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CAS No. : | 632-20-2 | MDL No. : | |
Formula : | C4H9NO3 | Boiling Point : | - |
Linear Structure Formula : | CH3CHOHCH(NH2)CO2H | InChI Key : | AYFVYJQAPQTCCC-STHAYSLISA-N |
M.W : | 119.12 | Pubchem ID : | 69435 |
Synonyms : |
H-D-Thr-OH
|
Chemical Name : | (2R,3S)-2-Amino-3-hydroxybutanoic acid |
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: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | Example 1; 2-chloro-4-((1R,2S)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile; Intermediate 1a; (2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid; <strong>[796600-15-2]2-chloro-4-fluoro-3-methylbenzonitrile</strong> (CAS 796600-15-2, 45g, 265.4 mmol) was mixed together with H-D-Thr-OH (37.92 g, 318.4 mmol) in DMSO (250 mL). K2CO3 (73.35 g, 530.7 mmol) was added to the reaction mixture and the reaction mixture stirred at 75 C. for 24 h. The reaction mixture was cooled to room temperature and poured slowly into a 10% citric acid solution and stirred for 10 min at room temperature. The solution was extracted with EtOAc several times to get the crude product. The crude product was chromatographed on silica gel with a gradient of hexanes/EtOAc and then with EtOAc, 100% to get the purified final product (39.0 g, 54%) 1H NMR (500 MHz, Acetone-d6, delta in ppm) 7.49 (d, J=9 Hz, 1H), 6.70 (d, J=9 Hz, 1H), 5.38 (d, J=10 Hz, 1H), 4.47 (d, J=6 Hz, 1H), 4.25 (m, 1H), 2.34 (s, 3H), 1.33 (d, J=6 Hz, 3H). | |
42% | Examples 17 and 18Example 17 Example 18 17aTo a stirred solution of D-Threonine (4.63 g, 38.8 mmol) in DMSO (50 mL), cooled to 0 C K2C03 (4.7 g, 34.8 mmol) was added. After being stirred for 15 min, <strong>[796600-15-2]2-chloro-4-fluoro-3-methylbenzonitrile</strong> (3.0 g, 17.7 mmol) was added to the reaction mixture. The resulting reaction mixture was heated to 80C for 36 h. After completion of reaction (by TLC), the reaction mixture was brought to room temperature, diluted with water (50 mL) and extracted with EtOAc (3 x 30 mL). The aqueous layer was acidified by citric acid (pH 2-3) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with ice-cold water (5 * 30 mL), dried over Na2S04 and concentrated under reduced pressure to give the crude product. The crude material was triturated with 10% EtOAc/Hexane to afford the acid 17a (2.0 g, 42%) as an off-white solid.TLC: 30% MeOH/DCM (Rf: 0.2)1H NMR (500MHz, DMSO-<?, delta in ppm): 7.54 (d, J= 8.5 Hz, 1H), 6.58 (d, J= 9.0 Hz, 1H), 5.46 (d, J= 9.0 Hz, 1H), 4.25-4.23 (dd, J= 6.5, 3.5Hz, 1H), 4.13-4.11 (dd, J= 8.5, 3.0 Hz, 1H), 2.26 (s, 3H), 1.19 (d, J= 6.5 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Under nitrogen atmosphere, to a stirred mixture of <strong>[457889-46-2][4-[4-(trifluoromethyl)-phenyl]-phenyl]-methanol</strong> (0.3 g, 1.19 mmol) in dry CH2Cl2 (2.0 mL), DMAP (0.015 g, 0.12 mmol) and di-2-pyridyl-carbonate (0.309 g, 1.43 mmol) were added. The reaction mixture was left to react at rt for 15 h, then diluted with CH2Cl2 and washed first with a saturated NH4Cl solution (3.0 mL) and subsequently with a saturated NaHCO3 solution (3×3 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford a colorless oil (0.3 g, 68%), as a mixture (ratio 1.8:1) of 2-pyridyl-[4-[4-(trifluoromethyl)-phenyl]-phenyl]-methyl carbonate and [4-[4-(trifluoromethyl)-phenyl]-phenyl]-methyl-2-oxopyridine-1-carboxylate. The mixture of isomers was not separated and used in the next step without any further purification. To a stirred mixture of D-threonine (0.063 g, 0.53 mmol) and NaHCO3 (0.067 g, 0.8 mmol) in H2O (3.0 mL), the crude mixture containing 2-pyridyl-[4-[4-(trifluoromethyl)-phenyl]-phenyl]-methyl carbonate and [4-[4-(trifluoromethyl)-phenyl]-phenyl]-methyl-2-oxopyridine-1-carboxylate (0.3 g, 0.8 mmol) in THF (3.0 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×5 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with EtOAc (3×10 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound as transparent oil (0.21 g, quant.), which was used in the next step without further purification. MS (ESI) m/z: 415 [M-NH4]+; (ESI) m/z: 396 [M-H]-. 1H NMR (DMSO-d6): delta 1.11 (d, J=6.4 Hz, 3H), 3.97 (dd, J=3.5, 8.9 Hz, 1H), 4.05-4.12 (dq, J=3.5, 6.4 Hz, 1H), 5.13 (s, 2H), 7.00 (d, J=8.9 Hz, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.75 (d, J=8.1 Hz, 2H), 7.82 (d, J=8.1 Hz, 2H), 7.91 (d, J=8.1 Hz, 2H), 12.59 (s, 1H). | |
0.21 g | To a stirred mixture of D-threonine (0.063 g, 0.53 mmol) and NaHC03 (0.067 g, 0.8 mmol) in H20 (3.0 mL), the crude mixture containing 2-pyridyl-[4-[4-(trifluoromethyl)- phenyl]-phenyl]-methyl carbonate and [4-[4-(trifluoromethyl)-phenyl]-phenyl]-methyl-2- oxopyridine-l-carboxylate (0.3 g, 0.8 mmol) in THF (3.0 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et20 (3x5 mL). The aqueous phase was acidified with 2.0 M HC1 solution to pH 2-3 and subsequently extracted with EtOAc (3x10 mL). The organic fraction was dried over Na2S04, filtered and concentrated to dryness to afford the title compound as transparent oil (0.21 g, quant.), which was used in the next step without further purification. MS (ESI) m/z: 415 [M- NH4]+; (ESI) m/z: 396 [M-H]-. 1H NMR (DMSO-d6): delta 1.1 1 (d, J= 6.4 Hz, 3H), 3.97 (dd, J= 3.5, 8.9 Hz, 1H), 4.05 - 4.12 (dq, J= 3.5, 6.4 Hz, 1H), 5.13 (s, 2H), 7.00 (d, J= 8.9 Hz, 1H), 7.51 (d, J= 8.1 Hz, 2H), 7.75 (d, J= 8.1 Hz, 2H), 7.82 (d, J= 8.1 Hz, 2H), 7.91 (d, J= 8.1 Hz, 2H), 12.59 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.2% | With sodium carbonate; In water; at 20℃; for 11h;Large scale; | In the 1000-liter reactor into the water 400 liters,D-threonine 45 kg,Sodium carbonate 52 kg,Stir until clear and clear,Circulating water under cooling,A mixed solution of 100 kg of N-ethyl-2,3-dioxopiperazinylcarboxyl chloride and 400 liters of methylene chloride was added dropwise,When the temperature is controlled at about 20 ,5 hours dripping finished,Insulation continued to react for 6 hours,Point plate confirms that the D-threonine reaction is complete.Stop stirring,Static stratification,Separate the lower aqueous phase,The aqueous layer was extracted with 200 liters of methylene chloride,Point plate to confirm the water phase of small polar impurities disappeared,With concentrated hydrochloric acid to adjust the pH to 1.5 ~ 2,To obtain 600 liters of an aqueous solution,Vacuum concentrated into a solid,And the mixture was refluxed with 500 liters of acetonitrile for 4 hours with stirring,Filter diatomaceous earth filter,Collecting filtrate,Solid with a small amount of hot acetonitrile bubble wash,Combined filtrate,Spin dry,Add 450 liters of dichloromethane 50 under reflux beating 2h,Centrifuge to get a solid,Stir the solid and then 450 liters of dichloromethane reflux beating 3 hours,After centrifugal filtration,60 vacuum drying,Get the product 98 kg,The yield was 90.2% and the HPLC content was 99.8%. |