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Chemical Structure| 192725-49-8 Chemical Structure| 192725-49-8

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Chemical Structure| 192725-49-8

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Product Details of [ 192725-49-8 ]

CAS No. :192725-49-8
Formula : C28H34N2O3
M.W : 446.58
SMILES Code : CC1=CC=CC(C)=C1OCC(=O)N[C@@H](CC1=CC=CC=C1)[C@@H](O)C[C@@H](N)CC1=CC=CC=C1
MDL No. :MFCD09835124

Safety of [ 192725-49-8 ]

Application In Synthesis of [ 192725-49-8 ]

* 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.

  • Downstream synthetic route of [ 192725-49-8 ]

[ 192725-49-8 ] Synthesis Path-Downstream   1~5

  • 1
  • [ 192725-49-8 ]
  • [ 192725-50-1 ]
  • [ 192725-17-0 ]
YieldReaction ConditionsOperation in experiment
90.1% 20.0 g (0.1 mol) of (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid and 100 ml of dichloromethane were added to the reaction flask.The mixture was placed under ice water, and the temperature was controlled below 10 C. 13.9 g (0.11 mol) of thionyl chloride was dropped into the reaction solution, and the addition was completed. The reaction was stirred at 0 to 10 C for 1 h.Then refluxing for 1 h to obtain (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutyryl chloride reaction solution;The reaction solution was lowered to 0-20 C, 25.3 g (0.25 mol) of triethylamine was added, and placed under ice water, and the temperature was controlled below 10 C.N-[(1S,2S,4S)-4-Amino-2-hydroxy-5-phenyl-1-(phenylmethyl)pentyl]-2-(2,6-dimethylphenoxy) Acetamide42.4g (0.095mol) was added to the reaction solution, and the addition was completed. The reaction was stirred at 0~10 C for 1 h.Then react at room temperature for 4 h,The lopinavir reaction solution was obtained; 10% sodium hydrogencarbonate 50 g was added to the lopinavir reaction solution, stirred for 1 hour, and layered.Then, the reaction liquid was washed with 25% sodium chloride 50 g and 50 g of purified water, and the layers were separated, and concentrated under reduced pressure to give an oily substance, 300 ml of ethyl acetate and 300 ml of n-heptane were added, and the mixture was heated to reflux and cooled to T=20~ At 25 C, and stir for 1 hour.Then cooled to 10 C, and stirred for 2 hours, filtered, filter cake vacuum drying at 50 C for 12 hours, 53.7 g of lopinavir finished product, yield 90.1%, HPLC purity ? 99.5%.
Example 1Thionyl chloride (18 ml) was added to the mixture of 2S-(1-tetrahydro- pyrimid-2-onyl)-3-methylbutanoic acid (25 gm), tetrahydrofuran (370 ml) and dimethylformamide (2 ml) at 0 - 10 deg C and the mass was stirred for 1 hour 15 minutes. The mass was subjected to distillation under reduced pressure to remove excess thionyl chloride, n-heptane (45 ml) was added to the residue obtained and the solvent was distilled off. The reaction mass was slurried in dimethylformamide (105 ml). (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3- hydroxy-5-amino-1 ,6-diphenylhexane (41 gm), imidazole (25 gm) and 4- (dimethylamino)pyridine (1.5 gm) were dissolved in ethyl acetate (420 ml). To the solution was added above slurried product at 0 - 10 deg C. The reaction mass was maintained for 14 hours and then ethyl acetate (165 ml) and water (250 ml) were added. The layers were separated, water (250 ml) was added to the organic layer and the pH was adjusted to 2.0 - 3.0 with dilute hydrochloric acid (6N HCI). The layers were separated, the organic layer was washed with aqueous sodium bicarbonate and then with water. The ethyl acetate was distilled off from the mass. The reaction mass was dissolved in ethyl acetate (80 ml) and n-heptane (80 ml) was added to the solution. The separated solid was stirred with ethyl acetate (290 ml) for 8 hours, filtered and dried the solid to obtain 33 gm of lopinavir ethyl acetate solvate.
  • 2
  • [ 192725-45-4 ]
  • [ 192725-49-8 ]
YieldReaction ConditionsOperation in experiment
100% N. (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-amino-1,6-diphenylhexane To 4.5 g of the compound from Example 1I was added 40 ml each of CH2 Cl2 and trifluoroacetic acid. The solution was left at RT for 1 h. Concentration of the solution in vacuo provided the desired compound (100%). 300 MHz 1 H NMR (CDCl3) δ1.48 (m, 1H), 1.62 (m, 1H), 2.05 (m, 1H), 2.24 (s, 6H), 2.50 (m, 1H), 2.80 (m, 1H), 3.0-3.10 (m, 4H), 3.90 (d, J=10 Hz, 1H), 4.17 (m, 1H), 4.26 (ABq, J=13.5 Hz, 2H), 7.0 (m, 3H), 7.10 (m, 2H), 7.30 (m, 7H), 7.41 (d, J=10 Hz, 1H). Mass spectrum: (M+H)+ =447.
With trifluoroacetic acid; In dichloromethane; at 20℃; for 3.33333h; To a stirred solution of (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3- hydroxy-5-(t-butyloxycarbonylamino)-l,6-diphenylhexane (5.1 g) in methylene chloride (50 rnL) was added trifluoroacetic acid (10.65 g) at room temperature over a period of 20 minutes. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and then water (100 mL) was added followed by methylene chloride (100 mL). To the cooled at about 10-15C biphasic mixture, solid sodium bicarbonate (12 g) was added portionwise, and finally its pH was adjusted to about 8.5 with aqueous sodium hydroxide. The organic layer was separated and washed with water (50 mL). Concentration of methylene chloride layer provided a residue as thick oil. Ethyl acetate (50 mL) was added into the above residue and stirred to yield a clear solution. To the stirred solution imidazole (2.1 g) was added at room temperature. The mixture was cooled to 00C. To the cold reaction mixture a suspension of acid chloride in dimethyl formamide (from step 1 of Example 5) was slowly added at about 0 to 50C during 30 minutes. The reaction mixture was stirred at 0 to 50C for next 30 minutes, then warmed to room temperature and stirred at room temperature for 12 hours. The reaction mixture was cooled down to 10C and quenched with aqueous hydrochloric acid (100 mL) at 10-150C. Ethyl acetate (50 mL) was added to the mixture and stirred at room temperature for 30 minutes. The organic layer was separated and washed with aqueous sodium bicarbonate (50 mL) followed by water (2 X 50 mL). Evaporation of the solvent under reduced pressure afforded crude material as an off-white solid which was dissolved in ethyl acetate (28 mL) at 45-5O0C and then heptane (28 mL) was slowly added at 50- 450C. The resulting clear solution was slowly allowed to cooled to room temperature and stirred at room temperature for 12 hours. A white solid, precipitated out from the solution was filtered and washed with 1:1 mixture of ethyl acetate and heptane (5 mL). The solid was dried under vacuum at 50-60C for 12 hours to yield the title compound as a white solid.Yield: 3.5 g
With trifluoroacetic acid; In dichloromethane; for 0.5h; General procedure: To the mixture of compound 16 and the phenol relatedacetic acid derivative in DMF was added TBTU and Et3N,and stirred at room temperature for 10 hours. After evaporationof the solvent, the residue was purified on silica gel columnto afford 18, or 19, or 20 in 50-70% yield. By usingsimilar procedure, compounds 15 and 17 were converted into the amides 21 and 22. Products 18, 19, 20, 21 and 22 wereconfirmed by LCMS. Then compounds 21 or 22 were treatedby TFA/CH2Cl2 (9:1) for 30 min. After removal of the solventby co-evaporation with toluene, the residue was treatedwith N-phenylsulfonyl-valine in dry DMF in the presence ofTBTU and Et3N for 10 hours at room temperature under nitrogen.The volatiles of the reaction mixture were evaporatedand the residue was diluted with aqueous NaHCO3 and extractedwith CH2Cl2. Then the combined extracts wereevaporated and the residue was dissolved into ether and precipitatedwith hexane and filtered. The precipitated solidswere then dissolved into a mixture of CH2Cl2/MeOH, andmixed with a minimum amount of silica gel. After evaporatingthe volatiles, the silica gel adsorbed with the compoundswas loaded onto a silica gel column, and was washed withdichloromethane/ethyl acetate (3:1), then using methanol towash the column. The methanol fraction was concentrated,and the residue was suspended in hexane/ethyl acetate (1:1)and the solid product was filtered and washed with the samemixture to obtain the desired products 3, 4, 5, 23a, 23b and23c in more than 90% purities based on LCMS analysis.
7.1 g With trifluoroacetic acid; In dichloromethane; at 0 - 25℃; for 0.00466667h;Inert atmosphere; Under the protection of nitrogen, 10.0g (18.3mmol) of the above white solid,After 100mL of dichloromethane is dissolved,20.8g (183mmol) of trifluoroacetic acid dissolved in 40mL of dichloromethane was added dropwise to the solution at 0-5C (after dripping in about 40min),This process needs to be added slowly to prevent side reactions.After the addition, the temperature was raised to 20-25C to react for 4 hours, and the reaction of the raw material intermediate 1 was monitored by HPLC to be complete. Vacuum distillation to recover unreacted trifluoroacetic acid,After evaporation to dryness, 200 mL of dichloromethane was added to dissolve, 200 mL of 10% NaHCO3 aqueous solution was washed to pH=8-9, and then the liquids were separated. Wash the organic phase again with 200 mL of water,Dry with anhydrous sodium sulfate, filter, and concentrate to obtain a pale yellow oil.Add 30mL of ethyl acetate/n-heptane (volume ratio 2:3) mixed solvent, and cool to 0,Stir and crystallize, filter, and vacuum dry at 40C to obtain 7.1g of white solid. Under nitrogen protection, 40mL of dry DMF, 1.1g (10.9mol) of dry triethylamine, 4.2g (9.1mmol) of this white solid, 2.0g (10mmol) ) Chiral acid, after 1.66g (12.3mmol) 1-hydroxybenzotriazole (HOBt),Stir at 0C for 20 minutes and then mix there,Add 2.1g (10.9mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC hydrochloride) in batches, raise it to 20-25 and react overnight (not low At 12h), HPLC monitored the reaction of Intermediate 2 to be complete. The DMF was evaporated under reduced pressure, 100mL ethyl acetate, 100mL 1.0mol/L dilute hydrochloric acid was added to wash, liquid separation, the organic phase was washed with 150mL 5wt% NaHCO3, 150mL distilled water, dried with anhydrous sodium sulfate and activated carbon decolorization, filtration and concentration A light yellow oily substance was obtained, crystallized with ethyl acetate and n-hexane 30g (ethyl acetate: n-hexane=1:1), filtered with suction, and dried at 40C to obtain a white solid, lopinavir, with a yield of 83 %, HPLC purity 99.76%.
With hydrogenchloride; In water; ethyl acetate; at 0 - 50℃; for 4h;Large scale; (2) Take 350.0 g of compound VI, put it in a three-necked flask, add 3.5 L of ethyl acetate, stir until the system is clear, after the solution is clear, cool to 0-5 oC and add 270ml of concentrated hydrochloric acid to the system. After the addition, the system was heated to 50 oC and reacted for 4 hours. TLC monitored the reaction to complete. Separate and collect the organic phase. Wash the aqueous phase with 2×700 ml ethyl acetate. After washing, separate and collect all the organic phases. The organic phase was saturated Wash with 1750 ml of brine, separate and collect the organic phase after washing, dry with anhydrous sodium sulfate for 2 h, filter with suction, spin dry the filtrate to obtain a pale yellow oily compound VII crude product for use.

  • 3
  • CF3 CO2 H [ No CAS ]
  • [ 75-09-2 ]
  • [ 192725-45-4 ]
  • [ 192725-49-8 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; sodium hydrogencarbonate; In diethyl ether; water; C. (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-amino-1,6-diphenylhexane (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(t-butyloxycarbonylamino)-1,6-diphenylhexane (175.1 g, 0.32 mol) and 500 ml CH2 Cl2 were mixed with stirring. CF3 CO2 H (249 ml, 3.2 mol) was added and stirred 20-25 minutes, then the reaction mixture was poured into a separatory funnel containing 1000 ml of water and 200 ml of CH2 Cl2. The resulting mixture was shaken carefully and the layers were separated. The organic layer was washed again with 500 ml of water, then 3*500 ml of NaHCO3 and finally 500 ml of brine. The organic solution was dried over MgSO4, filtered and concentrated to a golden oil that pulled into a foam 300 ml of diethyl ether was added to the crude product and shaken vigorously to dissolve. Within minutes solid began to crystallize and the mixture became thick. Enough diethyl ether was added to make the mixture stirrable and the mixture was stirred at room temperature for 1 hour. The solid was filtered and air dried to give the desired product as 115 g of white needles, 81% yield. A solution of HCl/diethyl ether was added to the filtrate to precipitate the remaining product as the HCl salt. This pinkish solid was collected by filtration, taking care to keep the solid flooded with N2 while it was wet with ether. When dry, transfered the amine salt to a separatory funnel and extracted with CH2 Cl2 and NaHCO3 (aq). The organic layer was washed with brine, dried over MgSO4, concentrated and treated as above to afford an additional 15 g of the desired product, the total yield is 91%.
  • 4
  • [ 192725-49-8 ]
  • [ 192725-17-0 ]
YieldReaction ConditionsOperation in experiment
Step 2:; (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyI)amino-3-hydroxy-5-[2s-(l- tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl]amino-l,6-diphenylhexaneImidazole (2.1 g) in ethyl acetate (50 ml) was added to a stirred solution of N-[(1S,2S,4S)- 4-amino-l-benzyl-2-hydroxy-5-phenylpentyl]-2-(2,6-dimethylphenoxy)acetamide (4.2 g), at room temperature (20-250C). The mixture was cooled to 00C. To the cold reaction mixture, the suspension of acid chloride in dimethyl formamide (obtained from Step 1 of Example 3) was slowly added at 0 to 5C during 30 minutes. The reaction mixture was stirred at 0 to 50C for next 30 minutes, and then warmed to room temperature (20-250C) and stirred at room temperature (20-250C) for 12 hours. The reaction mixture was again EPO <DP n="12"/>cooled to 1O0C and quenched with aqueous hydrochloric acid (100 ml, 0.2N) at 10-15C. Ethyl acetate (50 ml) was added into the mixture and stirred at room temperature (20 to 25C) for 30 minutes. The layers were separated and the organic layer was washed with aqueous sodium bicarbonate (50 ml, 5% w/v) followed by washing with water (2 X 50 ml). The solvent was evaporated under reduced pressure to get crude material as an off- white solid. The solid so obtained was dissolved in ethyl acetate (28 ml) at 45-500C and then heptane (28 ml) was slowly added at 50-450C. The resulting clear solution was slowly allowed to cool to room temperature and stirred at room temperature for 12 hours. A white solid, precipitated out from the solution was filtered and washed with 1 : 1 mixture of ethyl acetate and heptane (5 ml). It was dried under vacuum at 50-600C for 12 hours to get the title compound as a white solid.Yield: 3.5 g
  • 5
  • [ 192800-77-4 ]
  • [ 192725-49-8 ]
  • [ 192725-17-0 ]
YieldReaction ConditionsOperation in experiment
With 1H-imidazole; dmap; In ethyl acetate; N,N-dimethyl-formamide; at 0 - 10℃; for 14h; Example 1 Thionyl chloride (18 ml) was added to the mixture of 2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoic acid (25 gm), tetrahydrofuran (370 ml) and dimethylformamide (2 ml) at 0-10 deg C. and the mass was stirred for 1 hour 15 minutes. The mass was subjected to distillation under reduced pressure to remove excess thionyl chloride, n-heptane (45 ml) was added to the residue obtained and the solvent was distilled off. The reaction mass was slurried in dimethylformamide (105 ml). (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-amino-1,6-diphenylhexane (41 gm), imidazole (25 gm) and 4-(dimethylamino)pyridine (1.5 gm) were dissolved in ethyl acetate (420 ml). To the solution was added above slurried product at 0-10 deg C. The reaction mass was maintained for 14 hours and then ethyl acetate (165 ml) and water (250 ml) were added. The layers were separated, water (250 ml) was added to the organic layer and the pH was adjusted to 2.0-3.0 with dilute hydrochloric acid (6N HCl). The layers were separated, the organic layer was washed with aqueous sodium bicarbonate and then with water. The ethyl acetate was distilled off from the mass. The reaction mass was dissolved in ethyl acetate (80 ml) and n-heptane (80 ml) was added to the solution. The separated solid was stirred with ethyl acetate (290 ml) for 8 hours, filtered and dried the solid to obtain 33 gm of lopinavir ethyl acetate solvate.
 

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