* 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 ferric sulfate nonahydrate In water at 80℃; for 24 h;
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
With copper(II) choride dihydrate In water at 80℃; for 24 h;
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
Reference:
[1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
6
[ 77287-34-4 ]
[ 51953-18-5 ]
[ 1455-77-2 ]
[ 120-89-8 ]
[ 73-40-5 ]
[ 328-42-7 ]
[ 2491-15-8 ]
[ 110-15-6 ]
[ 71-30-7 ]
[ 120-73-0 ]
[ 144-62-7 ]
[ 113-00-8 ]
[ 127-17-3 ]
[ 66-22-8 ]
[ 66224-66-6 ]
[ 57-13-6 ]
[ 56-40-6 ]
[ 302-72-7 ]
Reference:
[1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
7
[ 71-30-7 ]
[ 74-88-4 ]
[ 1122-47-0 ]
Reference:
[1] European Journal of Medicinal Chemistry, 2009, vol. 44, # 3, p. 1172 - 1179
[2] New Journal of Chemistry, 2010, vol. 34, # 11, p. 2634 - 2642
[3] Journal of Biological Chemistry, 1909, vol. 5, p. 62[4] Chem. Zentralbl., 1908, vol. 79, # II, p. 1265
[5] Patent: US2013/245043, 2013, A1, . Location in patent: Paragraph 0527; 0528; 0529; 0530
8
[ 71-30-7 ]
[ 10504-60-6 ]
[ 1122-47-0 ]
Reference:
[1] Bulletin de la Societe Chimique de France, 1984, vol. 2, # 11-12, p. 431 - 434
9
[ 71-30-7 ]
[ 616-38-6 ]
[ 1122-47-0 ]
[ 6220-49-1 ]
[ 2228-27-5 ]
[ 124210-92-0 ]
Reference:
[1] Zeitschrift fuer Naturforschung, B: Chemical Sciences, 1989, vol. 44, # 7, p. 863 - 865
10
[ 512-56-1 ]
[ 71-30-7 ]
[ 4776-08-3 ]
[ 608-34-4 ]
[ 1122-47-0 ]
[ 6749-87-7 ]
Reference:
[1] Bulletin of the Chemical Society of Japan, 1980, vol. 53, # 1, p. 277 - 278
11
[ 512-56-1 ]
[ 71-30-7 ]
[ 4776-08-3 ]
[ 1122-47-0 ]
[ 6749-87-7 ]
Reference:
[1] Bulletin of the Chemical Society of Japan, 1980, vol. 53, # 1, p. 277 - 278
[2] Bulletin of the Chemical Society of Japan, 1980, vol. 53, # 1, p. 277 - 278
[3] Bulletin of the Chemical Society of Japan, 1980, vol. 53, # 1, p. 277 - 278
12
[ 71-30-7 ]
[ 616-38-6 ]
[ 1122-47-0 ]
[ 6220-49-1 ]
[ 874-14-6 ]
[ 2228-27-5 ]
[ 124210-93-1 ]
[ 124210-92-0 ]
Reference:
[1] Zeitschrift fuer Naturforschung, B: Chemical Sciences, 1989, vol. 44, # 7, p. 863 - 865
Reference:
[1] Synlett, 2002, # 12, p. 2043 - 2044
[2] Canadian Journal of Chemistry, 2007, vol. 85, # 4, p. 302 - 312
15
[ 554-01-8 ]
[ 1123-95-1 ]
[ 71-30-7 ]
[ 65-71-4 ]
Reference:
[1] Chemical Research in Toxicology, 1996, vol. 9, # 4, p. 745 - 750
16
[ 71-30-7 ]
[ 2022-85-7 ]
Yield
Reaction Conditions
Operation in experiment
95.7%
Stage #1: at -15 - 0℃; Inert atmosphere Stage #2: at -20℃; for 4 h; Inert atmosphere
(1) Under nitrogen, the temperature is 0 , the quality of anhydrous hydrogen fluoride was added 1150g 3450g cytosine, at a temperature of -15 deg.] C, into fluorine gas content of 15percent fluorine gas, a mixed gas of nitrogen, flow rate of 40g / h, fluorination reaction; document.write(""); After (2) a reaction for 4 hours in ventilation of nitrogen gas remove excess fluorine gas at -20 reaction of anhydrous hydrogen fluoride was distilled off in vacuo to dryness, water was added 8L, calcium carbonate was added to adjust the pH to 8; document.write(""); (3) The reaction was warmed to 90 deg.] C for 1 hour, filtered hot, 100g activated carbon was added, incubated 90 deg.] C for 0.5 hours and then filtered hot, cooled to 25 deg.] C for 0.5 hours, then cooled to 0 deg.] C, stirred for 1 hour , 5-fluorocytosine was filtered to give a white wet product; document.write(""); (4) the wet product 5-fluorocytosine after 70 deg.] C bake for 16 hours to give 5-fluorocytosine dried. document.write(""); Purity by HPLC and liquid phase titration analysis to analyze the content of 5-fluorocytosine purity and yield the following results: 95.7percent yield, 97.7percent pure.
87.4%
at 20℃; Inert atmosphere
(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 5molpercent 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 7percent) 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 molpercent 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 98.6percent and the product yield was 86.7percent. 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 20 ° C, ie the reaction temperature. Set the reaction pressure 0.15MPa. The reaction material 2 is a cytosine solution, that is, a mixture of cytosine and hexafluoroisopropanol, the mass concentration of uracil is 3percent and the feed rate is 80 g / min. The raw material 1 is 20 molpercent of the fluorine-nitrogen mixed gas, and the feed rate is 2.90 L / min. The molar ratio of fluorine to cytosine was 1.2: 1. The raw material 2 cytosine solution was pre-heated by the microchannel preheating module 3 into the "heart-shaped" microchannel reaction module 4. The fluorine-nitrogen mixed gas was directly introduced into the microchannel reaction module 4 through the gas mass flow meter, In the channel reaction module 4-9, the fluorine-nitrogen mixture reacts with cytosine. 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-fluorocytosine product. The reaction product was analyzed by liquid chromatography, and the purity of 5-fluorocytosine was 99.3percent and the product yield was 87.4percent.
63%
for 1.5 h; Flow reactor; Autoclave
1.0 M cytosine solution in formic acid was introduced at 4.0 mL/h (4.0 mmol/h) while fluorine (10 percent in N2) was introduced at 20 mL/min (5 mmol/h). The reaction was conducted for 90 minutes, the collected fraction was evaporated and the residue was recrystallized from water (7 mL). After filtration, the product was dried under reduced pressure to afford 5-fluorocytosine (0.49 g, 63 percent yield) as a tan powder. M.p.: 295 - 300 °C (decomposes), ([M]+ 129.0337, [M]+ requires: 129.0338); IR (cm"1): 3384, 3092, 2724, 1665, 1624, 1551, 1454, 1216; 1 H NMR (400 MHz, D2O+DCI) 7.83 (1 H, d, 3JHF 4.8 Hz); 19F NMR (400 MHz, D2O+DCI) -169.7 (1 F, d, 3JHF 4.8 Hz); 13C NMR (100 MHz, D2O+DCI): 130.67 (d, 2JCF 29.6 Hz), 135.25 (d, 1JCF 232 Hz), 147.88, 153.65 (d, 2JCF 23.4 Hz); MS (ASAP): 11 1 (37 percent, [M+H-F]+), 129 (8 percent, [M]+), 130 (100 percent, [M+H]+).
Reference:
[1] Patent: CN104326990, 2016, B, . Location in patent: Paragraph 0042-0043
[2] Patent: CN106432099, 2017, A, . Location in patent: Paragraph 0028-0031; 0047-0051
[3] Patent: WO2016/30662, 2016, A1, . Location in patent: Paragraph 00251
[4] Patent: CN107089952, 2017, A, . Location in patent: Paragraph 0036; 0037; 0038; 0039; 0040; 0041; 0042; 0043
17
[ 71-30-7 ]
[ 2022-85-7 ]
Yield
Reaction Conditions
Operation in experiment
66%
for 1.5 h; Flow reactor; Sealed tube
General procedure: 1.0 M cytosine solution in formic acid was introduced at 4.0 mL/h (4.0 mmol/h) while fluorine (10 percent in N2) was introduced at 20 mL/min (5 mmol/h). The reaction was conducted for 90 minutes, the collected fraction was evaporated and the residue was recrystallized from water (7 mL). After filtration, the product was dried under reduced pressure to afford 5-fluorocytosine (0.49 g, 63 percent yield) as a tan powder. M.p.: 295 - 300 °C (decomposes), ([M]+ 129.0337, [M]+ requires: 129.0338); IR (cm"1): 3384, 3092, 2724, 1665, 1624, 1551, 1454, 1216; 1 H NMR (400 MHz, D2O+DCI) 7.83 (1 H, d, 3JHF 4.8 Hz); 19F NMR (400 MHz, D2O+DCI) -169.7 (1 F, d, 3JHF 4.8 Hz); 13C NMR (100 MHz, D2O+DCI): 130.67 (d, 2JCF 29.6 Hz), 135.25 (d, 1JCF 232 Hz), 147.88, 153.65 (d, 2JCF 23.4 Hz); MS (ASAP): 11 1 (37 percent, [M+H-F]+), 129 (8 percent, [M]+), 130 (100 percent, [M+H]+).
Reference:
[1] Patent: WO2016/30662, 2016, A1, . Location in patent: Paragraph 00251; 00273
[2] Organic Process Research and Development, 2017, vol. 21, # 2, p. 273 - 276
18
[ 71-30-7 ]
[ 2022-85-7 ]
Reference:
[1] Journal of Fluorine Chemistry, 1984, vol. 24, p. 355 - 362
19
[ 71-30-7 ]
[ 2240-25-7 ]
Yield
Reaction Conditions
Operation in experiment
95.6%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 15℃; for 1 h; Sonication
The cytosine (55.6g, 0.5mol), N-bromosuccinimide (106.8g, 0 . 6mol) and DMF150mL in added in the reaction bottle, cooling to 15 °C ultrasonic reaction 1h, TLC raw material the reaction is complete, filtering, the filter cake is washed with water (20 ml × 2) washing, drying to obtain 5-bromocytosine (90.9g, 95.6percent).
Reference:
[1] Patent: CN103819412, 2016, B, . Location in patent: Paragraph 0023-0025; 0031-0032; 0037; 0038
[2] Synthesis, 2005, # 7, p. 1103 - 1108
[3] Tetrahedron Letters, 1992, vol. 33, # 50, p. 7779 - 7782
[4] Chemistry Letters, 1987, p. 2311 - 2312
[5] Bulletin of the Chemical Society of Japan, 1989, vol. 62, # 11, p. 3750 - 3751
[6] Journal of Organic Chemistry, 1982, vol. 47, # 6, p. 1018 - 1023
20
[ 71-30-7 ]
[ 51-20-7 ]
[ 2240-25-7 ]
Reference:
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 1994, vol. 34, # 7, p. 603 - 616
21
[ 71-30-7 ]
[ 2240-25-7 ]
Reference:
[1] Journal of the American Chemical Society, 1934, vol. 56, p. 134,138
22
[ 71-30-7 ]
[ 1122-44-7 ]
Yield
Reaction Conditions
Operation in experiment
99%
With N-iodo-succinimide In N,N-dimethyl-formamide for 12.5 h; Sonographic reaction; Inert atmosphere
DMF (50 mL) is added to a mixture of cytosine (8.333 g, 75 mmol) with N-iodosuccinimide (18.562 g, 82.5 mmol) under Ar. The vessel is covered in foil and ultrasonicated for 30 min to disrupt the solid mass at the bottom of the vessel. The mixture is then stirred for an additional 12 h, the still heterogeneous reaction mixture is added to water (150 mL). The insoluble material is collected by filtration, washed with water and dried over P2O5 to give the iodinated heterocycle is a pale tan solid (17.703 g, 99percent). The material is used without further purification.
Reference:
[1] Patent: US7741294, 2010, B1, . Location in patent: Page/Page column 17
[2] European Journal of Organic Chemistry, 2015, vol. 2015, # 32, p. 7160 - 7175
[3] Journal of Medicinal Chemistry, 1983, vol. 26, # 2, p. 152 - 156
[4] Tetrahedron, 2012, vol. 68, # 26, p. 5145 - 5151
[5] Journal of Heterocyclic Chemistry, 2015, vol. 52, # 5, p. 1382 - 1389
[6] Synthesis, 2003, # 7, p. 1039 - 1042
[7] Journal of the American Chemical Society, 2008, vol. 130, # 27, p. 8762 - 8768
[8] Journal of Biological Chemistry, 1906, vol. 1, p. 310[9] Chem. Zentralbl., 1906, vol. 77, # I, p. 1890
[10] Structural Chemistry, 2010, vol. 21, # 1, p. 245 - 254
[11] Molecules, 2017, vol. 22, # 12,
23
[ 71-30-7 ]
[ 108-24-7 ]
[ 14631-20-0 ]
Reference:
[1] Journal of Organic Chemistry, 1991, vol. 56, # 14, p. 4392 - 4397
[2] Journal of Polymer Science, Part A: Polymer Chemistry, 2015, vol. 53, # 9, p. 1151 - 1160
[3] Carbohydrate Research, 1980, vol. 78, p. 195 - 204
[4] Journal of the American Chemical Society, 1990, vol. 112, # 20, p. 7373 - 7381
[5] American Chemical Journal, 1903, vol. 29, p. 496[6] American Chemical Journal, 1904, vol. 31, p. 596
[7] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1991, vol. 27, # 4, p. 407 - 409[8] Khimiya Geterotsiklicheskikh Soedinenii, 1991, # 4, p. 512 - 515
[9] Chemical Research in Toxicology, 1998, vol. 11, # 9, p. 1082 - 1088
[10] Journal of the Chemical Society, 1956, p. 2388,2392[11] Journal of the Chemical Society, 1958, p. 3028,3032
[12] Bioorganic and Medicinal Chemistry, 2002, vol. 10, # 8, p. 2671 - 2680
[13] Journal of Pharmacology and Experimental Therapeutics, 2007, vol. 322, # 3, p. 1023 - 1035
[14] Journal of Chemical Research, 2007, # 5, p. 281 - 283
[15] Patent: WO2010/82128, 2010, A1, . Location in patent: Page/Page column 18
[16] Patent: US2011/282046, 2011, A1, . Location in patent: Page/Page column 8
[17] Croatica Chemica Acta, 2017, vol. 90, # 4, p. 625 - 636
24
[ 3650-93-9 ]
[ 23945-44-0 ]
[ 71-30-7 ]
Reference:
[1] Chemical Research in Toxicology, 1996, vol. 9, # 4, p. 745 - 750
25
[ 71-30-7 ]
[ 98-88-4 ]
[ 26661-13-2 ]
Yield
Reaction Conditions
Operation in experiment
40 kg
With dmap; triethylamine In acetonitrile at 5 - 45℃; for 3 h; Inert atmosphere; Large scale
Reactor after the replacement of nitrogen, adding 100L acetonitrile, 22 kg (196mol) no water cytosine, 25gDMAP, 24 kg triethylamine, in 5-8 °C lower, slowly dropping 34 kg benzoyl chloride, after dripping, natural to room temperature, in the 25 °C stirring for one hour, then slowly heated to 40-45 °C insulation two hours, then cooling down to room temperature, filter press, the filtrate collected after acetonitrile 60L recycling, the filter cake with water and ethanol washing, drying to obtain the kind of white solid 40 kg, liquid phase content is 99.2percent.
Reference:
[1] Patent: US2011/245458, 2011, A1,
[2] Chemical Communications, 2017, vol. 53, # 64, p. 8952 - 8955
[3] Heterocyclic Communications, 2007, vol. 13, # 4, p. 251 - 256
[4] Russian Journal of Organic Chemistry, 2008, vol. 44, # 3, p. 358 - 361
[5] Journal of the Chemical Society, 1956, p. 2388,2392[6] Journal of the Chemical Society, 1958, p. 3028,3032
[7] Chemistry of Natural Compounds, 1983, vol. 19, # 5, p. 580 - 582[8] Khimiya Prirodnykh Soedinenii, 1983, # 5, p. 617 - 619
[9] Patent: US6075143, 2000, A,
[10] Chemistry - A European Journal, 2011, vol. 17, # 51, p. 14508 - 14517
[11] Patent: CN105541728, 2016, A, . Location in patent: Paragraph 0023; 0024
26
[ 71-30-7 ]
[ 93-97-0 ]
[ 26661-13-2 ]
Yield
Reaction Conditions
Operation in experiment
41 kg
With dmap; triethylamine In acetonitrile at 5 - 50℃; for 3 h; Inert atmosphere; Large scale
Reactor after the replacement of nitrogen, adding 200L acetonitrile, 22 kg (196mol) no water cytosine, 50gDMAP, 28 kg triethylamine, in 5-10 °C lower, slowly dropping 96 kg (benzoic anhydride solution: 50 wt percent) acetonitrile solution of benzoic anhydride, after dripping, natural to room temperature, in the 25 °C stirring for one hour, then slowly heated to 45-50 °C thermal insulation 2 hours, then reduced to room temperature, filter press, the filtrate collected after acetonitrile 132L recycling, the filter cake is washed with water and ethanol, dried to obtain a white solid 41 kg, liquid phase content of 99.14percent.
Reference:
[1] Collection of Czechoslovak Chemical Communications, 1989, vol. 54, # 8, p. 2190 - 2210
[2] Patent: CN105541728, 2016, A, . Location in patent: Paragraph 0027; 0028
27
[ 123413-57-0 ]
[ 26661-13-2 ]
[ 71-30-7 ]
Reference:
[1] Chemical and Pharmaceutical Bulletin, 1989, vol. 37, # 9, p. 2547 - 2549
28
[ 77287-34-4 ]
[ 51953-18-5 ]
[ 156-81-0 ]
[ 120-89-8 ]
[ 108-53-2 ]
[ 71-30-7 ]
[ 144-62-7 ]
[ 113-00-8 ]
[ 127-17-3 ]
[ 66-22-8 ]
[ 56-06-4 ]
[ 66224-66-6 ]
[ 57-13-6 ]
[ 56-40-6 ]
Yield
Reaction Conditions
Operation in experiment
1.6 mg
With copper(II) choride dihydrate In water at 80℃; for 24 h;
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
Reference:
[1] Chemical and Pharmaceutical Bulletin, 1980, vol. 28, # 3, p. 932 - 938
32
[ 71-30-7 ]
[ 19263-02-6 ]
[ 55662-66-3 ]
Reference:
[1] Journal of Organic Chemistry, 1984, vol. 49, # 21, p. 4021 - 4025
33
[ 71-30-7 ]
[ 3018-12-0 ]
[ 506-77-4 ]
Reference:
[1] Environmental Science and Technology, 2000, vol. 34, # 9, p. 1721 - 1728
34
[ 77287-34-4 ]
[ 156-81-0 ]
[ 849585-22-4 ]
[ 617-48-1 ]
[ 2491-15-8 ]
[ 110-15-6 ]
[ 108-53-2 ]
[ 71-30-7 ]
[ 113-00-8 ]
[ 127-17-3 ]
[ 66-22-8 ]
[ 66224-66-6 ]
[ 56-40-6 ]
[ 302-72-7 ]
[ 18514-52-8 ]
Yield
Reaction Conditions
Operation in experiment
0.18 mg
With ferric sulfate nonahydrate In water at 80℃; for 24 h;
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
Sodium isopropoxide (61.6 g, 0.75 mol) was mixed with 270 mL of isopropanol Into the reactor and stir well;Followed by input 3-hydroxyacrylonitrile sodium salt(27.3 g,0.3 mol) and O-Methylisourea monomethyl sulfate (67.0 g, 0.36 mol);70 C and cyclization reaction for 8 hours to obtain a cyclization reaction solution; at atmospheric pressure to evaporate isopropyl alcohol, To give the intermediate; and further adding 100 mL of concentrated hydrochloric acid to the intermediate, raising the temperature to 100 C Incubate for 1 hour; heat and then add 60mL of water to the solution for hot filtration, the resulting filtrate cooled to room temperature; The filtrate was added with 10mol / L sodium hydroxide solution to adjust the pH value. When the pH was 7 ~ 7.5, it was cooled to 10 70 C. After cooling, the mixture was filtered, washed and dried to obtain cytosine 30.4g,The yield was 91.2% and the HPLC content was 99.2%.
With pyridine; dmap; In toluene; at 25 - 55℃; for 7h;
EXAMPLE 1PREPARATION OF N-ACETYLCYTOSINETo a suspension of cytosine (200 g, 1 .80 mol) in toluene (600 ml) at RT (25-3O0C), pyridine (216 g, 2.73 mol) and DMAP ( 1.0 g) was added. Acetic anhydride (217 g, 2.13 mol) was diluted with toluene (350 ml) and added slowly in ~60 min at 25- 45C. After addition, the reaction mass was heated to 50-550C and continued stirring for 6 h to complete the reaction (checked by TLC). Reaction mass was cooled to 25-280C and product was filtered and washed with toluene (350 ml). Further, product was washed with water (2 x 300 ml). Product was dried at 60-650C under reduced pressure to give title compound. Yield: 254 g1H NMR(DMSO-d6): delta 2.08 (s, 3H, CH3), 7.08-7.10, (d, I H, CH-cytosine), 7.79- 7.81(^, I H, CH-cytosine), 10.75(broad singlet, I H, NH), 1 1 .50(broad singlet, I H, NH).
With pyridine;dmap; In toluene; at 25 - 55℃; for 7h;
EXAMPLE 1 Preparation of N-Acetylcytosine To a suspension of cytosine (200 g, 1.80 mol) in toluene (600 ml) at RT (25-30 C.), pyridine (216 g, 2.73 mol) and DMAP (1.0 g) was added. Acetic anhydride (217 g, 2.13 mol) was diluted with toluene (350 ml) and added slowly in ~60 min at 25-45 C. After addition, the reaction mass was heated to 50-55 C. and continued stirring for 6 h to complete the reaction (checked by TLC). Reaction mass was cooled to 25-28 C. and product was filtered and washed with toluene (350 ml). Further, product was washed with water (2*300 ml). Product was dried at 60-65 C. under reduced pressure to give title compound.
With pyridine; dmap; In dichloromethane; at 20℃;Inert atmosphere;
General procedure: To a mixture of cytosine (5.55 g, 49.95 mmol, 1.00 equiv.), DMAP (305.14 mg, 2.50 mmol, 0.02 equiv.), and pyridine (6.03 mL,74.93 mmol, 1.50 equiv.) in DCM (25 mL), acid chloride (59.95 mmol, 1.20 equiv.) was added slowly. The reaction was continued over night at RT and concentrated to dryness. The residue was triturated with ethyl acetate and filtered. The filter cake was then stirred in 1 N aq. HCl (500 mL) at RT for 2 h and filtered.The obtained solid was stirred in sat. aq. NaHCO3 (500 mL) at RT for2 h and again filtered. The resulting white powder was eventually stirred in water (500 mL) at RT for 2 h, filtered, and dried to give products 6c, d, e.
65%
With pyridine; dmap; In dichloromethane; at 20℃;
<strong>[71-30-7]Cytosine</strong> (5.55g, 49.95mmol) and DMAP (305.14mg, 2.50mmol) were suspended in DCM (25mL), and pyridine (6.03mL, 74.93mmol) was added dropwise,After completion, p-nitrobenzoyl chloride (7.27 mL, 59.95 mmol) was slowly added to the reaction solution.The reaction was carried out at room temperature overnight. After TLC monitors the reaction of the raw materials, the reaction solution is concentrated to dryness.A white solid was obtained. The white solid was washed with ethyl acetate (300 mL) and filtered; the resulting filter cake was stirred in a 1N HCl solution (500 mL) for 2 hours and filtered; the resulting filter cake was stirred in a saturated sodium bicarbonate solution (500 mL) for 2 hours and filtered; Wash the filter cake obtained in the previous step with pure water,Stir for 2 hours, suction filter, and dry under vacuum to constant weight to obtain 5c (8.45 g, 32.47 mmol) as a white solid product. Yield: 65%.
With tetra(n-butyl)ammonium hydroxide; In methanol; N,N-dimethyl-formamide; isopropyl alcohol; at 20.0℃; for 2.0h;
A 0.1 M solution of tetra-N-butylammonium hydroxide in a mixture of MeOH and 2-propanol (90 mL, 9.0 mmol) was added dropwise to a stirred suspension of cytosine (1 g, 9.0 mmol) in DMF (70 mL). The solution became clear and benzyl bromide (2.14 mL, 18 mmol) was added dropwise. The reaction mixture was stirred at RT for 2 hours and then the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography (silica; MeOH in DCM with a gradient of 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo to yield 4-amino-1-benzyl-1H-pyrimidin-2-one (1 g, 57% yield) as a white solid.
With N-iodo-succinimide; In N,N-dimethyl-formamide; for 12.5h;Sonographic reaction; Inert atmosphere;
DMF (50 mL) is added to a mixture of cytosine (8.333 g, 75 mmol) with N-iodosuccinimide (18.562 g, 82.5 mmol) under Ar. The vessel is covered in foil and ultrasonicated for 30 min to disrupt the solid mass at the bottom of the vessel. The mixture is then stirred for an additional 12 h, the still heterogeneous reaction mixture is added to water (150 mL). The insoluble material is collected by filtration, washed with water and dried over P2O5 to give the iodinated heterocycle is a pale tan solid (17.703 g, 99%). The material is used without further purification.
<strong>[71-30-7]Cytosine</strong>, 6 (100 mg, 0.9 mmol) was added after 45 min to a stirred mixture of fuming HNO3 (0.62 mL) and concd sulfuric acid (0.124 mL). The resulting mixture was heated at 80 C for 18 h. A new spot was seen on TLC (MeOH/CHCl3 6:4) with Rf=0.64, indicating the formation of the product. The mixture was poured onto ice (5.25 g) and neutralized with satd NaOH. The solid was filtered off and washed with ice-cold water, ice-cold abs EtOH, and ice-cold diethyl ether, and dried in vacuum, yielding 77 mg (60%). Mp>250 C decomp. IR (ZnSe): nu 3381, 3168, 3077, 2418, 2050, 1951, 1877, 1681, 1650, 1599, 1567, 1511, 1435, 1343, 1318, 1238, 1137, 1102, 1031, 955, 852, 775, 618 cm-1. 1H NMR (600 MHz, DMSO-d6): delta 11.88 (br s,1H), 8.86 (s, 1H), 8.30 (br s, 1H), 8.10 (s, 1H) ppm. 13C NMR (150 MHz, DMSO-d6) delta: 157.5, 154.2, 151.9, 118.5 ppm. HRMS (CI/CH4) m/z: calculated for C4H4N4O3: 157.036 (MH+). Found: 157.036 (MH+).
To a stirred suspension of 1.44 g (36.0 mmol) of NaH (60% inmineral oil) in 50 ml of DMF at 0 C was added 1.00 g (9.01 mmol)of cytosine. The reaction mixture was stirred at 0 C for 1 h,then 1.35 mL (9.50 mmol) of benzyl chloroformate was added. The reaction mixture was stirred at room temperature for 14 h,then diluted with 100 mL of H2O and ice. After neutralization with5 N HCl, a colorless precipitate formed, and was filtered, washedwith five 50-mL portions of H2O and dried to give 1 as a colorlesspowder: yield 1.71 g (74%); mass spectrum (APCI), m/z 246.0890(M+H)+ (C12H12N3O3 requires m/z 246.0879). To a stirred suspensioncontaining 250 mg (1.02 mmol) of compound 1 in 5 mL ofDMSO was added 0.18 mL (183 mg, 1.20 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Within 15 min, a solution containing220 mg (1.20 mmol) of N-(tert-butoxycarbonyl)-L-serine b-lactone11in 5 mL of DMSO was added. The reaction mixture was stirredat room temperature for 2 h under an argon atmosphere, thendiluted with 10 mL of 0.5 N HCl and extracted with two 20-mLportions of EtOAc. The combined organic phase was dried (MgSO4)and concentrated under diminished pressure. The residue waspurified by chromatography on a silica gel column (10 2 cm).Elution with 5:1 ethyl acetate-methanol gave 2 as a colorlesssolid: yield 246 mg (56%); silica gel TLC Rf 0.31 (5:1 ethyl acetate/methanol). To a cooled (0 C) solution containing 246 mg(0.60 mmol) of 2 in 5 mL of anhydrous MeOH was added dropwise0.04 mL (67.7 mg, 0.60 mmol) of SOCl2. The reaction mixture wasallowed to warm slowly to room temperature with stirring for 2 h,then diluted with 50 mL of brine and extracted with two 50-mLportions of EtOAc. The combined organic phase was dried (MgSO4)and concentrated under diminished pressure. The residue waspurified by chromatography on a silica gel column (10 2 cm).Elution with 10:1 ethyl acetate/methanol gave 3 as a colorlesssolid: yield 165 mg (65%);
With hydrogenchloride; In pyridine; water;
EXAMPLE 7 Synthesis of N4-Benzyloxycarbonyl cytosine (9) Over a period of about 1 h, benzyloxycarbonyl chloride (52 mL, 0.36 mol) was added dropwise to a suspension of cytosine (8, 20 g, 0.18 mol) in dry pyridine (1000 mL) at 0 C. under nitrogen in oven-dried equipment. The solution then was stirred overnight, after which the pyridine suspension was evaporated to dryness, in vacuo. Water (200 mL) and 4 N hydrochloric acid were added to reach pH ~1. The resulting white precipitate was filtered off, washed with water and partially dried by air suction. The moist precipitate was refluxed with absolute ethanol (500 mL) for 10 minutes, cooled to 0 C., filtered, washed thoroughly with ether, and dried, in vacuo. Yield 24.7 g (54%). M.p.>250 C. Anal. for C12H11N3O3. Found(calc.); C: 58.59(58.77); H: 4.55(4.52); N: 17.17(17.13). No NMR spectra were recorded since it was not possible to get the product dissolved.
With hydrogenchloride; In pyridine; water;
EXAMPLE 24 N4 -Benzyloxycarbonyl cytosine (9) Over a period of about 1 h, benzyloxycarbonyl chloride (52 ml; 0.36 mol) was added dropwise to a suspension of cytosine (8, 20.0 g; 0.18 mol) in dry pyridine (1000 ml) at 0 C. under nitrogen in oven-dried equipment. The solution then was stirred overnight, after which the pyridine suspension was evaporated to dryness, in vacuo. Water (200 ml) and 4N hydrochloric acid were added to reach pH~1. The resulting white precipitate was filtered off, washed with water and partially dried by air suction. The still-wet precipitate was boiled with absolute ethanol (500 ml) for 10 min, cooled to 0 C., filtered, washed thoroughly with ether, and dried, in vacuo. Yield 24.7 g (54%). M.p.>250 C. Anal. for C12 H11 N3 O3. Found (calc.); C: 58.59(58.77); H: 4.55(4.52); N: 17.17(17.13). No NMR spectra were recorded since it was not possible to get the product dissolved.
With hydrogenchloride; In pyridine; water;
EXAMPLE 7 Synthesis of N4 -Benzyloxycarbonyl cytosine (9). Over a period of about 1 h, benzyloxycarbonyl chloride (52 mL, 0.36 mol) was added dropwise to a suspension of cytosine (8, 20 g, 0.18 mol) in dry pyridine (1000 mL) at 0 C. under nitrogen in oven-dried equipment. The solution then was stirred overnight, after which the pyridine suspension was evaporated to dryness, in vacuo. Water (200 mL) and 4N hydrochloric acid were added to reach pH~1. The resulting white precipitate was filtered off, washed with water and partially dried by air suction. The moist precipitate was refluxed with absolute ethanol (500 mL) for 10 minutes, cooled to 0 C., filtered, washed thoroughly with ether, and dried, in vacuo. Yield 24.7 g (54%). M.p.>250 C. Anal. for C12 H11 N3 O3. Found(calc.); C: 58.59(58.77); H: 4.55(4.52); N: 17.17(17.13). No NMR spectra were recorded since it was not possible to get the product dissolved.
With hydrogenchloride; In pyridine; water;
EXAMPLE 7 Synthesis of N4 -Benzyloxycarbonyl cytosine (9) Over a period of about 1 h, benzyloxycarbonyl chloride (52 mL, 0.36 mol) was added dropwise to a suspension of cytosine (8, 20 g, 0.18 mol) in dry pyridine (1000 mL) at 0 C. under nitrogen in oven-dried equipment. The solution then was stirred overnight, after which the pyridine suspension was evaporated to dryness, in vacuo. Water (200 mL) and 4N hydrochloric acid were added to reach pH~1. The resulting white precipitate was filtered off, washed with water and partially dried by air suction. The moist precipitate was refluxed with absolute ethanol (500 mL) for 10 minutes, cooled to 0 C., filtered, washed thoroughly with ether, and dried, in vacuo. Yield 24.7 g (54%). M.p.>250 C. Anal. for C12 H11 N3 O3. Found(talc.); C: 58.59(58.77); H: 4.55(4.52); N: 17.17(17.13). No NMR spectra were recorded since it was not possible to get the product dissolved.
With hydrogenchloride; In pyridine; water;
EXAMPLE 17 N4-Benzyloxycarbonyl cytosine (9) Over a period of about 1 h, benzyloxycarbonyl chloride (52 ml; 0.36 mol) was added dropwise to a suspension of cytosine (8, 20.0 g;0.18 mol) in dry pyridine (1000 ml) at 0 C. under nitrogen in oven-dried equipment. The solution then was stirred overnight, after which the pyridine suspension was evaporated to dryness, in vacuo. Water (200 ml) and 4 N hydrochloric acid were added to reach pH ~1. The resulting white precipitate was filtered off, washed with water and partially dried by air suction. The still-wet precipitate was boiled with absolute ethanol (500 ml) for 10 min, cooled to 0 C., filtered, washed thoroughly with ether, and dried, in vacuo. Yield 24.7 g (54%). M.p.>250 C. Anal. for C12H11N3O3. Found(calc.); C: 58.59(58.77); H: 4.55(4.52); N: 17.17(17.13). No NMR spectra were recorded since it was not possible to get the product dissolved.
With hydrogenchloride; In pyridine; water;
EXAMPLE 7 Synthesis of N4-Benzyloxycarbonyl <strong>[71-30-7]Cytosine</strong> (9) Over a period of about 1 h, benzyloxycarbonyl chloride (52 mL, 0.36 mol) was added dropwise to a suspension of cytosine (8, 20 g, 0.18 mol) in dry pyridine (1000 mL) at 0 C. under nitrogen in oven-dried equipment. The solution then was stirred overnight, after which the pyridine suspension was evaporated to dryness, in vacuo. Water (200 mL) and 4 N hydrochloric acid were added to reach pH ~1. The resulting white precipitate was filtered off, washed with water and partially dried by air suction. The moist precipitate was refluxed with absolute ethanol (500 mL) for 10 minutes, cooled to 0 C., filtered, washed thoroughly with ether, and dried, in vacuo. Yield 24.7 g (54%). M.p.>250 C. Anal. for C12H11N3O3. Found(calc.); C: 58.59(58.77); H: 4.55(4.52); N: 17.17(17.13). No NMR spectra were recorded since it was not possible to get the product dissolved.
Under a nitrogen atmosphere at ambient temperature a reactor was charged with cytosine, (S)-trityl glycidyl ether, potassium carbonate, and anhydrous N,N-dimethylformamide. The reaction mixture was heated and maintained at 85 to 95 C. until complete then cooled to 60 to 70 C. The reaction mixture was quenched with water, stirred at ambient temperature and filtered. The wet solids were dried by azeoptropic distillation with toluene, cooled to 25+/-5 C., and filtered. The solids were slurried in acetone at 35+/-5 C., filtered and dried under vacuum at 50+/-5 C. until the product contained less than or equal to 0.5% residual solvents. Yield: approximately 36.1 kg to 40.9 kg (84.4 to 95.6 moles) of CMX212; 75 to 85% based on cytosine. Process monitoring: HPLC-Reaction completion, starting material (cytosine) is 5% AUC.
65%
With potassium carbonate; In N,N-dimethyl-formamide; at 85 - 95℃; for 9h;Large scale;
Example 1Step 1: Preparation of (S)-N-1-[(2-hydroxy-3-triphenylmethoxy)propyl]cytosine (Compound 2)A slurry of (S)-trityl glycidyl ether (56.4 kg, 178.22 mol), cytosine (18.0 kg, 162.02 mol), and potassium carbonate (2.20 kg, 16.20 mol) in dimethylformamide (73.2 kg) was heated to 85-95 C. After 9 hours the reaction mixture was cooled down to 66-70 C. and quenched with toluene (216.0 kg). The resulting slurry was further cooled down to -10 to 5 C. and filtered to collect a solid. This material was washed with toluene (38.9 kg), re-suspended in toluene (168.8 Kg) at 15-25 C., and once again filtered. (0386) In order to further remove residual cytosine and process-related impurities a purification cycle was carried out, where the compound was washed with acetone (36.0 Kg), followed by trituration of the solid in water/acetone (90.0 kg/54.0 Kg) at 17-22 C., and ending with another acetone wash (36.0 Kg). This cycle was repeated several times to improve purity of the product but should be carried out at least once. (0387) A suspension of the filter cake in acetone (178.9 Kg) at 35-45 C. was prepared. After 3 hours, the reaction mixture was filtered and the resulting solid was washed with acetone (36.0 Kg) to afford Compound 2 (45.0 kg, 65% yield), and dried in vacuo at ?40 C. for 12 hours. Purity of the compound was determined via HPLC analysis (>99.0%
With potassium carbonate; In N,N-dimethyl-formamide; at 105℃; for 5h;
A procedure from the literature for synthesizing cidofovir (P.R. Brodfuehrer, et al., Tetrahedron Lett. 35, 1994, 3243-3246, herein incorporated by reference) was modified. The modified synthesis reaction is shown in Figure 3. The literature procedure of reacting tritylated R-glycidol and benzoyl protected cytosine produced low yields. Therefore, as shown in Figure 3, tritylated R-glycidol (compound 10), (5.0 mmol) was treated with unprotected cytosine (5.0 mmol) in the presence Of K2CO3 (5.0 mmol) in DMF (20 mL) for 5h at 105 0C to obtain regiospecific opening of the epoxide, giving compound 11, (S)-N1-[(2-hydroxy-3-triphenylmethoxy) propyl]cytosine). A benzoyl moiety was then introduced by reacting compound 11 (3.6 mmol) and benzoic anhydride (1.2 eq) in pyridine (15.5 mL) and DMF (8 mL) at 10C for 3 h to obtain the desired product, compound 12, (<S)-N1-[(3-triphenylmethoxy-2-hydroxy)propyl]-N4-benzoylcytosine. The other steps of the synthesis were carried out as described by Brodfuehrer et al
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 15℃; for 1h;Sonication;
The cytosine (55.6g, 0.5mol), N-bromosuccinimide (106.8g, 0 . 6mol) and DMF150mL in added in the reaction bottle, cooling to 15 C ultrasonic reaction 1h, TLC raw material the reaction is complete, filtering, the filter cake is washed with water (20 ml × 2) washing, drying to obtain 5-bromocytosine (90.9g, 95.6%).
93.6%
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 25℃; for 10h;Large scale;
To a solution of cytosine (300 g, 2.70 mol, 1.00 equiv) in DMF (1.5 L) was added NBS (480 g, 2.70 mol, 1.00 equiv). The mixture was stirred at 25 C for 10 h at which time the crude 1H NMR spectrum indicated that the reaction was complete. The reaction mixture was filtered and the filter cake was washed with water (1 L x 4). The solid was collected and dried under reduced pressure to afford 5-bromocytosine (480 g, 2.53 mol, 93.6% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) d 10.80 (br s, 1H), 11.36 - 10.16 (m, 1H), 7.74 (s, 1H), 6.83 (br s, 2H).
84.8%
With bromine; acetic acid; at 70℃; for 8h;
To a solution of 4-aminopyrimidin-2(1H)-one (2 g, 18 mmol) inacetic acid (10 mL) was added bromine (3.6 g, 22.5 mmol). The reactionmixture was stirred at 70 C for 8 h. The reaction mixture was dilutedwith H2O (30 mL) and the light yellow precipitate was filtered andwashed with water. The solid was then dried under reduced pressure togive the title compound (2.91 g, 84.8% yield). 1H NMR (300 MHz,DMSO-d6) delta 10.86 (s, 1H), 7.75 (s, 1H), 6.85 (s, 1H).
With ammonium sulfate; 1,1,1,3,3,3-hexamethyl-disilazane; potassium iodide; In acetonitrile; at 120℃; for 0.5h;Microwave irradiation; Autoclave;
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.
Prepared by a method known in the art. A mixture of cytosin (20 g, 0. 18 mol) and monomethoxytrityl chloride (70 g, 0. 23 mol) was suspended in dry pyridine (750 mL). Triethylamine (25 mL, 0. 18 mol) was added to the mixture in one portion. The mixture was heated gently (40 C) and stirred overnight. Water (150 mL) was added to the stirred suspension, followed by dichloromethane (150 mL). The resulting precipitate was collected by vacuum filtration (8 g). The filtrate was evaporated and the residue was triturated with a mixture of water and dichloromethane. A second crop of product (35 g) was obtained. The total yield was 43 g (62%), m. p. 264-265C decomp., m. p. lit. 255-258 C.
To a solution of cytosine (10 g, 90 mmol) in 400 mL of dry DMF was added NaH (2.2 g, 90 mmol) under N2 in an ice-water bath. This solution was then stirred for 2 h at rt, followed by the dropwise addition of methyl bromoacetate (15.1 g, 99 mmol). The reaction was stirred for an additional 48 h at rt, after which the solvent was evaporated in vacuo. The crude remains were mixed with 200 mL of cold H2O and stored at 4 C to maximize precipitate formation. The suspension was filtered and washed with minimal amounts of cold H2O and EtO2 and recrystallized from MeOH/H2O affording methyl cytosin-1-yl acetate as a light pink powder (9.9 g, 60%). 1H proton and 13C NMR shifts were confirmed in the report by Schwergold et al.
With 1,1,1,3,3,3-hexamethyl-disilazane; In methanol; dichloromethane; sodium hydrogencarbonate; acetonitrile;
EXAMPLE 11 5'-O-t-Butyldiphenylsilyl-4'-thio-2',3'-dideoxycytidine (13). A mixture of 10 (0.26 g, 0.63 mmol), cytosine (0.105 g, 0.95 mmol), and potassium nonafluorobutanesulfonate (0.77 g, 2.3 mmol) was suspended in 12 mL dry acetonitrile under nitrogen. HMDS (0.135 mL, 0.63 mmol) and TMS-Cl (0.37 mL, 2.9 mmol) were added sequentially via syringe and the reaction stirred at 25 C. overnight. The reaction was poured into a mixture of 20 mL dichloromethane and 15 mL saturated NaHCO3 and shaken. The organic phase was dried (MgSO4) and concentrated in vacuo. The anomeric mixture was separated by preparative TLC with 7.5% MeOH/CHCl3 with an ammonia atmosphere: yield of beta-anomer, 78 mg and 117 mg of the alpha-anomer to afford total yield of 195 mg (66.5%); FAB MS 466 (M+H)+; 1 H NMR (CDCl3) of alpha/beta anomer, delta 8.12 (d, 1, 6-H), 7.7 (m, 4, ArH), 7.4 (m, 6, ArH), 6.32 (m, 1, i'-H), 5.9-5.3 (hump, 1, NH2), 5.75 (d, 1, 5-H), 5.45 (d, 1, 5-H), 3. 75 (m, 3, 4'-Halpha,beta 's, 3'-Halpha,beta 's).
195 mg (66.5%)
With 1,1,1,3,3,3-hexamethyl-disilazane; In methanol; dichloromethane; sodium hydrogencarbonate; acetonitrile;
EXAMPLE 11 5'-O-t-Butyldiphenylsilyl-4'-thio-2',3'-dideoxycytidine (13) A mixture of 10 (0.26 g, 0.63 mmol), cytosine (0.105 g, 0.95 mmol), and potassium nonafluorobutanesulfonate (0.77 g, 2.3 mmol) was suspended in 12 mL dry acetonitrile under nitrogen. HMDS (0.135 mL, 0.63 mmol) and TMS-Cl (0.37 mL, 2.9 mmol) were added sequentially via syringe and the reaction stirred at 25 C. overnight. The reaction was poured into a mixture of 20 mL dichloromethane and 15 mL saturated NaHCO3 and shaken. The organic phase was dried (MgSO4) and concentrated in vacuo. The anomeric mixture was separated by preparative TLC with 7.5% MeOH/CHCl3 with an ammonia atmosphere: yield of beta-anomer, 78 mg and 117 mg of the alpha-anomer to afford total yield of 195 mg (66.5%); FAB MS 466 (M+H)+; 1 H NMR (CDCl3) of alpha/beta anomer, delta 8.12 (d, 1, 6-H), 7.7 (m, 4, ArH), 7.4 (m, 6, ArH), 6.32 (m, 1, 1'-H), 5.9-5.3 (hump, 1, NH2), 5.75 (d, 1, 5-H), 5.45 (d, 1, 5-H), 3.75 (m, 3, 4'-Halpha,beta 's, 3'-Halpha,beta 's).
With sodium ethanolate; acetic acid; urea; In 5,5-dimethyl-1,3-cyclohexadiene; water;
EXAMPLE 1 78.1 g (1.3 mols) of urea and 81.7 g (1.2 mols) of sodium ethylate were suspended in 240 g of xylene, and the suspension was heated to reflux temperature. Over a period of 60 minutes 143.2 g (1 mol) of cyanoacetaldehyde-diethylacetal were added. The resulting mixture was heated at the boiling point for an additional 3 hours, and then the alcohol which had formed during the reaction was distilled off. The residual suspension was admixed with 500 g of water, and the aqueous product phase which formed was separated from the xylene phase. By neutralization of the aqueous phase with 72 g (1.2 mols) of acetic acid, the cytosine was precipitated. Subsequent recrystallization from water in the presence of activated charcoal yielded 82.3 g (74.1% of theory) of pure cytosine.
With sodium ethanolate; urea; In water; toluene;
EXAMPLE 5 39 g (0.65 mol) of urea, 39.1 g (0.575 mol) of sodium ethylate and 71.6 g (0.5 mol) of cyanoacetaldehyde-diethylacetal were combined in 100 g of toluene, and the mixture was heated at its boiling point for 5 hours. Thereafter, the ethanol which had formed was removed by azeotropic distillation with toluene, and the residue was taken up in 250 g of water. After separation of the aqueous phase, cytosine was precipitated by addition of 34.5 g (0.575 mol) of acetic acid, filtered off and purified in analogy to Example 1. 34.1 g (61.3% of theory) of cytosine were obtained.
With sodium ethanolate; urea; In 5,5-dimethyl-1,3-cyclohexadiene; ethanol; water;
EXAMPLE 3 78.1 g (1.3 mols) of urea and 81.7 g (1.2 mols) of sodium ethylate were suspended in 240 g of xylene and the suspension was admixed with 23 g (0.5 mol) of ethanol. The mixture was heated to the reflux temperature, and over the course of 1 hour 143.2 g (1 mol) of cyanoacetaldehyde-diethylacetal were added, and the mixture was heated for 3 additional hours at the boiling point. The alcohol present in the reaction mixture was distilled off, and the residue was admixed with 500 g of water. Cytosine was precipitated from the aqueous phase by the addition of 72 g (1.2 mols) of acetic acid, filtered off and recrystallized from water in the presence of activated charcoal. 81.6 g (73.5% of theory) of cytosine were obtained.
Example 2; A mixture of cytosine (2.0 g, 18.0 mmol), ammonium sulfate (0.24 g, 1.82 mmol), and hexamethyldisilazane (16.13 g, 100 mmol) was heated to reflux for 45 minutes until a clear solution was obtained. Some gas evolved (ammonia). The reaction mixture was cooled to 52C and concentrated in the vacuum whereby a colourless solid precipitated. 26.4 g of dichloromethane, lithium trifluoromethane sulfonate (2.53 g, 16.2 mmol) and the "chloro sugar" C-137 (6.96 g, 16.2 mmol) were added. The slightly beige mixture was stirred for 2 hours at ambient temperature (20-25C), products (anomeric mixture [(beta-isomer) : (alpha-isomer) 59.5:40.1]) : starting material 99.1 : 0.9. Then the solvent was removed at 38C. A brownish solid was obtained. The solid was dissolved in 6.0 g ethyl acetate. The solution was added drop wise to a mixture of 11 g of aqueous sodium hydrogen carbonate (5 weight% solution in water), 11.0g of water, 17.4 g of ethyl acetate, 3.6 g of cyclohexane and 7.0 g of acetonitrile at 32C. The obtained reaction mixture was stirred over night at ambient temperature, and then for 3 hours at 0C. The precipitate of the blocked (protected) nucleoside was filtered off, washed with 6.0 g of water, and finally with 7.0 g of a mixture of acetonitrile and ethyl acetate (1:1). Yield: 3.63 g; 40.1%.
To the nucleobase suspension (0,06 g, <strong>[71-30-7]Cytosine</strong>; 0,07 g, Thymine; 0,06 g Uracil; 0,55 mmol) in 4 ml anhydrous CH3CN N,O-bis-trimethylsilylacetamide (0,45 g, 2,23 mmol) is added drop by drop and re-precipitating for 15 minutes. The reaction mixture is brought to r.t. and l-ter-butyl-2 -methyl (2S,4R)-4,5-bis(acetyl- oxy pyrrolidine- 1,2-dicarboxylate solution is dropped(8), (0,16 g, 0,46 mmol) in 4 ml of anhydrous CH3CN and then trimethylsilyltri- flate (0,15 g, 0,69 mmol). After re-precipitation for 1 hour the reaction is stopped, the solution is brought to r.t. and then at 00C and neutralised with a saturated solution OfNaHCO3. Then it is filtered on celite and the organic solvent is eliminated with a rotavapor. The remaining aqueous phase is treated with CH2Cl2 (3x10 ml), dried over sodium sulfate, evaporated to dryness and the obtained residues puri- fied by flash chromatography.; Elution mixture: Methanol/Dichloromethane 4-10-15-%. Rf = 0,1. Yield = 80%. Solid white: m.p. = 170,8-171,2 0C; [alpha]D25 = +1,88 (c = 0,80, CHCl3);1H NMR (CDCl3, 500 MHz, 27C): delta 1,39 (s, 6H), 1,44 ( s, 3H), 2,04 (dd, IH, J = 9,7, 14,3 Hz), 2,11 (s, 3H), 2,41 (dd, IH, J = 7,2, 14,3Hz), 3,75 (s, 3H), 4,49 (dd, IH, J = 7,2, 9,7 Hz), 5,27 (m, IH), 4,31 (m, IH), 6,03 (m, IH), 8,29 (d, IH, J = 7,4 Hz).13C NMR (CDCl3, 50 MHz, 27C): delta 21,0, 27,9, 32,8, 52,7, 58,3, 75,1, 76,6, 82,6, 94,9, 140,4, 153,1, 156,0, 166,1, 169,5, 172,7.Elemental analysis. Calculated for Ci7H24N4O7: C, 51,51; H, 6,10; N, 14,13. Found: C, 51,53; H, 6,07; N, 14,11. Theoretical mass for CnH24N4O7: 396,16. Found: 396,14.
With sodium hydroxide; In water; at 100℃; for 0.166667h;Microwave irradiation;
General procedure: To a mixtureof uracil (0.056 g, 0.5 mmol) and NaOH (0.014 g, 0.6 mmol) in neat H2O (2mL), allyl bromide (0.052 mL, 0.6 mmol) was added. Then themixture was put intothe microwave reactor and irradiated at 0-400W(internal temperature: 100C) for10 minutes. After completion of the reaction, the mixture was concentrated underreduced pressure and the residue was purified by column chromatography usingEtOAc-cyclohexane (9:1) as the eluent to afford 3a, yield 82%.
Example.Reaction with an aromatic aldehyde (general method)Magnesium (5 eq relative to cytosine, 1 mmol, 316 mg) was added to anhydrous methanol and heated until complete dissolution of magnesium filings. Next, the flask was charged with cytosine (2.703 mmol, 300 mg) and the appropriate aromatic aldehyde, such as furfuryl aldehyde (16.218 mmol, 1556 mg, 1.343 mL) or benzyl aldehyde (16.218 mmol, 1721 mg, 1.648 mL) (6 eq relative to cytosine). The reaction flask was placed in a drying oven at the temperature of 55C for 3 hours. The reaction progress was monitored by TLC (acetone/water 9: 1 for furfuryl aldehyde or 20: 1 for benzyl aldehyde). Next, NaBLU (1.5 eq relative to the aldehyde, 24.3 mmol, 923 mg) was added to cooled reaction mixture. The mixture was kept for about 15 minutes at room temperature. Next, aqueous HC1 solution was added to decompose the reducing agent and neutralize the reaction mixture.The solvent was evaporated, water was added to the residue and the product was extracted with ethyl acetate. The separated organic phase, i.e. the ethyl acetate layer containing the product and the aromatic (usually high-boiling) alcohol, such as furfuryl alcohol or benzyl alcohol was evaporated to dryness or extracted with aqueous HC1 solution to obtain pure solution of modified cytosine hydrochloride, which was then neutralized with KOH solution and again extracted with ethyl acetate. The organic layer was evaporated to dryness to obtain pure product in powder form. The yield of the synthetic process following purification ranged from 55 to 95% (depending on the aldehyde) (Table 1). Below are the example cytosine analogue products according to the invention and their parameters; structures and properties of cytosine analogues are also presented in Table 1.4-N-FurfurylcytosineES-MS: ES m/z 190 [M-H]+, 191 [M]; ES+ m/z 192 [M+H]+, 214 [M+K]+.lU NMR (300 MHz, DMSO) 6 4.5 (d, J=5.4 Hz, 2H, H-8); 5.6 (d, J=7.1 Hz, 1H, H-5); 6.3 (q, J=0.73 Hz, J=3.2 Hz, HI, H-9); 6.4 (q, J=1.9 Hz, J=3.2 Hz, 1H, H-10); 7.2 (d, J=7.1, 1H, H-6), 7.6 (q, J=0.73 Hz, 7=1 :9 Hz, 1H, H-l l); 7.9 (t, J=5.6 Hz, 1H, NH); 10.3 (s, 1H, NH). 13C NMR (75 MHz, DMSO) delta 20.88; 93.10; 107.16; 110.46; 125.59; 129.27; 141.82; 151.96; 156.55; 164.29.4-N-PicolylcytosineES-MS: ES+ m/z: 202 [M]; 225 [M+Na]+, 240 [M+K]+.'H-NMR (400 MHz, DMSO) delta 4.8 (d, J= 5.859 Hz, 2H, H-8); 5.8 (d, J= 7.324 Hz, IH, H-5); 7,3 (d, J= 7.813 Hz, IH, H-6); 7.4 (m, IH, H-10); 7.7 (d, J= 1.465 Hz, IH, H-9); 8,1 (t, J= 5.859 Hz, IH, N-H-7); 8.4 (m, 1H.H-11); 8.5 (d, J=1.297 Hz, IH, H12); 10.3 (s, IH, N-H-l).I3C-NMR (100 MHz, DMSO) delta 60.59; 93.15; 123.43; 134.72; 135.21; 141.91; 148.91; 148.08; 148.87; 156.56; 164.50.
89%
Example 1; Reaction with an Aromatic Aldehyde (General Method) Magnesium (5 eq relative to cytosine, 1 mmol, 316 mg) was added to anhydrous methanol and heated until complete dissolution of magnesium filings. Next, the flask was charged with cytosine (2.703 mmol, 300 mg) and the appropriate aromatic aldehyde, such as furfuryl aldehyde (16.218 mmol, 1556 mg, 1.343 mL) or benzyl aldehyde (16.218 mmol, 1721 mg, 1.648 mL) (6 eq relative to cytosine). The reaction flask was placed in a drying oven at the temperature of 55 C. for 3 hours. The reaction progress was monitored by TLC (acetone/water 9:1 for furfuryl aldehyde or 20:1 for benzyl aldehyde). Next, NaBH4 (1.5 eq relative to the aldehyde, 24.3 mmol, 923 mg) was added to cooled reaction mixture. The mixture was kept for about 15 minutes at room temperature. Next, aqueous HCl solution was added to decompose the reducing agent and neutralize the reaction mixture.The solvent was evaporated, water was added to the residue and the product was extracted with ethyl acetate. The separated organic phase, i.e. the ethyl acetate layer containing the product and the aromatic (usually high-boiling) alcohol, such as furfuryl alcohol or benzyl alcohol was evaporated to dryness or extracted with aqueous HCl solution to obtain pure solution of modified cytosine hydrochloride, which was then neutralized with KOH solution and again extracted with ethyl acetate. The organic layer was evaporated to dryness to obtain pure product in powder form. The yield of the synthetic process following purification ranged from 55 to 95% (depending on the aldehyde) (Table 1). Below are the example cytosine analogue products according to the invention and their parameters; structures and properties of cytosine analogues are also presented in Table 1.; 4-N-Furfurylcytosine ES-MS: ES- m/z 190 [M-H]+, 191 [M]; ES+ m/z 192 [M+H]+, 214 [M+K]+. 1H NMR (300 MHz, DMSO) delta 4.5 (d, J=5.4 Hz, 2H, H-8); 5.6 (d, J=7.1 Hz, 1H, H-5); 6.3 (q, J=0.73 Hz, J=3.2 Hz, H1, H-9); 6.4 (q, J=1.9 Hz, J=3.2 Hz, 1H, H-10); 7.2 (d, J=7.1, 1H, H-6), 7.6 (q, J=0.73 Hz, J=1.9 Hz, 1H, H-11); 7.9 (t, J=5.6 Hz, 1H, NH); 10.3 (s, 1H, NH). 13C NMR (75 MHz, DMSO) delta 20.88; 93.10; 107.16; 110.46; 125.59; 129.27; 141.82; 151.96; 156.55; 164.29.
Preparation of cis- and trans-2-Benzoyloxymethyl-5-cytosin-1'-yl-1,3-oxathiolaneCompound IX76.8 g (0.69 moles) of cytosine, 652.4 g (842 mL, 4.04 moles) of HMDS and 7.5 g (0.07 moles) of TMSCl were taken in a 3.0 L, 4-necked round bottom flask under nitrogen atmosphere. The contents were refluxed at 125-130 C. for 1-2 hours until a clear solution was obtained. The mass was cooled to 100 C. and the reagents in excess were distilled off completely under vacuum. 150 g (0.53 moles) of benzoyloxymethyl-acetoxy-1,3-oxathiolane, 1.5 L of DCM and 165.5 g (0.74 moles) of TMSTf were added to the residue. (Instead of TMSTf, 148.5 g of TMS-I may be used.) The reaction mixture was refluxed and when the reaction was complete, it was cooled to 0 C. and charged with 750 mL of DM water. (The initial 100 mL were added drop wise.) After stirring for 15 minutes, the organic layer was separated, washed with 1.5 L of saturated NaHCO3 solution and DCM was distilled off completely under vacuum (200 mm of Hg, 30-35 C.). Yield: 150-160 g (84.7-90.3%)MS: M++1=3341H NMR (DMSO d6): delta 3.10 (dd, 1H), 3.48 (dd, 1H), 4.64 (d, 2H), 5.50 (t, 1H), 5.6 (d, 1H) 6.25 (t, 1H), 7.27 (d, 2H), 7.50-7.72 (m, 4H), 7.95-7.98 (m, 2H)
Preparation of 6-amino-3-{2-[(2,2-dimethyl-1,1-diphenyl-1-silapropoxy)methyl]-1,3-oxathiolan-5-yl)}-3-hydropyrimidine-2-one (TBDPSi-<strong>[71-30-7]Cytosine</strong>)Compound IXA mixture of 72.8 g (0.65 moles) of <strong>[71-30-7]Cytosine</strong>, 527.5 mL (2.5 moles, 403.5 g) of Hexamethyldisilazane and 27.16 g (0.25 moles, 31 mL) of TMS-Cl was heated to 125-130 C. and refluxed for 2 hours in a nitrogen atmosphere. The reaction mixture was then cooled and the solvent was completely recovered under vacuum at 100-105 C. The residue was cooled to room temperature, dissolved in 2.1 L of DCM and 210 g (0.5 moles) of TBDPSi-acetoxy oxathiolane was added to it. 140 g (100 mL, 0.7 moles) of TMS-I was added to the reaction mixture slowly over 15-30 minutes. The reaction mixture was stirred for 4 hours. (14 mL of TMS-I can be added to the reaction mixture if the reaction has not reached completion.) It was then cooled to 0-5 C. and diluted with 1 L of DM water. After stirring for 15 minutes the organic layer was separated and washed with 1 L of aqueous NaHCO3 solution. The organic layer was separated and the solvent was recovered under vacuum at 40-45 C. Yield: 200-230 g (85.0-93.6%)MS: M+1=4681H NMR (CDCl3): delta 1.05 (s, 9H), 3.15-3.17 (dd, 1H), 3.46-3.55 (dd, 1H), 3.92-3.98 (dd, 1H), 4.09-4.11 (dd, 1H), 5.21-5.24 (t, 1H), 5.72-5.76 (d, 1H), 6.07-6.35 (m, 1H)
With triethylamine; In tetrahydrofuran; water; at 80℃; for 12h;
General procedure: Cyanuric chloride (0.422g, 0.25 mmol) in Tetrahydrofuran (25 ml), TEA (0.1mmol) and adenine (0.28g, 0.25 mmol) in water (25 ml) were placed into a 250 ml two neck round bottom flask which was fitted with reflux condenser and thermometer. The reaction mixture was refluxed at 80C for 4-16 hours. The progress of the reaction was monitored by TLC. After the completion of reaction it was cooled to room temperature. The product formed was washed with water and THF (2:1) mixture. The crude was further purified by column chromatography with the eluent dichloromethane and chloroform (1:9) mixture.
With triethylamine; In tetrahydrofuran; water; at 80℃; for 20h;
General procedure: Cyanuric chloride (0.422 g, 0.25 mmole) in Tetrahydrofuran (25 mL), TEA (0.1 mmole) and adenine (0.28 g, 0.25 mmole) in water (25 mL) were placed into a 250 mL two neck round bottom flask which was fitted with reflux condenser and thermometer. The reaction mixture was refluxed at 80 C for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature. The product formed was washed with water and THF (2:1) mixture. The crude was further purified by column chromatography with the eluent dichloromethane and chloroform (9:1) mixture (Scheme 1).
1,2,3-tri-O-acetyl-5-deoxy-5-C-ethynyl-4-C-methanesulfonyloxymethyl-α,β-D-xylofuranose[ No CAS ]
1-(2',3'-di-O-acetyl-5'-deoxy-5'-C-ethynyl-4'-C-methanesulfonyloxymethyl-β-D-xylofuranosyl)cytosine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
General procedure: N,O-bis(trimethysilyl)acetamide (BSA) (12.5 mL, 50.29 mmol) was added to an anomeric mixture of sugar derivatives 12a-12b (5.60 g, 14.27 mmol) and thymine/cytosine/N6-benzyoladenine (18.86 mmol) in dry acetonitrile (120 mL), under nitrogen atmosphere. Dichloroethane was used as solvent for coupling of N6-benzoyladenine instead of acetonitrile. The reaction mixture was refluxed for 1 h to get a clear solution, brought to RT and then trimethysilyl triflate (TMSOTf) (4.0 mL, 22.10 mmol) was added. The reaction mixture was refluxed for 10-14 h, cooled to room temperature and was extracted with chloroform (3 × 100 mL). The organic layer was washed with sat. NaHCO3 solution (3 × 100 mL) and brine (2 × 50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and residue thus obtained was purified by silica gel column chromatography using methanol in chloroform as a gradient solvent.
4-C-(acetoxymethyl)-1,2-di-O-acetyl-3-azido-3-deoxy-5-O-(p-toluenesulfonyl)-D-ribofuranose[ No CAS ]
4′-C-(acetoxymethyl)-2′-O-acetyl-3′-azido-3′-deoxy-5′-O-(p-toluenesulfonyl)cytidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
General procedure: To the stirred solution of compounds 11a-11b (1.0 g, 2.0 mmol)and thymine (0.38 g, 3.0 mmol)/uracil (0.34 g, 3.0 mmol) or cytosine(0.34 g, 3.0 mmol) in anhydrous acetonitrile (20 mL), N,Obis(trimethylsilyl)acetamide (1.97 mL, 8.06 mmol) was addeddropwise. 1,2-Dichloroethane was used as solvent for coupling of6-N-benzoyladenine (0.73 g, 3.0 mmol) instead of acetonitrile. Thereaction mixture was stirred at reflux for 1 h, and then cooled to0 C. In the cooled reaction mixture trimethylsilyltrifluoromethanesulfonate (0.61 mL, 3.37 mmol) was added dropwise under stirringand the reaction was heated at 70-80 C for 4-6 h. The reactionwas quenched with a cold saturated aqueous solution of sodiumhydrogen carbonate (50 mL) and extraction was performed withchloroform (3 × 100 mL). The combined organic phase was washedwith saturated aqueous solutions of NaHCO3 (2 × 100 mL) and brine(2 × 50 mL) and was dried over anhydrous Na2SO4. The excess ofsolvent was removed under reduced pressure and the residue thusobtained was purified by silica gel column chromatography usingmethanol in chloroform as gradient solvent system to afford nucleosides12a-d in 81-85% yields.
Preparation of Compound 14a: [00347] To a suspension of cytosine (4.71 mmol) in anhydrous 1 ,2-dichloroethane (10 mL/mmol) was added dropwise at room temperature N,0-bis(trimethylsilyl)acetamide (10.83 mmol). The reaction mixture was heated at reflux during 2 hours (colorless solution). Then, a solution of compound 13 (2.05 mmol) in anhydrous 1 ,2-dichloroethane (10 mL/mmol) was added at room temperature followed by trimethylsilyl trifluoromethanesulfonate (4.71 mmol) and the reaction mixture was heated at reflux during 2 hours. The reaction mixture was poured on a saturated solution of bicarbonate and the organic layer was washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel column (eluent: CH2C12/CH30H 0 to 5%) to give the expected compound as a colorless foam in quantitative yield. MS (ESI) m/z = 540.09 (MH ).
(1) Under nitrogen, the temperature is 0 , the quality of anhydrous hydrogen fluoride was added 1150g 3450g cytosine, at a temperature of -15 deg.] C, into fluorine gas content of 15% fluorine gas, a mixed gas of nitrogen, flow rate of 40g / h, fluorination reaction; document.write(""); After (2) a reaction for 4 hours in ventilation of nitrogen gas remove excess fluorine gas at -20 reaction of anhydrous hydrogen fluoride was distilled off in vacuo to dryness, water was added 8L, calcium carbonate was added to adjust the pH to 8; document.write(""); (3) The reaction was warmed to 90 deg.] C for 1 hour, filtered hot, 100g activated carbon was added, incubated 90 deg.] C for 0.5 hours and then filtered hot, cooled to 25 deg.] C for 0.5 hours, then cooled to 0 deg.] C, stirred for 1 hour , 5-fluorocytosine was filtered to give a white wet product; document.write(""); (4) the wet product 5-fluorocytosine after 70 deg.] C bake for 16 hours to give 5-fluorocytosine dried. document.write(""); Purity by HPLC and liquid phase titration analysis to analyze the content of 5-fluorocytosine purity and yield the following results: 95.7% yield, 97.7% pure.
87.4%
With 1,1,1,3',3',3'-hexafluoro-propanol; fluorine; at 20℃; under 1125.11 Torr;Inert atmosphere;
(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 20 C, ie the reaction temperature. Set the reaction pressure 0.15MPa. The reaction material 2 is a cytosine solution, that is, a mixture of cytosine and hexafluoroisopropanol, the mass concentration of uracil is 3% and the feed rate is 80 g / min. The raw material 1 is 20 mol% of the fluorine-nitrogen mixed gas, and the feed rate is 2.90 L / min. The molar ratio of fluorine to cytosine was 1.2: 1. The raw material 2 cytosine solution was pre-heated by the microchannel preheating module 3 into the "heart-shaped" microchannel reaction module 4. The fluorine-nitrogen mixed gas was directly introduced into the microchannel reaction module 4 through the gas mass flow meter, In the channel reaction module 4-9, the fluorine-nitrogen mixture reacts with cytosine. 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-fluorocytosine product. The reaction product was analyzed by liquid chromatography, and the purity of 5-fluorocytosine was 99.3% and the product yield was 87.4%.
63%
With formic acid; for 1.5h;Flow reactor; Autoclave;
1.0 M cytosine solution in formic acid was introduced at 4.0 mL/h (4.0 mmol/h) while fluorine (10 % in N2) was introduced at 20 mL/min (5 mmol/h). The reaction was conducted for 90 minutes, the collected fraction was evaporated and the residue was recrystallized from water (7 mL). After filtration, the product was dried under reduced pressure to afford 5-fluorocytosine (0.49 g, 63 % yield) as a tan powder. M.p.: 295 - 300 C (decomposes), ([M]+ 129.0337, [M]+ requires: 129.0338); IR (cm"1): 3384, 3092, 2724, 1665, 1624, 1551, 1454, 1216; 1 H NMR (400 MHz, D2O+DCI) 7.83 (1 H, d, 3JHF 4.8 Hz); 19F NMR (400 MHz, D2O+DCI) -169.7 (1 F, d, 3JHF 4.8 Hz); 13C NMR (100 MHz, D2O+DCI): 130.67 (d, 2JCF 29.6 Hz), 135.25 (d, 1JCF 232 Hz), 147.88, 153.65 (d, 2JCF 23.4 Hz); MS (ASAP): 11 1 (37 %, [M+H-F]+), 129 (8 %, [M]+), 130 (100 %, [M+H]+).
With formic acid; fluorine; at 9℃; for 0.0833333h;Inert atmosphere;
As shown in Fig. 1, using G1 SiC Reactor reaction equipment from Dow Corning,Use the metering pump<strong>[71-30-7]Cytosine</strong>Formic acid solution (10 wt%) and fluorine gas (mixed in nitrogen with a volume concentration of 10 vol%) were simultaneously pumped into a mixer of a microchannel reactor having a tubular structure of a DC type channel and having a T-shaped structure Mixed channel, controlling the flow rate of cytosolic solution (10wt% formic acid solution) 580g / h, fluorine gas (mixed in nitrogen, volume concentration 10vol%) flow 200g / h, controlled microchannel thermostatic reactor at 9 reaction , The reaction solution residence time of 300s. A product solution containing 5-fluorocytosine product was obtained. 500ml of n-butanol was added to precipitate a white product and the product was filtered and dried to obtain 5-fluorocytosine. The product was detected by liquid chromatography (HPLC). The results showed that the purity of 5-fluorocytosine was 99.7%The selectivity for 5-fluorocytosine was 95.2%.
With triethylamine; potassium iodide; In ethanol; at 50 - 80℃; for 3h;
2.22 g of cytosine (20 mmol), 2.0 g of triethylamine (20 mmol), 0.2 g of potassium iodide (1% eq) and 50 mL of anhydrous ethanol were added to a three-necked flask, heated to 50-55 C. and stirred until dissolved to a homogeneous system. 5.60 g of 3-chloro-4-methoxy-benzyl bromide (III) (24 mol) solution was added dropwise to the reaction solution slowly, then heated to 80 C. to continue 3 hours, then the reaction ended with the TLC monitoring. The mixture was cooled down to room temperature, and filtered to remove triethylamine hydrobromide. The filtrate was adjusted to pH 4-5 with hydrochloric acid. Ethanol was recovered under the reduced pressure and residue was recrystallized using ethyl acetate to get 4.78 g off-white solid N-(3-chloro-4-methoxybenzyl) cytosine (V) 4.78 g, with the yield of 90.2%.
Purine and pyrimidine compounds were synthesized in the formamide reaction. A ~5 mL volume of formamide (reagent grade, Sigma-Aldrich) was heated in an oven at 160 C for up to 120 h in a 20-mL scintillation vial covered with foil. Fractions of the reaction mixture were collected at 72 and 120 h time points and stored at 8 C for 24 h before workup. Reacted formamide mixture aliquots of 100 muL or ~120 mg were dissolved in 10 mL of deionized water and filtered through a 0.45 mum PTFE membrane before analysis.
A suspension of 1 mM cytosine and 1 mM 1-(B-D-arabinofuranosyl)uracil in aqueous 50 mM MES buffer was thermostated at 50 C. during 30 min. Then, NDT enzyme (SEQ ID NO: 2) was added (0.085 mg/ml) dropwise and the reaction was stirred at 50 C. during at least 1 day under the same conditions. Then, the suspension was hot filtered, and the solid was washed and dried. The aqueous filtrate was partially concentrated, cooled down and filtered. The recovered solid was allowed to partially precipitate and concentrate. Once filtered and washed, the solid was crystallized using a suitable solvent, such as a polar protic or polar aprotic solvent, in combination with water or a suitable apolar solvent.
With ferric sulfate nonahydrate; In water; at 80℃; for 24h;pH 7.57;
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 muL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0% w/w) at 80 C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 muL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0% w/w ofthe corresponding salt?s pellet) at 80 C for 24 h. For the innerenvironment, NH2CHO (200 muL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0% w/w) at80 C for 24 h. The reaction of NH2CHO (10% v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 muL) at 60C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 C, detector temperature 280 C, gradient 100 C for 2min, and 10 C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98% compared to that of the reference standards.The analysis was limited to products of ?1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
With magnesium sulfate; In water; at 80℃; for 24h;pH 7.57;
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 muL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0% w/w) at 80 C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 muL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0% w/w ofthe corresponding salt?s pellet) at 80 C for 24 h. For the innerenvironment, NH2CHO (200 muL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0% w/w) at80 C for 24 h. The reaction of NH2CHO (10% v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 muL) at 60C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 C, detector temperature 280 C, gradient 100 C for 2min, and 10 C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98% compared to that of the reference standards.The analysis was limited to products of ?1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
With copper(II) choride dihydrate; In water; at 80℃; for 24h;pH 7.57;
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 muL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0% w/w) at 80 C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 muL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0% w/w ofthe corresponding salt?s pellet) at 80 C for 24 h. For the innerenvironment, NH2CHO (200 muL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0% w/w) at80 C for 24 h. The reaction of NH2CHO (10% v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 muL) at 60C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 C, detector temperature 280 C, gradient 100 C for 2min, and 10 C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98% compared to that of the reference standards.The analysis was limited to products of ?1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
With sodium silicate solution; CuN2O6; In water; at 80℃; for 24h;pH 7.57;
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 muL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0% w/w) at 80 C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 muL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0% w/w ofthe corresponding salt?s pellet) at 80 C for 24 h. For the innerenvironment, NH2CHO (200 muL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0% w/w) at80 C for 24 h. The reaction of NH2CHO (10% v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 muL) at 60C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 C, detector temperature 280 C, gradient 100 C for 2min, and 10 C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98% compared to that of the reference standards.The analysis was limited to products of ?1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
(2R,3R,4S,5R)-2-(4-amino-2-oxopyrimidin-1(2H)-yl)-4-(benzyloxy)-5-(benzyloxymethyl)-5-vinyltetrahydrofuran-3-yl acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
BSA (0.976 g, 4.8 mmol) was added to a mixture of 4-aminopyrimidin-2(1H)-one (0.266 g, 2.4 mmol) in CH3CN (15 mL) at room temperature. After 3 h, 3 (0.53 g, 1.2 mmol) and SnCl4 (1.35 g) were added into the mixture. Once complete, the mixture was stirred at 65 C. for 1 h, cooled and then poured into a saturated aqueous solution of NaHCO3 (20 mL). The organic phase was extracted with ethyl acetate, washed with water, brine solution, dried (Na2SO4) and evaporated to dryness. Chromatography (dichloromethane:methanol 15:1) afforded 4 (0.564 g, 95%) as a brown solid. EC-MS: (M+H)=492.2
To a 35ml microwave reaction tube was added L5g cytosine, 18ml heavy water, (lambda 15gl0% dry Pd / C, 15mg molybdenum dioxide, 5mg of sodium borohydride. After stirring at room temperature for half an hour a microwave reactor 160 C 80min. The reaction after the added weight of the aqueous 3ml37% DC1, stirred for 20min filtration, the filtrate was concentrated to dryness to afford after 1. 98g of white solid, deuterated deuterated cytosine hydrochloride (compound No. 19-a), a yield of 97.5%.
β-1-(2’-deoxy-2’,2’-difluoro-3',5'-di-O-benzoyl-D-ribofuranosyl)-4-aminopyrimidin-2-one hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
<strong>[71-30-7]Cytosine</strong> (22.2g, 0.2mol), hexamethyldisilazane amine dioxane (84mL, 0.4mol), 0.10g of ammonium sulfate into 500mL three-neck flask with stirring, heated under reflux until cytosine was completely dissolved after clarification, insulation response until no ammonia released after 0.5-1h.The temperature was lowered to 100 concentrated under reduced pressure the remaining hexamethyldisilazane amine alkoxylates cytosine silyl ether protecting group obtained as a white solid.Was added to the reaction flask 500mL 100mL n-pentanol was stirred and heated to 70-80 deg.] C and the white solid was dissolved transferred to a dropping funnel incubation.To a 1L three-necked flask of 2-deoxy-2,2-difluoro--D- erythro - 3,5-furanose five benzhydryl-1-sulfonate (45g, 0.1mol), 1.0g phosphomolybdic acid, 100mL n-amyl alcohol is stirred and heated to 128-137 , then a solution of cytosine silyl ether protecting group, 2h after the addition was complete the reaction was heated to reflux insulation 3h, TLC detection to be 2-deoxy-2,2 -D- erythro-fluoro - 3,5-furanose five -1- diphenylmethyl ester methanesulfonate starting material disappeared after stopping point of the reaction, cooling to 40-50 suction filtered through diatomaceous earth, the filtrate was dropwise hydrochloric acid solution (200mL, 6M) was stirred crystallization 2.5h, a large amount of a white solid, after drying in the filter cake was a white solid 48.2g, 95% yield.
(1) <strong>[71-30-7]Cytosine</strong> and hexamethyldisilazane are refluxed under the catalysis of ammonium sulfate for 3 hours, then n-pentanol is added and heated to 63 C. to obtain a cytosine silyl ether protective base solution; The molar ratio of cytosine, hexamethyldisilazane, ammonium sulfate is 1:4:1; (2) Dissolve 2-deoxy-2,2-difluoro-D-erythro-pentafuranose-3,5-diphenylmethyl ester_1-methanesulfonate in isoamyl alcohol and stir well The catalyst phosphotungstic acid is added and heated to 64 C. to obtain a 2-deoxy-2,2-difluoro-D-erythro-pentafuranose-3,5-diphenylmethyl-1-methanesulfonate solution; The weight ratio of 2-deoxy-2,2-difluoro-D-erythro-pentafuranose-3,5-diphenylmethyl-1-methanesulfonate to the catalyst is 65:1; (3) adding hydroxyapatite powder to the cytosine silyl protecting group solution and heating to 40-50 C,Then add the solution obtained in step (2) dropwise Pyrimidine Silyl Protected Base Solution with 2-Deoxy-2,2-Difluoro-D-erythro-pentafuranose-3,5-diphenylmethyl ester-1-methanesulfonate The molar ratio of the solution is 2:1. The weight ratio (g/mL) of the base apatite powder to the cytosine silyl ether protecting group solution is 1:50. Constant temperature reaction 1.5h. After diatomaceous earth is suctioned and filtered, hydrochloric acid is added dropwise to the filtrate to precipitate solids .Obtain B-1 (2'-deoxy-2', 2'-difluoro) after drying-3',5'-di-O-benzoyl-D-ribofuranosyl)4-aminopyrimidin-2-one hydrochloride intermediate;
With methanesulfonic acid; triethylamine; 1,1,1,3,3,3-hexamethyl-disilazane; In dichloromethane; toluene; at 25 - 60℃; for 4h;Reflux;
Into the other reaction flask115. 5 g cytosine, 0.7 mL methanesulfonic acid, 242 OmL hexamethyldisilazane and290 mL of toluene,Heated to reflux; to be all the dissolved solids, the cooling to 25 C, then add 145mL of triethylamine, and then warmingTo 60 C, dropping the dichloromethane solution of the chlorinated product, dropping, heating to reflux, the reaction after 4 hours by the highThe relative amount of the diastereomer was determined to be 3.5% (relative to CME) by the performance liquid chromatography analysis. After cooling to 30-35 C,Ethylamine (73 mL) and water (1200 mL) was added, followed by addition of 1,200 mL of n-hexane, cooling to 25 C,To obtain 337. 0 g of white solid CME, the molar yield of 85%, HPLC purity of 99.6%.
With ammonium chloride; In 1-methyl-pyrrolidin-2-one; at 180℃; for 8h;
Decarboxylation Synthesis of cytosine was carried out by adding 77.5 g (0.5 mol) of intermediate 3, 26.8 g (0.5 mol) of ammonium chloride, 500 ml of N-methylpyrrolidone to a 1000 ml round bottom flask, , Stir the reaction evenly heated to 180C, and heat for 8 hours, heated to reflux until less bubbles removed, stop the reaction, cooled to room temperature, add 150 ml of ether, precipitation solid filtration, collecting white solid is the final product cells Pyrimidine, dried, 49 g of a white crystalline solid in 87% yield.
Sodium tert-butoxide (31.7g, 0.33mol) and 150mL tert-butanol into the reaction vessel and stirred well; 3-hydroxyacrylonitrile sequentially into sodium salt (27.3g, 0.3mol) and urea (18.9 g of , 0.315 mol); was warmed to 50 deg.] C and reacted for 8 hours cyclization; The t-butanol was distilled off under normal pressure, and slowly adding 180 mL of water to the residue; dropping concentrated hydrochloric acid to adjust the pH value, when the pH is 7 ~ 7.5, cooled to 10 C; after cooling, washed, after drying to obtain cytosine 30.5g,Yield 91.5%, HPLC content 99.5%.
Sodium methoxide (17.8g, 0.33mol) and 180mL of methanol into a reaction vessel and stirred well; 3-hydroxyacrylonitrile sequentially into sodium salt (27.3g, 0.3mol) and urea monosodium salt (36.9g, 0.45 mol); and warmed to 40C cyclization reaction for 6 hours; the methanol was distilled off at atmospheric pressure, and the residue was slowly added to 180mL of water; dropwise addition of concentrated hydrochloric acid to adjust the pH, when the pH of 7 to 7.5, was cooled to 15 deg.] C; after cooling was filtered, washed with water and dried to obtain 30.5 g of cytosine, yield 91.5%, HPLC content of 99.3%.
Sodium methoxide (17.8g, 0.33mol) and 180mL of methanol into a reaction vessel and stirred well; 3-hydroxyacrylonitrile sequentially into sodium salt (27.3g, 0.3mol) and urea monopotassium salt (44.2g, 0.45 mol); and warmed to 40 C cyclization reaction for 6 hours; the methanol was distilled off at atmospheric pressure, and the residue was slowly added to 180mL of water; dropwise addition of concentrated hydrochloric acid to adjust the pH, when the pH of 7 to 7.5, was cooled to 15 deg.] C; after cooling was filtered, washed with water and dried to obtain 30.5 g of cytosine, yield 91.5%, HPLC content of 99.2%.
tert-butyl 4-((4-amino-2-oxopyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 80℃;
The cytosine (1 eq),Example 14A (1.1 eq),Anhydrous cesium carbonate (1.1 eq) was dissolved in anhydrous DMF,80 overnight.After the completion of the reaction, cesium carbonate was removed by filtration and the DMF was removed.Add water and extract with ethyl acetate.The organic phase was removed to remove the solvent to give the title compound.The compound is further purified by recrystallization from ether or by column chromatography.
With dmap; In tetrahydrofuran; at 20℃;Inert atmosphere;
Under the protection of nitrogen,The cytosine Sa1 (500 mg, 2.7 mmol), DMAP (33.0 g, 0.27 mmol) was dissolved in dry THF, and Boc2O (3.9 g, 10.8 mmol) was slowly added in an ice water bath, and reacted at room temperature overnight, the system became The orange clear solution was quenched with methanol after TLC.It was then diluted with a large amount of EA and washed with saturated aqueous sodium bicarbonate and saturated NaCl, respectively.Dry over anhydrous sodium sulfate and concentrate.Put on the column and put it on the column for two hours.The column was quickly passed through (PE/EA = 1:1) to give the white solid product S1 (1.1 g, 82.0%).
(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (2R,5R)-5-(4-amino-2-oxo-1,2-dihydro-1-pyrimidinyl)-1,3-oxathiolane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
(1) (3 g) was added to dry DMF (1.0 ml) and dichloromethane (40 ml) in a reaction flask A, and cooled to about 5 C with stirring.Add a solution of thionyl chloride in dichloromethane (1.0 ml + 10 ml).After the dropwise addition, continue to stir at 18-24 C for about 10 h.Concentrate under reduced pressure at 40 C until no liquid dripping, and cool to room temperature to obtain a chloride. In another reaction vial B, cytosine (1.2 g) was added,Methanesulfonic acid (0.1 ml) of hexamethyldisilazane (5 ml) and toluene (10 ml) were heated under reflux for 3 h to give a clear solution.Tetrabutylammonium bromide (3.35 g) was added, and the chlorination liquid obtained in the above reaction flask A was added dropwise under a gentle reflux condition, and the dropping funnel was washed with dichloromethane (2 ml), and the resulting mixture was heated under reflux for 4 h. ,Cool to room temperature, add 30% potassium hydroxide 10 ml solution, stir the suspension for 2 h, add n-hexane (20 ml) at room temperature, stir for 6 hours, filter, wash the solid with 60-90 C petroleum ether,Drying white solid (2) (3.09 g, 78%), purity: 98.8%
3'-deoxy-3',4'-didehydro-1',2',5'-triacetylribose[ No CAS ]
3'-deoxy-3',4'-didehydro-2',5'-diacetyl riboside[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85.2%
<strong>[71-30-7]Cytosine</strong> (11.0 g, 0.1 mol) was suspended in 180 mL of anhydrous toluene, and 15 mL of anhydrous DMF, hexamethyldisilazane 20 mL was added, and the mixture was heated under reflux for 4 h. The system was completely clarified, cooled to 70 C, and evaporated to dryness under reduced pressure. . Add 3'-deoxy-3',4'-didehydro-1',2',5'-triacetylribose (25.8 g, 0.1 mol) at room temperature, 200 mL of anhydrous dichloromethane, titanium tetrachloride 1.0 The mixture was reacted for 5 h at room temperature, filtered, and the filtrate was washed with water.The intermediate compound 2 was obtained in an amount of 25.2 g, and the yield was 85.2%.
2,4-difluoro-N-(2-oxo-1,2-dihydropyrimidin-4-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With pyridine; dmap; In dichloromethane; at 20℃;Inert atmosphere;
General procedure: To a mixture of cytosine (5.55 g, 49.95 mmol, 1.00 equiv.), DMAP (305.14 mg, 2.50 mmol, 0.02 equiv.), and pyridine (6.03 mL,74.93 mmol, 1.50 equiv.) in DCM (25 mL), acid chloride (59.95 mmol, 1.20 equiv.) was added slowly. The reaction was continued over night at RT and concentrated to dryness. The residue was triturated with ethyl acetate and filtered. The filter cake was then stirred in 1 N aq. HCl (500 mL) at RT for 2 h and filtered.The obtained solid was stirred in sat. aq. NaHCO3 (500 mL) at RT for2 h and again filtered. The resulting white powder was eventually stirred in water (500 mL) at RT for 2 h, filtered, and dried to give products 6c, d, e.
63%
With pyridine; dmap; In dichloromethane; at 20℃;
Cytosine (5.55g, 49.95mmol) and DMAP (305.14mg, 2.50mmol) were suspended in DCM (25mL), and pyridine (6.03mL, 74.93mmol) was added dropwise. After completion, 2,4- Difluorobenzoyl chloride (10.58 g, 59.95 mmol) was reacted at room temperature overnight. After the reaction of the raw materials was monitored by TLC, the reaction solution was concentrated to dryness to obtain a white solid. The white solid was washed with ethyl acetate (300 mL) and filtered; the resulting filter cake was stirred in a 1N HCl solution (500 mL) for 2 hours and filtered; the resulting filter cake was stirred in a saturated sodium bicarbonate solution (500 mL) for 2 hours and filtered; The filter cake obtained in the previous step was washed with pure water, stirred for 2 hours, suction filtered, and dried under vacuum to constant weight to obtain a white solid product 5d (7.91 g, 31.47 mmol), yield: 63%.
4-chloro-N-(2-oxo-1,2-dihydropyrimidin-4-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With pyridine; dmap; In dichloromethane; at 20℃;Inert atmosphere;
General procedure: To a mixture of cytosine (5.55 g, 49.95 mmol, 1.00 equiv.), DMAP (305.14 mg, 2.50 mmol, 0.02 equiv.), and pyridine (6.03 mL,74.93 mmol, 1.50 equiv.) in DCM (25 mL), acid chloride (59.95 mmol, 1.20 equiv.) was added slowly. The reaction was continued over night at RT and concentrated to dryness. The residue was triturated with ethyl acetate and filtered. The filter cake was then stirred in 1 N aq. HCl (500 mL) at RT for 2 h and filtered.The obtained solid was stirred in sat. aq. NaHCO3 (500 mL) at RT for2 h and again filtered. The resulting white powder was eventually stirred in water (500 mL) at RT for 2 h, filtered, and dried to give products 6c, d, e.
91%
With pyridine; dmap; In dichloromethane; at 20℃;
<strong>[71-30-7]Cytosine</strong> (5.55g, 49.95mmol) and DMAP (305.14mg, 2.50mmol) were suspended in DCM (25mL), and pyridine (6.03mL, 74.93mmol) was added dropwise,After completion, p-chlorobenzoyl chloride (7.66 mL, 59.95 mmol) was slowly added to the reaction solution.The reaction was carried out at room temperature overnight. After TLC monitors the reaction of the raw materials, the reaction solution is concentrated to dryness.A white solid was obtained. The white solid was washed with ethyl acetate (300 mL) and filtered; the resulting filter cake was stirred in a 1N HCl solution (500 mL) and filtered; the resulting filter cake was stirred in a saturated sodium bicarbonate solution (500 mL) for 2 hours, filtered; and then purified water The filter cake obtained in the previous step was washed, stirred for 2 hours, filtered with suction, and dried under vacuum to constant weight to obtain 5e (11.35 g, 45.46 mmol) as a white solid, yield: 91%.
1. 135635g (5.5mmol) of diethylenetriamine pentaacetic acid dianhydride (dtpaa), 2.334mL of triethylamine (16.5mmol), anhydrous DMF (50mL), <strong>[73-24-5]adenine</strong> (A) 0.7432g (5.5mmol), In a three-necked round bottom flask. Stir at a constant temperature of 100 C, and condense and reflux for 24 h. Further, 0.6105 g (5.5 mmol) of cytosine was added to the above reaction solution, and the mixture was rapidly stirred at a constant temperature of 100 C, and condensed and refluxed for 24 hours. After completion of the reaction, the mixture was allowed to stand. After cooling to room temperature, the solvent was evaporated to give a white solid material, which was filtered, filtered, and then washed three times with acetonitrile and anhydrous diethyl ether (3×10 mL). After drying at 50 C, <strong>[73-24-5]adenine</strong>-diethylenetriamine pentaacetic acid-cytosine (dtpa-AC) was obtained.
With silica gel; In water; at 160℃; for 12h;High pressure;
In a typical experiment, 30 mg of silica were loaded in a UV-grade cuvette and contacted with2.65 mL of formamide (1:100 SiO2:formamide weight ratio). SiO2 was suspended in formamide bycontinuous magnetic stirring. The reaction mixture was rapidly heated to 160 C by a resistive element,then spectra collection began: 12 h of reaction were monitored. The adopted reaction conditionsare based on those reported by Saladino and coworkers on the same material [13]. The UV-Ramanspectra were collected by sampling the formamide-silica dispersion. Since the high flux of energeticphotons irradiating the sample for a long time framework is known to potentially cause the undesiredphotoinduced decomposition of reactants/products [37], the cuvette was kept in a continuous oscillatorymovement under the excitation beam. The spectra here reported are normalized to the intense featureof formamide at 1390 cm1, assuming its concentration is constant over the reaction time (in agreementwith the low conversion to nucleobases reported in the literature [13]). This procedure was necessary inorder to compensate the stochastic fluctuations due to instrumental reasons, as well as the progressivedrop in overall intensity associated to the formation of self-absorbing species.