[ CAS No. 39825-33-7 ] {[proInfo.proName]}

Name: 39825-33-7|2-Propyl (S)-2-aminopropanoate|98%
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SKU: A220772
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Quality Control of [ 39825-33-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 39825-33-7 ]

Product Details of [ 39825-33-7 ]

CAS No. :	39825-33-7	MDL No. :	MFCD12796134
Formula :	C₆H₁₃NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	131.17	Pubchem ID :	-
Synonyms :	Isopropyl L-alaninate;L-Alanine 2-propyl ester;O-Isopropyl-L-alanine	Chemical Name :	2-Propyl (S)-2-aminopropanoate

Safety of [ 39825-33-7 ]

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 [ 39825-33-7 ]

* 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 [ 39825-33-7 ]
Downstream synthetic route of [ 39825-33-7 ]

[ 39825-33-7 ] Synthesis Path-Upstream 1~11

1
[ 56-41-7 ]
[ 67-63-0 ]
[ 39825-33-7 ]

Yield	Reaction Conditions	Operation in experiment
87%	at 0 - 20℃;	SOCl2 (29 mL, 400 mmcl) was added dropwise at 0 °C to a suspension of the HCl salt of L-alanine (17.8 g, 200 mmcl) in isopropanol (700 mL). The suspension was stirred at roomtemperature over night, then concentrated, which gave the title compound (29.2 g, 87percent).
74%	at 120℃; for 0.333333 h; Microwave irradiation	General procedure: In a typical reaction, AMA 2:3 (498 g, 1 mol), the corresponding aminoacid(1 mol) and alcohol (1.5–2 mol) were mixed in the provided reaction glass tubeequipped with a screw cap and magnetic agitation until a wet mixture was achieved.The reaction mixture was irradiated with microwaves (Anton Parr Monowave 300reactor) at 120 C for 20 min. On cooling, the mixture was diluted with chloroform(41 mL), filtered with glass frit over celite under vacuum, and washed with chloroform;then the filtrate was washed with Na2CO3 (ss) and water. The organic layerwas dried over Na2SO4, filtered, and concentrated under reduced pressure to givethe ester.
69%	for 12 h; Reflux	General procedure: Synthesis of L-amino acid isopropyl esters Concentrated sulfuric acid was added to a suspension of the respective L-amino acid (1 g, amino acid:sulfuric acid ratio 1:1.2) in isopropanol (10 mL). The resulting solution was refluxed for 12 h. After this time, the solution was cooled to 0 °C and neutralized with concentrated NH₄OH. The ammonium sulfate formed was filtered and washed with isopropanol (3 * 5 mL). The filtrate was concentrated under reduced pressure (50 mm Hg, 50 °C) to a third of its volume. The ester was extracted with chloroform (3 * 5 mL), the organic phase was dried with anhydrous sodium sulfate, and chloroform was removed under reduced pressure (50 mm Hg, room temperature). L-Alanine isopropyl ester (C₆H₁₃NO₂·HOC₃H₇) b.p.125-127 °C , yield 69percent. ¹H NMR (CDCl₃) δ: 1.27 (d,6H, J = 6.8 Hz), 1.29 (d,6H, J = 6.4 Hz), 1.61 (d,3H, J = 7.2 Hz), 4.11 (q,1H, J = 7.2 Hz), 4.62 (heptet,1H, J = 6.4 Hz), 5.10 (heptet,1H, J = 6.4 Hz), ESI-MS: m/z 131.90 [M + H]⁺.

Reference： [1] Patent: WO2015/56213, 2015, A1, . Location in patent: Page/Page column 66
[2] Synthetic Communications, 2014, vol. 44, # 16, p. 2386 - 2392
[3] Journal of Molecular Structure, 2013, vol. 1041, p. 68 - 72
[4] Analytical Chemistry, 1991, vol. 63, # 4, p. 370 - 374
[5] Analytical Chemistry, 1997, vol. 69, # 5, p. 926 - 929
[6] Nucleosides, Nucleotides and Nucleic Acids, 2001, vol. 20, # 4-7, p. 621 - 628
[7] Patent: WO2015/40640, 2015, A2, . Location in patent: Page/Page column 18

2
[ 6003-05-0 ]
[ 67-63-0 ]
[ 39825-33-7 ]

Yield	Reaction Conditions	Operation in experiment
87%	at 0 - 20℃;	SOCl2 (29 mL, 400 mmol) was added dropwise at 0 00 to a suspension of the HCI salt of Lalanine (17.8 g, 200 mmol) in isopropanol (700 mL). The suspension was stirred at room temperature over night, then concentrated, which gave the title compound (29.2 g, 87percent).
87%	at 0 - 20℃;	SOCI₂ (29 mL, 400 mmol) was added dropwise at 0 °C to a suspension of the HCI salt of L- alanine (17.8 g, 200 mmol) in isopropanol (700 mL). The suspension was stirred at room temperature over night, then concentrated, which gave the title compound (29.2 g, 87percent).

Reference： [1] Patent: WO2015/34420, 2015, A1, . Location in patent: Page/Page column 64
[2] Patent: WO2016/30335, 2016, A1, . Location in patent: Page/Page column 47

3
[ 39613-92-8 ]
[ 39825-33-7 ]

Reference： [1] Patent: US2013/90473, 2013, A1, . Location in patent: Paragraph 0029; 0030
[2] Patent: US2017/56423, 2017, A1, . Location in patent: Paragraph 0296; 0297

4
[ 10065-72-2 ]
[ 67-63-0 ]
[ 39825-33-7 ]

Reference： [1] Tetrahedron, 1987, vol. 43, # 4, p. 771 - 778
[2] Bulletin of the Chemical Society of Japan, 1989, vol. 62, # 8, p. 2562 - 2566

5
[ 39825-33-7 ]
[ 379270-37-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: at -20℃; for 1 h; Stage #2: at -20 - 20℃; for 2 h;	To a suspension of Ph-PMPA 8 (1 .47g, 4.05 mmol) in iPrOAc (25 mL) thionyl chloride (0.7mL, 10.11 mmol, 2.5 equiv) was added and the reaction mixture was stirred at 80°C for 2h.Then, sulfolane (2.2 mL) was added and the resulting mixture was stirred at 80°C for 24 — 72 h (until d.e. of 70percent was achieved). After cooling to the room temperature, the volatile constituents were removed by distillation at a reduced pressure (45°C, 10 mbar). The obtained mixture of the chlorides of formula 7a/7b was suspended in iPrOAc (25 mL) and addedduring 1 h to a cooled (—20°C) solution of iPr-L-alanine (2.65g, 20.23 mmol, 5 equiv) in iPrOAc (15 mL). The reaction was stirred for lh at —20°C, and then after heating for lh at 20°C. The reaction mixture was washed with an aqueous solution of NaI12P04, aqueous solution of KFICO3, water and a saturated solution of NaC1 and further dried over Na2SO4. The resulting solution was concentrated to the volume of 15 mL, inoculated with TA of formula laand left to crystallize at the room temperature. The product was aspirated on fit, washed with cold iPrOAc and dried in a vacuum drier (40°C, 200 Pa) for 8 h, providing 1.3 g (68percent) of Tenofovir Alafenamide of formula la in the form of white powder (chemical purity 95percent, d.e.70percent). Tenofovir Alafenamide (chemical purity 95percent, d.c. 70percent) was dissolved at 85°C in iPrOAc (5 mL/mmol), cooled during 2h to 22°C and stirred at 22°C for 2h. The product was aspirated on frit, washed with cold iPrOAc and dried in a vacuum drier (40°C, 200 Pa) for 8 h, providing Tenofovir Alafenamide in the yield of 92percent and d.c. of 99.0percent.Tenofovir alafenamide (d.e. 99.0percent) was dissolved at 85°C in iPrOAc (5 mL/mmol), cooled during 2h to 22°C and stirred at 22°C for 2h. The product was aspirated on fit, washed with cold iPrOAc and dried in a vacuum drier (40°C, 200 Pa) for 8 h, providing Tenofovir Alafenamide of formula la in the yield of 95percent and d.e. of 99.8percent.‘H NMR (500 MHz, DMSO) ö = 8.12 (d, J 16.6 Hz, 2H), 7.29 (t, J= 7.9 Hz, 211), 7.23 (s, 2H), 7.13 (t, J= 7.4 Hz, 1H), 7.04 (d, J= 8.4 Hz, 2H), 5.69 — 5.61 (m, 111), 4.84 (hept, J 6.3 Hz, 1H), 4.27 (dd, J= 14.4, 3.6 Hz, 111), 4.14 (dd, J= 14.4, 6.6 Hz, 111), 3.97 —3.90 (m, 1H), 3.90 —3.81 (m, 2H), 3.76 (dd, J 13.4, 9.8 Hz, 1H), 1.15 (d, J’= 6.3 Hz, 6H), 1.12 (d, J 7.1Hz, 3H), 1.06 (d, J= 6.2 Hz, 3H) ppm.‘3C NMR (126 MHz, DMSO) ö = 172.92, 172.89, 155.99, 152.44, 150.26, 150.19, 149.80, 141.40, 129.50, 124.36, 120.57, 120.54, 118.39, 75.55, 75.45, 67.91, 64.75, 63.52, 49.07,46.84, 21.45, 21.42, 20.34, 20.30, 16.66 ppm.31P NMR (202 MHz, DMSO) = 22.11 ppm.
76.4%	at -25 - -20℃; for 1.25 h;	To a solution of isopropyl L-alanine ester 11 (4.50 equiv) in DCM (80 mL) at −25° C. was added a slurry containing compound 13a (1.00 equiv) that is at least 90percent diastereomerically pure in toluene (50 mL) over a minimum of 45 minutes, maintaining the internal temperature ≦−20° C. The mixture was then held at a temperature ≦−20° C. for at least 30 minutes, and the pH checked using water wet pH paper. If the pH was <4, it was adjusted with triethylamine to pH 4 to 7. The pot temperature was adjusted to room temperature (19° C. to 25° C.). The mixture was transferred to a separatory funnel and washed sequentially with 10percent w/v aqueous solution of sodium phosphate monobasic (2×50 mL), 15percent w/v aqueous solution of potassium bicarbonate (2×20 mL), and water (50 mL). The final organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a viscous amber oil. The oil was dissolved in toluene/acetonitrile (4:1) (50 mL), and the solution was seeded with 9-{(R)-2-[((R,S)-{ [(S)-1-(isopropoxycarbonyl)ethyl]amino}phenoxyphosphinyl)methoxy]propyl}adenine (about 1 mg, 99:1 diastereomeric ratio) and stirred for 2 hours at ambient temperature. The resultant slurry was filtered and the filter cake was washed with toluene/acetonitrile (4:1) (15 mL) and dried in a vacuum oven at 40° C. for 16 hours to give the product, 9-{(R)-2-[((R,S)-[(S)-1-(isopropoxycarbonyl)ethyl]amino}phenoxyphosphinyl)methoxy]propyl}adenine (compound 15), as a white solid (10.0 g, 76.4percent, 97.5:2.5 diastereomeric ratio in favor of compound 16). ¹H NMR (400 MHz, CDCl₃): δ1.20-1.33 (m, 12H), 3.62-3.74 (m, 1H), 3.86-4.22 (m, 5H), 4.30-4.44 (m, 1H), 4.83-5.10 (m, 1H), 6.02 (br s, 3H), 7.18-7.34 (m, 5H), 7.98-8.02 (m, 1H), 8.32-8.36 (m, 1H); ³¹P NMR (162 MHz, CDCl₃): δ21.5, 22.9.
75 g	With triethylamine In dichloromethane at -35 - 30℃; for 2.25 h;	To a mixture of [(R)-2-(Phenylphosphonomethoxy) propyl] adenine (100 gms, 0.275 mol) in acetonitrile (337 gms), thionyl chloride (73 gms, 0.619 mol) was added and heated to 75°C for lhr. The solvents were removed at atmospheric pressure under nitrogen at 80°C, cooled to 25°C, diluted with dichloromethane (530 gms) and further cooled to -35°C. A solution of L-alanine isopropyl ester (77.6 gms, 0.592 mol) in dichloromethane (397 gms) was added over 45 minutes at -35°C and followed by triethylamine (83 gms, 0.824 mol) over 30 minutes at -18°C. The reaction mixture was heated to 25-30°C and maintained for 1 hour, cooled to 10 to 20°C and washed with 10percent aq. sodium dihydrogenphosphate solution at 25°C. The organic solution was dried over anhydrous sodium sulfate, filtered and washed with dichloromethane. The organic layer was concentrated under reduced pressure to get an oil residue. Acetone (237 gms) was charged to the residue and die mixture concentrated under reduced pressure. Acetone (237 gms) was again charged to the residue, purified by chromatography over 1 100 gms of silica gel by eluting the column with acetone (7100 gms). Pure product fractions were concentrated under reduced pressure to get residue. Acetonitrile (2 X 157 gms) was charged to the residue and the mixture was distilled under reduced pressure and then charged methyl tert butyl ether (200 ml) to the obtained residue and stirred for 1 hour at 25°C to 35°C. The solid crystals obtained was filtered and washed with methyl tert butyl ether (50 ml) to get title compound (75 gms). HPLC Purity (chemical): 99.80 percent

Reference： [1] Patent: WO2017/157352, 2017, A1, . Location in patent: Page/Page column 10; 11
[2] Patent: US2013/90473, 2013, A1, . Location in patent: Paragraph 0036
[3] Patent: US2013/90473, 2013, A1,
[4] Patent: WO2015/40640, 2015, A2, . Location in patent: Page/Page column 19
[5] Patent: US2017/56423, 2017, A1,

6
[ 39825-33-7 ]
[ 379270-35-6 ]
[ 379270-37-8 ]

Yield	Reaction Conditions	Operation in experiment
68.6%	Stage #1: With thionyl chloride In toluene at 70℃; for 24 h; Stage #2: at -25 - -20℃; for 1.25 h;	((((R)-1-(6-Amino-9H-purin-9-yl)propan-2-yl)oxy)methyl) monophenyl phosphate (80.0 g, 220 mmol) and toluene (500 mL) After mixing, thionyl chloride (39.2 g, 330 mmol) was added and reacted at 70° C. for 24 h. Less After concentration to dryness, toluene (400 mL) was added for dissolution. The above acid chloride solution was added dropwise to a solution of L-alanine isopropyl ester (129.6 g, 990 mmol) and DCM (500 mL), and the temperature was controlled at -25 to -20°C for 45 minutes. After stirring at -20°C or lower for at least 30min, the temperature of the reaction solution is raised to 19-25°C and once with 10percent (w/w) sodium dihydrogen phosphate solution (2x400mL), 15percent potassium hydrogencarbonate (2x200mL) and Wash with water (500 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give an amber oil. The mixture was dissolved in a toluene/acetonitrile (4:1) mixed solvent (500 mL), seed crystals (10 mg, 99:1 diastereoisomeric ratio) were added, and the mixture was stirred at room temperature for 2 hours. After filtration, the filter cake was washed with a mixed solvent of toluene/acetonitrile (4:1) (100 mL), and then dried under reduced pressure at 40° C. for 16 h to obtain a white solid ((S)-(((R)-1-(6-amino (9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphono)-L-alanine isopropyl ester, 72.0 g, yield: 68.6percent.
10 g	With thionyl chloride In dichloromethane; toluene at -25 - 70℃; for 0.75 h;	To a sluny of monophenyl PMPA (10.0 gms) in toluene (60 mL) at ambient temperaturewas added thionyl chloride (3.0 mL). The sluny was heated to 70° C and agitated for 48 to96 hours until reaction and diastereomeric enrichment were deemed complete by HPLC(Target: >97.0percent and >90:10 diastereomeric ratio). The mixture was concentrated todryness by vacuum distillation, and the dry residue was taken up in toluene (50 mL). Thismixture was added to a solution of isopropyl L-alanine ester (4.50 eqts) in DCM (80 mL) at —25° C over a minimum of 45 minutes, maintaining the internal temperature —20° C. The mixture was then held at a temperature —20° C for at least 30 minutes, and the pH checked using water wet pH paper. If the pH was <4, it was adjusted with triethylamine topH 4 to 7. The pot temperature was adjusted to room temperature. The mixture was transfened to a separatory funnel and washed sequentially with 10percent w/v aqueous solution of sodium phosphate monobasic, 15percent w/v aqueous solution of potassium bicarbonate, and water. The final organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a viscous amber oil. The oil was dissolved in toluene/acetonitrile(4:1) (50 mL), and the solution was seeded with 9-{(R)-2-[((R,S)-[(S)-1- (isopropoxycarbonyl) ethyl] amino }phenoxyphosphinyl) methoxy] propyl } adenine (about 1 mg, 99:1 diastereomeric ratio) and stined for 2 hrs at ambient temperature. The resultant sluny was filtered and the filter cake was washed with toluene/acetonitrile (4:1) and dried in a vacuum oven at 40° C for 16 hrs to give the product, 9-{(R)-2-[((R,S)-[(S)-1-(isopropoxycarbonyl)ethyl] amino } phenoxy phosphinyl) methoxy]propyl } adenine, as a white solid (10.0 gms, 97.5:2.5 diastereomeric ratio).

Reference： [1] Patent: CN107445994, 2017, A, . Location in patent: Paragraph 0028; 0030
[2] Patent: WO2017/221189, 2017, A1, . Location in patent: Page/Page column 34

7
[ 39825-33-7 ]
[ 379270-35-6 ]
[ 379270-37-8 ]
[ 383365-04-6 ]

Reference： [1] Nucleosides, Nucleotides and Nucleic Acids, 2001, vol. 20, # 4-7, p. 621 - 628
[2] Patent: CN106478725, 2017, A, . Location in patent: Paragraph 0044; 0045; 0046; 0047; 0048; 0049; 0050-0064

8
[ 39825-33-7 ]
[ 379270-37-8 ]

Yield	Reaction Conditions	Operation in experiment
1.3 g	Stage #1: With thionyl chloride In acetonitrile at 50 - 80℃; for 0.5 h; Stage #2: at -30 - -18℃; for 0.5 h; Stage #3: With triethylamine In dichloromethane; acetonitrile at -18 - 20℃; for 2.25 h;	(0042) 7.1 g of product from the last step was added to 30 ml of acetonitrile, 6.2 g of sulfoxide chloride was added dropwise with stirring, and the temperature was kept below 50° C. The reaction mixture was heated at 75° C. until the solid was dissolved, and then heated to 80° C. and evaporated to dryness. Cooling to 25° C., 40 ml of dichloromethane was added and cooled to −30° C.; 6.5 g of L-alanine isopropyl ester was added to 35 ml of dichloromethane solution over 30 minutes and the temperature was kept at −18° C. Then, 7 ml of triethylamine was added dropwise over 15 minutes and the temperature was kept from −18° C. to −11° C. The mixture was stirred at room temperature for 2 hours, and washed with 10percent sodium dihydrogen phosphate solution (3×15 ml). The organic layer was dried by anhydrous sodium sulfate, and after filtering, the filtrate was evaporated under reduced pressure to dryness, the residue was separated by silica gel column chromatography, eluted with acetone, and the desired component was collected and evaporated under reduced pressure to dryness to obtain a 3.6 g of oily matter. The resulting oily matter was separated by chiral preparative chromatography (Diacel's Chiralpak AS), eluted with acetonitrile containing 30percent methanol, the second main peak was collected and evaporated under reduced pressure to dryness to obtain 1.3 g of brownish yellow solid. 25 ml of acetonitrile and 0.3 g of fumaric acid were added, heated to reflux until the solid was dissolved and filtered immediately. The filtrate was cooled to 5° C. and left to stand overnight. Then the filtrate was filtered and dried, to obtain 1.2 g of white solid, with the melting point of 120-122° C., [α]D²⁰−41.7° (c 1.0, acetic acid).

Reference： [1] Patent: US2016/115186, 2016, A1, . Location in patent: Paragraph 0042

9
[ 771-61-9 ]
[ 39825-33-7 ]
[ 770-12-7 ]
[ 1256490-52-4 ]

Reference： [1] Patent: US2016/257706, 2016, A1, . Location in patent: Paragraph 0579; 0580

10
[ 39825-33-7 ]
[ 1256490-52-4 ]

Reference： [1] Patent: WO2016/181313, 2016, A1,
[2] Patent: WO2018/48937, 2018, A1,

11
[ 39825-33-7 ]
[ 1334513-02-8 ]

Reference： [1] Patent: US2016/257706, 2016, A1,

[ 39825-33-7 ] Synthesis Path-Downstream 1~88

1
[ 39825-33-7 ]
[ 109345-32-6 ]
[ 111610-56-1 ]

Reference： [1]Tetrahedron Letters,1987,vol. 28,p. 1629 - 1632

2
[ 39825-33-7 ]
[ 5625-46-7 ]
[ 35590-65-9 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1986,p. 1557 - 1560

3
[ 39825-33-7 ]
[ 108-24-7 ]
[ 2256-79-3 ]

Reference： [1]Tetrahedron,1987,vol. 43,p. 771 - 778

4
[ 56-41-7 ]
[ 67-63-0 ]
[ 39825-33-7 ]

Yield	Reaction Conditions	Operation in experiment
87%	With hydrogenchloride; thionyl chloride; at 0 - 20℃;	SOCl2 (29 mL, 400 mmcl) was added dropwise at 0 C to a suspension of the HCl salt of L-alanine (17.8 g, 200 mmcl) in isopropanol (700 mL). The suspension was stirred at roomtemperature over night, then concentrated, which gave the title compound (29.2 g, 87%).
74%	With alumina methanesulfonic acid; at 120℃; for 0.333333h;Microwave irradiation;	General procedure: In a typical reaction, AMA 2:3 (498 g, 1 mol), the corresponding aminoacid(1 mol) and alcohol (1.5-2 mol) were mixed in the provided reaction glass tubeequipped with a screw cap and magnetic agitation until a wet mixture was achieved.The reaction mixture was irradiated with microwaves (Anton Parr Monowave 300reactor) at 120 C for 20 min. On cooling, the mixture was diluted with chloroform(41 mL), filtered with glass frit over celite under vacuum, and washed with chloroform;then the filtrate was washed with Na2CO3 (ss) and water. The organic layerwas dried over Na2SO4, filtered, and concentrated under reduced pressure to givethe ester.
69%	With sulfuric acid; for 12h;Reflux;	General procedure: Synthesis of L-amino acid isopropyl esters Concentrated sulfuric acid was added to a suspension of the respective L-amino acid (1 g, amino acid:sulfuric acid ratio 1:1.2) in isopropanol (10 mL). The resulting solution was refluxed for 12 h. After this time, the solution was cooled to 0 C and neutralized with concentrated NH4OH. The ammonium sulfate formed was filtered and washed with isopropanol (3 * 5 mL). The filtrate was concentrated under reduced pressure (50 mm Hg, 50 C) to a third of its volume. The ester was extracted with chloroform (3 * 5 mL), the organic phase was dried with anhydrous sodium sulfate, and chloroform was removed under reduced pressure (50 mm Hg, room temperature). L-Alanine isopropyl ester (C6H13NO2·HOC3H7) b.p.125-127 C , yield 69%. 1H NMR (CDCl3) delta: 1.27 (d,6H, J = 6.8 Hz), 1.29 (d,6H, J = 6.4 Hz), 1.61 (d,3H, J = 7.2 Hz), 4.11 (q,1H, J = 7.2 Hz), 4.62 (heptet,1H, J = 6.4 Hz), 5.10 (heptet,1H, J = 6.4 Hz), ESI-MS: m/z 131.90 [M + H]+.

With chloro-trimethyl-silane; for 9.25h;Reflux;

A mixture of L-alanine (100 gms, 1.122 mol) and isopropanol (501 gms) was heated to reflux and chlorotrimethylsilane (204 gms, 1.870 mol) was added over 75 minutes. Reflux was continued for 8 hours and volatiles were distilled at atmospheric pressure until the reaction mass temperature reached 115C. Reaction mass was stirred for 3-4 hours at same temperature and cooled to 65C. THF (2 X 178 gms) was charged to reaction mass, co- distilled at atmospheric pressure and applied reduced pressure at the end to get a residue. THF (356 gms) was charged to the residue at 45C and further cooled to 25C. A slurry of DABCO in THF (113 gms of DABCO in 178 gms of THF) was added to the reaction mass at 25 to 30C and stirred for 15 minutes. Filtered the solids, washed with THF (178 gms) and the filtrate was concentrated under reduced pressure at below 40C to get L-Alanine isopropyl ester as an oil.

Reference： [1]Patent: WO2015/56213,2015,A1 .Location in patent: Page/Page column 66
[2]Synthetic Communications,2014,vol. 44,p. 2386 - 2392
[3]Journal of Molecular Structure,2013,vol. 1041,p. 68 - 72
[4]Analytical Chemistry,1991,vol. 63,p. 370 - 374
[5]Analytical Chemistry,1997,vol. 69,p. 926 - 929
[6]Nucleosides, nucleotides and nucleic acids,2001,vol. 20,p. 621 - 628
[7]Patent: WO2015/40640,2015,A2 .Location in patent: Page/Page column 18

5
[ 10065-72-2 ]
[ 67-63-0 ]
[ 39825-33-7 ]

Reference： [1]Tetrahedron,1987,vol. 43,p. 771 - 778
[2]Bulletin of the Chemical Society of Japan,1989,vol. 62,p. 2562 - 2566

6
[ 39825-33-7 ]
[ 407-25-0 ]
[ 6823-43-4 ]

Reference： [1]Analytical Chemistry,1991,vol. 63,p. 370 - 374
[2]Bulletin of the Chemical Society of Japan,1989,vol. 62,p. 2562 - 2566
[3]Analytical Chemistry,1997,vol. 69,p. 926 - 929

7
[ 39825-33-7 ]
9-[(R)-2-[[(R)-1-[[(S)-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine monofumarate [ No CAS ]

Reference： [1]Nucleosides, nucleotides and nucleic acids,2001,vol. 20,p. 621 - 628

8
[ 39825-33-7 ]
isopropyl (-)-(R)-2-amino-4-fluoro-2-methylbutanoate [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2000,p. 3737 - 3743

9
[ 39825-33-7 ]
isopropyl (+)-(S)-2-amino-4-fluoro-2-methylbutanoate [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2000,p. 3737 - 3743

10
[ 39825-33-7 ]
(R)-4-Fluoro-2-[(1R,2R,5R)-2-hydroxy-2,6,6-trimethyl-bicyclo[3.1.1]hept-(3E)-ylideneamino]-2-methyl-butyric acid isopropyl ester [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2000,p. 3737 - 3743

11
[ 39825-33-7 ]
(S)-4-Fluoro-2-[(1R,2R,5R)-2-hydroxy-2,6,6-trimethyl-bicyclo[3.1.1]hept-(3E)-ylideneamino]-2-methyl-butyric acid isopropyl ester [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2000,p. 3737 - 3743

12
2-amino-5-isobutyl-4-[2-(5-phosphono)-furanyl]thiazole dichloridate [ No CAS ]
[ 39825-33-7 ]
[ 347870-27-3 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 4331 - 4339

13
C₁₃H₉Cl₂N₂O₂PS [ No CAS ]
[ 39825-33-7 ]
[ 1041402-62-3 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 4331 - 4339

14
C₁₀H₁₁Cl₂N₂O₂PS₂ [ No CAS ]
[ 39825-33-7 ]
[ 347870-14-8 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 4331 - 4339

15
C₁₂H₈ClN₂O₇P [ No CAS ]
[ 39825-33-7 ]
[ 1334513-00-6 ]
(S)-2-[(R)-(2,4-dinitro-phenoxy)-phenoxy-phosphorylamino]propionic acid isopropyl ester [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 8311 - 8319

16
[ 1191237-49-6 ]
[ 39825-33-7 ]
[ 1350735-87-3 ]

Yield	Reaction Conditions	Operation in experiment
		General procedure for preparation of bisamidate prodiPO(OMe)3 To a solution of compound 5 (0.5 mmol) in trimethoxyphosphate (1 mL) is added phosphorous oxychloride (1.0 mmol) at 0 C and the mixture is stirred for 1 h. The mixture is then added to a freshly neutralized alanine ester (5 -10 mmol) in THF (~5 mL) at 0 C, and is allowed to warm to room temperature for 1 h. The reaction is quenched with water. The mixture was extracted with ethyl acetate and the ethyl acetate extract was concentrated. The residue is purified by either silica gel chromatography or reverse-phase HPLC, to afford bisamidate 60.Using the general procedure for the synthesis of the bisamidate prodrugs 60, Compounds 61-63 were prepared. 814.P2FCompound 61Compound 61 : 1H NMR (400 MHz, CDC13): delta 8.03 (s, IH), 6.84 (d, J = 4.0 Hz, IH), 6.72 (d, J = 4.0 Hz, IH), 6.1 (brs, 2H), 5.02 (m, 2H), 4.57 (q, IH), 4.29 (dd, 2H), 3.95 (d, IH), 3.92 (m, 2H), 3.48 (m, 2H), 1.49 (d, 6H), 1.25 (t, 12H), 0.95 (s, 3H). 31P NMR (162.1 MHz, CDC13): delta 12.59. MS = 610.1 (M - H+).

Reference： [1]Patent: WO2011/150288,2011,A1 .Location in patent: Page/Page column 110-111

17
[ 39613-92-8 ]
[ 39825-33-7 ]

Yield	Reaction Conditions	Operation in experiment
96%	In dichloromethane; at 20℃;	L-Alanine isopropyl ester hydrochloride (10.0 g, 59.9 mmol) was added to the reaction flask.Add 40 ml of anhydrous dichloromethane to dissolve.Sodium bicarbonate (15.0 g, 149.7 mmol) was added.There is gas release,Stir at room temperature overnight,Filter to remove insoluble,The organic phase was washed 3 times with saturated brine.Dry over anhydrous sodium sulfate and concentrate to dryness to give the product 7.54 g.Yield:96.0%.
	With potassium hydrogencarbonate; In dichloromethane; at 19 - 25℃;Large scale;	a. Preparation of Compound 11. Isopropyl L-alanine ester hydrochloride (compound 10) (1 kg, 5.97 mol, 1.0 equiv) and potassium bicarbonate (1.45 kg, 14.5 mol, 2.43 equiv) were agitated in DCM (4 kg) for 10 to 14 hours with maximum agitation, maintaining the pot temperature between 19 C. and 25 C. The mixture was then filtered and rinsed forward with DCM (2 kg). The filtrate was dried over a bed of 4 ? molecular sieves until the water content of the solution was ?0.05%. The resultant stock solution containing compound 11 was then cooled to a pot temperature of -20 C. and held for further use
	With potassium hydrogencarbonate; In dichloromethane;Molecular sieve;	Isopropyl L-alanine ester hydrochloride 10 (1 kg, 5.97 mol, 1.0 equiv) and potassium bicarbonate (1.45 kg, 14.5 mol, 2.43 equiv) were agitated in DCM (4 kg) for 10-14 hours with maximum agitation, maintaining the pot temperature between 19 and 25 C. The mixture was then filtered and rinsed forward with DCM (2 kg). The filtrate was dried over a bed of 4 molecular sieves until the water content of the solution was ?0.05%. The resultant stock solution containing compound 11 was then cooled to a pot temperature of -20 C., and held for further use.

	With potassium hydrogencarbonate; In dichloromethane; at 20℃; for 12h;	L-alanine isopropyl ester hydrochloride 500gAnd potassium bicarbonate 730gIt was stirred at room temperature for 12 hours in DCM (2 kg).The mixture was then filtered and further rinsed with DCM (1 kg). The filtrate was dried on a molecular sieve bed until the water content of the solution was < 0.03%.The obtained L-alanine isopropyl ester was cooled to a pot temperature of -20 C for use.Weigh 500g of tenofovir (dried at 105 C in an oven for 3 hours before feeding) into a 2000ml flask, then add 1500g of thionyl chloride, heat to 55 C, after 10 minutes, continue to warm to 70 C and stir After 3 hours, pour into a 20 L rotary flask and distill the thionyl chloride under reduced pressure.After the end of the distillation, 7 kg of acetonitrile was added and refluxed at 85 C for 0.5 h.Add 630 g of 3-hexadecyloxy-1-propanol in 10 portions (add once every 10 minutes).After the addition, the stirring was continued for 0.5 h under reflux.After slowly cooling to 35 C, then add 3 kg of dichloromethane,After further stirring for 0.5 h, 458 g of L-alanine isopropyl ester was added dropwise within 0.5 h.After stirring for 0.5 h, 350 g of triethylamine was added dropwise.After stirring for 0.5 h, the system was cooled to room temperature, suction filtered, and the filtrate was evaporated to dryness to ethyl acetate.The filter cake was stirred with 1 kg of ethyl acetate for 1 hour, and then filtered with suction. The filtrate was combined with the above steps. The combined ethyl acetate solution was washed twice with 6 kg of 5% aqueous potassium hydrogencarbonate solution and twice with 6 kg of 20% aqueous sodium chloride solution. The ethyl acetate solution was cooled to -7 C. After 2 h, suction filtration was started and the filtrate was evaporated to dryness. After evaporation to dryness, the filtrate was crystallized from 2 kg of a mixed solvent of dichloromethane: acetonitrile = 1:20 at -10 C, crystallized, filtered, and the filter cake was recrystallized from 2 kg of acetonitrile, crystallized, and filtered to give a filter cake. Under the truthAfter empty drying, C0P130 was obtained in an amount of about 628 g (yield 52.1%, purity 98.6%).
	With potassium hydrogencarbonate; In dichloromethane; at 25℃; for 12h;	Synthesis of intermediate 6: L-alanine isopropyl ester hydrochloride (1 g, 0.00595 mol) was added to the reaction flask.Potassium hydrogencarbonate (1.45 g, 0.0145 mol) and 10 mL of dichloromethane, followed by stirring at 25 C for 12 h.After that, the dichloromethane is recovered by rotary distillation, and the product after spinning is dried to a water content of less than 0.05% to obtain Intermediate 6,Intermediate 6 was then stored at -20 C (Intermediate 6 was used in Example 6 without purification);

Reference： [1]Patent: CN109320553,2019,A .Location in patent: Paragraph 0317; 0318; 0320; 0321; 0322
[2]Patent: US2013/90473,2013,A1 .Location in patent: Paragraph 0029; 0030
[3]Patent: US2017/56423,2017,A1 .Location in patent: Paragraph 0296; 0297
[4]Patent: CN109400647,2019,A .Location in patent: Paragraph 0056-0063
[5]Patent: CN109485675,2019,A .Location in patent: Paragraph 0066; 0067

18
[ 39825-33-7 ]
9-[(2R)-2-[[chloro(phenoxy)phosphoryl]methoxy]propyl]purin-6-amine [ No CAS ]
(2S)-isopropyl2-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)amino)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	In dichloromethane; at -20 - -10℃; for 0.5h;	Synthesis of tenofovir alafenamide using PMPA monophenyl ester prepared by the inventionPMPA monophenyl ester (50 g, 0.138 mol) was added to a 500 ml four-necked flask.Thionyl chloride (15 ml, 0.205 mol) was added to 300 ml of toluene with stirring.The resulting mixture was heated to 80 C and stirred for 48 hours.The mixture was evaporated to dryness under reduced pressure at 40 to 45 C, and then 250 ml of toluene was added to the reaction flask.A PMPA monophenyl ester chlorotoluene suspension was obtained.Add <strong>[39825-33-7]L-alanine isopropyl ester</strong> (81.3 g, 6.21 mol) to a 1000 ml four-necked flask.400ml of dichloromethane, cooled and cooled to -15 C with stirring.The above-mentioned acid chloride toluene suspension was started to be added dropwise, and the internal temperature was maintained at -20 C to -10 C.After the dropwise addition, continue stirring for 30 minutes and move to room temperature.Wash with a 10% sodium dihydrogen phosphate solution (250 ml × 2), and separate the organic phase.Wash with 15% potassium bicarbonate solution 100 ml × 2, and then wash with 250 ml of purified water.The organic phase was dried over anhydrous sodium sulfate and filtered and evaporated.Add 200ml of toluene, 50ml of acetonitrile, heat and dissolve under stirring, cool down and crystallize.Crystallization at 0~5 C for 2 hours, suction filtration,The filter cake was washed with 100 ml of toluene/acetonitrile (4/1) and dried under vacuum at 40-45 C for 4 hours.Defolifoviral acetamide 45.3g,The yield was 69% and the HPLC purity was 99.3%.
	In dichloromethane; at -25 - -10℃; for 2.5h;	c. Preparation of Compound 15. To the stock solution of <strong>[39825-33-7]isopropyl L-alanine</strong> ester 11 (4.82 equiv) at -25 C. was added slurry containing compound 13a (1.0 equiv) over a minimum of 2 hours, maintaining the pot temperature ?-10 C. The mixture was then held at a temperature ?-10 C. for at least 30 minutes, then the pH checked using water wet pH paper. If the pH was sodium phosphate monobasic (2.2 kg, 18 mol, 6.90 equiv) in water (16 kg) was prepared. Half of the sodium phosphate monobasic solution was charged to the phosphonamidate reactor, and vigorously stirred. The layers were settled and partitioned. The organic layer was washed again with the remaining half of sodium phosphate monobasic solution. In a separate vessel, a solution of potassium bicarbonate (1.1 kg, 11 mol, 4.22 equiv) in water (5.5 kg) was prepared. Half of the potassium bicarbonate solution was charged to the organic phase, and vigorously stirred. The layers were settled and partitioned. The organic layer was washed again with the remaining half of the potassium bicarbonate solution, followed by a final water (3.3 kg) wash. The organic phase was then retained and distilled to a volume of approximately 6 L. The resultant solution was analyzed for water content. If the water content was >1.0%, DCM could be charged and the distillation to approximately 6 L repeated. When the solution water content was less than or about 1.0%, the pot temperature was adjusted to 19 C. to 25 C. prior to discharge of the stock solution in DCM to provide the diastereomeric mixture 9-{(R)-2-[((R,S)-[(S)-1-(isopropoxycarbonyl)ethyl]amino}phenoxyphosphinyl)methoxy]propyl}adenine (compound 15). 1H NMR (400 MHz, CDCl3): delta1.20-1.33 (m, 12H), 3.62-3.74 (m, 1H), 3.86-4.22 (m, 5H), 4.30-4.44 (m, 1H), 4.83-5.10 (m, 1H), 6.02 (br s, 3H), 7.18-7.34 (m, 5H), 7.98-8.02 (m, 1H), 8.32-8.36 (m, 1H); 31P NMR (162 MHz, CDCI3): S. 21.5, 22.9.
	In dichloromethane; at -25 - 25℃;	To the stock solution of <strong>[39825-33-7]isopropyl L-alanine</strong> ester 11 (4.82 equiv) at -25 C. was added slurry containing compound 13a (1.0 equiv) over a minimum of 2 hours, maintaining the pot temperature ?-10 C. The mixture was then held at a temperature ?-10 C. for at least 30 minutes, then the pH checked using water wet pH paper. If the pH was 1.0%, DCM could be charged and the distillation to ca. 6 L repeated. When the solution water content was less than or about 1.0%, the pot temperature was adjusted to 19-25 C. prior to discharge of the stock solution in DCM to provide the diastereomeric mixture of 9-[(R)-2-[[(R,S)-1-[[(S)-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine (15). 1H NMR (400 MHz, CDCl3): delta 1.20-1.33 (m, 12H), 3.62-3.74 (m, 1H), 3.86-4.22 (m, 5H), 4.30-4.44 (m, 1H), 4.83-5.10 (m, 1H), 6.02 (br s, 3H), 7.18-7.34 (m, 5H), 7.98-8.02 (m, 1H), 8.32-8.36 (m, 1H); 31P NMR (162 MHz, CDCl3): delta. 21.5, 22.9

2.22 kg

In dichloromethane; at -5 - 0℃; for 1h;Industrial scale;

(3) Take 3.2 kg of <strong>[39825-33-7]L-alanine isopropyl ester</strong>, 10 L of dichloromethane, and add to the 20 L reactor to start stirring.To the total solution, temperature control -5 ~ 0 C, drop the FAT-1 solution of DCM, add, to obtain a light yellow clear solution, stir the reaction for 1 h.The reaction solution is 15 C or less, washed twice with 20 L of saturated sodium carbonate solution, and washed twice with 20 L of saturated sodium chloride solution.Dry over anhydrous sodium sulfate for 1-2 h, concentrate to dryness under reduced pressure at 40 C.A yellow-brown oil was obtained, about 2.22 kg, in a crude yield of 81%.

Reference： [1]Patent: CN109836459,2019,A .Location in patent: Paragraph 0026
[2]Patent: US2013/90473,2013,A1 .Location in patent: Paragraph 0029; 0032
[3]Patent: US2017/56423,2017,A1 .Location in patent: Paragraph 0296; 0299
[4]Patent: CN108409790,2018,A .Location in patent: Paragraph 0042; 0047; 0050

19
[ 39825-33-7 ]
(((R)-1-(6-amino-9H-purin-9-yl)-1-methylethoxy)methyl)phenoxyphosphoryl chloride [ No CAS ]
[ 379270-37-8 ]

Yield	Reaction Conditions	Operation in experiment
95%		To a suspension of Ph-PMPA 8 (1 .47g, 4.05 mmol) in iPrOAc (25 mL) thionyl chloride (0.7mL, 10.11 mmol, 2.5 equiv) was added and the reaction mixture was stirred at 80C for 2h.Then, sulfolane (2.2 mL) was added and the resulting mixture was stirred at 80C for 24 - 72 h (until d.e. of 70% was achieved). After cooling to the room temperature, the volatile constituents were removed by distillation at a reduced pressure (45C, 10 mbar). The obtained mixture of the chlorides of formula 7a/7b was suspended in iPrOAc (25 mL) and addedduring 1 h to a cooled (-20C) solution of iPr-L-alanine (2.65g, 20.23 mmol, 5 equiv) in iPrOAc (15 mL). The reaction was stirred for lh at -20C, and then after heating for lh at 20C. The reaction mixture was washed with an aqueous solution of NaI12P04, aqueous solution of KFICO3, water and a saturated solution of NaC1 and further dried over Na2SO4. The resulting solution was concentrated to the volume of 15 mL, inoculated with TA of formula laand left to crystallize at the room temperature. The product was aspirated on fit, washed with cold iPrOAc and dried in a vacuum drier (40C, 200 Pa) for 8 h, providing 1.3 g (68%) of Tenofovir Alafenamide of formula la in the form of white powder (chemical purity 95%, d.e.70%). Tenofovir Alafenamide (chemical purity 95%, d.c. 70%) was dissolved at 85C in iPrOAc (5 mL/mmol), cooled during 2h to 22C and stirred at 22C for 2h. The product was aspirated on frit, washed with cold iPrOAc and dried in a vacuum drier (40C, 200 Pa) for 8 h, providing Tenofovir Alafenamide in the yield of 92% and d.c. of 99.0%.Tenofovir alafenamide (d.e. 99.0%) was dissolved at 85C in iPrOAc (5 mL/mmol), cooled during 2h to 22C and stirred at 22C for 2h. The product was aspirated on fit, washed with cold iPrOAc and dried in a vacuum drier (40C, 200 Pa) for 8 h, providing Tenofovir Alafenamide of formula la in the yield of 95% and d.e. of 99.8%.?H NMR (500 MHz, DMSO) oe = 8.12 (d, J 16.6 Hz, 2H), 7.29 (t, J= 7.9 Hz, 211), 7.23 (s, 2H), 7.13 (t, J= 7.4 Hz, 1H), 7.04 (d, J= 8.4 Hz, 2H), 5.69 - 5.61 (m, 111), 4.84 (hept, J 6.3 Hz, 1H), 4.27 (dd, J= 14.4, 3.6 Hz, 111), 4.14 (dd, J= 14.4, 6.6 Hz, 111), 3.97 -3.90 (m, 1H), 3.90 -3.81 (m, 2H), 3.76 (dd, J 13.4, 9.8 Hz, 1H), 1.15 (d, J?= 6.3 Hz, 6H), 1.12 (d, J 7.1Hz, 3H), 1.06 (d, J= 6.2 Hz, 3H) ppm.?3C NMR (126 MHz, DMSO) oe = 172.92, 172.89, 155.99, 152.44, 150.26, 150.19, 149.80, 141.40, 129.50, 124.36, 120.57, 120.54, 118.39, 75.55, 75.45, 67.91, 64.75, 63.52, 49.07,46.84, 21.45, 21.42, 20.34, 20.30, 16.66 ppm.31P NMR (202 MHz, DMSO) = 22.11 ppm.
76.4%	In dichloromethane; toluene; at -25 - -20℃; for 1.25h;	To a solution of <strong>[39825-33-7]isopropyl L-alanine</strong> ester 11 (4.50 equiv) in DCM (80 mL) at -25 C. was added a slurry containing compound 13a (1.00 equiv) that is at least 90% diastereomerically pure in toluene (50 mL) over a minimum of 45 minutes, maintaining the internal temperature ?-20 C. The mixture was then held at a temperature ?-20 C. for at least 30 minutes, and the pH checked using water wet pH paper. If the pH was <4, it was adjusted with triethylamine to pH 4 to 7. The pot temperature was adjusted to room temperature (19 C. to 25 C.). The mixture was transferred to a separatory funnel and washed sequentially with 10% w/v aqueous solution of sodium phosphate monobasic (2×50 mL), 15% w/v aqueous solution of potassium bicarbonate (2×20 mL), and water (50 mL). The final organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a viscous amber oil. The oil was dissolved in toluene/acetonitrile (4:1) (50 mL), and the solution was seeded with 9-{(R)-2-[((R,S)-{ [(S)-1-(isopropoxycarbonyl)ethyl]amino}phenoxyphosphinyl)methoxy]propyl}adenine (about 1 mg, 99:1 diastereomeric ratio) and stirred for 2 hours at ambient temperature. The resultant slurry was filtered and the filter cake was washed with toluene/acetonitrile (4:1) (15 mL) and dried in a vacuum oven at 40 C. for 16 hours to give the product, 9-{(R)-2-[((R,S)-[(S)-1-(isopropoxycarbonyl)ethyl]amino}phenoxyphosphinyl)methoxy]propyl}adenine (compound 15), as a white solid (10.0 g, 76.4%, 97.5:2.5 diastereomeric ratio in favor of compound 16). 1H NMR (400 MHz, CDCl3): delta1.20-1.33 (m, 12H), 3.62-3.74 (m, 1H), 3.86-4.22 (m, 5H), 4.30-4.44 (m, 1H), 4.83-5.10 (m, 1H), 6.02 (br s, 3H), 7.18-7.34 (m, 5H), 7.98-8.02 (m, 1H), 8.32-8.36 (m, 1H); 31P NMR (162 MHz, CDCl3): delta21.5, 22.9.
75 g	With triethylamine; In dichloromethane; at -35 - 30℃; for 2.25h;	To a mixture of [(R)-2-(Phenylphosphonomethoxy) propyl] adenine (100 gms, 0.275 mol) in acetonitrile (337 gms), thionyl chloride (73 gms, 0.619 mol) was added and heated to 75C for lhr. The solvents were removed at atmospheric pressure under nitrogen at 80C, cooled to 25C, diluted with dichloromethane (530 gms) and further cooled to -35C. A solution of <strong>[39825-33-7]L-alanine isopropyl ester</strong> (77.6 gms, 0.592 mol) in dichloromethane (397 gms) was added over 45 minutes at -35C and followed by triethylamine (83 gms, 0.824 mol) over 30 minutes at -18C. The reaction mixture was heated to 25-30C and maintained for 1 hour, cooled to 10 to 20C and washed with 10% aq. sodium dihydrogenphosphate solution at 25C. The organic solution was dried over anhydrous sodium sulfate, filtered and washed with dichloromethane. The organic layer was concentrated under reduced pressure to get an oil residue. Acetone (237 gms) was charged to the residue and die mixture concentrated under reduced pressure. Acetone (237 gms) was again charged to the residue, purified by chromatography over 1 100 gms of silica gel by eluting the column with acetone (7100 gms). Pure product fractions were concentrated under reduced pressure to get residue. Acetonitrile (2 X 157 gms) was charged to the residue and the mixture was distilled under reduced pressure and then charged methyl tert butyl ether (200 ml) to the obtained residue and stirred for 1 hour at 25C to 35C. The solid crystals obtained was filtered and washed with methyl tert butyl ether (50 ml) to get title compound (75 gms). HPLC Purity (chemical): 99.80 %

Reference： [1]Patent: WO2017/157352,2017,A1 .Location in patent: Page/Page column 10; 11
[2]Patent: US2013/90473,2013,A1 .Location in patent: Paragraph 0036
[3]Patent: US2013/90473,2013,A1
[4]Patent: WO2015/40640,2015,A2 .Location in patent: Page/Page column 19
[5]Patent: US2017/56423,2017,A1

20
[ 39825-33-7 ]
(2S)-isopropyl 2-(((((4R,5R,7R,8R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-8-hydroxy-1,6-dioxaspiro[3.4]octan-7-yl)methoxy)(phenoxy)-phosphoryl)amino)propanoate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 1836 - 1844

21
[ 39825-33-7 ]
[ 1255860-40-2 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 1836 - 1844

22
[ 39825-33-7 ]
[ 770-12-7 ]
[ 261909-49-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at -60 - 25℃; for 1.5h;Inert atmosphere;	phenyl phosphodichloridate (30.6g) was dissolved in dichloromethane , to this was added a solution of 1-alanine isopropyl ester free base (19.16g) in dichloromethane at-60C under nitrogen. Solution of triethylamine (20.7ml) was added to above reaction mass. Reaction mass was stirredat -60C for 30 min and then temperature was raised to 25 C. Reaction mass was stirred at 20-25 C for 60 min & filtered and washed with dichloromethane. Clear filtrate was distilled under reduced pressure obtained residue was stirred with diisopropyl ether & filtered. Clear filtrate was distilled under reduced pressure to get (2S)-isopropyl-2- ((chloro(phenoxy)posphoryl)amino)propanoate compound.
257 mg	With triethylamine; In dichloromethane; at -78 - 20℃; for 2h;	To a solution of compound Intermediate 7b (644 mg, 3.05 mmol, 1.0 eq) in DCM (15 mL) was added dropwise a mixture of Intermediate 7c (400 mg, 3.05 mmol, 1.0 eq) and TEA (308 mg, 3.05 mmol, 1.0 eq) in DCM (5 mL) at -78 C. The mixture was warmed to room temperature and stirred for 2 h. The solvent was removed under reduced pressure and ether (20 mL) was added. The mixture was filtered and the filter cake was washed with ether. The combined ether solution was dried over Na2S04 and the solvent was removed. The residue was purified by flash chromatography on silica (petroleum ether/ethyl acetate = 2: 1) to give Intermediate 7 (257 mg, 27%) as a colorless oil. (0231) LC-MS: 306 (M+l)+ 1H NMR (400 MHz, CDC13): delta 7.39-7.35 (m, 2 H), 7.27-7.21 (m, 3H), 5.10-5.05 (m, 1H), 4.40-4.25 (m, 1H), 4.12-4.03 (m, 1H), 1.50-1.48 (m, 3H), 1.29-1.22 (m, 6H).
	With triethylamine; In ethyl acetate; at -10℃; for 1h;	To a stirred solution of phenyl dichlorophosphate (250 g) in EtOAc (800 mL) was addedisopropyl L-alaninate (200 g) in triethylamine (120 g) at -10 C. The reaction was stirred at -10C for 1 h. 2,3,4,5,6-Pentafluorophenol (220 g) in triethylamine (120 g) and EtOAc (400 mL)was added at -5 C and stirred at -5 C for 0.5 h. The reaction mixture was allowed to warm to25 C and stirred at 25 C for 2 h. The solution was filtrated, washed with EtOAc (2 x 200 mL),and the combined organic phases were evaporated under vacuum to afford solid PPAL-RS(racemate).

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 8178 - 8193
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 1836 - 1844
[3]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 869 - 873
[4]Patent: WO2016/181313,2016,A1 .Location in patent: Page/Page column 7
[5]Patent: WO2017/79195,2017,A1 .Location in patent: Page/Page column 34; 35
[6]Patent: WO2018/48937,2018,A1 .Location in patent: Page/Page column 220; 221

23
[ 39825-33-7 ]
[ 1604813-62-8 ]
[ 1604813-64-0 ]

Yield	Reaction Conditions	Operation in experiment
		Dichloromethane containing POC13 (1 equiv.) wascooled to -78 C. To this solution was added drop-wise amixture of compound (11-1, 1 equiv.) andEt3N (1.1 equiv.) inCH2Cl2 over a period of20 min and stirred at this temperaturefor 5 min. <strong>[39825-33-7]L-alanine isopropyl ester</strong> (1 equiv.) in was added in5 min. The resulting mixture was stirred at -70 C. for 1 handthen allowed to warm to RT. Reaction mixture was dilutedwith TBME, and insoluble solid was filtered, washed withTBME. Filtrates were combined and concentrated to give11-2 which was taken to the next step without purification. Toa THF solution of compound (11-2) was added a solution of11-3 (1 equiv.) and NMI (5.25 equiv.) in THF at -7 C. Thereaction mixture was brought toRT and stirred for 2 h. MeOHwas added to quench the reaction and the mixture was concentratedand then purified by HPLC, affording compound 11as a mixture of isomers (chemical purity 96.5% ).

Reference： [1]Patent: US2014/112886,2014,A1 .Location in patent: Paragraph 0406; 0408

24
[ 39825-33-7 ]
C₂₇H₃₇N₆O₈P [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 869 - 873

25
[ 39825-33-7 ]
C₃₁H₄₃N₆O₉P [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 869 - 873

26
[ 39825-33-7 ]
C₂₈H₃₈N₅O₉P [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 869 - 873

27
[ 39825-33-7 ]
C₂₄H₃₂N₅O₈P [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 869 - 873

28
[ 39825-33-7 ]
[ 770-12-7 ]
C₂₄H₃₂N₅O₈P [ No CAS ]
C₂₄H₃₂N₅O₈P [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 869 - 873

29
[ 777-52-6 ]
[ 39825-33-7 ]
(2S)-isopropyl 2-(((((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(4-nitrophenoxy)phosphoryl)amino)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With triethylamine; In dichloromethane; at 20 - 60℃;	A solution of 4-nitrophenyl dichlorophosphate (1 .8 g 7 mmol) in DCM was added dropwise at -60 C to a solution of the amine 1-ha (2.35 g, 14 mmol) and triethylamine (7.7 mL, 56 mmol) inDCM. The reaction mixture was allowed to attain room temperature, stirred over night,concentrated and then diluted with ethyl acetate and ether and left at room temperatureovernight. The triethylamine-HOl salt was filtered of, the filtrate was concentrated under reducedpressure and the afforded residue was purified by chromatography on silica gel eluted with isohexane-ethyl acetate, which gave the title compound (1 .6 g, 50%).
50%	With triethylamine; In dichloromethane; at 20 - 60℃;	A solution of 4-nitrophenyl dichlorophosphate (1.8 g 7 mmol) in DCM was added dropwise at -60C to a solution of the amine 1-ha (2.35 g, 14 mmol) and triethylamine (7.7 mL, 56 mmol) in DCM. The reaction mixture was allowed to attain room temperature, stirred over night, concentrated and then diluted with ethyl acetate and ether and left at room temperature overnight. The triethylamine-HCl salt was filtered of, the filtrate was concentrated under reducedpressure and the afforded residue was purified by chromatography on silica gel eluted with isohexane-ethyl acetate, which gave the title compound (1.6 g, 50%).
50%	With triethylamine; In dichloromethane; at -60 - 20℃;	A solution of 4-nitrophenyl dichlorophosphate (1 .8 g 7 mmol) in DCM was added dropwise at - 60 C to a solution of the amine 1-1 1 a (2.35 g, 14 mmol) and triethylamine (7.7 mL, 56 mmol) in DCM. The reaction mixture was allowed to attain room temperature, stirred over night, concentrated and then diluted with ethyl acetate and ether and left at room temperature overnight. The triethylamine-HCI salt was filtered of, the filtrate was concentrated under reduced pressure and the afforded residue was purified by chromatography on silica gel eluted with iso- hexane-ethyl acetate, which gave the title compound (1 .6 g, 50%).

50%

With triethylamine; In dichloromethane; at -60 - 20℃;

Add amine I-11a (2.35 g, 14 mmol) and triethylamine (7.7 mL, 56 mmol) at -60 CTo the solution in DCM was added dropwise 4-nitrophenyl dichlorophosphate (1.8 g 7 mmol)Solution in DCM. The reaction mixture was allowed to reach room temperature and stirred overnight.Concentrated and then diluted with ethyl acetate and ether and left at room temperature overnight. The triethylamine-HCl salt was filtered off, the filtrate was concentrated under reduced pressure and the obtained residue was purified by chromatography on silica gel with isohexane-ethyl acetate, which gave the title compound (1.6 g, 50%)

Reference： [1]Patent: WO2015/34420,2015,A1 .Location in patent: Page/Page column 64
[2]Patent: WO2015/56213,2015,A1 .Location in patent: Page/Page column 66
[3]Patent: WO2016/30335,2016,A1 .Location in patent: Page/Page column 47
[4]Patent: TW2018/15396,2018,A .Location in patent: Page/Page column 76; 77

30
[ 916597-71-2 ]
[ 39825-33-7 ]
(2S)-2-(((benzo[d][1,3]dioxol-5-yloxy)(perfluorophenoxy)phosphoryl)amino)propionic acid isopropyl ester [ No CAS ]

Reference： [1]Patent: WO2015/34420,2015,A1
[2]Patent: WO2015/56213,2015,A1

31
[ 916597-71-2 ]
[ 39825-33-7 ]
C₁₃H₁₇ClNO₆P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at -78 - 20℃;Inert atmosphere;	POCl3 (1 .79 ml, 19.2 mmol) was added under N2 at -78 00 to a solution of sesamol (2.65 g, 19.2mmol) in DCM (60 mL), followed by drop wise addition of Et3N (2.67 ml, 19.2 mmol). Themixture was stirred for 4 h at -20 to -30 00 The mixture was cooled to -78 C and a solution of <strong>[39825-33-7](S)-isopropyl 2-aminopropanoate</strong> (3.22 g, 19.2 mmol) in DCM (10 mL) was added dropwise, followed by addition of Et3N (5.62 ml, 40.3 mmol) over 15 mm. The reaction mixture was allowed to attain rt and stirred over night. The temperature of the reaction mixture was then lowered toO 00 and pentafluorophenol (3.53 g, 19.2 mmol) was added in one portion followedby dropwise addition of Et3N (2.67 ml, 19.2 mmol). The obtained slurry was stirred at 0 00. When the reaction was completed as judged by LC-MS, the mixture was filtered and the solid was washed with cold DCM. The filtrate was concentrated and redissolved in tert-butyl ether, filtered again and then concentrated. EtOAc:Hexane 20:80 was added and the obtained slurry heated gently until a clear solution was obtained. The solution allowed to reach rt and then putat -20 0. After 1 hour crystals was formed, filtered off, washed several times with hexane and then dried under vacuum, yield: 1 .8 g. The mother liquid was concentrated and the crystals formed filtered off and dried under vacuum, yield: 5.5 g. Total yield: 7.3 g, 69%. MS ES+ 498.06 [M+H].
	With triethylamine; In dichloromethane; at 20℃; for 0.25h;	POCl3 (1.79 ml, 19.2 mmol) was added under N2 at-78 C to a solution of sesamol (2.65 g, 19.2mmcl) in DCM (60 mL), followed by drop wise addition of Et3N (2.67 ml, 19.2 mmol). Themixture was stirred for 4 h at -20 to -30 C. The mixture was cooled to -78 C and a solution of <strong>[39825-33-7](S)-isopropyl 2-aminopropanoate</strong> (3.22 g, 19.2 mmol) in DCM (10 mL) was added dropwise, followed by addition of Et3N (5.62 ml, 40.3 mmol) over 15 mm. The reaction mixture was allowed to attain rt and stirred over night. The temperature of the reaction mixture was thenlowered to 0 C and pentafluorophenol (3.53 g, 19.2 mmol) was added in one portion followed by dropwise addition of Et3N (2.67 ml, 19.2 mmol). The obtained slurry was stirred at 0 C. When the reaction was completed as judged by LC-MS, the mixture was filtered and the solid was washed with cold DCM. The filtrate was concentrated and redissolved in tert-butyl ether, filtered again and then concentrated. EtOAc:Hexane 20:80 was added and the obtained slurryheated gently until a clear solution was obtained. The solution allowed to reach rt and then put at -20 C. After 1 hour crystals was formed, filtered off, washed several times with hexane and then dried under vacuum, yield: 1 .8 g. The mother liquid was concentrated and the crystals formed filtered off and dried under vacuum, yield: 5.5 g. Total yield: 7.3 g, 69%. MS (ES+) 498.06 [M+H].
	With triethylamine; In dichloromethane; at -78 - 20℃; for 1h;	(0124) 2.6 g of (0.01 mol) benzo[1,3]dioxolan-5-yl)-oxyl-phosphorus oxydichloride and 1.6 g of (0.01 mol) <strong>[39825-33-7]L-alanine isopropyl ester</strong> were dissolved in 30 ml of anhydrous dichloromethane and cooled to -78 C. A solution of 2 ml of triethylamine dissolved in 20 ml of anhydrous dichloromethane was added dropwise with stirring, and the rate of dropwise adding was controlled to keep the reaction temperature at -78 C. After adding, when the reaction temperature was slowly raised to room temperature, stirring was continued for 1 hour. The solvent was evaporated under reduced pressure, and 30 ml of anhydrous diethyl ether was added to the residue, and then filtered. The filtrate was evaporated under reduced pressure to dryness so as to obtain a colourless oily matter, i.e., phosphoramide intermediate V3, which was directly used in the next step reaction.

With triethylamine; In dichloromethane; at -78 - 20℃; for 1h;

2.6 g of benzo[1,3]dioxopenta-5-yl)-oxy-dichlorophosphorus and 1.6 gL-Alanine isopropyl ester was dissolved in 30 mL of anhydrous dichloromethane and cooled to -78 C.A solution of 2.8 ml of triethylamine dissolved in 15 mL of anhydrous dichloromethane was added dropwise with stirring.The drop rate was controlled to maintain the reaction temperature -78 C. After the addition,The reaction temperature was allowed to rise to room temperature and stirring was continued for 1 hour.Then, the reaction mixture was cooled to 0 C, and a solution of 1.84 g of pentafluorophenol and 1.4 ml of triethylamine dissolved in 5 mL of anhydrous dichloromethane was added dropwise with stirring; while maintaining at 0 C, stirring was continued for 4 hours. filter,After washing with 20 ml of dichloromethane, the filtrate was combined and evaporated to dryness crystals.Add 40 ml of tert-butyl methyl ether, grind, and filter off the solid.The filter cake was washed with a little bit of butyl methyl ether, and the filtrate was combined and evaporated to dryness.Add 50 ml of petroleum ether: ethyl acetate mixed solvent (10:1) to dissolve.The solid was precipitated by cooling to room temperature; the solid was filtered, and then recrystallized from petroleum ether: ethyl acetate mixed solvent (10:1) 50ml.Obtained 2.5 g of intermediate Sp-iv-1; isomer purity de 98.6%

Reference： [1]Patent: WO2015/34420,2015,A1 .Location in patent: Page/Page column 69; 70
[2]Patent: WO2015/56213,2015,A1 .Location in patent: Page/Page column 71; 72
[3]Patent: US2016/115186,2016,A1 .Location in patent: Paragraph 0124
[4]Patent: CN109134568,2019,A .Location in patent: Paragraph 0085-0087; 0089

32
[ 1234490-70-0 ]
[ 39825-33-7 ]
C₁₅H₁₈ClN₂O₄P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; for 5h;Cooling;	Phosphorus oxychloride (1.5 mL, 16.4 mmol) was added to DCM (40 ml) and the mixture was cooled in a dry-ice/EtOH bath. 6-Hydroxyquinoline (2.38 g, 16.4 mmol) was added followed by drop wise addition of Et3N (2.28 mL, 16.4 mmol) in DCM (5 mL). The mixture was stirred with cooling for 3 h then isopropyl alanine (2.75 g, 16.4 mmol) was added followed by drop wiseaddition of Et3N (4,57 ml, 32.8 mmol). The mixture was stirred with cooling for 5 h.Pentafluorophenol (3.02 g, 16.4 mmol) was added followed by Et3N (2,28 ml, 16.4 mmol) and the mixture was stirred for 72h. The mixture was diluted with EtOAc (200 mL) and washed with0.1 M HCI (aq) x2, dried (Na2SO4) and concentrated. The residue was purified by silica using petroleum ether/EtOAc (1:1) to give a beige solution that solidified in EtOAc/p-Ether. The solidwas collected by filtration which gave the title compound (787 mg, 9.5 %).

Reference： [1]Patent: WO2015/34420,2015,A1 .Location in patent: Page/Page column 73; 74

33
[ 6003-05-0 ]
[ 67-63-0 ]
[ 39825-33-7 ]

Yield	Reaction Conditions	Operation in experiment
87%	With thionyl chloride; at 0 - 20℃;	SOCl2 (29 mL, 400 mmol) was added dropwise at 0 00 to a suspension of the HCI salt of Lalanine (17.8 g, 200 mmol) in isopropanol (700 mL). The suspension was stirred at room temperature over night, then concentrated, which gave the title compound (29.2 g, 87%).
87%	With thionyl chloride; at 0 - 20℃;	SOCI2 (29 mL, 400 mmol) was added dropwise at 0 C to a suspension of the HCI salt of L- alanine (17.8 g, 200 mmol) in isopropanol (700 mL). The suspension was stirred at room temperature over night, then concentrated, which gave the title compound (29.2 g, 87%).
87%	With thionyl chloride; at 0 - 20℃;	HCl salt of L-alanine (17.8 g, 200 mmol) in isopropanol (700 mL) at 0 CTo the suspension was added dropwise SOCl2 (29 mL, 400 mmol).The suspension was stirred at room temperature overnight and then concentrated, which gave the title compound (29.2 g, 87%)

Reference： [1]Patent: WO2015/34420,2015,A1 .Location in patent: Page/Page column 64
[2]Patent: WO2016/30335,2016,A1 .Location in patent: Page/Page column 47
[3]Patent: TW2018/15396,2018,A .Location in patent: Page/Page column 76; 77

34
[ 39825-33-7 ]
9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine monofumarate [ No CAS ]

Reference： [1]Patent: WO2015/40640,2015,A2

35
[ 39825-33-7 ]
9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine ferulate [ No CAS ]

Reference： [1]Patent: WO2015/40640,2015,A2

36
[ 39825-33-7 ]
9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine phosphate [ No CAS ]

Reference： [1]Patent: WO2015/40640,2015,A2

37
[ 39825-33-7 ]
9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine monosuccinate [ No CAS ]

Reference： [1]Patent: WO2015/40640,2015,A2

38
[ 39825-33-7 ]
9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine tartarate [ No CAS ]

Reference： [1]Patent: WO2015/40640,2015,A2

39
[ 39825-33-7 ]
9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine lactate [ No CAS ]

Reference： [1]Patent: WO2015/40640,2015,A2

40
[ 39825-33-7 ]
9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine methanesulfonate [ No CAS ]

Reference： [1]Patent: WO2015/40640,2015,A2

41
[ 6125-24-2 ]
[ 39825-33-7 ]
isopropyl (2-phenylacetyl)-L-alaninate [ No CAS ]

Reference： [1]Chemical Communications,2016,vol. 52,p. 152 - 155

42
[ 39825-33-7 ]
9-[(R)-2-[[((benzo[1,3]dioxolan-5-yl)oxyl)monochloro-phosphonyl]methoxyl]propyl]adenine [ No CAS ]
9-[(R)-2-[[(R)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]((benzo[1,3]dioxolan-5-yl)oxyl)phosphonyl]methoxyl]propyl]adenine [ No CAS ]
9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]((benzo[1,3]dioxolan-5-yl)oxyl)phosphonyl]methoxyl]propyl]adenine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.32 g; 0.35 g		Example 21 Preparation of 9-[(R)-2-[(((benzo[1,3]dioxolan-5-yl)-oxyl)-1-isopropoxycarbonylethylamino)-phosphonyl]-methoxyl]-propyl]-adenine (I21) and Isomers Thereof (0103) (0104) 2.84 g of III1 was added to 20 ml of acetonitrile, 2.6 g of sulfoxide chloride was added dropwise with stirring and the temperature was kept below 50 C. The reaction mixture was heated at 75 (2 until the solid was dissolved, and then heated to 80 C. and evaporated to dryness, to obtain IV1, which was directly used in the next step reaction. The IV1 was dissolved in 20 ml of dry dichloromethane and cooled to -301; a solution of 3.1 g of L-alanine methyl ester in 20 ml of dichloromethane was added dropwise over 30 minutes and the temperature was kept at -18 C. 2.8 ml of triethylamine was then added dropwise over 15 minutes, and the temperature was kept from -18 C. to -11 C. It was stirred at room temperature for 2 hours and washed with 10% sodium dihydrogen phosphate solution (3×20 ml). The organic layer was dried by anhydrous sodium sulfate, and after filtering, the filtrate was evaporated under reduced pressure to dryness, the residue was separated by silica gel column chromatography and eluted with acetone, the desired component was collected and evaporated under reduced pressure to dryness, the residue was separated by silica gel column chromatography and eluted with a mixed solvent of dichloromethane:isopropanol (95:5), and the desired component to be eluted was collected and evaporated under reduced pressure to dryness to obtain 0.75 g of I21. (0105) The I21 was separated by chiral preparative chromatography (Diacel's Chiralpak AS), eluted with acetonitrile containing 30% methanol, and the first main peak was collected and evaporated under reduced pressure to dryness to obtain 0.32 g of 9-[(R)-2-[[(R)-[[(S)-1-(isopropoxycarbonyl)-ethyl]-amino]-(benzo[1,3]dioxolan-5-yl)-oxyl)-phosphonyl]-methoxyl]-propyl]-adenine (I21-a); the second main peak was collected and evaporated under reduced pressure to dryness to obtain 0.35 g of 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)-ethyl]-amino]-(benzo[1,3]dioxolan-5-yl)-oxyl)-phosphonyl]-methoxyl]-propyl]-adenine (I21-b). (0106) H1-NMR of I21-a delta (ppm, DMSO-d6): 8.08 (s, 1H); 8.07 (s, 1H); 7.33 (b, 2H); 6.77-6.75 (d, 1H); 6.68 (s, 1H); 6.49-6.47 (d, 1H); 5.99 (s, 2H); 4.41 (m, 1H); 3.92-3.90 (m, 2H); 3.79-3.77 (d, 2H); 3.76 (m, 1H); 3.45 (m, 1H); 1.27 (d, 3H); 1.20 (d, 3H); 1.15 (d, 6H). (0107) H1-NMR of I21-b delta (ppm, DMSO-d6): 8.08 (s, 1H); 8.07 (s, 1H); 7.33 (b, 2H); 6.77-6.75 (d, 1H); 6.68 (s, 1H); 6.49-6.47 (d, 1H); 5.99 (s, 2H); 4.41 (m, 1H); 3.92-3.90 (m, 2H); 3.79-3.77 (d, 2H); 3.76 (m, 1H); 3.45 (m, 1H); 1.26 (d, 3H); 1.22 (d, 3H); 1.13 (d, 6H).

Reference： [1]Patent: US2016/115186,2016,A1 .Location in patent: Paragraph 0103; 0104; 0105; 0106; 0107

43
[ 39825-33-7 ]
[ 770-12-7 ]
chlorophosphoramidate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at -78 - 20℃; for 1h;	(0044) 2.1 g (0.01 mol) of phenoxyl-phosphorus oxydichloride and 1.6 g (0.01 mol) of <strong>[39825-33-7]L-alanine isopropyl ester</strong> were dissolved in 30 ml of anhydrous dichloromethane, and cooled to -78 C. A solution of 2 ml of triethylamine in 20 ml of anhydrous dichloromethane was added dropwise with stirring, the rate of the dropwise adding was controlled to keep the reaction temperature at -78 C. After adding, when the reaction temperature was slowly raised to room temperature, stirring was continued for 1 hour. The solvent was evaporated under reduced pressure, and 30 ml of anhydrous diethyl ether was added to the residue and then filtered. The filtrate was evaporated under reduced pressure to dryness to obtain a colourless oily matter, i.e., phosphoramide intermediate V2, which was directly used in the next step reaction.
	In dichloromethane; at -15 - -10℃; for 2h;Inert atmosphere;	Isopropyl L-alanine ester (20g) solution in Dichloromethane (512mL)was added drop wise to the solution of Dichloro phenyl phosphate (32.2g) in Dichloromethane (200. OmL) at -10 to - 15C under nitrogen atmosphere. Stirred the reaction mass at the same temperature for 2h then the mixture of Ethyl cyanoacetate Oxime (21.70g) and Triethyl amine(32.38g) in Dichloromethane(200.0mL) was added to the above reaction mass at -10 to -15Cover the period of 85min. and allowed the reaction to 25-30C, concentrated the reaction mass and added MTBE(200.0mL) to the residue and stirred for 5-10min then filter the solution to remove unwanted salts and repeated the same with 200. OmL of MTBE and concentrated the solution to afford title product. Yield: 52.0 g

Reference： [1]Patent: US2016/115186,2016,A1 .Location in patent: Paragraph 0044
[2]Patent: WO2017/9746,2017,A1 .Location in patent: Page/Page column 15

44
[ 39825-33-7 ]
[ 770-12-7 ]
[ 1190307-88-0 ]

Reference： [1]Patent: US2016/115186,2016,A1

45
[ 39825-33-7 ]
C₁₅H₁₈N₅O₄P [ No CAS ]
[ 379270-37-8 ]

Yield	Reaction Conditions	Operation in experiment
1.3 g		(0042) 7.1 g of product from the last step was added to 30 ml of acetonitrile, 6.2 g of sulfoxide chloride was added dropwise with stirring, and the temperature was kept below 50° C. The reaction mixture was heated at 75° C. until the solid was dissolved, and then heated to 80° C. and evaporated to dryness. Cooling to 25° C., 40 ml of dichloromethane was added and cooled to ?30° C.; 6.5 g of <strong>[39825-33-7]L-alanine isopropyl ester</strong> was added to 35 ml of dichloromethane solution over 30 minutes and the temperature was kept at ?18° C. Then, 7 ml of triethylamine was added dropwise over 15 minutes and the temperature was kept from ?18° C. to ?11° C. The mixture was stirred at room temperature for 2 hours, and washed with 10percent sodium dihydrogen phosphate solution (3×15 ml). The organic layer was dried by anhydrous sodium sulfate, and after filtering, the filtrate was evaporated under reduced pressure to dryness, the residue was separated by silica gel column chromatography, eluted with acetone, and the desired component was collected and evaporated under reduced pressure to dryness to obtain a 3.6 g of oily matter. The resulting oily matter was separated by chiral preparative chromatography (Diacel's Chiralpak AS), eluted with acetonitrile containing 30percent methanol, the second main peak was collected and evaporated under reduced pressure to dryness to obtain 1.3 g of brownish yellow solid. 25 ml of acetonitrile and 0.3 g of fumaric acid were added, heated to reflux until the solid was dissolved and filtered immediately. The filtrate was cooled to 5° C. and left to stand overnight. Then the filtrate was filtered and dried, to obtain 1.2 g of white solid, with the melting point of 120-122° C., [alpha]D20?41.7° (c 1.0, acetic acid).

Reference： [1]Patent: US2016/115186,2016,A1 .Location in patent: Paragraph 0042

46
[ 39825-33-7 ]
(benzo[1,3]dioxolan-4-yl)oxyl-phosphorus oxydichloride [ No CAS ]
C₁₃H₁₇ClNO₆P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at -78 - 20℃; for 1h;	(0159) 2.6 g of (0.01 mol) benzo[1,3]dioxolan-4-yl)-oxyl-phosphorus oxydichloride and 1.6 g of (0.01 mol) <strong>[39825-33-7]L-alanine isopropyl ester</strong> were dissolved in 30 ml of anhydrous dichloromethane and cooled to -78 C. A solution of 2 ml of triethylamine dissolved in 20 ml of anhydrous dichloromethane was added dropwise with stirring, and the rate of dropwise adding was controlled to keep the reaction temperature at -78 C. After adding, when the reaction temperature was slowly raised to room temperature, stirring was continued for 1 hour. The solvent was evaporated under reduced pressure, and 30 ml of anhydrous diethyl ether was added to the residue, and then filtered. The filtrate was evaporated under reduced pressure to dryness so as to obtain a colourless oily matter, i.e., phosphoramide intermediate V7, which was directly used in the next step reaction.

Reference： [1]Patent: US2016/115186,2016,A1 .Location in patent: Paragraph 0159

47
[ 777-52-6 ]
[ 39825-33-7 ]
[ 108-95-2 ]
[ 1256490-49-9 ]
[ 1256490-31-9 ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of 4-nitrophenyldichlorophosphate (5 g, 19.8 mmol) in dry DCM (40 ml) was added a solution of phenol (1 .86 g, 19.8 mmol) and triethylamine (3 mL, 21 .8 mmol) in dry DCM (50 mL) at -78 C over a period of 30 min. The mixture was stirred at this temperature for 60 min, then transferred to another flask containing a solution of compound (S)-isopropyl 2- aminopropanoate (3.3 g, 19.8 mmol) in dry DCM (40 ml_) at -5 C over a period of 15 min. To this mixture was added a second portion of TEA (6 ml_, 43.3 mmol) at -5 C over a period of 20 min. The mixture was stirred at 0 C for 3h, then the solvent was removed under reduced pressure. The residue was taken in EtOAc (200 mL) and washed with water (50 mL), dried over Na2S04 and the solvents were removed under reduced pressure to give the crude product as an oil, which was purified by column chromatography using 0-20% EtOAc/Hexane gradient and 230-400 mesh silica gel to give a mixture of diastereomers in about 1 :1 ratio. The two diastereomers were separated by SFC which gave the title compound, Isomer 1 (1 .5 g, 20%) and Isomer 2 (1 .5 g, 18%) as solids.

Reference： [1]Patent: WO2016/30335,2016,A1 .Location in patent: Page/Page column 52; 53

48
[ 39825-33-7 ]
[ 1365256-83-2 ]

Yield	Reaction Conditions	Operation in experiment
27.35%	With triethylamine; trichlorophosphate; In dichloromethane; at -78 - 20℃; for 6h;	To a stirred of suspension of phosphorous oxychloride (10.0 g, 65.7 mmol) and L-aniline isopropyl ester (21.97 g, 131.5 mmol) in anhydrous DCM (400 mL) was added a solution of TEA (26.57 g, 263 mmol) in DCM (15 mL) dropwise at -78 C. After addition, the mixture was warmed to R.T. and then stirred 6 hours. The solvent was removed, and the residue was dissolved in methyl-butyl ether. The precipitate was removed by filtration, and the filtrate was concentrated to give the crude compound, which was purified on a silica gel column to give (N,N'-bis((S)-1-(isopropoxycarbonyl)ethyl))phosphordiamidic chloride (5.6 g, yield: 27.35%) as colorless oil. To a solution of compound (1) (90 mg, 0.3 mmol) in anhydrous THF (5 mL) was added a solution of t-BuMgCl (0.50 mL, 1M in THF) dropwise at -78 C. The mixture was then stirred at R.T. for 30 min and re-cooled to -78 C. A solution of N,N-bis((S)-1-(isopropoxycarbonyl)ethyl)phosphordiamidic chloride (0.50 mL, 1M in THF) was added dropwise. After addition, the mixture was stirred at R.T. for 14 hours. The reaction was quenched with HCOOH. The solvent was removed, and the residue was purified by prep. HPLC (0.1% HCOOH in MeCN and water) to give (33) (22.6 mg, 12.5%) as a white solid. 1H NMR (CD3OD, 400 MHz) delta 7.64 (d, J=7.6 Hz, 1H), 6.45 (br s, 1H), 6.02 (d, J=7.6 Hz, 1H), 4.97-5.06 (m, 2H), 4.61 (t, J=12.0 Hz, 1H), 4.34 (d, J=6.4 Hz, 2H), 3.86-3.97 (m, 2H), 1.35-1.41 (m, 6H), 1.24-1.27 (m, 12H); 31P NMR (CD3OD, 162 MHz) delta 13.81; ESI-LCMS: m/z 611 [M+H]+.

Reference： [1]Patent: US9346848,2016,B2 .Location in patent: Page/Page column 117

49
[ 39825-33-7 ]
4'-azido-2'-deoxy-2'-difluorouridine-5'-(N,N-bis((S)-isopropoxycarbonyleth-1-yl))phosphordiamidate [ No CAS ]

Reference： [1]Patent: US9346848,2016,B2

50
[ 39825-33-7 ]
[ 1365257-31-3 ]

Reference： [1]Patent: US9346848,2016,B2

51
[ 39825-33-7 ]
4'-azido-2'-deoxy-2'-fluorocytidine-5'-{N,N'-bis[(S)-1-(isopropoxycarbonyl)ethyl]phosphorodiamidate} [ No CAS ]

Reference： [1]Patent: US9346848,2016,B2

52
[ 39825-33-7 ]
C₂₃H₃₆N₇O₁₂P [ No CAS ]

Reference： [1]Patent: US9346848,2016,B2

53
[ 771-61-9 ]
[ 39825-33-7 ]
[ 770-12-7 ]
[ 1256490-52-4 ]

Yield	Reaction Conditions	Operation in experiment
		Step 1. Preparation of Racemic PPAL (0580) To a stirred solution of phenyl dichlorophosphate (250 g) in EtOAc (800 mL) was added isopropyl L-alaninate (200 g) in triethylamine (120 g) at -10 C. The reaction was stirred at -10 C. for 1 h. The compound 2,3,4,5,6-pentafluorophenol (220 g) in triethylamine (120 g) and EtOAc (400 mL) was added at -5 C. and stirred at that temperature for 0.5 h. The reaction mixture was allowed to warm to 25 C. and stirred at that temperature for 2 h. The solution was filtrated and washed with EtOAc (2×200 mL), and the combined organic phases were evaporated under vacuum to afford the solid PPAL-RS (racemate).

Reference： [1]Patent: US2016/257706,2016,A1 .Location in patent: Paragraph 0579; 0580

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