* 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.
6-Methyluracyl (1 g, 7.93 mmol) was added to phosphoryl chloride (7 eq, 5 ml) and the mixture was heated at reflux for 3 h. The mixture was poured onto ice and the organic layer was extracted with chloroform (3times, 20 ml) and dried over anhydrous MgSO4. The solvents were evaporated to give the dichloride as yellow crystals (0.62 g, 48percent). 1H NMR (400 MHz, CDCI3) 5 8.35 (s, 1 H), 2.39(s, 3H); 13C NMR (100 MHz, CDCI3) 6 162.5, 160.0,158.2, 129.1, 15.8. The 1H NMR spectrum was in accordance with literature:Wang, H., K. Wen, L. Wang, Y. Xiang, X. Xu, Y. Shen and Z. Sun (2012).Molecules, 2012, 17(4), 4533-4544.
Reference：
[1] Journal of Fluorine Chemistry, 1996, vol. 77, # 1, p. 93 - 95
[2] Patent: WO2018/151681, 2018, A1, . Location in patent: Paragraph 0099
[3] Synthetic Communications, 1992, vol. 22, # 20, p. 2927 - 2934
[4] Tetrahedron Letters, 1997, vol. 38, # 7, p. 1111 - 1114
[5] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 18, p. 2961 - 2966
[6] Patent: US5525724, 1996, A,
[7] Patent: EP714896, 1996, A1,
[8] Patent: US2005/234046, 2005, A1, . Location in patent: Page/Page column 63
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[ 1780-31-0 ]
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[1] Molecules, 2012, vol. 17, # 4, p. 4533 - 4544
[2] Organic and Biomolecular Chemistry, 2003, vol. 1, # 19, p. 3353 - 3361
[3] Chemische Berichte, 1905, vol. 38, p. 3397
[4] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1900, vol. 29, p. 304
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[1] European Journal of Organic Chemistry, 2006, # 14, p. 3152 - 3168
[2] Tetrahedron Letters, 1992, vol. 33, # 37, p. 5335 - 5338
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[1] Chemical Research in Toxicology, 1996, vol. 9, # 4, p. 745 - 750
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[1] Chemistry Letters, 1986, p. 1319 - 1322
[2] Chemistry Letters, 1986, p. 1319 - 1322
[3] Journal of Organic Chemistry, 1988, vol. 53, # 15, p. 3421 - 3424
[4] Bulletin of the Chemical Society of Japan, 1994, vol. 67, # 8, p. 2257 - 2264
[5] Journal of Organic Chemistry, 1988, vol. 53, # 15, p. 3421 - 3424
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[ 4433-40-3 ]
[ 94705-75-6 ]
[ 696-04-8 ]
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[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 14, p. 2711 - 2712
9
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[ 4433-40-3 ]
[ 27284-91-9 ]
[ 20433-38-9 ]
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[1] Chemistry Letters, 1983, p. 1471 - 1474
10
[ 65-71-4 ]
[ 4433-40-3 ]
[ 2417-22-3 ]
[ 13514-92-6 ]
[ 20433-38-9 ]
Reference：
[1] Chemistry Letters, 1983, p. 1471 - 1474
11
[ 65-71-4 ]
[ 4433-40-3 ]
[ 1123-21-3 ]
[ 2943-56-8 ]
[ 13514-92-6 ]
Reference：
[1] Chemistry Letters, 1982, p. 1041 - 1044
12
[ 65-71-4 ]
[ 4433-40-3 ]
[ 1123-21-3 ]
[ 13514-92-6 ]
[ 696-04-8 ]
Reference：
[1] Chemistry Letters, 1982, p. 1041 - 1044
13
[ 65-71-4 ]
[ 4433-40-3 ]
[ 13514-92-6 ]
[ 20433-38-9 ]
[ 696-04-8 ]
Reference：
[1] Chemistry Letters, 1983, p. 1471 - 1474
14
[ 65-71-4 ]
[ 4433-40-3 ]
[ 13514-92-6 ]
[ 696-04-8 ]
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[1] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 7, p. 865 - 870
[2] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 7, p. 865 - 870
15
[ 65-71-4 ]
[ 4433-40-3 ]
[ 1124-84-1 ]
[ 13514-92-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 7, p. 865 - 870
16
[ 70-54-2 ]
[ 65-71-4 ]
[ 4433-40-3 ]
[ 13514-92-6 ]
[ 696-04-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 7, p. 865 - 870
Reference：
[1] Chemistry Letters, 1982, p. 1041 - 1044
19
[ 65-71-4 ]
[ 4433-40-3 ]
[ 2417-22-3 ]
[ 1123-21-3 ]
[ 1124-84-1 ]
[ 13514-92-6 ]
[ 696-04-8 ]
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[1] Bulletin of the Chemical Society of Japan, 1990, vol. 63, # 10, p. 3001 - 3005
20
[ 65-71-4 ]
[ 4433-40-3 ]
[ 2417-22-3 ]
[ 27284-91-9 ]
[ 13514-92-6 ]
[ 20433-38-9 ]
[ 696-04-8 ]
Reference：
[1] Chemistry Letters, 1983, p. 1471 - 1474
21
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[ 4433-40-3 ]
[ 2943-56-8 ]
[ 13514-92-6 ]
Reference：
[1] International Journal of Chemical Kinetics, 1994, vol. 26, # 7, p. 693 - 703
22
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[ 4433-40-3 ]
[ 2417-22-3 ]
[ 2943-56-8 ]
[ 27284-91-9 ]
[ 13514-92-6 ]
Reference：
[1] Canadian Journal of Chemistry, 1986, vol. 64, p. 2297 - 2300
23
[ 65-71-4 ]
[ 4433-40-3 ]
[ 2417-22-3 ]
[ 1123-21-3 ]
[ 13514-92-6 ]
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Reference：
[1] Canadian Journal of Chemistry, 1993, vol. 71, # 3, p. 307 - 312
24
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[ 4433-40-3 ]
[ 2943-56-8 ]
[ 27284-91-9 ]
[ 13514-92-6 ]
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Reference：
[1] Canadian Journal of Chemistry, 1986, vol. 64, p. 2297 - 2300
25
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[ 65-71-4 ]
[ 4433-40-3 ]
[ 1124-84-1 ]
[ 13514-92-6 ]
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Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 7, p. 865 - 870
26
[ 65-71-4 ]
[ 23945-44-0 ]
Yield
Reaction Conditions
Operation in experiment
96.1%
With dihydrogen peroxide; 1-hydroxy-1,2,3-benzotriazine-4(3H)-one In water at 130℃; for 3 h; Autoclave
Add 100 g of thymine and 300 mL of water to the autoclave, and add 35 mL of hydrogen peroxide at a concentration of 30percent.15 g of 1-hydroxy-1,2,3-benzotriazine-4(3H)-one and 35 g of the catalyst prepared in Example 3, replacing the inside of the autoclave with an oxygen atmosphere, and heating to 130 ° C for 3 h.The reaction solution was cooled, filtered, concentrated, and placed in an ice-water mixture to cool.150 g of a white solid was precipitated, the yield was 96.1percent, and the purity was 99.3percent.
Reference：
[1] Patent: CN108341785, 2018, A, . Location in patent: Paragraph 0014-0020
[2] Nucleic Acids Research, 2015, vol. 43, # 20, p. 10026 - 10038
[3] Nucleic Acids Research, 2015, vol. 43, # 20, p. 10026 - 10038
Stage #1: With potassium hydroxide In water at 20℃; for 0.166667 h; Stage #2: for 1.5 h;
willThymine(10.0 g, 79.3 mmol) was suspended in H2O (150 mL).Aqueous KOH solution (50 mL, 3.6 M) was added thereto.After the mixture was stirred at room temperature for 10 min,The solution gradually became clear.Then chloroacetic acid (15.0 g, 159 mmol) was added thereto.The reaction solution was heated to reflux for 90 min.After the reaction solution is cooled to room temperature,Acidified to pH=3 with concentrated hydrochloric acid,Then placed at 4 ° C overnight,A white crystalline precipitate precipitated.The white crystalline precipitate was obtained by filtration.P2O5 is vacuum dried,Get the target product4.5 g (yield 31percent).
Reference：
[1] Chemistry - A European Journal, 2000, vol. 6, # 1, p. 62 - 72
[2] Organic and Biomolecular Chemistry, 2006, vol. 4, # 2, p. 291 - 298
[3] Bioconjugate Chemistry, 2016, vol. 27, # 10, p. 2301 - 2306
[4] European Journal of Organic Chemistry, 2013, # 22, p. 4804 - 4815
[5] Patent: CN108478807, 2018, A, . Location in patent: Paragraph 0022; 0053; 0070; 0071
[6] Chinese Chemical Letters, 2012, vol. 23, # 6, p. 677 - 680
30
[ 79-08-3 ]
[ 65-71-4 ]
[ 20924-05-4 ]
Reference：
[1] Tetrahedron Letters, 1994, vol. 35, # 29, p. 5173 - 5176
[2] Organic and Biomolecular Chemistry, 2008, vol. 6, # 17, p. 3171 - 3176
[3] Biomacromolecules, 2012, vol. 13, # 9, p. 3004 - 3012
[4] Collection of Czechoslovak Chemical Communications, 1996, vol. 61, p. S234 - S237
[5] Chemical Biology and Drug Design, 2015, vol. 85, # 3, p. 336 - 347
[6] Journal of Organic Chemistry, 2016, vol. 81, # 23, p. 11612 - 11625
[7] Journal of Polymer Science, Part A: Polymer Chemistry, 2018, vol. 56, # 7, p. 789 - 796
Reference：
[1] Heterocycles, 1989, vol. 28, # 2, p. 643 - 652
[2] Journal of the American Chemical Society, 2003, vol. 125, # 23, p. 6878 - 6879
[3] Synthesis, 2003, # 8, p. 1171 - 1176
[4] Magnetic Resonance in Chemistry, 2003, vol. 41, # 6, p. 478 - 480
[5] Journal of Organic Chemistry, 1994, vol. 59, # 19, p. 5767 - 5773
[6] Angewandte Chemie, 1992, vol. 104, # 8, p. 1039 - 1041
[7] Journal of the American Chemical Society, 1992, vol. 114, # 5, p. 1895 - 1897
[8] ACS Combinatorial Science, 2014, vol. 16, # 9, p. 485 - 493
33
[ 65-71-4 ]
[ 20924-05-4 ]
Reference：
[1] Patent: EP720615, 2000, B1,
34
[ 105-36-2 ]
[ 65-71-4 ]
[ 20924-05-4 ]
Yield
Reaction Conditions
Operation in experiment
75%
With hydrogenchloride; sodium hydroxide; ammonium sulfate; 1,1,1,3,3,3-hexamethyl-disilazane In methanol; acetonitrile
Example 5 Synthesis of 2-(1'-thyminyl)acetic acid To 300 grams of thymine was added 750 mL hexamethyldisilazane and 15 grams of ammonium sulfate. The stirring reaction was heated at reflux until no more gas was evolved. The reaction was then cooled to 80° C. and then 160 mL of ethylbromoacetate was added. Gentle heating of the reaction was continued until tlc analysis indicated that 95percent of the starting material was consumed. The reaction was then cooled to 20° C. in an ice bath and then 150 mL of methanol was added dropwise while stirring in the ice bath. Once the addition of methanol was complete, 2.5 liters of 3N NaOH was added carefully. The ice bath was then removed and gas was passed over the reaction rapidly to vaporize excess silanes. Then 80 grams of sodium hydroxide was added and the reaction was allowed to stir overnight. In the morning, 1 L of 6N HCl was added to the reaction to cause the product to crystallize. The product was then collected by vacuum filtration and washed with dilute aqueous hydrochloric acid. The collected product was then suspended in 1.5 L of acetonitrile and the solution allowed to reflux with stirring. After cooling overnight, the solid was again collected by vacuum filtration, washed with acetonitrile, dichloromethane, and acetonitrile. Yield: 327 grams (75percent). 1 H--NMR (d6 DMSO): δ=12.06 (s, 1H), 11,31 (s, 1H), 7.48 (s,1H), 4.35 (s, 2H), 1.74 (s, 3H)
Reference：
[1] Patent: US6063569, 2000, A,
35
[ 79-11-8 ]
[ 65-71-4 ]
[ 20924-05-4 ]
Reference：
[1] Journal of the American Chemical Society, 1953, vol. 75, p. 5757,5758
36
[ 65-71-4 ]
[ 54-20-6 ]
Reference：
[1] Journal of Fluorine Chemistry, 1996, vol. 77, # 1, p. 93 - 95
37
[ 65-71-4 ]
[ 69256-17-3 ]
Reference：
[1] Journal of Organic Chemistry, 1988, vol. 53, p. 85 - 88
[2] Organic Letters, 2017, vol. 19, # 2, p. 404 - 407
Stage #1: With N,N-bis(trimethylsilyl)acetamide In acetonitrile at 20℃; for 3 h; Inert atmosphere Stage #2: With trimethylsilyl trifluoromethanesulfonate In acetonitrile at -30℃;
Was added to the reactor5-methylthymidine20-2 (0.530 g, 4.2 mmol),Compound 21-1 (0.328 g, 1.4 mmol) and40 ml of anhydrous acetonitrile, argon was added dropwise to the solution at room temperatureBis (trimethylsilyl) acetamide(2.2 mL, 8.7 mmol),After stirring for 3 hours, the temperature was lowered to -30 ° C,To the system was added trimethylsilyl trifluoromethanesulfonate (1 mL, 5.6 mmol)Stir at room temperature, TLC followed the reaction.The reaction product was added with dichloromethane,The organic layers were washed with saturated sodium bicarbonate solution, water and saturated brine, respectively,Dried, concentrated, column chromatography (MeOH: CHCl3 = 3: 100)And purified to give the title product 21-2 (yield 70percent).
Reference：
[1] Patent: CN106496130, 2017, A, . Location in patent: Page/Page column 0043
Stage #1: With potassium carbonate; phosphorus(V) oxybromide In acetonitrile at 0 - 80℃; for 72 h; Stage #2: With water; potassium carbonate In acetonitrile at 0℃;
Intermediate 12,4-Dibromo-5-methylpyrimidineTo thymine (3.7 g, 29 mmol) and phosphorus(V) oxybromide (25.0 g, 87.2 mmol) in acetonitrile (CH3CN) (150 mL) at 0 0C was added portion wise K2CO3 (12.1 g, 87.2 mmol). The mixture was allowed to warm to room temperature and then heated to 80 0C for 3 days. The reaction mixture was poured onto ice and the pH of the resulting slurry was adjusted to pH 7 by addition of K2CO3(S). The aqueous layer was extracted with methylene chloride (CH2Cl2). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. Purification by flash chromatography on silica gel (0 - 30 percent ethyl acetate (EtOAc)/hexanes) afforded the desired product (7.1 g, 96percent) as a white solid. LC-MS (ES) m/z = 251 , 253 and 255 [M+H]+.
With sodium hydroxide; In water; at 20 - 50℃; for 20.5h;
To a solution of sodium hydroxide (96 g, 2.4 mol) in H2O (1000 mL) was added into 5-methyl-2, 3-dihydropyrimidin-4(1H)-one (2, 100.8 g, 0.8 mol). When most of the solid dissolve, diethyl sulfate (252.3 g, 2 mol) was added dropwise in 30min. After stirring for 10h, diethyl sulfate (50.5 g, 0.4 mol) and sodium hydroxide (10 g, 0.25 mol) were added. The mixture was stirred for another 10h, then sodium chloride (200 g) was added. The mixture was extracted with ethyl acetate (3×500 mL). The combined organic layer was concentrated to get white solid 5-trimethyl-2, 3-dihydropyrimidin-4(1H)-one (3, 115.9 g), yield: 94%, mp 153.2-154.4Clit.1 mp 155C
willThymine(10.0 g, 79.3 mmol) was suspended in H2O (150 mL).Aqueous KOH solution (50 mL, 3.6 M) was added thereto.After the mixture was stirred at room temperature for 10 min,The solution gradually became clear.Then chloroacetic acid (15.0 g, 159 mmol) was added thereto.The reaction solution was heated to reflux for 90 min.After the reaction solution is cooled to room temperature,Acidified to pH=3 with concentrated hydrochloric acid,Then placed at 4 C overnight,A white crystalline precipitate precipitated.The white crystalline precipitate was obtained by filtration.P2O5 is vacuum dried,Get the target product4.5 g (yield 31%).
3-(3-benzyl-5-methyl-2,4-dioxo-3,4-dihydro-2<i>H</i>-pyrimidin-1-yl)-2-<i>tert</i>-butoxycarbonylamino-propionic acid benzyl ester[ No CAS ]
3-[3-(2-benzyloxycarbonyl-2-<i>tert</i>-butoxycarbonylamino-ethyl)-5-methyl-2,6-dioxo-3,6-dihydro-2<i>H</i>-pyrimidin-1-yl]-2-<i>tert</i>-butoxycarbonylamino-propionic acid benzyl ester[ No CAS ]
To a stirred suspension containing 280 mg (2.23 mmol) of thyminein 5 mL of DMSO was added 0.40 mL (407 mg, 2.68 mmol) ofDBU. Within 15 min, a solution containing 491 mg (2.68 mmol) ofN-(tert-butoxycarbonyl)-L-serine b-lactone in 5 mL of DMSO wasadded. The reaction mixture was stirred at room temperature for2 h under argon, then diluted with 10 mL of 0.5 N HCl andextracted with two 20-mL portions of EtOAc. The combinedorganic phase was dried (MgSO4) and concentrated under diminishedpressure. The residue was purified by chromatography on asilica gel column (10 2 cm). Elution with 10:1 ethyl acetate/methanol gave 13 as a colorless solid: yield 230 mg (33%); silicagel TLC Rf 0.30 (5:1 ethyl acetate/methanol). To a cooled (0 C)solution containing 230 mg (0.73 mmol) of 13 in 5 mL of anhydrousMeOH was added dropwise 0.05 mL (87.4 mg, 0.73 mmol)of SOCl2. The reaction mixture was allowed to warm slowly toroom temperature with stirring for 2 h, then diluted with 50 mLof brine and extracted with two 50-mL portions of EtOAc. The combinedorganic phase was dried (MgSO4) and concentrated underdiminished pressure. The residue was purified by chromatographyon a silica gel column (10 2 cm). Elution with 10:1 ethyl acetate/methanol gave 14 as a colorless solid: yield 156 mg (65%); silica gelTLC Rf 0.81 (5:1 ethyl acetate/methanol); 1H NMR (CDCl3) d 1.41 (s,9H), 1.88 (s, 3H), 3.78 (s, 3H), 4.03-4.20 (m, 2H), 4.47-4.50 (m, 1H),5.55 (s, 1H), 6.98 (s, 1H) and 9.34 (br s, 1H); 13C NMR (CD3OD) d12.4, 28.6, 50.0, 50.3, 53.1, 80.9, 110.7, 143.0, 152.6, 157.2, 166.5and 171.4; mass spectrum (APCI), m/z 328.1500 (M+H)+(C14H22N3O6 requires m/z 328.1509).
Intermediate 12,4-Dibromo-5-methylpyrimidineTo thymine (3.7 g, 29 mmol) and phosphorus(V) oxybromide (25.0 g, 87.2 mmol) in acetonitrile (CH3CN) (150 mL) at 0 0C was added portion wise K2CO3 (12.1 g, 87.2 mmol). The mixture was allowed to warm to room temperature and then heated to 80 0C for 3 days. The reaction mixture was poured onto ice and the pH of the resulting slurry was adjusted to pH 7 by addition of K2CO3(S). The aqueous layer was extracted with methylene chloride (CH2Cl2). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. Purification by flash chromatography on silica gel (0 - 30 % ethyl acetate (EtOAc)/hexanes) afforded the desired product (7.1 g, 96%) as a white solid. LC-MS (ES) m/z = 251 , 253 and 255 [M+H]+.
With N,O-bis-(trimethylsilyl)-acetamide; In dichloromethane;
EXAMPLE B 1-[(2-Acetoxyethoxy)Methyl]Thymine Thymine (0.63 g, 5 mmol) was added to <strong>[59278-00-1]2-acetoxyethyl acetoxymethyl ether</strong> (1.32 g, 7.5 mmol) dissolved in CH2Cl2 (15 mL). The reaction mixture was stirred at room temperature and N,O-bis(trimethylsilyl)acetamide (2.96 mL, 12 mmol) was added dropwise. After 3 hours of stirring, the clear solution was cooled to 0 C., and SnCl4 (0.12 mL, 1 mmol) was added. The reaction mixture was allowed to come to room temperature and stirred overnight. A mixture of saturated aqueous NaHCO3 (25 mL) and CHCl3 (50 mL) was prepared and cooled in ice. The reaction mixture was added slowly with vigorous stirring; a white foam formed immediately. After filtration, the aqueous layer was further extracted with ethyl acetate (3*25 mL) and CHCl3 (25 mL), and the combined organic layers were dried over anhydrous Na2SO4. After filtration of drying agent and removal of solvents in vacuo, an oily liquid was obtained. It was purified on a silica gel column using 2:1 CHCl3/CH3COCH3 as the eluent to give the desired product. Yield 36%; Wt. 4.0 g; mp 105-107 C.; 1 H NMR (DMSO-d6) 1.8 (s, CH3 C5 thymine), 2.0 (s, CH3 CO), 3.65 (m, CO O CH2 CH2), 4.1 (m, CO O CH2 CH2), 5.05 (s, O CH2 N), 7.55 (s, H C6 thymine), 11.3 (s, HN thymine).
To a stirred solution of 3-O-benzyl-4-C-hydroxymethyl-1,2-O-isopropylidene-beta-D-erythro-pentofuranose 1 (Youssefyeh, R. D.; Verheyden, J. P. H.; Moffatt, J. G. J. Org. Chem. 1979, 44, 1301-1309). (200 mg, 0.64 mmol) in acetic acid (3.69 mL, 64.4 mmol) at 0 C. was added acetic anhydride (0.61 mL, 6.44 mmol) and concd H2SO4 (0.34 muL, 6.44 mumol). After 25 min the reaction mixture was allowed to warm to rt. Stirring was continued for 2 h after which the mixture was poured into ice cooled sat. aq NaHCO3 (150 mL). The solution was extracted with dichloromethane (2x150 mL), and the combined organic phases were washed with sat. aq NaHCO3 (2x100 mL), dried (Na2SO4), filtered and evaporated to dryness in vacuo to give the crude anomeric mixture of the acetylated glycoside donor as a colorless liquid (258 mg, 0.59 mmol). The liquid (246 mg, 0.56 mmol) was dissolved in anhyd acetonitrile (5 mL) with stirring. Thymine (144 mg, 1.14 mmol) and N,O-bis(trimethylsilyl)acetamide (0.99 mL, 4.00 mmol) were added, and the mixture was heated to reflux for 1.5 h and then cooled to 0 C. Trimethylsilyl triflate (0.23 mL, 1.25 mmol) was added dropwise during 5 min and the mixture was heated to 80 C. for 3.5 h. The reaction mixture was allowed to cool to rt, and ice cooled sat. aq NaHCO3 (10 mL) was added. Extraction was performed with dichloromethane (2x20 mL), and the combined organic phases were washed successively with sat. aq NaHCO3 (2x20 mL) and brine (20 mL), dried (Na2SO4), filtered and evaporated to dryness in vacuo. The residue was purified by DCVC (0-1% MeOH in dichloromethane v/v) to give the nucleoside (259 mg, 91%) as a white solid material. FAB-MS m/z found 505.0 ([MH]+, calcd 505.2); 1H NMR (CDCl3) delta 9.93 (s, 1H, NH), 7.37-7.28 (m, 5H, Ph), 7.09 (d, J=0.9, 1H, H6), 5.79 (d, J=3.5, 1H, H1'), 5.53 (dd, J=6.3, 3.7, 1H, H2'), 4.64-4.08 (m, 7H, CH2Ph, H3', H5'a, H5'b, H1'a, H1'b), 2.11 (s, 3H, CH3C(O)), 2.10 (s, 3H, CH3C(O)), 2.07 (s, 3H, CH3C(O)), 1.91 (s, 3H, CH3); 13C NMR (CDCl3) ' 170.4, 169.9, 163.9, 149.9 (CH3C(O), C2, C4), 137.1, 136.8, 128.3, 128.0, 127.8 (C6, Ph), 111.0 (C5), 90.6 (C1'), 84.2 (C4'), 77.0 (C3'), 74.2 (CH2Ph), 73.7 (C2'), 63.6, 62.2 (C5', C1'), 20.6, 20.5 (CH3C(O)), 12.3 (CH3).
Step 1. Sodium hydride (60% in mineral oil, 85mg, 2.08mmol) was added to a mixture of thymine (265mg, 2.28mmol) and dry DMF (19ml). Reaction mixture was stirred at room temperature for 2h and cooled to -78C. A solution of (S)-(2-oxooxetan-3-yl)carbamate (460mg, 2.08mmol) in DMF (5ml) was added dropwise within 1h. The cooling bath was removed and the reaction mixture was stirred at room temperature for 18h. Volatiles were distilled off under reduced pressure. The residue (1.255g) was dissolved in water and acidified with 2M HCl to pH 2 and extracted with ethyl acetate (3×80ml). The extracts were combined and dried (MgSO4). Volatiles were distilled off under reduced pressure and the residue (0.74g) was subjected to column chromatography (DCM:MeOH:AcOH, 97:3:0.1, v/v/v then 90:10:0.1, v/v/v) to give (S)-2-(((benzyloxy)carbonyl)amino)-3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propanoic acid 2c as a white solid 0.265g (36%). [alpha] -85.1 (c 0.20 in MeOH). 1H NMR (500MHz, DMSO-d6): delta 1.68 (s, 3H); 3.58 and 4.24 (AB part of ABX system, 2JAB 13.6 3JAX 10.1Hz 3JBX 4.7Hz, 2H), 4.30-4.35 (X part of ABX system, 1H); 4.97 and 5.02 (AB quartet, 2JAB 10.0, 2H); 7.27-7.35 (m, 6H); 7.48 (br s, 1H); 11.25 (s, NH, 1H). 13C NMR (125MHz, DMSO-d6): delta 12.0; 48.7; 52.7; 65.4; 107.8; 127.4; 127.8; 128.4; 137.0; 142.0; 150.9; 156.0; 164.3; 171.3. Step 2. Thionyl chloride (0.1ml, 1.37mmol) was added drop by drop to a mixture of (S)-2-(((benzyloxy)carbonyl)amino)-3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propanoic acid 2c (85mg, 0.24mmol) and ethanol (8ml) cooled in ice-water bath (-5÷0C). The mixture was stirred at the cooling bath for 30min. The bath was removed and the mixture was left at room temperature overnight. Volatiles were distilled off under reduced pressure. The residue was dissolved in AcOEt (30ml) and washed with aqueous saturated solution of NaHCO3 (15ml) and water (15ml), brine (15ml) and dried (MgSO4). Volatiles were distilled off under reduced pressure to give (S)-ethyl 2-(((benzyloxy)carbonyl)amino)-3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propanoate 2a as a white solid (75mg, 83%). [alpha] -85.6 (c 0.11 in MeOH). 1H NMR (500MHz, DMSO-d6): delta 1.16 (t, 3JHH 7.1Hz, 3H); 1.70 (d, 4JHH 1.5Hz, 3H), 3.68 and 4.16 (part AB of ABX system, 2JAB 13.8Hz, 3JAX 9.0Hz, 3JBX 5.5Hz, 2H), 4.10 (q, 3JHH 7.1Hz, 2H); 4.38-4.43 (partXof ABX system, 1H); 5.01 and 5.04 (AB quartet, 2JAB 12.5Hz, 2H); 7.30-7.38 (m, 6H); 7.84 (d, 4JHH 8.5Hz, 1H, NH); 11.31 (br s, 1H, NH). 13C NMR (125MHz, DMSO-d6): delta 11.9, 13.9, 47.9, 52.2, 61.10, 65.6, 108.2, 127.5, 127.8, 128.4, 136.8, 141.7, 150.9, 156.0, 164.2, 169.7.
Example 5 1-(2,3,5-tri-O-benzoyl-beta-L-ribofuranosyl)thymine (3, B=thymine, R2=Bz)-direct condensation of 1 in the presence of catalyst) A mixture of thymine (12.6 g, 0.1 mol) and ammonium sulfate (10 mg) in hexamethyldisilazane (120 mL) is stirred and heated to reflux. When the mixture becomes clear, excess hexamethyldisilazane is removed in vacuo. The residue is dissolved in 1,2-dichloroethane (250 mL) and added to a solution of 1 (R1=Ac, R2=Bz) (50 g, 0.1 mol) in 1,2-dichloroethane (150 mL). To the stirred solution is added tin tetrachloride (25 mL), and the mixture is stirred overnight at room temperature, then poured into saturated sodium bicarbonate solution (500 mL). When the frothing ceased, the suspension is filtered through a Celite pad which is then thoroughly washed with methylene chloride (500 mL). The combined organic layers are washed with water (500 mL×2), dried over sodium sulfate, concentrated in vacuo, and the residue crystallized from ethyl acetate to give 3 (B=thymine, R2=Bz), 48.5 g (85%), mp 167-168 C. The 1H-NMR spectrum of this sample is identical to that of the D-counterpart. (Watanabe, K. A.; Fox, J. J. J. Heterocycl. Chem. 1969, 6, 109.)
With caesium carbonate; In dimethyl sulfoxide; at 120℃; for 3h;
General procedure: Nucleobase (1.5 mmol) and base (1.5 mmol) were heated at 100 C in dry DMF/DMSO (15 ml). Mesyl derivative (1 mmol) dissolved in dry DMF/DMSO (10 ml) was then added dropwise and the mixture was heated at 120 C for 3 h. The solvent was evaporated and product purified on a silica gel using flash chromatography.
AZT (13.4 mg, 0.05 mmol; 1.0 mM) and cysteine (60.7 mg, 0.5 mmol; 10 mM) were dissolved in 50 mL of phosphate buffer solution (pH 7.08; made from 1.56 g of NaH2PO4 ? 2H2O and 3.58 g of Na2HPO4 ?12 H2O in 1 L of Milli-Q water). The solution was divided into 5 vials of 9 mL each. The 5 vials of solution were saturated with N2O (or 9:1 N2O: O2) for 30 min before irradiated at 2 kGy, 4 kGy, and 6 kGy, which were equivalents to 313.3, 622.7, and 919.5 min in the gamma cell, respectively. At the equivalent time of the dosage, the sample was taken for HPLC and LCMS analysis.
tert-butyl (3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
19%; 33%
In a round bottom flask, 71 mg of thymine (CAS: 65-71-4, 126.1 g/mol, 0.56 mmol) and 52 mg of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, CAS: 6674-22-2, 152.2 g/mol, 0.341 mmol) were suspended in 5 mL of dry DMF. This mixture was stirred for 1 h at 70 C. Separately, 46 mg of mesylate 9b (253.0 g/mol; 0.18 mmol) and 22 mg of TBAI (tetrabutylammonium iodide, CAS: 311-28-4, 396.4 g/mol, 0.056 mmol), were dissolved in 3 mL of dry DMF in round bottom flask. This mixture was added to the initial mixture, and the reaction was stirred for 12 h at 70 C. Excess water was added to the reaction mixture, which was later extracted with AcOEt (3 times). The organic extract was washed with water (5 times). The organic extract was washed with water (5 times), dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure. Flash chromatography afforded 3.5 mg of cyclic carbamate 10c (Hexanes/AcOEt 95:5, 19% yield) and 17 mg of product 10a (Hexanes/AcOEt 9:1, 33%).
1-(2-deoxy-β-D-erythro-pentofuranosyl)-5-hydroxy-5-methylhydantoin[ No CAS ]
trans-5,6-dihydroxy-5,6-dihydrothymidine[ No CAS ]
N-(2-deoxy-β-D-erythro-pentouranosyl)([2-hydroxypropanoyl]carbamoyl)carbamic acid[ No CAS ]
[ 5116-24-5 ]
[ 41308-58-1 ]
[ 67145-02-2 ]
[ 65-71-4 ]
cis et trans 6-hydroxy-5,6-dihydrothymidine[ No CAS ]
[ 5627-00-9 ]
[ 38241-09-7 ]
[ 4494-26-2 ]
Yield
Reaction Conditions
Operation in experiment
at 25℃; for 0.5h;Sonication; Inert atmosphere;
General procedure: dT was purchased from Pharma Waldhof and used as such. All solutions were prepared in water purified by a Cascada Lab Water Systems and of resistivity 18.2 MOmega cm. Solutions of dT (10-4 mol/L, 250 mL) was subjected to sonolysis at four different frequencies (200, 350, 620 and 1000 kHz) at three different power densities, 10.5, 24.5 and 42 W/mL for 2 h. Two frequencies (620 kHz and 1 MHz), among the four studied, fall under the range used for the surgical non disruptive applications. The sonolysis was carried out in a glass reactor with an L3 ELAC Nautik ultrasound generator powered by an Allied Signal R/F generator (T & C power conversion, Model AG 1006). For the experiments under argon saturated atmosphere, the solution was bubbled with argon gas for half an hour at a pressure of 5 psi prior to sonolysis and Ar was bubbled throughout the experiment. Sonolysis was carried out only at a power density of 42 W/mL under argon atmosphere, where there was maximum degradation in the case of aerated conditions. Two transducers were used with resonances 212 and 620 kHz and 350 and 1000 kHz respectively. The temperature was maintained at 25 ± 1 C.
1-(2-deoxy-β-D-erythro-pentofuranosyl)-5-hydroxy-5-methylhydantoin[ No CAS ]
trans-5,6-dihydroxy-5,6-dihydrothymidine[ No CAS ]
5-formyl-5,6-dihydroxy-5,6-dihydro-2’-deoxyuridine[ No CAS ]
N-(2-deoxy-β-D-erythro-pentouranosyl)([2-hydroxypropanoyl]carbamoyl)carbamic acid[ No CAS ]
[ 5116-24-5 ]
[ 65-71-4 ]
[ 5627-00-9 ]
[ 38241-09-7 ]
[ 4494-26-2 ]
Yield
Reaction Conditions
Operation in experiment
With air; at 25℃; for 1h;Sonication;
General procedure: dT was purchased from Pharma Waldhof and used as such. All solutions were prepared in water purified by a Cascada Lab Water Systems and of resistivity 18.2 MOmega cm. Solutions of dT (10-4 mol/L, 250 mL) was subjected to sonolysis at four different frequencies (200, 350, 620 and 1000 kHz) at three different power densities, 10.5, 24.5 and 42 W/mL for 2 h. Two frequencies (620 kHz and 1 MHz), among the four studied, fall under the range used for the surgical non disruptive applications. The sonolysis was carried out in a glass reactor with an L3 ELAC Nautik ultrasound generator powered by an Allied Signal R/F generator (T & C power conversion, Model AG 1006). For the experiments under argon saturated atmosphere, the solution was bubbled with argon gas for half an hour at a pressure of 5 psi prior to sonolysis and Ar was bubbled throughout the experiment. Sonolysis was carried out only at a power density of 42 W/mL under argon atmosphere, where there was maximum degradation in the case of aerated conditions. Two transducers were used with resonances 212 and 620 kHz and 350 and 1000 kHz respectively. The temperature was maintained at 25 ± 1 C.
With dihydrogen peroxide; 1-hydroxy-1,2,3-benzotriazine-4(3H)-one; In water; at 130℃; for 3h;Autoclave;
Add 100 g of thymine and 300 mL of water to the autoclave, and add 35 mL of hydrogen peroxide at a concentration of 30percent.15 g of 1-hydroxy-1,2,3-benzotriazine-4(3H)-one and 35 g of the catalyst prepared in Example 3, replacing the inside of the autoclave with an oxygen atmosphere, and heating to 130 ° C for 3 h.The reaction solution was cooled, filtered, concentrated, and placed in an ice-water mixture to cool.150 g of a white solid was precipitated, the yield was 96.1percent, and the purity was 99.3percent.
Compound 2 (46.03g, 0.365mol) was added to the reaction flask, then added HMDS(117.8g, 0.73mol) and ammonium sulphate (1.4g, 0.011mol), heated to 145 deg.] C, heatingwas stopped after 10h the reaction was cooled to room temperature; the reaction systemwas added 500mL of chloroform and dried, was added intermediate 3 (107.1g, 0.402mol), atroom temperature, the reaction 6H; after completion of the reaction, 10% sodiumhydroxide solution with pH value adjusted to neutral, washed with water, divided layer,the organic layer was concentrated to dryness, 150mL acetone was added with stirring,suction filtration to give a white solid into 79.6 g, yield 90%, purity 98%. Meltingpoint: 187.5-188.0 (literature values: 188-190 )
Was added to the reactor5-methylthymidine20-2 (0.530 g, 4.2 mmol),Compound 21-1 (0.328 g, 1.4 mmol) and40 ml of anhydrous acetonitrile, argon was added dropwise to the solution at room temperatureBis (trimethylsilyl) acetamide(2.2 mL, 8.7 mmol),After stirring for 3 hours, the temperature was lowered to -30 C,To the system was added trimethylsilyl trifluoromethanesulfonate (1 mL, 5.6 mmol)Stir at room temperature, TLC followed the reaction.The reaction product was added with dichloromethane,The organic layers were washed with saturated sodium bicarbonate solution, water and saturated brine, respectively,Dried, concentrated, column chromatography (MeOH: CHCl3 = 3: 100)And purified to give the title product 21-2 (yield 70%).
To a 1 L glass vessel equipped with a stirrer, condenser and a thermometer probe were added the Formula II (50.0 g, 0.127 mol, 1.00 equiv.), Formula III (200 mL, 4.00 vol), Thymine (15.99 g, 0.127 mol, 1.00 equiv.) and Methanol (300 mL, 6.00 vol). The reaction mass was heated to 67±2 C. The reaction mass was maintained at 65±2 C under stirring. After completion of the reaction, Methanol (200 mL, 4.00 vol) was added to the reaction mass at constant rate. The reaction mass was maintained at the same temperature under stirring. The mass was cooled to 25±5 C and maintained at the same temperature. The mass was filtered and the solid was washed with Methanol (250 mL, 5.00 vol), suck dried and dried at 50±5 C under vacuum to obtain Dasatinib-Thymine co-crystal of Formula la as a crystalline solid (57.5 g, 91.38% w.r.t Formula II, 99.91% AUC, N-Oxide impurity:
1-(5'-hydroxy-5',6'-dihydrothymin-6'-yl)thymine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dipotassium peroxodisulfate; In water; for 0.0333333h;UV-irradiation;
Thymine (T) was purchased from Sigma Aldrich and K2S2O8from SRL. All the solutions were prepared with water purified by Cascada Lab Water Systems and of resistivity 18.2M Omega cm. The sulfate radicals were produced by the UV-photolysis of peroxide asreported elsewhere [39]. The solution containing T (10-4 M) and K2S2O8 (10-3 M) was subjected to UV irradiation at a wavelength of 254 nm for about 2 min. The solution was then directly subjected to UPLC-ESI-CID analysis.
With potassium dihydrogenphosphate; E. coli purine nucleoside phosphorylase; E. coli uridine phosphorylase; In aq. buffer; at 20℃; for 20h;pH 7.5;Enzymatic reaction;
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. Yield 58 mg (75%) as a white powder. M.p. 166-171 C dec. (Lit. 183-187 C [22]). Rf 0.74 (dichloromethane: ethanol, 9:1, v/v). 1H NMR (300 MHz, D2O, delta, J/Hz): 7.76 q (1H, 4JHMe= 1.2, H6 Thy), 5.99 d (1H, J1?2?=4.8, H1?), 4.42 dd (1H, J2?1?=4.8, J2?3?=5.4, H2?), 4.32 t (1H, J3?2?=J3?4?=5.4, H3?), 4.20 ddd (1H, J4?3?=5.4, J4?5?a=3.1, J4?5?b=4.3, H4?), 3.99 dd (1H, J5?a4?=3.1, J5?a5?b=-12.7, H5'a), 3.88 dd (1H, J5?b4?=4.3, J5?b5?a=-12.7, H5'b), 1.97 d (1H, 4JMe-H=1.2, CH3 Thy). UV (H2O): pH 2-7: lambdamax (epsilon)=266 nm (9600); pH 13: lambdamax (epsilon)=266 nm (7400).
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 40℃;Inert atmosphere;
General procedure: The nucleobase, K2CO3 and catalytic amounts of KI were mixedin dry DMF. The suspension was degassed with argon for 15 min. Asolution of <strong>[73870-24-3]4-(bromomethyl)pyridine hydrobromide</strong> in dry DMFwas added slowly to the suspension. The mixture was stirred underargon at 40C overnight and the reaction progress was followed byTLC. The crude was dried under vacuum and puried by columnchromatography (silica gel, MeOH: Et3N: DCM 1:0.2:20).
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