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Chemical Structure| 39825-33-7 Chemical Structure| 39825-33-7
Chemical Structure| 39825-33-7

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Synonyms: Isopropyl L-alaninate; L-Alanine 2-propyl ester; O-Isopropyl-L-alanine

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Product Details of L-Alanine isopropyl ester

CAS No. :39825-33-7
Formula : C6H13NO2
M.W : 131.17
SMILES Code : C[C@H](N)C(OC(C)C)=O
Synonyms :
Isopropyl L-alaninate; L-Alanine 2-propyl ester; O-Isopropyl-L-alanine
MDL No. :MFCD12796134

Safety of L-Alanine isopropyl ester

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Application In Synthesis of L-Alanine isopropyl ester

* 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   1~4

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

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