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Chemical Structure| 379270-37-8
Chemical Structure| 379270-37-8
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Product Details of [ 379270-37-8 ]

CAS No. :379270-37-8 MDL No. :MFCD23843796
Formula : C21H29N6O5P Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 476.47 Pubchem ID :-
Synonyms :
GS-7340;TAF

Calculated chemistry of [ 379270-37-8 ]

Physicochemical Properties

Num. heavy atoms : 33
Num. arom. heavy atoms : 15
Fraction Csp3 : 0.43
Num. rotatable bonds : 12
Num. H-bond acceptors : 9.0
Num. H-bond donors : 2.0
Molar Refractivity : 124.1
TPSA : 153.29 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -7.84 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.44
Log Po/w (XLOGP3) : 1.92
Log Po/w (WLOGP) : 2.98
Log Po/w (MLOGP) : 0.43
Log Po/w (SILICOS-IT) : 0.55
Consensus Log Po/w : 1.86

Druglikeness

Lipinski : 1.0
Ghose : None
Veber : 2.0
Egan : 1.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.55
Solubility : 0.135 mg/ml ; 0.000283 mol/l
Class : Soluble
Log S (Ali) : -4.76
Solubility : 0.00823 mg/ml ; 0.0000173 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -5.09
Solubility : 0.00387 mg/ml ; 0.00000813 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 5.64

Safety of [ 379270-37-8 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 379270-37-8 ]

* 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 [ 379270-37-8 ]
  • Downstream synthetic route of [ 379270-37-8 ]

[ 379270-37-8 ] Synthesis Path-Upstream   1~13

  • 1
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  • [ 379270-37-8 ]
YieldReaction ConditionsOperation 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,
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  • [ 379270-37-8 ]
YieldReaction ConditionsOperation 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
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YieldReaction ConditionsOperation in experiment
15 g With triethylamine In dichloromethane; toluene at -25℃; for 1 h; L-alanine isopropyl ester hydrochloride(52.5 g, 0.314 mol) was dissolved in dichloromethane(200 mL) solution, and then6-amino-9 - [(2R) -2 - [[chloro (phenoxy) phosphonoyl] methoxy] isopropyl] purine(Compound 2) (60 g of crude product) in toluene (300 mL) was added to the reaction solution,After completion of the addition, the mixture was cooled to -25 ° C and triethylamine (31.8 g, 0.314 mol)After the dropwise addition, the reaction was continued for 1 hour and the reaction was terminated.To the reaction solution was added 10percent aqueous sodium dihydrogenphosphate (400 mL)Fully stirred extraction layer,The organic phase was extracted with 15percent aqueous solution of potassium hydrogencarbonate (170 mL)The organic phase was washed successively with deionized water (150 mL x 1)Dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure(2S) -2 - [[[(1R) -2- (6-aminopurine-9-yl)1-methyl-ethoxy] methyl-phenoxy-phospho] amino]Isopropyl propionate(Compound 3) as a crude product.The crude product of compound 3 was added to a mixed solvent of acetonitrile (12 mL) and toluene (108 mL) (acetonitrile / toluene (v / v) = 1: 9). After stirring at room temperature for 6 hours, the solid was sufficiently precipitated, filtered, Washed with toluene (200 mL) and dried over the filter cake to give the purified product compound 3 (30 g, 35percent yield, 95.10percent HPLC purity, 96.04percent purity of the chiral HPLC diastereomer).Compound 3 (30 g) is added to acetonitrile (120 mL), heated to reflux for 1 hour, and then naturally cooled to room temperature, if desired, to obtain compound 3 with higher diastereomer purity, if necessary, After 6 hours of stirring, the solid was sufficiently precipitated and filtered. The filter cake was washed with acetonitrile (40 mL) and the cake was dried to give the purified product compound 3 (15 g, HPLC purity 99.40percent, chiral HPLC diastereomer purity 99.79 percent).
33.4 g With triethylamine In dichloromethane; toluene at -30 - 35℃; In a round bottom flask equipped with reflux condenser, a suspension of monophenylPMPA (50 gms) in toluene (600 mL) was heated to 110°C and water removedazeotropically. The reaction was cooled to 50°C, and N, N-dimethyl formamide (0.5 mL) and thionyl chloride (25 gms) were added. The temperature of the reaction mixture was raised to 67-73°C and maintained at the same temperature for 12-24hrs. The reaction mixture was concentrated under vacuum and the residue obtained was co-evaporated withtoluene. To the resulting residue, toluene (250 mL) and dichloromethane (300 mL) were added and the resultant sluny was gradually cooled to -30°C. To the sluny, L-Alanine isopropyl ester hydrochloride (66 gms) and triethyl amine (40 gms) were sequentially added, temperature was allowed to raise to 25-35°C and stined at the same temperature. The mixture was cooled to 13°C and sequentially washed with aq NaH2PO4, aq NaHCO3and water. The resulting organic layer was dried over sodium sulphate and then concentrated under vacuum. The obtained residue was treated with a mixture of isopropyl alcohol (50 mL) and methyl tertiary butyl ether (200 mL) at RT, seeded with tenofovir alafenamide and stined for another 4-6hrs. The precipitated solid was filtered, and the wet material in a mixture of isopropyl alcohol (35 mL) and methyl tertiary butyl ether (140mL) was heated to a temperature of 55-61°C and stined for 3hrs. The reaction mass was cooled to room temperature and stined for 4hrs at the same temperature. The resulting solids were filtered and dried under vacuum at 45-55°C for 12-l6hrs to afford Tenofovir alafenamide (33.4 gms). HPLC purity: 99.4percent; RRS diastereomer: 0.5percent.
Reference: [1] Patent: WO2014/195724, 2014, A1,
[2] Patent: TW2017/8236, 2017, A, . Location in patent: Page/Page column 18; 19; 20; 21; 22
[3] Patent: WO2017/221189, 2017, A1, . Location in patent: Page/Page column 31; 32
[4] Patent: CN108409788, 2018, A, . Location in patent: Paragraph 0069; 0073; 0074
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YieldReaction ConditionsOperation in experiment
190 g
Stage #1: With thionyl chloride In dichloromethane; toluene at 70 - 80℃; Inert atmosphere
Stage #2: With potassium hydrogencarbonate In dichloromethane; toluene at 15 - 40℃; Inert atmosphere
Acrylic chlorination step: 2.4 L of toluene was added to a 5 L reaction flask and TAF-Ml (400 g, prepared according to Example 1) was added,Heated to 70-80°C under nitrogen protection.Slowly add thionyl chloride (262g), add insulation 70-80°C, react for 40-50 hours, temperature below 75°C,Concentrate under reduced pressure until no significant distillate is produced, under nitrogen protection,Cool down to 20-40 °C, add 1600ml of methylene chloride, stir and disperse, wait for use;Dissociating step:Add 2.4L of methylene chloride to the 5L reaction flask, add TAF-SM2 (646g) and potassium bicarbonate (441g) at 15-25°C for 5-10 hours, filter, drain, and control the temperature at 30-40°C. Concentrate dry and press twice with fresh dichloromethane 400 ml*2 and add the residue to fresh dichloromethane 2.4L.Reaction steps:Under nitrogen protection cooling to -25 ~ -15 °C, slowly adding chlorine, adding insulation reaction for 1-2 hours, warming to 20-30 for 1-2 hours.Post-processing:Add 10percent of sodium dihydrogen phosphate aqueous solution 2000g, stir for 5-10 minutes, and stand for layering, the organic phase is respectively used 2000g 10percent sodium dihydrogen phosphate aqueous solution, 2000g*2 5percent potassium hydrogencarbonate aqueous solution, 2000g saturated chlorine The sodium solution and 2000 g of purified water were stirred for 5-10 minutes, and the mixture was allowed to stand for stratification. The organic phase was dried with 250 g-300 g of anhydrous sodium sulfate, filtered, and the mother liquor was dried under reduced pressure to obtain an oily substance under nitrogen protection. Add 400ml of acetonitrile and 1200ml of toluene, warm to 50-60°C, stir for 0.5-1 hour, clear the solution (about 20-30 minutes), slowly cool and crystallize (20-30°C, stir for 1-2 hours to start solidprecipitation) After precipitation of a large amount of solids, cool down to 0-10 °C for 1-2 hours, filter, drain, wash with toluene and dry to obtain crude product.Refining: Add the crude product to the reaction flask, add acetonitrile 1200ml, heat up to 60-70°C under nitrogen protectionSolution, the mother liquor slowly cooled and crystallized, 0-10 °C heat for 1-2 hours, filtered, pumped dry, filter cake 40-50 °C dried under reduced pressure for 10-12 hours to obtain the intermediate 190g TAF-M2.
15 kg
Stage #1: With thionyl chloride In toluene at 70℃; for 50 h; Reflux; Inert atmosphere; Large scale
Stage #2: With potassium hydrogencarbonate; sodium sulfate In dichloromethane at 20 - 70℃; for 24 h; Inert atmosphere; Large scale
Stage #3: at 20℃; for 2 h; Inert atmosphere; Large scale
250kg of toluene was pumped into 500L reactor I.Add the above TAF-IM vapor to reflux.The glass return pipe receives water from the bottle and no longer separates the water.After 2 hours of continuous cooling to room temperature,Nitrogen protection,Thionyl chloride 31kg in the high tank,Slowly and repeatedly into the kettle,Leave it at 70°C for 50 hours.Concentrate under reduced pressure to a thick state,After cooling down to room temperature, add 200 kg of n-heptane.Under nitrogen protection filter rejection to dryness,Collect solids,Dissolve complete solids with 200 kg of methylene chloride and transfer to the upper tank.Distill 250kg of dichloromethane into 500L reactor II.Add potassium bicarbonate 50kg,Anhydrous sodium sulfate 10kg and L-alanine isopropyl ester hydrochloride 75kg,Stir for 24 hours under nitrogen protection.Pump down to 500L reactor III.Proline catalyst SA (0.05 eq) was added.The nitrogen protection adds the batches in the high tank to the reactor III in multiple batches.Every time triethylamine 2kg is added,Total added 6kg,After the addition was completed, the mixture was stirred at room temperature for 2 hours.10percent aqueous solution of sodium dihydrogen phosphate in a concentration of 10percentSaturated brine extractionAfter drying over anhydrous sodium sulfate,Suction filtration to 500L dry clean reactorConcentrate under reduced pressure to 60L,Add 100kg of toluene,Then concentrate under reduced pressure to 100L.Then add 100kg of toluene and 50kg of acetonitrile.The solid precipitated slowly at room temperature.The frozen liquid is circulated and incubated for 4 hours.Rejection filter to dry,Acetonitrile beating,Agitate and rinse with acetonitrile.Rejection filter to dry,Drying at 40 °C under reduced pressure to obtain white solid TAF-II M15kg,Yield 45percent (calculated on the basis of "Tenofovir").
Reference: [1] Patent: CN107793452, 2018, A, . Location in patent: Paragraph 0010; 0040-0046; 0047
[2] Patent: CN107522743, 2017, A, . Location in patent: Paragraph 0057; 0059; 0069; 0072; 0073; 0074;0083-0087
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  • [ 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
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YieldReaction ConditionsOperation 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
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  • [ 147127-20-6 ]
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Reference: [1] Nucleosides, Nucleotides and Nucleic Acids, 2001, vol. 20, # 4-7, p. 621 - 628
[2] Patent: US2013/90473, 2013, A1,
[3] Patent: US2013/90473, 2013, A1,
[4] Patent: US2016/115186, 2016, A1,
[5] Patent: US2017/56423, 2017, A1,
[6] Patent: WO2017/221189, 2017, A1,
[7] Patent: WO2017/221189, 2017, A1,
[8] Patent: CN108409790, 2018, A,
[9] Patent: CN108409788, 2018, A,
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  • [ 379270-35-6 ]
  • [ 379270-37-8 ]
Reference: [1] Patent: US2013/90473, 2013, A1,
[2] Patent: US2013/90473, 2013, A1,
[3] Patent: WO2015/40640, 2015, A2,
[4] Patent: US2017/56423, 2017, A1,
[5] Patent: CN108409790, 2018, A,
  • 9
  • [ 101-02-0 ]
  • [ 379270-37-8 ]
Reference: [1] Patent: US2013/90473, 2013, A1,
[2] Patent: US2013/90473, 2013, A1,
[3] Patent: US2017/56423, 2017, A1,
[4] Patent: CN108409790, 2018, A,
[5] Patent: CN108409788, 2018, A,
  • 10
  • [ 108-95-2 ]
  • [ 379270-37-8 ]
Reference: [1] Patent: WO2015/40640, 2015, A2,
[2] Patent: US2016/115186, 2016, A1,
[3] Patent: CN106478725, 2017, A,
[4] Patent: WO2017/221189, 2017, A1,
[5] Patent: WO2017/221189, 2017, A1,
  • 11
  • [ 39613-92-8 ]
  • [ 379270-37-8 ]
Reference: [1] Patent: US2013/90473, 2013, A1,
[2] Patent: US2013/90473, 2013, A1,
[3] Patent: US2017/56423, 2017, A1,
  • 12
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Reference: [1] Patent: WO2015/79455, 2015, A2,
  • 13
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