[ CAS No. 136834-21-4 ] {[proInfo.proName]}

Name: 136834-21-4|N-(9-((2R,3R,4R,5R)-5-((Bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-3-fluoro-4-hydroxytetrahydrofuran-2-yl)-9H-purin-6-yl)benzamide|95%
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Quality Control of [ 136834-21-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 136834-21-4 ]

SDS Specification

Alternatived Products of [ 136834-21-4 ]

Product Details of [ 136834-21-4 ]

CAS No. :	136834-21-4	MDL No. :	MFCD15145191
Formula :	C₃₈H₃₄FN₅O₆	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DDOOVEXTSRBCMU-VYUOYPLNSA-N
M.W :	675.70	Pubchem ID :	11125261
Synonyms :		Chemical Name :	N-(9-((2R,3R,4R,5R)-5-((Bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-3-fluoro-4-hydroxytetrahydrofuran-2-yl)-9H-purin-6-yl)benzamide

Calculated chemistry of [ 136834-21-4 ]

Physicochemical Properties

Num. heavy atoms :	50
Num. arom. heavy atoms :	33
Fraction Csp3 :	0.21
Num. rotatable bonds :	12
Num. H-bond acceptors :	10.0
Num. H-bond donors :	2.0
Molar Refractivity :	182.43
TPSA :	129.85 Å²

Pharmacokinetics

GI absorption :	Low
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.5 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.8
Log Po/w (XLOGP3) :	5.53
Log Po/w (WLOGP) :	5.5
Log Po/w (MLOGP) :	2.32
Log Po/w (SILICOS-IT) :	4.42
Consensus Log Po/w :	4.31

Druglikeness

Lipinski :	2.0
Ghose :	None
Veber :	1.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.17

Water Solubility

Log S (ESOL) :	-7.21
Solubility :	0.0000417 mg/ml ; 0.0000000617 mol/l
Class :	Poorly soluble
Log S (Ali) :	-8.02
Solubility :	0.0000065 mg/ml ; 0.0000000096 mol/l
Class :	Poorly soluble
Log S (SILICOS-IT) :	-11.08
Solubility :	0.0000000056 mg/ml ; 0.0 mol/l
Class :	Insoluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	3.0
Synthetic accessibility :	5.93

Safety of [ 136834-21-4 ]

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 [ 136834-21-4 ]

* 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 [ 136834-21-4 ]
Downstream synthetic route of [ 136834-21-4 ]

[ 136834-21-4 ] Synthesis Path-Upstream 1~7

1
[ 40615-36-9 ]
[ 136834-20-3 ]
[ 136834-21-4 ]

Yield	Reaction Conditions	Operation in experiment
97%	at 0 - 20℃;	Compound 129 (570 g, 1.53 mol, 1 wt, 1 vol, 1 eq) was dissolved in pyridine (2.85 L, 35.2 mol, 4.89 wt, 5.0 vols, 23 eq). The mixture was cooled to 2.6 °C and treated with 4,4’- dimethoxytrityl chloride (DMTC1; 543 g, 1.60 mol, 0.953 wt, 1.05 eq). The mixture was stirred at 0 to 5 °C for 2 h and then allowed to warm to ambient temperature. The reaction was monitored by LC/MS and complete conversion was confirmed after overnight stirring. The reaction mixture was cooled to below 5 °C and quenched by treatment with MeOH (124 ml, 3.05 mol, 0.172 wt, 0.217 vol, 2.0 eq) for 15 minutes. The mixture was co-evaporated with toluene (2.00 L, 3.04 wt, 3.51 vol) under vacuum and then diluted with a mixture of EtOAc (2.850 L, 4.5 wt, 5.0 vol) and n-heptane (2.85 L, 3.42 wt, 5.0 vol). The organic layer was washed with saturated NaHCO3 (9 wtpercent solution in water; 2.0 L, 3.5 vol). An additional EtOAc (2.85 L, 4.5 wt, 5.0 vol) was added to completely dissolve the crude product. After stirred for 5 minutes, the two layers were separated. The organic layer was washed with water (2.0 L,3.5 wt, 3.5 vol). Solid began slowly precipitating out of the organic layer. The water layer was separated. The organic layer was then concentrated to approx. 1 vol. The crude product was slurried with a mixture of n-heptane (2.00 L, 2.40 wt, 3.51 vol) and toluene (0.50 L, 0.76 wt, 0.88 vol). After stirring for 15 minutes, the pale yellow solid was collected by vacuum filtration. The filter cake was sequentially rinsed with: (1) a mixture of n-heptane (0.60 L, 0.72 wt, 1.05 vol) and toluene (0.30 L, 0.46 wt, 0.53 vol), and then (2) n-heptane (3.00 L,3.6 wt, 5.26 vol). The solid was dried with no heat for 30 minutes and then transferred to trays for drying at 50 °C in a vacuum oven overnight to give Compound 130 as pale yelllow solid (996.7 g, 1.47 mol, 1.75 wt, 97percent yield).‘H NMR (400 IVIFIz, CHLOROFORM-d) = 8.99 (s, 1H), 8.76 (s, 1H), 8.21 (s, 1H), 8.04 - 8.00 (m, 2H), 7.64 - 7.59 (m, 1H), 7.57 - 7.50 (m, 2H), 7.41 - 7.36 (m, 2H), 7.32 - 7.15 (m, 7H), 6.83 - 6.76 (m, 4H), 6.31 (dd, J= 2.5, 17.0 Hz, 1H), 5.68 (ddd, J 2.3, 4.7, 52.7 Hz, 1H), 4.88 -4.77 (m, 1H), 4.26 -4.21 (m, 1H), 3.77 (s, 6H), 3.57 (dd, J 3.1, 10.9 Hz, 1H),3.43 (dd, J= 4.1, 10.7 Hz, 1H), 2.60 (br s, 1H)
84%	at 20℃; for 16 h;	To a solution of N- (9-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-9H-purin-6-yl)- benzamide (35 g, 93.7 mmol) in pyridine (180 mL) was added DMTrCI (38.12 g, 1 12.5 mmol, 1.2 eq) and the resulting mixture was stirred at RT for 16 h. The mixture was then diluted with CH2CI2 (800 mL), washed with sat NaHC0₃ (2x 400 mL) and brine (400 mL). The organic layer was dried over anhydrous Na₂S04, filtered and concentrated under reduced pressure. The residue was purified by S1O2 gel chromatography (petroleum ether / EtOAc=10/l to 1/4) to give the title compound as a white solid (53.0 g, 78.4 mmol, 84percent). [0291] ¹H-NMR (400 MHz, DMSO-de) δ ppm 11.26 (br s, 1H), 8.74 (s, 1H), 8.62 (s, 1H), 8.05 (d, J=7.4 Hz, 2H), 7.60 - 7.72 (m, 1H), 7.48 - 7.58 (m, 2H), 7.32 (d, J=7.2 Hz, 2H), 7.14 - 7.24 (m, 7H), 6.80 (dd, J=6.2, 8.7 Hz, 4H), 6.43 (d, J=20.0 Hz, 1H), 5.73 - 5.85 (m, 1H), 5.61 (d, J=4.4 Hz, 1H), 4.76 - 4.99 (m, 1H), 4.14 (br d, J=5.4 Hz, 1H), 3.64 - 3.79 (m, 7H), 3.19 - 3.33 (m, 2H).
31.2 g	at 20℃; for 3 h;	To a solution of compound 8b (30 g, 80.35 mmol) in pyridine (250 mL) was added4,4’-dimethoxytrityl chloride (54.45 g,160.71 mmol). After stirring at rt for 3 h, EtOAc (1L) was added and the mixture was filtered. The organic layer was successively washed with brine (300 mL x 3), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH in DCM = 0percent to 5percent) to give compound 8c (31.2 g) as a white solid. ESI-MS: m/z 676.3 [M + H] .

Reference： [1] Patent: WO2018/152450, 2018, A1, . Location in patent: Page/Page column 61; 62
[2] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 15, p. 4539 - 4543
[3] Patent: WO2018/156625, 2018, A1, . Location in patent: Paragraph 0290; 0291
[4] Journal of Medicinal Chemistry, 1993, vol. 36, # 7, p. 831 - 841
[5] Tetrahedron Letters, 1998, vol. 39, # 13, p. 1657 - 1660
[6] Patent: WO2018/138685, 2018, A2, . Location in patent: Page/Page column 109; 138; 174; 176

2
[ 146954-64-5 ]
[ 136834-21-4 ]

Reference： [1] Journal of Medicinal Chemistry, 1993, vol. 36, # 7, p. 831 - 841
[2] Patent: WO2003/99840, 2003, A1, . Location in patent: Page 221-222

3
[ 79896-97-2 ]
[ 136834-21-4 ]

Reference： [1] Journal of Medicinal Chemistry, 1993, vol. 36, # 7, p. 831 - 841

4
[ 136834-18-9 ]
[ 136834-21-4 ]

Reference： [1] Journal of Medicinal Chemistry, 1993, vol. 36, # 7, p. 831 - 841

5
[ 136834-19-0 ]
[ 136834-21-4 ]

Reference： [1] Journal of Medicinal Chemistry, 1993, vol. 36, # 7, p. 831 - 841

6
[ 20187-82-0 ]
[ 136834-21-4 ]

Reference： [1] Patent: WO2018/138685, 2018, A2,

7
[ 98-88-4 ]
[ 136834-21-4 ]

Reference： [1] Patent: WO2018/138685, 2018, A2,

[ 136834-21-4 ] Synthesis Path-Downstream 1~86

1
[ 40615-36-9 ]
[ 136834-20-3 ]
[ 136834-21-4 ]

Yield	Reaction Conditions	Operation in experiment
97%	With pyridine; at 0 - 20℃;	Compound 129 (570 g, 1.53 mol, 1 wt, 1 vol, 1 eq) was dissolved in pyridine (2.85 L, 35.2 mol, 4.89 wt, 5.0 vols, 23 eq). The mixture was cooled to 2.6 C and treated with 4,4?- dimethoxytrityl chloride (DMTC1; 543 g, 1.60 mol, 0.953 wt, 1.05 eq). The mixture was stirred at 0 to 5 C for 2 h and then allowed to warm to ambient temperature. The reaction was monitored by LC/MS and complete conversion was confirmed after overnight stirring. The reaction mixture was cooled to below 5 C and quenched by treatment with MeOH (124 ml, 3.05 mol, 0.172 wt, 0.217 vol, 2.0 eq) for 15 minutes. The mixture was co-evaporated with toluene (2.00 L, 3.04 wt, 3.51 vol) under vacuum and then diluted with a mixture of EtOAc (2.850 L, 4.5 wt, 5.0 vol) and n-heptane (2.85 L, 3.42 wt, 5.0 vol). The organic layer was washed with saturated NaHCO3 (9 wt% solution in water; 2.0 L, 3.5 vol). An additional EtOAc (2.85 L, 4.5 wt, 5.0 vol) was added to completely dissolve the crude product. After stirred for 5 minutes, the two layers were separated. The organic layer was washed with water (2.0 L,3.5 wt, 3.5 vol). Solid began slowly precipitating out of the organic layer. The water layer was separated. The organic layer was then concentrated to approx. 1 vol. The crude product was slurried with a mixture of n-heptane (2.00 L, 2.40 wt, 3.51 vol) and toluene (0.50 L, 0.76 wt, 0.88 vol). After stirring for 15 minutes, the pale yellow solid was collected by vacuum filtration. The filter cake was sequentially rinsed with: (1) a mixture of n-heptane (0.60 L, 0.72 wt, 1.05 vol) and toluene (0.30 L, 0.46 wt, 0.53 vol), and then (2) n-heptane (3.00 L,3.6 wt, 5.26 vol). The solid was dried with no heat for 30 minutes and then transferred to trays for drying at 50 C in a vacuum oven overnight to give Compound 130 as pale yelllow solid (996.7 g, 1.47 mol, 1.75 wt, 97% yield).?H NMR (400 IVIFIz, CHLOROFORM-d) = 8.99 (s, 1H), 8.76 (s, 1H), 8.21 (s, 1H), 8.04 - 8.00 (m, 2H), 7.64 - 7.59 (m, 1H), 7.57 - 7.50 (m, 2H), 7.41 - 7.36 (m, 2H), 7.32 - 7.15 (m, 7H), 6.83 - 6.76 (m, 4H), 6.31 (dd, J= 2.5, 17.0 Hz, 1H), 5.68 (ddd, J 2.3, 4.7, 52.7 Hz, 1H), 4.88 -4.77 (m, 1H), 4.26 -4.21 (m, 1H), 3.77 (s, 6H), 3.57 (dd, J 3.1, 10.9 Hz, 1H),3.43 (dd, J= 4.1, 10.7 Hz, 1H), 2.60 (br s, 1H)
84%	With pyridine; at 20℃; for 16h;	To a solution of N- (9-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-9H-purin-6-yl)- benzamide (35 g, 93.7 mmol) in pyridine (180 mL) was added DMTrCI (38.12 g, 1 12.5 mmol, 1.2 eq) and the resulting mixture was stirred at RT for 16 h. The mixture was then diluted with CH2CI2 (800 mL), washed with sat NaHC03 (2x 400 mL) and brine (400 mL). The organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by S1O2 gel chromatography (petroleum ether / EtOAc=10/l to 1/4) to give the title compound as a white solid (53.0 g, 78.4 mmol, 84%). [0291] 1H-NMR (400 MHz, DMSO-de) delta ppm 11.26 (br s, 1H), 8.74 (s, 1H), 8.62 (s, 1H), 8.05 (d, J=7.4 Hz, 2H), 7.60 - 7.72 (m, 1H), 7.48 - 7.58 (m, 2H), 7.32 (d, J=7.2 Hz, 2H), 7.14 - 7.24 (m, 7H), 6.80 (dd, J=6.2, 8.7 Hz, 4H), 6.43 (d, J=20.0 Hz, 1H), 5.73 - 5.85 (m, 1H), 5.61 (d, J=4.4 Hz, 1H), 4.76 - 4.99 (m, 1H), 4.14 (br d, J=5.4 Hz, 1H), 3.64 - 3.79 (m, 7H), 3.19 - 3.33 (m, 2H).
83.9%	With pyridine; at 25℃; for 2h;	N-(9-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2- yl)-9H-purin-6-yl)benzamide (5.0 g, 13.4 mmol, 1.0 eq) was co-evaporated with pyridine (30 mL). DMTrCl (6.81 g, 20.1 mmol, 1.5 eq) was added to a solution of N-(9-((2R,3R,4R,5R)-3- fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-9H-purin-6-yl)benzamide (5.0 g, 13.4 mmol, 1.0 eq) in pyridine (35 mL) at 25 C. The mixture was stirred at 25 C for 2 hours. Two parallel reactions were carried out. The combined mixtures were then diluted with DCM (15 mL), the organic layer was washed with sat.NaHCO3 solution (20 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated, the crude was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:2) to give compound N-(9- ((2R,3R,4R,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-3-fluoro-4- hydroxytetrahydrofuran-2-yl)-9H-purin-6-yl)benzamide (16.0 g, 22.5 mmol, 83.9% yield, 95% purity) as a light yellow solid. LCMS (ES, m/z) 676.2 (M+H).1H NMR (400 MHz, DMSO- d6) delta = 11.27 (br s, 1H), 8.75 (s, 1H), 8.63 (s, 1H), 8.06 (br d, J = 7.5 Hz, 2H), 7.69 - 7.62 (m, 1H), 7.60 - 7.51 (m, 2H), 7.33 (br d, J = 7.3 Hz, 2H), 7.28 - 7.15 (m, 7H), 6.82 (dd, J = 6.1, 8.6 Hz, 4H), 6.45 (d, J = 20.0 Hz, 1H), 5.82 - 5.72 (m, 2H), 4.97 - 4.75 (m, 1H), 4.15 (br d, J = 5.0 Hz, 1H), 3.72 (s, 6H), 3.35 - 3.22 (m, 2H).19F NMR (376 MHz, DMSO-d6) delta = -201.14 (s, 1F).

31.2 g	With pyridine; at 20℃; for 3h;	To a solution of compound 8b (30 g, 80.35 mmol) in pyridine (250 mL) was added4,4?-dimethoxytrityl chloride (54.45 g,160.71 mmol). After stirring at rt for 3 h, EtOAc (1L) was added and the mixture was filtered. The organic layer was successively washed with brine (300 mL x 3), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH in DCM = 0% to 5%) to give compound 8c (31.2 g) as a white solid. ESI-MS: m/z 676.3 [M + H] .
1.9 g	With pyridine; at 20℃;Inert atmosphere;	Step 2:Under the protection of nitrogen,Add DMTrCl (1.6g, 4.8mmol)To intermediate 4-1 (1.2g, 3.2mmol)Pyridine (15mL) solution,Stir at room temperature overnight.Add water (50mL) to the reaction solution,The mixture was extracted with ethyl acetate (40mL × 3),Combine the organic phases and dry with anhydrous sodium sulfate,Concentrate under reduced pressure,Flash column chromatography(2% methanol / dichloromethane) purified to obtain intermediate4-2 (1.9g) is a light yellow solid.

Reference： [1]Patent: WO2018/152450,2018,A1 .Location in patent: Page/Page column 61; 62
[2]Patent: WO2020/36199,2020,A1 .Location in patent: Paragraph 0054
[3]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 4539 - 4543
[4]Patent: WO2018/156625,2018,A1 .Location in patent: Paragraph 0290; 0291
[5]Patent: WO2019/43634,2019,A2 .Location in patent: Paragraph 00832; 00833; 00834
[6]Journal of Medicinal Chemistry,1993,vol. 36,p. 831 - 841
[7]Tetrahedron Letters,1998,vol. 39,p. 1657 - 1660
[8]Patent: WO2018/138685,2018,A2 .Location in patent: Page/Page column 109; 138; 174; 176
[9]Patent: CN110938104,2020,A .Location in patent: Paragraph 0432; 0433; 0435

2
2-(Cyanethoxy)-bis-N,N-(diisopropylamino)phosphane [ No CAS ]
[ 136834-21-4 ]
(2R,3R,4R,5R)-5-(6-benzamido-9H-purin-9-yl)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-fluorotetrahydrofuran-3-yl (2-cyanoethyl) diisopropylphosphoramidite [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 831 - 841

3
[ 124-63-0 ]
[ 136834-21-4 ]
[ 204633-61-4 ]

Reference： [1]Tetrahedron Letters,1998,vol. 39,p. 1657 - 1660

4
[ 136834-21-4 ]
[ 20187-82-0 ]

Reference： [1]Tetrahedron Letters,1998,vol. 39,p. 1657 - 1660

5
[ 136834-21-4 ]
[ 110143-10-7 ]

Reference： [1]Tetrahedron Letters,1998,vol. 39,p. 1657 - 1660

6
[ 136834-21-4 ]
[ 204633-62-5 ]

Reference： [1]Tetrahedron Letters,1998,vol. 39,p. 1657 - 1660

7
[ 136834-21-4 ]
[ 204633-63-6 ]

Reference： [1]Tetrahedron Letters,1998,vol. 39,p. 1657 - 1660

8
[ 79896-97-2 ]
[ 136834-21-4 ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 831 - 841

9
[ 136834-18-9 ]
[ 136834-21-4 ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 831 - 841

10
[ 146954-64-5 ]
[ 136834-21-4 ]

Yield	Reaction Conditions	Operation in experiment
		2'-fluoro oligonucleotides were synthesized as described previously [Kawasaki, et. [AL.,] J. Med. Chem., 1993,36, 831-841] and United States patent 5,670, 633, herein incorporated by reference. The preparation of 2'-fluoropyrimidines containing [A] 5-methyl substitution are described in US Patent 5,861, 493. Briefly, the protected nucleoside N6-benzoyl-2'-deoxy-2'-fluoroadenosine was synthesized utilizing commercially available 9-beta-D-arabinofuranosyladenine as starting material and whereby the 2'-alpha-fluoro atom is introduced by a SN2-displacement of a 2'-beta-triflate group. Thus N6-benzoyl-9-beta-D-arabinofuranosyladenine was selectively protected in moderate yield as the 3', 5'-ditetrahydropyranyl [(THP)] intermediate. Deprotection of the THP and N6-benzoyl groups was accomplished using standard methodologies to obtain the 5'-dimethoxytrityl- (DMT) and 5'-DMT-3'- phosphoramidite intermediates.

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 831 - 841
[2]Patent: WO2003/99840,2003,A1 .Location in patent: Page 221-222

11
[ 136834-19-0 ]
[ 136834-21-4 ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 831 - 841

13
[ 18162-48-6 ]
[ 136834-21-4 ]
[ 1244763-23-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	With 1H-imidazole; In N,N-dimethyl-formamide; at 0 - 35℃; for 23h;	Compound 130 (993 g, 1.47 mol, 1 wt, 1 vol, 1 eq) and imidazole (150 g, 2.20 mol, 0.15 1 wt, 1.5 eq) were dissolved in DMF (3.48 L, 3.28 kg, 3.3 wt, 3.5 vol) and the mixture was cooled to 5 C. TBS-Cl (244 g, 1.62 mol, 0.245 wt, 1.10 eq) was added. The reaction was stirred at 0 to 5 C for 2h, allowed to slowly warm to ambient temperature and monitored by LCMS. After 17 h, an additional imidazole (100 g, 1.47 mol, 0.10 wt, 1.0 eq) and TBS-Cl (111 g, 735 mmol, 0.112 wt, 0.50 eq) were added and stirring was continued at ambient temperature for 2h and at 35 C for 2h. The resulting mixture was cooled to 13.6 C and treated with MeOH (119 ml, 2.94 mol, 2 eq) for 10 minutes. In a separate reactor was added ice (5 kg, 5 wt) and saturated NH4C1 (28 wt% solution in water; 5.0 L, 5 vol). The reaction mixture was added to the ice/NH4C1 mixture. An off white solid began precipitating out of solution immediately. An additional 2kg of ice (2 kg, 2 wt) and water (3.0 L, 3 vol) were added to the mixture. The reaction flask was rinsed with water (0.50 L, 0.5 vol) and the rinsate was added to the mixture. n-heptane (2.00 L, 2 vol) was added to the mixture and sttirring was continued for 10 minutes. The off white solid was collected by vacuum filtration. The filter cake was rinsed with: (1) water (4.0 L, 4.0 vol), (2) water (4.0 L, 4.0 vol), (3) n-heptane (4.0 L, 4.0 vol), (4) n-heptane (4.0 L, 4.0 vol). The recovered solid was dried under vacuum at 45 C for 4 days to give Compound 131 as off-white solid (1.095 kg, 1.39 mol, 1.10 wt, 94% yield).?H NMR (400 IVIFIz, CHLOROFORM-d) = 9.09 (s, 1H), 8.78 (s, 1H), 8.28 (s, 1H), 8.02 (d, J 7.4 Hz, 2H), 7.63 - 7.59 (m, 1H), 7.55 - 7.50 (m, 2H), 7.37 (d, J= 7.1 Hz, 2H), 7.29 - 7.17 (m, 7H), 6.79 (d, J 7.9 Hz, 4H), 6.29 (dd, J 2.9, 16.2 Hz, 1H), 5.60 (ddd, J= 2.7,3.9, 53.1 Hz, 1H), 4.78 (ddd, J 4. 7, 6.4, 15.8 Hz, 1H), 4.26 -4.22 (m, 1H), 3.77 (s, 6H),3.58 (dd, J 3.1, 10.9 Hz, 1H), 3.26 (dd, J 3.7, 10.7 Hz, 1H), 0.85 (s, 9H), 0.10 (s, 3H),0.02 (s, 3H)

Reference： [1]Patent: WO2018/152450,2018,A1 .Location in patent: Page/Page column 61; 63; 64
[2]Patent: WO2020/36199,2020,A1 .Location in patent: Paragraph 0054; 0056
[3]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 4539 - 4543

14
sodium 2-(4-azidomethylphenoxy)acetate [ No CAS ]
[ 136834-21-4 ]
[ 1337865-40-3 ]

Reference： [1]Nucleosides, nucleotides and nucleic acids,2011,vol. 30,p. 475 - 489

15
[ 56183-63-2 ]
[ 136834-21-4 ]
C₅₀H₆₁FN₇O₆P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -20 - 20℃; for 2h;	Example 87 N6-Benzoyl-5'-O-(4,4'-dimethoxytrityl)-2'-fluoro-3'-O-[(N,N-diisopropylamino)[11-[(3,4,6-tri-O-acetyl-2-acetylamino-2-deoxy-beta-D-galactopyranosyl)oxy]-3,6,9-trioxaundecyl]phosphino]-2'-deoxyadenosine (58a) Solution of bis(N,N-diisopropylamino)chlorophosphite (347 mg, 1.30 mmol) in anhydrous dichloromethane (3 mL) was added dropwise to a stirred solution of N6-benzoyl-5'-O-(4,4'-dimethoxytrityl)-2'-fluoro-2'-deoxyadenosine, 50a, (703 mg, 1.4 mmol) and N-ethyl-N,N-diisopropylamine (255 mg, 1.98 mmol) in anhydrous dichloromethane (4 mL) at -20 C. The solution was allowed to stir at room temperature for 2 h. To the obtained mixture, compound 7d (653 mg, 1.25 mmol) and 1H-tetrazole (0.45 M in MeCN, 1.0 mL) were added followed by stirring at room temperature for 14 h. The reaction mixture was quenched by addition of excess 5% aqueous NaHCO3. The emulsion was diluted with 5% aqueous NaHCO3 (10 mL), and the product was extracted with ethyl acetate (3*50 mL). Extracts were washed with brine, dried over anhydrous Na2SO4, and evaporated to oil. Evaporation of fractions gave the title compound as a viscous oil in a yield of 995 mg (72.0%). 31P NMR (mixture of diastereomers, CD3CN): delta 148.23, 147.53.

Reference： [1]Patent: US2016/83414,2016,A1 .Location in patent: Paragraph 0260

16
[ 136834-21-4 ]
(2R,3R,4R,5R)-5-[6-(benzoylamino)-9H-purin-9-yl]-4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3-ylhydrogenphosphonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of hydroxytetrahydrofuran2yi)9ff-purin6yi)benzamide (1, 2.0 g, 3. () rnmoi, ChemGenes) in 1,4-dioxane (25 mL) and pyridine (8 inL) was added a solution of SaIPC1 (0.84 g, 4.1 rnmoi) in 1,4-dioxane (12 rnL). After 30 mm. to the stirred reaction mixture at room ernperature was introduced water (4 mL), and the resulting mixture was poured into a iN aqueous NaHCO3 solution (100 mL). This aqueous mixture was extracted with EtOAc (3 x 100 mL) and the layers were partitioned. The EtOAc extracts were combined and concentrated to dryness in vacuo as a colorless foam. The colorless foam was dissolved in CH2CI2 (30 mL) to give a. colorless soluLion. To this soiutjon was added water (0.5 rnL) and a 6% (viv) solution of DCA in CH2CI2 (30 mL). After ten mm of stirring at room temperature, to the red solution was charged pyridine (3.5 mL). The resulting white mixture was concentrated in vacuo and water was removed as an azeotrope after concentration with MeCN (30 mL). This azeotrope process was repeated two more times with MeCN (30 mL). On the last evaporation, the resulting white slurry of compound 2 was left in MeCN (15 mL).
		To a stirring solution of N-(9-((2R,3R,4R,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-3 - fluoro-4-hydroxytetrahydrofuran-2-yl)-9H-purin-6-yl)benzamide (11, 1.5 g, 2.3 mmol, ChemGenes) in 1,4-dioxane (20 mL) and pyridine (6.7 mL) was added a solution of SaIPC1 (0.45 g, 2.3 mmol) in 1,4-dioxane (10 mL). After 30 minutes, to the stirring reaction mixture at room temperature was introduced water (3 mL), and the mixture was poured into a iN aqueous NaHCO3 solution (60 mL). This aqueous mixture was extracted with EtOAc (2 x 120 mL) and the layers were separated. The EtOAc extracts were combined and concentrated to dryness as a colorless foam. The colorless foam was dissolved in CH2C12 (25 mL) to give a colorless solution. To this solution was added water (0.4 mL) and a 6% (v/v) solution of DCA in CH2C12 (23 mL). After ten minutes, to the red solution was charged pyridine (3.0 mL), which turned the red solution into a white mixture. This white mixture was concentrated in vacuo and water was removed as an azeotrope after concentration with MeCN (33 mL). This azeotrope process was repeated two more times with MeCN (33 mL). On the last evaporation, the white slurry of compound 12 was left in MeCN (10 mL).
		To a stirring solution of N- (9-((2R,3R,4R,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-3-fluoro-4- hydroxytetrahydrofuran-2-yl)-9H-purin-6-yl)benzamide (1, 1.5 g, 2.3 mmol, ChemGenes) in 1,4-dioxane (20 mL) and pyridine (6.7 mL) was added a solution of SalPCl (0.45 g, 2.3 mmol) in 1,4-dioxane (10 mL). After 30 min, to the stirring reaction mixture at room temperature was introduced water (3 mL), and the mixture was poured into a 1N aqueous NaHCO3 solution (60 mL). This aqueous mixture was extracted with EtOAc (2 x 120 mL) and the layers were separated. The EtOAc extracts were combined and concentrated to dryness as a colorless foam. The colorless foam was dissolved in CH2Cl2 (25 mL) to give a colorless solution. To this solution was added water (0.4 mL) and a 6% (v/v) solution of DCA in CH2Cl2 (23 mL). After 10 min, to the red solution was charged pyridine (3.0 mL), which turned the red solution into a white mixture. This white mixture was concentrated in vacuo and water was removed as an azeotrope after concentration with MeCN (33 mL). This azeotrope process was repeated two more times with MeCN (33 mL). On the last evaporation, the white slurry of compound 2 was left in MeCN (10 mL).

1.33 g

N- {9- [(2R,3R,4R, 5R)- 5- { [bis(4-methoxyphenyl)(phenyl)methoxy] methyl} -3 -fluoro4-hydroxytetrahydrofuran-2-yl] -9H-purin-6-yl} benzamide (2.64 g) was dissolved in anhydrous pyridine (18.0 mL) under argon, cooled with an ice bath. Diphenyl phosphite (1.60 mL) was added slowly over 1 mm. The reaction solution was allowed to warm to room temperature and stirred for 1 hour. The second portion of diphenyl phosphite (0.35 mL) was added slowly and the mixture was kept stirring for 30 more mm. The mixture was cooled with an ice bath. Water (2.0 mL) was added and the mixture was stirred at room temperature for 30 mm. The mixture was concentrated under reduced pressure and azeotroped with toluene to further remove pyridine and water. The residue was dried on vacuum pump. To the residue was added acetic acid (10.0 mL) and water (2.0 mL). The mixture was stirred at room temperature for 30 mm. The mixture was concentrated under reduced pressure and azeotroped with toluene, then dried on vacuum pump to give a crude oil, which was chromatographed on a silica column using MeOH/DCM (0/100 to 50 / 50) to afford 1.33 g of the title product as a white solid. MS: [M+H]+ 438.1.

Reference： [1]Patent: WO2016/145102,2016,A1 .Location in patent: Paragraph 00373; 00375
[2]Patent: WO2017/75477,2017,A1 .Location in patent: Paragraph 00465; 00466
[3]Patent: WO2017/106740,2017,A1 .Location in patent: Paragraph 00189; 00190
[4]Patent: WO2018/100558,2018,A2 .Location in patent: Paragraph 1651

17
[ 136834-21-4 ]
(2R,3S,4R,5R)-2-(6-benzamido-9H-purin-9-yl)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-fluoro-tetrahydrofuran-3-yl hydrogenphosphonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.3 g	With pyridine; 2-Chloro-4H-1,3,2-benzodioxaphosphorin-4-one; In 1,4-dioxane;	To a solution of N-(9-((2R,3R,4R,5R)-5-((bis(4- methoxyphenyl)(phenyl)methoxy)methyl)-3 -fluoro-4-hydroxytetrahydrofuran-2-yl)-9H- purin-6-yl)benzamide 11 (5.0 g, 7.4 mmole, 1 eq, ChemGenes) in dioxane (45 mL) was added pyridine (13 mL) followed by 2-chloro-4H- 1,3 ,2-benzodioxapho shorin-4-one (1.05 g, 5.18 mmole, 0.7 eq). The reaction mixture was stirred for 1 h and additional 2-chloro- 4H-1,3,2-benzodioxaphoshorin-4-one (2.0 g, 9.8 mmole, 1.3 eq) was added. The mixture was quenched with 7.5 mL of water followed by 300 mL of a sat. NaHCO3 solution. After extraction with EtOAc, the combined organic layers were dried with Na2SO4, filtered and concentrated to give 5.8 g crude compound 21. Prep MPLC-C18 (100% 10 mlvi TEAA to 60% acetonitrile in 10 mlvi TEAA) of 3.2 g of the crude material gave 1.3 g of compound 21.

Reference： [1]Patent: WO2017/75477,2017,A1 .Location in patent: Paragraph 00477; 00478

18
[ 136834-21-4 ]
(2R,3S,4R,5R)-2-(6-benzamido-9H-purin-9-yl)-4-fluoro-5-(hydroxymethyl)tetrahydrofuran-3-yl hydrogen phosphonate [ No CAS ]

Reference： [1]Patent: WO2017/75477,2017,A1

19
[ 136834-21-4 ]
(2R,3R,4R,5R)-5-(6-benzamido-9H-purin-9-yl)-2-((((2-cyanoethoxy)(((2R,3R,4R,5R)-2-(5-fluoro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-7(4H)-yl)-4-((3-hydroxy-1,1,3,3-tetraisopropyldisiloxanyl)oxy)-5-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)phosphorothioyl)oxy)methyl)-4-fluorotetrahydrofuran-3-yl hydrogenphosphonate [ No CAS ]