* 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:
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[2] Journal of Polymer Science, Part A: Polymer Chemistry, 2015, vol. 53, # 9, p. 1151 - 1160
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[5] American Chemical Journal, 1903, vol. 29, p. 496[6] American Chemical Journal, 1904, vol. 31, p. 596
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2
[ 32830-01-6 ]
[ 14631-20-0 ]
[ 84856-79-1 ]
[ 58538-06-0 ]
Reference:
[1] Collection of Czechoslovak Chemical Communications, 1982, vol. 47, # 11, p. 2961 - 2968
With pyridine; dmap; In toluene; at 25 - 55℃; for 7h;
EXAMPLE 1PREPARATION OF N-ACETYLCYTOSINETo a suspension of cytosine (200 g, 1 .80 mol) in toluene (600 ml) at RT (25-3O0C), pyridine (216 g, 2.73 mol) and DMAP ( 1.0 g) was added. Acetic anhydride (217 g, 2.13 mol) was diluted with toluene (350 ml) and added slowly in ~60 min at 25- 45C. After addition, the reaction mass was heated to 50-550C and continued stirring for 6 h to complete the reaction (checked by TLC). Reaction mass was cooled to 25-280C and product was filtered and washed with toluene (350 ml). Further, product was washed with water (2 x 300 ml). Product was dried at 60-650C under reduced pressure to give title compound. Yield: 254 g1H NMR(DMSO-d6): delta 2.08 (s, 3H, CH3), 7.08-7.10, (d, I H, CH-cytosine), 7.79- 7.81(^, I H, CH-cytosine), 10.75(broad singlet, I H, NH), 1 1 .50(broad singlet, I H, NH).
With pyridine;dmap; In toluene; at 25 - 55℃; for 7h;
EXAMPLE 1 Preparation of N-Acetylcytosine To a suspension of cytosine (200 g, 1.80 mol) in toluene (600 ml) at RT (25-30 C.), pyridine (216 g, 2.73 mol) and DMAP (1.0 g) was added. Acetic anhydride (217 g, 2.13 mol) was diluted with toluene (350 ml) and added slowly in ~60 min at 25-45 C. After addition, the reaction mass was heated to 50-55 C. and continued stirring for 6 h to complete the reaction (checked by TLC). Reaction mass was cooled to 25-28 C. and product was filtered and washed with toluene (350 ml). Further, product was washed with water (2*300 ml). Product was dried at 60-65 C. under reduced pressure to give title compound.
In a 5 lit three-necked round bottom flask fitted with a stirrer, condenser and a stopper, acetyl cytosine 97.36gms, 1,2 dichloroethane 21it, hexamethyl disilazane, 169ml and trimethyl silyl chloride, 5moi, were charged and the reaction mixture was heated to reflux under stirring. The reaction mixture slowly attained clarity and from that point the mixture was stirred at reflux for another 3 hours. Then dichloroethane was completely distilled off and fresh dichloroethane, 1250ml, was charged into the flask and the reaction mixture was cooled to 20 C to 25 C. The reaction system was maintained under nitrogen atmosphere and trimethyl silyl trifluoromethane sulfonate, 113ml, was added. Then 2-deoxy-2, 2-difluoro-D-ribofuranose-3, 5-dibenzoate, -1-methane sulfonate, 100gms, was also added into the flask. The reaction mixture was heated to 70 C to 75 C and maintained for 12-14 hours. Subsequently the reaction mixture was stirred under reflux for 2 hours. The progress of the reaction was checked by TLC (dichloromethane : methanol 9: 1). The reaction mixture was cooled to 20 C to 25 C and 5% aqueous hydrochloric. acid, 600ml, was added dropwise in about 30minutes. After the addition, the reaction mixture was stirred for 15minutes and allowed the layers to separate. The aqueous layer was washed with dichloroethane 2000ml and the combined dichloroethane extract was washed with a saturated solution of sodium chloride, 300moi. Then the organic layer was separated and dried with anhydrous sodium sulphate. The dichloroethane solution was filtered and concentrated under reduced pressure at 50 C. The residue was dissolved in 1. 5lit methanol and cooled to about 0 C to 5 C. Ammonia gas was bubbled into the methanolic solution for about 8 hours. Then the solution was brought to about 20 C to 25 C and ammonia gas was bubbled for further 8 hours. The reaction was checked by TLC for completion. The methanolic solution was treated with carbon, 15gms and filtered. The filtrate was concentrated under reduced pressure at 45 C. The residue was dissolved in about 400moi water and the aqueous solution was washed first ethyl acetate, 100ml and then with hexane, 100ml. The ethyl acetate and hexane extracts were separately washed with 50ml each of water and the water extracts were combined with the main aqueous solution. The aqueous extract was stirred with carbon, 10gms, filtered through a bed of hyflow and the hyflow bed was washed with water, 50ml. The aqueous solution was then concentrated. The residue was dissolved in 1500m1 isopropyl alcohol and then the solution was subjected to distillation. The addition of isopropyl alcohol and distillation was repeated two more times by adding 750mut of alcohol each time. Finally isopropyl alcohol, 700ml, was added to the residue and the solution was warmed to about 70 C. To the warm aqueous isopropyl alcohol, concentrated hydrochloric acid, 75ml, was added drop wise in about 30min. The solution was stirred at 70 C to 75 C for about 30min, then cooled to RT and stirred at RT for 12 hours. Later the solution was cooled to 0 C to 5 C, stirred at that temperature for 3 hours, the solid formed was filtered, washed with acetone and dried to give gm of product, which was >95% rich in the p-anomer and showed [a] D25 = +46 (C= 1. 0 D 20)
1-(2'-deoxy-2',2'-difluoro-3',5'-di-O-benzoyl-D-ribofuranosyl)-4-acetamidopyridin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With ammonium sulfate; trimethylsilyl trifluoromethanesulfonate; 1,1,1,3,3,3-hexamethyl-disilazane;Product distribution / selectivity;
Following the process disclosed in U.S. Pat. No. 4,965,374 and using the following reagents: 88.7 g of acetyl cytosine (0.579 mole), 280 g of hexamethyldisilazane (1.735 moles), 4.4 g of ammonium sulfate (0.033 mole), 116 g of trimethylsilyl triflate (0.522 mole), 115 g of mesylate obtained according to Example 4 (0.202 mole calculated), 135 g of a thick oil were obtained, which contained 52.1 g of protected Gemcitabine (determined by HPLC).
With ammonium sulfate; trimethylsilyl trifluoromethanesulfonate; 1,1,1,3,3,3-hexamethyl-disilazane;Product distribution / selectivity;
Following the process disclosed in US 4,965,374 and using the following reagents: 83.2 g of acetyl cytosine (0.543 mole), 333 g of hexamethyldisilazane (2.063 moles), 3.3 g of ammonium sulfate (0.025 mole), 132 g of trimethylsilyl triflate (0.594 mole), 115 g of mesylate (obtained according to Example 4) (0.202 mole calculated), 118 g of a thick oil were obtained
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 50℃; for 0.5h; Microwave irradiation;
Coupling of the Nucleobase; General Procedure
General procedure: To a solution/suspension of cyclopentenol 4 (1 equiv), PPh3 (1.5 equiv) and the appropriate nucleobase (1.5 equiv) in MeCN was added DIAD (1.5 equiv) dropwise. The reaction mixture was irradiated at 50 °C (100 W) until full conversion was achieved. The nucleobases were deprotected or further treated as indicated. Pyrimidines: The solvent was removed under reduced pressure and the resulting residue was dissolved in 1 M NaOH in MeOH and stirred at room temperature overnight. The reaction was neutralized with 1 M HCl and concentrated in vacuo. The crude product was purified as indicated. Purines: The solvent was removed under reduced pressure and the residue was purified as indicated. All coupling compounds contain impurities from DIAD due to difficult purification.