[ CAS No. 161599-46-8 ] {[proInfo.proName]}

Name: 161599-46-8|(2R,3R,4R,5R)-2-(4-Amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyltetrahydrofuran-3,4-diyl diacetate|95%
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Quality Control of [ 161599-46-8 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 161599-46-8 ]

SDS Specification

Alternatived Products of [ 161599-46-8 ]

Product Details of [ 161599-46-8 ]

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

Calculated chemistry of [ 161599-46-8 ]

Physicochemical Properties

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 Å²

Pharmacokinetics

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

Lipophilicity

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

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

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

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	4.32

Safety of [ 161599-46-8 ]

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:

Application In Synthesis of [ 161599-46-8 ]

* 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.

Upstream synthesis route of [ 161599-46-8 ]
Downstream synthetic route of [ 161599-46-8 ]

[ 161599-46-8 ] Synthesis Path-Upstream 1~5

1
[ 161599-46-8 ]
[ 66335-38-4 ]

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.

Reference： [1] Patent: US2009/209754, 2009, A1, . Location in patent: Page/Page column 9-10
[2] Patent: WO2018/2739, 2018, A1, . Location in patent: Paragraph 00166
[3] Patent: US2013/184451, 2013, A1, . Location in patent: Paragraph 0030; 0031

2
[ 638-41-5 ]
[ 161599-46-8 ]
[ 162204-20-8 ]

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.

Reference： [1] Patent: CN106478751, 2017, A, . Location in patent: Paragraph 0010; 0022; 0039; 0040; 0041; 0042; 0043-0060
[2] Patent: CN102212095, 2016, B, . Location in patent: Paragraph 0062; 0063; 0064
[3] Patent: CN104744537, 2018, B, . Location in patent: Paragraph 0018; 0019; 0020; 0022; 0025; 0028
[4] Tetrahedron Letters, 2015, vol. 56, # 43, p. 5909 - 5913
[5] Bioorganic and Medicinal Chemistry, 2000, vol. 8, # 7, p. 1697 - 1706
[6] Patent: WO2008/131062, 2008, A2, . Location in patent: Page/Page column 37
[7] Patent: US2008/300399, 2008, A1, . Location in patent: Page/Page column 1; 4
[8] Patent: US2008/300399, 2008, A1, . Location in patent: Page/Page column 1; 4-5
[9] Patent: WO2009/42613, 2009, A1, . Location in patent: Page/Page column 56
[10] Patent: US2009/209754, 2009, A1, . Location in patent: Page/Page column 8
[11] Patent: WO2010/65586, 2010, A2, . Location in patent: Page/Page column 9; 24
[12] Patent: US2011/21769, 2011, A1, . Location in patent: Page/Page column 3; 5-6
[13] European Journal of Medicinal Chemistry, 2012, vol. 54, p. 690 - 696
[14] Organic Process Research and Development, 2016, vol. 20, # 3, p. 609 - 614
[15] Patent: CN103570781, 2016, B, . Location in patent: Paragraph 0012; 0036; 0037
[16] Molecules, 2018, vol. 23, # 1,

3
[ 71-41-0 ]
[ 530-62-1 ]
[ 161599-46-8 ]
[ 162204-20-8 ]

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.

Reference： [1] Patent: CN107936075, 2018, A, . Location in patent: Paragraph 0024-0026

4
[ 161599-46-8 ]
[ 162204-30-0 ]

Reference： [1] European Journal of Medicinal Chemistry, 2012, vol. 54, p. 690 - 696

5
[ 161599-46-8 ]
[ 910129-15-6 ]

Reference： [1] European Journal of Medicinal Chemistry, 2012, vol. 54, p. 690 - 696

[ 161599-46-8 ] Synthesis Path-Downstream 1~88

1
[ 638-41-5 ]
[ 161599-46-8 ]
[ 162204-20-8 ]

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.

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