[ CAS No. 2353-33-5 ] {[proInfo.proName]}

Name: 2353-33-5|4-Amino-1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1,3,5-triazin-2(1H)-one|99%
Brand: Ambeed
SKU: A156645
Price: 5.0 USD
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Quality Control of [ 2353-33-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 2353-33-5 ]

SDS Specification

Alternatived Products of [ 2353-33-5 ]

Product Details of [ 2353-33-5 ]

CAS No. :	2353-33-5	MDL No. :
Formula :	C₈H₁₂N₄O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XAUDJQYHKZQPEU-KVQBGUIXSA-N
M.W :	228.21	Pubchem ID :	451668
Synonyms :	5-Aza-2'-deoxycytidine;5-AZA-CdR;US brand name: Dacogen. Abbreviations: 5AZA;dezocitidine;deoxyazacytidine;5-aza-dCyd;5-aza-2’-Deoxycytidine;DAC;NSC 127716	Chemical Name :	4-Amino-1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1,3,5-triazin-2(1H)-one

Calculated chemistry of [ 2353-33-5 ] Expand+

Physicochemical Properties

Num. heavy atoms :	16
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.62
Num. rotatable bonds :	2
Num. H-bond acceptors :	6.0
Num. H-bond donors :	3.0
Molar Refractivity :	52.48
TPSA :	123.49 Å²

Pharmacokinetics

GI absorption :	Low
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) :	-9.03 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.78
Log Po/w (XLOGP3) :	-1.89
Log Po/w (WLOGP) :	-2.46
Log Po/w (MLOGP) :	-2.61
Log Po/w (SILICOS-IT) :	-1.84
Consensus Log Po/w :	-1.6

Druglikeness

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

Water Solubility

Log S (ESOL) :	-0.21
Solubility :	141.0 mg/ml ; 0.617 mol/l
Class :	Very soluble
Log S (Ali) :	-0.18
Solubility :	150.0 mg/ml ; 0.656 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	0.58
Solubility :	860.0 mg/ml ; 3.77 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.46

Safety of [ 2353-33-5 ]

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 [ 2353-33-5 ]

* 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 [ 2353-33-5 ]
Downstream synthetic route of [ 2353-33-5 ]

[ 2353-33-5 ] Synthesis Path-Upstream 1~13

1
[ 2353-33-5 ]
[ 931-86-2 ]
[ 452-51-7 ]

Reference： [1] Patent: US2006/205685, 2006, A1, . Location in patent: Page/Page column 4; sheet 3

2
[ 52523-35-0 ]
[ 80184-05-0 ]
[ 2353-33-5 ]

Yield	Reaction Conditions	Operation in experiment
89.3%	Stage #1: With cobalt(II) nitrate; 1,1'-bi-2-naphthol In N,N-dimethyl-formamide at 60℃; Inert atmosphere Stage #2: With triethylamine In N,N-dimethyl-formamide at 40℃;	1) Under nitrogen protection,will1-Chloro-2-deoxy-D-ribofuranose (15.3 g, 100 mmol)Cobalt nitrate(60 mmol),(R) -1,1'-bi-2-naphthol (15.7 g, 55 mmol) were added to 150 ml of DMF, stirred and mixed at 60 ° C for 1-2 hours, then cooled to room temperature,Filtered to give a mixture M containing 1-chloro-2-deoxy-D-ribofuranose complex;2) 11.1 g (110 mmol) of triethylamine,2,4-bis-trimethylSilicon-S-triazine(200 mmol)Into the mixture M obtained in the step 1) for 6 to 8 hours while stirring at 40 ° C,Dumped into the water,Dichloromethane extraction,2M & lt; / RTI & gt; HCl,Washed with saturated sodium bicarbonate,Concentrated and recrystallized from ethanol to obtain 20.4 g of decitabine in a yield of 89.3percent and a purity of 99.57percent.
87.2%	Stage #1: With (S)-(1,1'-binaphthalene)-2,2'-diylbis(diphenylphosphine); palladium dichloride In N,N-dimethyl-formamide at 60℃; Inert atmosphere Stage #2: With triethylamine In N,N-dimethyl-formamide at 40℃; for 6 h;	In the preparation method of decitabine according to Example 1,Except that the amount of palladium dichloride used was 17.7 g,19.9 g of decitabine was obtained,The yield was 87.2percentPurity 96.48percent.

Reference： [1] Patent: CN106046089, 2016, A, . Location in patent: Paragraph 0026; 0027; 0028; 0029
[2] Patent: CN106117290, 2016, A, . Location in patent: Paragraph 0026; 0027; 0028; 0029; 0030; 0031; 0032-0061

3
[ 1034301-08-0 ]
[ 2353-33-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	Alcoholic medium	Example 2 The compound corresponding to formula (III) as obtained in Example 1 is further treated with in an alcoholic solution of ammonia in a known manner so that 2'-deoxy-5-azacytidine (Decitabine) is obtained in practically quantitative yield.
71.6%	at 25℃; for 3 h;	42.8g of intermediate D, 1.3L of anhydrous methanol and 2.8g of sodium methoxide were added to the reaction flask, and the reaction was stirred at 25 ° C for3 h. The reaction was quenched by adding 3.0 g of glacial acetic acid, and the filtrate was stirred and lysed at 0 ° C for 6 h. 8.1 g of an off-white solid were obtained in a yield of42.1percent.The relevant substances were detected by HPLC: purity 98.7percent, maximum single impurity 0.51percent.
2.8 g	at 20℃; for 12 h;	[0054] To a trimethylsilyl derivative of 5-azacytosine (6.9 g) dissolved in methylene chloride (34 mL) 1-chioro-3,5-di (4-chlorobenzoyl)-2-deoxy-D-ribose (125 eq) were added and the solution was brought to a temperature of from 0° C. to 10° C. SnCl4 (0.8 eq) was added to the solution and the temperature was left raise up to the room value. At the end of the reaction, the mixture was cooled up to a temperature of from 0° C. to 20° C. and DMSO (4 eq) was slowly added. The precipitated SnCl4-DMSO complex was isolated by filtration. Sodium bicarbonate (4 eq) was added to the organic phase and the mixture was kept under stirring for 1 hout The solid was removed by filtration and the organic phase was washed with cold watet The organic phases were separated, dried over sodium sulfate and the solvent was removed by distillation under low pressure to give a viscous residue. The residue was added with methanol (70 mL) and a 30percent solution of sodium methoxide in methanol (0.2 eq) was added to the resultant solution. The solution was kept under stirring at room temperature for 12 hours and the resultant solid was filtered, washed with methanol (300 mL) and dried. 2.8 g of decitabine with a purity of 9 8.8percent (determined by HPLC) and a tin content lower than 200 ppm was obtained.

Reference： [1] Patent: EP2050757, 2009, A1, . Location in patent: Page/Page column 4
[2] Patent: CN108239128, 2018, A, . Location in patent: Paragraph 0108; 0112; 0113; 0114; 0115; 0120; 0127; 0136
[3] Patent: US2014/135490, 2014, A1, . Location in patent: Paragraph 0054

4
[ 931-86-2 ]
[ 3601-89-6 ]
[ 2353-33-5 ]

Reference： [1] Patent: EP2371825, 2011, A1, . Location in patent: Page/Page column 9
[2] Patent: US2011/245485, 2011, A1, . Location in patent: Page/Page column 7

5
[ 931-86-2 ]
[ 21740-23-8 ]
[ 2353-33-5 ]

Reference： [1] Patent: EP2048151, 2009, A1, . Location in patent: Page/Page column 3

6
[ 1207459-15-1 ]
[ 52523-35-0 ]
[ 2353-33-5 ]

Reference： [1] Patent: US2010/36112, 2010, A1, . Location in patent: Page/Page column 7-8

7
[ 931-86-2 ]
[ 951-78-0 ]
[ 2353-33-5 ]

Reference： [1] Catalysis Today, 2016, vol. 259, p. 197 - 204

8
[ 1034301-08-0 ]
[ 1140891-02-6 ]
[ 2353-33-5 ]

Reference： [1] Patent: US2010/249394, 2010, A1, . Location in patent: Page/Page column 6

9
[ 931-86-2 ]
[ 17039-17-7 ]
[ 2353-33-5 ]

Reference： [1] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 2588 - 2601

10
[ 22432-93-5 ]
[ 2353-33-5 ]

Reference： [1] Patent: WO2010/129211, 2010, A2, . Location in patent: Page/Page column 28

11
[ 135567-49-6 ]
[ 2353-33-5 ]

Reference： [1] Patent: US2006/14949, 2006, A1, . Location in patent: Page/Page column 6; 15
[2] Patent: US2006/14949, 2006, A1, . Location in patent: Page/Page column 18

12
[ 135567-49-6 ]
[ 2353-33-5 ]

Reference： [1] Patent: US2006/14949, 2006, A1, . Location in patent: Page/Page column 15

13
[ 69304-64-9 ]
[ 2353-33-5 ]

Reference： [1] Journal of Pharmaceutical Sciences, 1981, vol. 70, # 11, p. 1228 - 1232

[ 2353-33-5 ] Synthesis Path-Downstream 1~109

1
[ 69304-37-6 ]
[ 2353-33-5 ]
[ 117399-71-0 ]

Reference： [1]Tetrahedron Letters,1988,vol. 29,p. 1767 - 1770

2
[ 2353-33-5 ]
[ 69304-64-9 ]

Reference： [1]Journal of Pharmaceutical Sciences,1981,vol. 70,p. 1228 - 1232

3
[ 69304-64-9 ]
[ 2353-33-5 ]

Reference： [1]Journal of Pharmaceutical Sciences,1981,vol. 70,p. 1228 - 1232

4
1-<3,5-bis(Fmoc)-2'-deoxyribofuranosyl>-5-azacytidine [ No CAS ]
[ 22432-95-7 ]
[ 2353-33-5 ]

Reference： [1]Journal of Organic Chemistry,1986,vol. 51,p. 3211 - 3213

5
[ 2353-33-5 ]
2-deoxy-D-erythropentofuranosylaminocarbonylguanidinium formate [ No CAS ]

Reference： [1]Collection of Czechoslovak Chemical Communications,1996,vol. 61,p. 656 - 662

6
[ 874-60-2 ]
[ 2353-33-5 ]
[ 10302-79-1 ]
2'-deoxy-5'-O-p-toluoyl-5-azacytidine [ No CAS ]

Reference： [1]Collection of Czechoslovak Chemical Communications,1996,vol. 61,p. S23 - S25

7
[ 4637-24-5 ]
[ 2353-33-5 ]
N'-[5-((2R,4S,5R)-4-Hydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-4-oxo-4,5-dihydro-[1,3,5]triazin-2-yl]-N,N-dimethyl-formamidine [ No CAS ]

Reference： [1]Collection of Czechoslovak Chemical Communications,1996,vol. 61,p. S23 - S25

8
[ 2353-33-5 ]
[ 999-97-3 ]
[ 431890-05-0 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide;	For example, decitabine (1.2 g) was twice co-distilled with anhydrous pyridine and dissolved in 20 ml dry DMF. Hexamethyldisilazane (2.8 mL) was added. The solution was stirred and left overnight. The solvent was evaporated in vacuo, and the remaining residue was dissolved in toluene and evaporated twice. The 3',5'-di trimethylsilyl <strong>[2353-33-5]5-aza-2'-deoxycytidine</strong> (Rf=0.67, 4:1 dichloromethane/methanol) was co-distilled twice with dry pyridine (~0 mL) and dissolved in dry pyridine (20 mL). Phenoxyacetic anhydride (1.5 g) was added, and the resulting solution was stirred for 1 hour. A further 0.18 g phenoxyacetic anhydride (0.18 g) was added and stirred for another hour. The reaction mixture was evaporated in vacuo to dryness and co-distilled (3*) with toluene. The residue was dissolved in dichloromethane (~50 mL) and extracted with 1M aqueous NaHCO3 solution (~50 mL), which was re-extracted with dichloromethane (~20 mL). The combined organic phases were dried over sodium sulfate and reduced in vacuo to yield crude 3',5'-di trimethylsilyl-N-phenoxyacetyl <strong>[2353-33-5]5-aza-2'-deoxycytidine</strong> (3g; Rf=0.82, 9:1 dichloromethane/methanol). The crude material was dissolved in anhydrous DMF (20 mL) and transferred to a 50 mL plastic falcon tube, and TAS-F (2.4 g) was added (gas evolved). The reaction proceeded for 4 hours at 22 C. (the vial was not fully closed to reduce pressure built up). The DMF was evaporated in vacuo and the remaining residue was subjected to column chromatography (30 g silica gel, 2.5 cm column, 99:1 to 9:1 dichloromethane/methanol). A white solid N-phenoxyacetyl 5-aza-2?-deoxycytidine (0.81 g; Rf=0.26, 9:1 dichloromethane/methanol) was obtained. This compound (0.6 g) was twice co-distilled with anhydrous pyridine and dissolved in anhydrous pyridine (20 mL) before dimethoxytrityl chloride (0.9 g) was added and stirred for 2 hours at 22 C. Solvents were removed in vacuo and co-distilled (3 x) with toluene. The residue was dissolved in dichloromethane (50 mL) and extracted with 1M aqueous NaHCO3 solution (?50 mL), which was re-extracted with dichloromethane (?20 mL). The combined organic phases were dried over sodium sulfate and reduced in vacuo. The residue was subjected to silica gel chromatography (dichloromethane-100% to 95:5 dichloromethane/methanol), which yielded 5?-dimethoxytrityl-N-phenoxyacetyl 5-aza-2?-deoxycytidine (0.35 g, 0.53 mmole, 32%; Rf=0.49, 9:1 dichloromethane/methanol). This intermediate (0.3 g) was dissolved in dry acetonitrile (2 mL) before 0.3 M benzylthiotetrazole (0.9 mL) solution in dry acetonitrile and cyanoethyltetraisopropyl phosphorodiamidite (0.17 mL) were added. The mixture was stirred at 22 C. for 1.5 hours. TLC (2:1 ethyl acetate/hexanes+2% TEA) showed a diastereoisomeric mixture with Rf=0.27 and 0.36. Solvent was removed in vacuo and the remaining residue subjected to column chromatography (20 g silica gel, 2.5 cm column, 9:1 hexanes/ethyl acetate+2% TEA (300 mL), 1:1 hexanes/ethyl acetate+1% TEA (200 mL), 1:2 hexanes/ethyl acetate+0% TEA (250 mL). The decitabine phosphoramidite building 1d, where R1=phenoxyacetyl (0.297 g, 0.34 mmol, 76%) eluted with the 1:2 hexanes/ethyl acetate. ESI-MS of 1d (calculated exact mass for C46H53N6O9P is 864.36) exhibited m/z 864.1 and 966.4 [M+NEt3+H+]+; 31P NMR (CDCl3, 500 MHz) exhibited 149.17 and 149.0 ppm; 1H NMR (CDCl3, 500 MHz) exhibited chemical shifts (ppm) 8.63 & 8.59 (1H, doublet, H-6), 7.4-6.6 (18H, multiplet, aromatic DMTr/Pac), 6.05 (1H, triplet, H-1?), 4.79 (2H, singlet, CH2 of Pac), 4.59 (1H, singlet, H4?), 4.25 to 4.20 (1H, doublet, H-3?), 3.8-3.7 (1H, multiplet, P-O-CH2), 3.70 (3H, singlet, CH3O of DMTr), 3.68 (3H, singlet, CH3O of DMTr), 3.6-3.48 (3H, multiplet, two CH's of isopropyl and one P-O-CH2), 3.36-3.27 (2H, multiplet, H-5?), 2.80 (1H, singlet, H-2?), 2.53 (1H, singlet, H-2?), 2.40 (2H, multiplet, CH2CN), 1.1 (12H, CH3 of isopropyl).

Reference： [1]Nucleosides and Nucleotides,1997,vol. 16,p. 1111 - 1114
[2]Patent: US2007/72796,2007,A1 .Location in patent: Page/Page column 22
[3]Angewandte Chemie - International Edition,2019,vol. 58,p. 6620 - 6624
Angew. Chem.,2019,vol. 131,p. 6692 - 6696,5

Yield	Reaction Conditions	Operation in experiment
	With water; potassium carbonate; at 20℃; for 648h;Relative humidity 43.2 %; Storage in a sealed chamber;Reactivity (does not react);	Example 4; In relative humidity (RH) stress analysis, open vials containing solid samples were placed inside chambers containing saturated salt solutions along with a small amount of the undissolved salt. The chambers were sealed and allowed to stand at ambient temperature for several days. Samples were analyzed by X-ray powder diffraction (XRPD) immediately after removing the sample from the RH chamber. The RH values these salt solutions were obtained from an ASTM standard. RH results are illustrated in Table 17 below:
	With water; potassium acetate; at 20℃; for 648h;23.1 % relative humidity; Storage in a sealed chamber;Reactivity (does not react);	Example 4; In relative humidity (RH) stress analysis, open vials containing solid samples were placed inside chambers containing saturated salt solutions along with a small amount of the undissolved salt. The chambers were sealed and allowed to stand at ambient temperature for several days. Samples were analyzed by X-ray powder diffraction (XRPD) immediately after removing the sample from the RH chamber. The RH values these salt solutions were obtained from an ASTM standard. RH results are illustrated in Table 17 below:
	With water; magnesium chloride; at 20℃; for 648h;Relative humidity 33.1 %; Storage in a sealed chamber;Reactivity (does not react);	Example 4; In relative humidity (RH) stress analysis, open vials containing solid samples were placed inside chambers containing saturated salt solutions along with a small amount of the undissolved salt. The chambers were sealed and allowed to stand at ambient temperature for several days. Samples were analyzed by X-ray powder diffraction (XRPD) immediately after removing the sample from the RH chamber. The RH values these salt solutions were obtained from an ASTM standard. RH results are illustrated in Table 17 below:

	In methanol; dimethyl sulfoxide; at 60 - 65℃;Reflux;Product distribution / selectivity;	EXAMPLE 4 - Purification of crude Decitabine with DMSO and MeOHCrude Decitabine (1.5 g, 90.6% purity by HPLC) and anhydrous MeOH (29 mL) are stirred and heated at reflux for 30 min. DMSO (9.3 mL} is slowly added to the solution resulting in almost complete dissolution in the mixed solvent at 60~65C. The mixture is filtered, and the filtrate is slowly cooled. Decitabine crystallises from the solution. At 4C, the slurry is filtered and the filtered cake is washed three times with MeOH (3 mL) and dried in vacuo at 500C to give dry API grade Decitabine {0.9 g, 99.82% pure as indicated by HPLC analysis) .
		EXAMPLE 8: Purification of decitabine.Decitabine (2 g, HPLC purity: 93.55%) and dimethylsulphoxide (12 mL) are charged at 25-350C into a clean round bottom flask, stirred for 5-10 minutes and cooled to 0-100C. The mass is filtered through a Hyflow bed and the filtrate is divided into two equal parts. i) Ethyl acetate (10 ml_) is charged into a round bottom flask at 25-350C and stirred for 5-10 minutes. The first part of the filtrate is added and stirred for 35- 40 minutes. The formed solid is filtered, washed with ethyl acetate (4 ml_) and suction dried at 25-350C. Yield: 0.65 g; HPLC purity: 96.23%. ii) The second part of the filtrate is charged into a round bottom flask, stirred for 5-10 minutes at 25-350C, then 2-butanol (10 ml_) is added and stirred for 35-40 minutes. The formed solid is filtered, washed with 2-butanol (4 ml_) and suction dried. Yield: 0.75 g. HPLC; purity: 98.47%.

11
[ 2353-33-5 ]
2'-deoxy-β-D-5-azacytidine 5'-monophosphate [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2000,vol. 35,p. 1011 - 1019

12
[ 64-18-6 ]
[ 2353-33-5 ]
2-(α-D-erythro-2-deoxypentofuranosylcarbamoyl)guanidinium formate [ No CAS ]
2-(β-D-erythro-2-deoxypentofuranosylcarbamoyl)guanidinium formate [ No CAS ]
2-(α-D-erythro-2-deoxypentopyranosylcarbamoyl)guanidinium formate [ No CAS ]
2-(β-D-erythro-2-deoxypentopyranosylcarbamoyl)guanidinium formate [ No CAS ]

Reference： [1]Collection of Czechoslovak Chemical Communications,2003,vol. 68,p. 711 - 743

13
[ 2353-33-5 ]
[ 431890-07-2 ]

Reference： [1]Nucleosides and Nucleotides,1997,vol. 16,p. 1111 - 1114

14
[ 2353-33-5 ]
[ 431890-06-1 ]

Reference： [1]Nucleosides and Nucleotides,1997,vol. 16,p. 1111 - 1114

15
[ 2353-33-5 ]
[ 431890-08-3 ]

Reference： [1]Nucleosides and Nucleotides,1997,vol. 16,p. 1111 - 1114

16
[ 2353-33-5 ]
C₄₃H₅₁N₆O₉P [ No CAS ]

Reference： [1]Nucleosides and Nucleotides,1997,vol. 16,p. 1111 - 1114

17
[ 2353-33-5 ]
[5-((2R,4S,5R)-5-[Bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-4-{diisopropylamino-[2-(4-nitro-phenyl)-ethoxy]-phosphanyloxy}-tetrahydro-furan-2-yl)-4-oxo-4,5-dihydro-[1,3,5]triazin-2-yl]-carbamic acid 2-(4-nitro-phenyl)-ethyl ester [ No CAS ]

Reference： [1]Nucleosides and Nucleotides,1997,vol. 16,p. 1111 - 1114

18
[ 2353-33-5 ]
2'-deoxy-3'-O-p-toluoyl-5-azacytidine [ No CAS ]

Reference： [1]Collection of Czechoslovak Chemical Communications,1996,vol. 61,p. S23 - S25

19
[ 2353-33-5 ]
4-Methyl-benzoic acid (2R,3S,5R)-5-(4-amino-2-oxo-2H-[1,3,5]triazin-1-yl)-3-phenoxythiocarbonyloxy-tetrahydro-furan-2-ylmethyl ester [ No CAS ]

Reference： [1]Collection of Czechoslovak Chemical Communications,1996,vol. 61,p. S23 - S25

20
[ 2353-33-5 ]
[ 117399-72-1 ]

Reference： [1]Tetrahedron Letters,1988,vol. 29,p. 1767 - 1770

21
[ 2353-33-5 ]
[ 117399-73-2 ]

Reference： [1]Tetrahedron Letters,1988,vol. 29,p. 1767 - 1770

22
[ 2353-33-5 ]
[ 117399-76-5 ]

Reference： [1]Tetrahedron Letters,1988,vol. 29,p. 1767 - 1770

23
[ 2353-33-5 ]
[ 117399-74-3 ]

Reference： [1]Tetrahedron Letters,1988,vol. 29,p. 1767 - 1770

24
[ 2353-33-5 ]
[ 117436-82-5 ]

Reference： [1]Tetrahedron Letters,1988,vol. 29,p. 1767 - 1770

25
[ 2353-33-5 ]
[ 117399-78-7 ]

Reference： [1]Tetrahedron Letters,1988,vol. 29,p. 1767 - 1770

26
[ 2353-33-5 ]
[ 117399-75-4 ]

Reference： [1]Tetrahedron Letters,1988,vol. 29,p. 1767 - 1770

27
[ 2353-33-5 ]
[ 117436-80-3 ]

Reference： [1]Tetrahedron Letters,1988,vol. 29,p. 1767 - 1770

28
[ 2353-33-5 ]
[ 117399-77-6 ]

Reference： [1]Tetrahedron Letters,1988,vol. 29,p. 1767 - 1770

29
[ 2353-33-5 ]
[ 117436-81-4 ]

Reference： [1]Tetrahedron Letters,1988,vol. 29,p. 1767 - 1770

30
[ 2353-33-5 ]
[ 135567-49-6 ]

Yield	Reaction Conditions	Operation in experiment
	With water;moisture sorption;Product distribution / selectivity;	Example 1; A sample of decitabine used for the polymorph screen was provided by SuperGen Inc. A representative XRPD pattern exhibited by this ample is provided in FIG. 1. The polymorph form of decitabine exhibiting this pattern is designated as form A. Form A is thermally stable but will readily hydrate to form B upon exposure to water or atmospheric moisture. Form B will convert to either form A or form C depending on the experimental conditions. Form C readily converts to form B in the presence of atmospheric moisture such that it is difficult to obtain a pure sample of form C in the laboratory.
	With potassium chloride; water; at 20℃; for 648h;Relative humidity 85.1 %; Storage in a sealed chamber;Product distribution / selectivity;	Example 4; In relative humidity (RH) stress analysis, open vials containing solid samples were placed inside chambers containing saturated salt solutions along with a small amount of the undissolved salt. The chambers were sealed and allowed to stand at ambient temperature for several days. Samples were analyzed by X-ray powder diffraction (XRPD) immediately after removing the sample from the RH chamber. The RH values these salt solutions were obtained from an ASTM standard. RH results are illustrated in Table 17 below:
	With water; sodium chloride; at 20℃; for 648h;Relative humidity 75.5 %; Storage in a sealed chamber;Product distribution / selectivity;	Example 4; In relative humidity (RH) stress analysis, open vials containing solid samples were placed inside chambers containing saturated salt solutions along with a small amount of the undissolved salt. The chambers were sealed and allowed to stand at ambient temperature for several days. Samples were analyzed by X-ray powder diffraction (XRPD) immediately after removing the sample from the RH chamber. The RH values these salt solutions were obtained from an ASTM standard. RH results are illustrated in Table 17 below:

		Example 1; A sample of decitabine used for the polymorph screen was provided by SuperGen Inc. A representative XRPD pattern exhibited by this ample is provided in FIG. 1. The polymorph form of decitabine exhibiting this pattern is designated as form A. Form A is thermally stable but will readily hydrate to form B upon exposure to water or atmospheric moisture. Form B will convert to either form A or form C depending on the experimental conditions. Form C readily converts to form B in the presence of atmospheric moisture such that it is difficult to obtain a pure sample of form C in the laboratory.
		Example 1; A sample of decitabine used for the polymorph screen was provided by SuperGen Inc. A representative XRPD pattern exhibited by this ample is provided in FIG. 1. The polymorph form of decitabine exhibiting this pattern is designated as form A. Form A is thermally stable but will readily hydrate to form B upon exposure to water or atmospheric moisture. Form B will convert to either form A or form C depending on the experimental conditions. Form C readily converts to form B in the presence of atmospheric moisture such that it is difficult to obtain a pure sample of form C in the laboratory.
	In 1,2-dimethoxyethane; at 20℃; for 648h;Product distribution / selectivity;	Example 1; A sample of decitabine used for the polymorph screen was provided by SuperGen Inc. A representative XRPD pattern exhibited by this ample is provided in FIG. 1. The polymorph form of decitabine exhibiting this pattern is designated as form A. Form A is thermally stable but will readily hydrate to form B upon exposure to water or atmospheric moisture. Form B will convert to either form A or form C depending on the experimental conditions. Form C readily converts to form B in the presence of atmospheric moisture such that it is difficult to obtain a pure sample of form C in the laboratory.
	In 1,1,1,3',3',3'-hexafluoro-propanol;Fast evaporation;Product distribution / selectivity;	Example 1; A sample of decitabine used for the polymorph screen was provided by SuperGen Inc. A representative XRPD pattern exhibited by this ample is provided in FIG. 1. The polymorph form of decitabine exhibiting this pattern is designated as form A. Form A is thermally stable but will readily hydrate to form B upon exposure to water or atmospheric moisture. Form B will convert to either form A or form C depending on the experimental conditions. Form C readily converts to form B in the presence of atmospheric moisture such that it is difficult to obtain a pure sample of form C in the laboratory.
	In 1,1,1,3',3',3'-hexafluoro-propanol;Slow evaporation;Product distribution / selectivity;	Example 1; A sample of decitabine used for the polymorph screen was provided by SuperGen Inc. A representative XRPD pattern exhibited by this ample is provided in FIG. 1. The polymorph form of decitabine exhibiting this pattern is designated as form A. Form A is thermally stable but will readily hydrate to form B upon exposure to water or atmospheric moisture. Form B will convert to either form A or form C depending on the experimental conditions. Form C readily converts to form B in the presence of atmospheric moisture such that it is difficult to obtain a pure sample of form C in the laboratory.
	In methanol;Fast evaporation;Product distribution / selectivity;	Example 1; A sample of decitabine used for the polymorph screen was provided by SuperGen Inc. A representative XRPD pattern exhibited by this ample is provided in FIG. 1. The polymorph form of decitabine exhibiting this pattern is designated as form A. Form A is thermally stable but will readily hydrate to form B upon exposure to water or atmospheric moisture. Form B will convert to either form A or form C depending on the experimental conditions. Form C readily converts to form B in the presence of atmospheric moisture such that it is difficult to obtain a pure sample of form C in the laboratory.
	In methanol;Product distribution / selectivity;	Example 1; A sample of decitabine used for the polymorph screen was provided by SuperGen Inc. A representative XRPD pattern exhibited by this ample is provided in FIG. 1. The polymorph form of decitabine exhibiting this pattern is designated as form A. Form A is thermally stable but will readily hydrate to form B upon exposure to water or atmospheric moisture. Form B will convert to either form A or form C depending on the experimental conditions. Form C readily converts to form B in the presence of atmospheric moisture such that it is difficult to obtain a pure sample of form C in the laboratory.

Reference： [1]Patent: US2006/14949,2006,A1 .Location in patent: Page/Page column 14
[2]Patent: US2006/14949,2006,A1 .Location in patent: Page/Page column 16
[3]Patent: US2006/14949,2006,A1 .Location in patent: Page/Page column 16
[4]Patent: US2006/14949,2006,A1 .Location in patent: Page/Page column 16
[5]Patent: US2006/14949,2006,A1 .Location in patent: Page/Page column 16
[6]Patent: US2006/14949,2006,A1 .Location in patent: Page/Page column 16
[7]Patent: US2006/14949,2006,A1 .Location in patent: Page/Page column 16
[8]Patent: US2006/14949,2006,A1 .Location in patent: Page/Page column 15
[9]Patent: US2006/14949,2006,A1 .Location in patent: Page/Page column 16
[10]Patent: US2006/14949,2006,A1 .Location in patent: Page/Page column 16
[11]Patent: US2006/14949,2006,A1 .Location in patent: Page/Page column 16
[12]Patent: US2006/14949,2006,A1 .Location in patent: Page/Page column 16
[13]Patent: US2006/14949,2006,A1 .Location in patent: Page/Page column 15
[14]Patent: US2006/14949,2006,A1 .Location in patent: Page/Page column 15
[15]Patent: US2006/14949,2006,A1 .Location in patent: Page/Page column 15
[16]Patent: US2006/14949,2006,A1 .Location in patent: Page/Page column 15
[17]Patent: US2006/14949,2006,A1 .Location in patent: Page/Page column 15

31
[ 2353-33-5 ]
decitabine hemi-hydrate [ No CAS ]

Reference： [1]Patent: US2006/14949,2006,A1 .Location in patent: Page/Page column 16
[2]Patent: US2006/14949,2006,A1 .Location in patent: Page/Page column 16

32
decitabine hemi-hydrate [ No CAS ]
[ 2353-33-5 ]
[ 135567-49-6 ]

Yield	Reaction Conditions	Operation in experiment
	In 1,2-dimethoxyethane; at 20℃; for 648h;Product distribution / selectivity;	Example 1; A sample of decitabine used for the polymorph screen was provided by SuperGen Inc. A representative XRPD pattern exhibited by this ample is provided in FIG. 1. The polymorph form of decitabine exhibiting this pattern is designated as form A. Form A is thermally stable but will readily hydrate to form B upon exposure to water or atmospheric moisture. Form B will convert to either form A or form C depending on the experimental conditions. Form C readily converts to form B in the presence of atmospheric moisture such that it is difficult to obtain a pure sample of form C in the laboratory.

Reference： [1]Patent: US2006/14949,2006,A1 .Location in patent: Page/Page column 15

33
[ 135567-49-6 ]
[ 2353-33-5 ]

Yield	Reaction Conditions	Operation in experiment
	at 150℃; for 0.166667h;Neat (no solvent);Product distribution / selectivity;	A sample of form B heated to a temperature of approximately 150 C. for ten minutes and then allowed to cool to room temperature converts to form A. This demonstrates that form A can be produced from form B if desired. On the other hand, form B converts to form C upon storage in a vacuum oven at room temperature for 6 days, and VT-XRPD experiments demonstrate that form B will partially heat to generate polymorph form C.
	at 150℃;TGA experiment in the precense of nitrogen atmosohere;Product distribution / selectivity;	Example 8; In VT-XRPD experiments, decitabine polymorph form B converted to a mixture of forms B and C, while in an experiment performed in the TGA furnace form B converted to form A at about 150 C. The only other difference in these two experiments apart from sample size is that in the VT-XRPD experiment the sample is heated in the presence of air while in the TGA experiment dry nitrogen is used.

Reference： [1]Patent: US2006/14949,2006,A1 .Location in patent: Page/Page column 6; 15
[2]Patent: US2006/14949,2006,A1 .Location in patent: Page/Page column 18

34
[ 135567-49-6 ]
decitabine hemi-hydrate [ No CAS ]
[ 2353-33-5 ]

Reference： [1]Patent: US2006/14949,2006,A1 .Location in patent: Page/Page column 15

35
[ 2353-33-5 ]
5-aza-2'-deoxycytidine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In methanol; at 22℃;	In some embodiments, decitabine salts were prepared from strong acids. In one embodiment, for example, decitabine hydrochloride (3), depicted above, was prepared by suspending decitabine (0.25 g, 3.7 mmol) in methanol (40 mL) in a round bottom flask (100-mL). The mixture was gently stirred at 22 C. HCl gas (not less than 2-fold excess) was bubbled into the stirred methanol solution until complete dissolution was reached. The solution was concentrated to volume, flushed with nitrogen, corked with a rubber septum and allowed to crystallize (0 C.) for NLT 12 h. The first crop of crystalline product was filtered, rinsed with anhydrous ether (5 mL) and dried in vacuo for NLT 12 h. The filtrate was poured back into the 50 mL Erlenmeyer flask, and enough anhydrous ether was added to a cloudy point. The solution was flushed with nitrogen, corked with a rubber septum and allowed to crystallize (0 C.) for NLT 12 h. The second crop of crystalline product was filtered, rinsed with anhydrous ether (40 mL) and dried in vacuo for NLT 12 h.

Reference： [1]Patent: US2006/63735,2006,A1 .Location in patent: Page/Page column 14

36
[ 2353-33-5 ]
5-aza-2'-deoxycytidine sulfite [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sulphurous acid; In methanol; at 20℃; for 1.16667h;	In some further embodiments, for example, decitabine sulfite (9) or phosphate (10), depicted above, was prepared by suspending decitabine (1.0 g, 3.7 mmol) in methanol (80 mL) in a round bottom flask (250 mL). The solution was flushed with nitrogen gas, corked with a rubber septum, and was gently stirred for 10 minutes at ambient temperature. Sulfurous acid (4.0 mL) or phosphoric acid (0.8 mL) was injected through the rubber septum slowly, and the mixture was gently stirred for 1 hr. The suspension of decitabine disappeared and the mixture became clear before decitabine salt recrystallized. The crystals were allowed to completely crystallize (0 C.) for NLT 4 hrs. The product was thoroughly washed with MeOH (50 mL) during filtration and dried in vacuo for NLT 12 hr. In methanol, decitabine formed 1:1 molar equivalent with sulfite (9) and phosphate (10) (see also Table 2 below).

Reference： [1]Patent: US2006/63735,2006,A1 .Location in patent: Page/Page column 15

37
[ 2353-33-5 ]
decitabine sulfite [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sulphurous acid; In methanol; for 1h;	In some further embodiments, for example, decitabine sulfite (9) or phosphate (10), depicted above, was prepared by suspending decitabine (1.0 g, 3.7 mmol) in methanol (80 mL) in a round bottom flask (250 mL). The solution was flushed with nitrogen gas, corked with a rubber septum, and was gently stirred for 10 minutes at ambient temperature. Sulfurous acid (4.0 mL) or phosphoric acid (0.8 mL) was injected through the rubber septum slowly, and the mixture was gently stirred for 1 hr. The suspension of decitabine disappeared and the mixture became clear before decitabine salt recrystallized. The crystals were allowed to completely crystallize (0 C.) for NLT 4 hrs. The product was thoroughly washed with MeOH (50 mL) during filtration and dried in vacuo for NLT 12 hr. In methanol, decitabine formed 1:1 molar equivalent with sulfite (9) and phosphate (10) (see also Table 2 below).

Reference： [1]Patent: US2006/69060,2006,A1 .Location in patent: Page/Page column 14; 15

38
[ 2353-33-5 ]
decitabine phosphate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With phosphoric acid; In methanol; for 1h;	In some further embodiments, for example, decitabine sulfite (9) or phosphate (10), depicted above, was prepared by suspending decitabine (1.0 g, 3.7 mmol) in methanol (80 mL) in a round bottom flask (250 mL). The solution was flushed with nitrogen gas, corked with a rubber septum, and was gently stirred for 10 minutes at ambient temperature. Sulfurous acid (4.0 mL) or phosphoric acid (0.8 mL) was injected through the rubber septum slowly, and the mixture was gently stirred for 1 hr. The suspension of decitabine disappeared and the mixture became clear before decitabine salt recrystallized. The crystals were allowed to completely crystallize (0 C.) for NLT 4 hrs. The product was thoroughly washed with MeOH (50 mL) during filtration and dried in vacuo for NLT 12 hr. In methanol, decitabine formed 1:1 molar equivalent with sulfite (9) and phosphate (10) (see also Table 2 below).

Reference： [1]Patent: US2006/69060,2006,A1 .Location in patent: Page/Page column 14; 15

39
[ 2353-33-5 ]
decitabine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In methanol; at 22℃;	In one embodiment, for example, decitabine hydrochloride (3), depicted above, was prepared by suspending decitabine (0.25 g, 3.7 mmol) in methanol (40 mL) in a round bottom flask (100-mL). The mixture was gently stirred at 22 C. HCl gas (not less than 2-fold excess) was bubbled into the stirred methanol solution until complete dissolution was reached. The solution was concentrated to volume, flushed with nitrogen, corked with a rubber septum and allowed to crystallize (0 C.) for NLT 12 h. The first crop of crystalline product was filtered, rinsed with anhydrous ether (5 mL) and dried in vacuo for NLT 12 h. The filtrate was poured back into the 50 mL Erlenmeyer flask, and enough anhydrous ether was added to a cloudy point. The solution was flushed with nitrogen, corked with a rubber septum and allowed to crystallize (0 C.) for NLT 12 h. The second crop of crystalline product was filtered, rinsed with anhydrous ether (40 mL) and dried in vacuo for NLT 12 h.

Reference： [1]Patent: US2006/69060,2006,A1 .Location in patent: Page/Page column 14

40
[ 87-69-4 ]
[ 2353-33-5 ]
5-aza-2'-deoxycytidine (+)-L-tartrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 30 - 55℃;Sonication;	In still some embodiments, decitabine salts were prepared from weak acids (3.0

Reference： [1]Patent: US2006/63735,2006,A1 .Location in patent: Page/Page column 15

41
[ 147-71-7 ]
[ 2353-33-5 ]
decitabine (+)-L-tartate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 30 - 55℃; for 0.5h;Heated in sonicator;	In still some embodiments, decitabine salts were prepared from weak acids (3.0

Reference： [1]Patent: US2006/69060,2006,A1 .Location in patent: Page/Page column 15

42
[ 75-75-2 ]
[ 2353-33-5 ]
[ 879492-57-6 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 20℃; for 1.16667h;	In one embodiment, for example, decitabine mesylate (4), depicted above, was prepared by suspending decitabine (1.0 g, 3.7 mmol) in methanol (80 mL) in a round bottom flask (250-mL). The solution was flushed with nitrogen gas, corked with a rubber septum, and was gently stirred for 10 minutes at ambient temperature. Methanesulfonic acid (4.0 mL) was injected through the rubber septum slowly, and the mixture was gently stirred for 1 h. The suspension of decitabine immediately disappeared and the mixture became clear before decitabine mesylate recrystallized. The crystals were allowed to completely crystallize (0 C.) for NLT 4 h. The product was thoroughly washed with MeOH (50 mL) during filtration and dried in vacuo for NLT 12 h.
	In methanol; for 1h;	In one embodiment, for example, decitabine mesylate (4), depicted above, was prepared by suspending decitabine (1.0 g, 3.7 mmol) in methanol (80 mL) in a round bottom flask (250-mL). The solution was flushed with nitrogen gas, corked with a rubber septum, and was gently stirred for 10 minutes at ambient temperature. Methanesulfonic acid (4.0 mL) was injected through the rubber septum slowly, and the mixture was gently stirred for 1 h. The suspension of decitabine immediately disappeared and the mixture became clear before decitabine mesylate recrystallized. The crystals were allowed to completely crystallize (0 C.) for NLT 4 h. The product was thoroughly washed with MeOH (50 mL) during filtration and dried in vacuo for NLT 12 h.

Reference： [1]Patent: US2006/63735,2006,A1 .Location in patent: Page/Page column 14-15
[2]Patent: US2006/69060,2006,A1 .Location in patent: Page/Page column 14

43
[ 110-15-6 ]
[ 2353-33-5 ]
decitabine succinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 30 - 55℃; for 0.5h;Heated in sonicator;	In still some embodiments, decitabine salts were prepared from weak acids (3.0

Reference： [1]Patent: US2006/69060,2006,A1 .Location in patent: Page/Page column 15

44
[ 79-33-4 ]
[ 2353-33-5 ]
decitabine L-lactate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 30 - 55℃; for 0.5h;Heated in sonicator;	In still some embodiments, decitabine salts were prepared from weak acids (3.0

Reference： [1]Patent: US2006/69060,2006,A1 .Location in patent: Page/Page column 15

45
[ 60-00-4 ]
[ 2353-33-5 ]
5-aza-2'-deoxycytidine ethylenediaminetetraacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 50℃; for 1h;	Decitabine salts were also prepared from moderate acids. In some embodiments, for example, decitabine EDTA (5), L-aspartate (6), maleate (7) or L-glutamate (8), depicted above, can be prepared by the following procedure. Ethylenediaminetetraacetic acid (EDTA, 1.409 g, 4.8 mmol), L-Aspartic acid (641 mg), maleic acid (610 mg, 5.3 mmol) or L-glutamic acid (709 mg) was weighed in a 250 ml round bottom flask before adding methanol (100 mL) and decitabine (1.0 g), and the mixture was stirred at 50 C. for 1 hr or longer until the solution was clear. The filtrate was concentrated to about ½ volume to allow crystallization to occur. The solution was flushed with nitrogen, corked with a rubber septum and allowed to crystallize (0 C.) for NLT 4 hrs. The first crop of crystalline product was filtered and dried in vacuo for NLT 12 hrs. In methanol, decitabine formed 1:1 molar equivalent with EDTA (5), 1:1.5 with L-aspartate (6), 0.78 molar equivalent of maleate (7), and 1:1.5 with L-glutamate (8) (see also Table 2 below).

Reference： [1]Patent: US2006/63735,2006,A1 .Location in patent: Page/Page column 15

46
[ 2353-33-5 ]
[ 107-92-6 ]
decitabine butyrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 30 - 55℃; for 0.5h;Heated in sonicator;	In still some embodiments, decitabine salts were prepared from weak acids (3.0

Reference： [1]Patent: US2006/69060,2006,A1 .Location in patent: Page/Page column 15

47
[ 2353-33-5 ]
[ 77-92-9 ]
decitabine citrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 30 - 55℃; for 0.5h;Heated in sonicator;	In still some embodiments, decitabine salts were prepared from weak acids (3.0

Reference： [1]Patent: US2006/69060,2006,A1 .Location in patent: Page/Page column 15

48
[ 64-19-7 ]
[ 2353-33-5 ]
decitabine acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 30 - 55℃; for 0.5h;Heated in sonicator;	In still some embodiments, decitabine salts were prepared from weak acids (3.0

Reference： [1]Patent: US2006/69060,2006,A1 .Location in patent: Page/Page column 15

49
[ 802294-64-0 ]
[ 2353-33-5 ]
decitabine propionate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 30 - 55℃; for 0.5h;Heated in sonicator;	In still some embodiments, decitabine salts were prepared from weak acids (3.0

Reference： [1]Patent: US2006/69060,2006,A1 .Location in patent: Page/Page column 15

50
[ 2353-33-5 ]
[ 142-62-1 ]
decitabine hexanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 30 - 55℃; for 0.5h;Heated in sonicator;	In still some embodiments, decitabine salts were prepared from weak acids (3.0

Reference： [1]Patent: US2006/69060,2006,A1 .Location in patent: Page/Page column 15

51
[ 2353-33-5 ]
[ 931-86-2 ]
[ 452-51-7 ]

Yield	Reaction Conditions	Operation in experiment
	With water; at 20℃;Acidic aqueous solution;	Decitabine and azacitidine are unstable in aqueous media and undergo hydrolytic degradation. In acidic medium, decitabine is hydrolyzed at room temperature to 5-azacytosine (1e) and 2-deoxyribose (1f, FIG. 3A). In neutral medium at room temperature, the opening of the triazine ring takes place at the 6-position to form the transient intermediate formyl derivative (1g), which is further hydrolyzed to the amidino-urea derivative (1h) and formic acid (FIG. 3B) (Piskala, A.; Synackova, M.; Tomankova, H.; Fiedler, P.; Zizkowsky, V. Nucleic Acids Res. 1978, 4, s109-s-113.). This hydrolysis at the 6-position also occurs in acidic and basic aqueous media at even faster rates.

Reference： [1]Patent: US2006/205685,2006,A1 .Location in patent: Page/Page column 4; sheet 3

52
[ 2353-33-5 ]
β-D-2'-deoxyribofuranosyl-3-guanylurea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With water; at 20℃;	Decitabine and azacitidine are unstable in aqueous media and undergo hydrolytic degradation. In acidic medium, decitabine is hydrolyzed at room temperature to 5-azacytosine (1e) and 2-deoxyribose (1f, FIG. 3A). In neutral medium at room temperature, the opening of the triazine ring takes place at the 6-position to form the transient intermediate formyl derivative (1g), which is further hydrolyzed to the amidino-urea derivative (1h) and formic acid (FIG. 3B) (Piskala, A.; Synackova, M.; Tomankova, H.; Fiedler, P.; Zizkowsky, V. Nucleic Acids Res. 1978, 4, s109-s-113.). This hydrolysis at the 6-position also occurs in acidic and basic aqueous media at even faster rates.
	With water;Alkaline aqueous solution;	As described above, in aqueous media of varying pH, decitabine undergoes rapid hydrolytic cleavages. In alkaline medium the hydrolysis to the amidino-urea derivative (1h) occurs even faster, within a few minutes. Azacitidine also undergoes similar degradation in aqueous media at all pHs.

Reference： [1]Patent: US2006/205685,2006,A1 .Location in patent: Page/Page column 4; sheet 3
[2]Patent: US2006/205685,2006,A1 .Location in patent: Page/Page column 4
[3]Nucleic Acids Research,2012,vol. 40,p. 9788 - 9801

53
[ 2353-33-5 ]
N₁-(2-deoxy-β-D-erythro-pentofuranosyl)biuret [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With water;cytidine deaminase;Enzyme kinetics;	Decitabine and azacitidine are also unstable in biological fluid due to deamination. The deamination of decitabine to 5-aza-2'-deoxyuridine is catalyzed by cytidine deaminase. Chabot et al. (1983) Biochemical Pharmacology 22:1327-1328. The estimated Km of decitabine was 250 muM for the enzyme purified from human liver as compared to the Km of 12 muM for the natural substrate, deoxycytidine. The rate of deamination of deoxycytidine was about 6-fold greater than that of decitabine by cytidine deaminase at equal concentrations. The enol derivative after deamination (1, FIG. 3D) should have retained its capacity to bind and inhibit methyltransferase; however, the more thermodynamically favorable keto tautomer (1') has a carbonyl functional group at the 4-position, which makes the 6-position highly electrophilic and undergoes hydrolytic cleavage. Thus, a possible mechanism of resistance to decitabine is an increase in the levels of the deaminating enzyme cytidine deaminase. Treatment with decitabine has been associated with an increase in the cytidine deaminase activity in HL-60 cells and in leukemic cells in some patients. To increase the stability of cytosine nucleotides such as decitabine and azacitidine, the inventors believe that this susceptibility toward deamination and predisposition toward hydrolytic cleavage of the triazine ring before and after deamination of the 4-position NH2 group by cytidine deaminase should be removed by modifying the ring in various ways as provided below (examples shown in FIGS. 4B, C, D; 6B, C; 8D, E, F, G). When the 4-position is substituted by stronger bases (1'b-1'g, 1b-1g, FIG. 4D) or substituted by an equivalent electron-donating group that does not tautomerize (1'a, 1a, 2a, 3a, 4a, 5a, 6a, 7a, 8a, 9a, 10a, 11a, FIGS. 4B, C, D), the potential for deamination and subsequent hydrolytic cleavage is minimized. When the 6-position is substituted electron-donating groups (FIGS. 4B, C; 6B, C; 8A, B), the propensity toward hydrolytic cleavage is also minimized.

Reference： [1]Patent: US2006/205685,2006,A1 .Location in patent: Page/Page column 4; sheet 4

54
[ 931-86-2 ]
[ 21740-23-8 ]
[ 2353-33-5 ]

Yield	Reaction Conditions	Operation in experiment
		Example 1; (A); A mixture of 5-azacytosine (20 g, 178.4 mmol), ammonium sulfate (2.4 g, 18.16 mmol), and hexamethyldisilazane (160 g, 991.3 mmol) is heated to reflux until a clear solution is obtained. The excess of hexamethyldisilazane is removed in the vacuum at 60C.; (B); A mixture of 264 g of dichloromethane, lithium trifluoromethane sulfonate (13.92 g, 89.2 mmol) and the "chloro sugar" C-137 (3,5-Dip-chloro-benzoyl-2deoxy-alpha-ribofuranosylchloride) [46.0 g, 107.1 mmol) are prepared and added to the residue obtained in step (A).; (C); The mixture is stirred for 4 hours at ambient temperature (20-25C). Then the solvent is removed at 40C in the vacuum and the obtained residue is dissolved in 60 g ethyl acetate. The solution is added drop wise to a mixture of 220 g of aqueous sodium hydrogen carbonate (2.5% w-solution), 174 g ethyl acetate, 36 g cyclohexane and 70 g acetonitrile at 0C and the obtained reaction mixture stirred for 4 h at 0C. The precipitate of the blocked (protected) aminotriazine is filtered off, washed with aqueous sodium hydrogen carbonate (2.5% w-solution), water, and finally with a mixture of acetonitrile and ethyl acetate (1:1). Yield: 38.2 g; 49.5% [assay (beta-isomer): 70.1%; purity (beta-isomer): 64.7%].; (D); The compound corresponding to formula (III) as obtained in Section (C) is further treated with an alcoholic solution of ammonia in a known manner so that 2'-deoxy-5-azacytidine (Decitabine) is obtained in practically quantitative yield.

Reference： [1]Patent: EP2048151,2009,A1 .Location in patent: Page/Page column 3

55
[ 1034301-08-0 ]
[ 2353-33-5 ]

Yield	Reaction Conditions	Operation in experiment
~ 100%	With ammonia;Alcoholic medium;	Example 2 The compound corresponding to formula (III) as obtained in Example 1 is further treated with in an alcoholic solution of ammonia in a known manner so that 2'-deoxy-5-azacytidine (Decitabine) is obtained in practically quantitative yield.
71.6%	With methanol; sodium methylate; at 25℃; for 3h;	42.8g of intermediate D, 1.3L of anhydrous methanol and 2.8g of sodium methoxide were added to the reaction flask, and the reaction was stirred at 25 C for3 h. The reaction was quenched by adding 3.0 g of glacial acetic acid, and the filtrate was stirred and lysed at 0 C for 6 h. 8.1 g of an off-white solid were obtained in a yield of42.1%.The relevant substances were detected by HPLC: purity 98.7%, maximum single impurity 0.51%.
2.8 g	With methanol; sodium methylate; at 20℃; for 12h;	[0054] To a trimethylsilyl derivative of 5-azacytosine (6.9 g) dissolved in methylene chloride (34 mL) 1-chioro-3,5-di (4-chlorobenzoyl)-2-deoxy-D-ribose (125 eq) were added and the solution was brought to a temperature of from 0 C. to 10 C. SnCl4 (0.8 eq) was added to the solution and the temperature was left raise up to the room value. At the end of the reaction, the mixture was cooled up to a temperature of from 0 C. to 20 C. and DMSO (4 eq) was slowly added. The precipitated SnCl4-DMSO complex was isolated by filtration. Sodium bicarbonate (4 eq) was added to the organic phase and the mixture was kept under stirring for 1 hout The solid was removed by filtration and the organic phase was washed with cold watet The organic phases were separated, dried over sodium sulfate and the solvent was removed by distillation under low pressure to give a viscous residue. The residue was added with methanol (70 mL) and a 30% solution of sodium methoxide in methanol (0.2 eq) was added to the resultant solution. The solution was kept under stirring at room temperature for 12 hours and the resultant solid was filtered, washed with methanol (300 mL) and dried. 2.8 g of decitabine with a purity of 9 8.8% (determined by HPLC) and a tin content lower than 200 ppm was obtained.

34.24 g

With methanol; sodium methylate; at 65℃; for 6h;Inert atmosphere;

Under argon protection,1L in the reaction bottle,The result obtained in Example 41-(3,5-di-O-p-chlorobenzoyl-2-deoxy-D-ribose)-5-azacytosine 126.35G (250.03 mmol) was dissolved in 500 mL of methanol containing 20 g of sodium methoxide.The temperature was raised to 65 C and refluxed for 6 hours.After the reaction,Cool down to 50 C,Add cationic resin to adjust pH<3.5,Weighing,And wash the resin with an appropriate amount of methanol,The eluent and the filtrate are combined,Then rotary evaporation to remove the methanol solvent,200 mL of acetone was added to the obtained slurry, and the mixture was heated to reflux at 70 C for 3 hours.Then cool down to 10 C and keep warm for 30 min ~ 1 h, filter,The filter cake was washed twice with 50 mL of acetone.Then dried in a vacuum oven to obtain the final product 4-amino-1-(2-deoxy-beta-D-erythro-ribofuranose-1,3,5-triazin-2-one (decitabine). 34.24 g (150.02 mmol).Purity: 99.9%,

Reference： [1]Patent: EP2050757,2009,A1 .Location in patent: Page/Page column 4
[2]Patent: CN108239128,2018,A .Location in patent: Paragraph 0108; 0112; 0113; 0114; 0115; 0120; 0127; 0136
[3]Patent: US2014/135490,2014,A1 .Location in patent: Paragraph 0054
[4]Patent: CN110028537,2019,A .Location in patent: Paragraph 0052; 0053

56
[ 1207459-15-1 ]
[ 52523-35-0 ]
[ 2353-33-5 ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of MeCN (45 mL), 1-O-acetyl-3,5-di-O-(4-chlorobenzoyl)-2-deoxy-D-ribofuranose (3.0 g), 2-[(trimethylsilyl)amino]4-[(trimethylsilyl)oxy]-s-triazine (1.78 g) and TfOH (0.5 g) were stirred at about 0 C. for 24 hours. DMSO (6 mL) was added and the mixture was evaporated at 3050 C. under reduced pressure to remove the MeCN. A 29% solution of MeONa in MeOH (1.8 g, 9.9 mmol, 1.5 eq.) was added with stirring at about 2025 C. After the reaction was complete, MeOH was added to effect precipitation and the solid was filtered, washed and dried to give crude decitabine. API grade decitabine (>99.0 HPLC purity) is prepared by the recrystallization of crude decitabine from MeOH, followed by three washes with MeOH and drying at 40 C. under vacuum.

Reference： [1]Patent: US2010/36112,2010,A1 .Location in patent: Page/Page column 7-8

57
[ 2353-33-5 ]
C₈H₁₁Cl₂N₄O₅P [ No CAS ]

Reference： [1]Nucleosides, nucleotides and nucleic acids,2010,vol. 29,p. 14 - 26

58
[ 1034301-08-0 ]
[ 1140891-02-6 ]
[ 2353-33-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; In methanol; at 20℃; for 4h;Inert atmosphere;	Example 8 Preparation of Decitabine Into a dry 4-neck 1L RB flask was charged crude 4-amino-1-[3,5-di-O-(p-chlorobenzoyl)]-2-deoxy-alpha-D-ribofuranosyl-1,3,5-triazin-2(1H)-one and 4-amino-1-[3,5-di-O-(p-chlorobenzoyl)]-2-deoxy-beta-D-ribofuranosyl-1,3,5-triazin-2(1H)-one product (25 g, from Example 5) and anhydrous methanol (300 mL) under nitrogen and at room temperature. While mixing, 25 wt % NaOMe in methanol (5.41 g) was added. The slurry was mixed for 4 hours at room temperature then cooled to 3 C. and held for 30 min. The solid formed was collected via vacuum filtration and was rinsed with anhydrous methanol (20 mL). The product was dried under high vacuum to give crude decitabine as white solid (1.95 g).

Reference： [1]Patent: US2010/249394,2010,A1 .Location in patent: Page/Page column 6

59
C₂₂H₁₈Cl₂N₄O₆ [ No CAS ]
[ 2353-33-5 ]

Yield	Reaction Conditions	Operation in experiment
	With methanol; sodium methylate; at 20 - 25℃; for 0.5h;	EXAMPLE 2 - Crude Decitabinep-CI-Bz-in/14 Crude Decitabine; MeOH (1.8 Kg) and 3, 5-di-O- (p-chlorobenzoyl) - Decitabine (455 g, 63.9% HPLC pure equivalent to 0.58 mol) are stirred at 20-250C. A 29% MeONa in MeOH solution (42.8 g, 0.23 mol) is added to the mixture which is then stirred at 20-25 0C for 30 min . The solid is filtered, washed three times with Omega-heptane (120 mL each) and then dried at 5O0C in vacuo to give 42.5 g of crude Decitabine in 93.6% purity as indicated by HPLC analysis.

Reference： [1]Patent: WO2010/40056,2010,A1 .Location in patent: Page/Page column 5-6

60
[ 22432-93-5 ]
[ 2353-33-5 ]

Yield	Reaction Conditions	Operation in experiment
	With methanol; ammonia; at 10 - 20℃;Product distribution / selectivity;	EXAMPLE 6: Preparation of decitabine.1 -(3,5-di-O-acetyl-2-deoxy-D-hbofuranosyl)-5-azacytosine (5 g) and methanol (10 mL) are charged into a round bottom flask. The mixture is stirred at 25-3O0C for 5-10 minutes and cooled to 10-150C. 10% Methanolic ammonia solution (2x13.62 g) is added and stirred for 5-10 minutes at 10-150C. The temperature is raised to room temperature and the mass is stirred for 3-3.5 hours. The mass is cooled to about 1O0C and stirred for 10-15 minutes. The formed solid is filtered, washed with methanol (2.5 mL), and suction dried to obtain decitabine. Yield: 1.55 g (83%); Purity by HPLC: 89%.

Reference： [1]Patent: WO2010/129211,2010,A2 .Location in patent: Page/Page column 28

61
[ 931-86-2 ]
[ 3601-89-6 ]
[ 2353-33-5 ]

Yield	Reaction Conditions	Operation in experiment
		34 mL of BSTFA are added to a suspension of 6.4 g of azacytosine in 300 mL of acetonitrile. The mixture is brought to 50C and it is stirred for 90 minutes, It is cooled to ambient temperature, 6.3 mL of trimethylsilyltriflate and 11.1 g of 1-chloro-3,5-di-p-toluoyl-2-deoxy-D-ribofuranose are added to the solution, in about ten minutes. It is stirred for 140 minutes, 400 mL of methanol are added controlling the temperature in an ice bath. Concentration is carried out at low pressure until a viscous residue is obtained, 400 mL of methanol are added, it is heated to 50C and 36 mL of 30% solution of sodium methylate in methanol are added. It is stirred for 1 hour, it is cooled to 0C, it is stirred to complete precipitation and the solid is filtered by washing it on the filter with methanol. 2.3 g of decitabine with HPLC purity (UV 254 nm) of 99.2% are obtained after drying at low pressure. After recrystallisation from methanol the HPLC purity (UV 254 nm) is 99.8%.
		Example 9 Preparation of Decitabine 34 mL of BSTFA are added to a suspension of 6.4 g of azacytosine in 300 mL of acetonitrile. The mixture is brought to 50 C. and it is stirred for 90 minutes. It is cooled to ambient temperature, 6.3 mL of trimethylsilyltriflate and 11.1 g of 1-chloro-3,5-di-p-toluoyl-2-deoxy-D-ribofuranose are added to the solution, in about ten minutes. It is stirred for 140 minutes, 400 mL of methanol are added controlling the temperature in an ice bath. Concentration is carried out at low pressure until a viscous residue is obtained, 400 mL of methanol are added, it is heated to 50 C. and 36 mL of 30% solution of sodium methylate in methanol are added. It is stirred for 1 hour, it is cooled to 0 C., it is stirred to complete precipitation and the solid is filtered by washing it on the filter with methanol. 2.3 g of decitabine with HPLC purity (UV 254 nm) of 99.2% are obtained after drying at low pressure. After recrystallisation from methanol the HPLC purity (UV 254 nm) is 99.8%.

Reference： [1]Patent: EP2371825,2011,A1 .Location in patent: Page/Page column 9
[2]Patent: US2011/245485,2011,A1 .Location in patent: Page/Page column 7

62
[ 1149-26-4 ]
[ 2353-33-5 ]
[ 1422465-21-1 ]

Reference： [1]Molecular Pharmaceutics,2013,vol. 10,p. 3195 - 3202

63
[ 1149-26-4 ]
[ 2353-33-5 ]
[ 1423539-59-6 ]

Reference： [1]Molecular Pharmaceutics,2013,vol. 10,p. 3195 - 3202

64
[ 1685-33-2 ]
[ 2353-33-5 ]
[ 1423539-51-8 ]

Reference： [1]Molecular Pharmaceutics,2013,vol. 10,p. 3195 - 3202

65
[ 1685-33-2 ]
[ 2353-33-5 ]
[ 1423539-61-0 ]

Reference： [1]Molecular Pharmaceutics,2013,vol. 10,p. 3195 - 3202

66
[ 1161-13-3 ]
[ 2353-33-5 ]
[ 1423539-55-2 ]

Reference： [1]Molecular Pharmaceutics,2013,vol. 10,p. 3195 - 3202

67
[ 1161-13-3 ]
[ 2353-33-5 ]
[ 1423539-65-4 ]

Reference： [1]Molecular Pharmaceutics,2013,vol. 10,p. 3195 - 3202

68
[ 3160-59-6 ]
[ 2353-33-5 ]
[ 1423539-63-2 ]

Reference： [1]Molecular Pharmaceutics,2013,vol. 10,p. 3195 - 3202

69
[ 3160-59-6 ]
[ 2353-33-5 ]
[ 1423539-53-0 ]

Reference： [1]Molecular Pharmaceutics,2013,vol. 10,p. 3195 - 3202

70
[ 2353-33-5 ]
carbobenzyloxy-L-tryptophan [ No CAS ]
C₂₇H₂₈N₆O₇ [ No CAS ]

Reference： [1]Molecular Pharmaceutics,2013,vol. 10,p. 3195 - 3202

71
[ 931-86-2 ]
[ 951-78-0 ]
[ 2353-33-5 ]

Yield	Reaction Conditions	Operation in experiment
	With immobilized NDT from Bacillus psychrosaccharolyticus; In aq. phosphate buffer; at 37℃; for 3h;pH 7.5;Enzymatic reaction;	Nucleoside analogues synthesis was performed by adding100 mg of immobilized biocatalyst (displaying 1.8 IU with thestandard assay) to 5 mL of 10 mM potassium phosphate bufferpH 7.5 with different concentrations of trifluorothymine and2-deoxyuridine (from 10 to 40 mM), for 5-trifluorothymidine syn-thesis (trifluridine), or 5-azacytosine and 2-deoxyuridine (from10 to 20 mM), for 5-aza-2-deoxycytidine synthesis (decytabine).Reactions were performed at 37C for 3 h and, at different reac-tion times, samples were withdrawn and filtered off using a pipettefilter device. Afterwards, the supernatant was analyzed by HPLCto quantitatively measure the reaction products as aforemen-tioned (section 2.6. of Materials and methods). Retention timeswere: uracil (Ura): 5.41 min; 2-deoxyuridine (dUrd): 9.16 min;5-trifluorothymine (5-tFThy): 8.0 min; 5-trifluorothymidine (5-tFThd): 13.5 min; 5-azacytosine (5-azaCyt): 4.5 min; 5-aza-2-deoxycytidine (5-azadCyd): 8.9 min. The produced nucleoside wasidentified by comparison of its HPLC retention time with that ofauthentic samples.

Reference： [1]Catalysis Today,2016,vol. 259,p. 197 - 204

72
C₃₈H₃₂N₄O₈ [ No CAS ]
[ 2353-33-5 ]

Yield	Reaction Conditions	Operation in experiment
37.6%	With pyridine; at 20℃;	The obtained intermediate V(beta) is dissolved in 1000 ml of pyridine, and reacted at room temperature with stirring, and detected by TLC. After the reaction is completed,Evaporation to dryness under reduced pressure, and then, 7 L of anhydrous methanol, and 20 g of activated carbon, heated under reflux for 1 hour, filtered, and the filtrate was sealed and crystallized. The filter cake was added with 5 L of anhydrous methanol and heated to reflux for 0.5 hour, filtered, and the filtrate was sealed and crystallized. . Dry at 40 C in vacuo to give a white product. The yield was determined to be decitabine, the yield was 37.6%, and the purity by HPLC was 99.7%.
		The intermediate V 190g dissolved in 1500 ml of triethylamine, the reaction at room temperature under stirring 10h, to dryness under reduced pressure, the obtained solid is transferred to the reactor, by adding 15.2L water-free methanol and 60g activated carbon, heating to reflux 2 hours, filtration, filtrate closed placing crystallization, the filter cake re-shift to 30L adding glass autoclave 15.2L water-free methanol heating to reflux, 2 hours, filtration, filtrate closed placing crystallization; filtering, will be 2 times the crystal devitrifying merger, 40 C vacuum drying, the 40g the white product. The 40g the white product by adding 3200 ml anhydrous methanol, and 10g activated carbon, heating reflux for 1 hour, filtering, the filtrate closed placing crystallization, filtration, washing, 40 C vacuum drying, to obtain white product is a Decitabine. HPLC detection its purity.

Reference： [1]Patent: CN103739645,2016,B .Location in patent: Paragraph 0069; 0070; 0073; 0077; 0081; 0085
[2]Patent: CN103739636,2016,B .Location in patent: Paragraph 0090

73
methyl ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-valinate [ No CAS ]
[ 2353-33-5 ]
methyl ((((2R,3S,5R)-5-(4-amino-2-oxo-1,3,5-triazin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-valinate [ No CAS ]
methyl ((((2R,3S,5R)-5-(4-amino-2-oxo-1,3,5-triazin-1(2H)-yl)-2-((((((S)-1-methoxy-3-methyl-1-oxobutan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran-3-yl)oxy)(phenoxy)phosphoryl)-L-valinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22.8%; 22 mg		Example 15: Preparation of methyl ((((2R,3S,5R)-5-(4-amino-2-oxo-1 ,3,5-triazin-1 (2H)-yl)-3- hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-valinate (compound 21 ): Following the procedure described for compound 9, using decitabine (compound 3), 20 mg, 0.088 mmol) and methyl ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-valinate (compound 5, 47 mg, 0.1 14 mmol), methyl ((((2R,3S,5R)-5-(4-amino-2-oxo-1 ,3,5-triazin-1 (2H)-yl)-3- hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-valinate (compound 21 , 10 mg, 22.8 % yield) was obtained. Simultaneously, methyl ((((2R,3S,5R)-5-(4-amino-2-oxo-1 ,3,5-triazin-1 (2H)-yl)-2-((((((S)-1 - methoxy-3-methyl-1 -oxobutan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran- 3-yl)oxy)(phenoxy)phosphoryl)-L-valinate (compound 22, 22 mg) was obtained. Compound 21 : MS-ESI (+): (m/z): [M+Na]+ =520, [M+K]+ =536 MS-ESI (-): (m/z): [M-H] -496 Compound 22: MS-ESI (+): (m/z): [M+Na]+ =789

Reference： [1]Patent: WO2016/146808,2016,A1 .Location in patent: Page/Page column 38; 39

74
[ 2353-33-5 ]
methyl ((((2R,3S,5R)-5-(2,4-dioxo-3,4-dihydro-1,3,5-triazin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-valinate [ No CAS ]

Reference： [1]Patent: WO2016/146808,2016,A1

75
[ 2353-33-5 ]
methyl ((((2R,3S,5R)-5-(3-carbamoylureido)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-valinate [ No CAS ]

Reference： [1]Patent: WO2016/146808,2016,A1

76
[ 52523-35-0 ]
[ 80184-05-0 ]
[ 2353-33-5 ]

Yield	Reaction Conditions	Operation in experiment
89.3%		1) Under nitrogen protection,will1-Chloro-2-deoxy-D-ribofuranose (15.3 g, 100 mmol)Cobalt nitrate(60 mmol),(R) -1,1'-bi-2-naphthol (15.7 g, 55 mmol) were added to 150 ml of DMF, stirred and mixed at 60 C for 1-2 hours, then cooled to room temperature,Filtered to give a mixture M containing 1-chloro-2-deoxy-D-ribofuranose complex;2) 11.1 g (110 mmol) of triethylamine,2,4-bis-trimethylSilicon-S-triazine(200 mmol)Into the mixture M obtained in the step 1) for 6 to 8 hours while stirring at 40 C,Dumped into the water,Dichloromethane extraction,2M & lt; / RTI & gt; HCl,Washed with saturated sodium bicarbonate,Concentrated and recrystallized from ethanol to obtain 20.4 g of decitabine in a yield of 89.3% and a purity of 99.57%.
87.2%		In the preparation method of decitabine according to Example 1,Except that the amount of palladium dichloride used was 17.7 g,19.9 g of decitabine was obtained,The yield was 87.2%Purity 96.48%.

Reference： [1]Patent: CN106046089,2016,A .Location in patent: Paragraph 0026; 0027; 0028; 0029
[2]Patent: CN106117290,2016,A .Location in patent: Paragraph 0026; 0027; 0028; 0029; 0030; 0031; 0032-0061

77
[ 931-86-2 ]
[ 17039-17-7 ]
[ 2353-33-5 ]

Reference： [1]Beilstein Journal of Organic Chemistry,2016,vol. 12,p. 2588 - 2601

78
[ 75-77-4 ]
[ 2353-33-5 ]
[ 431890-05-0 ]

Yield	Reaction Conditions	Operation in experiment
70%	With 1H-imidazole; In N,N-dimethyl-formamide; at 15 - 30℃; for 1h;Cooling with ice;	A suspension of 5-azacytidine (I) (1 mM) in anhydrous N, N-dimethylformamide (3 mL) Imidazole (2 mM) was added to the solution, and the corresponding silyl chloride (1.5 mM) was added dropwise over about 10 minutes under ice cooling, then gradually warmed to room temperature (several hours) until the material disappeared (several hours) did. The reaction solution was poured into 50 mL of a mixture of ethyl acetate-saturated brine (2: 1) and extracted with ethyl acetate. The extract was washed with saturated brine (10 mL) twice and then dried over anhydrous sodium sulfate. The insoluble matter was removed, and the extract was evaporated to dryness under reduced pressure. The resulting oily residue was applied to a silica gel pack column (Yamazen Separating and purifying the intended 5-azacytidine 5 'azacytidine derivative (a compound of the formula (1b) wherein R is a hydroxyl group or a hydrogen atom, and R1 and A compound in which R 2 is a tri-substituted silyl group) can be isolated as a white powder. Hereinafter, this is referred to as synthesis method B. [0066] 3 ', 5'-Di (O-trimethylsilyl) -2'-deoxy-5-azacytidine: (Compound M) (1b), R = H, R 1 = R2 = Trimethylsilyl group) Synthetic method: Method B (reaction time: about 1 hour, column eluent: ethyl acetate-methanol, isolation yield: 70%).

Reference： [1]Patent: JP6162349,2017,B1 .Location in patent: Paragraph 0051; 0066

79
[ 18162-84-0 ]
[ 2353-33-5 ]
C₂₈H₅₆N₄O₄Si₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 2h;Cooling with ice;	[0051] 5-azacytidines (I) (1 mM) Of anhydrous N, N-dimethylformamide (3 mL) Imidazole (2 mM) was added to the solution, The corresponding silyl chloride (1.5 mM) was added dropwise over about 10 minutes under ice cooling, Subsequently, the mixture was gradually returned to room temperature and stirred until the raw material disappeared (several hours). The reaction solution was poured into 50 mL of a mixed solution of ethyl acetate-saturated brine (2: 1) And extracted with ethyl acetate. The extract was washed twice with saturated brine (10 mL) Dried over anhydrous sodium sulfate, The insoluble matter was removed from the extract, and the residue was evaporated to dryness under reduced pressure, and the resulting oily residue was separated and purified on a silica gel pack column (Yamazen Smart Flash MS system apparatus) The 3 ', 5' position disilyl ether derivative of the objective 5-azacytidine (in the formula (1b), R is a hydroxyl group or a hydrogen atom, R 1 and R 2 are tri-substituted silyl groups. ) Could be isolated as a white powder. Hereinafter, this is referred to as synthesis method B.[0067] 3 ', 5'-di (O-nomooctyldimethylsilyl) -2'-deoxy-5-azacytidine (Compound N) : 3 ', 5'-Di (O-n-octyldimethylsilyl) -2'-deoxy-5-azacytidine: (R = H, R1 = R2 = n-Octyldimethylsilyl group in the formula (1b)) Synthesis method: Method B (reaction time: about 2 hours, column elution solvent: ethyl acetate-n-hexane system, isolation yield: 54%)

Reference： [1]Patent: JP6162349,2017,B1 .Location in patent: Paragraph 0051; 0067

80
1-<3,5-bis(Fmoc)-2'-deoxyribofuranosyl>-5-azacytidine [ No CAS ]
[ 2353-33-5 ]

Yield	Reaction Conditions	Operation in experiment
78.5%	With pyridine; triethylamine; at 20℃; for 2h;	Intermediate 5 (1.06kg), pyridine (12L) and triethylamine (3L) were added to the 20L reaction flask, stirring was started.The reaction was stirred at room temperature for two hours, controlling the reaction is complete by TLC, at a bath temperature ?70 deg.] C, under a vacuum of ?-0.07MPa solvent was distilled off under reduced pressure to 20L rotary evaporator, and then purified by silica gel column chromatography to give an off-white the solid was added methanol (6.5L) was heated and dissolved, crystallization filtrate was allowed to cool naturally and filtered to give crude decitabine 145.0 g, yield: 40.3%. The crude decitabine (145.0 g) and methanol (14L) 20L into the reaction flask, was heated to a clear solution, filtered hot, the filtrate was allowed to cool naturally crystallization, filtration, and dried in vacuo to give the solid decitabine finished 113.8g yield: 78.5%

Reference： [1]Patent: CN102827224,2016,B .Location in patent: Paragraph 0041; 0053-0056

81
[ 2353-33-5 ]
5’-O-tert-butyldimethylsilyl-2’-deoxy-5-azacytidine-3’-O-[(2-cyanoethyl)-N,N-diisopropylphosphoramidite] [ No CAS ]

Reference： [1]Patent: WO2019/14286,2019,A2

82
[ 2353-33-5 ]
5'-O-tert-butyldimethylsilyl-P(O)-(2-cyanoethyl)-P-deoxo-2'-deoxy-5-azacytidylyl-(3'→5')-3'-O-tert-butyldimethylsilyl-2'-deoxyguanosine [ No CAS ]

Reference： [1]Patent: WO2019/14286,2019,A2
[2]Patent: WO2019/14286,2019,A2

83
[ 2353-33-5 ]
5’-O-tert-butyldimethylsilyl-P-(2-cyanoethyl)-2’-deoxy-5-azacytidylyl-(3'→5')-3’-O-tert-butyldimethylsilyl-2’-deoxyguanosine [ No CAS ]

Reference： [1]Patent: WO2019/14286,2019,A2
[2]Patent: WO2019/14286,2019,A2

84
[ 2353-33-5 ]
[ 929904-84-7 ]

Reference： [1]Patent: WO2019/14286,2019,A2
[2]Patent: WO2019/14286,2019,A2

85
[ 2353-33-5 ]
guadecitabine guanidinium salt [ No CAS ]

Reference： [1]Patent: WO2019/14286,2019,A2
[2]Patent: WO2019/14286,2019,A2

86
[ 2353-33-5 ]
[ 929904-85-8 ]

Reference： [1]Patent: WO2019/14286,2019,A2
[2]Patent: WO2019/14286,2019,A2
[3]Patent: WO2019/14286,2019,A2
[4]Patent: WO2019/14286,2019,A2

87
[ 18162-48-6 ]
[ 2353-33-5 ]
5’-O-tert-butyldimethylsilyl-2’-deoxy-5-azacytidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26.8 g	With 1H-imidazole; In N,N-dimethyl-formamide; at 0 - 50℃; for 2.5h;Inert atmosphere;	Decitabine (100.0 g; 438 mmol) and imidazole (74.6 g; 1.095 mol) were suspended in dry DMF (1000 ml) under N2 atm. The mixture was heated to 50 C until suspension was dissolved then the solution was cooled to 0 C. t-Butyldimethylsilyl chloride (TBDSCl, 74.9 g; 482 mmol) was added portionwise during 30 min, so that the temperature of the reaction mixture did not exceed 5 C. Then the reaction mixture was stirred at 0C for 2 h. Water (3 1) was added. The formed suspension was stirred for 20 min and filtered. Solids were washed with water (2x 1 1) and dried in vacuum oven (40 C, 50 mBar, 24 h). Yield 133.7 g (89%). The obtained product was dissolved in i-PrOH (1.3 1) at 65 C then n-hexane (1 1) was added during 30 min. The formed suspension was cooled to 0C. Next n-hexane (900 ml) was added and suspension was stirred for 2 h at 0C. Product was filtered, washed with n-hexane (500 ml) and dried in vacuum oven (40 C, 50 mBar, 12 h). Yield 83.5 g (56%). The obtained product (30 g) was dissolved in boiling i-PrOH (195 ml) then n-hexane (300 ml) was added during 30 min. The formed suspension was cooled to 20 C and stirred for next 1 h. Product was filtered, washed by n-hexane (100 ml) and dried in vacuum oven (40C, 50 mBar, 12 h). Yield 26.8 g (89%). The obtained product was analyzed by XRPD and the pattern is shown in Figures 2 and 3.

Reference： [1]Patent: WO2019/14286,2019,A2 .Location in patent: Paragraph 0160; 0259; 0260-0261; 0275-0276

88
[ 2353-33-5 ]
4-amino-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl](6-²H₁)-5,6-dihydro-1,3,5-triazin-2(1H)-one [ No CAS ]

Reference： [1]Helvetica Chimica Acta,2019,vol. 102

89
[ 2353-33-5 ]
C₈H₁₄N₄O₅ [ No CAS ]

Reference： [1]Helvetica Chimica Acta,2019,vol. 102

90
[ 2353-33-5 ]
4-amino-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)-oxolan-2-yl]-5,6-dihydro-1,3,5-triazin-2(1H)-one [ No CAS ]

Reference： [1]Helvetica Chimica Acta,2019,vol. 102

91
[ 2353-33-5 ]
C₃₂H₃₅N₅O₆ [ No CAS ]

Reference： [1]Patent: CN109232692,2019,A

92
[ 4637-24-5 ]
[ 2353-33-5 ]
C₁₁H₁₇N₅O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	5 g of decitabine (21.90 mmol, 1 eq) was dissolved in 50 mL of N,N-dimethylformamide, and 2.6 g of N,N-dimethylformamide dimethyl acetal (175.2 mmol, 8 eq) was added. The reaction was carried out under nitrogen atmosphere, and the mixture was stirred at room temperature overnight, and DMF was evaporated under reduced pressure. To the residue, 200 ml of dichloromethane was added, and the mixture was stirred to precipitate white insolubles, filtered, and the filter cake was rinsed with dichloromethane.After drying, 4.9 g of white powder of I-2-A was obtained, yield: 79.0%.

Reference： [1]Patent: CN109232692,2019,A .Location in patent: Paragraph 0031; 0035; 0036

93
[ 40615-36-9 ]
[ 2353-33-5 ]
[ 107036-47-5 ]

Yield	Reaction Conditions	Operation in experiment
92%	With pyridine; at 20℃;Inert atmosphere;	10 g of decitabine (43.82 mmol, 1 eq) was added to 60 mL of pyridine, and distilled under reduced pressure three times to remove the water content in the raw material, and dissolved in 50 mL of dry pyridine. 22.27 g of 4,4'-dimethoxytriphenylchloromethane (65.7 mmol, 1.5 eq) was dissolved in 30 mL of pyridine, and the system was added dropwise at room temperature under nitrogen. After the reaction was completed, dichloromethane and water were added, and the organic layer was washed with saturated sodium hydrogen sulfate. Filtration and evaporation of the solvent under reduced pressure gave a crude material. After the crude product was separated and purified by chromatography (V (CH2CI2):V (MeOH) =45:1), 2,2 g of white solid of I-2-B was obtained, yield: 92.0%.

Reference： [1]Patent: CN109232692,2019,A .Location in patent: Paragraph 0037; 0038; 0039

94
[ 2353-33-5 ]
C₂₃H₂₇N₅O₈ [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 6620 - 6624
Angew. Chem.,2019,vol. 131,p. 6692 - 6696,5

95
[ 2353-33-5 ]
C₂₉H₄₃N₅O₈Si₂ [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 6620 - 6624
Angew. Chem.,2019,vol. 131,p. 6692 - 6696,5

96
[ 2353-33-5 ]
C₂₃H₃₅N₅O₈Si₂ [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 6620 - 6624
Angew. Chem.,2019,vol. 131,p. 6692 - 6696,5

97
[ 2353-33-5 ]
C₂₅H₃₉N₅O₁₀Si₂ [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 6620 - 6624
Angew. Chem.,2019,vol. 131,p. 6692 - 6696,5

98
[ 2353-33-5 ]
2′-deoxy-3′-[mono-7-((diethylamino)-2-oxochroman-4-yl)methoxycarbonyl]-5-azacytidine [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 6620 - 6624
Angew. Chem.,2019,vol. 131,p. 6692 - 6696,5

99
[ 2353-33-5 ]
C₁₇H₁₉N₅O₈ [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 6620 - 6624
Angew. Chem.,2019,vol. 131,p. 6692 - 6696,5

100
[ 2353-33-5 ]
C₁₉H₂₃N₅O₁₀ [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 6620 - 6624
Angew. Chem.,2019,vol. 131,p. 6692 - 6696,5

101
(7-(diethylamino)-2-oxochroman-4-yl)methyl(perfluorophenyl)carbonate [ No CAS ]
[ 2353-33-5 ]
C₂₃H₂₇N₅O₈ [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 6620 - 6624
Angew. Chem.,2019,vol. 131,p. 6692 - 6696,5

102
[ 13154-24-0 ]
[ 2353-33-5 ]
2′-deoxy-5′-triisopropyl-5-azacytidine [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 6620 - 6624
Angew. Chem.,2019,vol. 131,p. 6692 - 6696,5

103
[ 13154-24-0 ]
[ 2353-33-5 ]
2′-deoxy-3′-[mono-7-((diethylamino)-2-oxochroman-4-yl)methoxycarbonyl]-5′-triisopropyl-5-azacytidine [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 6620 - 6624
Angew. Chem.,2019,vol. 131,p. 6692 - 6696,5

104
[ 2353-33-5 ]
1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-4-(((4-methoxyphenyl)diphenylmethyl)amino)-1,3,5-triazin-2(1H)-one [ No CAS ]

Reference： [1]Patent: WO2020/13712,2020,A1

105
[ 2353-33-5 ]
1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-4-(((4-methoxyphenyl)diphenylmethyl)amino)-5,6-dihydro-1,3,5-triazin-2(1H)-one [ No CAS ]

Reference： [1]Patent: WO2020/13712,2020,A1

106
[ 2353-33-5 ]
methyl 5-(3-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-6-(((4-methoxyphenyl)diphenylmethyl)amino)-4-oxo-3,4-dihydro-1,3,5-triazin-1(2H)-yl)pentanoate [ No CAS ]

Reference： [1]Patent: WO2020/13712,2020,A1

107
[ 2353-33-5 ]
1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-5-(5-hydroxypentyl)-4-(((4-methoxyphenyl)diphenylmethyl)amino)-5,6-dihydro-1,3,5-triazin-2(1H)-one [ No CAS ]

Reference： [1]Patent: WO2020/13712,2020,A1

108
[ 2353-33-5 ]
C₄₅H₆₆N₄O₆Si₂ [ No CAS ]

Reference： [1]Patent: WO2020/13712,2020,A1

109
[ 18162-48-6 ]
[ 2353-33-5 ]
4-amino-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-1,3,5-triazin-2(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 6h;Inert atmosphere;	Commercially availa ble <strong>[2353-33-5]5-aza-2'-deoxycytidine</strong> (495 mg, 2.17 mmol), tert- butyld imethylsi lyl chloride (1.3 g, 8.7 mmol, 4equiv.) and imidazole (0.901 g, 8.7 mmol, 4equiv.) were dissolved in dry N,N-dimethylformamide (7 mL) . The reaction was stirred at room temperature, under argon, for 6 hours until TLC showed the reaction was complete. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (3x10 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by recrystallization in diethyl ether to afford 4-amino- l-((2R,4S,5R)-4-((tert- butyld imethylsi iyl)oxy) -5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-l,3,5- triazin-2( lH)-one 77 (0.990 g, quant.) as a white powder. Rf = 0.50 (10% methanol / dichloromethane) . NMR (500 MHz, Chloroform-d) d 8.60 (s, 1H), 6.17 (dd, J = 6.4, 5.1 Hz, 1H), 5.63 (s, 1H), 5.37 (s, 1H), 4.40 (dt, J = 6.2, 4.8 Hz, 1H), 3.96 (dt, J = 4.6, 2.4 Hz, 1H), 3.92 (dd, J = 11.5, 2.8 Hz, 1H), 3.77 (dd, J = 11.5, 2.2 Hz, 1H), 2.51 (ddd, J = 13.5, 6.5, 5.2 Hz, 1H), 2.16 (ddd, J = 13.5, 6.3, 5.0 Hz, 1H), 0.92 (s, 9H), 0.88 (s, 9H), 0.11 (s, 3H), 0.11 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H) . 13C NMR ( 126 MHz, CDCI3) d 166.35, 162.49, 155.93, 87.99, 86.53, 70.54, 62.03, 42.55, 25.94, 25.70, 18.38, 17.95, -0.02, -4.59, -4.92, -5.49. HRMS (m/z) calcd . for C2oH4iN404Si2 [M + H]+ 457.2666, found 457.2661.

Reference： [1]Patent: WO2020/13712,2020,A1 .Location in patent: Page/Page column 47

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Precautionary Statements-General
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Code	Phrase
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P320
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P321
P322
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P342	If experiencing respiratory symptoms:
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P378
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P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
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H260	In contact with water releases flammable gases which may ignite spontaneously
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Code	Phrase
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Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
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H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 2353-33-5 ] {[proInfo.proName]}

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[ 2353-33-5 ] Synthesis Path-Upstream 1~13

[ 2353-33-5 ] Synthesis Path-Downstream 1~109

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