[ CAS No. 154361-50-9 ] {[proInfo.proName]}

Name: 154361-50-9|Pentyl (1-((2R,3R,4S,5R)-3,4-dihydroxy-5-methyltetrahydrofuran-2-yl)-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)carbamate|98%
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Quality Control of [ 154361-50-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 154361-50-9 ]

Product Details of [ 154361-50-9 ]

CAS No. :	154361-50-9	MDL No. :	MFCD00930626
Formula :	C₁₅H₂₂FN₃O₆	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GAGWJHPBXLXJQN-UORFTKCHSA-N
M.W :	359.35	Pubchem ID :	60953
Synonyms :	Ro 09-1978	Chemical Name :	Pentyl (1-((2R,3R,4S,5R)-3,4-dihydroxy-5-methyltetrahydrofuran-2-yl)-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)carbamate

Calculated chemistry of [ 154361-50-9 ]

Physicochemical Properties

Num. heavy atoms :	25
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.67
Num. rotatable bonds :	8
Num. H-bond acceptors :	8.0
Num. H-bond donors :	3.0
Molar Refractivity :	85.25
TPSA :	122.91 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-8.09 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.24
Log Po/w (XLOGP3) :	0.56
Log Po/w (WLOGP) :	0.67
Log Po/w (MLOGP) :	0.12
Log Po/w (SILICOS-IT) :	0.15
Consensus Log Po/w :	0.75

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.07
Solubility :	3.06 mg/ml ; 0.0085 mol/l
Class :	Soluble
Log S (Ali) :	-2.71
Solubility :	0.695 mg/ml ; 0.00193 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.88
Solubility :	4.74 mg/ml ; 0.0132 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	4.67

Safety of [ 154361-50-9 ]

Signal Word:	Danger	Class:	N/A
Precautionary Statements:	P201-P202-P273-P280-P308+P313-P405-P501	UN#:	N/A
Hazard Statements:	H341-H350-H360-H402	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 154361-50-9 ]

* 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 [ 154361-50-9 ]
Downstream synthetic route of [ 154361-50-9 ]

[ 154361-50-9 ] Synthesis Path-Upstream 1~1

1
[ 154361-50-9 ]
[ 66335-38-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate In methanol; N,N-dimethyl-formamide for 24 h; Heating / reflux	Capecitabine (5'-deoxy-5-fluoro-N⁴-(pentyloxycarbonyl)cytidine, 4.5 g, 12.5 mmol) was suspended in methanol (250 mL) and DMF (10 mL) together with potassium carbonate (8.8 g, 63.77 mmol) and the solution heated under reflux for 24 h. The solution was then cooled and evaporated to dryness (below 45 °C). The residue was redissolved in hot methanol, filtered and washed with hot methanol. The filtrate was preabsorbed onto silica gel and puified by flash chromatography, eluting with 50 percent methanol / ethyl acetate to give 3.0 g (90 percent) of l-[3,4-dihydroxy-5-methyl- tetrahydrofuran-2-yl]-4-amino-lH-pyrimidin-2-one. This material was suspended in chloroform (125 mL) and the solution heated to 50 ⁰C. Acetic acid (2 mL, 34 mmol) was added and after 10 minutes at 50 ⁰C, acetyl chloride (20 mL, 206 mmol) was added. The suspension was stirred at 50 ⁰C for 7 h and then at 20 °C for 72 h. Ether (100 mL) was added and the solid filtered and washed with ether to give 4.0 g (90 percent) l-[3,4-Diacetoxy-5-methyl-tetrahydrofuran-2-yl]-4-amino-lH-pyrimidin-2-one hydrochloride. This material (2.07g, 5.7 mmol) together with 5-nitrothien-2- ylmethanol (1.47 g, 9.3 mmol), was dissolved in pyridine (1.4 mL, 17.4 mmol) and DCM (15 mL). Phosgene solution (3.6 mL of a 2M solution in toluene, 7.2 mmol) was slowly added to the above cooled (O⁰C) solution, the solution was stirred at O⁰C for 2.5 h and then a further 3.6 mL of phosgene solution added and the solution stirred at O⁰C for a further 2h and refrigerated for 18 h. The solution was partitioned (ethyl EPO <DP n="39"/>acetate and brine), the aqueous phase extracted (ethyl acetate) dried and evaporated.The residue was purified on silica, eluting with 2percent methanol / DCM, to give an off- white foam (400 mg, 14 percent); TLC R_f=0.45, 2percent methanol / ethyl acetate. LC-RT 4.68 min (TFA20-50percent); MS m/z 201/159/143. ¹H NMR (500 MHz, DMSO) δ 11.20 (IH, bs, NH), 8.3 (IH, b, NCH=CF), 8.05 (IH, s, HarH), 7.30 (s, IH, HarH), 5.80 (IH, s, NCHO), 5.42 (3H, m, HarCH₂OCONH, CHOAc), 5.15 (IH, s, CHOAc), 4.05 (IH, m, OCHCH₃), 3.45 (2H, m, 2 x CHOAc), 2.48 (3H, s, OAc), 2.05 (3H, s, OAc), 1.37 (3H, s, OCHCH₃) ppm.

Reference： [1] Patent: WO2006/32921, 2006, A1, . Location in patent: Page/Page column 37-38

[ 154361-50-9 ] Synthesis Path-Downstream 1~52

1
[ 162204-20-8 ]
[ 154361-50-9 ]

Yield	Reaction Conditions	Operation in experiment
98%		5'-Deoxy-5-fluoro-N4-(n-pentyloxycarbonyl)cytidine, capecitabine (1); A solution of NaOH (2 mg, 0.05 mmol) in water (0.5 mL) was slowly added to a solution of 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N4- (n-pentyloxycarbonyl)cytidine (20 mg, 0.045 mmol) in methanol (1.0 mL) at -15 ºC. The reaction mixture was stirred at that temperature for 20 hours. It was taken to pH = 5 with HCl 5% keeping the temperature at -15C and it was partitioned in CH2Cl2 (10 mL) and saturated solution of NaCl (5 mL). The organic phase was washed with a saturated solution of NaCl (5 mL), it was dried (Na2SO4), and the solvent was evaporated. 16 mg of capecitabine (98% yield) were obtained as a crystalline white solid. 1H RMN (CDCl3-DMSO-d6, 500 MHz) delta 0.91 (t, J = 6.9 Hz, 3H, H-5"), 1.36 (m, 7H, H-3", H-4", H-5'), 1.67 (quint, 2H, J = 6.6 Hz, H-2"), 3.69 (s a, 1H, H-3'), 4.03 (s a, 1H, H-4'), 4.09 (m, 1H, H-2'), 4.14 (s a, 2H, H-1 "), 4.80 (s a, 1H, 3'-OH), 5.44 (s a, 1H, 2'-OH), 5.70 (d, J = 2.3 Hz, H-1'), 7.85 (s a, 1H, H-6), 10.22 (s a, 0.61H, NH), 11.77 (s a, 0.39H, NH).
96.1%	With potassium hydroxide; In methanol; at 0 - 15℃; for 1h;	To a 100 mL three-necked flask was added the above reaction product N-pentyloxycarbonyl-2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine (5 g) and methanol (40 mL).After cooling to 0C, 2M potassium hydroxide 10mL was added dropwiseAnd 2M of 15beta-hydroxyjufenamine 2mL,The temperature was maintained at 5 to 15C, and after 1 hour of reaction, 2M hydrochloric acid was added dropwise to adjust the pH to about 6.After extracting three times with dichloromethane (150 mL), the organic phases were combined and washed with saturated aqueous sodium bicarbonate (100 mL) and water (100 mL), respectively.The organic phase is dried over anhydrous sodium sulfate and concentrated.Recrystallization from ethyl acetate (16 mL) gave 3.9 g of capecitabine white powder. Yield: 96.1%.
87.5%	With sodium hydroxide; In methanol; water; at -10 - 5℃; for 1h;Autoclave;	28.55 g of the compound of formula V and 48 g of MeOH were charged into the autoclave, cooled to -10 to -5 C with stirring, and 7.93 g of sodium hydroxide /65.5g purified water solution, dropping temperature ? -5 , dropping completed, the reaction 1 hour. Dropping 11g concentrated hydrochloric acid adjust the feed solution pH = 5 ~ 6, dropping temperature ? -5 . The mixture was stirred for 103 g of dichloromethane. After standing, the mixture was separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed twice with purified water and the aqueous layer was back-extracted once with dichloromethane. The organic layers were combined, 52 g of purified water was added, the mixture was stirred, layered and separated to obtain an organic layer. Activated carbon was added to the organic layer, stirred and filtered to remove the activated carbon. The filtrate was concentrated to dryness under reduced pressure to give 21.3 g crude capecitabine. The capecitabine crude 21.3g was dissolved in 2.3 times the amount of methylene chloride, activated carbon was added after stirring and stirred to remove activated carbon, the filtrate was concentrated to dryness under reduced pressure, 1.5 times the amount of ethyl acetate was added, dissolved with stirring, dropping 1.7 times the amount of n-hexane, dropping completed, stirred at room temperature for 1h, standing crystallization, filtration, filter cake drying, capecitabine (20.1 g, 0.056 mol, 87.5%), HPLC content 99.93%.

85%	With sodium hydroxide; In methanol; dichloromethane; water; at 5℃;Product distribution / selectivity;	To a vessel is added of 2',3'-di-O-acetyl-5-deoxy-5-fluoro-N4-(pentyl-oxycarbonyl)cytidine (20 g, 45.1 mmol), methylene chloride (160 g) and methanol (20 mL) at below 5 C. Subsequently 25% NaOH (16 g, 100 mmol) is added at below 5 C. The resulting solution is maintained at below 5 C. and stirred for at least 0.5 hour. After the completion of the reaction, citric acid (60 g) is added for quenching the reaction and doing phase separation. The organic layer is collected and the aqueous is continued to wash with methylene chloride (40 mL). After phase separation, the methylene chloride layer is collected and combined with the previous organic layer. The resulting organic layer is washed with water (100 g) and the organic layer is collected. The organic layer is concentrated and then is swap with ethyl acetate (60 mL) under vacuum at less than 60 C. After solvent swap, n-heptane (20 mL) is added and the resulting solution is heated at 40-55 C. and seeded with capecitabine. The mixture is held for about 1 hour at 40-55 C. and cooled to -5 to 5 C. The slurry is stirred at -5 to 5 C. for about 2 hours. The resulting solid is filtered, washed with n-heptane and dried under vacuum to afford capecitabine. The purity is 99.5%, impurity F0.3%, impurity G0.2%, impurity H0.3%, M20.1%, impurity M0.10% and the maximum individual impurity is 0.1%. Yield: 85%.
85%	With sodium methylate; In methanol; at 20℃; for 1h;	5'-fluoro-N - [(pentyloxy) carbonyl] cytidine (10) (12 g, 27 mmol)Dissolved in methanol (120ml), add sodium methoxide (0.5g), stirring at room temperature 1h, 2mol / L hydrochloric acid to adjust the pH to neutral,The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The organic layer was washed with water and dried over anhydrous magnesium sulfate. Dry to 20ml, stirring petroleum ether (40ml), precipitation of solid, filtration, ethyl acetate: petroleum ether volume ratio of about 1: 3 washing, drying to capecitabine (11) (8.2g, 85%) , & Lt;
79%	With sodium hydroxide; In methanol; water; for 0.333333h;Cooling; Industrial scale;	The crude 2 ', 3'-di-O-acetyl-5'-deoxy-5-fluoro-N- [(pentyloxy) carbonyl]5It was dissolved in 28 L of methanol, until the reaction kettle temperature dropped to -10OC or less, and began dropping 9.6 kg NaOH (240 mol, 4 eq)in 24 L H2O solution was maintained (10 mol / L), during the internal temperature of not higher than -5Othe C, after dropping to maintain a low temperature (-5Othe C or less) the reaction 20 min, followed by dropwise addition of concentrated hydrochloric acid to about 20 L, adjusted PH to 4-5, keeping the internal temperature not higher than the period -5OC, was added 10 L of water after the completion of dropping, 100 L of methylene chloride, standing layered organic phase was separated.The organic phase was washed with water (20 L * 2).The aqueous phase was stripped with dichloromethane (50 L * 2).The organic phases are combined, anhydrous Na2SO4Dried and concentrated under reduced pressure to give a slightly yellow oil.Add 25 liters of dichloromethane and slowly add 100 liters of n-hexane with stirring. White precipitate was formed and stirred for 2 h. After filtration, a white (yellowish) solid was obtained. The solid was redissolved in 30 L of dichloromethane , Slowly add 100 L of n-hexane, stir 3 h, filter, filter cake washed twice with ether (each time soaked completely), dried to 17.7 kg.This solid was redissolved in 30 L of methylene chloride and 100 L of n-hexane was slowly added and stirred for 3 h. The filter cake was washed twice with ether (complete soaking) and dried to obtain purity The standard capecitabine was 17 kg and the two-step yield was 79%
		Methanol (99 lit) was charged to the resultant reaction crude obtained from above process at 25-30 C and stirred for 30-45 minutes. The reaction solution was cooled to -5 to -15 0C. Sodium hydroxide solution (obtained by dissolution of 6.3 kg of sodium hydroxide in 158 lit of deminaralized water) was added slowly to the reaction mixture at temperature -5 to -15 0C for a period of 11/2 to 2 hours under nitrogen atmosphere followed by stirring for 15 minutes. Hydrochloric acid (17 lit) was added drop wise to the reaction mass to adjust the pH between 4 and 5 at temperature -5 to -15 0C. The reaction mass was allowed to raise the temperature to 25-30 0C followed by addition of dichloromethane (297 lit) to the reaction mass and stirred the whole reaction mixture for 15 minutes. Two layers were separated and the obtained organic layer was washed with demineralized water (99 lit). Sodium sulphate (19 kg) was charged to the organic layer and stirred for 5 minutes and then allowed to settle for 15 minutes. The reaction <n="39"/>solution was filtered and washed the cake with dichloromethane (30 lit). To the filtrate, activated carbon (5 kg) was added and stirred the whole solution for 15 minutes. The resultant solution was filtered on hyflow super cell and washed the hyflow super cell bed with dichloromethane (30 lit). The total filtrate was concentrated at a temperature below 45 C under vacuum between not less than 600 mmHg till no more solvent distills off. The reaction crude was cooled to the temperature 30 to 35 0C and dissolved in ethyl acetate (74 lit). The reaction solution was allowed to raise the temperature to 30-35 0C and stirred the reaction mixture for 15 minutes, n-hexane (1 11.5 lit) was charged to the reaction mixture and cooled to 15-20 0C followed by stirring for 1 hour. The reaction mixture was subjected to centrifuge and then washed the wet cake with mixture of ethyl acetate and n-hexane (14.6 lit+22.5 lit) followed by washing with n-hexane (25 lit). The obtained solid was dried at temperature 35 to 40 0C under vacuum not less than 650 mmHg for 12 hours to obtain 22.6 kg of title compound.Seiving:Capecitabine (25 kg) was charged into container, which was arranged with shifter. The material was sieved through shifter and then weighed to obtain 22.5 kg.XRPD pattern - As shown in Figure 1 DSC: 119.84 0CTGA: no weight loss up to 100 0C Particle size distribution:D10: 1.82 mum D90: 40.51 mumWater content: 0.06 % by Karl Fisher method (KF method) Purity: 99.6 % w/w assay by HPLC. (Single impurity: 0.005 %; Total impurities: 0.15 %)Micronization: <n="40"/>Capecitabine (3.9 kg), obtained according to above process, was charged into micronizer. Micronization was started slowly through the product feed funnel for micronizer through the hopper at the feed rate of 2 to 3 kgs / hour and the material was collected into the collector at feed pressure 3-4 kgs/cm2. Finally the collector was removed from the micronizer and the material was unloaded to obtain 3.83kgs.XRPD pattern has shown in Figure 5 DSC: 120.07 0C TGA: no weight loss up to 100 0C Particle size distribution:10% less than 1.08 mum50% less than 2.46 mum90% less than 5.04 mum Water content: 0.05 % w/wPurity: 99.8 % assay by HPLC. (Single maximum impurity: 0.05%; Total impurities: 0.13%) Example 10: PROCESS FOR PREPARING CAPECITABINE OF FORMULA I 5'-deoxy-2',3'-O-acetyl-N-[(pentyloxy) carbonyl]-5-fluorocytidine of Formula C (20 g) was dissolved in methanol (40 ml) and cooled the whole solution to -10 to -150C. 1 N sodium hydroxide was added to the obtained reaction solution over a period of 30 minutes at a temperature of -5 to -10 0C. After completion of the reaction, the reaction mixture was adjusted pH to 4.24 by using conc.hydroxhloric acid (6.1 ml). Dichloromethane (200 ml) was charged to the reaction mixture followed by two layers were separated. The resultant organic layer was washed with demineralized water (100 ml) and then concentrated the organic layer up to reach 2 volumes (32 ml) of the solvent in the reaction solution. Then the reaction solution was cooled to room temperature. Toluene (160 ml) was charged to the reaction solution and stirred for 2 to 3 hours and then the suspension was filtered.The solid was washed with toluene (16 ml) and then dried for 4 to 5 hours at 40 0C to afford 11.4 g of title compound.Purity: 99.74 % by HPLC.
		1.2 g of the oil from the Example 2 was dissolved in 3 ml of methanol. A solution of 0.4 g NaOH in 2 ml water was added at 0 C. After stirring for 30 minutes at 0 C., the pH was adjusted to about 5 by addition of concentrated HCl. Then, 10 ml dichloromethane and 5 ml water were added. Mixed for 5 minutes. The layers were separated. The organic layer was washed with 5 ml of water, dried on Na2SO4 and concentrated under reduced pressure. To the oil was added 1 ml of ethyl acetate. To the resulting solution 2 ml of n-heptane was added. An oily precipitate was formed. Seeded with a seed of capecitabine crystals, the oil slowly solidified. After 2 hours the solid was filtered off and dried in a vacuum oven at 40 C. for 16 hours.Yield: 0.58 gNMR: confirmed the structureHPLC: purity >99.8%
		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 sodium hydroxide; water; In dichloromethane; at 0℃; for 1h;	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.
		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.
		Formula Il (5 g) is dissolved in methanol (10 mL) at room temperature and then cooled to -5 to 00C. 1 N sodium hydroxide solution (15.9 mL) is added slowly at -5 to 0C and stirred for 30 minutes. The pH of the mixture is adjusted to about 4.3 with concentrated hydrochloric acid (1 .5 mL) at -5 to 5C. Dichloromethane (30 mL) is added and stirred for 15 minutes at room temperature. The layers are separated and the aqueous layer is extracted with dichloromethane (20 mL) followed by washing the organic layer with water (10 mL). The combined organic layer is distilled to about 8 mL at 40-450C. Toluene (40 mL) is added and stirred for 2 hours at 25-30C. The suspension is filtered. The solid is washed with toluene (5 mL) and dried for 4 hours at 40-45C under vacuum, to give 2.7 g of title compound.Purity: 99.78% by HPLC; impurity at 1 .23 RRT: 0.1 %; impurity at 0.75 RRT: 0.02%
	With sodium hydroxide; In acetone; at -15 - 10℃; for 2h;	General procedure: To a solution of K2CO3 (0.626 g, 0.0453 mol) in acetone (80 mL) was added 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine (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 sodium hydroxide; In methanol;	Capecitabine 2 was obtained by sodium hydroxide in methanol hydrolysis of 2',3'-diacetyl groups of 10b, as reported in literature,1 following the reaction progress by TLC.

Reference： [1]Patent: EP2241556,2010,A1 .Location in patent: Page/Page column 10
[2]Patent: CN104744537,2018,B .Location in patent: Paragraph 0020; 0023; 0026; 0027; 0029
[3]Patent: CN106478751,2017,A .Location in patent: Paragraph 0024; 0063; 0064; 0065
[4]Patent: US2011/21769,2011,A1 .Location in patent: Page/Page column 3; 7
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[17]Tetrahedron Letters,2015,vol. 56,p. 5909 - 5913

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[ 154361-50-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2000,vol. 8,p. 1697 - 1706
[2]Patent: WO2011/104540,2011,A1
[3]Patent: WO2011/104540,2011,A1
[4]Patent: WO2011/104540,2011,A1
[5]Organic Letters,2012,vol. 14,p. 3348 - 3351
[6]European Journal of Medicinal Chemistry,2012,vol. 54,p. 690 - 696
[7]Tetrahedron Letters,2015,vol. 56,p. 5909 - 5913
[8]Tetrahedron Letters,2015,vol. 56,p. 5909 - 5913

3
[ 161599-46-8 ]
[ 154361-50-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2000,vol. 8,p. 1697 - 1706
[2]European Journal of Medicinal Chemistry,2012,vol. 54,p. 690 - 696

4
[ 27821-07-4 ]
[ 154361-50-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2000,vol. 8,p. 1697 - 1706
[2]Organic Process Research and Development,2016,vol. 20,p. 609 - 614
[3]Patent: CN102212095,2016,B
[4]Patent: CN106478751,2017,A

Yield	Reaction Conditions	Operation in experiment
		For the effective combination of the 5'-deoxycytidine derivative represented by the formula (I) with 5-FU or its derivative for the treatment of cancer with an improved efficacy and safety profile, a 5-FU derivative can be selected from the group consisting of: ... 5'-deoxy-5-fluoro-N4 -(n-propoxycarbonyl)cytidine, N4 -(n-butoxycarbonyl)-5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluoro-N4 -(n-pentyloxycarbonyl)cytidine, 5'-deoxy-5-fluoro-N4 -(isopentyloxycarbonyl)cytidine, ...
		For the combination of a 5'-deoxy-cytidine derivative represented by the formula (I) with 5-FU or a derivative thereof for the treatment of cancer with an improved efficacy and safety profile, the 5-FU derivative is preferably selected from the group consisting of: ... 1-(n-hexyloxycarbonyl)-5-fluorouracil, 5'-deoxy-5-fluorouridine, 5'-deoxy-5-fluoro-N4 -(n-propoxycarbonyl)cytidine, N4 -(n-butoxycarbonyl)-5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluoro-N4 -(n-pentyloxycarbonyl)cytidine, 5'-deoxy-5-fluoro-N4 -(isopentyloxycarbonyl)cytidine, 5'-deoxy-5-fluoro-N4 -(n-hexyloxycarbonyl)cytidine, 5'-deoxy-N4 -[(2-ethylbutyl)oxycarbonyl]-5-fluorocytidine, ...
		The compounds according to claim 1, selected from a group consisting of: ... N4 -(cyclohexyloxycarbonyl)-5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluoro-N4 -[(3-phenylpropyl)oxycarbonyl]cytidine, 5'-deoxy-5-fluoro-N4 -[(2-methoxyethoxy)carbonyl]cytidine, N4 -(butoxycarbonyl)-5'-deoxy-5-fluorocytidine and 5'-deoxy-5-fluoro-N4 -(pentyloxycarbonyl)cytidine.

		Ten microliters (10 muCi) of 3H-Gemcitabine was dried under a Speedvac to remove ethanol, then mixed with 250 mul of 30 mg/ml gemcitabine to get a final solution with radiospecificity of 0.4 mCi/mmol. The final concentration of this 3H-Gemcitabine solution was 30 mg/ml. Preparation of capecitabine solution from capecitabine tablet:
		claim 18 , wherein said anti-neoplastic agent or salt thereof is vincristine, vinblastine, etoposide, teniposide, Ara-A (adenoside-arabinoside), Ara-C (cytarabine), fluorouracil, procarbazine, vinorelbine, gemcitabine, or a mixture of paclitaxel and carboplatin, paclitaxel and an anthracycline, ... docetaxel and doxorubicin, docetaxel and vinorelbine, docetaxel and trastuzumab, docetaxel and capecitabine, cisplatin and cyclophosphamide, cisplatin and irinotecan, carboplatin and topotecan, ...

6
[ 154361-50-9 ]
[ 66335-38-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate; In methanol; N,N-dimethyl-formamide; for 24h;Heating / reflux;	Capecitabine (5'-deoxy-5-fluoro-N4-(pentyloxycarbonyl)cytidine, 4.5 g, 12.5 mmol) was suspended in methanol (250 mL) and DMF (10 mL) together with potassium carbonate (8.8 g, 63.77 mmol) and the solution heated under reflux for 24 h. The solution was then cooled and evaporated to dryness (below 45 °C). The residue was redissolved in hot methanol, filtered and washed with hot methanol. The filtrate was preabsorbed onto silica gel and puified by flash chromatography, eluting with 50 percent methanol / ethyl acetate to give 3.0 g (90 percent) of l-[3,4-dihydroxy-5-methyl- tetrahydrofuran-2-yl]-4-amino-lH-pyrimidin-2-one. This material was suspended in chloroform (125 mL) and the solution heated to 50 0C. Acetic acid (2 mL, 34 mmol) was added and after 10 minutes at 50 0C, acetyl chloride (20 mL, 206 mmol) was added. The suspension was stirred at 50 0C for 7 h and then at 20 °C for 72 h. Ether (100 mL) was added and the solid filtered and washed with ether to give 4.0 g (90 percent) l-[3,4-Diacetoxy-5-methyl-tetrahydrofuran-2-yl]-4-amino-lH-pyrimidin-2-one hydrochloride. This material (2.07g, 5.7 mmol) together with 5-nitrothien-2- ylmethanol (1.47 g, 9.3 mmol), was dissolved in pyridine (1.4 mL, 17.4 mmol) and DCM (15 mL). Phosgene solution (3.6 mL of a 2M solution in toluene, 7.2 mmol) was slowly added to the above cooled (O0C) solution, the solution was stirred at O0C for 2.5 h and then a further 3.6 mL of phosgene solution added and the solution stirred at O0C for a further 2h and refrigerated for 18 h. The solution was partitioned (ethyl EPO <DP n="39"/>acetate and brine), the aqueous phase extracted (ethyl acetate) dried and evaporated.The residue was purified on silica, eluting with 2percent methanol / DCM, to give an off- white foam (400 mg, 14 percent); TLC Rf=0.45, 2percent methanol / ethyl acetate. LC-RT 4.68 min (TFA20-50percent); MS m/z 201/159/143. 1H NMR (500 MHz, DMSO) delta 11.20 (IH, bs, NH), 8.3 (IH, b, NCH=CF), 8.05 (IH, s, HarH), 7.30 (s, IH, HarH), 5.80 (IH, s, NCHO), 5.42 (3H, m, HarCH2OCONH, CHOAc), 5.15 (IH, s, CHOAc), 4.05 (IH, m, OCHCH3), 3.45 (2H, m, 2 x CHOAc), 2.48 (3H, s, OAc), 2.05 (3H, s, OAc), 1.37 (3H, s, OCHCH3) ppm.

Reference： [1]Patent: WO2006/32921,2006,A1 .Location in patent: Page/Page column 37-38

7
[ 934385-83-8 ]
[ 154361-50-9 ]

Yield	Reaction Conditions	Operation in experiment
87%	With hydrogenchloride; In methanol; for 8h;Reflux;	The above compound II was dissolved in 150 mL of methanol, 2.5 mL of concentrated hydrochloric acid was added, and the mixture was heated under reflux for 8 hours. Wash with n-hexane The organic phase was washed with purified water, dried over anhydrous sodium sulfate, filtered and concentrated, the acetone /Isopropyl ether to give 24.7 g of white crystals (capecitabine) in a yield of 87%.
	With ethanol; water;Amberlist 15 catalyst; at 25 - 30℃; for 8 - 9h;Product distribution / selectivity;	EXAMPLE 5: PREPARATION OF CAPECITABINE (FORMULA I) delta'-deoxy^'.S'-O-isopropylidene-N-KpentyloxyJcarbonylJ-delta-fluorocytidine ofFormula Il (460 mg), obtained in Example 4, absolute ethanol (22 ml), Amberlyst 15 catalyst (3.5 g) and demineralized water (0.6 ml) were charged into a clean and dry 4 neck round bottom flask followed by stirring for 9 hours at 25-30 0C. Conversion of 5'-deoxy-2',3'-O-isopropylidene-N-[(pentyloxy) carbonyl]- 5-fluorocytidine was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a celite bed and the celite was washed with ethanol (5 ml). The filtrate obtained was distilled completely at 40 0C. Diisopropyl ether (10 ml) was added to the residue and stirred at 25-30 C for 15 minutes, and distilled completely at 40 C under a vacuum of 600 mm Hg. Ethyl acetate (1.5 ml) was added to the residue and cooled to 0-5 0C. The solution was stirred for 30 minutes, n-hexane (2 ml) was charged, solid was precipitate and stirred at 25- 30 0C for 30 minutes. The solid that formed was filtered and the solid was washed with precooled ethyl acetate (0.5 ml) to afford 0.12 g of the title compound. <n="36"/>NMR: 0.88 (t, 3H), 1.291.6 (m, 6H), 1.33 (d, 3H), 3.67 (q, 1 H), 3.86 (t, 1 H), 3.86 (s, 1 H), 4.09 (t, 2H), 5.07 (d, 1 H), 5.43 (d, 1 H), 8.06 (s, OH), 10.56 (t, OH), 1 1.65 (S1NH).Mass: m/z 359.9[m++H] EXAMPLE 8: PREPARATION OF CAPECITABINE (FORMULA I)5'-deoxy-2',3'-O-isopropylidene-n-[(pentyloxy) carbonyl]-5-fluorocytidine of Formula Il (5.5 g), obtained in Example 7, was charged into a clean and dry 4 neck round bottom flask. Ethanol (110 ml) and water (5 ml) were charged followed by stirring for about 10 minutes. Amberlyst 15 catalyst (5.5 g) was charged to the reaction solution and stirred for 8 hours. After completion of the reaction, the reaction mixture was filtered and then the obtained filtrate was distilled completely at 45 0C under a vacuum of 600 mm Hg. Ethyl acetate (9.3 ml) was charged to the residue and heated to 45-50 0C for 15 minutes. The solution was cooled to 25-30 C and stirred for 30 minutes. The solution was further cooled to 0 0C and the suspension was stirred for 1 hour. The solid that formed was filtered and the solid was washed with precooled ethyl acetate (3 ml). The solid obtained was dried at 35 0C under a vacuum of 600 mm Hg for 4 hours to afford 1 g of the title compound.

Reference： [1]Patent: CN103897004,2017,B .Location in patent: Paragraph 0028; 0029
[2]Patent: WO2008/131062,2008,A2 .Location in patent: Page/Page column 34-35; 36

8
C₂₁H₃₈FN₃O₆Si₂ [ No CAS ]
[ 154361-50-9 ]

Yield	Reaction Conditions	Operation in experiment
		Example 11 Preparation of 5'-Deoxy-5-fluoro-[N4-(pentyloxy)carbonyl]-cytidine 30 g of 5'deoxy-5-fluoro-cytidine from the preceding step was dissolved in 90 g of pyridine (3 volumes) and 90 ml of dichloromethane (3 volumes), the solution was cooled to 0-5 C. and chlorotrimethylsilane (3 equivalents, 30 g) was added and the temperature was left to rise until RT and kept for 30 minutes, 200 ml of dichloromethane (about 7 volumes) were added the suspension was cooled to -15/-10 C. 30 g of n-pentyl chloroformate (2.1 equivalents) were added and the temperature rose until 0-5 C. and kept for 2 hours. 300 ml of water (10 volumes) were added and, keeping the temperature below 5 C., the mixture was acidified with dilute sulphuric acid until pH 1.0-1.5. Phases were separated and the water phase was discarded. Organic phase was cooled to -10/-15 C. and 30 g of sodium hydroxide 32% in water (2,6 equivalents) dissolved in 60 ml of methanol were added, keeping the temperature between -15 C. and -10 C. After 30 minutes, the reaction was completed and 210 ml of salted water was added and the pH was corrected to 6-7 with dilute sulphuric acid. Phases were separated and the water one was back-extracted with dichloromethane (75 ml*2). All the organic phases were combined and were concentrated under vacuum at a temperature of less than about 40 C. until 30 ml of residual volume. 210 ml of toluene were added and the solution was concentrated again under vacuum until 150 ml of residual volume, other 150 ml of toluene were added and the solution was kept at room temperature for 8 hours. The suspension was filtered and the solid washed with toluene and was dried under vacuum at 50 C. Yield: 36.6 g equivalent to 82% from 2',3'-di-O-acetyl-5'deoxy-5-fluorocytidine.

Reference： [1]Patent: US2009/209754,2009,A1 .Location in patent: Page/Page column 10

9
[ 1158844-54-2 ]
[ 154361-50-9 ]

Yield	Reaction Conditions	Operation in experiment
	With methanol; sodium hydroxide; water; at -5 - 0℃; for 0.5h;	Example 4: Preparation of5'-deoxy-5-fluoro-N4-(pentyloxycarbonyl)cytidine (the compound of formula 1); 42.9 g of the compound obtained in Example 3 was added to 215 ml of methanol, and the mixture was stirred and cooled to -5 to 0 C . 10.8 g of NaOH was dissolved in 107 ml of water, and NaOH solution was added thereto while maintaining the reaction mixture temperature at less than 0C . The resulting mixture was stirred for 30 min, and 48 ml of 6 N HCl was added dropwise thereto until the pH of the reaction mixture became 5.3. The resulting mixture was successively washed twice with 215 ml of dichloromethane and once with 108 ml of dichloromethane, and the combined organic layer was washed with 215 ml of water, dried over anhydrous sodium sulfate, filtered and concentrated under a reduced pressure. After adding 129 ml of ethylacetate thereto, the residue was mixed with 97 ml of ethylacetate by stirring to be crystallized. 97 ml of hexane was added dropwise thereto to allow the crystal to be matured, and the resulting mixture was stirred for 1 hr, cooled to 0 "C and again stirred for 1 hr. The resulting solid was filtered, washed with 86 ml of a solid mixture of ethylacetate and hexane (1 : l(v/v)) cooled to 0 C , and dried in a 35 C vacuum oven overnight, to obtain 28.6 g of the title compound as a light white solid.1H NMR(CD3OD) delta 0.91(3H5 t), 1.36~1.40(4H, m), 1.41(3H, d), 1.68~1.73(2H, m), 3.72(1H, dd), 4.08(1H, dd), 4.13~4.21(3H, m), 5.7O(1H, s), 7.96(1H, d)

Reference： [1]Patent: WO2009/66892,2009,A1 .Location in patent: Page/Page column 13

Yield	Reaction Conditions	Operation in experiment
	In ethyl acetate; at 25 - 30℃; for 1h;Purification / work up;	This solid (1.45 g, 1 equivalent) was further purified by dissolving in ethyl acetate (7.25 ml, 5 vol) at 25-30C and stirring for 30 minutes. A white precipitation was observed and stirred for 30 minutes. The slurry was filtered and washed with 1:1 ethyl acetate : n-hexane (4 vol) and dried to afford white coloured <strong>[154361-50-9]capecitabine</strong> (1).Yield (molar) = 1.16 g (80%)Specific Optical Rotation [oc]20D = +97.73 (c = 1, MeOH)HPLC: RT matches with USP standardHPLC Purity = 98.8 %

11
[ 638-41-5 ]
[ 66335-38-4 ]
[ 154361-50-9 ]

Yield	Reaction Conditions	Operation in experiment
80%		5-Fluoro-5'-deoxycytidine (0101) (5.0 g, 1 equivalent, 0.020 mol) was added to acetonitrile (50 ml) and stirred at 25-30°C for 15 minutes. A colourless mass was observed. The mixture was cooled to -5°C to 0°C and thionyl chloride (4.45 ml, 3 equivalents, 0.061 mol) was added dropwise in about 15 minutes. Pyridine (6.6 ml, 4 equivalents, 0.0814 mol) was also added dropwise in about 20-25 minutes, whilst maintaining the temperature at -5°C to 0°C. The reaction mixture was stirred for a further 2 hours and, after completion of the reaction was observed by TLC, the mixture was cooled to -5°C to 0°C. N-Pentyl chloro formate (3.03 ml, 1 equivalent, 0.020 mol) was then added dropwise in about 20-25 minutes, whilst maintaining the temperature at -5°C to 0°C. The reaction mixture was stirred for 15 minutes, before it was allowed to warm to ambient temperature gradually, and then stirred for a further 2 hours. The solvent was removed under vacuum at 40°C, methanol (50 ml, 10 vol) was added and the mixture stirred at 25-30°C for 15 minutes. The mixture was cooled to -5°C to 0°C before IN NaOH (70 ml) was added dropwise in about 20-25 minutes, whilst mamtaining the temperature at -5°C to 0°C. The reaction mixture was stirred for 1 hour. After stirring for 1 hour, water was added (50 ml, 10 vol), the pH of the reaction mixture was adjusted to 4 to 6 using HC1 and the reaction mixture was then stirred for 30 minutes. Dichloromethane (50 ml, 10 vol) was added and the mixture stirred for 30 minutes before separating the organic layer. The aqueous layer was further extracted with dichloromethane (2 x 50 ml, 2 x 10 vol) and removal of the solvent from the combined DCM layers afforded capecitabine (1).Yield (molar) = 5.86 g (80percent)Specific Optical Rotation [oc]20D = +98.0° (c = 1, MeOH)HPLC Purity > 99.50 percent

Reference： [1]Patent: WO2011/67588,2011,A1 .Location in patent: Page/Page column 41

12
[ 66335-38-4 ]
[ 154361-50-9 ]

Reference： [1]Patent: WO2011/67588,2011,A1
[2]Patent: CN106699825,2017,A

13
[ 1309454-52-1 ]
[ 154361-50-9 ]

Yield	Reaction Conditions	Operation in experiment
82%		Cyclic sulfinyl ester (0302) (2 g, 1 equivalent, 0.0049 mol) was added to methanol (20 ml, 10 vol) and stirred at 25-30C for 15 minutes. The mixture was cooled to -5C to 0C and IN NaOH (13.6 ml) was added dropwise in about 20-25 minutes, whilst maintaining d e temperature at -5C to 0C. The reaction mixture was stirred for 1 hour. After stirring for 1 hour, water was added (20 ml, 10 vol), the pH of the reaction was adjusted to 4 to 6 using HC1 and the reaction mixture was then stirred for a further 30 minutes. Dichloromethane (20 ml, 10 vol) was added to the reaction mass and the mixture was stirred for a further 30 minutes. The organic layer was separated and the aqueous layer further extracted with dichloromethane (2 x 20 ml, 2 x 10 vol). Removal of the DCM extracts afforded capecitabine (1).Yield (molar) = 1.45 g (82%) Specific Optical Rotation [oc]20D = +97. (c = 1, MeOH)HPLC Purity = 97.2 %

Reference： [1]Patent: WO2011/67588,2011,A1 .Location in patent: Page/Page column 39-40

14
[ 1309454-51-0 ]
[ 154361-50-9 ]

Reference： [1]Patent: WO2011/67588,2011,A1

15
[ 67036-14-0 ]
[ 66335-38-4 ]
[ 154361-50-9 ]

Yield	Reaction Conditions	Operation in experiment
55%	pyridine; In tetrahydrofuran; for 9 - 10h;Reflux;	(b) Preparation of capecitabine 1 by reaction of 5-fluoro-5'-deoxycytidine (0101) with pentyloxycarbonyl-4-nitrophenoxy (0302, X = -O-4-nitrophenyl)5- Fluoro-5'-deoxycytidine (3 g, 1 mol equivalent) was added to THF (60 ml) before pentyloxycarbonyl-4-nitrophenoxy (3.1 g, 1 mol equivalent) and pyridine (0.9 ml, 1 mol equivalent) were added. The reaction mixture was heated to reflux for 9-10 hours before the solvent was removed by vacuum distillation. Water (100 ml) was added to the residue followed by addition of ethyl acetate (150 ml). After stirring for 15 minutes, the organic layer was separated and washed with sodium bicarbonate solution (100 ml, 2.5 w/w). The solvent was removed under vacuum distillation from the organic layer to afford a gummy residue, which was dissolved in ethyl acetate (10 ml) and then cooled to 0-5°C to give capecitabine 1 as a white solid which was isolated by filtration and drying in a vacuum oven at 50-55°C for 8 hours.Yield = 2.4 g (55percent)Specific Optical Rotation: within the USP 32 range of [oc] 0D = +96.0° to +100.0° (c = lOmg/ml, MeOH)]HPLC: RT matches with USP standard HPLC Purity = 99.2percent

Reference： [1]Patent: WO2011/104540,2011,A1 .Location in patent: Page/Page column 20-21

16
[ 1332927-90-8 ]
[ 66335-38-4 ]
[ 154361-50-9 ]

Yield	Reaction Conditions	Operation in experiment
67%	pyridine; In tetrahydrofuran; for 9 - 10h;Reflux;	(b) Preparation of capecitabine 1 by reaction of 5-fluoro-5'-deoxycytidine (0101) with pentyloxycarbonyl-pentafiuorophenoxy (0302, X = -O-pentafiuorophenyl)5-Fluoro~5'-deoxycytidine (4 g, 1 mol equivalent) was added to THF (80 ml) before pentyloxycarbonyl-pentafluorophenoxy (9.7 g, 2.5 mol equivalent) and pyridine (1.3 ml, 1 mol equivalent) were added. The reaction mixture was heated to reflux for 9-10 hours before the solvent was removed by vacuum distillation. Water (100 ml) was added to the residue followed by addition of ethyl acetate (150 ml). After stirring for 15 minutes, the organic layer was separated and washed with sodium bicarbonate solution (100 ml, 2.5 w/w). The solvent was removed under vacuum distillation to afford a gummy residue. The residue was dissolved in ethyl acetate (10 ml) and then cooled to 0-5°C to give capecitabine 1 as a white solid which was isolated by filtration and drying in a vacuum oven at 50-55°C for 8 hours.Yield = 3.9 g (67percent)Specific Optical Rotation: within the USP 32 range of [oc]20D = +96.0° to +100.0° (c = lOmg/ml, MeOH)]HPLC: RT matches with USP standardHPLC Purity = 99.10percent

Reference： [1]Patent: WO2011/104540,2011,A1 .Location in patent: Page/Page column 21

17
1-(pentyloxycarbonyl)imidazole [ No CAS ]
[ 66335-38-4 ]
[ 154361-50-9 ]

Yield	Reaction Conditions	Operation in experiment
50%		(b) Preparation of capecitabine 1 by reaction of 5-fluoro-5'-deoxycytidine (0101) with pentyloxycarbonyl-imidazole (0302, X = imidazolyl)5-Fluoro-5'-deoxycytidine (3 g, 1 mol equivalent) was added to acetonitrile (60 ml) and stirred at 25-30°C for 15 minutes. To the stirring suspension, DCM HCl solution (5percent w/w of HCl gas in DCM, 10 ml) was added and stirred for 30 minutes. Pentyloxycarbonyl- imidazole (2.45 g, 1 mol equivalent) was added and the reaction mixture was heated at reflux for 5 hours. The solvent was removed under vacuum to afford a gummy residue. Ethyl acetate (10 ml) was added to the residue and stirred vigorously before the organic layer was decanted and then cooled to 0-5°C for 30 minutes to afford capecitabine 1 as a white solid which was isolated by filtration and drying in a vacuum oven at 50-55°C for 8 hours.Yield = 2.1 g (50percent)Specific Optical Rotation: within the USP 32 range of [oc]20D = +96.0° to +100.0° (c = lOmg/ml, MeOH)]HPLC: RT matches with USP standardHPLC Purity = 99.20percent

Reference： [1]Patent: WO2011/104540,2011,A1 .Location in patent: Page/Page column 19

18
pentyloxycarbonyl-1-hydroxybenzotriazole [ No CAS ]
[ 66335-38-4 ]
[ 154361-50-9 ]

Yield	Reaction Conditions	Operation in experiment
66%	In tetrahydrofuran; at 25℃; for 10h;Reflux;	(b) Preparation of capecitabine 1 by reaction of 5-fluoro-5'-deoxycytidine (0101) with pentyloxycarbonyl-l-hydroxybenzottiazole (0302, X = -OBt)5-Fluoro-5'-deoxycytidine (5 g, 1 mol equivalent) and pentyloxycarbonyl-1- hydroxybenzotriazole (0302, X = -OBt, 5.45 g, 1 mol equivalent) were added to THF (100 ml, 20 vol) and stirred at 25-30°C for 15 minutes. The reaction mixture was heated to reflux for 9-10 hours before the solvent was removed by vacuum distillation. Water (100 ml) was added to the residue followed by the addition of ethyl acetate (150 ml). After stirring for 15 minutes, the organic layer was separated and washed with sodium bicarbonate solution (100 ml, 2.5 w/w). The solvent was removed under vacuum cUstillation from the organic layer to afford a gummy residue. The residue was dissolved in ethyl acetate (5 ml) and then cooled to 0-5°C to give capecitabine 1 as a white solid which was isolated by filtration and drying in a vacuum oven at 50-55°C for 8 hours.Yield = 4.8 g (66percent)Specific Optical Rotation: [oc]20D = +96.93° (c = lOmg/ml, MeOH)[which is within the USP 32 range of [o ]20D = +96.0° to +100.0° (c = lOmg/ml, MeOH)]HPLC: RT matches with USP standardHPLC Purity = 98.8percent

Reference： [1]Patent: WO2011/104540,2011,A1 .Location in patent: Page/Page column 18

19
[ 862508-03-0 ]
[ 154361-50-9 ]

Reference： [1]Organic Letters,2012,vol. 14,p. 3348 - 3351

20
[ 1071455-34-9 ]
[ 154361-50-9 ]

Reference： [1]Organic Letters,2012,vol. 14,p. 3348 - 3351

21
[ 638-41-5 ]
[ 27821-07-4 ]
[ 154361-50-9 ]

Reference： [1]Organic Letters,2012,vol. 14,p. 3348 - 3351

22
[ 71-41-0 ]
[ 154361-50-9 ]

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

23
[ 530-62-1 ]
[ 154361-50-9 ]
[ 921769-65-5 ]

Yield	Reaction Conditions	Operation in experiment
88%	In dichloromethane; at 20℃;Inert atmosphere;	General procedure: Methylene dichloride (120 mL) was taken in a 500 mL 4-necked RB flask fitted with magnetic bar, thermo pocket, guard tube and nitrogen inlet. 5'-Deoxy-5-fluoro-N4-(2-methyl-1-butyloxycarbonyl)-cytidine (4 g, 0.0114 mol) was added in one lot, once the clear solution was formed, CDI (2.257 g, 0.01393 mol) was added in one lot under nitrogen atmosphere and the reaction mixture was stirred over 10-12 h. After the completion of the reaction (TLC), the reaction mixture was filtered and washed with 2 volumes (20 mL) of methylene dichloride. Thus obtained crude product was further purified by column chromatography (1:1 hexane/EtOAc) to get the title compound. The desired product was isolated and concentrated in rota evaporator. Finally it is dried under vacuum at 50 C to get the pure product.

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

24
[ 638-41-5 ]
[ 161599-46-8 ]
[ 154361-50-9 ]

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%.

Reference： [1]Organic Process Research and Development,2019,vol. 23,p. 2516 - 2520
[2]Patent: CN103897005,2017,B .Location in patent: Paragraph 0025-0026
[3]Tetrahedron Letters,2015,vol. 56,p. 5909 - 5913
[4]Patent: CN102212095,2016,B
[5]Patent: CN106478751,2017,A

25
[ 128963-10-0 ]
[ 154361-50-9 ]

Reference： [1]Tetrahedron Letters,2015,vol. 56,p. 5909 - 5913
[2]Tetrahedron Letters,2015,vol. 56,p. 5909 - 5913
[3]Tetrahedron Letters,2015,vol. 56,p. 5909 - 5913

26
[ 396684-34-7 ]
[ 154361-50-9 ]

Reference： [1]Tetrahedron Letters,2015,vol. 56,p. 5909 - 5913
[2]Tetrahedron Letters,2015,vol. 56,p. 5909 - 5913
[3]Tetrahedron Letters,2015,vol. 56,p. 5909 - 5913

27
2',3'-di-O-acetyl-5-fluoro-N4-(pentyloxycarbonyl)cytidine [ No CAS ]
[ 154361-50-9 ]

Reference： [1]Tetrahedron Letters,2015,vol. 56,p. 5909 - 5913
[2]Tetrahedron Letters,2015,vol. 56,p. 5909 - 5913
[3]Tetrahedron Letters,2015,vol. 56,p. 5909 - 5913

28
5'-bromo-2',3'-di-O-acetyl-5-fluoro-N4-(pentyloxycarbonyl)cytidine [ No CAS ]
[ 154361-50-9 ]

Reference： [1]Tetrahedron Letters,2015,vol. 56,p. 5909 - 5913
[2]Tetrahedron Letters,2015,vol. 56,p. 5909 - 5913

29
5'-iodo-2',3'-di-O-acetyl-5-fluoro-N4-(pentyloxycarbonyl)cytidine [ No CAS ]
[ 154361-50-9 ]

Reference： [1]Tetrahedron Letters,2015,vol. 56,p. 5909 - 5913

30
[ 4137-56-8 ]
[ 154361-50-9 ]