* 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.
Reference：
[1] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1982, vol. 36, # 10, p. 707 - 712
2
[ 77287-34-4 ]
[ 557-01-7 ]
[ 151-51-9 ]
[ 108-53-2 ]
[ 120-73-0 ]
[ 66224-66-6 ]
Reference：
[1] Journal of the American Chemical Society, 2008, vol. 130, # 46, p. 15512 - 15518
3
[ 77287-34-4 ]
[ 557-01-7 ]
[ 151-51-9 ]
[ 108-53-2 ]
[ 120-73-0 ]
[ 144-62-7 ]
[ 66224-66-6 ]
Reference：
[1] Journal of the American Chemical Society, 2008, vol. 130, # 46, p. 15512 - 15518
4
[ 77287-34-4 ]
[ 557-01-7 ]
[ 151-51-9 ]
[ 108-53-2 ]
[ 120-73-0 ]
[ 66224-66-6 ]
[ 57-13-6 ]
Reference：
[1] Journal of the American Chemical Society, 2008, vol. 130, # 46, p. 15512 - 15518
5
[ 77287-34-4 ]
[ 557-01-7 ]
[ 108-53-2 ]
[ 120-73-0 ]
[ 144-62-7 ]
[ 66224-66-6 ]
[ 57-13-6 ]
Reference：
[1] Journal of the American Chemical Society, 2008, vol. 130, # 46, p. 15512 - 15518
6
[ 77287-34-4 ]
[ 557-01-7 ]
[ 151-51-9 ]
[ 108-53-2 ]
[ 120-73-0 ]
[ 144-62-7 ]
[ 66224-66-6 ]
[ 57-13-6 ]
Reference：
[1] Journal of the American Chemical Society, 2008, vol. 130, # 46, p. 15512 - 15518
7
[ 77287-34-4 ]
[ 557-01-7 ]
[ 151-51-9 ]
[ 108-53-2 ]
[ 120-73-0 ]
[ 452-06-2 ]
[ 66224-66-6 ]
[ 57-13-6 ]
Reference：
[1] Journal of the American Chemical Society, 2008, vol. 130, # 46, p. 15512 - 15518
8
[ 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.
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.
With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 7 h; Inert atmosphere
6-amino-9-ethyl-9H-purine was synthesized by the addition of ethyl iodide (3.6 ml, 45 mmol) to a white suspension of adenine (5.00 g, 37.0 mmol) and cesium carbonate (14.5 g, 44.4 mmol) in dry DMF (60 ml) under nitrogen. The suspension was heated at 60 °C for 7 h. A white solid was filtered off, the yellow solution was quenched with water (5 ml) and the solvents were removed under reduced pressure. The yellow solid was partially dissolved in CHCl3 and MeOH and the insoluble material was removed by filtration. Removal of the solvents under reduced pressure resulted in a crude yellow solid that was purified by flash column chromatography (gradient, 2-10percent v/v MeOH in CHCl3). 6-Amino-9-ethyl-9H-purine was isolated as a white solid (3.97 g, 24.3 mmol, 66percent). Mp 191-194 °C (lit. 192-193 °C, 38 185-187 °C 39 ). The 1H NMR data were consistent with that in the literature. 39 1H NMR (DMSO-d6): 8.14 (s, 1H), 8.13 (s, 1H), 7.16 (br s, 2H), 4.16 (q, J 7.3 Hz, 2H), 1.39 (t, J 7.3 Hz, 3H); 13C NMR (DMSO-d6, 1): 155.9, 152.3, 149.3, 140.4, 118.8, 38.0, 15.3; νmax (DMSO) 3250, 2250, 2120, 1640 cm-1; HRMS m/z [M+H]+ calculated for C7H9N5: 164.0936. Found: 164.0935. The regioisomer (6-amino-7-ethyl-7H-purine) was also isolated as a white solid (0.60 g, 3.68 mmol, 10percent).
Reference：
[1] Tetrahedron, 2013, vol. 69, # 42, p. 8857 - 8864
[2] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 7, p. 2812 - 2822
[3] European Journal of Pharmacology, 2005, vol. 512, # 2-3, p. 157 - 164
15
[ 5324-30-1 ]
[ 66224-66-6 ]
[ 121149-94-8 ]
[ 2715-68-6 ]
Yield
Reaction Conditions
Operation in experiment
71%
With potassium carbonate In N,N-dimethyl-formamide at 153℃; for 15 h;
Potassium carbonate, 5.1 g (37 mmol), was added to a mixture of 1.8 g (7.41 mmol) of diethyl 2-bromoethylphosphonate and 1 g (7.41 mmol) of adenine in 20 mL of DMF. The mixture was refluxed for 15 h, the precipitate of potassium carbonate was filtered off, and the solvent was removed under reduced pressure. The residue was washed with acetone, and the white precipitate was filtered off and dried under reduced pressure (oil pump) until constant weight. Yield 1.6 g (71percent), mp >250°C. IR spectrum, ν,cm–1: 3143 (NH2), 1699 (C=C), 1029 (P=O). 1H NMRspectrum (DMSO-d6), δ, ppm: 1.24 t (6H, CH3, J =7.1 Hz), 2.55 d.t (2H, CH2, J = 18.2, 7.1 Hz), 4.004.09 m (4H, OCH2), 4.53 d.t (2H, CH2, J = 15.8,7.1 Hz), 8.15 s (1H, Harom), 8.24 s (1H, Harom). 31P NMR spectrum (DMSO-d6): δP 27.75 ppm. Mass spectrum: m/z 300.1 [M + H]+. Found, percent: C 44.33; H 5.81; N 23.18; P 10.54. C11H18N5O3P. Calculated, percent:C 44.15; H 6.06; N 23.40; P 10.35. M 299.3. 9-Ethyl-9H-purin-6-amine (2). The filtrate obtained after separation of compound 1 was left to stand for 12 h. The crystalline solid precipitated therefrom was filtered off and dried under reduced pressure (oil pump) until constant weight. Yield 0.1 g (9percent), mp 94-96°C. IR spectrum, ν, cm–1: 3270, 3105 (NH2), 1673 (C=C). 1H NMR spectrum (CDCl3), δ, ppm: 1.10 t(3H, CH3, J = 7.4 Hz), 3.67 q (2H, CH2, J = 7.3 Hz),7.48 s (1H, Harom), 7.53 s (1H, Harom). Mass spectrum: m/z 202 [M + K]+. Found, percent: C 51.68; H 5.70;N 43.17. C7H9N5. Calculated, percent: C 51.52; H 5.56;N 42.92. M 163.
Reference：
[1] Russian Journal of Organic Chemistry, 2018, vol. 54, # 6, p. 938 - 942[2] Zh. Org. Khim., 2018, vol. 54, # 6, p. 932 - 935,4
16
[ 74-96-4 ]
[ 66224-66-6 ]
[ 2715-68-6 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1983, # 12, p. 1807 - 1814
[2] Journal of the American Chemical Society, 1993, vol. 115, # 17, p. 7636 - 7644
[3] European Journal of Medicinal Chemistry, 2014, vol. 83, p. 455 - 465
17
[ 75-03-6 ]
[ 66224-66-6 ]
[ 2715-68-6 ]
Reference：
[1] Dalton Transactions, 2015, vol. 44, # 8, p. 3540 - 3543
[2] Bioorganic and Medicinal Chemistry, 1998, vol. 6, # 5, p. 523 - 533
Reference：
[1] Journal of Organic Chemistry, 1980, vol. 45, # 20, p. 3969 - 3974
20
[ 66224-66-6 ]
[ 2715-68-6 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1994, # 8, p. 1089 - 1098
[2] Journal of the Chemical Society - Series Chemical Communications, 1992, # 6, p. 513 - 514
21
[ 66224-66-6 ]
[ 6974-78-3 ]
Yield
Reaction Conditions
Operation in experiment
85.7%
at 20℃; for 3 h;
Adenine (40g) was first added to the flask, liquid bromine (107 ml) was added under mechanical stirring, the addition process was slow, and then stirred at room temperature for 3 hours;After the completion of the reaction, the excess liquid bromine was removed by adding sodium hydrogen sulfite solution, and the reaction liquid was adjusted to neutrality with ammonia water to precipitate a white powdery solid. Filtration, the solid was washed with ice water to give 8-bromo adenine, pale yellow solid 54 g, yield 85.7percent;
74%
at 20℃;
Example 8Preparation of 2-(3-(6-amino-9-(pent-4-ynyl)-9H-purin-8-ylthio)phenoxy)-N-hydroxyacetamide (Compound 14)Step 8a. 8-Bromo-9H-purin-6-amine (compound 302); Bromine (9.36 g, 58.5 mmol) was added to H2O (25 mL) with stirring, then the compound 301 (1.1 g, 8.1 mmol) was added into the solution. The mixture was stirred at room temperature overnight. The excess bromine was removed and the solvent was evaporated to give compound 302 as a light yellow solid (1.28 g, 74percent). The crude product was used without further purification: LC-MS: 214 [M+1]+.
Reference：
[1] Patent: CN108503643, 2018, A, . Location in patent: Paragraph 0023; 0036; 0037; 0038
[2] Patent: US2008/234297, 2008, A1, . Location in patent: Page/Page column 33; 38
[3] Synthetic Communications, 2013, vol. 43, # 11, p. 1469 - 1476
[4] Journal of Medicinal Chemistry, 2009, vol. 52, # 19, p. 5974 - 5989
[5] Collection of Czechoslovak Chemical Communications, 2000, vol. 65, # 7, p. 1126 - 1144
[6] Collection of Czechoslovak Chemical Communications, 2000, vol. 65, # 7, p. 1109 - 1125
[7] Chemistry - An Asian Journal, 2011, vol. 6, # 8, p. 2048 - 2054
[8] Journal of Medicinal Chemistry, 2005, vol. 48, # 8, p. 2892 - 2905
[9] Patent: WO2015/23976, 2015, A2, . Location in patent: Paragraph 0270
[10] Journal of Medicinal Chemistry, 2015, vol. 58, # 9, p. 3922 - 3943
22
[ 77070-97-4 ]
[ 5404-86-4 ]
[ 66224-66-6 ]
Reference：
[1] Journal of Organic Chemistry, 1981, vol. 46, # 11, p. 2203 - 2207
23
[ 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] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
25
[ 7440-02-0 ]
[ 66224-66-6 ]
[ 443-72-1 ]
Yield
Reaction Conditions
Operation in experiment
15%
With sodium hydroxide; methylamine In ethanol; water
EXAMPLE 15 A solution prepared by absorbing 18.9 g. (0.61 mole) of methylamine into 100 ml. of ethanol, a catalyst prepared by developing 1.35 g. of Raney nickel containing 8percent by weight of nickel, 100 ml. of ethanol and 13.5 g. (0.1 mole) of adenine were placed into an autoclave and the reaction was carried out at 150° C. for 4.5 hours. After completing the reaction, the ethanol was removed by distillation, and 600 ml. of water and then 15 g. of a 20percent by weight aqueous solution of sodium hydroxide were added. The resultant was heated under reflux to dissolve the reaction product and the insoluble material was filtered off under heating. After cooling, the filtrate was neutralized with sulfuric acid to precipitate crystals. The precipitate was filtered, washed with water and dried at 70° C. for 15 hours to give 14.2 g. of N6 -methyladenine The purity was 15.5percent by weight and the yield was 15percent.
Reference：
[1] Recueil: Journal of the Royal Netherlands Chemical Society, 1980, vol. 99, # 9, p. 267 - 270
28
[ 96-49-1 ]
[ 66224-66-6 ]
[ 707-99-3 ]
Yield
Reaction Conditions
Operation in experiment
95%
With triethylamine In acetonitrile at 125℃; for 14 h; Inert atmosphere
In the 500 ml in the reaction bottle, adenine 37g (0.273 µM) suspended in acetonitrile 93 ml in, adding dioxolan 29.4g (0.334 µM), triethylamine 14.8g (0.146 µM) in N2 under protection 125 °C reaction 14h, slightly cold, pressure reducing recovery acetonitrile to obtain the solid particles, slightly cold, adds anhydrously ethanol 74 ml, heating to reflux and thermal insulation 1.5h, the ice-bath is cold to 0 °C under stirring 2h after-filtration, to obtain job filters the cake to dry 47.3g white powdery solid namely target product, yield 95percent.
93.3%
With sodium hydroxide In DMF (N,N-dimethyl-formamide) for 3.33333 h; Heating / reflux
Example 5 Preparation of 9-(2-Hydroxyethyl)adenine (5) A 12 L, 3-necked round bottom flask was equipped with a mechanical stirrer, condenser, thermometer and heating mantle. The flask was flushed with nitrogen and charged with adenine (504 g), ethylene carbonate (343 g), DMF (3.7 L) and sodium hydroxide (7.80 g). The stirred mixture was heated to reflux (approximately 80 minutes to reach reflux, pot temperature=145° C.), and then refluxed for 2 hours. The heating mantle was removed and the yellow solution was cooled to below 100° C. The resulting mixture was then cooled to 5° C. in an ice bath and diluted with toluene (3.8 L). The resulting mixture was stirred at <10° C. for 2 hours and then filtered. The collected solid was washed with toluene (2*0.5) and cold ethanol (1.5 L), then dried to constant weight (-30 in. Hg, 50° C., 14 h). The solid 5 was analyzed by HPLC and 1H-NMR (DMSO-d6).
82.7%
With sodium hydroxide In N,N-dimethyl-formamide for 4 h; Reflux; Large scale
The mechanical stirrer, reflux condenser and thermometer were installed in a 10 L reaction flask.To this, 3 kg (22.22 mol) of adenine, 2.14 kg (24.32 mol) of ethylene carbonate, 20 g (0.5 mol) of sodium hydroxide and 7 L of DMF were added thereto in turn, followed by stirring and heating under reflux for 4 hours.The reaction was terminated, cooled to room temperature, filtered, and the filter cake was dried under vacuum at 70 ° C for 6 hours.9-hydroxyethyl adenine as an off-white solid powder 3.29kg, Mp: 225 ~ 227 (decomposition), the yield of 82.7percent.
Reference：
[1] Patent: CN106699814, 2017, A, . Location in patent: Paragraph 0020-0021
[2] Molecules, 2012, vol. 17, # 11, p. 13290 - 13306
[3] Patent: US2003/225277, 2003, A1, . Location in patent: Page 10-11
[4] Tetrahedron Letters, 2006, vol. 47, # 11, p. 1767 - 1770
[5] Patent: CN104387421, 2016, B, . Location in patent: Paragraph 0026-0028
[6] Collection of Czechoslovak Chemical Communications, 1986, vol. 51, # 2, p. 459 - 477
[7] Macromolecules, 2010, vol. 43, # 3, p. 1245 - 1252
[8] Biomacromolecules, 2011, vol. 12, # 4, p. 1370 - 1379
[9] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 12, p. 1347 - 1350
[10] Journal of Organic Chemistry, 1999, vol. 64, # 13, p. 4627 - 4634
[11] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 17, p. 6218 - 6232
29
[ 96-49-1 ]
[ 66224-66-6 ]
[ 707-99-3 ]
[ 126595-74-2 ]
Yield
Reaction Conditions
Operation in experiment
77 - 97 %Chromat.
With sodium hydroxide In DMF (N,N-dimethyl-formamide) at 150 - 160℃; for 3 h; Heating / reflux
In general, a mixture of alkylene carbonate (11.0 mmole), the heterocyclic base (10.0 mmole) and solid [NAOH] (0.5 mmol) in a solvent (e. g., DMA) (20 ml) was heated at [150°C] for 3 h. Then, the solvent was either evaporated and the residue taken up with a wash solvent, or diluted with a first solvent to precipitate the reaction products followed by a wash step with a wash solvent or wash solvent mixture (optionally followed by crystallization [FROMAPOS;A] crystallization solvent). Analysis of the reaction products was performed using HPLC and conditions as described in Figure 4, and a typical elution profile using such HPLC conditions is shown in Figure 5. Selected results of various reaction conditions, solvents, and wash/crystallization procedures are shown in Tables 1-3. For better visualization of the numerical differences in selectivity and yield, the following grayscale of Table A was used: Total Yield (in Shade Selectivity (as percent N9 alkylated percent) product) 50-64 Less than 76 65-74 77-83 r 75-84'i'84-87 88-90 a.. 3 _ s. 96-100 97-100 96-100,,, o 97_100 Table A Interestingly, as can be seen from Table 1 of Figure 1, when the solvent for dilution and crystallization was, or contained an aprotic and [APOLAR] solvent (here: toluene), and when DMF was used as a reaction solvent (and further depending on reaction temperature and workup), either the total yield was desirable at relatively undesirable selectivity, or the selectivity was desirable at relatively undesirable total yield. Replacement of the reaction solvent DMF with alternative solvents (shown here: DEF and DMA) appeared to improve the disparity between total yield and selectivity in a relatively unpredictable manner. Moreover, where the disparity between total yield and selectivity improved, total yields and selectivities were generally lower and frequently were at undesirable levels. After numerous further modifications (date not shown), the inventors eliminated the step of dilution of the reaction solvent by evaporation to force the reaction product from the solvent, and exemplary data on total yield and selectivity are shown in Table 2 of Figure 2. These data suggested that elimination of the dilution step tended to increase the total yield to at least some degree. However, improvement of the selectivity while maintaining relatively high total yields was inconsistent. In still further experiments, the inventors replaced the non-polar solvents for [DILUTION.] of the reaction solvent with relatively high polar solvents (IPA, ethyl acetate, acetonitrile, etc. ) when DMA was used as a reaction solvent. Surprisingly, and especially where DMA was the reaction solvent and IPA was the dilution and wash solvent, consistent high yields at high selectivity could be achieved under several reaction conditions as shown in the exemplary data on total yield and selectivity in Table 3 of Figure 3. Specifically, the total yield of product was as high as [91 percent] at an N9-alkylated product content of 97percent and an N7- alkylated byproduct content of 1.34percent (with [NAOH] as catalyst and 150 centigrade reaction temperature). Similarly, the total yield of product was as high as 87percent at an N9-alkylated product content of 97percent and an N7-alkylated byproduct content of 1.15percent (with [NAOH] as catalyst and 160 centigrade reaction temperature), and the total yield of product was as high as 82percent at a N9-alkylated product content of 98percent and a N7-alkylated byproduct content of 0.96percent (with [NAOH] as catalyst and 140 centigrade reaction temperature). Moreover, by using DMA as a reaction solvent various advantages other than higher total yield and an increase of selectivity may be achieved. Among other things, the solubility of various heterocyclic bases, and especially adenine, is significantly increased as shown in Table B below. Solvent Solubility at RT Solubility at 150°C DMF 2.90 m/ml 29. 0 mg/ml DEF 1. 36 mg/ml 13. 9 mg/ml DMA 4. 00 mg/ml 37.0 mg/ml [ TABLE B] Consequently, overall consumption of solvent may be significantly reduced by virtue of the increased solubility of the heterocyclic base in DMA (at least compared to DMF as reaction solvent), which in turn reduces the cost of preparing the alkylated heterocyclic base. Still further, due to the higher boiling point of DMA as compared to DMF (166.1 Centigrade as compared to 155 Centigrade, respectively) the reaction may be performed at a temperature that is further away from the boiling point of the reaction solvent, which increases the operational safety of the reaction. Moreover, while addition of a basic catalyst is generally not required, a basic catalyst, and preferably [NAOH] will benefit the total yield and selectivity.
98 %Chromat.
With sodium ethanolate In DMF (N,N-dimethyl-formamide) at 130℃; for 3 h;
In general, a mixture of alkylene carbonate (11.0 mmole), the heterocyclic base (10.0 mmole) and solid [NAOH] (0.5 mmol) in a solvent (e. g., DMA) (20 ml) was heated at [150°C] for 3 h. Then, the solvent was either evaporated and the residue taken up with a wash solvent, or diluted with a first solvent to precipitate the reaction products followed by a wash step with a wash solvent or wash solvent mixture (optionally followed by crystallization [FROMAPOS;A] crystallization solvent). Analysis of the reaction products was performed using HPLC and conditions as described in Figure 4, and a typical elution profile using such HPLC conditions is shown in Figure 5. Selected results of various reaction conditions, solvents, and wash/crystallization procedures are shown in Tables 1-3. For better visualization of the numerical differences in selectivity and yield, the following grayscale of Table A was used: Total Yield (in Shade Selectivity (as percent N9 alkylated percent) product) 50-64 Less than 76 65-74 77-83 r 75-84'i'84-87 88-90 a.. 3 _ s. 96-100 97-100 96-100,,, o 97_100 Table A Interestingly, as can be seen from Table 1 of Figure 1, when the solvent for dilution and crystallization was, or contained an aprotic and [APOLAR] solvent (here: toluene), and when DMF was used as a reaction solvent (and further depending on reaction temperature and workup), either the total yield was desirable at relatively undesirable selectivity, or the selectivity was desirable at relatively undesirable total yield. Replacement of the reaction solvent DMF with alternative solvents (shown here: DEF and DMA) appeared to improve the disparity between total yield and selectivity in a relatively unpredictable manner. Moreover, where the disparity between total yield and selectivity improved, total yields and selectivities were generally lower and frequently were at undesirable levels. After numerous further modifications (date not shown), the inventors eliminated the step of dilution of the reaction solvent by evaporation to force the reaction product from the solvent, and exemplary data on total yield and selectivity are shown in Table 2 of Figure 2. These data suggested that elimination of the dilution step tended to increase the total yield to at least some degree. However, improvement of the selectivity while maintaining relatively high total yields was inconsistent. In still further experiments, the inventors replaced the non-polar solvents for [DILUTION.] of the reaction solvent with relatively high polar solvents (IPA, ethyl acetate, acetonitrile, etc. ) when DMA was used as a reaction solvent. Surprisingly, and especially where DMA was the reaction solvent and IPA was the dilution and wash solvent, consistent high yields at high selectivity could be achieved under several reaction conditions as shown in the exemplary data on total yield and selectivity in Table 3 of Figure 3. Specifically, the total yield of product was as high as [91 percent] at an N9-alkylated product content of 97percent and an N7- alkylated byproduct content of 1.34percent (with [NAOH] as catalyst and 150 centigrade reaction temperature). Similarly, the total yield of product was as high as 87percent at an N9-alkylated product content of 97percent and an N7-alkylated byproduct content of 1.15percent (with [NAOH] as catalyst and 160 centigrade reaction temperature), and the total yield of product was as high as 82percent at a N9-alkylated product content of 98percent and a N7-alkylated byproduct content of 0.96percent (with [NAOH] as catalyst and 140 centigrade reaction temperature). Moreover, by using DMA as a reaction solvent various advantages other than higher total yield and an increase of selectivity may be achieved. Among other things, the solubility of various heterocyclic bases, and especially adenine, is significantly increased as shown in Table B below. Solvent Solubility at RT Solubility at 150°C DMF 2.90 m/ml 29. 0 mg/ml DEF 1. 36 mg/ml 13. 9 mg/ml DMA 4. 00 mg/ml 37.0 mg/ml [ TABLE B] Consequently, overall consumption of solvent may be significantly reduced by virtue of the increased solubility of the heterocyclic base in DMA (at least compared to DMF as reaction solvent), which in turn reduces the cost of preparing the alkylated heterocyclic base. Still further, due to the higher boiling point of DMA as compared to DMF (166.1 Centigrade as compared to 155 Centigrade, respectively) the reaction may be performed at a temperature that is further away from the boiling point of the reaction solvent, which increases the operational safety of the reaction. Moreover, while addition of a basic catalyst is generally not required, a basic catalyst, and preferably [NAOH] will benefit the total yield and selectivity.
76 - 98 %Chromat.
With sodium hydroxide In ISOPROPYLAMIDE at 140 - 160℃; for 3 h;
In general, a mixture of alkylene carbonate (11.0 mmole), the heterocyclic base (10.0 mmole) and solid [NAOH] (0.5 mmol) in a solvent (e. g., DMA) (20 ml) was heated at [150°C] for 3 h. Then, the solvent was either evaporated and the residue taken up with a wash solvent, or diluted with a first solvent to precipitate the reaction products followed by a wash step with a wash solvent or wash solvent mixture (optionally followed by crystallization [FROMAPOS;A] crystallization solvent). Analysis of the reaction products was performed using HPLC and conditions as described in Figure 4, and a typical elution profile using such HPLC conditions is shown in Figure 5. Selected results of various reaction conditions, solvents, and wash/crystallization procedures are shown in Tables 1-3. For better visualization of the numerical differences in selectivity and yield, the following grayscale of Table A was used: Total Yield (in Shade Selectivity (as percent N9 alkylated percent) product) 50-64 Less than 76 65-74 77-83 r 75-84'i'84-87 88-90 a.. 3 _ s. 96-100 97-100 96-100,,, o 97_100 Table A Interestingly, as can be seen from Table 1 of Figure 1, when the solvent for dilution and crystallization was, or contained an aprotic and [APOLAR] solvent (here: toluene), and when DMF was used as a reaction solvent (and further depending on reaction temperature and workup), either the total yield was desirable at relatively undesirable selectivity, or the selectivity was desirable at relatively undesirable total yield. Replacement of the reaction solvent DMF with alternative solvents (shown here: DEF and DMA) appeared to improve the disparity between total yield and selectivity in a relatively unpredictable manner. Moreover, where the disparity between total yield and selectivity improved, total yields and selectivities were generally lower and frequently were at undesirable levels. After numerous further modifications (date not shown), the inventors eliminated the step of dilution of the reaction solvent by evaporation to force the reaction product from the solvent, and exemplary data on total yield and selectivity are shown in Table 2 of Figure 2. These data suggested that elimination of the dilution step tended to increase the total yield to at least some degree. However, improvement of the selectivity while maintaining relatively high total yields was inconsistent. In still further experiments, the inventors replaced the non-polar solvents for [DILUTION.] of the reaction solvent with relatively high polar solvents (IPA, ethyl acetate, acetonitrile, etc. ) when DMA was used as a reaction solvent. Surprisingly, and especially where DMA was the reaction solvent and IPA was the dilution and wash solvent, consistent high yields at high selectivity could be achieved under several reaction conditions as shown in the exemplary data on total yield and selectivity in Table 3 of Figure 3. Specifically, the total yield of product was as high as [91 percent] at an N9-alkylated product content of 97percent and an N7- alkylated byproduct content of 1.34percent (with [NAOH] as catalyst and 150 centigrade reaction temperature). Similarly, the total yield of product was as high as 87percent at an N9-alkylated product content of 97percent and an N7-alkylated byproduct content of 1.15percent (with [NAOH] as catalyst and 160 centigrade reaction temperature), and the total yield of product was as high as 82percent at a N9-alkylated product content of 98percent and a N7-alkylated byproduct content of 0.96percent (with [NAOH] as catalyst and 140 centigrade reaction temperature). Moreover, by using DMA as a reaction solvent various advantages other than higher total yield and an increase of selectivity may be achieved. Among other things, the solubility of various heterocyclic bases, and especially adenine, is significantly increased as shown in Table B below. Solvent Solubility at RT Solubility at 150°C DMF 2.90 m/ml 29. 0 mg/ml DEF 1. 36 mg/ml 13. 9 mg/ml DMA 4. 00 mg/ml 37.0 mg/ml [ TABLE B] Consequently, overall consumption of solvent may be significantly reduced by virtue of the increased solubility of the heterocyclic base in DMA (at least compared to DMF as reaction solvent), which in turn reduces the cost of preparing the alkylated heterocyclic base. Still further, due to the higher boiling point of DMA as compared to DMF (166.1 Centigrade as compared to 155 Centigrade, respectively) the reaction may be performed at a temperature that is further away from the boiling point of the reaction solvent, which increases the operational safety of the reaction. Moreover, while addition of a basic catalyst is generally not required, a basic catalyst, and preferably [NAOH] will benefit the total yield and selectivity.
77 %Chromat.
With sodium hydroxide In N-formyldiethylamine at 150℃; for 3 h;
In general, a mixture of alkylene carbonate (11.0 mmole), the heterocyclic base (10.0 mmole) and solid [NAOH] (0.5 mmol) in a solvent (e. g., DMA) (20 ml) was heated at [150°C] for 3 h. Then, the solvent was either evaporated and the residue taken up with a wash solvent, or diluted with a first solvent to precipitate the reaction products followed by a wash step with a wash solvent or wash solvent mixture (optionally followed by crystallization [FROMAPOS;A] crystallization solvent). Analysis of the reaction products was performed using HPLC and conditions as described in Figure 4, and a typical elution profile using such HPLC conditions is shown in Figure 5. Selected results of various reaction conditions, solvents, and wash/crystallization procedures are shown in Tables 1-3. For better visualization of the numerical differences in selectivity and yield, the following grayscale of Table A was used: Total Yield (in Shade Selectivity (as percent N9 alkylated percent) product) 50-64 Less than 76 65-74 77-83 r 75-84'i'84-87 88-90 a.. 3 _ s. 96-100 97-100 96-100,,, o 97_100 Table A Interestingly, as can be seen from Table 1 of Figure 1, when the solvent for dilution and crystallization was, or contained an aprotic and [APOLAR] solvent (here: toluene), and when DMF was used as a reaction solvent (and further depending on reaction temperature and workup), either the total yield was desirable at relatively undesirable selectivity, or the selectivity was desirable at relatively undesirable total yield. Replacement of the reaction solvent DMF with alternative solvents (shown here: DEF and DMA) appeared to improve the disparity between total yield and selectivity in a relatively unpredictable manner. Moreover, where the disparity between total yield and selectivity improved, total yields and selectivities were generally lower and frequently were at undesirable levels. After numerous further modifications (date not shown), the inventors eliminated the step of dilution of the reaction solvent by evaporation to force the reaction product from the solvent, and exemplary data on total yield and selectivity are shown in Table 2 of Figure 2. These data suggested that elimination of the dilution step tended to increase the total yield to at least some degree. However, improvement of the selectivity while maintaining relatively high total yields was inconsistent. In still further experiments, the inventors replaced the non-polar solvents for [DILUTION.] of the reaction solvent with relatively high polar solvents (IPA, ethyl acetate, acetonitrile, etc. ) when DMA was used as a reaction solvent. Surprisingly, and especially where DMA was the reaction solvent and IPA was the dilution and wash solvent, consistent high yields at high selectivity could be achieved under several reaction conditions as shown in the exemplary data on total yield and selectivity in Table 3 of Figure 3. Specifically, the total yield of product was as high as [91 percent] at an N9-alkylated product content of 97percent and an N7- alkylated byproduct content of 1.34percent (with [NAOH] as catalyst and 150 centigrade reaction temperature). Similarly, the total yield of product was as high as 87percent at an N9-alkylated product content of 97percent and an N7-alkylated byproduct content of 1.15percent (with [NAOH] as catalyst and 160 centigrade reaction temperature), and the total yield of product was as high as 82percent at a N9-alkylated product content of 98percent and a N7-alkylated byproduct content of 0.96percent (with [NAOH] as catalyst and 140 centigrade reaction temperature). Moreover, by using DMA as a reaction solvent various advantages other than higher total yield and an increase of selectivity may be achieved. Among other things, the solubility of various heterocyclic bases, and especially adenine, is significantly increased as shown in Table B below. Solvent Solubility at RT Solubility at 150°C DMF 2.90 m/ml 29. 0 mg/ml DEF 1. 36 mg/ml 13. 9 mg/ml DMA 4. 00 mg/ml 37.0 mg/ml [ TABLE B] Consequently, overall consumption of solvent may be significantly reduced by virtue of the increased solubility of the heterocyclic base in DMA (at least compared to DMF as reaction solvent), which in turn reduces the cost of preparing the alkylated heterocyclic base. Still further, due to the higher boiling point of DMA as compared to DMF (166.1 Centigrade as compared to 155 Centigrade, respectively) the reaction may be performed at a temperature that is further away from the boiling point of the reaction solvent, which increases the operational safety of the reaction. Moreover, while addition of a basic catalyst is generally not required, a basic catalyst, and preferably [NAOH] will benefit the total yield and selectivity.
55 - 83 %Chromat.
at 150 - 160℃; for 3 h;
In general, a mixture of alkylene carbonate (11.0 mmole), the heterocyclic base (10.0 mmole) and solid [NAOH] (0.5 mmol) in a solvent (e. g., DMA) (20 ml) was heated at [150°C] for 3 h. Then, the solvent was either evaporated and the residue taken up with a wash solvent, or diluted with a first solvent to precipitate the reaction products followed by a wash step with a wash solvent or wash solvent mixture (optionally followed by crystallization [FROMAPOS;A] crystallization solvent). Analysis of the reaction products was performed using HPLC and conditions as described in Figure 4, and a typical elution profile using such HPLC conditions is shown in Figure 5. Selected results of various reaction conditions, solvents, and wash/crystallization procedures are shown in Tables 1-3. For better visualization of the numerical differences in selectivity and yield, the following grayscale of Table A was used: Total Yield (in Shade Selectivity (as percent N9 alkylated percent) product) 50-64 Less than 76 65-74 77-83 r 75-84'i'84-87 88-90 a.. 3 _ s. 96-100 97-100 96-100,,, o 97_100 Table A Interestingly, as can be seen from Table 1 of Figure 1, when the solvent for dilution and crystallization was, or contained an aprotic and [APOLAR] solvent (here: toluene), and when DMF was used as a reaction solvent (and further depending on reaction temperature and workup), either the total yield was desirable at relatively undesirable selectivity, or the selectivity was desirable at relatively undesirable total yield. Replacement of the reaction solvent DMF with alternative solvents (shown here: DEF and DMA) appeared to improve the disparity between total yield and selectivity in a relatively unpredictable manner. Moreover, where the disparity between total yield and selectivity improved, total yields and selectivities were generally lower and frequently were at undesirable levels. After numerous further modifications (date not shown), the inventors eliminated the step of dilution of the reaction solvent by evaporation to force the reaction product from the solvent, and exemplary data on total yield and selectivity are shown in Table 2 of Figure 2. These data suggested that elimination of the dilution step tended to increase the total yield to at least some degree. However, improvement of the selectivity while maintaining relatively high total yields was inconsistent. In still further experiments, the inventors replaced the non-polar solvents for [DILUTION.] of the reaction solvent with relatively high polar solvents (IPA, ethyl acetate, acetonitrile, etc. ) when DMA was used as a reaction solvent. Surprisingly, and especially where DMA was the reaction solvent and IPA was the dilution and wash solvent, consistent high yields at high selectivity could be achieved under several reaction conditions as shown in the exemplary data on total yield and selectivity in Table 3 of Figure 3. Specifically, the total yield of product was as high as [91 percent] at an N9-alkylated product content of 97percent and an N7- alkylated byproduct content of 1.34percent (with [NAOH] as catalyst and 150 centigrade reaction temperature). Similarly, the total yield of product was as high as 87percent at an N9-alkylated product content of 97percent and an N7-alkylated byproduct content of 1.15percent (with [NAOH] as catalyst and 160 centigrade reaction temperature), and the total yield of product was as high as 82percent at a N9-alkylated product content of 98percent and a N7-alkylated byproduct content of 0.96percent (with [NAOH] as catalyst and 140 centigrade reaction temperature). Moreover, by using DMA as a reaction solvent various advantages other than higher total yield and an increase of selectivity may be achieved. Among other things, the solubility of various heterocyclic bases, and especially adenine, is significantly increased as shown in Table B below. Solvent Solubility at RT Solubility at 150°C DMF 2.90 m/ml 29. 0 mg/ml DEF 1. 36 mg/ml 13. 9 mg/ml DMA 4. 00 mg/ml 37.0 mg/ml [ TABLE B] Consequently, overall consumption of solvent may be significantly reduced by virtue of the increased solubility of the heterocyclic base in DMA (at least compared to DMF as reaction solvent), which in turn reduces the cost of preparing the alkylated heterocyclic base. Still further, due to the higher boiling point of DMA as compared to DMF (166.1 Centigrade as compared to 155 Centigrade, respectively) the reaction may be performed at a temperature that is further away from the boiling point of the reaction solvent, which increases the operational safety of the reaction. Moreover, while addition of a basic catalyst is generally not required, a basic catalyst, and preferably [NAOH] will benefit the total yield and selectivity.
73 %Chromat.
at 150℃; for 3 h;
In general, a mixture of alkylene carbonate (11.0 mmole), the heterocyclic base (10.0 mmole) and solid [NAOH] (0.5 mmol) in a solvent (e. g., DMA) (20 ml) was heated at [150°C] for 3 h. Then, the solvent was either evaporated and the residue taken up with a wash solvent, or diluted with a first solvent to precipitate the reaction products followed by a wash step with a wash solvent or wash solvent mixture (optionally followed by crystallization [FROMAPOS;A] crystallization solvent). Analysis of the reaction products was performed using HPLC and conditions as described in Figure 4, and a typical elution profile using such HPLC conditions is shown in Figure 5. Selected results of various reaction conditions, solvents, and wash/crystallization procedures are shown in Tables 1-3. For better visualization of the numerical differences in selectivity and yield, the following grayscale of Table A was used: Total Yield (in Shade Selectivity (as percent N9 alkylated percent) product) 50-64 Less than 76 65-74 77-83 r 75-84'i'84-87 88-90 a.. 3 _ s. 96-100 97-100 96-100,,, o 97_100 Table A Interestingly, as can be seen from Table 1 of Figure 1, when the solvent for dilution and crystallization was, or contained an aprotic and [APOLAR] solvent (here: toluene), and when DMF was used as a reaction solvent (and further depending on reaction temperature and workup), either the total yield was desirable at relatively undesirable selectivity, or the selectivity was desirable at relatively undesirable total yield. Replacement of the reaction solvent DMF with alternative solvents (shown here: DEF and DMA) appeared to improve the disparity between total yield and selectivity in a relatively unpredictable manner. Moreover, where the disparity between total yield and selectivity improved, total yields and selectivities were generally lower and frequently were at undesirable levels. After numerous further modifications (date not shown), the inventors eliminated the step of dilution of the reaction solvent by evaporation to force the reaction product from the solvent, and exemplary data on total yield and selectivity are shown in Table 2 of Figure 2. These data suggested that elimination of the dilution step tended to increase the total yield to at least some degree. However, improvement of the selectivity while maintaining relatively high total yields was inconsistent. In still further experiments, the inventors replaced the non-polar solvents for [DILUTION.] of the reaction solvent with relatively high polar solvents (IPA, ethyl acetate, acetonitrile, etc. ) when DMA was used as a reaction solvent. Surprisingly, and especially where DMA was the reaction solvent and IPA was the dilution and wash solvent, consistent high yields at high selectivity could be achieved under several reaction conditions as shown in the exemplary data on total yield and selectivity in Table 3 of Figure 3. Specifically, the total yield of product was as high as [91 percent] at an N9-alkylated product content of 97percent and an N7- alkylated byproduct content of 1.34percent (with [NAOH] as catalyst and 150 centigrade reaction temperature). Similarly, the total yield of product was as high as 87percent at an N9-alkylated product content of 97percent and an N7-alkylated byproduct content of 1.15percent (with [NAOH] as catalyst and 160 centigrade reaction temperature), and the total yield of product was as high as 82percent at a N9-alkylated product content of 98percent and a N7-alkylated byproduct content of 0.96percent (with [NAOH] as catalyst and 140 centigrade reaction temperature). Moreover, by using DMA as a reaction solvent various advantages other than higher total yield and an increase of selectivity may be achieved. Among other things, the solubility of various heterocyclic bases, and especially adenine, is significantly increased as shown in Table B below. Solvent Solubility at RT Solubility at 150°C DMF 2.90 m/ml 29. 0 mg/ml DEF 1. 36 mg/ml 13. 9 mg/ml DMA 4. 00 mg/ml 37.0 mg/ml [ TABLE B] Consequently, overall consumption of solvent may be significantly reduced by virtue of the increased solubility of the heterocyclic base in DMA (at least compared to DMF as reaction solvent), which in turn reduces the cost of preparing the alkylated heterocyclic base. Still further, due to the higher boiling point of DMA as compared to DMF (166.1 Centigrade as compared to 155 Centigrade, respectively) the reaction may be performed at a temperature that is further away from the boiling point of the reaction solvent, which increases the operational safety of the reaction. Moreover, while addition of a basic catalyst is generally not required, a basic catalyst, and preferably [NAOH] will benefit the total yield and selectivity.
With sodium hydroxide In N,N-dimethyl-formamide; toluene
EXAMPLE 1a Adenine to PMEA using Magnesium Isopropoxide. To a suspension of adenine (16.8 g, 0.124 mol) in DMF (41.9 ml) was added ethylene carbonate (12.1 g, 0.137 mol) and sodium hydroxide (0.100 g, 0.0025 mol). The mixture was heated at 130° C. overnight. The reaction was cooled to below 50° C. and toluene (62.1 ml) was added. The slurry was further cooled to 5° C. for 2 hours, filtered, and rinsed with toluene (2*). The wet solid was dried in vacuo at 65° C. to yield 20.0 g (90percent) of 9-(2hydroxyethyl)adenine as an off-white solid. Mp: 238-240° C.
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[3] Patent: CN106008510, 2016, A,
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Yield
Reaction Conditions
Operation in experiment
20%
With potassium carbonate In water; N,N-dimethyl-formamide
EXAMPLE 26 Synthesis of 9-carboxymethyladenine ethyl ester Adenine (10 g, 74 mmol) and potassium carbonate (10.29 g, 74 mmol) were suspended in DMF and ethyl bromoacetate (8.24 mL, 74 mmol) was added. The suspension was stirred for 2.5 h under nitrogen at room temperature and then filtered. The solid residue was washed three times with DMF (10 mL). The combined filtrate was evaporated to dryness, in vacuo. Water (200 mL) was added to the yellowish-orange solid material and the pH adjusted to 6 with 4 N HCl. After stirring at 0° C. for 10 minutes, the solid was filtered off, washed with water, and recrystallized from 96percent ethanol (150 mL). The title compound was isolated by filtration and washed thoroughly with ether. Yield: 3.4 g (20percent). M.p. 215.5-220° C. Anal. for C9H11N5O2 found(calc.): C: 48.86(48.65); H: 5.01(4.91); N: 31.66(31.42). 1H-NMR (250 MHz; DMSO-d6): 7.25 (bs, 2H, NH), 5.06 (s, 2H, NCH2), 4.17 (q, 2H, J=7.11 Hz, OCH2) and 1.21 (t, 3H, J=7.13 Hz, NCH2). 13C-NMR. 152.70, 141.30, 61.41, 43.97 and 14.07. FAB-MS. 222 (MH+). IR: Frequency in cm-1 (intensity). 3855 (54.3), 3274(10.4), 3246(14.0), 3117(5.3), 2989(22.3), 2940(33.9), 2876(43.4), 2753(49.0), 2346(56.1), 2106(57.1), 1899(55.7), 1762(14.2), 1742(14.2), 1742(1.0), 1671(1.8), 1644(10.9), 1606(0.6), 1582(7.1), 1522(43.8), 1477(7.2), 1445(35.8) and 1422(8.6).
20%
With potassium carbonate In water; N,N-dimethyl-formamide
EXAMPLE 26 Synthesis of 9-carboxymethyladenine ethyl ester Adenine (10 g, 74 mmol) and potassium carbonate (10.29 g, 74 mmol) were suspended in DMF and ethyl bromoacetate (8.24 mL, 74 mmol) was added. The suspension was stirred for 2.5 h under nitrogen at room temperature and then filtered. The solid residue was washed three times with DMF (10 mL). The combined filtrate was evaporated to dryness, in vacuo. Water (200 mL) was added to the yellowish-orange solid material and the pH adjusted to 6 with 4N HCl. After stirring at 0° C. for 10 minutes, the solid was filtered off, washed with water, and recrystallized from 96percent ethanol (150 mL). The title compound was isolated by filtration and washed thoroughly with ether. Yield: 3.4 g (20percent). M.p. 215.5°-220° C. Anal. for C9 H11 N5 O2 found(calc.): C: 48.86(48.65); H: 5.01(4.91); N: 31.66(31.42). 1 H-NMR (250 MHz; DMSO-d6): 7.25 (bs, 2H, NH2), 5.06 (s, 2H, NCH2), 4.17 (q, 2H, J=7.11 Hz, OCH2) and 1.21 (t, 3H, J=7.13 Hz, NCH2). 13 C-NMR. 152.70, 141.30, 61.41, 43.97 and 14.07. FAB-MS. 222 (MH+). IR: Frequency in cm-1: 3855, 3274, 3246, 3117, 2989, 2940, 2876, 2753, 2346, 2106, 1899, 1762, 1742, 1742, 1671, 1644, 1606, 1582, 1522, 1477, 1445 and 1422.
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[ 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.
Reference：
[1] Organic and Biomolecular Chemistry, 2006, vol. 4, # 16, p. 3056 - 3066
57
[ 66224-66-6 ]
[ 142340-99-6 ]
Reference：
[1] Patent: US2012/238753, 2012, A1,
[2] European Journal of Medicinal Chemistry, 2013, vol. 63, p. 869 - 881
[3] Patent: CN106699814, 2017, A,
58
[ 66224-66-6 ]
[ 16606-55-6 ]
[ 14047-28-0 ]
Yield
Reaction Conditions
Operation in experiment
87%
With sodium hydroxide In N,N-dimethyl-formamide at 90 - 140℃; for 12 h; Inert atmosphere
To the reaction flask was added 200 ml of N, N-dimethylformamide (DMF)N2 protection,Adenine (30.0 g, 0.222 mol, 1 eq.) Was added,Stirring,NaOH (0.45 g, 0.011 mol) and was addedPropylene carbonate (28.5 g, 0.279 mol, 1.26 eq.),And the temperature was raised to 130 to 140 ° C.12 hours after the sampling test,When the adenine content in 1percent or less,The reaction can be stopped.The temperature slowly reduced to 90 below,200 ml of toluene,Continue to cool to 0 ~ 5 ,And the mixture was stirred for 2 hours.Filtered and dried to give 38.13 g of a white solid,Yield 87percent
87%
With sodium hydroxide In N,N-dimethyl-formamide at 130 - 140℃; for 12 h; Inert atmosphere
To the reaction flask was added 200 ml of N, N-dimethylformamide (DMF), protected with N2, added adenine (30.0 g, 0.222 mol, 1eq .), stirred, NaOH (0 · 45 g, mol) and R-propylene carbonate (28.5 g, 0. 279 mol, 1.3 eq.) and heated to 130 to 140 ° C. 12 hours after the sampling test, when the adenine content of 1percent or less, can stop the reaction. The temperature slowly drops below 90 ° C, add 200 ml of toluene, continue to cool to 0 ~ 5 ° C and stir for 2 hours. Filtered and dried to give 38.13 g of a white solid, 87percent yield,
81%
With sodium hydroxide In N,N-dimethyl-formamide at 140℃; for 16 h;
A solution of adenine (3.85g, 28.49 mmol) , (R) - propylene carbonate (2.7 mL, 31.34 mmol), and pulverized sodium hydroxide (60 mg, 1.42 mmol) in anhydrous DMF (80 mL) was heated at 1400C with stirring for 16 h. After cooling, the mixture was then filtered to remove insoluble materials, the filtrate was evaporated under reduced pressure and co-evaporated three times with toluene. The residue was triturated with EtOAc then filtered to give a white solid which was immediately recrystallized in ethanol to afford compound 7 (4.5 g, 81 percent) : mp 193°C (Lit. 192-195°C) ; 1H NMR (DMSO-.d5) δ : 8.15 (s, IH, H-2), 8.06 (s, IH, H-8) , 7.22 (bs, 2H, NH2), 5.06 (bs, IH, OH), 4.06 (m, 3H, CH2N and CHO), 1.12 (d, J = 5.7 Hz, 3H, CH3). 13C NMR (OMSO-d6) δ: 155.87, 152.21, 149.67, 141.44, 118.50, 64.57, 50.07, 20.80. MS (GT, FAB+): 136 (B+1H) \\ 194 (M+1H)+, 216 (MH-Na)+, 232 (M+K) +, 387 (2MH-IH)+.
81%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 100 - 120℃; Inert atmosphere Stage #2: at 120℃; for 8 h;
The Buchi reactor (10 L) was preheated to 150 °C and traces of moisture were blown away with the nitrogen stream. The reactor was filled with argon and cooled down to ~ 70 °C, dry DMF (4 L, ~ 20 ppm of H2O, distilled from P2O5) was added and stirring was switched on (200 rev/min) with heating at 100 °C. When the desired temperature was reached, adenine (A, 150 g, 1 mol) and K2CO3 (72.5 g, 0.525 mol) were added. The reaction temperature was increased to 120 °C. The coarse suspension changed into fine suspension of the potassium salt of adenine and CO2 was being released at the same time. When temperature of 120 °C was reached, carbonate (R)-C (133 g, 1.3 mol) was immediately and quickly added. The reaction mixture was stirred at 120 °C and continuously monitored by TLC. The full conversion was observed at ~ 8 h. The reaction mixture was then cooled to RT and precipitated solid was filtered off, the reactor was rinsed with EtOH, and the solid washed quickly with EtOH (2 x 100 mL). The filtrate was concentrated in vacuo at 60 °C, so that ~ 200 mL of DMF are left in the flask, i.e. ~ 400 mL of solvents were removed. The product usually started to crystallize during the concentration/evaporation process. EtOH (400 mL) was added to the residue and this mixture was sonicated at 70 °C for 2 h to convert the formylated by-product to the desired product 1 and to afford nicely crystallized product 1. After cooling in an ice bath, the product was filtered off, washed (2 x 50 mL iced EtOH), and dried at 60°C for 4 days (under vacuum with P2O5) to give 149 g (72percent) of 1 (98percent purity, HPLC). Repeated experiments afforded up to 81 percent yields of the product 1
72%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 100 - 120℃; Inert atmosphere Stage #2: at 120℃; for 8 h;
The Buchi reactor (10 L) was preheated to 150 °C and traces of moisture were blown away with the nitrogen stream. The reactor was filled with argon and cooled down to ~ 70 °C, dry DMF (4 L, ~ 20 ppm of H2O, distilled from P2O5) was added and stirring was switched on (200 rev/min) with heating at 100 °C. When the desired temperature was reached, adenine (A, 150 g, 1 mol) and K2CO3 (72.5 g, 0.525 mol) were added. The reaction temperature was increased to 120 °C. The coarse suspension changed into fine suspension of the potassium salt of adenine and CO2 was being released at the same time. When temperature of 120 °C was reached, carbonate (R)-C (133 g, 1.3 mol) was immediately and quickly added. The reaction mixture was stirred at 120 °C and continuously monitored by TLC. The full conversion was observed at ~ 8 h. The reaction mixture was then cooled to RT and precipitated solid was filtered off, the reactor was rinsed with EtOH, and the solid washed quickly with EtOH (2 x 100 mL). The filtrate was concentrated in vacuo at 60 °C, so that ~ 200 mL of DMF are left in the flask, i.e. ~ 400 mL of solvents were removed. The product usually started to crystallize during the concentration/evaporation process. EtOH (400 mL) was added to the residue and this mixture was sonicated at 70 °C for 2 h to convert the formylated by-product to the desired product 1 and to afford nicely crystallized product 1. After cooling in an ice bath, the product was filtered off, washed (2 x 50 mL iced EtOH), and dried at 60°C for 4 days (under vacuum with P2O5) to give 149 g (72percent) of 1 (98percent purity, HPLC). Repeated experiments afforded up to 81 percent yields of the product 1
71.8%
Stage #1: With sodium hydroxide In N,N-dimethyl-formamide at 20℃; for 0.333333 h; Stage #2: at 120℃; for 24.5 h;
40 g (0.296 mol) of adenine To 200 ml of dimethylformamide (DMF)And dissolved 0.94 g (0.0235 mol, 0.08 equiv.) Of sodium hydroxide (NaOH)Followed by stirring at room temperature for 20 minutes39.2 g (0.390 mol, 1.32 Equiv.) Of (R) -propylene carbonate ((R) -propylene carbonate) was added and stirred for 30 minutes.The reaction temperature was 120 [And heated and condensed for 24 hours.Thereafter, the reaction was checked by TLC and HPLC. After the reaction was almost completed (90percent or more), the reaction temperature was cooled to 70 ° C and 240 ml of isopropyl alcohol (IPA) was added to crystallize. Thereafter, the solution was continuously stirred and cooled. The crystals were filtered at 10 ° C, washed with IPA, and dried in a vacuum dryer at 70 ° C to obtain 41 g of HPA (yield: 71.8percent).
71.8%
Stage #1: With sodium hydroxide In N,N-dimethyl-formamide at 20℃; for 0.333333 h; Stage #2: at 120℃; for 24.5 h;
40 g (0.296 mol) of 6 adenine was dissolved in 200 ml of 7 dimethylformamide (DMF), and 0.94 (0.0235 mol, 0.08 eq.) of 8 sodium hydroxide (NaOH) was added. After 20-min agitation at the room temperature, 39.2 g (0.390 mol, 1.32 eq.) of 9 (R)-propylene carbonate was added and the resultant solution was stirred for 30 minutes. The reaction temperature was elevated to 120° C., and a thermal condensation reaction was activated for 24 hours. Subsequently, the reaction status was examined through TLC and HPLC. After the completion of the reaction (90percent or above), the reaction temperature was reduced to 70° C. and 240 ml of isopropyl alcohol (IPA) was added to active crystallization. Under continuous agitation and cooling, crystals were collected through filtration at 10° C., washed with IPA and then dried out at 70° C. in a low-pressure dryer to obtain 41 g of 5 HPA (yield 71.8percent).
65%
Stage #1: With potassium hydroxide In N,N-dimethyl-formamide at 25 - 30℃; for 0.166667 h; Stage #2: at 25 - 120℃; Stage #3: With methanol In N,N-dimethyl-formamide; isopropyl alcohol at 55 - 70℃; for 0.166667 h;
Example 2 (Stage 1 using KOH)Adenine 4 (40 g, 296 mmol, 1.0 eq) and potassium hydroxide (1.66 g, 29.6 mmol, 0.1 eq) were mixed with DMF (190 ml) at 25-30 °C and the mixture was stirred for 10 mm at 25-30 °C. (R)-propylene carbonate 5 (33.6 ml, 39.9 g, 391 mmol, 1.32 eq) was added drop-wise to the reaction mass over10-15 mm at 25-30 °C. The mixture was heated to 120 °C and held at that temperature for 48 h. A clear solution resulted, and the reaction mixture was cooled to 70 °C. A mixture of methanol (120 ml) and iso-propanol (120 ml) was added drop-wise to the reaction mixture over 10 mm, during which time the reaction mixture was allowed to cool to 55 °C, and precipitation of produt was observed. The reaction mixturewas cooled to 5 °C and held at this temperature for I h. The product was isolated by filtration and the cake was washed with a chilled mixture of methanol (10 ml) and isopropanol (10 ml). The resulting solid was dried under vacuum at 70-75 °C, affording HPA 6 as an off-white solid (37 g, 65percent).
Reference：
[1] Patent: CN103848869, 2016, B, . Location in patent: Paragraph 0053; 0054
[2] Patent: CN103848868, 2017, B, . Location in patent: Paragraph 0055; 0058; 0059
[3] Journal of Medicinal Chemistry, 2006, vol. 49, # 26, p. 7799 - 7806
[4] Patent: WO2008/56264, 2008, A2, . Location in patent: Page/Page column 69-70; 75; 81
[5] Patent: WO2015/51874, 2015, A1, . Location in patent: Page/Page column 6; 20; 21
[6] Patent: EP2860185, 2015, A1, . Location in patent: Paragraph 0018; 0027
[7] Patent: KR2016/135112, 2016, A, . Location in patent: Paragraph 0070; 0071; 0072; 0073
[8] Patent: US2017/354668, 2017, A1, . Location in patent: Paragraph 0101; 0102
[9] Organic Process Research and Development, 2010, vol. 14, # 5, p. 1194 - 1201
[10] Patent: WO2014/33688, 2014, A1, . Location in patent: Page/Page column 23
[11] Organic Process Research and Development, 2016, vol. 20, # 4, p. 742 - 750
[12] Tetrahedron Letters, 1998, vol. 39, # 14, p. 1853 - 1856
[13] Patent: EP1243590, 2002, A2, . Location in patent: Page 9
[14] Patent: US2010/216822, 2010, A1, . Location in patent: Page/Page column 14
[15] Patent: CN102977146, 2016, B, . Location in patent: Paragraph 0016; 0024-0025
[16] Patent: CN105859781, 2016, A, . Location in patent: Paragraph 0013-0014
[17] Patent: CN104262397, 2016, B, . Location in patent: Paragraph 0029; 0030
[18] Patent: CN106349289, 2017, A, . Location in patent: Paragraph 0026; 0027; 0028; 0031; 0032
[19] Patent: CN108358968, 2018, A, . Location in patent: Paragraph 0073; 0087; 0091; 0134; 0138; 0142; 0146; 0150
59
[ 66224-66-6 ]
[ 15448-47-2 ]
[ 14047-28-0 ]
Yield
Reaction Conditions
Operation in experiment
69%
With sodium carbonate In N,N-dimethyl-formamide at 95℃; for 6 h;
Addition of adenine (200.00 g), sodium carbonate (7.80 g) and DMF (100 ml) was carried out in a dry three-necked flask at room temperature (R) -propylene oxide (150.50 g) was slowly added, followed by reaction at 95 ° C for 6 h. The reaction was cooled to room temperature and toluene (2000 ml) was slowly added. After the addition, the mixture was stirred at 0 ° C Filtered and the filter cake was washed with n-hexane and dried in vacuo to afford 197.20g (69percent yield) (2R)-1-(6-amino-9H-purin-9-yl)propan-2-ol (II)
Stage #1: With sodium hydroxide In N,N-dimethyl-formamide at 20℃; for 0.333333 h; Stage #2: at 120 - 130℃; for 16 h;
Step 1: The crude R-9- (2-hydroxypropyl) adenine was obtained100 g of adenine (0.74 mol) and 2.35 g (0.058 mol) of sodium hydroxide were added to 500 mlAnd stirred at room temperature for 20 minutes. 96.5 g (0.946 mol) of R-propylene carbonate was added and the temperature was raised to 120-130 ° C to maintain the temperature of the reaction mixtureShould be 16h;After the completion of the reaction by HPLC, the solution of R-9- (2-hydroxypropyl) adenine which had been reacted was distilled off under reduced pressure for 70 ~80percent of the DMF solvent, adding 300ml toluene, stirring evenly, 0 degrees heat 2h, filtration, drying, in the R-9- (2-hydroxypropyl)The crude product of adenine was 136 g, the crude yield was 95.7percent, the purity was 90.8percent, and the isomer was 8.0percent.Step two: packed column, pretreatmentA 150 g of PRP-6A resin was weighed, poured into a glass column, rinsed three times with ethanol, and the column was compactedNo bubbles, the resin height of 28cm, the cylinder uniform, and then rinse with ethyl acetate 3 times, and finally replaced with ethanol, ethyl acetateTo the test without ethyl acetate so far, the column installed backup.Step 3: LoadingThe crude R-9- (2-hydroxypropyl) adenine 6g dissolved in a small amount of water 20ml, into the PRP-6A resin chromatography column,To the sample solution completely adsorbed to the resin column for the sample is completed.Step 4: Elution80percent ethanol as the eluant, pour into the resin column, with air pump pressure elution, flow controlAt 15 ml / min, the eluent was received in 100 ml portions of the receiver bottle, and the content of the product in each bottle was detected by HPLC.Step 5: ConcentrationThe R-9- (2-hydroxypropyl) adenine and the isomer were collected together under vacuum conditions with a purity of more than 99percentConcentrated to dry, distilled ethanol water recovery applied to get more than 99percent purity of R-9- (2-hydroxypropyl) adenine white crystalline powderAnd 4.7 g of isomer having a purity of more than 99percent, and the chromatographic separation yield was 92.9percent of the product and 97.9percent of the isomer.Step 6: Wash the columnRinse the column with 90percent ethanol in water until no liquid is detected. This indicates that the PRP-6A resin column has been flushedClean, you can continue to use the next time.Step 6: Repeat steps 3 through 6 to cycle through the column 6 timesThe results are shown in Table 1 below:Note: In Table 1 above, the chromatographic separation results were obtained in the longitudinal direction for six times. The yield was chromatographic yield,HPLC area integral purity.
With dmap In tetrahydrofuran at 20℃; for 5 h; Inert atmosphere
To a solution of adenine (1.35 g, 10 mmol) and DMAP (122 mg, 1 mmol) in THF (50 mL) under argon was added Boc2O (9.38 g, 43 mmol). The reaction was stirred 5 h at room temperature. After removal of the solvent, EtOAc (400 mL) was added and the solution was washed with HCl 1 N (30 mL) and then with NaCl (3 * 100 mL). After drying over Na2SO4, filtration and removal of the solvents under reduced pressure, the residue was dissolved in methanol (100 mL) and NaHCO3 sat. (45 mL). The reaction was then stirred for 1h30 at 50 °C and after removal of the solvent, water (100 mL) was added. The aqueous phase was then extracted with CHCl3 (2 * 300 mL) and, after drying over Na2SO4, the solvent was removed under reduced pressure. The resulting crude product was purified by flash chromatography (cyclohexane/AcOEt, 10:90) to afford compound 30 (2.44 g, 73percent) as a white solid. 1H NMR (DMSO-d6) δ: 13.69 (s, 1H, NH), 8.80 (s, 1H, H-2), 8.63 (s, 1H, H-8), 1.36 (s, 18H, C(CH3)3) ppm.
With triethylamine; In acetonitrile; at 125℃; for 14h;Inert atmosphere;
In the 500 ml in the reaction bottle, adenine 37g (0.273 muM) suspended in acetonitrile 93 ml in, adding dioxolan 29.4g (0.334 muM), triethylamine 14.8g (0.146 muM) in N2 under protection 125 C reaction 14h, slightly cold, pressure reducing recovery acetonitrile to obtain the solid particles, slightly cold, adds anhydrously ethanol 74 ml, heating to reflux and thermal insulation 1.5h, the ice-bath is cold to 0 C under stirring 2h after-filtration, to obtain job filters the cake to dry 47.3g white powdery solid namely target product, yield 95%.
93.3%
With sodium hydroxide; In DMF (N,N-dimethyl-formamide); for 3.33333h;Heating / reflux;
Example 5 Preparation of 9-(2-Hydroxyethyl)adenine (5) A 12 L, 3-necked round bottom flask was equipped with a mechanical stirrer, condenser, thermometer and heating mantle. The flask was flushed with nitrogen and charged with adenine (504 g), ethylene carbonate (343 g), DMF (3.7 L) and sodium hydroxide (7.80 g). The stirred mixture was heated to reflux (approximately 80 minutes to reach reflux, pot temperature=145 C.), and then refluxed for 2 hours. The heating mantle was removed and the yellow solution was cooled to below 100 C. The resulting mixture was then cooled to 5 C. in an ice bath and diluted with toluene (3.8 L). The resulting mixture was stirred at <10 C. for 2 hours and then filtered. The collected solid was washed with toluene (2*0.5) and cold ethanol (1.5 L), then dried to constant weight (-30 in. Hg, 50 C., 14 h). The solid 5 was analyzed by HPLC and 1H-NMR (DMSO-d6).
82.7%
With sodium hydroxide; In N,N-dimethyl-formamide; for 4h;Reflux; Large scale;
The mechanical stirrer, reflux condenser and thermometer were installed in a 10 L reaction flask.To this, 3 kg (22.22 mol) of adenine, 2.14 kg (24.32 mol) of ethylene carbonate, 20 g (0.5 mol) of sodium hydroxide and 7 L of DMF were added thereto in turn, followed by stirring and heating under reflux for 4 hours.The reaction was terminated, cooled to room temperature, filtered, and the filter cake was dried under vacuum at 70 C for 6 hours.9-hydroxyethyl adenine as an off-white solid powder 3.29kg, Mp: 225 ~ 227 (decomposition), the yield of 82.7%.
With sodium hydroxide; In N,N-dimethyl-formamide; at 90 - 140℃; for 12h;Inert atmosphere;
To the reaction flask was added 200 ml of N, N-dimethylformamide (DMF)N2 protection,Adenine (30.0 g, 0.222 mol, 1 eq.) Was added,Stirring,NaOH (0.45 g, 0.011 mol) and was addedPropylene carbonate (28.5 g, 0.279 mol, 1.26 eq.),And the temperature was raised to 130 to 140 C.12 hours after the sampling test,When the adenine content in 1% or less,The reaction can be stopped.The temperature slowly reduced to 90 below,200 ml of toluene,Continue to cool to 0 ~ 5 ,And the mixture was stirred for 2 hours.Filtered and dried to give 38.13 g of a white solid,Yield 87%
87%
With sodium hydroxide; In N,N-dimethyl-formamide; at 130 - 140℃; for 12h;Inert atmosphere;
To the reaction flask was added 200 ml of N, N-dimethylformamide (DMF), protected with N2, added adenine (30.0 g, 0.222 mol, 1eq .), stirred, NaOH (0 · 45 g, mol) and R-propylene carbonate (28.5 g, 0. 279 mol, 1.3 eq.) and heated to 130 to 140 C. 12 hours after the sampling test, when the adenine content of 1% or less, can stop the reaction. The temperature slowly drops below 90 C, add 200 ml of toluene, continue to cool to 0 ~ 5 C and stir for 2 hours. Filtered and dried to give 38.13 g of a white solid, 87% yield,
81%
With sodium hydroxide; In N,N-dimethyl-formamide; at 140℃; for 16h;
A solution of adenine (3.85g, 28.49 mmol) , (R) - propylene carbonate (2.7 mL, 31.34 mmol), and pulverized sodium hydroxide (60 mg, 1.42 mmol) in anhydrous DMF (80 mL) was heated at 1400C with stirring for 16 h. After cooling, the mixture was then filtered to remove insoluble materials, the filtrate was evaporated under reduced pressure and co-evaporated three times with toluene. The residue was triturated with EtOAc then filtered to give a white solid which was immediately recrystallized in ethanol to afford compound 7 (4.5 g, 81 %) : mp 193C (Lit. 192-195C) ; 1H NMR (DMSO-.d5) delta : 8.15 (s, IH, H-2), 8.06 (s, IH, H-8) , 7.22 (bs, 2H, NH2), 5.06 (bs, IH, OH), 4.06 (m, 3H, CH2N and CHO), 1.12 (d, J = 5.7 Hz, 3H, CH3). 13C NMR (OMSO-d6) delta: 155.87, 152.21, 149.67, 141.44, 118.50, 64.57, 50.07, 20.80. MS (GT, FAB+): 136 (B+1H) 194 (M+1H)+, 216 (MH-Na)+, 232 (M+K) +, 387 (2MH-IH)+.
81%
The Buchi reactor (10 L) was preheated to 150 C and traces of moisture were blown away with the nitrogen stream. The reactor was filled with argon and cooled down to ~ 70 C, dry DMF (4 L, ~ 20 ppm of H2O, distilled from P2O5) was added and stirring was switched on (200 rev/min) with heating at 100 C. When the desired temperature was reached, adenine (A, 150 g, 1 mol) and K2CO3 (72.5 g, 0.525 mol) were added. The reaction temperature was increased to 120 C. The coarse suspension changed into fine suspension of the potassium salt of adenine and CO2 was being released at the same time. When temperature of 120 C was reached, carbonate (R)-C (133 g, 1.3 mol) was immediately and quickly added. The reaction mixture was stirred at 120 C and continuously monitored by TLC. The full conversion was observed at ~ 8 h. The reaction mixture was then cooled to RT and precipitated solid was filtered off, the reactor was rinsed with EtOH, and the solid washed quickly with EtOH (2 x 100 mL). The filtrate was concentrated in vacuo at 60 C, so that ~ 200 mL of DMF are left in the flask, i.e. ~ 400 mL of solvents were removed. The product usually started to crystallize during the concentration/evaporation process. EtOH (400 mL) was added to the residue and this mixture was sonicated at 70 C for 2 h to convert the formylated by-product to the desired product 1 and to afford nicely crystallized product 1. After cooling in an ice bath, the product was filtered off, washed (2 x 50 mL iced EtOH), and dried at 60C for 4 days (under vacuum with P2O5) to give 149 g (72%) of 1 (98% purity, HPLC). Repeated experiments afforded up to 81 % yields of the product 1
77%
With sodium hydroxide; In N,N-dimethyl-formamide; at 130℃; for 7h;Inert atmosphere;
(1) 40 g of adenine (II) and 39.32 g of (R) -propylene carbonate (III) are dissolved in 120 g of DMFAdd 2g of sodium hydroxide as a catalyst, and after mixing well, protect with nitrogen.The temperature was raised to 130 C for 7 hours, and the residual amount of the raw materials in the liquid phase detection was less than 0.5%;Reduce to room temperature, then add 160g of toluene crystals, lower the temperature to 5 C, and grow the crystals for 1h.Filtration, washing and drying at 80 C. for 7 h to obtain 44 g of (R) -9- (2-hydroxypropyl) adenine (IV);The purity of the product was> 99%, and the molar yield was 77%.
72%
The Buchi reactor (10 L) was preheated to 150 C and traces of moisture were blown away with the nitrogen stream. The reactor was filled with argon and cooled down to ~ 70 C, dry DMF (4 L, ~ 20 ppm of H2O, distilled from P2O5) was added and stirring was switched on (200 rev/min) with heating at 100 C. When the desired temperature was reached, adenine (A, 150 g, 1 mol) and K2CO3 (72.5 g, 0.525 mol) were added. The reaction temperature was increased to 120 C. The coarse suspension changed into fine suspension of the potassium salt of adenine and CO2 was being released at the same time. When temperature of 120 C was reached, carbonate (R)-C (133 g, 1.3 mol) was immediately and quickly added. The reaction mixture was stirred at 120 C and continuously monitored by TLC. The full conversion was observed at ~ 8 h. The reaction mixture was then cooled to RT and precipitated solid was filtered off, the reactor was rinsed with EtOH, and the solid washed quickly with EtOH (2 x 100 mL). The filtrate was concentrated in vacuo at 60 C, so that ~ 200 mL of DMF are left in the flask, i.e. ~ 400 mL of solvents were removed. The product usually started to crystallize during the concentration/evaporation process. EtOH (400 mL) was added to the residue and this mixture was sonicated at 70 C for 2 h to convert the formylated by-product to the desired product 1 and to afford nicely crystallized product 1. After cooling in an ice bath, the product was filtered off, washed (2 x 50 mL iced EtOH), and dried at 60C for 4 days (under vacuum with P2O5) to give 149 g (72%) of 1 (98% purity, HPLC). Repeated experiments afforded up to 81 % yields of the product 1
72.6%
With sodium hydroxide; In methanol; N,N-dimethyl-formamide; isopropyl alcohol; at 4 - 120℃; for 39h;
Add 40.00 g (0.296 mol) of adenine to a three-necked flask.Add 190 ml of N,N-dimethylformamide (DMF),0.94 g (0.0235 mol) of sodium hydroxide was added with stirring.Further, (R)-propylene carbonate 39.20 g (0.384 mol) was added.The temperature was raised to 120 C and the reaction was carried out for 27 hours.Stop the reaction and cool to 70 C.A mixed solution of 120 ml of methanol and 120 ml of isopropyl alcohol was added.Cool down to 15 C,Constant temperature crystallization for 12 hours, filtration,The filter cake was washed with a mixed solution of methanol 20 ml and isopropyl alcohol 20 ml (4 C).Drain,Place it in a vacuum oven at 60 C for 2 hours under vacuum.Obtained 45.51 g (0.215 mol) of a white solid.The molar yield was 72.6%
71.8%
40 g (0.296 mol) of adenine To 200 ml of dimethylformamide (DMF)And dissolved 0.94 g (0.0235 mol, 0.08 equiv.) Of sodium hydroxide (NaOH)Followed by stirring at room temperature for 20 minutes39.2 g (0.390 mol, 1.32 Equiv.) Of (R) -propylene carbonate ((R) -propylene carbonate) was added and stirred for 30 minutes.The reaction temperature was 120 [And heated and condensed for 24 hours.Thereafter, the reaction was checked by TLC and HPLC. After the reaction was almost completed (90% or more), the reaction temperature was cooled to 70 C and 240 ml of isopropyl alcohol (IPA) was added to crystallize. Thereafter, the solution was continuously stirred and cooled. The crystals were filtered at 10 C, washed with IPA, and dried in a vacuum dryer at 70 C to obtain 41 g of HPA (yield: 71.8%).
71.8%
40 g (0.296 mol) of 6 adenine was dissolved in 200 ml of 7 dimethylformamide (DMF), and 0.94 (0.0235 mol, 0.08 eq.) of 8 sodium hydroxide (NaOH) was added. After 20-min agitation at the room temperature, 39.2 g (0.390 mol, 1.32 eq.) of 9 (R)-propylene carbonate was added and the resultant solution was stirred for 30 minutes. The reaction temperature was elevated to 120 C., and a thermal condensation reaction was activated for 24 hours. Subsequently, the reaction status was examined through TLC and HPLC. After the completion of the reaction (90% or above), the reaction temperature was reduced to 70 C. and 240 ml of isopropyl alcohol (IPA) was added to active crystallization. Under continuous agitation and cooling, crystals were collected through filtration at 10 C., washed with IPA and then dried out at 70 C. in a low-pressure dryer to obtain 41 g of 5 HPA (yield 71.8%).
65%
Example 2 (Stage 1 using KOH)Adenine 4 (40 g, 296 mmol, 1.0 eq) and potassium hydroxide (1.66 g, 29.6 mmol, 0.1 eq) were mixed with DMF (190 ml) at 25-30 C and the mixture was stirred for 10 mm at 25-30 C. (R)-propylene carbonate 5 (33.6 ml, 39.9 g, 391 mmol, 1.32 eq) was added drop-wise to the reaction mass over10-15 mm at 25-30 C. The mixture was heated to 120 C and held at that temperature for 48 h. A clear solution resulted, and the reaction mixture was cooled to 70 C. A mixture of methanol (120 ml) and iso-propanol (120 ml) was added drop-wise to the reaction mixture over 10 mm, during which time the reaction mixture was allowed to cool to 55 C, and precipitation of produt was observed. The reaction mixturewas cooled to 5 C and held at this temperature for I h. The product was isolated by filtration and the cake was washed with a chilled mixture of methanol (10 ml) and isopropanol (10 ml). The resulting solid was dried under vacuum at 70-75 C, affording HPA 6 as an off-white solid (37 g, 65%).
With sodium hydroxide; In N,N-dimethyl-formamide; at 130℃; for 30h;Inert atmosphere;
Example 3 Preparation of (R)-9-[2-(diethoxyphosphinylmethoxy)propyl]adenine Under an inert atmosphere (nitrogen), adenine (100 g), sodium hydroxide (1.2 g), (R)-4-methyl-1,3-dioxolan-2-one (84 g) and N,N-dimethylformamide (700 ml) were mixed together and stirred at 130 C. for 30 hours until TLC (10% methanol in CH2Cl2 (V/V)) showed the residual adenine was no more than 0.5%. After cooling to 25 C., LiH (8 g) was added, the resulting mixture was heated to 70 C. for 2 hours under nitrogen. Then cooled to room temperature, diethyl p-toluenesulfonyloxymethylphosphonate (300 g) was added. The resulting mixture was maintained at 60 C. until TLC showed the completion of reaction, concentrated under vacuum at the temperature of no more than 80 C. The residue was dissolved in water (500 ml), extracted with dichloromethane continuously, the resulting extracts were combined and concentrated under vacuum at the temperature of no more than 80 C. to give 200 g of viscous orange oil, with 65% purity by HPLC. The crude (R)-9-[2-(diethoxyphosphinylmethoxy)propyl]adenine can be used directly for the subsequent reaction without further purification.
With lithium hydride; sodium hydroxide; In N,N-dimethyl-formamide; at 25 - 130℃; for 2h;
In a 1000 ml three-necked flask, 100 g of adenine, 1.2 g of sodium hydroxide, 84 g of R-carbon-1,2-propanediol and 700 ml of DMF were added and the temperature was raised to 130 C with stirring. The reaction mixture was cooled to 25 C, 8 g of lithium hydride was added, and then heated to 70 C. The reaction was allowed to react for 2 hours and then cooled to room temperature,300 g of p-toluenesulfonyloxymethyl phosphate was added and the reaction mixture was maintained at 60 C until TLC showed a complete reaction. The reaction mixture was concentrated in vacuo at a temperature not exceeding 80 C, 500 ml of water was added and the mixture was stirred and the aqueous solution was continuously extracted with methylene chloride. The dichloromethane extract was combined and the extract was concentrated in vacuo at not higher than 80 C to give a viscous orange (R) -9- [2- (diethylphosphonoylmethoxy) propyl] adenine in the orange oil containing 65% (Diethylphosphonoylmethoxy) propyl] adenine crude can be used directly in the subsequent reaction without purification.
With sodium hydroxide; In N,N-dimethyl-formamide; at 120 - 130℃;Autoclave;
Adding glass autoclave convenient replacement adenine (7.5 kg, 55 . 50mol), R-propylene carbonate (8.25 kg, 80 . 81mol), DMF (30 kg, 410 . 45mol) and NaOH (0.23 kg, 5 . 75mol), stirring the mixture at room temperature for 10 minutes, the system, to start-up of heating 120-130C, thermal reaction, every 1 hour detecting TLC, the reaction is complete, to stop the reaction, cooling to 45-60C, joins uncleding Chunmei in the reaction liquid (7.4 kg, 43 . 39mol), then heating to 60-80C, start dropping paratoluene sulfonyloxy phosphoric acid diethyl ester (30 kg, 93 . 08mol), add reaction is preserved after the 6-hour, tracking of the reaction, to be (R) - 9 - (2-hydroxy-propyl) adenine after the reaction is complete, cooling to 60 C, plus 4.5 kg acetic acid, stirring 10 minutes, to concentrated under reduced pressure, to obtain R-9 [(diethyl phosphinylidyne methoxy ) propyl] purine, cooling to 50 C, by adding the mass concentration is 30% hydrochloric acid of 37.5 kg, stirring to dissolve, cooling to 15 C the following stirring 1 hour, a large number of solid precipitation, filtration of the solid, the filtrate in the 85 C sustained-access access 6kgHCL gas, reaction 18 hours, to after the reaction is complete, reaction solution is concentrated under reduced pressure to the slurry, by adding 45 kg water, stirring to dissolve, PH value is adjusted with ammonia water to the 3.0-3.5, obtained crude PMPA, filtering out the solid, using 10 times the crystallization is provided, to filter out solid and atmospheric drying is 9 kg of refined PMPA, ? 99% purity, the yield is 120%.
With sodium hydroxide; In N,N-dimethyl-formamide; at 125 - 135℃;Inert atmosphere;
In sequence under nitrogen protection, DMF (50g), R-propylene carbonate (17.2g, 168mmol), adenine (20g, 148mmol), and NaOH (0.2g, 5mmol), heating to 125-135C, and thermal insulation reaction 6-8 hours; cooling to 60-70C, ding Chunmeijoins uncle (20.3g, 119mmol), then dropwise DESMP (64g, 199mmol), the drop finishes, 60-70 C insulation reaction 6-8 hours, esterification reaction is over, cooling, adds the second grade acid is neutralized, decompression does thickly DMF (80 C, the [...] 5mmHg), added 48% hydrobromic acid of (160g) dissolves uniform, heating to 90-100 C insulation reaction 3-5 hours, cooling to 20-25C, then adding 40% NaOH solution regulating PH value to 3.0, cooling to 5-8 C crystallization 3 hours, filtered, to crude PMPA 48g, PMPA crude in 20-25 C with 5% hydrochloric acid (140g) dissolved, then using 5% sodium hydroxide (175g) adjusting PH value to 2.5, cooling to 0-5C, thermal insulation 1h, filtering, washing two times with water, 100 C -105 C drying to obtain the finished product 24.7g, HPLC purity 99.6%. (Molar yield to adenine as 58%).
With sodium hydroxide; In dimethyl sulfoxide; at 150 - 180℃;
Step S1 in, said reaction to dimethyl sulfoxide as reaction solvent, sodium hydroxide as catalyst under the condition of, the reaction temperature is 150 - 180 C.The compound 1 with sodium hydroxide in a molar ratio of 3 - 6:1.
With potassium hydroxide; In N,N-dimethyl-formamide;Inert atmosphere;
(3) under nitrogen protection mixing adenine with R-propylene carbonate in the first solvent, under base catalysis, heating, carry on insulation reaction, reaction termination, obtained 9-(2-hydroxypropyl) adenine as a crude product, filtering, and concentrated under reduced pressure to give a concentrated liquid; into the concentrate add a second solvent, warm up at 60 C, carry on insulation reaction 2h, cool down at room temperature, insulation for 1h, Cool down at 2 C, keep warm for 1 h, filter, dry at 60 C for 20 h under reduced pressure, obtained 9-(2-hydroxypropyl) adenine; the first solvent is N,N-dimethylformamide; the second solvent is methanol and tetrahydrofuran; in the second solvent the volume ratio of the methanol and the tetrahydrofuran is 1:0.3; the alkali is potassium hydroxide;
With tert.-butyl lithium; In N,N-dimethyl-formamide;
(R)-9-(2-hydroxypropyl) adenine preparation: diethyl phosphite and paraformaldehyde are first condensed and esterified to obtain diethyl p-toluenesulfonic acid hydroxymethyl phosphate.Then (R)-1,2-propylene carbonate is reacted with adenine to give 9-(2-hydroxypropyl)Adenine, followed by reaction of diethyl p-toluenesulfonic acid hydroxymethyl phosphate and 9-(2-hydroxypropyl) adenine under the action of a catalyst(R)-9-(2-hydroxypropyl)adenine, aside; wherein the catalyst in step A) is an anhydrous DMF solution of lithium t-butoxide.
Adenine (40g) was first added to the flask, liquid bromine (107 ml) was added under mechanical stirring, the addition process was slow, and then stirred at room temperature for 3 hours;After the completion of the reaction, the excess liquid bromine was removed by adding sodium hydrogen sulfite solution, and the reaction liquid was adjusted to neutrality with ammonia water to precipitate a white powdery solid. Filtration, the solid was washed with ice water to give 8-bromo adenine, pale yellow solid 54 g, yield 85.7%;
74%
With water; bromine; at 20℃;
Example 8Preparation of 2-(3-(6-amino-9-(pent-4-ynyl)-9H-purin-8-ylthio)phenoxy)-N-hydroxyacetamide (Compound 14)Step 8a. 8-Bromo-9H-purin-6-amine (compound 302); Bromine (9.36 g, 58.5 mmol) was added to H2O (25 mL) with stirring, then the compound 301 (1.1 g, 8.1 mmol) was added into the solution. The mixture was stirred at room temperature overnight. The excess bromine was removed and the solvent was evaporated to give compound 302 as a light yellow solid (1.28 g, 74%). The crude product was used without further purification: LC-MS: 214 [M+1]+.
With bromine; In water; at 20℃;
Adenine (2.2 g, 16.3 mmol) was added to a solution of bromine (6.0 mL, 1 17.7 mmol) in water (200 mL), and the resulting mixture was stirred overnight at room temperature. The solvent was evaporated to dryness, and the brominated product 6 was used further without additional purification. MS (ESI): m/z 213.5/215.6 [M + H]+.
4.1.1.22. N6-Benzoyl-adenine (7). Benzoyl chloride (3.41 mL,29.6 mmol) was added into the solution of adenine (2 g,14.8 mmol) in anhydrous pyridine (25 mL) and the resulted mixturewas stirred at 60 C overnight. The solvent was removed invacuo and the residue was dissolved in methanol (30 mL). It wasadjusted to pH = 9-10 with 2 N NaOH solution and stirred foranother 30 min. After neutralization with 20% HCl solution, the solventwas removed in vacuo and the crude powder was obtained,which was recrystallized in ethanol to obtain N6-benzoyl-adenineas white powder (3.198 g, yield: 90.3%). The purity was 95% byHPLC analysis. HRMS (TOF) m/z calcd for C12H10N5O[M+H]+240.0885, found 240.0888. 1H NMR (CD3OD, 300 MHz) 7.57 (t,J = 7.2 Hz, 2H), 7.65 (t, J = 7.5 Hz, 1H), 8.10 (d, J = 6.9 Hz, 2H), 8.48(s, 1H), 8.71 (s, 1H). 13C NMR (DMSO-d6) 93.3, 128.5 (2C), 128.6(2C), 132.1, 132.7, 133.0, 145.9, 151.2, 161.0, 166.6.
2.15 g (90%)
In pyridine; isopropyl alcohol;
N6-Benzoyladenine (8). Benzoyl chloride (1.3 mL, 11 mmol) was added dropwise over 30 min to a stirred suspension of adenine (1.35 g, 10 mmol) in dry pyridine, and stirring was continued at 100 C. for a further 3 h, and the reaction mixture was allowed to stand overnight at room temperature. The reaction was quenched with methanol and the solvents were removed under reduced pressure. The residue was triturated in hot isopropanol and dried in vacuo to give 8 as a white solid: yield 2.15 g (90%); MS (+ESI): m/z 240 [M+H]+; 1H NMR (400 MHz, d-DMSO): delta11.50 (s, 1H), 8.74 (s, 1H), 8.52 (s, 1H), 8.11 (d, 2H, J=7.2 Hz), 7.66 (t, 1H, J=7.2 Hz), 7.58 (t, 2H, J=7.2 Hz).
With sodium hydroxide; In N,N-dimethyl-formamide;Inert atmosphere; Reflux;
To a stirred solution of adenine (14.9 g, 110 mmol, 1.00 equiv) in distilled N,N-dimethylformamide (80 mL) at room temperature under nitrogen was added ethylene carbonate (10.0 g, 113 mmol, 1.13 equiv) and sodium hydroxide (0.50 g, 12.5 mmol). The reaction mixture heated to reflux and allowed to stir until it was evident that the starting material, adenine, had been consumed by TLC (Rf = 0.05 - eluent: 10% MeOH in CH2Cl2). On cooling, the solvent was removed in vacuo and the off-white/yellow solid residues, containing a 9:1 mixture of the N9 and N7 regioisomers by 1H NMR analysis, were recrystallized from methanol yielding the title compound as an off-white powder (14.20 g, 75 mmol, 68%). Spectroscopic data are consistent with those reported in the literature. Melting Point (MeOH): 238-239 C (lit: 238-239 C) [1] 1H NMR? (400 MHz, DMSO-d6): 3.40 (1H, bs, OH), 3.74 (2H, t, J = 5.45 Hz, CH2OH), 4.19 (2H, t, J = 5.45 Hz, N-CH2), 7.22 (2H, bs, NH2), 8.08 (1H, s, Ar-H), 8.14 (1H, s, Ar-H). 13C NMR? (75 MHz, DMSO-d6): 45.68 (NCH2), 59.21 (CH2-O), 118.62 (ArC), 141.32 (ArC), 149.49 (ArC), 152.22 (ArC), 155.87 (ArC). IR (KBr, cm-1): 3311, 3246, 3056, 2930, 2865, 1687, 1607, 1574, 1067, 1018.
77 - 97%Chromat.; 1.5 - 19%Chromat.
With sodium hydroxide; In DMF (N,N-dimethyl-formamide); at 150 - 160℃; for 3h;Heating / reflux;
In general, a mixture of alkylene carbonate (11.0 mmole), the heterocyclic base (10.0 mmole) and solid [NAOH] (0.5 mmol) in a solvent (e. g., DMA) (20 ml) was heated at [150C] for 3 h. Then, the solvent was either evaporated and the residue taken up with a wash solvent, or diluted with a first solvent to precipitate the reaction products followed by a wash step with a wash solvent or wash solvent mixture (optionally followed by crystallization [FROM'A] crystallization solvent). Analysis of the reaction products was performed using HPLC and conditions as described in Figure 4, and a typical elution profile using such HPLC conditions is shown in Figure 5. Selected results of various reaction conditions, solvents, and wash/crystallization procedures are shown in Tables 1-3. For better visualization of the numerical differences in selectivity and yield, the following grayscale of Table A was used: Total Yield (in Shade Selectivity (as % N9 alkylated %) product) 50-64 Less than 76 65-74 77-83 r 75-84'i'84-87 88-90 a.. 3 _ s. 96-100 97-100 96-100,,, o 97_100 Table A Interestingly, as can be seen from Table 1 of Figure 1, when the solvent for dilution and crystallization was, or contained an aprotic and [APOLAR] solvent (here: toluene), and when DMF was used as a reaction solvent (and further depending on reaction temperature and workup), either the total yield was desirable at relatively undesirable selectivity, or the selectivity was desirable at relatively undesirable total yield. Replacement of the reaction solvent DMF with alternative solvents (shown here: DEF and DMA) appeared to improve the disparity between total yield and selectivity in a relatively unpredictable manner. Moreover, where the disparity between total yield and selectivity improved, total yields and selectivities were generally lower and frequently were at undesirable levels. After numerous further modifications (date not shown), the inventors eliminated the step of dilution of the reaction solvent by evaporation to force the reaction product from the solvent, and exemplary data on total yield and selectivity are shown in Table 2 of Figure 2. These data suggested that elimination of the dilution step tended to increase the total yield to at least some degree. However, improvement of the selectivity while maintaining relatively high total yields was inconsistent. In still further experiments, the inventors replaced the non-polar solvents for [DILUTION.] of the reaction solvent with relatively high polar solvents (IPA, ethyl acetate, acetonitrile, etc. ) when DMA was used as a reaction solvent. Surprisingly, and especially where DMA was the reaction solvent and IPA was the dilution and wash solvent, consistent high yields at high selectivity could be achieved under several reaction conditions as shown in the exemplary data on total yield and selectivity in Table 3 of Figure 3. Specifically, the total yield of product was as high as [91 %] at an N9-alkylated product content of 97% and an N7- alkylated byproduct content of 1.34% (with [NAOH] as catalyst and 150 centigrade reaction temperature). Similarly, the total yield of product was as high as 87% at an N9-alkylated product content of 97% and an N7-alkylated byproduct content of 1.15% (with [NAOH] as catalyst and 160 centigrade reaction temperature), and the total yield of product was as high as 82% at a N9-alkylated product content of 98% and a N7-alkylated byproduct content of 0.96% (with [NAOH] as catalyst and 140 centigrade reaction temperature). Moreover, by using DMA as a reaction solvent various advantages other than higher total yield and an increase of selectivity may be achieved. Among other things, the solubility of various heterocyclic bases, and especially adenine, is significantly increased as shown in Table B below. Solvent Solubility at RT Solubility at 150C DMF 2.90 m/ml 29. 0 mg/ml DEF 1. 36 mg/ml 13. 9 mg/ml DMA 4. 00 mg/ml 37.0 mg/ml [ TABLE B] Consequently, overall consumption of solvent may be significantly reduced by virtue of the increased solubility of the heterocyclic base in DMA (at least compared to DMF as reaction solvent), which in turn reduces the cost of preparing the alkylated heterocyclic base. Still further, due to the higher boiling point of DMA as compared to DMF (166.1 Centigrade as compared to 155 Centigrade, respectively) the reaction may be performed at a temperature that is further away from the boiling point of the reaction solvent, which increases the operational safety of the reaction. Moreover, while addition of a basic catalyst is generally not required, a basic catalyst, and preferably [NAOH] will benefit the total yield and selectivity.
98%Chromat.; 1.56%Chromat.
With sodium ethanolate; In DMF (N,N-dimethyl-formamide); at 130℃; for 3h;
In general, a mixture of alkylene carbonate (11.0 mmole), the heterocyclic base (10.0 mmole) and solid [NAOH] (0.5 mmol) in a solvent (e. g., DMA) (20 ml) was heated at [150C] for 3 h. Then, the solvent was either evaporated and the residue taken up with a wash solvent, or diluted with a first solvent to precipitate the reaction products followed by a wash step with a wash solvent or wash solvent mixture (optionally followed by crystallization [FROM'A] crystallization solvent). Analysis of the reaction products was performed using HPLC and conditions as described in Figure 4, and a typical elution profile using such HPLC conditions is shown in Figure 5. Selected results of various reaction conditions, solvents, and wash/crystallization procedures are shown in Tables 1-3. For better visualization of the numerical differences in selectivity and yield, the following grayscale of Table A was used: Total Yield (in Shade Selectivity (as % N9 alkylated %) product) 50-64 Less than 76 65-74 77-83 r 75-84'i'84-87 88-90 a.. 3 _ s. 96-100 97-100 96-100,,, o 97_100 Table A Interestingly, as can be seen from Table 1 of Figure 1, when the solvent for dilution and crystallization was, or contained an aprotic and [APOLAR] solvent (here: toluene), and when DMF was used as a reaction solvent (and further depending on reaction temperature and workup), either the total yield was desirable at relatively undesirable selectivity, or the selectivity was desirable at relatively undesirable total yield. Replacement of the reaction solvent DMF with alternative solvents (shown here: DEF and DMA) appeared to improve the disparity between total yield and selectivity in a relatively unpredictable manner. Moreover, where the disparity between total yield and selectivity improved, total yields and selectivities were generally lower and frequently were at undesirable levels. After numerous further modifications (date not shown), the inventors eliminated the step of dilution of the reaction solvent by evaporation to force the reaction product from the solvent, and exemplary data on total yield and selectivity are shown in Table 2 of Figure 2. These data suggested that elimination of the dilution step tended to increase the total yield to at least some degree. However, improvement of the selectivity while maintaining relatively high total yields was inconsistent. In still further experiments, the inventors replaced the non-polar solvents for [DILUTION.] of the reaction solvent with relatively high polar solvents (IPA, ethyl acetate, acetonitrile, etc. ) when DMA was used as a reaction solvent. Surprisingly, and especially where DMA was the reaction solvent and IPA was the dilution and wash solvent, consistent high yields at high selectivity could be achieved under several reaction conditions as shown in the exemplary data on total yield and selectivity in Table 3 of Figure 3. Specifically, the total yield of product was as high as [91 %] at an N9-alkylated product content of 97% and an N7- alkylated byproduct content of 1.34% (with [NAOH] as catalyst and 150 centigrade reaction temperature). Similarly, the total yield of product was as high as 87% at an N9-alkylated product content of 97% and an N7-alkylated byproduct content of 1.15% (with [NAOH] as catalyst and 160 centigrade reaction temperature), and the total yield of product was as high as 82% at a N9-alkylated product content of 98% and a N7-alkylated byproduct content of 0.96% (with [NAOH] as catalyst and 140 centigrade reaction temperature). Moreover, by using DMA as a reaction solvent various advantages other than higher total yield and an increase of selectivity may be achieved. Among other things, the solubility of various heterocyclic bases, and especially adenine, is significantly increased as shown in Table B below. Solvent Solubility at RT Solubility at 150C DMF 2.90 m/ml 29. 0 mg/ml DEF 1. 36 mg/ml 13. 9 mg/ml DMA 4. 00 mg/ml 37.0 mg/ml [ TABLE B] Consequently, overall consumption of solvent may be significantly reduced by virtue of the increased solubility of the heterocyclic base in DMA (at least compared to DMF as reaction solvent), which in turn reduces the cost of preparing the alkylated heterocyclic base. Still further, due to the higher boiling point of DMA as compared to DMF (166.1 Centigrade as compared to 155 Centigrade, respectively) the reaction may be performed at a temperature that is further away from the boiling point of the reaction solvent, which increases the operational safety of the reaction. Moreover, while addition of a basic catalyst is generally not required, a basic catalyst, and preferably [NAOH] will benefit the total yield and selectivity.
76 - 98%Chromat.; 1.18 - 20%Chromat.
With sodium hydroxide; In ISOPROPYLAMIDE; at 140 - 160℃; for 3h;
In general, a mixture of alkylene carbonate (11.0 mmole), the heterocyclic base (10.0 mmole) and solid [NAOH] (0.5 mmol) in a solvent (e. g., DMA) (20 ml) was heated at [150C] for 3 h. Then, the solvent was either evaporated and the residue taken up with a wash solvent, or diluted with a first solvent to precipitate the reaction products followed by a wash step with a wash solvent or wash solvent mixture (optionally followed by crystallization [FROM'A] crystallization solvent). Analysis of the reaction products was performed using HPLC and conditions as described in Figure 4, and a typical elution profile using such HPLC conditions is shown in Figure 5. Selected results of various reaction conditions, solvents, and wash/crystallization procedures are shown in Tables 1-3. For better visualization of the numerical differences in selectivity and yield, the following grayscale of Table A was used: Total Yield (in Shade Selectivity (as % N9 alkylated %) product) 50-64 Less than 76 65-74 77-83 r 75-84'i'84-87 88-90 a.. 3 _ s. 96-100 97-100 96-100,,, o 97_100 Table A Interestingly, as can be seen from Table 1 of Figure 1, when the solvent for dilution and crystallization was, or contained an aprotic and [APOLAR] solvent (here: toluene), and when DMF was used as a reaction solvent (and further depending on reaction temperature and workup), either the total yield was desirable at relatively undesirable selectivity, or the selectivity was desirable at relatively undesirable total yield. Replacement of the reaction solvent DMF with alternative solvents (shown here: DEF and DMA) appeared to improve the disparity between total yield and selectivity in a relatively unpredictable manner. Moreover, where the disparity between total yield and selectivity improved, total yields and selectivities were generally lower and frequently were at undesirable levels. After numerous further modifications (date not shown), the inventors eliminated the step of dilution of the reaction solvent by evaporation to force the reaction product from the solvent, and exemplary data on total yield and selectivity are shown in Table 2 of Figure 2. These data suggested that elimination of the dilution step tended to increase the total yield to at least some degree. However, improvement of the selectivity while maintaining relatively high total yields was inconsistent. In still further experiments, the inventors replaced the non-polar solvents for [DILUTION.] of the reaction solvent with relatively high polar solvents (IPA, ethyl acetate, acetonitrile, etc. ) when DMA was used as a reaction solvent. Surprisingly, and especially where DMA was the reaction solvent and IPA was the dilution and wash solvent, consistent high yields at high selectivity could be achieved under several reaction conditions as shown in the exemplary data on total yield and selectivity in Table 3 of Figure 3. Specifically, the total yield of product was as high as [91 %] at an N9-alkylated product content of 97% and an N7- alkylated byproduct content of 1.34% (with [NAOH] as catalyst and 150 centigrade reaction temperature). Similarly, the total yield of product was as high as 87% at an N9-alkylated product content of 97% and an N7-alkylated byproduct content of 1.15% (with [NAOH] as catalyst and 160 centigrade reaction temperature), and the total yield of product was as high as 82% at a N9-alkylated product content of 98% and a N7-alkylated byproduct content of 0.96% (with [NAOH] as catalyst and 140 centigrade reaction temperature). Moreover, by using DMA as a reaction solvent various advantages other than higher total yield and an increase of selectivity may be achieved. Among other things, the solubility of various heterocyclic bases, and especially adenine, is significantly increased as shown in Table B below. Solvent Solubility at RT Solubility at 150C DMF 2.90 m/ml 29. 0 mg/ml DEF 1. 36 mg/ml 13. 9 mg/ml DMA 4. 00 mg/ml 37.0 mg/ml [ TABLE B] Consequently, overall consumption of solvent may be significantly reduced by virtue of the increased solubility of the heterocyclic base in DMA (at least compared to DMF as reaction solvent), which in turn reduces the cost of preparing the alkylated heterocyclic base. Still further, due to the higher boiling point of DMA as compared to DMF (166.1 Centigrade as compared to 155 Centigrade, respectively) the reaction may be performed at a temperature that is further away from the boiling point of the reaction solvent, which increases the operational safety of the reaction. Moreover, while addition of a basic catalyst is generally not required, a basic catalyst, and preferably [NAOH] will benefit the total yield and selectivity.
77%Chromat.; 21%Chromat.
With sodium hydroxide; In N-formyldiethylamine; at 150℃; for 3h;
In general, a mixture of alkylene carbonate (11.0 mmole), the heterocyclic base (10.0 mmole) and solid [NAOH] (0.5 mmol) in a solvent (e. g., DMA) (20 ml) was heated at [150C] for 3 h. Then, the solvent was either evaporated and the residue taken up with a wash solvent, or diluted with a first solvent to precipitate the reaction products followed by a wash step with a wash solvent or wash solvent mixture (optionally followed by crystallization [FROM'A] crystallization solvent). Analysis of the reaction products was performed using HPLC and conditions as described in Figure 4, and a typical elution profile using such HPLC conditions is shown in Figure 5. Selected results of various reaction conditions, solvents, and wash/crystallization procedures are shown in Tables 1-3. For better visualization of the numerical differences in selectivity and yield, the following grayscale of Table A was used: Total Yield (in Shade Selectivity (as % N9 alkylated %) product) 50-64 Less than 76 65-74 77-83 r 75-84'i'84-87 88-90 a.. 3 _ s. 96-100 97-100 96-100,,, o 97_100 Table A Interestingly, as can be seen from Table 1 of Figure 1, when the solvent for dilution and crystallization was, or contained an aprotic and [APOLAR] solvent (here: toluene), and when DMF was used as a reaction solvent (and further depending on reaction temperature and workup), either the total yield was desirable at relatively undesirable selectivity, or the selectivity was desirable at relatively undesirable total yield. Replacement of the reaction solvent DMF with alternative solvents (shown here: DEF and DMA) appeared to improve the disparity between total yield and selectivity in a relatively unpredictable manner. Moreover, where the disparity between total yield and selectivity improved, total yields and selectivities were generally lower and frequently were at undesirable levels. After numerous further modifications (date not shown), the inventors eliminated the step of dilution of the reaction solvent by evaporation to force the reaction product from the solvent, and exemplary data on total yield and selectivity are shown in Table 2 of Figure 2. These data suggested that elimination of the dilution step tended to increase the total yield to at least some degree. However, improvement of the selectivity while maintaining relatively high total yields was inconsistent. In still further experiments, the inventors replaced the non-polar solvents for [DILUTION.] of the reaction solvent with relatively high polar solvents (IPA, ethyl acetate, acetonitrile, etc. ) when DMA was used as a reaction solvent. Surprisingly, and especially where DMA was the reaction solvent and IPA was the dilution and wash solvent, consistent high yields at high selectivity could be achieved under several reaction conditions as shown in the exemplary data on total yield and selectivity in Table 3 of Figure 3. Specifically, the total yield of product was as high as [91 %] at an N9-alkylated product content of 97% and an N7- alkylated byproduct content of 1.34% (with [NAOH] as catalyst and 150 centigrade reaction temperature). Similarly, the total yield of product was as high as 87% at an N9-alkylated product content of 97% and an N7-alkylated byproduct content of 1.15% (with [NAOH] as catalyst and 160 centigrade reaction temperature), and the total yield of product was as high as 82% at a N9-alkylated product content of 98% and a N7-alkylated byproduct content of 0.96% (with [NAOH] as catalyst and 140 centigrade reaction temperature). Moreover, by using DMA as a reaction solvent various advantages other than higher total yield and an increase of selectivity may be achieved. Among other things, the solubility of various heterocyclic bases, and especially adenine, is significantly increased as shown in Table B below. Solvent Solubility at RT Solubility at 150C DMF 2.90 m/ml 29. 0 mg/ml DEF 1. 36 mg/ml 13. 9 mg/ml DMA 4. 00 mg/ml 37.0 mg/ml [ TABLE B] Consequently, overall consumption of solvent may be significantly reduced by virtue of the increased solubility of the heterocyclic base in DMA (at least compared to DMF as reaction solvent), which in turn reduces the cost of preparing the alkylated heterocyclic base. Still further, due to the higher boiling point of DMA as compared to DMF (166.1 Centigrade as compared to 155 Centigrade, respectively) the reaction may be performed at a temperature that is further away from the boiling point of the reaction solvent, which increases the operational safety of the reaction. Moreover, while addition of a basic catalyst is generally not required, a basic catalyst, and preferably [NAOH] will benefit the total yield and selectivity.
55 - 83%Chromat.; 6 - 12%Chromat.
In DMF (N,N-dimethyl-formamide); at 150 - 160℃; for 3h;
In general, a mixture of alkylene carbonate (11.0 mmole), the heterocyclic base (10.0 mmole) and solid [NAOH] (0.5 mmol) in a solvent (e. g., DMA) (20 ml) was heated at [150C] for 3 h. Then, the solvent was either evaporated and the residue taken up with a wash solvent, or diluted with a first solvent to precipitate the reaction products followed by a wash step with a wash solvent or wash solvent mixture (optionally followed by crystallization [FROM'A] crystallization solvent). Analysis of the reaction products was performed using HPLC and conditions as described in Figure 4, and a typical elution profile using such HPLC conditions is shown in Figure 5. Selected results of various reaction conditions, solvents, and wash/crystallization procedures are shown in Tables 1-3. For better visualization of the numerical differences in selectivity and yield, the following grayscale of Table A was used: Total Yield (in Shade Selectivity (as % N9 alkylated %) product) 50-64 Less than 76 65-74 77-83 r 75-84'i'84-87 88-90 a.. 3 _ s. 96-100 97-100 96-100,,, o 97_100 Table A Interestingly, as can be seen from Table 1 of Figure 1, when the solvent for dilution and crystallization was, or contained an aprotic and [APOLAR] solvent (here: toluene), and when DMF was used as a reaction solvent (and further depending on reaction temperature and workup), either the total yield was desirable at relatively undesirable selectivity, or the selectivity was desirable at relatively undesirable total yield. Replacement of the reaction solvent DMF with alternative solvents (shown here: DEF and DMA) appeared to improve the disparity between total yield and selectivity in a relatively unpredictable manner. Moreover, where the disparity between total yield and selectivity improved, total yields and selectivities were generally lower and frequently were at undesirable levels. After numerous further modifications (date not shown), the inventors eliminated the step of dilution of the reaction solvent by evaporation to force the reaction product from the solvent, and exemplary data on total yield and selectivity are shown in Table 2 of Figure 2. These data suggested that elimination of the dilution step tended to increase the total yield to at least some degree. However, improvement of the selectivity while maintaining relatively high total yields was inconsistent. In still further experiments, the inventors replaced the non-polar solvents for [DILUTION.] of the reaction solvent with relatively high polar solvents (IPA, ethyl acetate, acetonitrile, etc. ) when DMA was used as a reaction solvent. Surprisingly, and especially where DMA was the reaction solvent and IPA was the dilution and wash solvent, consistent high yields at high selectivity could be achieved under several reaction conditions as shown in the exemplary data on total yield and selectivity in Table 3 of Figure 3. Specifically, the total yield of product was as high as [91 %] at an N9-alkylated product content of 97% and an N7- alkylated byproduct content of 1.34% (with [NAOH] as catalyst and 150 centigrade reaction temperature). Similarly, the total yield of product was as high as 87% at an N9-alkylated product content of 97% and an N7-alkylated byproduct content of 1.15% (with [NAOH] as catalyst and 160 centigrade reaction temperature), and the total yield of product was as high as 82% at a N9-alkylated product content of 98% and a N7-alkylated byproduct content of 0.96% (with [NAOH] as catalyst and 140 centigrade reaction temperature). Moreover, by using DMA as a reaction solvent various advantages other than higher total yield and an increase of selectivity may be achieved. Among other things, the solubility of various heterocyclic bases, and especially adenine, is significantly increased as shown in Table B below. Solvent Solubility at RT Solubility at 150C DMF 2.90 m/ml 29. 0 mg/ml DEF 1. 36 mg/ml 13. 9 mg/ml DMA 4. 00 mg/ml 37.0 mg/ml [ TABLE B] Consequently, overall consumption of solvent may be significantly reduced by virtue of the increased solubility of the heterocyclic base in DMA (at least compared to DMF as reaction solvent), which in turn reduces the cost of preparing the alkylated heterocyclic base. Still further, due to the higher boiling point of DMA as compared to DMF (166.1 Centigrade as compared to 155 Centigrade, respectively) the reaction may be performed at a temperature that is further away from the boiling point of the reaction solvent, which increases the operational safety of the reaction. Moreover, while addition of a basic catalyst is generally not required, a basic catalyst, and preferably [NAOH] will benefit the total yield and selectivity.
73%Chromat.; 19.5%Chromat.
In ISOPROPYLAMIDE; at 150℃; for 3h;
In general, a mixture of alkylene carbonate (11.0 mmole), the heterocyclic base (10.0 mmole) and solid [NAOH] (0.5 mmol) in a solvent (e. g., DMA) (20 ml) was heated at [150C] for 3 h. Then, the solvent was either evaporated and the residue taken up with a wash solvent, or diluted with a first solvent to precipitate the reaction products followed by a wash step with a wash solvent or wash solvent mixture (optionally followed by crystallization [FROM'A] crystallization solvent). Analysis of the reaction products was performed using HPLC and conditions as described in Figure 4, and a typical elution profile using such HPLC conditions is shown in Figure 5. Selected results of various reaction conditions, solvents, and wash/crystallization procedures are shown in Tables 1-3. For better visualization of the numerical differences in selectivity and yield, the following grayscale of Table A was used: Total Yield (in Shade Selectivity (as % N9 alkylated %) product) 50-64 Less than 76 65-74 77-83 r 75-84'i'84-87 88-90 a.. 3 _ s. 96-100 97-100 96-100,,, o 97_100 Table A Interestingly, as can be seen from Table 1 of Figure 1, when the solvent for dilution and crystallization was, or contained an aprotic and [APOLAR] solvent (here: toluene), and when DMF was used as a reaction solvent (and further depending on reaction temperature and workup), either the total yield was desirable at relatively undesirable selectivity, or the selectivity was desirable at relatively undesirable total yield. Replacement of the reaction solvent DMF with alternative solvents (shown here: DEF and DMA) appeared to improve the disparity between total yield and selectivity in a relatively unpredictable manner. Moreover, where the disparity between total yield and selectivity improved, total yields and selectivities were generally lower and frequently were at undesirable levels. After numerous further modifications (date not shown), the inventors eliminated the step of dilution of the reaction solvent by evaporation to force the reaction product from the solvent, and exemplary data on total yield and selectivity are shown in Table 2 of Figure 2. These data suggested that elimination of the dilution step tended to increase the total yield to at least some degree. However, improvement of the selectivity while maintaining relatively high total yields was inconsistent. In still further experiments, the inventors replaced the non-polar solvents for [DILUTION.] of the reaction solvent with relatively high polar solvents (IPA, ethyl acetate, acetonitrile, etc. ) when DMA was used as a reaction solvent. Surprisingly, and especially where DMA was the reaction solvent and IPA was the dilution and wash solvent, consistent high yields at high selectivity could be achieved under several reaction conditions as shown in the exemplary data on total yield and selectivity in Table 3 of Figure 3. Specifically, the total yield of product was as high as [91 %] at an N9-alkylated product content of 97% and an N7- alkylated byproduct content of 1.34% (with [NAOH] as catalyst and 150 centigrade reaction temperature). Similarly, the total yield of product was as high as 87% at an N9-alkylated product content of 97% and an N7-alkylated byproduct content of 1.15% (with [NAOH] as catalyst and 160 centigrade reaction temperature), and the total yield of product was as high as 82% at a N9-alkylated product content of 98% and a N7-alkylated byproduct content of 0.96% (with [NAOH] as catalyst and 140 centigrade reaction temperature). Moreover, by using DMA as a reaction solvent various advantages other than higher total yield and an increase of selectivity may be achieved. Among other things, the solubility of various heterocyclic bases, and especially adenine, is significantly increased as shown in Table B below. Solvent Solubility at RT Solubility at 150C DMF 2.90 m/ml 29. 0 mg/ml DEF 1. 36 mg/ml 13. 9 mg/ml DMA 4. 00 mg/ml 37.0 mg/ml [ TABLE B] Consequently, overall consumption of solvent may be significantly reduced by virtue of the increased solubility of the heterocyclic base in DMA (at least compared to DMF as reaction solvent), which in turn reduces the cost of preparing the alkylated heterocyclic base. Still further, due to the higher boiling point of DMA as compared to DMF (166.1 Centigrade as compared to 155 Centigrade, respectively) the reaction may be performed at a temperature that is further away from the boiling point of the reaction solvent, which increases the operational safety of the reaction. Moreover, while addition of a basic catalyst is generally not required, a basic catalyst, and preferably [NAOH] will benefit the total yield and selectivity.
With ammonia; sodium hydrogencarbonate;tin(IV) chloride; In methanol; water; ethyl acetate; acetonitrile;
Synthesis of Various 1-beta-Xylofuranosyl-5-Alkyluracils and Related Nucleosides. Nucleosides, Nucleotides, 1, 139-146 (1982). Adenine (19.6 g, 144 mmol) was suspended in acetonitrile (400 ml) with 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-L-ribofuranose 143 (60 g, 119 mmol). To this suspension was added stannic chloride fuming (22 ml, 187 mmol). After 12 hrs, the reaction was concentrated to a small volume (about 100 ml), and sodium hydrogencarbonate (110 g) and water (120 ml) were added. The resulting white solid (tin salts) was extracted with hot chloroform (5*200 ml). The combined extracts were filtered on a cellite bed. The organic phase was washed with a NaHCO3 5% solution and water, dried over sodium sulfate, filtered and evaporated to give compound 144 (60 g, colorless foam). The foam was treated with methanol saturated with ammonia (220 ml) in sealed vessel at room temperature under stirring for 4 days. The solvent was evaporated off under reduced pressure and the resulting powder was suspended in ethyl acetate (400 ml) at reflux for 1 hr. After filtration, the powder was recrystallized from water (220 ml) to give L-adenosine 145 (24 g, crystals, 75%)
With sodium hydroxide; methylamine;aluminum nickel; In ethanol; water;
EXAMPLE 15 A solution prepared by absorbing 18.9 g. (0.61 mole) of methylamine into 100 ml. of ethanol, a catalyst prepared by developing 1.35 g. of Raney nickel containing 8% by weight of nickel, 100 ml. of ethanol and 13.5 g. (0.1 mole) of adenine were placed into an autoclave and the reaction was carried out at 150 C. for 4.5 hours. After completing the reaction, the ethanol was removed by distillation, and 600 ml. of water and then 15 g. of a 20% by weight aqueous solution of sodium hydroxide were added. The resultant was heated under reflux to dissolve the reaction product and the insoluble material was filtered off under heating. After cooling, the filtrate was neutralized with sulfuric acid to precipitate crystals. The precipitate was filtered, washed with water and dried at 70 C. for 15 hours to give 14.2 g. of N6 -methyladenine The purity was 15.5% by weight and the yield was 15%.
With sodium hydroxide; In N,N-dimethyl-formamide; toluene;
EXAMPLE 1a Adenine to PMEA using Magnesium Isopropoxide. To a suspension of adenine (16.8 g, 0.124 mol) in DMF (41.9 ml) was added ethylene carbonate (12.1 g, 0.137 mol) and sodium hydroxide (0.100 g, 0.0025 mol). The mixture was heated at 130 C. overnight. The reaction was cooled to below 50 C. and toluene (62.1 ml) was added. The slurry was further cooled to 5 C. for 2 hours, filtered, and rinsed with toluene (2*). The wet solid was dried in vacuo at 65 C. to yield 20.0 g (90%) of 9-(2hydroxyethyl)adenine as an off-white solid. Mp: 238-240 C.
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;Product distribution / selectivity;
Example 2: 3-(tert-Butyloxycarbonyl-methyl-amino)-N(9H-purin-6-yl)propionamide. [Show Image] Reaction conditions: According to general procedure C (2.0 mmol scale) in 10.2% yield (method A), 12.5% yield (method B), 32.7% yield (method C), and 26.9% yield (method D). RP-HPLC was performed using a gradient from 25% methanol in water to 100% methanol. Analytical data: mp 205 C. 1H-NMR (500 MHz, DMSO-d6, 2 isomers): delta 1.29 (s, 9H), 2.75 (t, 2H, J = 6.85 Hz), 2.82 (s, 3H), 3.53 (t, 2H, J = 6.85 Hz), 8.39 (s, 1 H), 8.62 (s, 1H), 11.21 (s (br), 1 H), 12.18 (s (br), 1H). 13C-NMR (125 MHz, DMSO-d6, 2 isomers) 6 28.07, 34.27, 34.84, 44.94, 78.71, 113.86, 144.33, 145.68, 151.35, 154.70, 161.34, 171.69. LCMS (m/z): 319 ([M-H]-), 321 ([M+H]+). Anal. (C14H20N6O8 · 0.55 H2O) C, H, N. Purity by HPLC-UV (254 nm)-ESI-MS: 99%.; (c) Carboxylic acid (2.0 mmol), PyBOP (1.14 g, 2.2 mmol), and HOBt (0.30 g, 2.2 mmol) were dissolved in dry DMF (6 ml). DIPEA (0.30 ml, 2.2 mmol) was added and 1 min later adenine (0.54 g, 4.0 mmol) was added. All steps were performed under argon. The suspension was stirred under argon at room temperature overnight. DMF was evaporated under reduced pressure. The product was purified by column chromatography on silica gel eluting with 5% methanol in DCM. The appropriate fractions were separated from remaining adenine by RP-HPLC (method C).
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;Product distribution / selectivity;
Example Compound 147:; 8-[(6-Bromo-l ,3-benzodioxol-5-yl)thio]-9-(2-piperidin-4-ylethyl)-9H-purin-6-amine; Stepl: tert-Butyl 4-[2-(6-amino-9H-purin-9-yl)ethyl]piperidine-l-carboxylate and tert-buty 4-[2-(6-amino-3H-purin-3-yl)ethyl]piperidine-l-carboxylate; Method A; A mixture of adenine (82.1 mmol, 11.1 g), 4-(2-bromo-ethyl)-piperidine-l- carboxylic acid tert-butyl ester (68.4 mmol, 20 g) and Cs2CO3 (136.9 mmol, 44.6 g) in DMF (100 mL) was stirred at room temperature for 12 h. The reaction mixture was filtered to remove Cs2CO3 and the filtrate was diluted with CHCl3 (250 mL) and washed with water (2 x 200 mL) and brine (200 mL), organic layer was dried over Na2SO4, filtered and evaporated under vacuum to afford a 9: 1 mixture of N-9 and N-3 isomers (19.2 g, 82%) LC-MS [M+H]+ 347.1. This product was used for the next step without further purifications.
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;
[0132] A mixture of adenine (82.1 mmol, 11.1 g), 4-(2-bromo-ethyl)-piperidine-l-carboxylic acid tert-butyl ester (68.4 mmol, 20 g) and Cs2C03 (136.9 mmol, 44.6 g) in DMF (100 mL) was stirred at room temperature for 12 h. The reaction mixture was filtered to remove Cs2C03 and the filtrate was diluted with CHC13 (250 mL) and washed with water (2 x 200 mL) and brine (200 mL), organic layer was dried over Na2S04, filtered and evaporated under vacuum to afford a 9: 1 mixture ofN-9 and N-3 isomers (19.2 g, 82%) LC-MS [M+H]+ 347.1. This product was used for the next step without further purifications.
70 ml of DMF was charged into the reaction flask, 13.5 g of adenine and 0.2 g of NaOH were added with stirring, and the mixture was stirred for 10 to 15 minutes. 12.2 g of (R)-propylene carbonate was charged and heated. Sampling HPLC detection, cooling. Put the magnesium di-tert-butoxide, heating up. A mixture of 51.5 g of diethyl (tosyloxy)methylphosphonate and 35 ml of DMF was added dropwise. Insulation. The reaction was followed by TLC, the reaction was finished, cooled, and the pH was adjusted with glacial acetic acid. DMF was removed under reduced pressure, concentrated, and water and methylene chloride were added. The mixture was stirred and allowed to stand. The aqueous layer was extracted twice with methylene chloride. The organic phases were combined and the solvent was removed under reduced pressure to give a pale yellow oily liquid. Put 200ml of ethyl acetate, stir the temperature. Heated to 70-75 C, put 21g citric acid, reflux insulation 1h. Cooling precipitation, slow down to 0-5 . Insulation 2-3h. Suction, leaching, wet goods 65-75 C vacuum degree of -0.08KPa ~ -0.1KPa vacuum drying 12 hours or more, to give 53.5 g of R-9-[2-(diethoxyphosphorylmethoxy)propyl]adenine citrate. HPLC purity of 98%, the PXRD pattern shown in Figure 1, HPLC spectrum shown in Figure 2.
With dmap; In tetrahydrofuran; at 20℃; for 5h;Inert atmosphere;
To a solution of adenine (1.35 g, 10 mmol) and DMAP (122 mg, 1 mmol) in THF (50 mL) under argon was added Boc2O (9.38 g, 43 mmol). The reaction was stirred 5 h at room temperature. After removal of the solvent, EtOAc (400 mL) was added and the solution was washed with HCl 1 N (30 mL) and then with NaCl (3 * 100 mL). After drying over Na2SO4, filtration and removal of the solvents under reduced pressure, the residue was dissolved in methanol (100 mL) and NaHCO3 sat. (45 mL). The reaction was then stirred for 1h30 at 50 C and after removal of the solvent, water (100 mL) was added. The aqueous phase was then extracted with CHCl3 (2 * 300 mL) and, after drying over Na2SO4, the solvent was removed under reduced pressure. The resulting crude product was purified by flash chromatography (cyclohexane/AcOEt, 10:90) to afford compound 30 (2.44 g, 73%) as a white solid. 1H NMR (DMSO-d6) delta: 13.69 (s, 1H, NH), 8.80 (s, 1H, H-2), 8.63 (s, 1H, H-8), 1.36 (s, 18H, C(CH3)3) ppm.
Aliphatic acid (0.015 mol) was dissolved/suspended in THF/MeCN (~20 mL), Nhydroxysuccinamide(1.8 g, 0.015 mol) and N,N?-dicyclohexylcarbodiimide (3.3 g, 0.015mol) were added to the solution and stirred at rt overnight. The reaction mixture was cooled tobelow 0 C for 1 h before filtering, the filtrate was concentrated in vacuo to give the Nhydroxysuccinamideester as white solid. The reaction was carried out using hexanoic-,octanoic-, or decanoic acid to give the respective N-hydroxysuccinamide ester, with 80-85%yield. The crude product was used in the next step without purification.Adenine (1.9 g, 0.014 mol), N-hydroxysuccinamide ester (3.0 g, 0.014 mol) andK2CO3 (9.6 g, 0.074 mol) were dissolved/suspended in MeCN (~20 mL) and refluxedovernight. The reaction mixture was cooled to rt, quenched with water (10 mL) and extractedwith CHCl3 (3 × 15 mL), the organic layer was washed with water, brine and dried overanhydrous MgSO4, which was filtered out and the filtrate concentrated in vacuo to obtainwhite amorphous solid. The crude product was purified using a normal phase silica column(100% CHCl3 - 10% MeOH/CHCl3), to give 6N-acyl adenine. The reaction was carried outusing N-hydroxysuccinamide ester hexanoic acid, -octanoic acid, or -decanoic acid to give6N-hexanoyl adenine (1c), 6N-octanoyl adenine (1d) or 6N-decanoyl adenine (1e),respectively.
N<SUP>6</SUP>-(2,5-dimethoxybenzoyl)adenine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
21%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 130℃; for 10h;Inert atmosphere;
General procedure: The appropriate benzoic acid (1.2equiv), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.2equiv) and 4-(dimethylamino)pyridine (1.2equiv) were added to a suspension of adenine (1.0equiv) in anhydrous DMF (0.6M), and the mixture was stirred for 10h at 130C. The resulting mixture was diluted with water and extracted with AcOEt. The combined organic layer was washed with brine and dried over Na2SO4. After removal of the solvent, the residue was purified by silica gel column chromatography (MeOH/CHCl3) to afford the product.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl acetamide; at 100 - 130℃;
General procedure: Benzoic acid (1.0 eq) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.2 eq) were added to a suspension of adenine (1.0 eq) in anhydrous N-dimethylacetamide (DMA), and the mixture was stirred at 100-130C. After completion of the reaction, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (MeOH-CHCl3) and by washing with AcOEt and/or CH2Cl2-hexane (1 : 1 or 1 : 0) to afford the product.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 100 - 130℃;Inert atmosphere;
General procedure: The appropriate benzoic acid (1.0equiv) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.2equiv) were added to a suspension of adenine (1.0equiv) in anhydrous DMF (0.6M), and the mixture was stirred at 100-130C. After completion of the reaction, the solvent was removed under reduced pressure. The residue was then purified by silica gel column chromatography (MeOH/CHCl3) and by washing with CH2Cl2/hexane (1:1 or 1:0) to afford the product.
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 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl acetamide; at 100 - 130℃;
General procedure: Benzoic acid (1.0 eq) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.2 eq) were added to a suspension of adenine (1.0 eq) in anhydrous N-dimethylacetamide (DMA), and the mixture was stirred at 100-130C. After completion of the reaction, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (MeOH-CHCl3) and by washing with AcOEt and/or CH2Cl2-hexane (1 : 1 or 1 : 0) to afford the product.
Step 1: The crude R-9- (2-hydroxypropyl) adenine was obtained100 g of adenine (0.74 mol) and 2.35 g (0.058 mol) of sodium hydroxide were added to 500 mlAnd stirred at room temperature for 20 minutes. 96.5 g (0.946 mol) of R-propylene carbonate was added and the temperature was raised to 120-130 C to maintain the temperature of the reaction mixtureShould be 16h;After the completion of the reaction by HPLC, the solution of R-9- (2-hydroxypropyl) adenine which had been reacted was distilled off under reduced pressure for 70 ~80% of the DMF solvent, adding 300ml toluene, stirring evenly, 0 degrees heat 2h, filtration, drying, in the R-9- (2-hydroxypropyl)The crude product of adenine was 136 g, the crude yield was 95.7%, the purity was 90.8%, and the isomer was 8.0%.Step two: packed column, pretreatmentA 150 g of PRP-6A resin was weighed, poured into a glass column, rinsed three times with ethanol, and the column was compactedNo bubbles, the resin height of 28cm, the cylinder uniform, and then rinse with ethyl acetate 3 times, and finally replaced with ethanol, ethyl acetateTo the test without ethyl acetate so far, the column installed backup.Step 3: LoadingThe crude R-9- (2-hydroxypropyl) adenine 6g dissolved in a small amount of water 20ml, into the PRP-6A resin chromatography column,To the sample solution completely adsorbed to the resin column for the sample is completed.Step 4: Elution80% ethanol as the eluant, pour into the resin column, with air pump pressure elution, flow controlAt 15 ml / min, the eluent was received in 100 ml portions of the receiver bottle, and the content of the product in each bottle was detected by HPLC.Step 5: ConcentrationThe R-9- (2-hydroxypropyl) adenine and the isomer were collected together under vacuum conditions with a purity of more than 99%Concentrated to dry, distilled ethanol water recovery applied to get more than 99% purity of R-9- (2-hydroxypropyl) adenine white crystalline powderAnd 4.7 g of isomer having a purity of more than 99%, and the chromatographic separation yield was 92.9% of the product and 97.9% of the isomer.Step 6: Wash the columnRinse the column with 90% ethanol in water until no liquid is detected. This indicates that the PRP-6A resin column has been flushedClean, you can continue to use the next time.Step 6: Repeat steps 3 through 6 to cycle through the column 6 timesThe results are shown in Table 1 below:Note: In Table 1 above, the chromatographic separation results were obtained in the longitudinal direction for six times. The yield was chromatographic yield,HPLC area integral purity.
With sodium carbonate; In N,N-dimethyl-formamide; at 95℃; for 6h;
Addition of adenine (200.00 g), sodium carbonate (7.80 g) and DMF (100 ml) was carried out in a dry three-necked flask at room temperature (R) -propylene oxide (150.50 g) was slowly added, followed by reaction at 95 C for 6 h. The reaction was cooled to room temperature and toluene (2000 ml) was slowly added. After the addition, the mixture was stirred at 0 C Filtered and the filter cake was washed with n-hexane and dried in vacuo to afford 197.20g (69% yield) (2R)-1-(6-amino-9H-purin-9-yl)propan-2-ol (II)
15 mL of 98% concentrated sulfuric acid was added to the <strong>[118-70-7]4,5,6-triaminopyrimidine</strong> solution obtained in the previous step,Heated to 120 C,Insulation 0.5h.After cooling,filter,Filter cake with water recrystallization,drying,To give 68.5 g of white solid adenine,The overall yield was 50.4% (based on malononitrile). The cyclization compound used was changed to 1 L of triethyl orthoformate, and the other conditions were the same as those of the examplesStep 6. 75.4 g of white solid adenine was obtained in a total yield of 55.4% (based on malononitrile).
15 mL of 98% concentrated sulfuric acid was added to the <strong>[118-70-7]4,5,6-triaminopyrimidine</strong> solution obtained in the previous step,Heated to 120 C,Insulation 0.5h.After cooling,filter,Filter cake with water recrystallization,drying,To give 68.5 g of white solid adenine, The overall yield was 50.4% (based on malononitrile). The cyclization compound used was changed to formic acid 0.8 L, and the other conditions were the same as those of the examplesStep 6.To give 67.3 g of white solid adenine in a total yield of 49.5% (based on malononitrile).
15 mL of 98% concentrated sulfuric acid was added to the <strong>[118-70-7]4,5,6-triaminopyrimidine</strong> solution obtained in the previous step,Heated to 120 C,Insulation 0.5h.After cooling,filter,Filter cake with water recrystallization,drying,To give 68.5 g of white solid adenine,The overall yield was 50.4% (based on malononitrile). The cyclization compound used was changed to 1 L of trimethyl orthoformate, with the other conditions being the same as Example step 6.To give 72.4 g of white solid adenine in a total yield of 53.2% (based on malononitrile).
<strong>[118-70-7]4,5,6-triaminopyrimidine</strong> obtained in the previous step was added to 0.8 L formamide, 20 mL of 96% concentrated sulfuric acid was added and heated at 150 C for 3 h.cool down.The filter cake was a crude adenine and was recrystallized from water to give 69.5 g of white solid adenine in a total yield of 51.1% (in terms of malononitrile).
96 mg of zoledronic acid was ground with 65 mg of adenine and 60 LL of water was added to the solid mixture. The solids gathered after grinding were stored in screw cap vials for subsequent analysis. The material was characterized by PXRD and FTIR corresponding to FIG. 13 and FIG. 14, respectively.
N6-[(3-methylthiophen-2-yl)carbonyl]adenine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
24%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl acetamide; at 110℃;
General procedure: Heteroaryl carboxylic acid (1.0eq) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.2 eq) were added to a suspension of adenine (1.0 eq) in anhydrous DMA, and the mixture was stirred at 110 C. Aftercompletion of the reaction, the solvent was removed under reduced pressure. The residue was purified bysilica gel column chromatography (MeOH/CHCl3) and by washing with CH2Cl2/hexane (2:1 or 1:1) toafford the product. Several by-products arising from EDCI and adenine (but not from carboxylic acid)existed in the crude materials. Therefore, we set up column chromatography several times for eachproducts
N6-[(3-chlorothiophen-2-yl)carbonyl]adenine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl acetamide; at 110℃;
General procedure: Heteroaryl carboxylic acid (1.0eq) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.2 eq) were added to a suspension of adenine (1.0 eq) in anhydrous DMA, and the mixture was stirred at 110 °C. Aftercompletion of the reaction, the solvent was removed under reduced pressure. The residue was purified bysilica gel column chromatography (MeOH/CHCl3) and by washing with CH2Cl2/hexane (2:1 or 1:1) toafford the product. Several by-products arising from EDCI and adenine (but not from carboxylic acid)existed in the crude materials. Therefore, we set up column chromatography several times for eachproducts
N6-[(3-bromothiophen-2-yl)carbonyl]adenine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
9%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl acetamide; at 110℃;
General procedure: Heteroaryl carboxylic acid (1.0eq) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.2 eq) were added to a suspension of adenine (1.0 eq) in anhydrous DMA, and the mixture was stirred at 110 C. Aftercompletion of the reaction, the solvent was removed under reduced pressure. The residue was purified bysilica gel column chromatography (MeOH/CHCl3) and by washing with CH2Cl2/hexane (2:1 or 1:1) toafford the product. Several by-products arising from EDCI and adenine (but not from carboxylic acid)existed in the crude materials. Therefore, we set up column chromatography several times for eachproducts
With sodium hydroxide; In N,N-dimethyl-formamide; at 90℃;Reflux;
Adenine (5.50 g, 0.04 mol), sodium hydroxide powder (0.12 g, 0.003 mol) was added to a 50 mL three-necked flask, add N,N-dimethylformamide (25 mL). Under magnetic stirring, add R-propylene carbonate (5.70 g, 0.056 mol). Reflux ends. Cool to 90 deg.C. Afterwards, drop toluene (30 mL). Precipitate out solid, crystallized from 0-5 C in an ice bath, filtered and dried. The crude product was passed through CH2Cl2-MeOH (4: 1) to give the compound of formula (Ia) (R)-3-(2'-hydroxypropyl)adenine.
With Selectfluor; riboflavin; In water; acetonitrile; for 3h;Inert atmosphere; UV-irradiation;
demethylation of N6-methyladenine by using vitamin B2 as a photosensitizer under 470nm wavelength blue light and Selectfluor: and then into the reaction tube added the N6-methyladenine (0.2mmol, 29.8mg), Selectfluor (0.44mmol, 155.8mg), Vitamin B2 (0.2mmol, 7.5 mg), under nitrogen protection added 4 ml of H20 / CH3CN (1/1) solution, 470nm wavelength of blue light, stirring 3 hours, add the appropriate amount of sodium bicarbonate to the reaction solution at pH 7, spin dry liquid, after column chromatography (n-BuOH/H2O/MeOH=4/1/1) separation obtained adenine 19mg, yield is 71%.
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