 1.1 mmol of DCC is dissolved in 10 ml DCM and added to the Fmoc-Asp-OtBu mixture. The reaction is carried out for 30 minutes on cold ice and continued for another 2 hours at room temperature. The white crystals that appear in the mixture are filtered out. One mmol of solid 2,4-dioxo-5-fluoropyrimidine is added to the clear solution of activated Fmoc-Asp-OtBu. The reaction is carried out for 20 hours in room temperature. The mixture is filtered and the DCM is evaporated. The product is washed several times with water and ethanol and air-dried. Cleavage of the protecting groups (OtBu) is carried out in 1 ml TFA+5% water for 3 hours. TFA is evaporated in a vacuum over KOH pellet. Fmoc-Asp(5-FU)-OH is washed several times with diethyl ether and dried.
Stage #1: 5-fluorouracil With N,O-bis-(trimethylsilyl)-acetamide In acetonitrile for 0.333333h; Inert atmosphere; Reflux;
Stage #2: (2R,3S,4R,5R)-1-(tert-butoxycarbonyl)piperidine-2,3,4,5-tetrayl tetraacetate With trimethylsilyl trifluoromethanesulfonate In acetonitrile at 0℃; for 1h; Inert atmosphere;
Stage #3: With sodium hydrogencarbonate In water; acetonitrile Inert atmosphere; Cooling;
4.29. (2S,3R,4R,5R)-1-(tert-Butoxycarbonyl)-2-(5-fluoro-uracil-1-yl) piperidine-3,4,5-triyl triacetate (12a)
General procedure: To a stirred solution of 5-fluoro-uracil (50 mg, 0.36 mmol) in anhydrous acetonitrile (2 mL) under argon was added N,O-bis(trimethylsilyl)acetamide (0.14 mL, 0.58 mmol). The reaction mixture was stirred under reflux for 20 min. After cooled to 0 °C, compound 10a (30 mg, 0.072 mmol) in anhydrous acetonitrile (5 mL) was added and TMSOTf (26 μL, 0.144 mmol) was added dropwise. The solution was stirred at 0 °C for 1 h. The reaction was then quenched with cold saturated sodium bicarbonate aqueous solution (6 mL) and the resulting mixture was extracted with CH2Cl2 (40 mL × 3). The combined organic phases were washed with brine and dried over anhydrous Na2SO4. After removal of the solvent, the resulting residue was purified by flash column chromatography (petroleum ether/ethyl acetate, 5:1→CH2Cl2/MeOH, 80:1) to give 12a (31 mg, 87%) as a colorless foam.
General procedure: 5-Fluorouracil (0.013 g, 10 mmol) was dissolved in aqueous (10 ml) solution containing a few drops of concentrated ammonia and stirred. When 5-fluorouracil was completely dissolved, an aqueous (10 ml) solution of appropriate metal salt (10 mmol, 0.025 g Ni(CH3COO)2.4H2O or 0.020 g Cu(CH3COO)2.H2O or 0.022 g Zn(CH3COO)2.2H2O) solution was added dropwise and stirred at room temperature (Scheme 1). To this solution, aqueous solution (10 ml) of imidazole (0.007 g, 10 mmol) or benzimidazole (0.012 g, 10 mmol) was added and the reaction mixture was refluxed for 6-8 h on a water bath. The pH (=6.8) of the reaction mixture was adjusted by adding few drops of aqueous Na2CO3 solution (0.011 g, 10 mmol). The resulting solution were reduced to 1/3 of its original volume by water bath and kept aside. On standing, the mixed ligand complexes were obtained and collected by vacuum filtration, washed several times with cold water, ethanol and anhydrous ether. The mixed ligand complexes were obtained as powder and dried in air and stored in vacuo over anhydrous CaCl2 at room temperature. The yield of the isolated complexes was found to be 55-70%.
General procedure: 5-Fluorouracil (0.013 g, 10 mmol) was dissolved in aqueous (10 ml) solution containing a few drops of concentrated ammonia and stirred. When 5-fluorouracil was completely dissolved, an aqueous (10 ml) solution of appropriate metal salt (10 mmol, 0.025 g Ni(CH3COO)2.4H2O or 0.020 g Cu(CH3COO)2.H2O or 0.022 g Zn(CH3COO)2.2H2O) solution was added dropwise and stirred at room temperature (Scheme 1). To this solution, aqueous solution (10 ml) of imidazole (0.007 g, 10 mmol) or benzimidazole (0.012 g, 10 mmol) was added and the reaction mixture was refluxed for 6-8 h on a water bath. The pH (=6.8) of the reaction mixture was adjusted by adding few drops of aqueous Na2CO3 solution (0.011 g, 10 mmol). The resulting solution were reduced to 1/3 of its original volume by water bath and kept aside. On standing, the mixed ligand complexes were obtained and collected by vacuum filtration, washed several times with cold water, ethanol and anhydrous ether. The mixed ligand complexes were obtained as powder and dried in air and stored in vacuo over anhydrous CaCl2 at room temperature. The yield of the isolated complexes was found to be 55-70%.
General procedure: 5-Fluorouracil (0.013 g, 10 mmol) was dissolved in aqueous (10 ml) solution containing a few drops of concentrated ammonia and stirred. When 5-fluorouracil was completely dissolved, an aqueous (10 ml) solution of appropriate metal salt (10 mmol, 0.025 g Ni(CH3COO)2.4H2O or 0.020 g Cu(CH3COO)2.H2O or 0.022 g Zn(CH3COO)2.2H2O) solution was added dropwise and stirred at room temperature (Scheme 1). To this solution, aqueous solution (10 ml) of imidazole (0.007 g, 10 mmol) or benzimidazole (0.012 g, 10 mmol) was added and the reaction mixture was refluxed for 6-8 h on a water bath. The pH (=6.8) of the reaction mixture was adjusted by adding few drops of aqueous Na2CO3 solution (0.011 g, 10 mmol). The resulting solution were reduced to 1/3 of its original volume by water bath and kept aside. On standing, the mixed ligand complexes were obtained and collected by vacuum filtration, washed several times with cold water, ethanol and anhydrous ether. The mixed ligand complexes were obtained as powder and dried in air and stored in vacuo over anhydrous CaCl2 at room temperature. The yield of the isolated complexes was found to be 55-70%.
With Lactobacillus animalis ATCC 35046 2?-N-deoxyribosyltransferase immobilized in DEAE-Sepharose; In aq. buffer; at 30℃;pH 7.0;Green chemistry; Enzymatic reaction;
General procedure: Thymidine (dThd) and 2'-deoxyuridine (dUrd) were assayed as sugar donors. Different purine and pyrimidine bases were tested: 5-fluorouracil (5FUra), 5-bromouracil (5BrUra), 5-chlorouracil (5ClUra), 6-chloropurine (6ClPur), 6-bromopurine (6BrPur) and 6-chloro-2-fluoropurine (6Cl2FPur). Reactions were performed using 100 mg/mL of immobilized LaNDT, 6 mM nucleoside and 2 mM base, 30 C and 200 rpm. At different times (5-8 h), 20 muL aliquots were taken and centrifuged at 10,000 x g, and the supernatant was analyzed by HPLC to evaluate yield expressed as percentage and product conversion expressed as mg of product per gram of support.
With ammonium dihydrogen phosphate; ammonia; In water; at 45 - 55℃; for 45h;pH 6.6;Large scale; Enzymatic reaction;
35Kg beta-thymidine, 21Kg 5-fluorouracil,8.4Kg ammonium dihydrogen phosphate used1750L pure water stirring suspended,With 2.8L concentrated ammonia to adjust the pH = 6.6,Adding 0.75Kg of industrial nucleoside phosphorylase,Stir,Temperature control 45-55 C reaction.After 45 hours of reaction,HPLC monitoring to complete reaction.After the reaction is complete,The reaction system was cooled to room temperature,Centrifugal,Remove insoluble matter,Centrifuge the mother liquor to adjust pH = 8-9,It was then purified with 900 L Cl-type strongly basic resin (eluted with deionized water)A fraction containing 5-fluoro-deoxyuridine and a beta-thymidine content of less than 3%The partially collected solution was then concentrated to dryness at 60 C under reduced pressure,Remove the solid,At 60-65 C under the blast drying to less than 1% moisture,This is the 5 - fluoro - deoxyuridine nucleoside crude,HPLC purity 90.5%
5-fluoro-1-((4'-methyl-[2,2'-bipyridin]-4-yl)methyl)pyrimidine-2,4(1H,3H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
10080] A mixture of 5-fluorouracil (0.130 g, 1 mmol),K2C03 (0.276 g, 2.0 mmol) and KI (ca. 25 mg) in 10 mL ofDMSO was stirred under N2 for 10 mi 4-(bromomethyl)-4?-methyl-2,2?-bipyridine (0.644 g, 2.45 mmol) predissolvedin DM50 (5 mE) was then slowly added via a syringe and the resultant chocolate brown mixture was stirred under N2 at room temperature for 3 h. Water (100 mE) was then added and the suspension was extracted with dichloromethane. The collected organic layers were dried over anhydrous sodium sulphate and the solvent removed in vacuum to give a half-white solid. The crude was subjected to the silica colunm chromatography using dichloromethane and acetone as solvent mixture 99:1% (v/v). The second spot from the bottom on the TEC plate was collected as E, (0.150 g, 48%). Electron impact (El) mass spectrum: mIz=334.93[E,+Na]. ?H NMR (200 MHz, methanol-d4) oH 8.89 (1H, s), 8.68 (d, 1H, J=4.8 Hz), 8.54 (d, 1H, J=4.8Hz), 8.33 (1H, s), 8.25 (1H, s), 7.19 (d, 2H, J=10.3 Hz), 5.77 (d, 1H, J=7.7 Hz), 5.00 (2H, s), 2.45 (1H, s). ?9F NMR (400 MHz, MeOD-d4) 0 -74.85 ppm. (Refer FIG. 3, 4, 5)
5-chloro-5-fluoro-6-hydroxy-5,6-dihydrouracil[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With sulfuric acid; potassium chloride; dihydrogen peroxide In water at 20℃;
Synthesis of 5-fluoro-5-halo-6-hydroxy-5,6-dihydrouracils 2, 3
General procedure: A portion of 33% H2O2 (0.6 ml, 6.0 mmol) was added dropwise to a mixture of 5-fluorouracil (1) (0.20 g, 1.5 mmol) and KCl or KBr(3.0 mmol) in 20% H2SO4 (2.0 ml). The mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with H2O and extracted with Et2O (3×25 ml). The combined extracts were washed with H2O, dried over Na2SO4, concentrated, and recrystallized from acetone.
5-fluoro-6-hydroxy-5-nitro-5,6-dihydrouracil[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With sulfuric acid; nitric acid In water at 0 - 10℃;
5-Fluoro-6-hydroxy-5-nitro-5,6-dihydrouracil (4).
5-Fluorouracil (1) (0.30 g, 2.3 mmol) was gradually added to conc. H2SO4 (0.6 ml). After the starting compound dissolved completely, the mixture was cooled to 0°C, HNO3 (d 1.4 g/ml, 0.6 ml) and conc. H2SO4 (0.3 ml) were successively added dropwise, and the mixture was kept at 0-10°C for 4 h. The reaction mixture was diluted with H2O and extracted with Et2O (3×25 ml). The combined extracts were washed with H2O, dried over Na2SO4, concentrated,and recrystallized from acetone. Yield 0.42 g (95%), white crystals, mp 171-173°C (mp 179-182°C (H2O)5).
Stage #1: 5-fluorouracil With sodium hydride In tetrahydrofuran; mineral oil at -20℃; for 0.0833333h; Inert atmosphere;
Stage #2: 1-Iodoheptane In tetrahydrofuran; mineral oil at 0℃; for 5h; Inert atmosphere;
4.5. General Procedure for the Synthesis of Uracil Derivatives 19-21
General procedure: A solution of uracil derivative (0.5 mmol) in THF (3 mL) was added slowly to a suspension of NaH(60% in mineral oil, 30 mg) in anhydrous THF (5 mL) under a nitrogen atmosphere at 20 °C. Afterstirring for 5 min at 20 °C, a solution of the appropriate iodide (0.6 mmol) in THF (2 mL) was slowlyadded. The reaction mixture was stirred at 0 °C for 5 h and then quenched with saturated aqueousammonium chloride solution (5 mL) followed by extraction with EtOAc (3 5 mL). The combinedorganic layers were dried over anhydrous Na2SO4 and filtered. The concentrated residue was purifiedby flash chromatography on silica gel to afford compounds 19-21.
(3R,4S,5R)-5-(4-acetoxybenzyl)tetrahydrofuran-2,3,4-triyl triacetate[ No CAS ]
C21H21FN2O9[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
Stage #1: 5-fluorouracil; (3R,4S,5R)-5-(4-acetoxybenzyl)tetrahydrofuran-2,3,4-triyl triacetate With N,O-bis-(trimethylsilyl)-acetamide In acetonitrile at 80℃; for 2h; Inert atmosphere;
Stage #2: With trimethylsilyl trifluoromethanesulfonate In acetonitrile at 0 - 40℃; for 16h; Inert atmosphere;
Peracetylated Uracil Nucleoside 16
General procedure: Compound 15 (600 mg, 1.5 mmol) and uracil (previously dried under high vacuum; 494 mg, 4.4 mmol) were dissolved in anhydrous CH3CN (20 mL) and treated with N,O-bis(trimethylsilyl)acetamide (BSA; 1.8 mL, 7.35 mmol), and the solution was stirred at 80 °C under argon atmosphere for 2 h. The mixture was then cooled to 0 °C, treated with TMSOTf (0.7 mL, 3.8 mmol), and warmed slowly to r.t. and heated at 40 °C for 16 h. The solution was then cooled to 0 °C and the reaction mixture quenched by the addition of sat. NaHCO3 (5 mL), then extracted with CH2Cl2 (3 × 20 mL). The combined organic phase was dried with Na2SO4, filtered and concentrated. The crude was purifiedby silica gel column chromatography (petroleum ether-EtOAc, 7:3) to procure nucleoside 16.
With dihydrogen peroxide; copper diacetate; In N,N-dimethyl-formamide; at 40℃; for 5h;
5-Fluorouracil (13.00 g, 0.10 mol), tetrahydrofuran (11.54 g, 0.16 mol), copper acetate (399.30 mg, 2.0 mmol), hydrogen peroxide solution (28.33 g, 0.25 mol, 30%),N, N-dimethylformamide (150mL) was added to the flask, stirred, heated to 40 C, reacted for 5h, filtered, and the filtrate was poured into a mixed solution of ice water (500mL) and ethyl acetate (300mL). After stirring for 15 min, the layers were separated. The organic phase was washed with purified water (100 mL × 3) and saturated brine (100 mL) in that order, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to dryness to obtain the crude tegafur. After recrystallization, a tegafur refined product was obtained with a yield of 92.35%. According to HPLC detection, tR = 13.926min was tegafur with a purity of 99.952% and a maximum single impurity of 0.016%.
82%
With carbon tetrabromide; potassium carbonate; In ethanol; water; at 50 - 60℃; for 9.5h;Inert atmosphere;
Under a nitrogen atmosphere, to a dry reaction tube were sequentially added 5-fluorouracil (10 mmol)Potassium carbonate (15 mmol),Carbon tetrabromide (15 mmol),And tetrahydrofuran 100 mL,Heated to 60 , the reaction 8 h end,The solid is simply filtered and the solvent is spin-dried. Add 150 mL aqueous ethanol (absolute ethanol: water = 1: 1, volume ratio),Heated at 50 1.5h, the reaction was completed.The absolute ethanol was recrystallized to give the corresponding product as a white solid in 82% yield,HPLC purity> 99%. The product name is: Tegafur.
With hydrogenchloride; In methanol; at 28℃; for 5h;
500 g of methanol was placed in a constant-temperature reaction bath, and hydrogen chloride gas was introduced until the methanol increased weight to 543 g-556 g to stop aeration. The prepared methanol solution of hydrogen chloride was placed in a refrigerator for use.In a dry and clean 500 mL four-neck flask, 250 g of hydrochloric acid in methanol was added, and 50 g of <strong>[1480-96-2]2-methoxy-5-fluorouracil</strong> was stirred. When the temperature was raised to 28 C., incubation was started. After 5 h, samples were taken for HPLC detection. At 0.07%, the reaction was completed, the temperature was lowered to 15C, and the resulting solid was suction filtered.The refined 5-fluorouracil is refined and the mother liquor is concentrated after suction filtrationShrink the recovered methanol for use. The resulting 5-fluorouracil dry weight was 35.4 g, with a purity of 99.82% and a yield of 78.3%.
65.24 kg
With hydrogenchloride; In water; at 55℃; for 3h;Large scale;
90 kg of the yellow cyclic compound obtained above was added, and 198 kg of concentrated hydrochloric acid was added, and reacted at a temperature of 55 C. for 3 hours until the reaction was completed. After the reaction is completed, the solution is cooled to an internal temperature of 5 to 15 C with cold brine. The feed liquid is transferred to a centrifuge, centrifuged, washed with water to pH 5 to 6, and dried to obtain crude 5-fluorouracil.(65.24 kg, yield 80.3%, HPLC purity 98.45%).
Add 5 mL of anhydrous solvent N,N-dimethylformamide (DMF) to a 25 mL eggplant-shaped flask, and slowly add 5-fluorouracil(1.05 g, 8.0 mmol, Beijing Coupling Technology Co., Ltd.) under stirring, and mix well. After being placed in an ice bath, sodium hydride (0.23 g, 9.6 mmol) was slowly added portion wise, and the mixture was transferred to room temperature for 1 hour, andethyl bromoacetate (1.60 g, 9.6 mmol) was slowly added dropwise, and the reaction was continued for 2 h. Filtration, washed three times with water (5×3 mL), the filtrate was combined, 0.96 g of sodium hydroxide (24.0 mmol) was added, and the mixturewas stirred at room temperature for 1 h, placed in an ice bath, adjusted to pH 3.0 with 4M HCl, and stirred for 30 min. Themixture was allowed to stand, suction filtered, and the filter cake was washed with water and dried to give the object product white powder solid, intermediate 6 (0.58 g, 38.7%). LC-MS (ESI, M-H ) m/z 187.4.
With potassium dihydrogenphosphate; E. coli purine nucleoside phosphorylase; E. coli uridine phosphorylase; In aq. buffer; at 20℃; for 20h;pH 7.5;Enzymatic reaction;
General procedure: To a solution of Thy (37 mg, 0.3 mmol), 7-MeGuo hydroiodide (191 mg, 0.45 mmol) and potassium dihydrophosphate (KH2PO4, 20 mg, 0.15 mmol) in 50mM Tris-HCl buffer, pH 7.5, 80 mL) at ambient temperature, 5 muL of 32 mg/mL E. coli purine nucleoside phosphorylase (PNP) solution (1.48 U) and 12.5 muL E. coli uridine phosphorylase (UP) (8.60 U) were added in one portion. The reaction mixture was allowed to stand for 5 h at ambient temperature under neat stirring and then allowed to stand for 15 h at ambient temperature without stirring. The conversion of the initial 7-MeGuo was controlled by HPLC. The reaction mixture was cooled to 0 C and then filtered through nitrocellulose membrane Whatman (0.2 mum, 25 mm) to remove the white precipitate of 7-methylguanine (7-MeGua). The precipitate was washed with milli-Q water (15 mL). The combined transparent filtrate was concentrated under reduced pressure using a rotary evaporator to ca. 2 mL (bath temperature (5 mL) was then added to the suspension. The resulting mixture was concentrated to near dryness and co-evaporated with ethanol (2×20 mL). The dry residue was applied on a chromatographic column (diameter 20 mm) with silica gel (20 mL) for purification. For the protection, the silica gel layer was topped with ca 0.5-cm layer of sand. The column was washed with dichloromethane (25 mL), a mixture of dichloromethane and ethanol (95:5, v/v, 50 mL), and a mixture of dichloromethane and ethanol (90:10, v/v, 100 mL). The product was eluted with dichloromethane: ethanol (80:20, v/v, 100 mL) and 10 mL fractions were collected and evaporated in vacuo to dryness. The residue was co-evaporated 5 times with dichloromethane and dried using a vacuum pump at r.t. for 1 h.
With sodium acetate; tetra-(n-butyl)ammonium iodide; In dichloromethane; water; at 35℃; for 2h;
Add 5-fluorouracil (13.00 g, 0.10 mol), sodium acetate (16.40 g, 0.20 mol), tetrabutylammonium iodide (1.48 g, 4.00 mmol) to 150 mL of purified water, and stir until the solids are completely dissolved. A solution of 2-benzoyloxytetrahydrofuran (27.00 g, 0.14 mol) in dichloromethane (150 mL) was added. The reaction system was heated to 35 C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and the dichloromethane layer was separated, washed with purified water (100 mL × 3), washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain tegafur with a yield of 95.20%. According to HPLC detection, tR = 13.930min was tegafur with a purity of 99.973% and a maximum single impurity of 0.011%.
5-fluoro-1-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)pyrimidine-2,4(1H,3H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 2h;
Method B.
General procedure: A mixture of 5-halopyrimidine (1mmol), alkylating agent 3a(1.1mmol, 215mg) and potassium carbonate (0.5mmol, 69mg) in DMF(10ml) was heated at 90 °C for 2 hours. Then the DMF was evaporated underreduced pressure to dryness. The residue was purified by flash chromatographyeluting with (CH2Cl2/MeOH= 99:1) to obtain pure product 4d-g.
1-8 Example 1
Weigh 1.30 g of 5-fluorouracil and 2.86 g of kaempferol, add 30 ml of absolute ethanol to obtain a suspension, place the suspension at room temperature and stir for 5 hours. After filtration, the obtained white solid was dried at 40°C to obtain a solid sample of co-crystal of 5-fluorouracil and kaempferol with a yield of 83.3%.
Stage #1: 5‐fluorouracil With anhydrous ammonium sulphate; 1,1,1,3,3,3-hexamethyl-disilazane In toluene at 120℃;
Stage #2: 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose With anhydrous tin tetrachloride In toluene; acetonitrile for 1h; Cooling with ice;
1 Example 1: Synthesis of 1'-(5-fluorouracil)-3'-deoxy-3',4'-didehydroribonucleoside (compound 1a, B=5-fluorouracil in general formula 1)
After the base 5-fluorouracil (2.01 g, 15.46 mmol) was azeotropically dehydrated with toluene, anhydrous toluene (150 mL) was added, placed on an oil bath at 120°C, and hexamethyldisilazane (57 mL) was added. , 273.5 mmol) and ammonium sulfate (200 mg), stirred and refluxed until the system was clear, cooled a little and concentrated under reduced pressure. Then take compound I (6 g, 11.9 mmol) after azeotropic dehydration with toluene, dissolve it with acetonitrile (250 mL) and transfer it to the above-mentioned base-containing system, place it in an ice bath and stir for 10 min, then add anhydrous tin tetrachloride (8.9 mL, 77.3 mmol), reacted for 1 h, the raw materials reacted completely, added saturated NaHCO 3 solution to quench the reaction, transferred to a separatory funnel, extracted three times with ethyl acetate, combined the ethyl acetate layers, dried over anhydrous sodium sulfate and filtered, and the filtrate Concentration under reduced pressure gave compound II (6.57 g, 96.3%).
Stage #1: 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose; 5‐fluorouracil With BSA In 1,2-dichloro-ethane at 20℃; for 1h; Inert atmosphere;
Stage #2: With anhydrous tin tetrachloride In 1,2-dichloro-ethane at 20℃; for 12h; Inert atmosphere;
Stage #1: 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose; 5‐fluorouracil With N,O-bis-(trimethylsilyl)-acetamide In 1,2-dichloro-ethane at 20℃; for 1h; Inert atmosphere;
Stage #2: With anhydrous tin tetrachloride In 1,2-dichloro-ethane at 20℃; for 12h; Inert atmosphere;
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