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CAS No. : | 161599-46-8 | MDL No. : | MFCD07369302 |
Formula : | C13H16FN3O6 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NWJBWNIUGNXJGO-RPULLILYSA-N |
M.W : | 329.28 | Pubchem ID : | 11809635 |
Synonyms : |
2',3'-Di-O-acetyl-5'-deoxy-5-fluoro-D-cytidine
|
Chemical Name : | (2R,3R,4R,5R)-2-(4-Amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyltetrahydrofuran-3,4-diyl diacetate |
Num. heavy atoms : | 23 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.54 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 8.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 74.12 |
TPSA : | 122.74 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -8.78 cm/s |
Log Po/w (iLOGP) : | 1.26 |
Log Po/w (XLOGP3) : | -0.67 |
Log Po/w (WLOGP) : | -0.15 |
Log Po/w (MLOGP) : | -0.47 |
Log Po/w (SILICOS-IT) : | -0.38 |
Consensus Log Po/w : | -0.08 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.32 |
Solubility : | 15.7 mg/ml ; 0.0476 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.43 |
Solubility : | 12.1 mg/ml ; 0.0369 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.1 |
Solubility : | 26.3 mg/ml ; 0.08 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 4.32 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With ammonia In methanol; water at 45 - 55℃; | Example 10 Preparation of 5'-Deoxy-5-fluorocytidine from 2',3'-di-O-acetyl-5'deoxy-5-fluorocytidine 30.0 g of 2',3'-di-O-acetyl-5'deoxy-5-fluorocytidine were dissolved in 180 ml of methanol, 10.5 ml of 25percent ammonia in water solution were added and the solution was heated at 45-55° C. for 2-3 hours. The solution was concentrated at atmospheric pressure until 90 ml, then 210 ml of toluene were added and the mixture was distilled at atmospheric pressure until internal temperature of 75-85° C. (in these conditions the azeotrope toluene/methanol has a boiling point of 63.8° C.). 30 ml of acetonitrile were added and the mixture was stirred at 70-80° C. for 30 minutes, then 60 ml of toluene were added. At the end the suspension was cooled to 5° C. for 3 hours. The solid was filtered and dried under vacuum at 60° C. for 12 hours. Yield: 21.0 g equivalent to 95percent mol/mol. Purity: 99.70percent (A percent) by HPLC. |
80% | at 20 - 50℃; for 2 h; Inert atmosphere | To a stirred solution of (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-l(2H)-yl)-5- methyltetrahydrofuran-3,4-diyl-diacetate (20 g, 60.77 mmol) in MeOH (140 mL) was added Diethyl amine (0.64 mL, 6.07 mmol) at RT under nitrogen atmosphere and stirred the reaction mixture at 50 °C for 2 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with Toluene (240 mL) at 50 °C, allowed to stir the reaction mixture at RT for 30 min and the solid formed was filtered, washed with Toluene (10 mL) followed by Hexane (10 mL), dried under vacuum to afford 4-amino-l-((2R,3R,4S,5R)-3,4-dihydroxy-5- methyltetrahydrofuran-2-yl)-5-fluoropyrimidin-2(lH)-one (12 g, 80percent yield) as off white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.2% | With potassium phosphate In dichloromethane; isopropyl alcohol at 0 - 25℃; for 4 h; Inert atmosphere | The compound of formula IV (100 g, 0.30 mol), K3PO4 (95.5 g, 0.45 mol), solvent (800 mL isopropanol: dichloromethane = 1.0:2.0, volume ratio) into the reaction flask, nitrogen protection, cooled to 0-10 ° C, was added dropwise under stirring n-pentyl chloroformate (54.2g, 0.36 mol) solution (200 mL, isopropanol: dichloromethane = 1.0: 2.0, volume ratio). The temperature of the dropping process was controlled at 0-10 ° C. and completed in 1 h. After the dropping, the temperature was naturally raised to 20-25 ° C and reacted for 4 hours. The reaction was completed until the raw material was completely detected. 400 mL of purified water was added to the feed solution, stirred for half an hour and then separated. The organic layer was washed once with 400 mL of hydrochloric acid solution (1 mol / L), the combined aqueous layers were extracted with 200 mL of dichloromethane, and the organic layers were combined. Washed once with 400 mL saturated brine, once with 400 mL of 5percent aqueous sodium bicarbonate, once with 400 mL of saturated brine and dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated to dryness under reduced pressure at 40 ° C. The residue was beaten with 80 mL of ether, filtered and dried to give a white solid (125.3 g, 0.28 mol, 94.2percent). HPLC content was 99.09percent. |
93% | With pyridine In dichloromethane at 0℃; for 1 h; | 2 ', 3'-di-O-acetyl-5'-deoxy-5-fluorocytidine (8)48.6 mmol) was dissolved in dichloromethane (160 ml)Pyridine (16 ml) was added, cooled to 0 ° C, n-amyl chloroformate (9) (16 g) was added, stirred at 0 ° C for 1 h,The organic phase was washed with water (50 ml), dried over anhydrous magnesium sulfate, evaporated to dryness under reduced pressure, and the residue was taken up by the addition of methylene chloride (100 ml). The residue was extracted with dichloromethane Ethyl acetate (16 ml) was added, and petroleum ether (160 ml) was added dropwise. The mixture was stirred until the solid precipitated completely and filtrated to give a solid compound of 2 ', 3'-di-O-acetyl-5'-deoxy- - [(pentyloxy) carbonyl] cytidine (10) (20 g, 93percent). |
90.6% | With dmap; potassium carbonate In dichloromethane at 5℃; for 0.75 h; | In an ice bath, the temperature is controlled at 5°C.Slowly dropping n-amyl chloroformate (21.5 mmol) into K2CO3 (21.7 mmol),Dimethylaminopyridine (2.46 mmol)The reaction was incubated for 45 min with a solution of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine (14.5 mmol) in dichloromethane (30 mL).The mixture was filtered, and the filtrate was washed successively with 0.2 M hydrochloric acid (10 mL), water (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate.The solvent was removed under reduced pressure to give a white solid (6.1 g, yield 90.6percent). |
2.55 g | With pyridine In dichloromethaneReflux | Place 2.00 g (6 mmol; 1.0 eq.) of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytydine and 12 mL ofdichloromethane in a 100 mL 3-neck round bottom flask equipped with a dropping funnel, reflux condenser, and magnetic stirring bar. After solid dissolution, 0.7 mL (9 mmol; 1.5 eq.) of pyridine was added. Next, 1.1 mL of n-pentyl chloroformate was placed in the dropping funnel and addeddrop-by-drop to the vigorously stirred starting solution, while maintaining the reacting mixture under soft reflux. When the n-pentyl chloroformate addition was completed, the solution was stirred for 1 h and then cooled to room temperature, poured into the separation funnel, and washed with 10 mLof aq. CuSO4, 10 mL of brine, and 10 mL of water, then dried over MgSO4. The clear solution was evaporated twice from 5 mL of the toluene solution giving 2.55 g of 1 as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.6% | at 20℃; for 4 h; | To a 1000 ml reaction flask, 600 ml of methylene chloride, 84.8 g of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine, 48.6 g of carbonyldiimidazole, and 25.2 g of n-pentanol were charged. The reaction was carried out at 20° C. for 4 hours. The end of the reaction was monitored by TLC (developer, dichloromethane:methanol=20:1). 220 ml of 10percent hydrochloric acid solution was added to the reaction mixture. The organic layer was separated, washed with 220 ml of purified water, and separated. The organic layer was controlled at a bath temperature of 60° C., and the organic layer was concentrated under reduced pressure to dryness. To the residue was added 160 ml of ethyl acetate and 320 ml of n-hexane was stirred for 30 minutes. The temperature was lowered to 10° C. or lower, and suction filtration was started to obtain a white solid. °C, 104.8 g of 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N4-n-pentyloxycarbonyl cytidine was dried, yielding 91.6percent, purity 99.7percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.2% | With potassium phosphate; In dichloromethane; isopropyl alcohol; at 0 - 25℃; for 4h;Inert atmosphere; | The compound of formula IV (100 g, 0.30 mol), K3PO4 (95.5 g, 0.45 mol), solvent (800 mL isopropanol: dichloromethane = 1.0:2.0, volume ratio) into the reaction flask, nitrogen protection, cooled to 0-10 C, was added dropwise under stirring n-pentyl chloroformate (54.2g, 0.36 mol) solution (200 mL, isopropanol: dichloromethane = 1.0: 2.0, volume ratio). The temperature of the dropping process was controlled at 0-10 C. and completed in 1 h. After the dropping, the temperature was naturally raised to 20-25 C and reacted for 4 hours. The reaction was completed until the raw material was completely detected. 400 mL of purified water was added to the feed solution, stirred for half an hour and then separated. The organic layer was washed once with 400 mL of hydrochloric acid solution (1 mol / L), the combined aqueous layers were extracted with 200 mL of dichloromethane, and the organic layers were combined. Washed once with 400 mL saturated brine, once with 400 mL of 5% aqueous sodium bicarbonate, once with 400 mL of saturated brine and dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated to dryness under reduced pressure at 40 C. The residue was beaten with 80 mL of ether, filtered and dried to give a white solid (125.3 g, 0.28 mol, 94.2%). HPLC content was 99.09%. |
93% | With pyridine; In dichloromethane; at 0℃; for 1h; | 2 ', 3'-di-O-acetyl-5'-deoxy-5-fluorocytidine (8)48.6 mmol) was dissolved in dichloromethane (160 ml)Pyridine (16 ml) was added, cooled to 0 C, n-amyl chloroformate (9) (16 g) was added, stirred at 0 C for 1 h,The organic phase was washed with water (50 ml), dried over anhydrous magnesium sulfate, evaporated to dryness under reduced pressure, and the residue was taken up by the addition of methylene chloride (100 ml). The residue was extracted with dichloromethane Ethyl acetate (16 ml) was added, and petroleum ether (160 ml) was added dropwise. The mixture was stirred until the solid precipitated completely and filtrated to give a solid compound of 2 ', 3'-di-O-acetyl-5'-deoxy- - [(pentyloxy) carbonyl] cytidine (10) (20 g, 93%). |
90.6% | With dmap; potassium carbonate; In dichloromethane; at 5℃; for 0.75h; | In an ice bath, the temperature is controlled at 5C.Slowly dropping n-amyl chloroformate (21.5 mmol) into K2CO3 (21.7 mmol),Dimethylaminopyridine (2.46 mmol)The reaction was incubated for 45 min with a solution of <strong>[161599-46-8]2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine</strong> (14.5 mmol) in dichloromethane (30 mL).The mixture was filtered, and the filtrate was washed successively with 0.2 M hydrochloric acid (10 mL), water (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate.The solvent was removed under reduced pressure to give a white solid (6.1 g, yield 90.6%). |
With pyridine; at -15 - 5℃; for 4.5 - 6.5h; | EXAMPLE 9: PROCESS FOR PREPARING CAPECITABINE OF FORMULA I5'-deoxy-2',3'-O-acetyl- 5-fluorocytidine (33 kg) and dichloromethane (1 15.5 lit) were charged into the reactor at room temperature and stirred for 10 minutes. Pyridine (16.5 lit) was charged to the obtained reaction mass and applied nitrogen gas to the reactor followed by cooling to -10 to -15 0C by using methylene glycol solution into the jacket of the reactor, n-pentyl chloroformate (33 lit) was added slowly to the reaction mixture for a period of 3 to 5 hours at temperature less than 5 0C and stirred for 1 hour 30 minutes. After completion of the reaction, methanol (2 lit) was charged to the reaction mixture at temperature between 0 to -5 0C and stirred the reaction mixture for 15 minutes. Dichloromethane (132 lit) and demineralized water (66 lit) were charged to the reaction mass and stirred for 5 minutes. Two layers were separated from the obtained solution. The obtained organic layer was dried with sodium sulphate (14.5 kg)and then concentrated at temperature less than 40 0C under vacuum not less than 650 mmHg till no more solvent distill off followed by applying nitrogen gas to remove the pyridine traces. The reaction crude was cooled to the temperature 30 to 35 0C and released the vacuum with nitrogen.Purity: 96.4 % by HPLC. | |
With pyridine; at 0 - 20℃; for 0.583333h;Product distribution / selectivity; | 0.8 g of 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-cytidine (Example 1) was dissolved in 2 ml dry Cl2 and 0.4 ml of pyridine was added. The mixture was cooled on an ice-water bath. 0.5 ml of n-pentylchloroformate was added dropwise in 5 minutes. The clear colorless solution was allowed to warm up to room temperature upon stirring. A suspension was formed. After 30 minutes, the reaction mixture was concentrated at reduced pressure. 5 ml of diethylether was added to the residue. The resulting suspension was filtered. The filtrate was concentrated under reduced pressure. Yield: 1.3 g (colorless oil). | |
With pyridine; In dichloromethane; at 0 - 4℃; for 0.666667h;Product distribution / selectivity; | 2.58 g of 5-fluorocytosine and 5.93 g of 5-deoxy-1,2,3,-tri-O-acetyl-beta-D-furanoside were added to 33 ml of dichloromethane, the mixture was cooled to 0-4 C., stirred and 6.25 g of stannic chloride was added dropwise in about 10 minutes. The mixture was allowed to heat up to room temperature and stirred for about 2.5 hours. 10.1 g of sodium bicarbonate was added. 35 ml of water was added dropwise over a period of 20 minutes. (CO2 formation) The reaction mixture was stirred overnight. About 2 g of Na2SO4 was added to the organic phase and stirred for 30 minutes. The solid was filtered off, washed with 10 ml of dichloromethane. The combined filtrates were reduced in volume to about 20 ml. by reduced pressure. To the resulting solution was added 3.9 ml of pyridine. The mixture was cooled to 0-4 C. (ice-bath). 4.9 ml n-pentylchloroformate was added dropwise. The ice-bath was removed and after 40 minutes 13 ml of methanol was added. The mixture was cooled on an ice bath. A solution of 4.68 g of NaOH in 6.5 ml of water was added dropwise in 10 minutes. Then 9.8 ml of concentrated HCl was added dropwise. After addition the pH was about 5 (pH-paper). 65 ml of dichloromethane and 13 ml water was added. The layers were mixed and allowed to separate. The organic layer was washed with 13 ml of water, dried on Na2SO4 and filtered. The filtrate was evaporated to dryness under reduced pressure. The oily residue was dissolved in 8.6 ml of ethyl acetate and 17 ml n-hexane was added. A solid was formed. After stirring overnight, the solid was isolated by filtration and washed with a mixture of 8.6 ml ethyl acetate and 17 ml n-hexane. Dried in a vacuum oven at 40 C.Yield: 4.3 g (60%), purity HPLC: 98.7% | |
With pyridine; In dichloromethane; at 0 - 20℃; for 0.5h; | 5'-Deoxy-5-fluorocytidine is dissolved in pyridine and reacted with acetic anhydride to afford diacetyl compound K. Reaction of K with n-pentylchloroformate provided diacylcapecitabine L. Hydrolysis of the acetyl groups in compound L is performed by treating the compound with aqueous NaOH for 1 h in an ice bath to give capecitabine. | |
With pyridine; In toluene; at 23 - 25℃; for 3h;Product distribution / selectivity; | Example 2Preparation of 5'-Deoxy-5-fluoro-[N4-(pentyloxy)carbonyl]-cytidine (Capecitabine)10 g of 2',3'-di-O-acetyl-5'deoxy-5-fluoro-cytidine were suspended in 60 ml of MeTHF, 4.2 ml of pyridine (1.7 equivalents) were added and the suspension was kept at 23-25 C. 6.9 ml (1.55 equivalents) of n-pentyl chloroformate were added portion wise during 2.5 hours, after -30' minutes the reaction was completed, HPLC analysis showed a purity of about 98.0% with about 1.2% of dipentyl impurity. 30 ml of water were added.The mixture was kept under stirring for 10 minutes, and then the phases were separated.Organic phase was cooled to -17 C. and 1.6 g (1.3 equivalents) of sodium hydroxide that were dissolved in 15 ml of 1:2 water/methanol mixture were added, keeping the temperature between -20 C. and -15 C.The reaction was completed in 30 minutes, HPLC analysis showed a purity of about 98% with a content of impurity A of about 0.5% and dipentyl impurities (of both protected and deprotected 5'deoxy-5-fluoro-cytidine) less than 0.5%.30 ml of salted water were added and the pH was corrected to 6-7 with dilute sulphuric acid.The phases were separated and the water phase was back-extracted with MeTHF (25 ml×2).The combined organic phases were concentrated under vacuum at T<40 C. until 30 ml of residual volume was obtained. Then, 70 ml of toluene were added and the solution was concentrated again under vacuum until 50 ml of residual volume was obtained. Additional 50 ml of toluene were added and the solution was kept at RT for 8 hours.The suspension was filtered and the solid was washed with toluene and dried under vacuum at 65 C.Yield: 9.5 g equivalent to 86%.Purity: 99.7% by HPLC. | |
With pyridine; In dichloromethane; at -5 - 20℃; | <strong>[161599-46-8]2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine</strong> of Formula III (15 g) is dissolved in dichloromethane (75 ml_) at room temperature with stirring. Pyridine (6.1 ml_) is added and the mixture is cooled to -5C to 100C. N-pentylchloroformate (10.23 ml_) is added slowly below 100C over 20 minutes and the mixture is stirred for 30 minutes at room temperature. Methanol (0.9 ml_) and water (30 ml_) are added and stirred for 15 minutes. The layers are separated and the obtained organic layer is washed with water (30 ml_). The organic layer is concentrated completely under vacuum at 40-45C and then diisopropyl ether (2*30 ml_) is charged and distilled completely, to obtain a product having 0.30% of the impurity at 1 .14 RRT.Acetonithle (6 ml_) and diisopropyl ether (75 ml_) are charged to the product and the mixture is heated to 35C, stirred for 1 hour at 35-400C, then cooled to room temperature and stirred for 1 hour. The mass is filtered and the solid is washed with diisopropyl ether (15 ml_). The solid is dried for 4 hours at 40C under vacuum, to afford 14.7 g of the title compound.Purity: 99.8%; impurity at 1 .14 RRT: 0.05% | |
With pyridine; In dichloromethane; at 5 - 10℃; | Example 2 A process for producing and purification of 2',3'-di-O-acetyl-5-deoxy-5-fluoro-N4-(pentyl-oxycarbonyl)cytidine (II) To a vessel is added of <strong>[161599-46-8]2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine</strong> (0.2 kg, 0.6 mol), methylene chloride (1.59 Kg) and pyridine (190.0 g, 2.4 mol) at 20-30 C. The mixture is cooled to below 5 C. and subsequently is added of n-pentylchloroformate (137.2 g, 0.9 mol) at below 10 C. The resulting solution is stirred at less than 10 C. for at least 0.5 hour. After completion of the reaction, water (2 Kg) is added for phase separation. The organic layer is collected and washed with water (2 kg) for three times. Then organic layer is collected and swapped with toluene (0.4 Kg) under vacuum at less than 60 C. After solvent swap, n-heptane (0.3 kg) is added to cloud point at 40-50 C. After stirring at 40-50 C. for about 1 hour, n-heptane (0.4 kg) is added and the slurry is cooled to less than 10 C. The solution keeps stirring for at least 1 hour. The resulting solid is filtered, washed with toluene/n-heptane (1:9) and dried under vacuum to afford 2',3'-di-O-acetyl-5-deoxy-5-fluoro-N4-(pentyl-oxycarbonyl)cytidine. The purity is >=99.5% and the maximum impurity is <=0.2%. Yield: 1H NMR (CDCl3, 400 MHz) delta 8.05 (d, J=6.4 Hz, 1H), 5.93 (m, 1H), 5.52 (m, 1H), 5.15 (m, 1H), 4.24 (m, 1H), 4.15 (m, 2H), 2.06 (s, 6H), 1.68 (m, 2H), 1.47 (d, J=6.4 Hz, 3H), 1.38 (m, 4H), 0.91 (m, 3H). | |
With potassium carbonate; In acetone; at 20 - 30℃;Inert atmosphere; | General procedure: To a solution of K2CO3 (0.626 g, 0.0453 mol) in acetone (80 mL) was added <strong>[161599-46-8]2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine</strong> (14 g, 0.0425 mol) in a 500 mL 4-necked RB flask fitted with magnetic bar, thermo pocket, guard tube and nitrogen inlet and stirred for 10-15 min 2-Methyl-1-butyl chloroformate first half (2.279 g, 0.0151 mol) was added through additional funnel over a period of 15-20 min at room temperature and continued to stirred for 3 h. After completion of 3 h, second half of 3-methyl-1-butyl chloroformate (1.129 g, 0.0075 mol) added at 25-30 C, progress of the reaction was monitored by TLC (ethylacetate: hexane 1:1). After completion of the reaction, the mixture was filtered and washed with 2 volumes (50 mL) of acetone. To the acetone layer 4 volumes of 10% NaOH solution added at -10 to -15 C over 2 h. After completion of the reaction indicated by TLC, the pH of the reaction mixture adjusted to 6.0 by using concentrated HCl. The acetone was distilled off completely by using rota evaporator. Thus obtained aqueous layer extracted with ethyl acetate 5 volumes (50 mL) and ethyl acetate layer reduced to 1 volume stirred for 30 min then 5 volumes of tertiary methyl butyl ether (TBME) (50 mL) was added, the obtained precipitate was stirred for 1 h at 20-25 C and 2 h at 0-5 C filtered off washed with 9:1 volumes of TBME and ethyl acetate and suck dried to obtained the crude product and it was further purified by column chromatography (1:1 hexane/EtOAc) to get the title compound. | |
With pyridine; In dichloromethane; at -15 - -5℃;Industrial scale; | Compound 2 ', 3'-di-O-acetyl-5'-deoxy-5-fluorocytidine319.76 kg (60 mol, 1 eq )was dissolved in 49.4 L of methylene chloride (1 kg: 2.5 L), pyridine was added 9.66 L (120 mol, 2 eq ),to be within the reactor temperature dropped to -15OC or less, The dropwise addition of n-pentyl chloroformate was started412.17 L (84 mol, 1.4 eq ),maintained during the internal temperature not higher than -5OC.After the addition, the reaction was spontaneously recovered and the reaction was monitored completely by TLC.Add 20 L H2The organic phase was separated and washed with water (20 L * 2); the aqueous phase was back-extracted with dichloromethane (50 L * 2); the organic phase was combined and the combined organic layer was dried Dried over anhydrous sodium sulfate and the solvent removed under reduced pressure to give the product as a yellow oil. 2 ', 3'-Di-O-acetyl-5'-deoxy-5-fluoro-N - [(pentyloxy) carbonyl]5(Directly for the next step). | |
2.55 g | With pyridine; In dichloromethane;Reflux; | Place 2.00 g (6 mmol; 1.0 eq.) of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytydine and 12 mL ofdichloromethane in a 100 mL 3-neck round bottom flask equipped with a dropping funnel, reflux condenser, and magnetic stirring bar. After solid dissolution, 0.7 mL (9 mmol; 1.5 eq.) of pyridine was added. Next, 1.1 mL of n-pentyl chloroformate was placed in the dropping funnel and addeddrop-by-drop to the vigorously stirred starting solution, while maintaining the reacting mixture under soft reflux. When the n-pentyl chloroformate addition was completed, the solution was stirred for 1 h and then cooled to room temperature, poured into the separation funnel, and washed with 10 mLof aq. CuSO4, 10 mL of brine, and 10 mL of water, then dried over MgSO4. The clear solution was evaporated twice from 5 mL of the toluene solution giving 2.55 g of 1 as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Then, a solution of the trimethylsilylated 5-fluorocytosine, freshly prepared from 5-fluorocytosine (1.12 g), in dry acetonitrile (5 ml) was added at 0 C. and stirring was continued for 3 h at room temperature. The mixture was filtered, the filtrate was concentrated in vacuo, and the residue was partitioned between dichloromethane and saturated aq. sodium bicarbonate solution. The aqueous layer was extracted with CH2 Cl2 /MeOH (10:1). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography using CH2 Cl2 /MeOH (15:1) as an eluent, followed by recrystallization from isopropanol to give 1.24 g of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.12 g (64.4%) | Example 2 1.29 of 5-fluorocytosine was suspended in a solution of 16.5 ml of methylene chloride and 3.4 ml of acetonitrile. After adding 2.97 g of 5-deoxy-1,2,3-tri-0-acetyl-beta-D-ribofuranoside to the suspension, 3.91 g of anhydrous stannic chloride was dropwise added thereto in 5 minutes at room temperature. This solution was stirred at room temperature for 3 more hours, followed by subjecting the same after treatment as in Example 1. After recrystallizing the residue by adding 7.4 ml of ethanol thereto, crystals were filtered off to give 2.12 g (64.4%) of 5'-deoxy-2',3'-di-0-acetyl-5-fluorocytidine. The results of instrumental analysis of the obtained compound were identical with those of Example 1. | |
0.69 g (52.4%) | Example 3 0.52 g pf 5-fluorocytosine was suspended in a solution of 2 ml of toluene and 0.42 g of hexamethyldisilazane, and the mixture was heated at 110 C. for 3 hours. After concentrating the reaction mixture under reduced pressure, 6.6 ml of methylene chloride and 1.19 g of 5'-deoxy-1,2,3-tri-0-acetyl-beta-D-ribofuranoside were added to the residue. Then, 1.07 g of trimethylsilyl trifluoromethanesulfonate was added thereto at room temperature. After stirring the mixture at room temperature for overnight, 13 ml of saturated sodium bicarbonate was added thereto. The mixture was stirred at room temperature for 30 minutes. After separation of the organic layer, the aqueous layer was extracted with 5 ml of methylene chloride. The organic layers were combined, and washed with water. After removal of the solvent under reduced pressure, the residue was recrystallized from 6 ml of isopropanol to give 0.69 g (52.4%) of 5'-deoxy-2',3'-di-0-acetyl-5-fluorocytidine. The results of instrumental analysis of the obtained compound were identical with those of Example 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.2 g (96.4%) | Example 4 38 g of 5'-deoxy-2',3'-di-0-acetyl-5-fluorocytidine obtained according to the method of Example 1 was dissolved in 190 ml of methylene chloride, followed by addition of 14.3 g of pyridine. To this solution, was added 34.6 g of 3,4,5-trimethoxybenzoyl chloride at room temperature. After stirring at room temperature for overnight, the resulting solution was extracted with 152 ml of methylene chloride and 76 ml of water. The organic layer was separated and washed with 76 ml of 4% sodium bicarbonate solution, and the solvent was distilled under reduced pressure. The residue was recrystallized by adding 620 ml of methanol thereto to obtain 58.2 g (96.4%) of 5'-deoxy-2',3'-di-0-acetyl-5-fluoro-N4 -(3,4,5-trimethoxybenzoyl)cytidine as crystalline powder. The melting point of a product obtained by recrystallizing these crystals from ethylacetate was 130.8-133.2 C., UV Absorption Spectrum: lambda max (H2 O) nm: 314 (epsilon=16,300), 255 (epsilon=11,100), 209 (epsilon=36,800) Optical Rotation: [alpha]D(20 C.):+45 (CHCl3, C=1) 1 H-NMR (90 MHz, CDCl13): 1.48 (d J=6.4 Hz 3H) 2.10 (s, 3H), 2.12 (s, 3H), 3.92 (s, 3H) 3.93 (s, 6H) 5.98 (dd (J=4.9 Hz, 1.0 Hz), 1H), 7.48 (d, (J=5.4 Hz, 1H), 7.5 (s, 2H) |
Yield | Reaction Conditions | Operation in experiment |
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84% | With pyridine; sodium hydroxide; sodium carbonate; In methanol; ethanol; dichloromethane; | Example 28 Preparation of 5'-deoxy-5-fluoro-N4 -(neopentyloxycarbonyl)cytidine 5'-Deoxy-2',3'-di-O-acetyl-5-fluorocytidine (1.5 g) and dry pyridine (0.74 ml) were dissolved in dry dichloromethane (15 ml). To the mixture, toluene solution of neopentyl chloroformate (3 eq.) was added dropwise at 0 C., and stirred at room temperature for 1 hour. After the solvent was removed under reduced pressure, the residue was partitioned between ether and saturated aqueous solution of sodium carbonate. The organic layer was successively washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N4 (neopentyloxycarbonyl)cytidine as pale yellow oil. This crude product was dissolved in ethanol (15 ml) and cooled on ice-bath. Then 1N aqueous sodium hydroxide solution was added dropwise while maintaining the temperature below 15 C. After the addition was completed, the reaction mixture was neutralized with concentrated. hydrochloric acid at 0 C. The solution was concentrated under reduced pressure, and the concentrate was partitioned between water and a mixed solution of CH2 Cl 2 /MeOH (95:5). The aqueous layer was back-extracted with CH2 Cl2 /MeOH (95:5) ten times (20 ml each). All organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using CH2 Cl2 /MeOH (20:1) as an eluent to give 5'-deoxy-5-fluoro-N4 -(neopentyloxycarbonyl)cytidine (1.37 g: 84% yield) as amorphous powder: FAB-MS m/z 360 (MH+); 1 H-NMR (d6 -DMSO) delta0.93 (9H, s), 1.31 (3H, d,J=6.3 Hz), 3.68 (1H,q,J=5.9 Hz), 3.81 (2H, br. s), 3.87-3.92 (1H, m), 4.04-4.09 (1H, m), 5.05 (1H,d,J=5.9 Hz), 5.41 (1H, br. d, J=5.3 Hz), 5.67 (1H,dd,J=1.3, 3.6 Hz), 8.04 (1H, br. s), 10.53 (~1H, br. s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic anhydride; In pyridine; water; | (a) From 5'-deoxy-5-fluorocytidine 5'-Deoxy-5-fluorocytidine (50 mg) was dissolved in dry pyridine (1.3 ml). To the solution was added acetic anhydride (39 ml) with stirring at 0° C. The reaction mixture was stirred for 3 hours at 0° C. After removal of the solvent under reduced pressure, the residue was partitioned between ethyl acetate and ice cooled water. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=9/1 as an eluent) followed by recrystallization from isopropanol to give 37 mg of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine: 191.5°-193° C., FAB-MS m/z 330 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; isopropyl alcohol;Irradiation;G-values; | In the hypoxic environments of solid tumours, prodrugs can be reduced by one- electron processes that are inhibited in the normoxic environments of normal tissues. Radiolysis demonstrates the ability of bioreductively-activated prodrugs to release the active drug after one-electron reduction. Compounds were dissolved in an isopropanol/water mixture (50:50) at a concentration of 50muM or below. Solutions, in gas-tight syringes, were saturated with nitrous oxide before irradiation in a 60Co source at a dose rate of 3.9Gy min'1 (as determined by Fricke dosimetry: H. Fricke and EJ. Hart, "Chemical Dosimetry" in Radiation Dosimetry Vol. 2 (F.H. Attrix and W. C. Roesch. Eds.), pp 167-239. Academic Press New York, 1966.). Solutions were analyzed for released drug by HPLC. In this test example compounds of the invention produced cytotoxic nucleosides (or their ester prodrugs) efficiently with radiation chemical yields (G- value) as shown in Table 1.Table 1. Radiation chemical yields of cytotoxic nucleosides released by gamma radiolysis * rate of prodrug loss EPO <DP n="27"/>Pulse Radiolysis |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; at 0℃; for 3h; | 5'-Deoxy-5-fluorocytidine is dissolved in pyridine and reacted with acetic anhydride to afford diacetyl compound K. Reaction of K with n-pentylchloroformate provided diacylcapecitabine L. Hydrolysis of the acetyl groups in compound L is performed by treating the compound with aqueous NaOH for 1 h in an ice bath to give capecitabine. | |
With pyridine; at 0℃; for 3h; | Example 1Preparation of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine of compound 1a (according to U.S. Pat. No. 5,472,949) (a) From 5'-deoxy-5-fluorocytidine 5'-Deoxy-5-fluorocytidine (50 mg) was dissolved in dry pyridine (1.3 ml). To the solution was added acetic anhydride (39 ml) with stirring at 0° C. The reaction mixture was stirred for 3 hours at 0° C. After removal of the solvent under reduced pressure, the residue was partitioned between ethyl acetate and ice cooled water. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=9/1 as an eluent) followed by recrystallization from isopropanol to give 37 mg of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine: 191.5° C.-193° C., FAB-MS m/z 330 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With ammonia; In methanol; water; at 45 - 55℃;Product distribution / selectivity; | Example 10 Preparation of 5'-Deoxy-5-fluorocytidine from 2',3'-di-O-acetyl-5'deoxy-5-fluorocytidine 30.0 g of 2',3'-di-O-acetyl-5'deoxy-5-fluorocytidine were dissolved in 180 ml of methanol, 10.5 ml of 25percent ammonia in water solution were added and the solution was heated at 45-55° C. for 2-3 hours. The solution was concentrated at atmospheric pressure until 90 ml, then 210 ml of toluene were added and the mixture was distilled at atmospheric pressure until internal temperature of 75-85° C. (in these conditions the azeotrope toluene/methanol has a boiling point of 63.8° C.). 30 ml of acetonitrile were added and the mixture was stirred at 70-80° C. for 30 minutes, then 60 ml of toluene were added. At the end the suspension was cooled to 5° C. for 3 hours. The solid was filtered and dried under vacuum at 60° C. for 12 hours. Yield: 21.0 g equivalent to 95percent mol/mol. Purity: 99.70percent (A percent) by HPLC. |
80% | With methanol; diethylamine; at 20 - 50℃; for 2h;Inert atmosphere; | To a stirred solution of (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-l(2H)-yl)-5- methyltetrahydrofuran-3,4-diyl-diacetate (20 g, 60.77 mmol) in MeOH (140 mL) was added Diethyl amine (0.64 mL, 6.07 mmol) at RT under nitrogen atmosphere and stirred the reaction mixture at 50 °C for 2 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with Toluene (240 mL) at 50 °C, allowed to stir the reaction mixture at RT for 30 min and the solid formed was filtered, washed with Toluene (10 mL) followed by Hexane (10 mL), dried under vacuum to afford 4-amino-l-((2R,3R,4S,5R)-3,4-dihydroxy-5- methyltetrahydrofuran-2-yl)-5-fluoropyrimidin-2(lH)-one (12 g, 80percent yield) as off white solid. |
With methanol; diethylamine; at 55℃; for 2h; | Example 2 Synthesis of 5'-deoxy-5-fluorocytidine (Compound 3) Compound 2 (5 g, 15 mmol), methanol (15 mL), and diethylamine (0.15 mL) were charged into a 50 ml round-bottom flask. The reaction mixture was heated at 55° C. for 2 hrs. Toluene (60 was then added to the mixture at 55° C.-60° C. A white solid precipitate was formed. After cooling to room temperature, the precipitate was collected by filtration to obtain crude compound 3 (yield: 3.12 g). MASS: m/z 267.94 [m+Na+]; 1H NMR (DMSO-d6): delta 1.26 (3H, d), 3.64-3.51 (1H, m), 3.78-3.84 (1H, m), 3.97-3.98 (1H, m), 5.03 (1H, br d), 5.28 (1H, br d), 5.67 (1H, d), 7.58 (1H, br s), 7.73 (1H, d), 7.76 (1H, br s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5-fluorocytosine (2.32 g), HMDS (hexamethyldisilazane) (3.75 ml_), and TMS-CI (trimethylsilyl chloride) (0.4 ml_) are suspended in toluene (15 ml_) and heated to 1100C. The mixture is stirred for 30 minutes and cooled to 50-550C, then is distilled until no solvent distills at 50-60C under high vacuum. Dichloromethane (100 ml_) is charged to the residue at room temperature and the mixture is cooled to 0-50C. 5-deoxy-D-ribofuranose triacetate of Formula IV (5 g) and SnCI4 (2.4 ml_) are added and the temperature is raised to 25-30C. The mixture is stirred for 90 minutes. Sodium bicarbonate (8.1 g) and water (2.5 ml_) are added, followed by stirring for about 2 hours. The mixture is filtered and the filtrate is washed with 5% sodium bicarbonate solution (25 ml_). The obtained clear organic layer is concentrated completely under vacuum below 45C. The residue is stripped with isopropyl alcohol (5 ml_). lsopropyl alcohol (12.5 ml_) is charged to the obtained solid and heated to 40-500C. The mixture is cooled to room temperature and stirred for 15 minutes, then is further cooled to 0-5 C and stirred for 90 minutes. The obtained suspension is filtered and the solid is washed with isopropyl alcohol (2.5 ml_). The solid is dried at 47C under vacuum for 4-5 hours, to afford 3.7 g of the title compound.Purity: 98.28%; impurity at 1.56 RRT: 0.73%.2',3'-di-O-acetyl-5'-deoxy-5-fluoro-cytidine of Formula III (5 g) obtained above is dissolved in acetonitrile (9 ml_) at 500C with stirring for 15 minutes. The solution is cooled to room temperature and stirred for 2 hours, then is cooled to 0- 5C and stirred for 1 hour. The obtained suspension is filtered and the solid is dried for 3 hours at 40-45C under vacuum, to afford 2.9 g of the title compound. Purity: 99.56%; impurity at 1.56 RRT: 0.35% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tin(IV) chloride; In dichloromethane; at 0℃; for 2h; | 7+8 to 9 : The mixture of 5-fluorocytosine (8, 0.30 g, 2.32 mmol commercially available) in toluene (1.5 mL) and HMDS (0.38 g, 2.32 mmol) was refluxed for 3 h. The solvent was removed by evaporation and the residue was dissolved in dichloromethane (5 mL). Compound 7 (0.66 g, 2.54 mmol) and SnCl4 (0.72 g, 0.32 mmol) were added to the solution at 00C. The mixture was stirred at 00C for 2 h. NaHCtheta3 (1.2 g) and H2O (0.5 mL) was added to the mixture. After the mixture was stirred at room temperature for 3 h, filtration gave a solution, which was washed by IN NaHCtheta3. The solvent was removed by evaporation to give a crude product, which was purified by flash column chromatography (1 :20 MeOH/EtOAc) to give a vacuum dried product as a white solid 9 (0.60 g, 78%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In dichloromethane; at 0℃; for 1h; | 9+13 to 14 : The mixture of compound 9 (1.5 mmol) in dichloromethane (75 mL) and pyridine (6 mL) was cooled to 00C and compound 13 (2.2 mmol) was added to the mixture. The mixture was stirred at 00C for 1 h. After evaporation, the crude product was purified by flash column chromatography to give a vacuum dried product as a light yellow solid 14. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetone; at 20 - 30℃;Inert atmosphere; | General procedure: To a solution of K2CO3 (0.626 g, 0.0453 mol) in acetone (80 mL) was added <strong>[161599-46-8]2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine</strong> (14 g, 0.0425 mol) in a 500 mL 4-necked RB flask fitted with magnetic bar, thermo pocket, guard tube and nitrogen inlet and stirred for 10-15 min 2-Methyl-1-butyl chloroformate first half (2.279 g, 0.0151 mol) was added through additional funnel over a period of 15-20 min at room temperature and continued to stirred for 3 h. After completion of 3 h, second half of 3-methyl-1-butyl chloroformate (1.129 g, 0.0075 mol) added at 25-30 C, progress of the reaction was monitored by TLC (ethylacetate: hexane 1:1). After completion of the reaction, the mixture was filtered and washed with 2 volumes (50 mL) of acetone. To the acetone layer 4 volumes of 10% NaOH solution added at -10 to -15 C over 2 h. After completion of the reaction indicated by TLC, the pH of the reaction mixture adjusted to 6.0 by using concentrated HCl. The acetone was distilled off completely by using rota evaporator. Thus obtained aqueous layer extracted with ethyl acetate 5 volumes (50 mL) and ethyl acetate layer reduced to 1 volume stirred for 30 min then 5 volumes of tertiary methyl butyl ether (TBME) (50 mL) was added, the obtained precipitate was stirred for 1 h at 20-25 C and 2 h at 0-5 C filtered off washed with 9:1 volumes of TBME and ethyl acetate and suck dried to obtained the crude product and it was further purified by column chromatography (1:1 hexane/EtOAc) to get the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetone; at 20 - 30℃;Inert atmosphere; | To a solution of K2CO3 (0.626 g, 0.0453 mol) in acetone (80 mL) was added <strong>[161599-46-8]2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine</strong> (14 g, 0.0425 mol) in a 500 mL 4-necked RB flask fitted with magnetic bar, thermo pocket, guard tube and nitrogen inlet and stirred for 10-15 min 2-Methyl-1-butyl chloroformate first half (2.279 g, 0.0151 mol) was added through additional funnel over a period of 15-20 min at room temperature and continued to stirred for 3 h. After completion of 3 h, second half of 3-methyl-1-butyl chloroformate (1.129 g, 0.0075 mol) added at 25-30 C, progress of the reaction was monitored by TLC (ethylacetate: hexane 1:1). After completion of the reaction, the mixture was filtered and washed with 2 volumes (50 mL) of acetone. To the acetone layer 4 volumes of 10% NaOH solution added at -10 to -15 C over 2 h. After completion of the reaction indicated by TLC, the pH of the reaction mixture adjusted to 6.0 by using concentrated HCl. The acetone was distilled off completely by using rota evaporator. Thus obtained aqueous layer extracted with ethyl acetate 5 volumes (50 mL) and ethyl acetate layer reduced to 1 volume stirred for 30 min then 5 volumes of tertiary methyl butyl ether (TBME) (50 mL) was added, the obtained precipitate was stirred for 1 h at 20-25 C and 2 h at 0-5 C filtered off washed with 9:1 volumes of TBME and ethyl acetate and suck dried to obtained the crude product and it was further purified by column chromatography (1:1 hexane/EtOAc) to get the title compound. | |
With potassium carbonate; In acetone; for 1h;Inert atmosphere; | (b) Add potassium carbonate (23.5 g, 2.0 eq) to a 500 mL three-necked flask,2',3'-Di-O-acetyl-5'-deoxy-5-fluorocytidine (CAS: 161599-46-8, 22g, 0.8eq)And acetone (100ml),Replaced with nitrogen three times,A solution of Compound 2 in acetone (50 mL) was slowly added dropwise twice.1 hour apart,After the addition is completed, the temperature is naturally raised overnight;The reaction solution is filtered,The filter cake was washed twice with acetone.The filtrate is the reaction liquid of the second mixture (ie, the reaction liquid of the compound 3,Directly cast a step reaction); | |
With potassium carbonate; In acetone;Inert atmosphere; | (b) Add potassium carbonate (23.5 g, 2.0 eq) to a 500 mL three-necked flask, <strong>[161599-46-8]2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine</strong> (CAS: 161599-46-8, 22 g, 0.8 eq) and acetone (100 ml), replaced with nitrogen three times, A solution of Compound 2 in acetone (50 mL) was slowly added dropwise in two portions at intervals of 1 hour. After the addition was completed, the temperature was naturally raised overnight; the reaction solution was filtered. The filter cake is washed twice with acetone, and the filtrate is the reaction liquid of the second mixture.(ie, the reaction solution of compound 3, directly cast the reaction); |
With potassium carbonate; In acetone; | (b) Add potassium carbonate (23.5 g, 2.0 eq) to a 500 mL three-neck bottle, <strong>[161599-46-8]2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine</strong> (CAS: 161599-46-8, 22g, 0.8eq)And acetone (100ml), nitrogen replacement 3 times,A solution of Compound 2 in acetone (50 mL) was slowly added in two portions with an interval of 1 hour.After the completion of the dropwise addition, the temperature was naturally raised overnight; the reaction solution was filtered, and the filter cake was washed twice with acetone.The filtrate is the reaction solution of the second mixture(ie, the reaction solution of compound 3, directly cast the reaction); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetone; at 20 - 30℃;Inert atmosphere; | General procedure: To a solution of K2CO3 (0.626 g, 0.0453 mol) in acetone (80 mL) was added <strong>[161599-46-8]2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine</strong> (14 g, 0.0425 mol) in a 500 mL 4-necked RB flask fitted with magnetic bar, thermo pocket, guard tube and nitrogen inlet and stirred for 10-15 min 2-Methyl-1-butyl chloroformate first half (2.279 g, 0.0151 mol) was added through additional funnel over a period of 15-20 min at room temperature and continued to stirred for 3 h. After completion of 3 h, second half of 3-methyl-1-butyl chloroformate (1.129 g, 0.0075 mol) added at 25-30 C, progress of the reaction was monitored by TLC (ethylacetate: hexane 1:1). After completion of the reaction, the mixture was filtered and washed with 2 volumes (50 mL) of acetone. To the acetone layer 4 volumes of 10% NaOH solution added at -10 to -15 C over 2 h. After completion of the reaction indicated by TLC, the pH of the reaction mixture adjusted to 6.0 by using concentrated HCl. The acetone was distilled off completely by using rota evaporator. Thus obtained aqueous layer extracted with ethyl acetate 5 volumes (50 mL) and ethyl acetate layer reduced to 1 volume stirred for 30 min then 5 volumes of tertiary methyl butyl ether (TBME) (50 mL) was added, the obtained precipitate was stirred for 1 h at 20-25 C and 2 h at 0-5 C filtered off washed with 9:1 volumes of TBME and ethyl acetate and suck dried to obtained the crude product and it was further purified by column chromatography (1:1 hexane/EtOAc) to get the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetone; at 20 - 30℃;Inert atmosphere; | General procedure: To a solution of K2CO3 (0.626 g, 0.0453 mol) in acetone (80 mL) was added <strong>[161599-46-8]2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine</strong> (14 g, 0.0425 mol) in a 500 mL 4-necked RB flask fitted with magnetic bar, thermo pocket, guard tube and nitrogen inlet and stirred for 10-15 min 2-Methyl-1-butyl chloroformate first half (2.279 g, 0.0151 mol) was added through additional funnel over a period of 15-20 min at room temperature and continued to stirred for 3 h. After completion of 3 h, second half of 3-methyl-1-butyl chloroformate (1.129 g, 0.0075 mol) added at 25-30 C, progress of the reaction was monitored by TLC (ethylacetate: hexane 1:1). After completion of the reaction, the mixture was filtered and washed with 2 volumes (50 mL) of acetone. To the acetone layer 4 volumes of 10% NaOH solution added at -10 to -15 C over 2 h. After completion of the reaction indicated by TLC, the pH of the reaction mixture adjusted to 6.0 by using concentrated HCl. The acetone was distilled off completely by using rota evaporator. Thus obtained aqueous layer extracted with ethyl acetate 5 volumes (50 mL) and ethyl acetate layer reduced to 1 volume stirred for 30 min then 5 volumes of tertiary methyl butyl ether (TBME) (50 mL) was added, the obtained precipitate was stirred for 1 h at 20-25 C and 2 h at 0-5 C filtered off washed with 9:1 volumes of TBME and ethyl acetate and suck dried to obtained the crude product and it was further purified by column chromatography (1:1 hexane/EtOAc) to get the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.2% | 5'-deoxy-2 ', 3'-di-O-acetyl-5-fluorocytidine 12 g and 5 mL of pyridine were dissolved in 40 mL of dichloromethane and cooled to -10 C,9 mL of n-amyl chloroformate was added dropwise.0 below the incubation reaction 1 hour.24 mL of pure water twice.Organic layer cooling to -5 ~ 0 ,Add 32 mL of 4 mol / L aqueous sodium hydroxide solution.After mixing, add 6 mL of absolute ethanol.TLC monitoring reaction,Should be completed after 14min reaction.Start dropping 6mol / L hydrochloric acid to adjust the pH to 6 ~ 7.Static stratification,20 mL of dichloromethane.Combined organic layer,12mL pure water twice.The solvent is evaporated,After dissolving in 21 mL of acetone,Add 46 mL of isopropyl ether to crystallize.Solid separation after dryingCapecitabine 10.5g,Yield 80.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31 g | With tin(IV) chloride; In dichloromethane; at -1 - 10℃;Inert atmosphere; | Under the protection of nitrogen,14g 5-fluorocytosine and 23.5mL HMDS,0.25 mL of methanesulfonic acid was added to 50 mL of toluene.Heating to reflux, the reaction is completed (about 3 to 3.5 hours)Down to room temperature; under nitrogen protection,Transfer the reaction solution to a three-necked flask.Then 24.5 g of triacetyl ribose and 100 mL of dichloromethane were added to the reaction system.After stirring and stirring, it was cooled to -1 to 1 C with an ice brine bath.Then add 11.8mL Anhydrous tin tetrachlorideversusa mixed solution of 30 mL of dichloromethane,The dropping rate needs to control the internal temperature of the reaction system at 5 to 10 C and complete the dropwise addition within 3 to 4 hours;Stirring at 5-10 C;At the end of the reaction, the reaction solution was slowly poured into an aqueous solution of sodium hydrogencarbonate.Stir, separate the separated solution, collect the organic phase,Wash with distilled water and dry over anhydrous sodium sulfate.The concentrated solvent is then concentrated under reduced pressure.Obtaining a pale yellow solid (ie, the capecitabine intermediate of formula I) 31 g,The molar yield is ?97%, and the HPLC purity is 99.36%.The single maximum impurity content is 0.19%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | 14.2 kg (110 mol, 1.1 eq) of 5-fluorocytosine was added1Was added to a 50 L autoclave, followed by the addition of 29.8 L of HMDS (143 mol, 1.43 eq) followed by 20 L of toluene. The reaction mixture was stirred and heated and reflux for 4 h.Under reduced pressure (rotary evaporator at a bath temperature no higher than 70Othe C) to remove the solvent to give a white solid powder.The above white solid powder and 5-deoxy-1,2,3-triacetyl deoxyribose are added226 kg (100 mol, 1eq) was suspended in 100 L of dichloromethane, cooling the reaction vessel to a temperature below 2oC, the constant pressure funnel with a solution of 15.2 L (130 mol, 1.3eq) SnCl410 L of methylene chloride solution (temperature dropping within the range of 2oCto. 8OC), Bi drops slowly brought to room temperature, stirring was continued at room temperature the reaction 12 h, added to the system at a low temperature 97.5 kg of anhydrous Na2CO3(920 mol, 9.2 eq), and H was added dropwise slowly2O 26 L (period keeping the internal temperature not higher than 25oC), after the completion of the dropping maintain the internal temperature not higher than 25oCcontinue stirring 3h.(100 L +90 L + 90 L) soaked filter cake, and then suction filtration, liquid phase and then joined the 80 L saturated sodium carbonate solution, stirring evenly after standing layered, the separation of organic The aqueous phase was stripped with dichloromethane (50 L * 2) and the organic phases were combined and dried over anhydrous NaSO ?.4Dried and concentrated under reduced pressure to give a whiteish yellow amorphous solid.Add isopropyl alcohol 88 L, heating dissolved solids, shaking stationary 96 h, suction filtration, washing with isopropyl alcohol (10 L +5 L +5 L) filter cake, and then wash the filter cake with ether (10L * 3) cake 40Othe C and dried in vacuo to afford a white crystal of 2 ', 3'-di -O- acetyl-5'-deoxy-5-fluoro-cytidine324.5 kg, 74% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.4% | With tin(IV) chloride; sodium hydrogencarbonate; In dichloromethane; water; at 0 - 20℃; for 0.5h; | 5-fluorocytosine (30 g, 0.23 mol), hexamethyldisilanamine (38 g) and toluene (150 ml) were refluxed for 3 h and toluene was distilled off under reduced pressure,The residue was dissolved in dichloromethane (400 ml), compound 6 (66 g, 0.25 mol) was added, cooled to 0 C,Was added tin tetrachloride (72g), stirred at 0 2h,Sodium bicarbonate (100g), ice water (200ml), stirred at room temperature 0.5h, filtered,The organic phase was washed successively with 1 mol / L sodium hydrogencarbonate solution, and dichloromethane was added to the residue. Ethyl acetate (150 ml) was added and the mixture was dissolved with stirring. Petrolether (450 ml) was added dropwise, and the solid 2 ' Acetyl-5'-deoxy-5-fluorocytidine (8) (60 g, yield 78.4%), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.6% | In dichloromethane; at 20℃; for 4h; | To a 1000 ml reaction flask, 600 ml of methylene chloride, 84.8 g of <strong>[161599-46-8]2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine</strong>, 48.6 g of carbonyldiimidazole, and 25.2 g of n-pentanol were charged. The reaction was carried out at 20 C. for 4 hours. The end of the reaction was monitored by TLC (developer, dichloromethane:methanol=20:1). 220 ml of 10% hydrochloric acid solution was added to the reaction mixture. The organic layer was separated, washed with 220 ml of purified water, and separated. The organic layer was controlled at a bath temperature of 60 C., and the organic layer was concentrated under reduced pressure to dryness. To the residue was added 160 ml of ethyl acetate and 320 ml of n-hexane was stirred for 30 minutes. The temperature was lowered to 10 C. or lower, and suction filtration was started to obtain a white solid. C, 104.8 g of 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N4-n-pentyloxycarbonyl cytidine was dried, yielding 91.6%, purity 99.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.1% | With pyridine; In dichloromethane; at 20℃; | To the ice-cooled solution containing 2?,3?-Di-O-acetyl-5?-deoxy-5-fluoroocytidine (5) (9.76g, 29.64mmol) in dryCH2Cl2 (40ml) and anhydrous pyridine (5ml), phytanyl chloroformate (12g, 33mmol) (6a) was added dropwise in orderto keep the low reaction temperature. After stirring the mixture for overnight at room temperature, MeOH (1.3ml) wasadded in one portion to stop the reaction. The mixture was evaporated to a syrup mass under reduced pressure. To thisresidue, diethyl ether (50ml) was added and the suspension was stirred for 30min at room temperature. The insolubleprecipitate was filtered through a glass filter. The precipitate was washed with 30ml of diethyl ether. The filtrate and thewashings were collected, dried over anhydrous Na2SO4, and evaporated to dryness. The crude target compound wasfurther purified using silica column chromatography CH2Cl2:MeOH=5:1 to give 2?,3?-Di-O-acetyl-5?-deoxy-5-fluoro-N4-(phytanyloxycarbonyl) cytidine (16.7g, 84.1%) (7a). 1H NMR in CDCl3: delta0.83, 0.85, 0.86, 0.88 (4s, each 3H, CH3),0.91 (d, 3H, J=6.6Hz, CH3), 0.96-1.88 (m, 24H, CH2+CH), 1.47(d, 3H, J=6.6Hz, H-5), 2.10, 2.12 (2s, each 3H, OMe),4.13-4.37 (m, 3H, H-4 + CH2OC=ONH), 5.01 (t, 1H, J=5.4Hz, H-2), 5.29 (t, 1H, J=5.8Hz, H-3), 5.96 (d, 1H, J=3.8Hz, H-1), 7.39 (br s, 1H, N-CH=C-F). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In dichloromethane; at 20℃;Cooling with ice; | 2?,3?-Di-O-acetyl-5?-deoxy-5-fluorocytidine (compound 5) was synthesised by the same procedures describedin example 1. Cetyl (hexadecyl) chloroformate was purchased from Sigma-Aldrich with 96% purity. Compound 5 (3.97g,12.06mmol) was dissolved in a mixture of dry CH2Cl2 (20ml) and anhydrous pyridine (2.5ml). To the ice-cooled solution,cetyl chloroformate (4.41g, 14.47mmol) was added dropwise and stirred overnight at room temperature. After smallportion of MeOH (600ml) was added, the mixture was evaporated to a syrup mass under reduced pressure using rotaryevaporator. To this syrup residue, diethyl ether (50ml) was added and the suspension was stirred for 30min at roomtemperature. The insoluble precipitate was filtered through a glass filter. The precipitate was washed further with diethylether. The filtrate and the washings were collected, dried over anhydrous Na2SO4, and evaporated to dryness to givecrude compound (7b). MS (APCI): 598.38. The crude compound 7 was dissolved in 50ml of MeOH and stirred on anice bath. NaOH solution (20ml, 8M) was added dropwise to maintain the reaction temperature at 4C. After immediateneutralization of the reaction mixture with dropwise addition of HCI (2.3M) solution, the organic layer was combined andwashed with water, dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated to dryness under reducedpressure. The pure white crystal compound (8b) (3.5g, 56.5%) was obtained by crystallization from acetone |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In dichloromethane; at 20℃;Cooling with ice; | 2?,3?-Di-O-acetyl-5?-deoxy-5-fluorocytidine (compound 5) was synthesized following the procedures describedpreviously. Compound 5 (3.53g, 10.72mmol) was dissolved in a mixture of dry CH2Cl2 (20ml) and anhydrous pyridine(2.3ml). To the ice-cooled solution, oleyl chloroformate (4.26g, 12.86mmol) was added dropwise and stirred overnightat room temperature. After small portion of MeOH (500ml) was added, the mixture was evaporated to a syrup massunder reduced pressure using rotary evaporator. To this residue, diethyl ether (60ml) was added and the suspensionwas stirred for 30min at room temperature. The insoluble precipitate was filtered through a filter paper. The precipitatewas washed further with diethyl ether. The filtrate and the washings were collected, dried over anhydrous Na2SO4, andevaporated to dryness to give crude compound (7c). MS (APCI): 624.00. This crude sample was dissolved in 50ml ofMeOH and stirred on an ice bath. NaOH solution (20ml, 8M) was added dropwise to ensure the low temperature reactioncondition maintained. After immediate neutralization of the reaction mixture with dropwise addition of HCl solution (2.3M), the mixture was then partitioned between CH2Cl2 and water. The organic layer was combined and washed withwater, dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated to dryness under reduced pressure. Thepure compound (8c) was obtained by flash column chromatography purification using CHCl2 and MeOH eluent, startingfrom 100% CH2Cl2 and gradually increased the concentration to 10%. MeOH. The title compound was obtained as ayellow solid (3.46g, 59.8% yield). 1H NMR(CDCl3): delta0.88 (t, 3H, J=6.0Hz, CH3), 1.28 (d, 22H, J=4.0Hz, CH2), 1.42 (d,3H, J=6.5Hz, H-5), 1.58-1.77 (m, 2H, betaCH2), 2.01 (d, 4H, J=5.1 Hz, -CH2-CH=CH-CH2-), 3.73 (br s, 1H, H-3), 3.87 (t,1H, J=4.7Hz, H-4), 4.18 (t, 2H, J=6.4Hz, alphaCH2), 4.27 (d, 1H, J=4.5Hz, H-2), 5.35 (t, 2H, J=5.7Hz, -CH=CH-), 5.71 (d,1H, J=2.9Hz, H-1), 7.79 (br s, 1H, N-CH=C-F). 13C NMR(CDCl3,100MHz): delta14.07(CH3), 18.54(C5), [22.64, 25.76, 27.16,27.18, 28.54, 29.21, 29.28, 29.41, 29.48, 29.72, 31.86](CH2), 66.85(OCH2), [74.94, 75.12(br), 80.70](C2,C3,C4),92.00(br)(C1), [129.71, 129.95](CH), 124.3-128.0(br), 135.0-138.0(br), 153.15(NHCOO). MS (APCI): 540.28. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In dichloromethane; at 20℃;Cooling with ice; | 2?,3?-Di-O-acetyl-5?-deoxy-5-fluorocytidine (compound 5) was synthesized following the procedures describedpreviously. Compound 5 (1.5g, 0.0046 mol) was dissolved in a mixture of dry CH2Cl2 (20ml) and anhydrous pyridine(1ml) over an ice bath. To the ice-cooled solution, compound 6d (1.82 g, 0.0055 mol, 1.2 equiv.) was added dropwiseand stirred overnight at room temperature. After a small portion of MeOH (250ml) was added, the mixture was evaporatedto dryness. To this residue, diethyl ether (50ml) was added and the suspension was stirred for 60min at room temperature.The insoluble precipitate was filtered through a filter paper. The precipitate was washed further with diethyl ether. Thefiltrate and the washings were collected, dried over anhydrous Na2SO4, and evaporated to dryness to give crude compound(7d). This crude sample was dissolved in 20ml of MeOH and stirred on an ice bath. NaOH solution (10ml, 8M)was added dropwise to ensure the low temperature reaction condition maintained. After immediate neutralization of thereaction mixture with dropwise addition of HCI solution (4 M), the mixture was then partitioned between CH2Cl2 andwater. The organic layer was combined and washed with water, dried over anhydrous Na2SO4 and filtered. The filtratewas evaporated to dryness under reduced pressure. The pure compound (8d) was obtained by flash column chromatographypurification using CHCl2 and MeOH eluent, starting from 100% CH2Cl2 and gradually increasing the concentrationto 10% MeOH. The title compound 8d was obtained as a white solid (1.97g, 78% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In dichloromethane; at 20℃;Cooling with ice; | 2?,3?-Di-O-acetyl-5?-deoxy-5-fluorocytidine (compound 5) was synthesized following the procedures describedpreviously. Compound 5 (2.43g, 0.0074 mol) was dissolved in a mixture of dry CH2Cl2 (20ml) and anhydrous pyridine(1ml) over an ice bath. To the ice-cooled solution, compound 6e (2.43 g, 0.0074 mol, 1 equiv.) was added dropwise andstirred overnight at room temperature. Due to the light sensitive nature of the unsaturated chloroformate the reactionwas kept insulated from ambient light. After a small portion of MeOH (250ml) was added, the mixture was evaporatedto dryness. To this residue, diethyl ether (100ml) was added and the suspension was stirred for 10min at room temperature.The insoluble precipitate was filtered through a filter paper. The precipitate was washed further with diethyl ether. Thefiltrate and the washings were collected, dried over anhydrous Na2SO4, and evaporated to dryness to give crude compound(7e). This crude sample was dissolved in 20ml of MeOH and stirred on an ice bath. NaOH solution (10ml, 8M)was added dropwise to ensure the low temperature reaction condition maintained. After immediate neutralization of thereaction mixture with dropwise addition of HCI solution (4 M), the mixture was then partitioned between CH2Cl2 andwater. The organic layer was combined and washed with water, dried over anhydrous Na2SO4 and filtered. The filtratewas evaporated to dryness under reduced pressure. The pure compound (8e) was obtained by flash column chromatographypurification using CHCl2 and MeOH eluent, starting from 100% CH2Cl2 and gradually increasing the concentrationto 10% MeOH. The title compound 8e was obtained as a yellowish wax (3.1g, 75% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70 g | To an ice cold stirred solution of (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5- methyltetrahydrofuran-3,4-diyl diacetate 3 (97.40 g, 0.296 mol) in DCM (2.0 L) was added DMAP (15.087 g, 0.123 mol) followed by the addition of pyridine (156.1 mL, 1.97 mol). After 5 minutes of stirring at same temperature, 2-propylpentanoyl chloride 2 (40.0 g, 0.246 mol, dissolved in 100 mL of DCM) was added to the reaction mixture in drop wise manner under inert atmosphere. The reaction mixture was stirred at room temperature for next l6h at room temperature. After completion of reaction (TLC monitoring), reaction mixture was washed sequentially with 1N HC1 (3 x 500 mL), sat. NaHC03 solution (500 mL) and brine solution (500 mL). The organic layer was dried over anhydrous sodium sulfate and solvent was removed under reduced pressure. The crude was triturated with diethyl ether and pentane to afford the desired product 4 (CLX-SYN-G155A-C03) as Off white solid. Yield: 70.0 g, 56%. |
[ 66335-38-4 ]
4-Amino-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-methyltetrahydrofuran-2-yl)-5-fluoropyrimidin-2(1H)-one
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