[ CAS No. 108549-23-1 ] {[proInfo.proName]}

Name: 108549-23-1|Dibenzyl diisopropylphosphoramidite|95%
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Quality Control of [ 108549-23-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 108549-23-1 ]

Product Details of [ 108549-23-1 ]

CAS No. :	108549-23-1	MDL No. :	MFCD00191988
Formula :	C₂₀H₂₈NO₂P	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ANPWLBTUUNFQIO-UHFFFAOYSA-N
M.W :	345.42	Pubchem ID :	196621
Synonyms :

Calculated chemistry of [ 108549-23-1 ]

Physicochemical Properties

Num. heavy atoms :	24
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.4
Num. rotatable bonds :	9
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	102.59
TPSA :	35.29 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-4.96 cm/s

Lipophilicity

Log Po/w (iLOGP) :	4.2
Log Po/w (XLOGP3) :	4.85
Log Po/w (WLOGP) :	5.46
Log Po/w (MLOGP) :	3.79
Log Po/w (SILICOS-IT) :	4.52
Consensus Log Po/w :	4.56

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.81
Solubility :	0.00531 mg/ml ; 0.0000154 mol/l
Class :	Moderately soluble
Log S (Ali) :	-5.33
Solubility :	0.00163 mg/ml ; 0.00000473 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-6.26
Solubility :	0.000189 mg/ml ; 0.000000548 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	4.04

Safety of [ 108549-23-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 108549-23-1 ]

* 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 [ 108549-23-1 ]
Downstream synthetic route of [ 108549-23-1 ]

[ 108549-23-1 ] Synthesis Path-Upstream 1~12

1
[ 108549-23-1 ]
[ 17176-77-1 ]

Yield	Reaction Conditions	Operation in experiment
76%	With 1H-tetrazole; 3-chloro-benzenecarboperoxoic acid In aqueous Na₂SO₃; dichloromethane; sodium hydrogencarbonate	Example 66 Dibenzylphosphonate 77: A solution of 76 (0.39 g, 0.61 mmol) and 1H-tetrazole (54 mg, 0.92 mmol) in CH₂Cl₂ (8 mL) was treated with dibenzyldiisopropylphosphoramidite (0.32 g, 0.92 mmol) and stirred at room temperature overnight. The solution was cooled to 0° C., treated with mCPBA, stirred for 1 h at 0° C. and then warmed to room temperature for 1 h. The reaction mixture was poured into a mixture of aqueous Na₂SO₃ and NaHCO₃ and extracted with CH₂Cl₂. The organic layer was washed with H₂O, dried with Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (3percent 2-propanol/CH₂Cl₂) to give the dibenzylphosphonate (0.42 g, 76percent) as a white solid.
76%	With 1H-tetrazole; 3-chloro-benzenecarboperoxoic acid In aqueous Na₂SO₃; dichloromethane; sodium hydrogencarbonate	Example M66 Dibenzylphosphonate 77: A solution of 76 (0.39 g, 0.61 mmol) and 1H-tetrazole (54 mg, 0.92 mmol) in CH₂Cl₂ (8 mL) was treated with dibenzyldiisopropylphosphoramidite (0.32 g, 0.92 mmol) and stirred at room temperature overnight. The solution was cooled to 0° C., treated with mCPBA, stirred for 1 h at 0° C. and then warmed to room temperature for 1 h. The reaction mixture was poured into a mixture of aqueous Na₂SO₃ and NaHCO₃ and extracted with CH₂Cl₂. The organic layer was washed with H₂O, dried with Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (3percent 2-propanol/CH₂Cl₂) to give the dibenzylphosphonate (0.42 g, 76percent) as a white solid.

Reference： [1] Patent: US2004/121316, 2004, A1,
[2] Patent: US2005/239054, 2005, A1,

2
[ 3240-34-4 ]
[ 108549-23-1 ]
[ 108-68-9 ]
[ 17176-77-1 ]

Yield	Reaction Conditions	Operation in experiment
52%	With 1H-tetrazole In dichloromethane; acetonitrile	Example 8 Dibenzylphosphonate 11: A solution of 10 (85 mg, 0.15 mmol) and 1H-tetrazole (14 mg, 0.20 mmol) in CH₂Cl₂ (2 mL) was treated with Dibenzyldiisopropylphosphoramidite (60 μL, 0.20 mmol) and stirred at room temperature overnight. The product was partitioned between CH₂Cl₂ and H₂O, dried with Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography to give the intermediate dibenzylphosphite (85 mg, 0.11 mmol) which was dissolved in CH₃CN (2 mL) and treated with iodobenzenediacetate (51 mg, 0.16 mmol). The reaction mixture was stirred at room temperature for 3 h and concentrated. The residue was partitioned between EtOAc and NaHCO₃. The organic layer was washed with H₂O, dried with Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (3percent 2-propanol/CH₂Cl₂) to give the dibenzylphosphonate (45 mg, 52percent) as a white solid.
52%	With 1H-tetrazole In dichloromethane; acetonitrile	Example W8 Dibenzylphosphonate 11: A solution of 10 (85 mg, 0.15 mmol) and 1H-tetrazole (14 mg, 0.20 mmol) in CH₂Cl₂ (2 mL) was treated with Dibenzyldiisopropylphosphoramidite (60 μL, 0.20 mmol) and stirred at room temperature overnight. The product was partitioned between CH₂Cl₂ and H₂O, dried with Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography to give the intermediate dibenzylphosphite (85 mg, 0.11 mmol) which was dissolved in CH₃CN (2 mL) and treated with iodobenzenediacetate (51 mg, 0.16 mmol). The reaction mixture was stirred at room temperature for 3 h and concentrated. The residue was partitioned between EtOAc and NaHCO₃. The organic layer was washed with H₂O, dried with Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (3percent 2-propanoUICH₂Cl₂) to give the dibenzylphosphonate (45 mg, 52percent) as a white solid.

Reference： [1] Patent: US2004/121316, 2004, A1,
[2] Patent: US2005/239054, 2005, A1,

3
[ 921-26-6 ]
[ 100-51-6 ]
[ 108549-23-1 ]

Yield	Reaction Conditions	Operation in experiment
75.3%	With triethylamine In tetrahydrofuran at 0℃; for 1 h; Inert atmosphere; Cooling with ice	Take compound 3-9, 42g (207.92mmo1) was placed in a 500mL round bottomed flask, was added 300mL of anhydrous tetrahydrofuran, 66mL (455.44mmol, 46g) of anhydrous triethylamine were dissolved with stirring. When the flask was placed in an ice-salt bath until the system temperature was lowered to 0 the right, under nitrogen was added dropwise over anhydrous benzyl alcohol 45mL (416.67mmol, 45g), was added dropwise maintaining temperature of the system is always near 0 , IH complete after the suspension was added dropwise to give a white solid containing the ice bath was removed to room temperature, stirring was continued at room temperature for 3h stirring was stopped to stand 10min, filtered off with suction, washed solid was tetrahydrofuran, the filtrate was collected, rotary evaporated to give tetrahydrofuran was no liquid column liquid chromatography to give an oil 54.0g, a yield of 75.3percent.

Reference： [1] Tetrahedron, 1991, vol. 47, # 26, p. 4709 - 4722
[2] Patent: CN102977145, 2017, B, . Location in patent: Paragraph 0196; 0197
[3] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1993, # 11, p. 1239 - 1246
[4] Journal of Medicinal Chemistry, 1994, vol. 37, # 23, p. 3918 - 3927
[5] Journal of Organic Chemistry, 1996, vol. 61, # 22, p. 7719 - 7726
[6] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 14, p. 1717 - 1727
[7] Tetrahedron, 1999, vol. 55, # 23, p. 7251 - 7270
[8] Carbohydrate research, 2002, vol. 337, # 20, p. 1795 - 1801

4
[ 108-18-9 ]
[ 100-51-6 ]
[ 108549-23-1 ]
[ 108549-21-9 ]

Reference： [1] Amino Acids, 2010, vol. 39, # 2, p. 367 - 373

5
[ 108-18-9 ]
[ 108549-23-1 ]

Reference： [1] Tetrahedron, 1999, vol. 55, # 23, p. 7251 - 7270
[2] Journal of Medicinal Chemistry, 1994, vol. 37, # 23, p. 3918 - 3927
[3] Patent: CN102977145, 2017, B,

6
[ 108-18-9 ]
[ 100-51-6 ]
[ 108549-23-1 ]

Reference： [1] Organic and Biomolecular Chemistry, 2013, vol. 11, # 34, p. 5702 - 5713

7
[ 108549-21-9 ]
[ 100-51-6 ]
[ 108549-23-1 ]

Reference： [1] Helvetica Chimica Acta, 1987, vol. 70, p. 175 - 186

8
[ 76101-29-6 ]
[ 108549-23-1 ]

Reference： [1] Helvetica Chimica Acta, 1987, vol. 70, p. 175 - 186

9
[ 34637-22-4 ]
[ 921-26-6 ]
[ 108549-23-1 ]
[ 145471-95-0 ]

Reference： [1] Carbohydrate Research, 1992, vol. 230, # 1, p. 63 - 78

10
[ 921-26-6 ]
[ 100-51-6 ]
[ 108549-23-1 ]
[ 145471-95-0 ]

Reference： [1] Carbohydrate Research, 1992, vol. 230, # 1, p. 63 - 78

11
[ 34637-22-4 ]
[ 921-26-6 ]
[ 100-51-6 ]
[ 108549-23-1 ]
[ 145471-95-0 ]

Reference： [1] Carbohydrate Research, 1992, vol. 230, # 1, p. 63 - 78

12
[ 108549-23-1 ]
[ 1277151-44-6 ]

Reference： [1] Organic Letters, 2011, vol. 13, # 7, p. 1824 - 1827

[ 108549-23-1 ] Synthesis Path-Downstream 1~43

1
[ 57224-63-2 ]
[ 108549-23-1 ]
N-benzyloxycarbonyl-O³-<bis(benzyloxy)phosphoryl>-L-threonine methyl ester [ No CAS ]

Reference： [1]Helvetica Chimica Acta,1987,vol. 70,p. 175 - 186

2
[ 111-58-0 ]
[ 108549-23-1 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	With 1H-tetrazole

Reference： [1]Hopper, Darrin W.; Catalano, John G.; Macdonald, Timothy L. [Tetrahedron Letters, 1996, vol. 37, # 44, p. 7871 - 7874]

3
[ 108549-23-1 ]
[ 2791-84-6 ]
[ 215099-82-4 ]

Reference： [1]Tetrahedron Letters,1998,vol. 39,p. 7471 - 7474

4
[ 537-55-3 ]
[ 108549-23-1 ]
(S)-2-Acetylamino-3-[4-(bis-benzyloxy-phosphanyloxy)-phenyl]-propionic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 722 - 729

5
[ 488-59-5 ]
[ 108549-23-1 ]
[ 260560-27-8 ]

Yield	Reaction Conditions	Operation in experiment
55%	Stage #1: myo-inositol; Dibenzyl N,N-diisopropylphosphoramidite With 1H-tetrazole In N,N-dimethyl-formamide; acetonitrile at 20℃; for 24h; Stage #2: With dihydrogen peroxide In water; N,N-dimethyl-formamide; acetonitrile at 0 - 20℃; for 12h; Aqueous sodium phosphate buffer;	To a solution of scy//o-inositol (360 mg, 2 mmol, 1 eq) in DMF (40 mL) tetrazole in CH3CN (0.45 M, 53.3 mL, 24 mmol, 12 eq) was added at room temperature followed by dibenzyl N,N-diisopropylphosphoramidite (5.9 mL, 18 mmol, 9 eq). After being stirred for 24 h, the reaction mixture was cooled to 0 0C. Then sodium phosphate buffer (1 N, pH=7, 50 mL) was added followed by 30% H2O2 (50 mL) and stirred from 0 0C to room temperature for 12 h. The reaction mixture was diluted with EtOAc and the aqueous phase was separated. The organic layer was washed with IN HCl, saturated NaHCO3, brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/ n-heptane, 10:90 to 80:20) to obtain 1.94 g (55%) of 5cy//o-inositol hexakis(dibenzyl phoshphate) (Scheme 5, Compound 1) as light yellow oil. TLC (SiO2): Rf = 0.25 (EtOAc/n-heptane, 50:50); 1H NMR (CDCl3, 400 MHz, 25 0C): δ = 7.22-7.18 (m, 60 H), 5.18 (d, 3JHP = 7.4 Hz, 6 H), 5.07- 4.95 (m, 24 H); 13C NMR (CDCl3, 100 MHz, 25 0C): δ = 135.6 (d, 3JCP = 7.0 Hz), 128.37, 128.27, 128.02, 76.6 (d, J = 7.7 Hz), 69.9 (d, 2JCP = 5.6 Hz); 31P NMR (CDCl3, 121 MHz, 25 0C): δ = -0.73; HRMS (ESI-MS): m/z: calcd for C90H90O24P6NaLi: 885.2148 [M+Na+Li]+2; found: 885.2293.
44%	Stage #1: myo-inositol; Dibenzyl N,N-diisopropylphosphoramidite With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 24h; Stage #2: With dihydrogen peroxide In phosphate buffer at 20℃;
40%	Stage #1: myo-inositol; Dibenzyl N,N-diisopropylphosphoramidite With 1H-tetrazole In acetonitrile at 20℃; for 15h; Stage #2: With 3-chloro-benzenecarboperoxoic acid at -78 - 20℃;	3.2.2. Synthesis of 1,2,3,4,5,6-Hexakis-O-(dibenzyloxyphosphoryl)-Scyllo-Inositol (3) Dibenzyl N,N-diisopropylphosphoramidite (2.3 g, 6.66 mmol) was added to a mixtureof scyllo-inositol (2) (100 mg, 0.55 mmol) and 1H-tetrazole (0.46 g, 6.66 mmol) in acetonitrile(10 mL). The mixture was stirred for 15 h at room temperature. After 15 h, temperatureof the reaction mixture was cooled down to -78 °C, then m-CPBA (1.3 g, 8.3mmol) was added and the reaction mixture was slowly warmed to room temperature. Thereaction mass was extracted with ethyl acetate and washed successfully with sat. aq.Na2SO3, sat. aq. NaHCO3, water and brine. The organic layer was dried over anhydrousNa2SO4 and the solvent was evaporated under reduced pressure. The crude product thusobtained was purified by column chromatography using ethyl acetate and petroleumether (1:1, v/v) as eluent, to get compound 3 (380 mg, 0.22 mmol, 40%) as sticky liquid. 1Hand 31P-NMR of compound 3 were identical with the reported data.[46]

Reference： [1]Current Patent Assignee: NORMOXYS; UNIVERSITY OF STRASBOURG - WO2008/82658, 2008, A2 Location in patent: Page/Page column 37; 54-55
[2]Chung, Sung-Kee; Kwon, Yong-Uk; Chang, Young-Tae; Sohn, Kwang-Hoon; Shin, Jung-Han; Park, Kyu-Hwan; Hong, Bong-Jin; Chung, In-Hee [Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 11, p. 2577 - 2589]
[3]Bhandari, Rashna; Ganguli, Shubhra; Madhusudhanan, Mithun C.; Manorama, Ruth; Mohanrao, Raja; Sureshan, Kana M. [Molecules, 2021, vol. 26, # 12]

6
[ 30334-71-5 ]
[ 108549-23-1 ]
[ 608880-27-9 ]
[ 608880-28-0 ]

Yield	Reaction Conditions	Operation in experiment
68%	Stage #1: 1,2-dipalmitoyl-sn-glycerol; Dibenzyl N,N-diisopropylphosphoramidite With 1H-tetrazole In dichloromethane at 20℃; for 1h; Stage #2: D-6-O-levulinoyl-myo-inositol 3,5-bis(dibenzyl phosphate) With 2,6-dimethylpyridine; pyridinium hydrobromide perbromide In pyridine; dichloromethane at -22 - 20℃; Further stages.;

Reference： [1]Han, Fushe; Hayashi, Minoru; Watanabe, Yutaka [European Journal of Organic Chemistry, 2004, # 3, p. 558 - 566]

7
[ 30334-71-5 ]
[ 108549-23-1 ]
[ 195303-22-1 ]

Yield	Reaction Conditions	Operation in experiment
	With 1H-tetrazole In dichloromethane at 20℃; for 1h;

Reference： [1]Han, Fushe; Hayashi, Minoru; Watanabe, Yutaka [European Journal of Organic Chemistry, 2004, # 3, p. 558 - 566]

8
[ 111-58-0 ]
[ 108549-23-1 ]
[ 183323-44-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: N-oleoylethanolamine; Dibenzyl N,N-diisopropylphosphoramidite With 1H-tetrazole In dichloromethane for 1h; Stage #2: With dihydrogen peroxide In dichloromethane for 2h;

Reference： [1]Lynch, Kevin R.; Hopper, Darrin W.; Carlisle, Steven J.; Catalano, John G.; Zhang, Ming; Macdonald, Timothy L. [Molecular Pharmacology, 1997, vol. 52, # 1, p. 75 - 81]

9
[ 69304-45-6 ]
[ 108549-23-1 ]
Phosphorous acid (2R,3R,3aR,9aR)-2-(6-amino-purin-9-yl)-5,5,7,7-tetraisopropyl-tetrahydro-1,4,6,8-tetraoxa-5,7-disila-cyclopentacycloocten-3-yl ester dibenzyl ester [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2004,vol. 43,p. 4637 - 4640
[2]Nucleosides, nucleotides and nucleic acids,2005,vol. 24,p. 513 - 518

10
[ 58917-85-4 ]
[ 108549-23-1 ]
C₃₁H₃₂NO₆P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With 1H-tetrazole; 3-chloro-benzenecarboperoxoic acid; In acetonitrile; at 25℃; for 3h;	To an acetonitrile solution (40 mL) of the alcohol 19a (1. 58 g, 5.54 mmol) and I H-tetrazole (1. 05 g, 15 mmol) was added dibenzyl N, N-diisopropylphosphoramidite (3.72 mL, 11. 1 mmol) at 25 C. After 3 h, MCPBA (4.19 g, 70% pure, 13.85 mmol) was added to the suspension. The solution was diluted with EtOAc (100 mL), washed with concentrated NaHSO3 solution (2x80 mL), dried over MGSO4 and concentrated in vacuo. The residue was purified by column chromatography (10-30% EtOAc in hexanes) to give 2.88 g of the compound 20a in 95% yield. 1H NMR (CDCl3) : delta 7. 47-7. 05 (20H, m), 5. 19-4.96 (7H, m), 4.09-3. 83 (3H, m), 2.93-2. 67 (2H, m); MS (positive ESP): 568 (M+NA+) ; MS (negative ESP): 580 (M+Cl)-.

Reference： [1]Patent: WO2004/87720,2004,A1 .Location in patent: Page 45

11
[ 112-92-5 ]
[ 108549-23-1 ]
[ 852395-86-9 ]

Yield	Reaction Conditions	Operation in experiment
82%	With 1H-tetrazole In dichloromethane at 20℃; for 2h;	1(i) A solution of bis (benzyloxy) (diisopropylamino) phosphine (570 mg, 1.69 mmol) in dichloromethane (15 mL) was cannulated onto a mixture of 1-octadecanol (209 mg, 0.773 mmol) and 1H-tetrazole (54.0 mg, 0.771 mmol) under argon. The reaction mixture was stirred at RT for 2 hrs when the solvent was removed at reduced pressure to give the crude product that was purified by column chromatography on silica gel. Elution with Et3N/EtOAc/petroleum ether (3: 10: 90) afforded the title compound 45 (322 mg, 0.634 mmol, 82%) as an oil ; 1H NMR (300 MHz, CDC13) 8 7.39-7. 20 (m,5H), 4.80-4. 60 (m, 2H), 3.69- 3.52 (m, 4H), 1.65-1. 58 (m, 2H), 1.29-1. 20 (m, 42H), 0.89-0. 81 (m, 3H); 13C NMR (75 MHz, CDC13) 8 140.2, 128. 6,127. 5,127. 4,65. 7,65. 5,64. 2,64. 0,43. 4,43. 2,32. 3,31. 8,31. 7,30. 1, 29.7, 26.4, 25.1, 25.0, 23.1, 14.5 ; 31p NMR (121.5 MHz, CDC13) 8 147.7 ; HRMS-ESI (+ve) (Found: mlz 526.4372 (M +H30) +, C31H6iNO3P requires mlz 526.4384).

Reference： [1]Current Patent Assignee: MALAGHAN INSTITUTE OF MEDICAL RESEARCH; AGRESEARCH LTD; UNIVERSITY OF OTAGO - WO2005/49631, 2005, A1 Location in patent: Page/Page column 58

12
[ 111-60-4 ]
[ 108549-23-1 ]
[ 852395-89-2 ]

Yield	Reaction Conditions	Operation in experiment
83%	With 1H-tetrazole In dichloromethane at 20℃; for 1.5h;	1(j) A solution of bis (benzyloxy) (diisopropylamino) phosphine (510 mg, 1.51 mmol) in dichloromethane (15 mL) was cannulated onto a mixture of 2-hydroxyethyl octadecanoate 48 (238 mg, 0.309 mmol) and 1H-tetrazole (50.0 mg, 0.714 mmol) under argon. The reaction mixture was stirred at RT for 1.5 hrs when the solvent was removed at reduced pressure to give the crude product that was purified by column chromatography on silica gel. Elution withEt3N/EtOAc/petroleum ether (3: 10: 90) afforded2- (benzyloxy-diisopropylamino- phosphoramidite) -ethyl octadecanoate 49 (366 mg, 0.600 mmol, 83%) as an oil; 1H NMR (300 MHz,CDC13) 8 7.35-7. 20 (m,5H), 4.80-4. 60 (m, 2H), 4.25-4. 20 (m, 2H), 3.89-5. 58 (m, 4H), 2.30 (t, 2H,J7=8. 0 Hz), 1.62-1. 55 (m, 2H), 1.29-1. 17 (m, 40H), 0.89-0. 81 (m, 3H) ; 31p NMR(CDC13) 8 149.5 ; HRMS-ESI (+ve) (Found:m/z 584.4399 (M + H30)+.C33H63NO4Prequires m/z 584. 4438).

Reference： [1]Current Patent Assignee: MALAGHAN INSTITUTE OF MEDICAL RESEARCH; AGRESEARCH LTD; UNIVERSITY OF OTAGO - WO2005/49631, 2005, A1 Location in patent: Page/Page column 61-62

13
[ 58917-85-4 ]
[ 108549-23-1 ]
C₃₁H₃₂NO₅P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1H-tetrazole; In acetonitrile; at 25℃; for 3h;	To an acetonitrile solution (40 mL) of the alcohol 19a (1.58 g, 5.54 mmol) and 1H-tetrazole (1.05 g, 15 mmol) was added dibenzyl N,N-diisopropylphosphoramidite (3.72 mL, 11.1 mmol) at 25 C. After 3 h, MCPBA (4.19 g, 70% pure, 13.85 mmol) was added to the suspension. The solution was diluted with EtOAc (100 mL), washed with concentrated NaHSO3 solution (2×80 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (10-30% EtOAc in hexanes) to give 2.88 g of the compound 20a in 95% yield. 1H NMR (CDCl3): delta 7.47-7.05 (20H, m), 5.19-4.96 (7H, m), 4.09-3.83 (3H, m), 2.93-2.67 (2H, m); MS (positive ESP): 568 (M+Na+); MS (negative ESP): 580 (M+Cl)-.

Reference： [1]Patent: US2005/250742,2005,A1 .Location in patent: Page/Page column 32
[2]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 5613 - 5616

14
[ 108549-23-1 ]
[ 137234-62-9 ]
[ 194798-92-0 ]

Yield	Reaction Conditions	Operation in experiment
	With 1H-tetrazole; dmap; m-chloroperoxybenzoic acid; In dichloromethane;	(a) Dibenzyl (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butyl phosphate A solution of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl) butan-2-ol (the compound of Example 7, EP 0440372, also known as <strong>[137234-62-9]voriconazole</strong>, 17.0 g, 48.7 mmol), 4-dimethylaminopyridine (10.2 g, 83.5 mmol), 1H-tetrazole (10.2 g, 146 mmol) and dibenzyl diisopropylphosphoramidite (33.6 g, 97.4 mmol) in methylene chloride (100 ml) was stirred at reflux for 2 hours and a further 16 hours at room temperature under a nitrogen atmosphere. The reaction mixture was then washed with hydrochloric acid and then sodium bicarbonate, dried (MgSO4) and concentrated. The crude product phosphite was purified by column chromatography (silica gel, 300 g, eluding with 3:1 to 1:1 hexane:ethyl acetate gradient) to give a pale yellow oil. This was dissolved in methylene chloride (100 ml) and cooled to -10 C., whereupon a solution of 3-chloroperoxybenzoic acid (14.8 g, 57% w/w, 46.9 mmol) in methylene chloride (00 ml) was added maintaining the temperature below 0 C. The resulting mixture was allowed to warm to room temperature for 10 minutes before washing with aqueous sodium metabisulphite and sodium bicarbonate. After drying (MgSO4) and concentrating the crude product was purified by column chromatography (silica gel, 300 g, eluding with ethyl acetate) to give the subtitle compound as a viscous syrup (17.86 g, 60%). m/z 610 (MH+) 1H NMR (300 MHz, CDCl3) delta=1.39 (d, 3H), 4.41 (q, 1H), 4.79 (d, 2H), 4.96 (d, 2H), 5.34 (d, 1H), 5.40 (d, 1H), 6.59-6.66 (m, 1H), 6.72-6.82 (m, 1H), 7.02-7.18 (m, 3H), 7.23-7.37 (m, 8H), 7.79 (s, 1H), 8.46 (d, 1H), 8.52 (s, 1H), 8.90 (d, 1H)

Reference： [1]Patent: US2003/144250,2003,A1

15
[ 873054-44-5 ]
[ 108549-23-1 ]
C₃₈H₄₁N₂O₅P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1H-tetrazole; In dichloromethane; acetonitrile; at 20℃; for 2h;	Example 1 [5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-2,4-ditert-butyl-phenoxy]phosphonic acid dibenzyl ester Tetrazole (0.45 M solution in CH3CN, 1.24 mL, 0.56 mmol) was added to a mixture of N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (78 mg, 0.2 mmol) and dibenzyl diisopropylphosphoramidite (184 muL, 0.56 mmol) in dichloromethane (2 mL) and the reaction was stirred at room temperature for 2 h, then tert-butyl hydroperoxide (5.5M solution in decane, 102 muL, 0.56 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was adsorbed onto silica gel and purified by column chromatography (silica gel, 50-100% ethyl acetate-hexanes) to yield [5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-2,4-ditert-butyl-phenoxy]phosphonic acid dibenzyl ester as a clear oil (80 mg, 61%). 1H-NMR (400 MHz, d-DMSO) delta 13.04 (br s, 1H), 12.05 (s, 1H), 8.91 (s, 1H), 8.35 (dd, J=8.1, 1.0 Hz, 1H), 7.88 (s, 1H), 7.82 (m, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.53 (m, 1H), 7.37-7.31 (m, 11H), 5.19 (m, 4H), 1.44 (s, 9H), 1.33 (s, 9H); HPLC ret. time 3.77 min, 30-99% CH3CN, 5 min run; ESI-MS 653.4 m/z [M+H]+.

Reference： [1]Patent: US2009/105272,2009,A1 .Location in patent: Page/Page column 19

16
[ 1485-07-0 ]
[ 108549-23-1 ]
[ 1301120-91-1 ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: naphthalen-2-ethanol; Dibenzyl N,N-diisopropylphosphoramidite With 1H-tetrazole In dichloromethane at 0 - 20℃; for 3.16667h; Inert atmosphere; Stage #2: With 3-chloro-benzenecarboperoxoic acid In dichloromethane at -40℃; for 1h; Cooling with ice; Inert atmosphere;	To a solution of 2-(naphthalen-2-yl)ethanol (500 mg, 2.90 mmol) and 1H-tetrazole (610mg, 8.71 mmol) in CH2Cl2 (25 mL) was slowly added dibenzyl (N,N-diisopropyl)phosphoramidite (2.01 mL, 5.81 mmol) at 0 °C over a period of 10 min. The mixture was gradually warmed to room temperature, and stirred for 3 h. The mixture was then cooled to -40 °C, and m-CPBA (2.67 g, 75% max., 15.48 mmol) was added. The mixture wasallowed to warm in an ice bath over 1 h. The mixture was diluted with CH2Cl2, washed with saturated Na2S2O3, NaHCO3 (aq), and brine. The organic phase was dried over MgSO4, filtered,and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (EtOAc/hexane = 1:5) to give dibenzyl 2-(naphth-2-yl)ethyl phosphate(1.00g, 80%).

Reference： [1]Lin, Teng-Chi; Fang, Jim-Min [Tetrahedron Letters, 2011, vol. 52, # 17, p. 2232 - 2234]

17
[ 69610-40-8 ]
[ 108549-23-1 ]
[ 615583-02-3 ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: N-(tert-butoxycarbonyl)-L-prolinol; Dibenzyl N,N-diisopropylphosphoramidite With 1H-tetrazole In dichloromethane at 20℃; for 2.5h; Inert atmosphere; Stage #2: With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 2h; Inert atmosphere;	A solution of commercially available (S)-N-Boc-2-hydroxymethyl-pyrrolidinol (250 mg,1.24 mmol) and 1H-tetrazole (261 mg, 3.73 mmol) in CH2Cl2 (13 mL) was added dibenzyl(N,N-diisopropyl) phosphoramidite (0.86 mL, 2.48 mmol). The mixture was stirred for 2.5 h at room temperature, added m-CPBA (1.14 g, 75% max., 6.62 mmol), and continued stirring for additional 2 h. The mixture was diluted with CH2Cl2, washed with saturated Na2S2O3,S6NaHCO3(aq), and brine. The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography(EtOAc/hexane = 3:7) to give dibenzyl (S)-N-Boc-2-hydroxymethyl-pyrrolidyl monophosphate (460 mg, 80%).
65.1%	Stage #1: N-(tert-butoxycarbonyl)-L-prolinol; Dibenzyl N,N-diisopropylphosphoramidite With 1H-tetrazole In acetonitrile at 20℃; for 4h; Inert atmosphere; Stage #2: With dihydrogen peroxide In acetonitrile at 0℃; for 0.333333h;	19.19A 19A: (S)-tert- Butyl 2-(((/>A(benzyloxy)phosphoryl)oxy)methyl)pyrrolidine- 1 -carboxylate To a stirred suspension of (S)-tert- butyl 2-(hydroxymethyl)pyrrolidine-l- carboxylate (3 g, 14.91 mmol) in liT-tetrazole in acetonitrile (57.3 mL, 19.38 mmol), was added dibenzyl A./V’-diisopropylphosphoramidite (7.72 g, 22.36 mmol) at room temperature. After being stirred for 4 h under nitrogen, the reaction mixture was cooled to 0 °C. H2O2 (4.35 g, 44.7 mmol) was added. The mixture was stirred for 20 min at 0 °C. The reaction mixture was partitioned between sodium bicarbonate solution and EtOAc. The EtOAc layer was washed with H2O and saturated NaCl solution, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude product was purified using CombiFlash (silica gel 60-120 mesh; 45% ethyl acetate in pet. ether as eluent) to afford {S)-tert- butyl 2-(((Z>A(benzyloxy)phosphoryl)oxy)methyl)pyrrolidine-l- carboxylate (6.4 g, 9.71 mmol, 65.1%) as brownish semi-solid. Tf NMR (300 MHz, methanol-) d ppm 7.28 - 7.51 (m, 10H), 4.96 - 5.20 (m, 4H), 3.79 - 4.25 (m, 4H), 3.29 (m, 1H), 2.03 (m, 4H), 1.35 - 1.55 (m, 9H); LCMS (ES): m/z 462.2 [M+H]+.

Reference： [1]Lin, Teng-Chi; Fang, Jim-Min [Tetrahedron Letters, 2011, vol. 52, # 17, p. 2232 - 2234]
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2019/136112, 2019, A1 Location in patent: Page/Page column 87; 88

18
[ 108549-23-1 ]
[ 1277151-44-6 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 1824 - 1827

19
[ 2162-31-4 ]
[ 108549-23-1 ]
[ 1167440-15-4 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-(tetrahydropyran-2-yloxy)ethanol; Dibenzyl N,N-diisopropylphosphoramidite With 1H-tetrazole In dichloromethane at 20℃; Stage #2: With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 0.5h;	1 More specifically, a solution of 1.7 mmol of the compound represented by the formula (II) in 10 mL of dichloromethane was mixed with 2.5 mmol of 1H-tetrazole and 3.4 mmol of N,N-dibenzyl diisopropylphosphoramidite, and the resultant mixture was stirred overnight at room temperature. Then, 3.4 mmol of m-chloroperbenzoic acid was added to the mixture, and the mixture was stirred for 30 minutes at room temperature. 30 mL of chloroform was then added to the mixture. The organic layer was washed three times with 10 mL of saturated sodium bicarbonate aqueous solution and brine, respectively, and the solvent was removed by distillation. The obtained residue was subjected to silica gel column chromatography, and eluted with ethyl acetate : hexane = 1:1 ∼ ethyl acetate, to obtain the corresponding compound represented by the formula (IV) as a colorless oily substance.

Reference： [1]Current Patent Assignee: LTT BIO-PHARMA CO LTD - EP2361918, 2011, A1 Location in patent: Page/Page column 9

20
[ 14199-15-6 ]
[ 108549-23-1 ]
[ 948843-02-5 ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: Methyl 4-hydroxyphenylacetate; Dibenzyl N,N-diisopropylphosphoramidite With 1H-tetrazole In dichloromethane; acetonitrile at 25℃; for 3h; Inert atmosphere; Stage #2: With dihydrogen peroxide In dichloromethane; acetonitrile at 0℃; for 1h;	4.1 Step 1. Synthesis of methyl 2-(4-(bis(benzyloxy)phosphoryloxy)phenyl)acetate[00100] To a solution of methyl 2-(4-hydroxyphenyl)acetate (5 g, 30 mmol) in CH2CI2 (25 mL) at 25 °C under nitrogen was added dibenzyl diisopropylphosphoramidite (20.8 g, 60.2 mmol) followed by lH-tetrazole (0.45 mol solution in acetonitrile). The mixture contained some solids that dissolved after several minutes. The reaction appeared complete after 3 h by TLC monitoring. The reaction flask was cooled to 0 °C and ¾(¾ (2 mL) was added dropwise over 5 min. The reaction appeared complete after 1 h byTLC, and then the mixture was diluted with EtOAc (150 mL), and washed with brine (2 x 20 mL). The organic layer was dried over sodium sulfate and concentrated to give crude product, which was purified by column chromatography using a mixture of EtOAc and hexanes (1 :3) to afford 10 g (23 mmol, 78% yield) of methyl 2-(-4- bis(benzyloxy)phosphoryloxy)phenyl) acetate. LCMS: (CHROMOLITH SpeedROD C18, 30 4.6 mm, 5 μιη; Solvent A = 10% MeOH: 90% H20: 0.1% TFA; Solvent B = 90% MeOH: 10% H20: 0.1% TFA; gradient 0-100% B over 2 min) retention time: 2.03 min; LCMS (ES-API), m/z 427.0 (M+H).
51%	Stage #1: Methyl 4-hydroxyphenylacetate; Dibenzyl N,N-diisopropylphosphoramidite With 1H-tetrazole In acetonitrile at 20℃; for 8h; Stage #2: With dihydrogen peroxide In acetonitrile at 0℃; for 0.166667h;	31.31A 31 A: Methyl 2-(4-((/>A(benzyloxy)phosphoryl)oxy)phenyl)acetate A mixture of methyl 4-hydroxyphenylacetate (5.5 g, 33.1 mmol), dibenzyl NN- diisopropylphosphoramidite (16.68 ml, 49.6 mmol) and 1//-Tetrazole (0.45 M in acetonitrile) (110 ml, 49.6 mmol) was stirred at room temperature for 8 h.The reaction was cooled to 0 °C, to which was added H2O2 (2.028 ml, 66.2 mmol). After being stirred for 10 min, the reaction mixture was partitioned between ethyl acetate (200 mL) and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to get colorless oil. The crude material was purified by CombfFlash (silica gel 60-120 mesh; 30% ethyl acetate in hexane as eluent) to get methyl 2-(4-((fos(benzyloxy)phosphoryl)oxy)phenyl)acetate (7.2 g, 16.89 mmol, 51.0%) as a colorless oil . NMR (300 MHz, chloroform-rf) d ppm 7.27 - 7.40 (m, 10H), 7.19 - 7.26 (m, 2H), 7.08 - 7.16 (m, 2H), 5.14 (d, =8.3 l Hz, 4H), 3.72 (s, 3H), 3.61 (s, 2H); LCMS (ES): m/z 427.4 [M + H]+.

Reference： [1]Current Patent Assignee: EXELIXIS INC - WO2012/135082, 2012, A1 Location in patent: Page/Page column 29
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2019/136112, 2019, A1 Location in patent: Page/Page column 126; 127

21
[ 108549-23-1 ]
[ 108149-63-9 ]
[ 1415820-89-1 ]

Yield	Reaction Conditions	Operation in experiment
	With 1H-tetrazole; In acetonitrile; for 1h;	Scheme 21Dibenzyl diisopropylphosphoramidite (1.067 mL, 3.24 mmol) is added to te/ -butyl (4S)-4- (hydroxymethyl)-2,2-dimethyl-1 ,3-oxazolidine-3-carboxylate (0.5 g, 2.162 mmol) (106) [prepared from D-serine as described for the enantiomer in Organic Syntheses, Coll. Vol. 10, p. 320 (2004) and Vol. 77, p. 64 (2000)] and 1H-tetrazole (0.454 g, 6.49 mmol) in CH3CN (10 mL) and the mixture stirred for 1 h. The solvent is evaporated and the residue flash chromatographed (EtOAc-hexanes, 1 :9 v/v) to give tert-butyl (4R)-4- ([bis(benzyloxy)phosphanyl]oxy}methyl)-2,2-dimethyl-1 ,3-oxazolidine-3-carboxylate as a colourless oil. This is dissolved in CH2CI2 (10 mL) cooled in ice-water and MCPBA (m- chloroperoxybenzoic acid) (0.995 g, 4.32 mmol) added and stirred for 30 min. The mixture is diluted with CH2CI2 (50 mL) and washed with sat. aq. Na2S03, sat. aq. NaHC03 (3x) then brine, dried and the solvent evaporated. The residue is flash chromatographed (DCM-hexanes-EtOAc, 4:3:1 v/v/v) to give terf-butyl (4R)-4- ([bis(benzyloxy)phosphoryl]oxy}methyl)-2,2-dimethyl-1 ,3-oxazolidine-3-carboxylate(107) as a colourless oil (0.816 g, 77%). [a]^2 +21.5 (c 0.57, CHCI3). 1H NMR (500 MHz, CDCI3) 7.34 (s, 10H), 5.08-5.00 (m, 4H), 4.22-4.16 (m, 0.5H), 4.13-4.06 (m, 1 H), 3.97- 3.83 (m, 3H), 3.77 (q, J = 8.6, 0.5H), 1.52-1.41 (m, 15H). 13C NMR (125.7 MHz) 152.1 , 151.4 (C), 135.7 (C), 128.6 (CH), 127.9 (CH), 94.1 , 93.6 (C), 80.6, 80.3 (C), 69.4 (CH2j, 65.7, 65.3 (CH2), 64.8, 64.6 (CH2), 56.6, 56.5, 56.32, 56.26 (CH), 28.3 (CH3), 27.4, 24.3 (CH3), 26.6, 23.0 (CH3). Referenced to the centre line of CDCI3 at delta 77.0. 31 P NMR (202.3 MHz, CDCI3) -1.0 (s), -1.1 (s). ESI-HRMS for C25H34NNa07P [M+Na]+ calcd 514.1971 ; found 514.1968. The NMR spectra indicated (107) is a ~1 :1 mixture of conformational isomers.
	With 1H-tetrazole; In acetonitrile; for 1h;	Dibenzyl diisopropylphosphoramidite (1.067 mL, 3.24 mmol) is added to compound 8540,41 (0.5 g, 2.162 mmol) and 1H-tetrazole (0.454 g, 6.49 mmol) in CH3CN (10 mL) and the mixture stirred for 1 h. The solvent is evaporated and the residue flash chromatographed (EtOAc-hexanes, 1:9 v/v) to give tert-butyl (4R)-4-([bis(benzyloxy)phosphanyl]oxy}methyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate as a colourless oil. This is dissolved in CH2Cl2 (10 mL) cooled in ice-water and MCPBA (m-chloroperoxybenzoic acid) (0.995 g, 4.32 mmol) added and stirred for 30 min. The mixture is diluted with CH2Cl2 (50 mL) and washed with satd aq Na2SO3, satd aq NaHCO3 (3) then brine, dried and the solvent evaporated. The residue is flash chromatographed (DCM-hexanes-EtOAc, 4:3:1 v/v/v) to give tert-butyl (4R)-4-([bis(benzyloxy)phosphoryl]oxy}methyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate as a colourless oil (0.816 g, 77%). [alpha]22D +21.5 (c 0.57, CHCl3). 1H NMR (500 MHz, CDCl3) 7.34 (s, 10H), 5.08-5.00 (m, 4H), 4.22-4.16 (m, 0.5H), 4.13-4.06 (m, 1H), 3.97-3.83 (m, 3H), 3.77 (q, J = 8.6, 0.5H), 1.52-1.41 (m, 15H). 13C NMR (125.7 MHz) 152.1, 151.4 (C), 135.7 (C), 128.6 (CH), 127.9 (CH), 94.1, 93.6 (C), 80.6, 80.3 (C), 69.4 (CH2), 65.7, 65.3 (CH2), 64.8, 64.6 (CH2), 56.6, 56.5, 56.32, 56.26 (CH), 28.3 (CH3), 27.4, 24.3 (CH3), 26.6, 23.0 (CH3). Referenced to the centre line of CDCl3 at delta 77.0. 31P NMR (202.3 MHz, CDCl3) -1.0 (s), -1.1 (s). ESI-HRMS for C25H34NNaO7P [M+Na]+ calcd 514.1971; found 514.1968. This material (0.77 g, 1.567 mmol) and 10% Pd-C (100 mg) are stirred in EtOH (15 mL) under a hydrogen atmosphere at ambient temperature and pressure for 16 h. The mixture is filtered through cellulose paper and the solvent is evaporated to give [(4R)-3-[(tert-butoxy)carbonyl]-2,2-dimethyl-1,3-oxazolidin-4-yl]methoxy}phosphonic acid as a colourless gum (480 mg). This is dissolved in 80% aq TFA (10 mL) and left at room temperature for 2 h. The solvent is evaporated and the residue dissolved in H2O (10 mL) and washed with CH2Cl2 (2 10 mL) then evaporated. The residue is dissolved in H2O and chromatographed on RP 18 silica gel (H2O) to give 86 as a colourless gum which solidified (0.26 g, 97%). [alpha]22D 0 (c 0.565, H2O). No measurable rotation observed. 1H NMR (500 MHz, D2O) 4.19-4.12 (m, 1H), 4.11-4.03 (m, 1H), 3.90 (dd, J = 12.3, 4.7, 1H), 3.81 (dd, J = 12.3, 6.7, 1H), 3.63 (m, 1H). Referenced to HOD at delta 4.79. 13C NMR (125.7 MHz, D2O) 62.9 (d, J = 3.2, CH2), 59.1 (CH2), 53.5 (d, J = 7.4, CH). Referenced to internal CH3CN at delta delta 1.47. 31P NMR (202.3 MHz, D2O) 0.0 (s). ESI-HRMS for C3H9NO5P [M-H]- calcd 170.0218; found 170.0211.

Reference： [1]Patent: WO2012/150866,2012,A1 .Location in patent: Page/Page column 81-82
[2]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 5629 - 5646

22
[ 1415481-52-5 ]
[ 108549-23-1 ]
[ 1623-08-1 ]
[ 1415481-53-6 ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: biphenyl-4-yl 2,4,6-tri-O-benzoyl-α-D-mannopyranoside; Dibenzyl N,N-diisopropylphosphoramidite With 1,2,4-Triazole In acetonitrile at 0 - 20℃; for 24.3333h; Stage #2: With tert.-butylhydroperoxide In acetonitrile at 0 - 20℃; for 1h;	23 To a mixture of 26 (21 1 mg, 0.335 mmol) and 1 ,2,4-triazole (92.5 mg, 1 .34 mmol) in dry acetonitrile (5.0 mL) was added dibenzyl Λ/,/V-diisopropylphosphoramidite (90%) (0.25 mL, 0.67 mmol) at 0°C. The reaction mixture was stirred at 0°C for 20 min and further stirred at rt under argon for 24 h. Then ie f-butylhydroperoxide (190 μ, 1.34 mmol) was added to the reaction mixture at 0°C and the solution was stirred vigorously at rt for 1 h. The mixture was quenched with 1 M aq. Na2S203 and 1 M aq. NaHC03, and then extracted with DCM. The combined organic phases were washed with brine and dried over Na2S04. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (petrol ether/EtOAc 6:1 -4:1 ) to afford a mixture of 2- dibenzylphosphate and 27 (3:2, by NMR) (245 mg, 80%) as white solid.1H NMR (CDCI3, 500 MHz): δ 4.62 (m, 2H, H-5, H-6a), 4.76 (dd, J = 12.0, 7.5 Hz, 1 H, H- 6b), 4.85-5.1 1 (m, 4H, OCH2Ph), 5.55 (td, J = 3.5, 9.0 Hz, 1 H, H-3), 5.81 (d, J = 1 .5 Hz, 1 H, H-1 ), 5.87 {dd, J = 1 .9, 3.4 Hz, 1 H, H-2), 6.04 (m, 1 H, H-4), 6.92-8.1 1 (m, 34 H, Ar-H); 13C NMR (CDCI3, 125 MHz) δ 62.76 (C-5), 67.58 (d, J = 5.63 Hz, C-4), 69.51 (C-6), 69.75 (d, J = 5.63 Hz, OCH2Ph), 69.81 (d, J = 6.0 Hz, OCH2Ph), 70.95 (d, J = 2.0 Hz, C-2), 73.69 (d, J = 5.13 Hz, C-3), 95.69 (C-1 ), 1 16.82, 126.82, 127.55, 127.67, 127.85, 127.96, 128.20, 128.23, 128.27, 128.32, 128.41 , 128.50, 128.54, 128.57, 128.62, 129.71 , 129.85, 129.99, 132.99, 133.48, 133.64, 136.09, 140.35, 155.08 (Ar-C), 165.35, 165.46, 166.01 (3 CO); ESI-MS calcd for C53H45NaOi2P [M+Na]+: 927.25, found: 927.23.

Reference： [1]Current Patent Assignee: UNIVERSITY OF BASEL - WO2012/164074, 2012, A1 Location in patent: Page/Page column 45

23
[ 108549-23-1 ]
[ 86386-73-4 ]
C₂₇H₂₅F₂N₆O₃P [ No CAS ]

Reference： [1]Organic Process Research and Development,2002,vol. 6,p. 109 - 112

24
[ 26690-80-2 ]
[ 108549-23-1 ]
[ 1076199-25-1 ]

Yield	Reaction Conditions	Operation in experiment
76%	Stage #1: 2-(N-tert-butoxycarbonylamino)ethanol; Dibenzyl N,N-diisopropylphosphoramidite With 1H-tetrazole In dichloromethane; acetonitrile at 0 - 20℃; Stage #2: With tert.-butylhydroperoxide In dichloromethane; water; acetonitrile at 0 - 20℃; for 1h;	18.18A Example 18 A: tert-butyl (2-[bis(benzyloxy)phosphoryl]oxy}ethyl)carbamate To a solution of tert- butyl (2-hydroxyethyl)carbamate (2.4 mL, 16 mmol) and H- tetrazole (69 mL, 31 mmol, 0.45 M in acetonitrile) in anhydrous CH2CI2 (31 mL) at 0 °C was added dibenzyl diisopropylphosphoramidite (7.8 mL, 23 mmol), and the resulting solution was allowed to warm to ambient temperature and stirred overnight. The solution was then cooled to 0 °C, and /-butyl hydroperoxide (70% aqueous solution, 6.4 mL, 47 mmol) was added. The resulting mixture was allowed to warm to ambient temperature, stirred for 1 hour and then was washed with saturated aqueous NarSrCh solution (50 mL), followed by water (50 mL). The organic layer was dried over anhydrous NarSOr. filtered, and concentrated under reduced pressure to give the title intermediate (5 g, 12 mmol, 76% yield), which was used without further purification. NMR (400 MHz, DMSO-rie) d ppm 7.43 - 7.33 (m, 10H), 5.06 (dd, J = 13.4,.6 Hz, 4H), 4.02 - 3.88 (m, 2H), 3.21 (q, J = 5.9 Hz, 2H), 1.37 (d, J = 3.8 Hz, 9H); MS (ESI+) m/z 322 (M-Boc+H)+.
68%	Stage #1: 2-(N-tert-butoxycarbonylamino)ethanol; Dibenzyl N,N-diisopropylphosphoramidite With 1H-tetrazole In acetonitrile at 20℃; for 4h; Stage #2: With 3-chloro-benzenecarboperoxoic acid In acetonitrile at 20℃; for 1h;
2.6 g	Stage #1: 2-(N-tert-butoxycarbonylamino)ethanol; Dibenzyl N,N-diisopropylphosphoramidite With 1H-tetrazole In acetonitrile at 20℃; for 4h; Stage #2: With water; 3-chloro-benzenecarboperoxoic acid In acetonitrile for 1h;	2.1 Step 1. tert-butyl (2-((bis(benzyloxy)phosphoryl)oxy)ethyl)carbamate To a mixture of ie/t-butyl (2-hydroxyethyl)carbamate (1.0 g, 6.2 mmol) and dibenzyl diisopropylphosphoramidite (4.2 mL, 12.4 mmol) was added a 0.45 M acetonitrile solution of tetrazole (42 mL, 18.6 mmol) at ambient temperature. The resulting solution was stirred at ambient temperature for 4 h. Then, at ambient temperature, m-CPBA (70%, 4.59 g, 18.6 mmol) was added to the reaction mixture that was stirred for further 1 h. The precipitate in the mixture was filtered through a pad of celite, and the filter cake was further washed with dichloromethane (100 mL). The combined filtrate was diluted with dichloromethane (50 mL) and washed with a saturated aqueous solution of sodium bicarbonate (100 mL, five times) and brine (100 mL). The organic layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (4% methanol-dichloromethane) to provide ie/t-butyl (2- ((bis(benzyloxy)phosphoryl)oxy)ethyl)carbamate (2.6 g, 68% over two steps) as a white solid. 1H NMR 400 MHz (DMSO δ 7.31-7.40 (m, 10H), 6.99 (m, 1H), 5.01 (d, J = 1.2 Hz, 4H), 3.94 (q, J = 6.0 Hz, 2H), 3.17 (q, J = 5.4 Hz, 2H), 1.33 (s, 9H); MS m/z: 421.87 (M+l).

10.47 g

Stage #1: 2-(N-tert-butoxycarbonylamino)ethanol; Dibenzyl N,N-diisopropylphosphoramidite With 1H-tetrazole In dichloromethane; acetonitrile at 20℃; for 3h; Stage #2: With tert.-butylhydroperoxide In dichloromethane; acetonitrile for 1h; Cooling with ice;

28.28-1 Example 28 (28-1) tert-Butyl (2-[bis (benzyloxy) phosphoryl] oxy} ethyl) carbamate (Example compound 28-1) tert-Butyl (2-hydroxyethyl) carbamate (5.0 g),Dichloromethane (50 mL),1H-tetrazole (4.34g)After adding acetonitrile (25 mL) to the suspension ofAdd dibenzyl N, N-diisopropylphosphoroamidite (20.8 mL)After stirring at room temperature for 3 hoursUnder ice-cooling, tert-butyl hydroperoxide (70% aqueous solution, 12.4 mL) was added, and the mixture was stirred as it was for 1 hour.After concentrating the reaction solution, Add hexane to the residue,Filter out the insoluble matter,The mother liquor was concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 100: 0-40: 60).The title compound (10.47 g) was obtained as a white solid.

Reference： [1]Current Patent Assignee: GOOGLE INC - WO2020/77217, 2020, A1 Location in patent: Paragraph 00300
[2]Lim, Sang Min; Westover, Kenneth D.; Ficarro, Scott B.; Harrison, Rane A.; Choi, Hwan Geun; Pacold, Michael E.; Carrasco, Martin; Hunter, John; Kim, Nam Doo; Xie, Ting; Sim, Taebo; Jaenne, Pasi A.; Meyerson, Matthew; Marto, Jarrod A.; Engen, John R.; Gray, Nathanael S. [Angewandte Chemie - International Edition, 2014, vol. 53, # 1, p. 199 - 204][Angew. Chem., 2013, vol. 126, # 1, p. 203 - 208,6]
[3]Current Patent Assignee: DANA-FARBER CANCER INSTITUTE - WO2014/160200, 2014, A1 Location in patent: Paragraph 000269
[4]Current Patent Assignee: OSAKA UNIVERSITY; MITSUBISHI CHEMICAL HOLDINGS CORPORATION - JP2021/80183, 2021, A Location in patent: Paragraph 0475-0477

25
[ 149-32-6 ]
[ 108549-23-1 ]
[ 1610451-76-7 ]

Yield	Reaction Conditions	Operation in experiment
63%	Stage #1: meso-erythritol; Dibenzyl N,N-diisopropylphosphoramidite With 1H-tetrazole; 3-chloro-benzenecarboperoxoic acid In N,N-dimethyl-formamide; acetonitrile at 20℃; for 24h; Stage #2: With 3-chloro-benzenecarboperoxoic acid In N,N-dimethyl-formamide; acetonitrile at -40 - 20℃; for 12h;	1 1,2,3,4-Tetrakis(dibenzylphospho)-meso-erythritol 1,2,3,4-Tetrakis(dibenzylphospho)-meso-erythritol To a solution of meso-erythritol (368 mg, 3.01 mmol, 1 eq) in dry DMF (20 mL) at room temperature was added tetrazole (0.45 M in acetonitrile) (40.1 mL, 18.0 mmol, 6 eq), followed by dibenzyl N,N-diisopropylphosphoramidite (5.94 mL, 18.0 mmol, 6 eq). After being stirred for 24 h at room temperature, the reaction mixture was cooled to -40° C., then 3-chloroperbenzoic acid (3.3 g, 19.2 mmol, 6.4 eq) in DMF (10 mL) was added slowly and the reaction was allowed to stir from -40° C. to room temperature over a period of 12 h. Then the reaction mixture was diluted with EtOAc, washed with 10% Na2SO3, saturated NaHCO3, brine then dried over Na2SO4 and concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (EtOAc/n-heptane, 20:80 to 90:10) to obtain 1,2,3,4-tetrakis(dibenzylphospho)-meso-erythritol (2.2 g, 63%). TLC (SiO2): Rf=0.25 (EtOAc/n-heptane, 60:30); IR: ν=3033, 1497, 1455, 1381, 1277, 1215, 998, 880, 736, 696 μm-1; 1H NMR (CDCl3, 400 MHz, 25° C.): δ=7.29-7.21 (m, 40H), 5.02-4.97 (m, 16H), 4.79-4.72 (m, 2H), 4.32-4.25 (m, 2H), 4.14 (dt, J=11.4, 4.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz, 25° C.): 135.6 (t, 3JCP=6.0 Hz), 128.59, 128.56, 128.52, 128.03, 127.97, 127.96, 75.1 (dd, JCP=14.3, 6.0 Hz), 69.7 (dd, JCP=5.5, 3.7 Hz), 69.6 (d, JCP=5.5 Hz), 65.4 (d, JCP=3.6 Hz); 31P NMR (CDCl3, 162 MHz, 25° C.): δ=-1.03, -1.60; HRMS (ESI): m/z: calcd for C60H62Na1O16P4: 1185.2881 [M+Na]+. found: 1185.2811.

Reference： [1]Current Patent Assignee: UNIVERSITY OF STRASBOURG; NORMOXYS - US2014/142052, 2014, A1 Location in patent: Paragraph 0098; 0129

26
[ 108549-23-1 ]
[ 41107-82-8 ]
[ 1610451-89-2 ]

Yield	Reaction Conditions	Operation in experiment
76%	Stage #1: Dibenzyl N,N-diisopropylphosphoramidite; 2,5-anhydro-D-mannitol With 1H-tetrazole In dichloromethane; acetonitrile at 20℃; for 48h; Stage #2: With 3-chloro-benzenecarboperoxoic acid In water; acetonitrile at -40 - 20℃; for 9h;	1 1,3,4,6-Tetrakis(dibenzylphospho) 2,5-anhydro-D-mannitol 1,3,4,6-Tetrakis(dibenzylphospho) 2,5-anhydro-D-mannitol To a solution of 2,5-anhydro-D-mannitol (250 mg, 1.71 mmol, 1 eq) in dry DCM (30 mL) at room temperature was added tetrazole (0.45 M in acetonitrile) (22.8 mL, 10.26 mmol, 6 eq), followed by dibenzyl N,N-diisopropylphosphoramidite (3.37 mL, 10.26 mmol, 6 eq). After being stirred for 48 h at room temperature, the reaction mixture was cooled to -40° C., then 3-chloroperbenzoic acid (2.65 g, 15.39 mmol, 9 eq) in DCM (30 mL) was added slowly and the reaction was allowed to stir from -40° C. to room temperature over a period of 9 h. Then the reaction mixture was diluted with EtOAc, washed with 10% Na2SO3, saturated NaHCO3, brine then dried over Na2SO4 and concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (EtOAc/n-heptane, 20:80 to 100:0) to obtain 1,3,4,6-tetrakis(dibenzylphospho) 2,5-anhydro-D-mannitol (1.58 g, 76%) as a white solid. TLC (SiO2): Rf=0.23 (EtOAc/n-heptane, 80:20); [α]20D 12.2 (c 1.0, CHCl3); IR: ν=3033, 1497, 1455, 1381, 1277, 1215, 1007, 998, 884, 737, 696 cm-1; 1H NMR (CDCl3, 400 MHz, 25° C.): δ=7.31-7.25 (m, 40H), 5.05-4.98 (m, 18H), 4.19-4.15 (m, 2H), 4.13-4.10 (m, 4H); 13C NMR (CDCl3, 100 MHz, 25° C.): 135.6 (d, 3JCP=7.0 Hz, 4C), 135.2 (d, 3JCP=6.6 Hz, 2C), 135.6 (d, 3JCP=6.5 Hz, 2C), 128.52, 128.48, 128.46, 128.42, 128.36, 127.95, 127.94, 127.82, 127.79, 80.9 (dd, JCP=7.4, 3.8 Hz), 80.7 (t, JCP=6.1 Hz), 69.7 (t, JCP=5.5 Hz), 69.3 (dd, JCP=5.3, 2.9 Hz), 65.7 (d, JCP=5.5 Hz); 31P NMR (CDCl3, 162 MHz, 25° C.): δ=-0.92, -1.78.

Reference： [1]Current Patent Assignee: UNIVERSITY OF STRASBOURG; NORMOXYS - US2014/142052, 2014, A1 Location in patent: Paragraph 0100; 0149

27
[ 480-44-4 ]
[ 108549-23-1 ]
C₃₀H₂₅O₈P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	Stage #1: 5,7-dihydroxy-2-(4'-methoxyphenyl)-4H-1-benzopyran-4-one; Dibenzyl N,N-diisopropylphosphoramidite With 1H-tetrazole In acetonitrile at 20℃; for 12h; Stage #2: With tert.-butylhydroperoxide In acetonitrile at 20℃; for 0.0833333h;	1 Compound A-1 Compound A-1 To an acetonitrile (35 mL) solution of acacetin (4 g, 14.1 mmol) was added 1.1 g of tetrazole (15.51 mmol) and 5.4 g of dibenzyl N,N-diisopropylphosphoramidite (15.51 mmol). After 12 h of stirring at room temperature, 9.75 mL of 70% of 1,1-dimethylethyl hydroperoxide in water was added and stirred for 5 min under room temperature. The mixture was extracted with 0.5M TBME/phosphate buffer (pH=7) and preparative HPLC was carried out by using 90% acetonitrile/10% H2O. After evaporating the solvent, 5.8 g of yellow solid of compound A-1 was obtained. Compound A-1: Yellow Solid. Yield 76%. C30H25O8P (544.49). EI-MS: m/z 545.14 [M]. 1H NMR (400 MHz, CDCl3): δ=12.81 (s, 1H), 7.83 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 6.84 (s, 1H), 6.62 (s, 1H), 6.54 (s, 1H), 5.19 (s, 2H), 5.17 (s, 2H), 3.91 (s, 3H) ppm.

Reference： [1]Current Patent Assignee: THE UNIVERSITY OF HONG KONG - US2015/218193, 2015, A1 Location in patent: Paragraph 0215-0217

28
[ 108549-23-1 ]
[ 7473-45-2 ]
methyl 5-O-[bis(benzyloxy)phosphoryl]-β-D-ribofuranoside [ No CAS ]

Reference： [1]Helvetica Chimica Acta,2018,vol. 101

29
[ 3943-74-6 ]
[ 108549-23-1 ]
methyl 4-((bis(benzyloxy)phosphoryl)oxy)-3-methoxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With 1H-tetrazole; dihydrogen peroxide In dichloromethane; water at 0 - 20℃; for 1h;	434.434A 434A: To a mixture of methyl vanillate (250 mg, 1.372 mmol) in DCM (2745 μ) was added dibenzyl N,N-diisopropylphosphoramidite (677 μ, 2.058 mmol) followed by tetrazole (0.45 M in acetonitrile) (4574 μ, 2.058 mmol). The resulting mixture was stirred at rt 1 h. TLC indicated the starting material had been consumed. The reaction mixture was cooled to 0 °C and hydrogen peroxide (35% in water) (1180 μ, 13.72 mmol) was added. The mixture was allowed to come to rt and stir for 1 h. TLC indicated the product of step 1 had been consumed. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over MgS04, filtered and concentrated in vacuo. Purification by flash chromatography (silica, 24g, 0-75% EtOAc/Hexanes) gave methyl 4-((bis(benzyloxy)phosphoryl)oxy)-3-methoxybenzoate (594 mg, 1.343 mmol, 98 % yield). MSESI m/z 443.1 (M+H) 1H NMR (400MHz, DMSO-d6) δ 7.63-7.54 (m, 2H), 7.40-7.37 (m, 10H), 7.35-7.31 (m, 1H), 5.22-5.20 (m, 2H), 5.19 (s, 2H), 3.87 (s, 3H), 3.86-3.85 (m, 3H).
97%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester; Dibenzyl N,N-diisopropylphosphoramidite With 1H-tetrazole In dichloromethane; acetonitrile at 20℃; for 8h; Stage #2: With dihydrogen peroxide In dichloromethane; acetonitrile at 20℃; for 2h;	2.2A 2 A: Methyl 4-((/>A(benzyloxy)phosphoryl)oxy)-3-methoxybenzoate To a stirred solution of methyl 4-hydroxy-3-methoxybenzoate (3.000 g, 16.47 mmol) in dry dichloromethane (30 mL), was added dibenzyl N,N- diisopropylphosphoramidite (8.30 mL, 24.70 mmol), and liTtetrazole (0.4 M in acetonitrile, 73.0 mL, 24.70 mmol). The mixture was stirred at room temperature for 8 h and cooled to 0 °C. H2O2 (5.05 mL, 165 mmol) was added. The mixture was stirred at room temperature for 2 h, diluted with water and extracted with dichloromethane (3 xlOO mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum at ~30 °C to give colorless oil. The crude product was purified by ISCO (silica gel 60-120 mesh; 30% ethyl acetate in hexane as eluent) to give methyl 4-((/>A(benzyloxy)phosphoryl)oxy)-3-methoxybenzoate (8.200 g, 15.94 mmol, 97%) as a colorless oil. NMK (400 MHz, chloroform-tf) d ppm = 7.59 - 7.56 (m, 2H), 7.37 - 7.33 (m, 10H), 7.27 (dd, J=8.3, 1.1 Hz, 1H), 5.17 (d, =8.3 Hz, 4H), 3.91 (s, 3H), 3.84 (s, 3H). LC-MS (ES): m/z= 443 [M+H]+.
97%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester; Dibenzyl N,N-diisopropylphosphoramidite With 1H-tetrazole In dichloromethane; acetonitrile at 20℃; for 8h; Stage #2: With dihydrogen peroxide In dichloromethane; acetonitrile at 0 - 20℃; for 2h;	5.1 Step 1 (0215) Methyl 4-((bis(benzyloxy)phosphoryl)oxy)-3-methoxybenzoate To a solution of methyl 4-hydroxy-3-methoxybenzoate (3.000 g, 16.47 mmol) in dichloromethane (30 mL), was added dibenzyl-/V,/V-diisopropylphosphoramidite (8.30 mL, 24.70 mmol) followed by 1H-tetrazole (73.0 mL, 24.70 mmol) (0.45 M in acetonitrile) and the mixture was stirred at room temperature for 8 h. The reaction was cooled at 0 °C. H2O2 (5.05 mL, 165 mmol) was added. After being stirred at room temperature for 2 h, the reaction mixture was concentrated to remove acetonitrile and the remaining aqueous layer was diluted with water, and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by ISCO [silica gel 60- 120 mesh, column size 80 g, ethyl acetate in hexane as eluent]. The product was eluted at 30% ethyl acetate in hexane to get the title compound (8.200 g, 15.94 mmol, 97% yield) as a colourless oil. 1H NMR (400 MHz, CDCl3) d 3.84 (s, 3H), 3.91 (s, 3H), 5.16 (s, 2H), 5.18 (s, 2H), 7.25 (d, J= 8.00 Hz, 1H), 7.31-7.37 (m, 10H), 7.57 (d, J= 9.20 Hz, 2H).; LC-MS (ES): m/z = 443.2 [M+H]+

Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester; Dibenzyl N,N-diisopropylphosphoramidite With 1H-tetrazole In dichloromethane; acetonitrile at 20℃; for 8h; Stage #2: With dihydrogen peroxide In dichloromethane; acetonitrile at 0 - 20℃; for 2h;

429A 429A: Methyl 4-((bis(benzyloxy)phosphoryl)oxy)-3-methoxybenzoate: To a solution of methyl 4-hydroxy-3-methoxybenzoate (5.00 g, 27.4 mmol) in dichloromethane (50 mL)was added dibenzyl N,N-diisopropylphosphoramidite (13.83 mL, 41.2 mmol) followed by 1H-tetrazole (0.45 M in acetonitrile) (122 mL, 41.2 mmol) and the mixture stirred at rt for 8 h. The reaction was cooled at 0 °C and H202 (8.41 mL, 274 mmol) was added. The mixture was then stirred at rt for 2 h. The reaction was concentrated to remove the acetonitrile and the obtained aqueous layer was diluted and extracted with ethyl acetate (3x 100 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to get a colorless oil. The cmde material was purified by silica gel chromatography, eluting with ethyl acetate in hexane. The product was eluted at 30% ethyl acetate in hexane to give methyl 4- ((bis(benzyloxy)phosphoryl)oxy)-3-methoxybenzoate (10. 600 g, 20.61 mmol, 75 %yield) as a colorless oil. MS ESI m/z 443.2 (M+H).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2019/89442, 2019, A1 Location in patent: Page/Page column 232
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2019/136112, 2019, A1 Location in patent: Page/Page column 47; 48
[3]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2021/11513, 2021, A1 Location in patent: Page/Page column 43-44
[4]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2018/148626, 2018, A1 Location in patent: Page/Page column 413

30
[ 108549-23-1 ]
[ 198904-31-3 ]
methyl ((5S,8S,9S,14S)-8-benzyl-9-((bis(benzyloxy)phosphoryl)-oxy)-5-(tert-butyl)-15,15-dimethyl-3,6,13-trioxo-11-(4-(pyridin-2-yl)benzyl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3553 - 3574

31
[ 108549-23-1 ]
[ 134098-64-9 ]
[ 153910-63-5 ]

Yield	Reaction Conditions	Operation in experiment
85%		To a solution of 2-(4-((ter/-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-3,5- dimethylphenol (4.500 g, 13.95 mmol) in dry dichloromethane (5 mL), was added dibenzyl N A-diisopropylphosphoramidite (7.03 mL, 20.93 mmol) followed by 1 H- tetrazole (0.4 M in acetonitrile) (46.5 mL, 20.93 mmol). After being stirred at room temperature for 8 h, the reaction was cooled at 0 C. H2O2 (2.138 mL, 69.8 mmol) was added. After being stirred at room temperature for 2 h, the reaction mixture was diluted with water and extracted with dichloromethane (3 x 100 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum at ~30 C to give colorless oil. The crude product was purified by ISCO (silica gel 60-120 mesh; 30% ethyl acetate in hexane as eluent) to give dibenzyl (2-(4-(( ter t- butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-3,5-dimethylphenyl) phosphate (7.000 g, 11.89 mmol, 85%) as a colorless oil. NMR (300 MHz, DMSO-i) <7 ppm = 7.44 - 7.28 (m, 10H), 6.95 (s, 1H), 6.76 (s, 1H), 5.13 (d, J=1.9 Hz, 4H), 3.40 (t, =7.4 Hz, 2H), 2.45 (s, 3H), 2.11 (s, 3H), 2.00 (t, =7.4 Hz, 2H), 1.45 (s, 6H), 0.77 (s, 9H), 0.86 (s, 6H); LC- MS (ES): m/z= 583 [M+H]+.

Reference： [1]Patent: WO2019/136112,2019,A1 .Location in patent: Page/Page column 50; 51; 52; 53

32
[ 33689-29-1 ]
[ 108549-23-1 ]
methyl 1-((bis(benzyloxy)phosphoryl)oxy)cyclopropanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70.1%		A mixture of methyl l-hydroxycyclopropanecarboxylate (1.1 g, 9.47 mmol), dibenzyl N A-diisopropylphosphoramidite (4.77 mL, 14.21 mmol) and 1 //-tetrazole (0.45 M in acetonitrile) (31.6 mL, 14.21 mmol) was stirred at room temperatue for 8 h. The reaction was cooled to 0 C. was added hydrogen peroxide (0.581 mL, 18.95 mmol). The mixture was partitioned between ethyl acetate (100 mL) and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude material was purified by CombiFlash (silica gel 60-120 mesh; 30% ethyl acetate in hexane as eluent) to get methyl 1 -((/v.s(benzyloxy)phosphoryl)oxy) cyclopropanecarboxylate (2.5 g, 6.64 mmol, 70.1%) as a colorless oil. NMR (400 MHz, chloroform-^ d = 7.41 - 7.30 (m, 10H), 5.17 - 5.05 (m, 4H), 3.71 (s, 3H), 1.48 - 1.31 (m, 4H); LCMS (ES): m/z 378.0 [M + H]+.

Reference： [1]Patent: WO2019/136112,2019,A1 .Location in patent: Page/Page column 133; 134

33
[ 108549-23-1 ]
[ 24347-63-5 ]
C₂₀H₂₅O₅P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1H-tetrazole; In acetonitrile; at 0 - 20℃; for 5h;	To a stirred solution of fV)-m ethyl 2-hydroxy-3-methylbutanoate (600 mg, 4.54 mmol) in anhydrous acetonitrile (10 mL) at 0 C, was added 1 //-tetrazole (232 mg, 6.81 mmol), followed by dibenzyl N, N?-di i sopropy 1 phosphorami di te (2352 mg, 6.81 mmol) dropwise. The reaction mixture was brought to room temperature and stirred for 5 h. After cooling the reaction mixture to 0 C, H2O2 (0.795 mL, 9.08 mmol) was added dropwise. After being stirred for 30 min., the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 25 mL). EtOAc layer was washed with H2O and saturated NaCl solution. The organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified using CombiFlash (silica gel 60-120 mesh; 40% ethyl acetate in pet. ether as eluent) to afford (ri)-m ethyl 2- ((/> .v(benzyloxy)phosphoryl)oxy)-3-methylbutanoate (2.2 g, 3.81 mmol, 84%) as colourless oil. NMR (400 MHz, chloroform-^/) d ppm 7.32 - 7.37 (m, 10H), 5.02 - 5.14 (m, 4H), 4.65 (dd, =8.0l, 4.25 Hz, 1H), 3.70 (s, 3H), 2.11 - 2.23 (m, 1H), 0.99 (d, =7.00 Hz, 3H), 0.93 (d, =7.00 Hz, 3H); LCMS(ES): m/z = 393.8 [M+H]+.

Reference： [1]Patent: WO2019/136112,2019,A1 .Location in patent: Page/Page column 93; 94; 95

34
[ 22381-54-0 ]
[ 108549-23-1 ]
C₂₃H₂₅O₆PS [ No CAS ]

Reference： [1]Patent: WO2019/195494,2019,A1 .Location in patent: Page/Page column 75

35
[ 108549-23-1 ]
[ 171228-49-2 ]
[ 185961-10-8 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: Dibenzyl N,N-diisopropylphosphoramidite; posaconazote With 1H-tetrazole In dichloromethane at 20℃; for 3h; Stage #2: With tert.-butylhydroperoxide In dichloromethane at 20℃; for 1h;	9.1 9.1 Preparation of Compound (ST0009-001) 1.0 g of posaconazole (posa) was weighted and dissolved in 10 ml DCM, 0.3 g of tetrazole was added, and 0.7 g of dibenzyl N,N-diisopropylphosphoramidite was added dropwise at room temperature. The mixture was reacted at room temperature for 3 hours. Under TLC monitoring, the raw materials were completely reacted. 0.4 g of t-butyl hydroperoxide was directly added dropwise to the above reaction solution at room temperature, and the mixture was reacted at room temperature for 1 hr. Under TLC monitoring, the raw materials were completely reacted. The reaction was quenched with 10% (w/v) sodium sulfite solution. After it was peroxide-free determined by starch-potassium iodide test paper, the solution was separated and the aqueous phase was further extracted once with DCM. The combined DCM layers were washed with saturated brine and dried over anhydrous MgSO4, filtered, and concentrated to dryness. Purification by column chromatography gave the compound (ST0009-001).

Reference： [1]Current Patent Assignee: WUHAN LL SCIENCE AND TECH DEVELOPMENT CO LTD - US10517867, 2019, B2 Location in patent: Page/Page column 219-220

36
[ 22446-37-3 ]
[ 108549-23-1 ]
methyl (2-[bis(benzyloxy)phosphoryl]oxy}phenyl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%		Dibenzyl diisopropylphosphoramidite (1.35 mL, 3.61 mmol) was added to a stirred solution of <strong>[22446-37-3]methyl 2-(2-hydroxyphenyl)acetate</strong> (0.48 g, 2.89 mmol; Advanced ChemBlocks) and l//-tctrazolc (0.45 M in acetonitrile, 16.05 mL) in dimethylacetamide (5.8 mL). The reaction mixture was stirred at ambient temperature for 1 hour and was then cooled to 0 C. Hydrogen peroxide solution (30 weight %, 0.738 mL) was added dropwise. The reaction mixture was slowly warmed up to ambient temperature over a period of 30 minutes and stirred for another 2 hours before being cooled back to 0 C. Saturated, aqueous sodium bicarbonate solution (30 mL) was added in one portion, and the resulting mixture was partitioned between ethyl acetate (2 x 50 mL) and aqueous sodium thiosulfate solution (1.0 M, 30 mL). The organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC [YMC TriArt Cl 8 Hybrid 5 pm column, 50 c 100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (1.12 g, 2.63 mmol, 91% yield). MS (ESI+) m/z 427 (M+H)+.

Reference： [1]Patent: WO2020/77217,2020,A1 .Location in patent: Paragraph 00291

37
[ 108549-23-1 ]
[ 86386-73-4 ]
[ 194602-25-0 ]

Yield	Reaction Conditions	Operation in experiment
86.8%	Stage #1: Dibenzyl N,N-diisopropylphosphoramidite; fluconazole With 1H-tetrazole In dichloromethane at 20℃; for 2h; Inert atmosphere; Stage #2: With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; for 1h; Inert atmosphere;	3 According to the preparation method of Example 1 in CN1210540A, forsfluconazole was prepared: A dichloromethane (1000 ml) solution of 100 g of fluconazole, 68.5 g of 1H-tetrazole and 225.5 g of dibenzyl diisopropyl phosphoramidate was stirred at room temperature in a nitrogen atmosphere for 2 hours.Then, the mixture was cooled to 0°C, maintained at 0°C, and a solution of 135 g of 3-chloroperoxybenzoic acid, 50-55% w/w in dichloromethane (500 ml) was added. Warm the reaction mixture to room temperature for 1 hour,Then wash with sodium metabisulfite and sodium bicarbonate aqueous solution, then dry with MgSO4, remove the solvent, replace with methyl isobutyl ketone (370ml) and tert-butyl methyl ether (740ml), granulate at -10 for 1 hour, filter , Washed with ice-cold methyl isobutyl ketone and tert-butyl methyl ether (1:3, 150ml), and then dried at 50°C under vacuum for 18 hours to obtain solid fluconazole dibenzyl phosphate. The solid fluconazole dibenzyl phosphate 160.5g, 5% palladium-carbon catalyst (50% humidity, 10g) and 22.7g sodium hydroxide aqueous solution (600ml) were hydrogenated at room temperature and 414kPa (60p.si). The solution was filtered and washed with water (100ml). The toluene phase was separated, and 27.8 g of sulfuric acid was added to the water phase and cooled to 0°C. The resulting slurry was granulated at 0°C for 1 hour. Then it was filtered, washed with water (2×100ml), and then dried under vacuum at 50°C to obtain forsfluconazole.

Reference： [1]Current Patent Assignee: JIANGSU SIHUAN BIOENGINEERING CO., LTD. - CN111171075, 2020, A Location in patent: Paragraph 0062

38
[ 108549-23-1 ]
[ 150683-30-0 ]
[ 1056613-14-9 ]

Yield	Reaction Conditions	Operation in experiment
	With 2H-tetrazole In dichloromethane at 20℃; for 2h;

Reference： [1]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2020/196814, 2020, A1 Location in patent: Paragraph 0042; 0043

39
[ 108549-23-1 ]
[ 150683-30-0 ]
[ 942619-72-9 ]

Yield	Reaction Conditions	Operation in experiment
97.2%	Stage #1: Dibenzyl N,N-diisopropylphosphoramidite; tolvaptan With 1H-tetrazole In dichloromethane at 20℃; for 2h; Stage #2: With 3-chloro-benzenecarboperoxoic acid In dichloromethane at -40 - 0℃; for 1h;	A 1.0 g quantity of tolvaptan and 460 mg of 1H-tetrazole were dissolved in 30 ml of methylene chloride; and 1.2 g of dibenzyl diisopropylphosphoramidite was added dropwise to this solution with stirring at room temperature, followed by stirring at the same temperature for 2 hours.[0046]The obtained reaction mixture was cooled to -40°C, and a solution of 920 mg of metachloroperbenzoic acid in methylene chloride (6 ml) was added dropwise thereto. The mixture was stirred at the same temperature for 30 minutes, and at 0°C for another 30 minutes. The reaction mixture was washed with an aqueous sodium thiosulfate solution and saturated aqueous sodium bicarbonate solution, and then dried over anhydrous sodium sulfate. The obtained reaction mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate = 1:1) to obtain 1.5 g of compound (1a-1) in an amorphous form (yield: 97.2%).
	Multi-step reaction with 2 steps 1: 2H-tetrazole / dichloromethane / 2 h / 20 °C 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 1 h / -40 - 0 °C

Reference： [1]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2020/196816, 2020, A1 Location in patent: Paragraph 0045-0046
[2]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2020/196814, 2020, A1

40
[ 645-08-9 ]
[ 108549-23-1 ]
3-((bis(benzyloxy)phosphoryl)oxy)-4-methoxybenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45.3%	Stage #1: Isovanillic acid; Dibenzyl N,N-diisopropylphosphoramidite With 1H-tetrazole In acetonitrile at 0 - 20℃; for 16h; Stage #2: With dihydrogen peroxide In acetonitrile at 0℃; for 0.333333h;	12.1 Step 1 (0297) 3-((Bis(benzyloxy)phosphoryl)oxy)-4-methoxybenzoic acid To a stirred solution of 3-hydroxy-4-methoxybenzoic acid (300 mg, 1.784 mmol) in anhydrous acetonitrile (10 mL) at 0 °C, was added lH-tetrazole (91 mg, 2.68 mmol) followed by dibenzyldiisopropylphosphoramidite (678 mg, 1.963 mmol) drop-wise. (0300) After the addition, the reaction mixture was brought to room temperature and stirred for 16 h. The mixture was cooled to 0 °C, and H2O2 (0.312 mL, 3.57 mmol) was added drop- wise. After stirring for 20 min, the reaction mixture was extracted with ethyl acetate (2 x 25 mL). The organic layer was washed with H2O (1 x 10 mL) and saturated NaCl (1 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. (0301) The crude compound was purified in reverse phase prep-HPLC. (Preparative column: SUNFIRE Cl 8 (150 x 19 mm; 5 micron), mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile, flow rate: 18 mL/min, gradient: 0/10, 10/55). The prep fraction containing the desired product was concentrated under high vacuum at 30 °C to afford the title compound (350 mg, 0.809 mmol, 45.3% yield) as a pale yellow oil. 1H NMR (300 MHz, DMSO-d6) d 3.85 (s, 3 H), 5.16 (s, 2 H), 5.19 (s, 2 H), 7.22 (d, J= 8.31 Hz, 1 H), 7.75 - 7.77 (m, 10 H), 7.80 (d, J= 8.69 Hz, 2 H), 12.88 (br. s, 1 H); LC-MS (ES): m/z = 429.0 [M+H]+

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2021/11513, 2021, A1 Location in patent: Page/Page column 62-63

41
[ 108549-23-1 ]
[ 66937-71-1 ]
tert-butyl N-(2-((bis(benzyloxy)phosphoryl)oxy)ethyl)glycinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	Stage #1: Dibenzyl N,N-diisopropylphosphoramidite; N-(2-Hydroxyethyl)-glycine tert-butyl ester With 1H-tetrazole In dichloromethane; acetonitrile at 20℃; for 4h; Inert atmosphere; Stage #2: With tert.-butylhydroperoxide In dichloromethane; water; acetonitrile at 0 - 20℃; Inert atmosphere;	16 tert-Butyl (2-((bis(benzyloxy)phosphoryl)oxy)ethyl)glycinate In a pre-dried round-bottom flask, tert- butyl (2-hydroxyethyl)glycinate (0.40 g, 2.26 mmol) was dissolved in anhydrous DCM (60 ml_), added dibenzyl N,N- diisopropylphosphoramidite (0.75 ml_, 2.26 mmol) and tetrazole (0.45 M in MeCN, 5.07 ml_), and the reaction was allowed to stir at rt for 4 h. The reaction mixture was cooled to 0 °C, added Luperox TBH70X (70 wt. % in water, 2.23 ml_), then brought to rt and stirred vigorously overnight at rt under nitrogen atmosphere. The reaction was diluted in DCM (50 ml_), the organic phase washed with sat. NaHCCh (2x40 ml_), dried over Na2SC>4, and the title compound was obtained after flash chromatography (0482) (EtOAc EtOAc + 5% MeOH) as a clear oil (502 mg, 51%). Rf = 0.50 (EtOAc + 2% MeOH); 1 H NMR (400 MHz, Chloroform-d) d 7.37 - 7.32 (m, 10H), 5.08 - 5.02 (m, 4H), 4.1 1 (dt, J = 7.5, 5.2 Hz, 2H), 3.31 (s, 2H), 2.86 (t, J = 5.2 Hz, 2H), 2.02 (s, 1 H), 1.45 (s, 9H); UPLC-MS (ESI) m/z found 436.2 [M+H]+, calc. 436.19 [C22H3I N06P]+.

Reference： [1]Current Patent Assignee: TECHNICAL UNIVERSITY OF DENMARK - WO2020/260597, 2020, A1 Location in patent: Page/Page column 85; 86

42
[ 1445790-55-5 ]
[ 108549-23-1 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
30%	Stage #1: NVR-3-778; Dibenzyl N,N-diisopropylphosphoramidite With 1H-imidazole In dichloromethane for 4h; Stage #2: With 3-chlorobenzoate In dichloromethane at 0℃; for 6h;	4.1.3. Dibenzyl (1-((2-Fluoro-5-((3,4,5-trifluorophenyl)carbamoyl)phenyl)sulfonyl)piperidin-4-yl)Phosphate (N4) N3 (2.30 mmol, 1.00 g), 1H-imidazole (3.50 mmol, 0.25 g), and dibenzyl diisopropylphosphoramidite(4.60 mmol, 1.56 mL) were dissolved in 20 mL dichloromethane andstirred for four hours, then 3-chlorobenzoic acid (4.60 mmol, 0.79 g) was added at 0 Cand stirred for an additional 6 h. After the completion of the reaction, 20 mL saturatedsodium bicarbonate was added, and then dichloromethane (3 10 mL) was added forextraction. The organic phases were combined and washed with saturated sodium chloride(3 15 mL). The organic phase was dried over anhydrous sodium sulfate and subjected to column chromatography after stirring with silica gel. White solid, yield: 30.0%. EI-MS:693.06 [M + H]+, C32H29F4N2O7PS (692.14).

Reference： [1]Ji, Xiangkai; Jiang, Xiangyi; Kobayashi, Chisa; Ren, Yujie; Hu, Lide; Gao, Zhen; Kang, Dongwei; Jia, Ruifang; Zhang, Xujie; Zhao, Shujie; Watashi, Koichi; Liu, Xinyong; Zhan, Peng [Molecules, 2022, vol. 27, # 18]

43
[ 330784-47-9 ]
[ 108549-23-1 ]
[ 2850195-75-2 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: avanafil With 1H-tetrazole In dichloromethane at 20℃; Inert atmosphere; Stage #2: Dibenzyl N,N-diisopropylphosphoramidite In dichloromethane at -78℃; Inert atmosphere;	2 preparation of (S)-(1-(4-((3-chloro-4-methoxybenzyl)amino)5-((pyrimidine-2-methylene)carbamoyl)-2-pyrimidinyl)-2-pyrrolidinyl) dibenzyl methyl phosphate (formula III), the reaction formula is as follows: Avanafil (2.0 g, 4.13 mmol) was dissolved in DCM (50 mL),Add tetrazolium (350mg, 4.96mmol), nitrogen protection,Stir at room temperature for 5 minutes, add diphenyl N,N'-diisopropylphosphoramidite (1.72g, 4.96mmol) with a syringe, and stir overnight. The reaction solution was transferred to a -78°C cold trap for cooling and stirring for 15 min, and the m-CPBA solution in dichloromethane (1.43 g, 10 mL DCM) was added to the constant-pressure dropping funnel, and m-CPBA was added dropwise to the reaction solution. Allow to warm to room temperature. The reaction was monitored by TLC (5% MeOH/DCM), and the reaction was stopped after 6 h at room temperature. Add 100 mL of water, separate the layers, extract the aqueous layer with 50 mL of DCM × 2, combine the dichloromethane layers, wash with saturated sodium chloride 50 mL × 1, dry over anhydrous sodium sulfate, evaporate to dryness, and purify by 3% MeOH/DCM column chromatography to obtain a yellow oil Product 1.7g, yield 55.4%.

Reference： [1]Current Patent Assignee: XEON BIOPHARMACEUTICAL; SUZHOU FEIMOSI BIOMEDICAL TECH - CN114957332, 2022, A Location in patent: Paragraph 0097-0100

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