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CAS No. : | 13335-71-2 | MDL No. : | MFCD00156912 |
Formula : | C10H12O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MLBCURLNKYKBEQ-UHFFFAOYSA-N |
M.W : | 180.20 | Pubchem ID : | 101369 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.3 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 49.44 |
TPSA : | 46.53 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.55 cm/s |
Log Po/w (iLOGP) : | 1.63 |
Log Po/w (XLOGP3) : | 2.61 |
Log Po/w (WLOGP) : | 1.77 |
Log Po/w (MLOGP) : | 1.67 |
Log Po/w (SILICOS-IT) : | 2.04 |
Consensus Log Po/w : | 1.94 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.85 |
Log S (ESOL) : | -2.75 |
Solubility : | 0.324 mg/ml ; 0.0018 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.24 |
Solubility : | 0.104 mg/ml ; 0.00058 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.69 |
Solubility : | 0.368 mg/ml ; 0.00204 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.65 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P264-P270-P273-P280-P301+P312+P330-P305+P351+P338+P310-P501 | UN#: | 3261 |
Hazard Statements: | H302-H318-H412 | Packing Group: | Ⅲ |
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 |
---|---|---|
76.7% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 16 h; | [00289] Example 18. Preparation of tert-butyl ( 1 S,3S,4S> 1 -benzyl-4- { [(2,6-dimethy.phenoxy)acetyl] amino} -S-hydroxy-5-phenylpentylcarbamate; [00290] A solution of /erf-butyl (lS,3S,4ιS)-l-benzyI-3-hydroxy-5-phenyl-4-amino-pentylcarbamate (38.5 mg, 0.1 mmol), (2,6-dimethyl-phenoxy)-acetic acid (18.9 mg, 1.05 equivalents), l-(3-dimethyl aminopropyl)-3-ethylcarbodiimide hydrochloride (29.7 mg, 1.5 equivalents), and 1-hydroxybenzotriazole (20.4 mg, 1.5 equivalents) in N,N-dimethylformamide (1 mL) was stirred for 4 minutes at room temperature. To this mixture was added N-methylmorpholine (27.5 μL, 2.5 equivalents) and the solution was stirred for 16 hours. The reaction mixture was quenched with saturated sodium bicarbonate, extracted with EtOAc, washed with 10percent citric acid, dried (Na2SO4), and concentrated in vacuo. Column chromatography on silica (3percent MeOH/ CH2CI2) gave a white solid (240 mg, 76.7percent). IH NMR (300 MHz, DMSO-D6) δ ppm 1.31 (s, 9 H), 1.39 - 1.55 (m, J=6.99 Hz, 2 H), 2.14 (s, 6 H), 2.61 (d, ./=6.99 Hz, 2 H), 2.80 (d, 7=7.35 Hz, 2 H), 3.61 - 3.70 (m, 1 H), 3.84 (m, 1 H), 4.00 - 4.11 (m, 2 H), 4.20 - 4.38 (m, 1 H), 4.99 (d, 1 H), 6.66 (d, ./=9.19 Hz, 1 H), 6.88 - 7.28 (m, 13 H), 7.43 (d, 7=9.56 Hz, 1 H); MS m/z 547.4 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With sodium hydroxide In water at 110 - 120℃; for 3h; | |
70% | With sodium hydroxide for 0.005h; microwave irradiation; | |
With sodium hydroxide at 100℃; |
With sodium hydroxide | ||
With sodium ethanolate | ||
Stage #1: 2.6-dimethylphenol With sodium hydroxide In water Stage #2: chloroacetic acid With sodium hydrogencarbonate In water for 1h; Heating; Reflux; | 2.4 2.4 Synthesis of 2,6-dimethyl-, 2,4,6-trimethyl-, 2-chlor-6-methyl-, and (4-chlor-2-methylphenoxy)acetic acid Solution of 0.3 mole NaOH in 250 ml water was prepared in a 750 ml round-bottomed flask. Then 0.3 mole of appropriate phenol was added. Separately, 0.3 mole of chloracetic acid in 300 ml 10% NaHCO3 was prepared in a flask, and the mixture was added to the formerly prepared solution of appropriate sodium phenolate and heated refluxed for 1 h. | |
80 g | With sodium hydroxide In water for 2h; Reflux; Large scale; | 1 Water 480 kg, 2,6-dimethylphenol 61.8 kg and chloroacetic acid 96 kg were mixed and stirred. Temperature control is less than 30 ° C, slow drop 21% sodium hydroxide 382kg. After the dropwise addition, the temperature was raised and refluxed for 2 hours. Dosing: sodium 40kg 20.9kg + drinking water, stirred well and cooled to room temperature after the standby. Add 24% of chloroacetic acid and then continue to drop with a good solution of sodium hydroxide, after the drop is completed, the reaction process to monitor the pH value,8 12 samples sent to HPLC detection, After completion of the reaction, the first liquid to 40 ° C, the row of jacket to the circulating water, use ice salt to cool to 5 ° C, add 195kg hydrochloric acid, keep heating for 1 hour. Centrifugal rejection filter, add 10kg of ethanol to the filter cake, drinking water 112kg, heated 70 ° C to the whole solution, the whole solution, the material slowly cooling, precipitation of crystals, the temperature dropped to 0 ~ 5 ° C, The crude red (2,6 g, HPLC 966% yield, 88%) was obtained by filtration. |
With sodium hydrogencarbonate; sodium hydroxide In water for 1h; Reflux; | ||
With sodium hydroxide In water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With lithium hydroxide In methanol; water | 1.H H. H. 2,6-Dimethylphenoxy acetic acid To a solution of the compound from Example 1G (5.15 g, 24.7 mmole) in methanol (170 ml) and water (56 ml) was added 5.3 g of lithium hydroxide at 0° C., the solution was stirred for 1.5 h at RT and concentrated in vacuo. The residue was acidified with 0.5M HCl and extracted with ethyl acetate (300 ml). The organic layer was dried and concentrated to give a white solid (4.05 g, 91%). 300 MHz 1 H NMR (CDCl3) δ2.30 (s, 6H), 4.48 (s, 2H), 7.0 (m, 3H). |
91% | With lithium hydroxide In methanol; water at 20℃; for 1.5h; | |
90% | With lithium hydroxide In methanol; water at 0 - 20℃; for 1.5h; | Step 2: To a solution of ethyl 2,6-dimethylphenoxy acetate (30.4 mmol) in MeOH (170 mL) and water (56 mL), LiOH (304.40 mmol) was added at 0oC and then the solution was stirred for 1.5 h at room temperature. The solution was acidified with1 M HCl to pH=1 and extracted with ethyl acetate (300 mL). The organic layer was dried (MgSO4) and concentrated to give the desired compound 2-(2,6-dimethylphenoxy)acetic acid, as a white solid (90% yield). |
88% | With lithium hydroxide; water In tetrahydrofuran at 5℃; for 3h; | 108.2 To an ice cold solution of ethyl 2',6'-dimethylphenoxyacetate (8.79 g, 42.4 mmol) in tetrahydrofuran/water (120 mL, 3:1) was added lithium hydroxide monohydrate (3.55 g, 84.8 mmol). After stirring for 3 hours at 5° C., the tetrahydrofuran was removed in vacuo and the residual aqueous was diluted with water (70 mL) and extracted with ether (60 mL). The aqueous was then cooled in an ice bath and acidified to pH 2 with 1N hydrochloric acid. The resulting precipitate was extracted into ethyl acetate (150 mL), washed with water (50 mL), dried (magnesium sulfate) and concentrated in vacuo to afford the title compound (6.76 g, 88%) as a white solid. 1H NMR (CDCl3): δ 2.28 (6H, s), 4.46 (2H, s), 6.93-7.01 (3H, m), 10.25 (1H, broad) |
With lithium hydroxide In tetrahydrofuran | ||
With sodium hydroxide for 4h; Heating; | ||
With sodium hydroxide at 25℃; | 1 (2) Hydrolysis reaction 1. Add 328g of 10% NaOH aqueous solution dropwise to the above-mentioned mother liquor containing intermediate esters, and control the internal temperature to be less than 25°C (the system exotherms obviously in the first half of the dropping, and the dropping acceleration can be accelerated in the later stage), and the reaction is 20-30°C after dropping ~40min, TLC (petroleum ether: methyl tertiary ether = 10:1) 254nm ultraviolet showed that the intermediate ester disappeared;2. Under a water bath at 30°C, the acetone in the reaction solution was concentrated under reduced pressure to almost no fraction (the system was concentrated to a volume of about 400 mL) to obtain a hydrolyzed solution;3. Cool the hydrolyzate to 2030, add 65.3g of concentrated hydrochloric acid dropwise to adjust the pH of the system to 23 (the specific dosage is based on the system pH), the dripping time is not less than 1h, and after the dripping, stir for 1h at 2030 , Suction filtration, rinse the filter cake three times with 25mL water to obtain a wet product;The material can be discharged under vacuum at 4.50°C until the moisture content is less than 0.10% to obtain 2,6-dimethylphenoxyacetic acid with HPLC purity ≥99.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride | ||
With thionyl chloride In ethyl acetate at 20 - 50℃; for 6h; | ||
With thionyl chloride In ethyl acetate at 20 - 50℃; for 1.5h; | 4.1 2,6-Dimethylphenyl acetic acid (2.3 g) in ethyl acetate (30 mL), was added thionyl chloride (1.82 g) at room temperature followed by 2 drops of dimethyl formamide. The reaction mixture was stirred at about 5O0C for 1.5 hours, cooled to room temperature and concentrated to dryness under reduced pressure. The excess thionyl chloride was further removed azeotropically with ethyl acetate (2 X 30 mL) and the residue was redissolved in ethyl acetate (30 mL) and used immediately to couple with the succinate salt obtained from Example 3. |
With thionyl chloride In ethyl acetate at 50℃; for 2h; | 4.1 Thionyl chloride ( 12.5 g, 0. 105 mol) was added to a stirred suspension of 2,6- dimethylphenoxyacetic acid ( 1 5. 12 g, 0.084 mol) in ethyl acetate (50 ml) followed by a drop of N,N-dimethylformamide. The reaction mixture was heated to 5O0C and stirred for an additional 2 h. The resulting acid chloride solution was cooled to 20-250C and held at this temperature for the coupling reaction (Step-2). | |
With thionyl chloride In DMF (N,N-dimethyl-formamide); ethyl acetate at 50℃; for 5h; | ||
With thionyl chloride | ||
With thionyl chloride In ethyl acetate at 50℃; for 2h; | 4.1 Thionyl chloride (12.5 g, 0.105 mol) was added to a stirred suspension of 2,6-dimethylphenoxyacetic acid (15.12 g, 0.084 mol) in ethyl acetate (50 ml) followed by a drop of N,N-dimethylformamide. The reaction mixture was heated to 50° C. and stirred for an additional 2 h. The resulting acid chloride solution was cooled to 20-25° C. and held at this temperature for the coupling reaction (Step-2). | |
With thionyl chloride for 0.5h; Heating; Reflux; | 2.5 2.5 Synthesis of 2,6-dimethyl-, 2,4,6-trimethyl-, 2-chlor-6-methyl-, and (4-chlor-2-methylphenoxy)acetic acid chlorides0.15 mole of appropriate (phenoxy)acetic acid was put into a 500 ml round-bottomed flask and 0.75 mole of SOCl2 (d=1.63 g/cm3) was added, and the mixture was heated under reflux for ca. 30 min. Afterwards, excess of thionyl chloride was distilled off under reduced pressure, and the remaining liquid acid chloride was added toluene until 100 ml and the solution of the crude chloride was used for the reactions with an appropriate aminoalkanol. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; Inert atmosphere; Reflux; | ||
With thionyl chloride | ||
With thionyl chloride; N,N-dimethyl-formamide In ethyl acetate at 20 - 50℃; for 5h; Inert atmosphere; | ||
With thionyl chloride; N,N-dimethyl-formamide at 55℃; for 5.5h; | Step 3: To a solution of 2-(2,6-dimethylphenoxy)acetic acid (3.5 mmol) in ethyl acetate (10 mL), SOCl2 (10.419 mmol) was added and three drops of DMF and the solution was stirred for 5.5 h at 55oC. The solvent and the excess of thionyl chloride were distilled under vacuum and the residue, the 2-(2,6-dimethylphenoxy) acetyl chloride, was used immediately in the next step. | |
With thionyl chloride In benzene for 1h; Reflux; | ||
With thionyl chloride; N,N-dimethyl-formamide In ethyl acetate at 50 - 55℃; | 3 2,6-dimethylphenoxyacetic acid (28.7 g), ethyl acetate (100 mL), thionyl chloride (25 g) and dimethyl formamide (1 mL) were charged in reaction flask at 25-35°C. Reaction mass was heated to 50-55°C and stirred for 2-3 hrs at same temperature, and then added to a mixture of pyroglutamic acid salt of Formula VI (100 g), ethyl acetate (750 mL), water (750 mL) and sodium bicarbonate (82.5 g) at 25-35°C and stir for 60 min at same temperature. After completion of the reaction, organic layer was separated and treated with 5% sodium bicarbonate solution (25 g dissolved in 500 mL). Then the organic layer was separated and concentrated under vacuum at below 60°C to get the title compound as a residue. Yield: 100 g; HPLC purity: 99%; Formula D by HPLC: 0.15%; Formula E by HPLC: Not detected; and Formula F by HPLC: 0.8%. | |
With thionyl chloride In ethyl acetate at 50 - 55℃; for 2h; | Synthesis of leucine analogue of lopinavir (18): To a suspension of 2,6-dimethylphenoxyacetic acid (2.75 g, 15.27 mmol) in ethyl acetate (10 mL) was added SOCl2 (2.05 g, 17.24 mmol) at 20-25 °C. The reaction mixture was stirred for 2 h at 50-55 °C and then cooled the reaction mixture to 20-25 °C. To a solution of compound 17 (10 g, 16.42 mmol), NaHCO3 (8 g, 95.89 mmol) in ethyl acetate (75 mL), demineralized water (75 mL) and 2,6-dimethylphenoxyacetyl chloride solution at 10-15 °C were added. The reaction mixture was stirred for 30 min to complete the reaction. The organic layer was separated and washed with demineralized water (50 mL) followed by brine solution (50 mL). The resulting organic layer was concentrated under reduced pressure 45-50 °C yielding white coloured leucine analogue of lopinavir compound, which was crystallized from hexane give 18 (4.5 g, 34%) (Scheme-I). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.7% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 16h; | [00289] Example 18. Preparation of tert-butyl ( 1 S,3S,4S> 1 -benzyl-4- { [(2,6-dimethy.phenoxy)acetyl] amino} -S-hydroxy-5-phenylpentylcarbamate; [00290] A solution of /erf-butyl (lS,3S,4iotaS)-l-benzyI-3-hydroxy-5-phenyl-4-amino-pentylcarbamate (38.5 mg, 0.1 mmol), (2,6-dimethyl-phenoxy)-acetic acid (18.9 mg, 1.05 equivalents), l-(3-dimethyl aminopropyl)-3-ethylcarbodiimide hydrochloride (29.7 mg, 1.5 equivalents), and 1-hydroxybenzotriazole (20.4 mg, 1.5 equivalents) in N,N-dimethylformamide (1 mL) was stirred for 4 minutes at room temperature. To this mixture was added N-methylmorpholine (27.5 muL, 2.5 equivalents) and the solution was stirred for 16 hours. The reaction mixture was quenched with saturated sodium bicarbonate, extracted with EtOAc, washed with 10% citric acid, dried (Na2SO4), and concentrated in vacuo. Column chromatography on silica (3% MeOH/ CH2CI2) gave a white solid (240 mg, 76.7%). IH NMR (300 MHz, DMSO-D6) delta ppm 1.31 (s, 9 H), 1.39 - 1.55 (m, J=6.99 Hz, 2 H), 2.14 (s, 6 H), 2.61 (d, ./=6.99 Hz, 2 H), 2.80 (d, 7=7.35 Hz, 2 H), 3.61 - 3.70 (m, 1 H), 3.84 (m, 1 H), 4.00 - 4.11 (m, 2 H), 4.20 - 4.38 (m, 1 H), 4.99 (d, 1 H), 6.66 (d, ./=9.19 Hz, 1 H), 6.88 - 7.28 (m, 13 H), 7.43 (d, 7=9.56 Hz, 1 H); MS m/z 547.4 (M+H)+. |
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 10h; | 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In N,N-dimethyl-formamide at 20℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In tetrahydrofuran at 0 - 25℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃; for 1.08333h; | AN Example AN; TPTU (1.5 mg, 1.3 eq.) was added to (2,6-dimethyl-phenoxy)-acetic acid (9 ing, 1.3 eq.) in 0.5 mL DMF at 0°C. The mixture was stirred at 00C for 5 minutes. Compound 52 (20 mg, 0.038 mmol, 1.0 eq.) and DIEA (14 μL, 2.0 eq.) were added. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was purified by reverse phase HPLC (Phenomenex Synergi column, 0.05% TFA in MeCN/water) and silica gel chromatography (2-8% MeOH/DCM) to give Example AN as a white solid (6 mg, 23%). LC-MS shows 681.2 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 8.60 (d, 1 H), 7.90 (m, 4 H), 7.60 (d, 2 H), 7.38 (m, 1 H), 7.24 (m, 4 H), 7.18 (m, 1 H), 6.90 (m, 3 H), 5.58 (d, 1 H), 4.98 (m, 1 H), 4.12 (m, 3 H), 3.64-4.10 (m, 7 H), 2.84 (m, 5 H), 1.55 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50.9% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 16h; | [00265] Example 6. Preparation of l^-thiazol-S-ylmethylOS^S^SH-benzyM-^.delta-dimethyl phenoxy)acetyi]amino}-2-hydroxy-5-phenylpentylcarbamate; [00266] A solution of 1 ,3-thiazol-5-ylmethyl ( 1 S,2S,4S)-4-amino- 1 -benzyI-2-hydroxy-5-phenylpentyI carbamate (100 mg, 0.2 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60 mg, 1.5 equivalents), and 1-hydroxybenzotriazole (40.8 mg, 1.5 equivalents) in N,N-dimethylformamide (1 mL) was stirred for 5 minutes at room temperature. To this mixture was added (2,6-Dimethyl-phenoxy)- acetic acid (38 mg, 1.05 equivalents) followed by N-methylmorpholine (100 muL, 4.5 equivalents) and the solution was stirred for 16 hours. The reaction mixture was quenched with saturated sodium bicarbonate, extracted with EtOAc, washed with 10% citric acid, dried (Na2SO1O, an^ concentrated in vacuo. Column chromatography on silica (80% EtOAc/hexane) gave a white foam (60 mg, 50.9%). IH NMR (300 MHz, DMSO-D6) delta ppm 1.59 (m, 2 H), 2.13 (s, 6 H), 2.64 - 2.84 (m, 4 H), 3.59 (m, 1 H), 3.84 - 4.16 (m, 3 H), 4.70 (d, J=6.25 Hz, 1 H), 5.04 - 5.32 (m, 2 H), 6.86 - 7.07 (m, 4 H), 7.08 - 7.29 (m, 10 H), 7.80 (d,J=9.19 Hz, 1 H), 7.88 (s, 1 H); MS(ESI) m/z 558.3 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: SOCl2 / DMF / ethyl acetate / 6 h / 20 - 50 °C 2: aq. NaHCO3 / ethyl acetate / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: SOCl2 / DMF / ethyl acetate / 6 h / 20 - 50 °C 2: aq. NaHCO3 / ethyl acetate / 1 h / 20 °C 3: HCO2NH4 / Pd/C / methanol / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: SOCl2 / DMF / ethyl acetate / 6 h / 20 - 50 °C 2: aq. NaHCO3 / ethyl acetate / 1 h / 20 °C 3: HCO2NH4 / Pd/C / methanol / 50 °C 4: Et3N / tetrahydrofuran / 8 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: SOCl2 / DMF / ethyl acetate / 6 h / 20 - 50 °C 2: aq. NaHCO3 / ethyl acetate / 1 h / 20 °C 3: HCO2NH4 / Pd/C / methanol / 50 °C 4: Et3N / tetrahydrofuran / 8 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: NaH 2: aq. LiOH / tetrahydrofuran | ||
Multi-step reaction with 2 steps 1: K2CO3 / acetone / 56 h / 20 °C 2: 1N aq. NaOH / 4 h / Heating | ||
Multi-step reaction with 2 steps 1: K2CO3 / dimethylformamide 2: aq. NaOH / methanol |
Multi-step reaction with 2 steps 1: caesium carbonate / 1,4-dioxane / 48 h / Reflux 2: lithium hydroxide / water; methanol / 1.5 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 1.5h; | 108.3 To a stirred solution of N-{(2R,3S)-3-amino-4-[4-(benzyloxy)phenyl]-2-hydroxybutyl}-N-isobutyl-1,3-benzodioxole-5-sulfonamide (360 mg, 0.68 mmol), 2',6'-dimethylphenoxyacetic acid (160 mg, 0.89 mmol) and N,N-diisopropylethylamine (0.47 mL, 2.7 mmol) in acetonitrile (7 mL) was added O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (390 mg, 1.0 mmol). After stirring at ambient temperature for 1.5 h, the reaction was concentrated in vacuo, taken up in ethyl acetate (60 mL), washed with 0.1N sodium hydroxide (3×50 mL) followed by brine (40 mL), dried (magnesium sulfate) and concentrated. The residue was purified by silica gel chromatography (60:40; hexane:ethyl acetate) to afford the title compound (450 mg, 95%) as a white foam. 1H NMR (DMSO-d6): δ 0.78 (6H, dd), 1.94 (1H, m), 2.09 (6H, s), 2.63 (1H, dd), 2.72 (1H, dd), 2.83 (1H, dd), 2.93-3.02 (2H, m), 3.28-3.35 (1H, m), 3.64-3.72 (1H, m), 3.88 (1H, d), 3.89-3.96 (1H, m), 4.06 (1H, d), 5.01 (2H, s), 5.07 (1H, d), 6.11 (2H, s), 6.82-7.12 (8H, m), 7.25-7.40 (7H, m), 7.86 (1H, d); MS: 689 (MH+); C38H44N2O8S. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With N-ethyl-N,N-diisopropylamine; 3-[(diethoxyphosphinyl)oxy]-1,2,3-benzotriazin-4(3H)-one In tetrahydrofuran at 25℃; for 2h; | 49 A solution containing the product from Example 1H (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with 2,6-dimethylphenoxy acetic acid (U.S. Pat. No. 5,914,332, see Example 1H) (0.008 g, 0.044 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.030 mL, 0.172 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane to give the title compound (0.019 g, 73% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.76 (s, 9H), 1.41 (t, J=11.77 Hz, 1H), 1.58 (m, 1H), 2.10 (s, 6H), 2.77 (m, 4H), 3.57 (s, 3H), 3.65 (m, 1H), 3.81 (d, J=9.56 Hz, 1H), 4.07 (m, 4H), 5.02 (d, J=5.52Hz, 1H), 6.92 (m, 4H), 7.25 (m, 8H), 7.56 (d, J=9.56 Hz, 1H), 7.85 (m, 3H), 7.96 (d, J=8.46 Hz, 2H), 8.64 (d, J=4.41 Hz, 1H). |
73% | With N-ethyl-N,N-diisopropylamine; 3-[(diethoxyphosphinyl)oxy]-1,2,3-benzotriazin-4(3H)-one In tetrahydrofuran at 25℃; for 2h; | 49 methyl (1S)-1-[({(1R,3S,4S)-4-[(2,6-dimethylphenoxy)acetyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate EXAMPLE 49 methyl(1S)-1-[({(1R,3S,4S)-4-[(2,6-dimethylphenoxy)acetyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate A solution containing the product from Example 1H (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with 2,6-dimethylphenoxy acetic acid (U.S. Pat. No. 5,914,332, see Example 1H) (0.008 g, 0.044 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.030 mL, 0.172 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluding with 0-100% ethyl acetate/dichloromethane to give the title compound (0.019 g, 73% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.76 (s, 9 H), 1.41 (t, J=11.77 Hz, 1 H), 1.58 (m, 1 H), 2.10 (s, 6 H), 2.77 (m, 4 H), 3.57 (s, 3 H), 3.65 (m, 1 H), 3.81 (d, J=9.56 Hz, 1 H), 4.07 (m, 4 H), 5.02 (d, J=5.52 Hz, 1 H), 6.92 (m, 4 H), 7.25 (m, 8 H), 7.56 (d, J=9.56 Hz, 1 H), 7.85 (m, 3 H), 7.96 (d, J=8.46 Hz, 2 H), 8.64 (d,J=4.41 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With N-ethyl-N,N-diisopropylamine; 3-[(diethoxyphosphinyl)oxy]-1,2,3-benzotriazin-4(3H)-one In tetrahydrofuran at 25℃; for 16h; | 38 A solution containing the product from Example 2C (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with 2,6-dimethylphenoxy acetic acid (U.S. Pat. No. 5,914,332, see Example 1H) (0.008 g, 0.044 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.030 mL, 0.172 mmol), stirred at 25° C. for 16 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-80% ethyl acetate/chloroform to give the title compound (0.021 g, 77% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.83 (s, 9H), 1.52 (m, 2H), 2.08 (s, 6H), 2.72 (m, 2H), 2.80 (m, 2H), 3.51 (s, 3H), 3.72 (m, 1H), 3.85 (d, J=9.19 Hz, 1H), 4.01 (s, 2H), 4.22 (m, 2H), 5.05 (d, J=5.88 Hz, 1H), 6.71 (d, J=9.93 Hz, 1H), 6.92 (m, 3H), 7.26 (m, 8H), 7.45 (d, J=9.56 Hz, 1H), 7.85 (m, 5H), 8.62 (d, J=4.78 Hz, 1H). |
77% | With N-ethyl-N,N-diisopropylamine; 3-[(diethoxyphosphinyl)oxy]-1,2,3-benzotriazin-4(3H)-one In tetrahydrofuran at 25℃; for 16h; | 38 methyl (1S)-1-[({(1S,3S,4S)-4-[(2,6-dimethylphenoxy)acetyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate EXAMPLE 38 methyl(1S)-1-[({(1S,3S,4S)-4-[(2,6-dimethylphenoxy)acetyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate A solution containing the product from Example 2C (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with 2,6-dimethylphenoxy acetic acid (U.S. Pat. No. 5,914,332, see Example 1H) (0.008 g, 0.044 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.030 mL, 0.172 mmol), stirred at 25° C. for 16 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluding with 0-80% ethyl acetate/chloroform to give the title compound (0.021 g, 77% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.83 (s, 9 H), 1.52 (m, 2 H), 2.08 (s, 6 H), 2.72 (m, 2 H), 2.80 (m, 2 H), 3.51 (s, 3 H), 3.72 (m, 1 H), 3.85 (d, J=9.19 Hz, 1 H), 4.01 (s, 2 H), 4.22 (m, 2 H), 5.05 (d, J=5.88 Hz, 1 H), 6.71 (d, J=9.93 Hz, 1 H), 6.92(m, 3 H), 7.26 (m, 8 H), 7.45 (d, J=9.56 Hz, 1 H), 7.85 (m, 5 H), 8.62 (d, J=4.78 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With N-ethyl-N,N-diisopropylamine; 3-[(diethoxyphosphinyl)oxy]-1,2,3-benzotriazin-4(3H)-one In tetrahydrofuran at 25℃; for 16h; | 39 A solution containing the product from Example 23S (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with 2,6-dimethylphenoxy acetic acid (U.S. Pat. No. 5,914,332, see Example 1H) (0.008 g, 0.044 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.030 mL, 0.172 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-80% ethyl acetate/chloroform to give the title compound (0.016 g, 61% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.86 (s, 9H), 1.63 (m, 2H), 2.07 (s, 6H), 2.78 (m, 4H), 3.51 (s, 3H), 3.62 (m, 1H), 3.94 (m, 3H), 4.25 (m, 2H), 4.87 (d, J=5.15 Hz, 1H), 6.89 (m, 4H), 7.19 (m, 5H), 7.31 (m, 3H), 7.61 (d, J=8.46 Hz, 1H), 7.84 (m, 5H), 8.62 (d, J=4.41 Hz, 1H). |
61% | With N-ethyl-N,N-diisopropylamine; 3-[(diethoxyphosphinyl)oxy]-1,2,3-benzotriazin-4(3H)-one In tetrahydrofuran at 25℃; for 16h; | 39 methyl (1S)-1-[({(1S,2S,4S)-4-[(2,6-dimethylphenoxy)acetyl]amino}-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate EXAMPLE 39 methyl(1S)-1-[({(1S,2S,4S)-4-[(2,6-dimethylphenoxy)acetyl]amino}-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate A solution containing the product from Example 23S (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with 2,6-dimethylphenoxy acetic acid (U.S. Pat. No. 5,914,332, see Example 1H) (0.008 g, 0.044 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.030 mL, 0.172 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluding with 0-80% ethyl acetate/chloroform to give the title compound (0.016 g, 61% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.86 (s, 9 H), 1.63 (m, 2 H), 2.07 (s, 6 H), 2.78 (m, 4 H), 3.51 (s, 3 H), 3.62 (m, 1 H), 3.94 (m, 3 H), 4.25 (m, 2 H), 4.87 (d, J=5.15 Hz, 1 H), 6.89 (m, 4 H), 7.19 (m, 5 H), 7.31 (m, 3 H), 7.61 (d, *8.46 Hz, 1 H), 7.84 (m, 5 H), 8.62 (d, J=4.41 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With benzotriazol-1-ol In dichloromethane at 20℃; for 4h; | 1 Example 1; Preparation of compound 8; Intermediate 1-e; 25 g of lH-benzimidazol-2-yl-carbamic acid, methyl ester 1-a were dissolved in 45 mL of chlorosulfonic acid, at 0°C. The reaction mixture was then warmed up to 50°C and stirred during 4 hours. The reaction mixture was poured onto a mixture of ice and water and was stirred until a white precipitate was formed. The precipitate was next filtered and washed successively with an acidic aqueous solution (pH<2), a basic aqueous solution (pH>10) and a neutral aqueous solution (pH = 7 to 8), and dried in a vacuum oven, yielding 24 g (64%) of the desired intermediate 1-b, methyl [5- (chlorosulfonyl)- 1 H-benzimidazol-2-yl] carbamate. 2 g of intermediate 1 c [2R-hydroxy-3-[(2-methylpropyl) amino]-1 S-(phenylmethyl)- propyl] carbamic acid, 1, 1-dimethylethyl ester were dissolved in 50 mL of DCM. 1.8 g of triethylamine were then added to the reaction mixture, followed by portion-wise addition of 1. 81 g of intermediate 1-b. After 5 hours stirring at room temperature, the reaction mixture was washed with water, dried over MgS04, filtered and evaporated to yield 3 g (85%) of the desired intermediate 1-d, [ (1S, 2R)-2-hydroxy-3- [ [ [2- [ (methoxy- carbonyl) amino]-1 H-benzimidazol-5-yl] sulfonyl]- (2-methylpropyl) amino]-1- (phenyl- methyl) propyl] carbamic acid, 1, 1-dimethylethyl ester. 3 g of intermediate 1-d were dissolved in a mixture of 8 mL of HCI in isopropanol and 40 mL of ethanol. The reaction mixture was stirred at room temperature overnight, then the solid was filtered off and was redissolved in a mixture DCM/saturated solution of NaHC03 in water. The organic layer was dried over MgS04 and evaporated to yield 1.4 g (60%) of the intermediate 1-e [5-[[[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]- (2-methylpropyl) amino] sulfonyl]-lH-benzimidazol-2-yl] carbamic acid, methyl ester as a free base. Compound 8 1 g of intermediate 1-e was dissolved in 20 mL of DCM. 0.37 g of 2, 6-dimethyl- phenoxyacetic acid, 0.42 g of DCC and 0.27 g of HOBt were then added to the reaction mixture, which was stirred at room temperature during 4 hours. The reaction mixture was evaporated and the residue dissolved in 20 mL of ethylacetate. The reaction mixture was cooled down to 0°C and the precipitate of dicyclohexylurea was filtered off. The organic layer was then washed with a solution of Na2CO3 in water, brine, dried over MgS04 and evaporated. The crude compound was purified on silica gel eluting with 5% methanol in DCM, yielding 1.29 g (97%) of the desired final compound [ (1 S, 2R)-2-hydroxy-3- [ [ [2- [ (methoxycarbonyl) amino]-1 H-benzimidazol-5-yl] sulfonyl] (2-methylpropyl) amino]-1- (phenylmethyl) propyl]- (2, 6-dimethylphenoxy) acetamide (compound 8). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | 5 Example 5; Preparation of Compound 9; Compound 9; 20 g of intermediate C-1 (PG = dibenzyl, R4 = isobutyl) were dissolved in 250 mL of DCM. 23 mL of triethylamine were then added to the reaction mixture, followed by 12.7 g of intermediate 1-b, added portion-wise. After overnight stirring at room temperature, the reaction mixture was washed with water, dried over MgSO4, filtered and evaporated to yield 1 Ig (40%) of the desired intermediate 5-a, [5- [ [ [ (2R, 3s)-3- (dibenzylamino)-2-hydroxy-4-phenylbutyl] (2-methylpropyl) amino] sulfonyl]-1 H- benzimidazol-2-yl] carbamic acid, methyl ester. 11 g of intermediate 5-a were dissolved in 150 mL of dioxane. Then 18 g of Na2CO3 dissolved in 150 mL of water were added to the reaction mixture, which was stirred at 90°C during 24 hours. The reaction mixture was then concentrated and the residue extracted with DCM, then ethylacetate. The residue was then dried by concentration with toluene, then mixed with isopropanol and filtered. The cristals were further dried in a vacuum oven at 50°C, to give 7.76 g (79%) of intermediate 5-b N- [ (2R, 3S)-3- (dibenzylamino)-2-hydroxy-4-phenylbutyl]-N- (2-methylpropyl)- [2-aminobenzimida- zol-5-yl] sulfonamide. 3 g of intermediate 5-b and 0.76 mL triethylamine were mixed in 150 mL of THF, at 0°C. Then 0.39 g of acetylchloride dissolved in THF were added to the reaction mixture, which was stirred during 3 hours at room temperature. 0.7 g of 4-dimethyl- aminopyridine were added and the reaction stirred overnight. 0.39 g of acetylchloride and 0.7 g of 4-dimethylaminopyridine were then added to the reaction mixture which was further stirred until all intermediate 5-b has reacted. The reaction mixture was then washed with water and extracted with DCM. The organic layer was dried over MgSO4, filtered and evaporated to yield l. lg (34%) of the desired intermediate 5-c N-[(2R, 3S)- 3- (dibenzylamino)-2-hydroxy-4-phenylbutyl]-N- (2-methylpropyl) [2- (acetylamino)- benzimidazol-5-yl] sulfonamide. 1.1 g of intermediate 5-c was dissolved in 200 mL of methanol. Then the reaction mixture was hydrogenated in the presence of 0.5 g of palladium on charcoal (10%), at room temperature, overnight. After filtration of the catalyst, the reaction mixture was hydrogenated again in the presence of newly added palladium on charcoal (10%). This step was again repeated twice then the reaction mixture was concentrated and the crude compound was purified on silica gel eluting with 2% methanol in DCM, yielding 0.2 g (25%) of the desired intermediate N-[(2R, 3S)-3-amino-2-hydroxy-4-phenylbutyl]-N- (2-methylpropyl) [2-(acetylamino) benzimidazol-5-yl] sulfonamide (5-d). 200 mg of intermediate 5-d were dissolved in 2 mL of DCM, then 25 mg of 2, 6-di- methylphenoxyacetic acid, 27 mg of EDCI and 19 mg of HOBt were added to the reaction mixture, which was stirred at room temperature overnight then evaporated. The crude compound was purified by preparative HPLC, yielding 27 mg (30%) of the final compound [ S, 2R)-3-[[[2-(acetylamino)benzimidazol-5-yl]sulfonyl](2-methyl- propyl) amino]-2-hydroxy-1-(phenylmethyl) propyl]-(2, 6-dimethyl phenoxy) acetamide (compound 9). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In DMF (N,N-dimethyl-formamide) for 16h; | 9 In this order, HOBT (19 mg, 0.14 mmol), EDC (28 mg, 0.15 mmol), NMM (31 µl, 0.28 mmol) and diaminodiol tert-butyl (1S,2S,3S)-1-benzyl-2,3-dihydroxy-3-[(2S)- pyrrolidin-2-yl]propylcarbamate (10) of example 1.g) (50 mg, 0.14 mmol) are added to a solution of phenoxyacetic acid (POA) (22 mg, 0.14 mmol) in anhydrous DMF (1 mL). The mixture is stirred for 16 hours and the product isolated by following the procedure described in example 6. The crude product is deprotected from the Boc by treating with TFA as described in 1.h). The residue (49 mg, 0.13 mmol) is dissolved in anhydrous DMF (0.5 mL) and added to a solution of 2,6- dimethyl-phenoxyacetic acid (DmPoa) (25 mg, 0.14 mmol), HOBT (19 mg, 0.14 mmol), EDC (28 mg, 0.15 mmol), NMM (31 µL, 0.28 mmol). The mixture is agitated for 16 hours and the product is isolated by following the procedure of example 6. The crude product is purified by flash chromatography on a silica gel column using a 9:1 dichloromethane/methanol mixture as eluant. 18 mg (24%) of a white solid are obtained. (at)H NMR (No.-CDCl3) : 1.90 (m, 3H, CH2 e HCH), 2.06 (s, 6H, 2xCH3), 2.27 (m, 1H, HCH), 2.86 (dd, 1 H, CH2Ph, Ji=8.8 Hz, J2=14.3 Hz), 3.15 (dd, 1H, CH2, J1=5.1 Hz, J2=9.1 Hz), 3.20 (dd, 1 H, CH2, Ji=6.9 Hz, J2=9.1 Hz), 3.32 (dd, 1 H, CHzPh, Ji=8.8 Hz, J2=14.3 Hz), 3.48 (m, 2H, CHOH), 3.93 (d, 1 H, OH, J=6.2 Hz), 4.11 (dd, 2H, CH20, Ji=15.4 Hz, J2=24.5 Hz), 4.36 (m, 2H, CHNH), 4.65 (dd, 2H, CH2O, J(at)=14.6 Hz, J2=19.04 Hz), 4.83 (d, 1 H, OH, J=4.7 Hz), 6.72 (d, 1H, NH, J=9.1 Hz), 6.97 (m, 7H, CH Ar e NH), 7.25 (m, 7H, CH Ar). ¹3C NMR (No.-CDCl3) : 15.91 (CH3), 16.06 (CH3), 23.55 (CH2), 26.93 (CH2), 37.14 (CH2Ph), 46.70 (CH2NH), 51.01 (CHNH), 59.01 (CHNH), 67.50 (CH20), 69.85 (CH20), 70.10 (CHOH), 70.93 (CHOH), 121.82,124.84, (C Ar), 126.62,128.60, 129.05,129.12, 129.30,129.37, 129.62, 129.69,130.25 (CH Ar), 137.65 (C Ar), 153.92,157.62 (CO), 169.45,169.75 (CONH). MS m/z: 546 [MH] +, 585 [MNa] (at), 569 [MK](at). | |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 0 - 25℃; for 17h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.5h; | 3 To a solution of compound I (0.93 g, 2.0 mmol) and compound II (0.38 g, 2.1 mmol) in 20 ml dry DMF was added HBTU (a peptide coupling reagent, 0.80 g, 2.1 mmol) followed by DIEA (0.5 mL, 4.2 mmol) at 20° C. under Ar atmosphere. After stirring for 30 minutes, the reaction mixture was quenched by addition of brine and then extracted with EtOAc. After washing the organic layer with 1 M HCl, a saturated NaHCO3 aqueous solution, and brine, it was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product thus obtained was purified by flash chromatography to give the compound III in a 90 % yield. |
86% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; chloroacetic acid In water | 24.A A. A. 2,6-Dimethylphenoxyacetic acid 2,6-Dimethylphenol (102.8 g, 0.842 mol) and chloroacetic acid (159.6 g, 1.68 mol) in 1000 ml of H2 O was added to a 3-L, 3-necked round bottom flask with mechanical stirring and a water-cooled condenser. A solution of NaOH (134.9 g, 3.37 mol) dissolved in 500 ml of water was slowly added to the above mixture via addition funnel and heat to reflux. After 2 hours, additional chloroacetic acid (79.4 g, 0.84 mol) and NaOH solution (67.2 g, 1.68 mol in in 200 ml water) was added to the reaction mixture. After 19 hours, additional chloroacetic acid (39.8 g, 0.42 mol) and NaOH solution (33.6 g, 0.84 mol in in 100 ml water) was added to the reaction mixture and refluxing was continued until starting phenol was consumed. The reaction flask was cooled in and ice-water bath and acidified to pH=1 with conc. HCl, causing a precipitate to form. The resulting slurry was stirred in the ice bath for 1 hour then filtered. The solid was dissolved in hot (100° C.) water and cooled to crystallize the product as white plates, mp=136-137° C., yield=78.8 g, 52%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In water | 10.F.A Part A Part A Preparation of 2,6-Dimethylphenoxyacetic acid 2,6-Dimethylphenol (6.1 g, 50.0 mmol), bromoacetic acid (6.9 g, 50.0 mmol) and 2.5 N aqueous sodium hyroxide (50.0 mL, 125.0 mmol) were refluxed in water (125 mL) for 4 hrs. Bromoacetic acid (6.9 g, 50.0 mmol) and 2.5 N aqueous sodium hydroxide (20.0 mL, 62.5 mmol) were added and the solution refluxed for an additional 16 hrs. The solution was cooled to room temperature and water (200 mL) was added. The pH of the solution was adjusted to 1.0 with concentrated aqueous hydrochloric acid. The resulting precipitate was collected and recrystallized from ethyl acetate/hexanes (1:9, 700 mL). | |
79 g | With sodium hydroxide In water for 2h; Reflux; Large scale; | 2 Water 480 kg, 2,6-dimethylphenol 61.8 kg and bromoacetic acid 96 kg were mixed and stirred. Temperature control about 25 ° C, slow drop 30wt% sodium hydroxide 382kg. After the completion of the dropwise addition, the temperature was raised and refluxed for 2 hours. After adding 24 g of bromoacetic acid, 61 kg of 20 wt% sodium hydroxide solution was added dropwise. After completion of the dropwise addition, the pH was monitored during the reaction, and the reaction was continued until 8 PH less than 8 or pH> 12 sampling to send the HPLC test, the reaction is complete, the first liquid to 40 ° C, the row of circulating water, remove the ice salt to 5 ° C, add 195kg hydrochloric acid, Stir for 1 hour. Centrifugal rejection filter, add 10kg of ethanol to the filter cake, drinking water 112kg, heated 70 ° C to the whole solution, the whole solution, the material slowly cooling, precipitation of crystals, the temperature dropped to 0 ~ 5 ° C, The crude reddish 2,6-dimethylphenoxyacetic acid (79 g, HPLC purity 95.4%) was obtained by filtration. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 65h; | (2,6-Dimethylphenoxy)acetic acid (5.41 g; 30 mmol), diisopropylethylamine (19.39 g; 150 mmol), <strong>[219511-71-4]tert-butyl amino(imino)methylcarbamate</strong> (5.73 g; 36 mmol), and 1-hydroxybenzotriazole monohydrate (5.52 g; 36 mmol) were dissolved in N,N-dimethylformamide (120 mL), 2-(1H)-benzotriazol-1-yl-1,1,3,3-tetramethyluronium hexafluorophosphate (13.66 g; 36 mmol) was added thereto, and the mixture was stirred for 65 hours at room temperature. To the reaction solution, ethyl acetate (400 mL) was added, and the mixture was washed with 10% aqueous citric acid solution, brine, saturated aqueous sodium bicarbonate solution, and then brine. The organic layer was dried over anhydrous magnesium sulfate and then distilled under reduced pressure. The resulting crystals were dispersed in diethyl ether, collected by filtration and dried to give 9.03 g of the title compound (yield 94%). 1H-NMR (CDCl3) delta: 1.51 (9H, s), 2.25 (6H, s), 4.35 (2H, s), 6.97-6.99 (1H, m), 7.02-7.03 (2H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With trichlorophosphate at 90℃; for 8h; | 1.1 5.2 General procedure for the syntheses of 3-tert-butyl-7-(aryloxymethyl)-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-4-ones (5a-5n) General procedure: An equimolar mixtures of 4-amino-6-tert-butyl-3-mercapto-1,2,4-triazine-5(H)-one (0.01mol) (3) and substituted aryloxyacetic acids (0.01mol) (4) were condensed in presence of POCl3 at 90°C, for 8h. The reactions were carried out in dry condition. The reaction mixtures were cooled and poured into crushed ice drop wise with vigorous shaking, yielded solid product, filtered and recrystallized from ethanol to afford analytical samples (5a-5n) (Scheme 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In N,N-dimethyl-formamide at 20℃; for 10h; | 3.3. General Procedures for Converting Compounds 15,16 and 17 to Compounds 3, 4, 5, 20, 21, 22, 23, 23a, 23band 23c 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. | |
With 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 10h; | 1.9 (9) Add compound 15 and an equimolar amount of 2,6-dimethylphenol acetic acid to tetramethylurea tetrafluoroborate (TBTU), triethylamine (Et3N) and dimethylformamide (DMF) Stir at room temperature for 10 hours to obtain compound 21 in the mixed solvent of, and then remove the Boc group of compound 21 under acidic conditions. Dissolve 15 mg of compound 21 in 9:1 trifluoroacetic acid: H2O, stir at room temperature for 30 minutes, and add toluene After evaporation to dryness, the obtained residue was coupled with N-benzenesulfonylvaline in a mixed solvent of tetramethylurea tetrafluoroborate, triethylamine and dimethylformamide to obtain compound 4, which was confirmed by LCMS The obtained compound 4 is the structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 12h; | General procedure for preparation of compoundsM1-M16 General procedure: Fibiric acids derivatives L1-L16 (0.015 mol), podophyllotoxin(0.01 mol), 4-dimethyaminopyridine (DMAP) (0.001mol) and N,N-dicyclohexylcarbodiimide (DCC) (0.02 mol)were dissolved in dichloromethane (30 mL) and stirred for12 h at room temperature. Then, a proper amount of silicagel were added and the solvent was condensed by vacuumconcentration. Finally, the target compounds were collectedby column chromatography (V(acetone): V(dichloromethane)= 1: 50). Chemical structures of the targetcompounds (M1-M16) were shown in Fig. 2. All the targetcompounds were reported for the first time. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere; | Peptide coupling - Method 2: General procedure: To a solution of the above intermediate (0.21 mmol) in anhydrous DMF (3 mL), a solution of a carboxylic acid (0.22 mmol) in DMF (1 mL) was added dropwise followed by the addition of HBTU (0.22 mmol) and DIPEA (0.43 mmol). The reaction mixture was stirred at room temperature for 1h under Ar. Brine (10 mL) was added and the solid formed was filtered, washed with water (2 x 10 mL), hexane (10 mL) and hexane:EtOAc (4:1 mixture, 5 mL) and dried to give the desired compound which was recrystallized from DMSO:H2O. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In acetonitrile at 25℃; for 1h; | 3.3-1-3.3-2 Example 3-2 Dissolve 21.6g (0.12mol) of 2,6-dimethylphenoxyacetic acid in 200ml of acetonitrile and 8.8g of pyridine,A solution was obtained, 38.7g (0.11mol) of DPhC was added in batches at 25 ° C, and stirred at room temperature for 1h.59.5g (0.1mol) THP and 10.1g (0.1mol) triethylamine were added to the reaction solution at 25 ° C, and stirring was continued at room temperature for 8h until the reaction was complete.The reaction solution was quenched with 2g (0.02mol) N, N-dimethyl-1,3-propanediamine, and stirred at room temperature for 2h,The reaction solution was concentrated in vacuo, 150 ml of EA was added to dissolve the distillation residue, and the EA solution was 5% citric acid solution.After washing with 5% sodium bicarbonate solution and water, EA was evaporated to dryness under vacuum not exceeding 50 ° C to obtain 55.9 g (89% yield) of lopinavir. | |
With pyridine In acetonitrile at 25℃; for 1h; | 3-1; 3-2 Example 3-2 2,1.6 g (0.12 mol) of 2,6-dimethylphenoxyacetic acid was dissolved in 200 ml of acetonitrile and 8.8 g of pyridine to form a solution, and 38.7 g (0.11 mol) of DPhC was added in batches at 25 ° C, and stirred at room temperature for 1 h. 59.5g (0.1mol) THP and 10.1g (0.1mol) triethylamine were added to the reaction solution at 25 ° C, and stirring was continued at room temperature for 8h until the reaction was complete. The reaction solution was quenched with 2g (0.02mol) N, N-dimethyl-1,3-propanediamine, and stirring was continued at room temperature for 2h. The reaction solution was concentrated in vacuo, 150ml of EA was added to dissolve the distillation residue, and the EA solution was 5% citric acid The solution, 5% sodium bicarbonate solution and water were washed, and the EA was evaporated to dryness under vacuum not exceeding 50 ° C to obtain 55.9 g (89% yield) of lopinavi |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In N,N-dimethyl-formamide at 25℃; for 1h; | 4.4-1-4.4-2 Exampke 4-1 Dissolve 21.6g (0.12mol) of 2,6-dimethylphenoxyacetic acid in 80ml DMF and 8.8g pyridine,A solution was formed, 42.2g (0.11mol) of DMC was added in batches at 25 ° C, and stirred at room temperature for 1h.59.5g (0.1mol) THP and 10.1g (0.1mol) triethylamine were added to the reaction solution at 25 ° C, and stirring was continued at room temperature for 8h until the reaction was complete.The reaction solution was quenched with 2g (0.02mol) N, N-dimethyl-1,3-propanediamine, and stirred at room temperature for 2h,Add 200ml of 5% citric acid to the reaction solution, cool to 5 , stir for 2h to crystallize,Filter, wash the filter cake with 5% citric acid solution, 5% sodium bicarbonate solution and water,The filter cake was dried under vacuum at 50 ° C to obtain 57.8 g (92% yield) of lopinavir. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dicyclohexyl-carbodiimide In ethyl acetate at -5 - 25℃; for 8h; | 5.5-1-5.5-2 Example 5-1 Dissolve 2,6-dimethylphenoxyacetic acid 21.6g (0.12mol) in 250mlEA and 13.8g (0.12mol) N-hydroxysuccinimide to form a solution,-22.7 g (0.11 mol) of DCC was added in one portion at -5 ° C, the reaction solution was warmed to room temperature and stirred at room temperature for 8 hours, and the by-product dicyclohexylurea was filtered off.59.5g (0.1mol) THP and 10.1g (0.1mol) triethylamine were added to the reaction solution at 25 ° C, and stirring was continued at room temperature for 8h until the reaction was complete.The reaction solution was quenched with 2g (0.02mol) N, N-dimethyl-1,3-propanediamine, and stirred at room temperature for 2h,The reaction solution was washed three times with 100ml of 5% citric acid solution, 100ml of 5% sodium bicarbonate solution, and 50ml of water.The organic phase was concentrated under vacuum at a concentration temperature not exceeding 50 ° C to obtain 60.3 g (96% yield) of lopinavir. | |
With dicyclohexyl-carbodiimide In ethyl acetate at 20℃; for 8h; | 5-1; 5-2 Example 5-2 Dissolve 21.6g (0.12mol) of 2,6-dimethylphenoxyacetic acid in 250mlEA and 13.8g (0.12mol) N-hydroxysuccinimide to form a solution, add 22.7g (0.11 at a time at -5 ) mol) DCC, the reaction solution was warmed to room temperature and stirred at room temperature for 8 hours, and the by-product dicyclohexylurea was removed by filtration. 59.5g (0.1mol) THP and 10.1g (0.1mol) triethylamine were added to the reaction solution at 25 ° C, and stirring was continued at room temperature for 8h until the reaction was complete. The reaction solution was quenched with 2g (0.02mol) N, N-dimethyl-1,3-propanediamine, and stirring was continued at room temperature for 2h. The reaction solution was successively used with 100ml of 5% citric acid solution and 100ml of 5% sodium bicarbonate solution. Wash three times with 50 ml of water and concentrate the organic phase under vacuum. The concentration temperature does not exceed 50 ° C. to obtain 60.3 g (96% yield) of lopinav |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane at 25℃; for 2h; | 1.1-1-1.1-3 Example 1-1 Disperse 21.6g (0.12mol) 2,6-dimethylphenoxyacetic acid in 150ml dichloromethane to form a suspension,Add 17.8g CDI (0.11mol) solid to the reaction solution in batches at room temperature at 25 ° C,After the addition was completed, the solution was stirred at 25 ° C for 2 hours, then 59.5 g (0.1 mol) of THP was added to the reaction solution, and stirring was continued at 25 ° C for 8 hours until the reaction was complete.Quench the reaction with 2g (0.02mol) N, N-dimethyl-1,3-propanediamine and continue stirring at room temperature for 2h,The reaction solution was washed three times with 100ml of 5% citric acid solution, 100ml of 5% sodium bicarbonate solution, and 50ml of water.The organic phase was concentrated under vacuum at a concentration temperature not exceeding 50 ° C to obtain 60.3 g (96% yield) of lopinavir. | |
In ethyl acetate at 25℃; for 2h; | 1-1a; 1-2; 1-3 Examples 1-3 Dissolve 21.6 g (0.12 mol) of 2,6-dimethylphenoxyacetic acid in 250 ml of EA to form a solution, add 17.8 g (0.11 mol) of CDI in batches at 25 ° C, and stir at room temperature for 2 h. 59.5g (0.1mol) THP was added to the reaction solution at 25 ° C, and stirring was continued at room temperature for 8h until the reaction was complete. The reaction solution was quenched with 2g (0.02mol) N, N-dimethyl-1,3-propanediamine, and stirring was continued at room temperature for 2h. The reaction solution was successively used with 100ml of 5% citric acid solution and 100ml of 5% sodium bicarbonate solution. After washing 3 times with 50 ml of water, the organic phase was concentrated under vacuum, and the concentration temperature did not exceed 50 ° C. to obt |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In N,N-dimethyl-formamide at 25℃; for 1h; | 2.2-1-2.2-2 Example 2-1 Dissolve 21.6g (0.12mol) of 2,6-dimethylphenoxyacetic acid in 80ml DMF and 8.8g pyridine,A solution was obtained, 28.1 g (0.11 mol) of DSC was added in batches at 25 ° C, and stirred at room temperature for 1 h.59.5g (0.1mol) THP and 10.1g (0.1mol) triethylamine were added to the reaction solution at 25 ° C, and stirring was continued at room temperature for 8h until the reaction was complete.The reaction solution was quenched with 2g (0.02mol) N, N-dimethyl-1,3-propanediamine, and stirred at room temperature for 2h,Add 200ml of 5% citric acid to the reaction solution, cool to 5 , stir for 2h to crystallize,Filter, wash the filter cake with 5% citric acid solution, 5% sodium bicarbonate solution and water,The filter cake was dried under vacuum at 50 ° C to obtain 56.5 g (90% yield) of lopinavir. | |
With pyridine In N,N-dimethyl-formamide at 25℃; for 2h; | 2-1; 2-2 Example 2-1 Dissolve 21.6g (0.12mol) of 2,6-dimethylphenoxyacetic acid in 80ml DMF and 8.8g pyridine to form a solution, add 28.1g (0.11mol) DSC in batches at 25 ° C,Stir at room temperature for 1h.59.5g (0.1mol) THP and 10.1g (0.1mol) triethylamine were added to the reaction solution at 25 ° C, and stirring was continued at room temperature for 8h until the reaction was complete. The reaction solution was quenched with 2g (0.02mol) N, N-dimethyl-1,3-propanediamine, and stirring was continued at room temperature for 2h. 200ml of 5% citric acid was added to the reaction solution, cooled to 5 ° C, and stirred for 2h Crystallized, filtered, the filter cake was washed with 5% citric acid solution, 5% sodium bicarbonate solution and water, and the filter cake was dried in vacuum at 50 ° C to obtain 56.5 g (90% yield) of lopinavir. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In acetonitrile at 25℃; for 1h; | 4-1; 4-2 Example 4-1 Dissolve 21.6 g (0.12 mol) of 2,6-dimethylphenoxyacetic acid in 80 ml of DMF and 8.8 g of pyridine to form a solution, add 42.2 g (0.11 mol) of DMC in batches at 25 ° C, and stir at room temperature for 1 h. 59.5g (0.1mol) THP and 10.1g (0.1mol) triethylamine were added to the reaction solution at 25 ° C, and stirring was continued at room temperature for 8h until the reaction was complete. The reaction solution was quenched with 2g (0.02mol) N, N-dimethyl-1,3-propanediamine, and stirring was continued at room temperature for 2h. 200ml of 5% citric acid was added to the reaction solution, cooled to 5 ° C and stirred for 2h The crystals were crystallized, filtered, and the filter cake was washed with 5% citric acid solution, 5% sodium bicarbonate solution, and water. The filter cake was dried under vacuum at 50 ° C to obtain 57.8 g (92% yield) of lopinavir. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 57% 2: 21% | With water; sodium hydroxide In N,N-dimethyl-formamide at 90℃; | 4.2.6 Ethyl 2-(2,6-dimethylphenoxy)acetate (12a) and 2-(2,6-dimethyl phenoxy)acetic acid (13a) 2,6-Dimethylphenol (11a, 300mg, 2.46mmol) was dissolved in DMF (15mL), NaOH (491mg, 12.3mmol), a few drops of water and ethyl bromoacetate(1.64g, 9.8mmol) were added and the resulting mixture was stirred at 90°C overnight. After cooling to rt, the solvent was removed. The crude product was dissolved in dichloromethane (40mL) and washed with 10% HCl (2×40mL) and water (2×40mL). The organic layer was dried over Na2SO4, the solvent was removed and the crude product was purified via column chromatography (petroleum ether/ethyl acetate 5:1→1:1) to give 12a (291mg, 57%) and 13a (93mg, 21%) both as a colorless oil. NMR and MS data are in accordance with the previously published [16]. |
Tags: 13335-71-2 synthesis path| 13335-71-2 SDS| 13335-71-2 COA| 13335-71-2 purity| 13335-71-2 application| 13335-71-2 NMR| 13335-71-2 COA| 13335-71-2 structure
[ 13334-49-1 ]
2-(2,4-Dimethylphenoxy)acetic acid
Similarity: 1.00
[ 7356-41-4 ]
2-(2,5-Dimethylphenoxy)acetic acid
Similarity: 0.97
[ 2935-63-9 ]
2-(2,3-Dimethylphenoxy)acetic acid
Similarity: 0.95
[ 13334-49-1 ]
2-(2,4-Dimethylphenoxy)acetic acid
Similarity: 1.00
[ 7356-41-4 ]
2-(2,5-Dimethylphenoxy)acetic acid
Similarity: 0.97
[ 2935-63-9 ]
2-(2,3-Dimethylphenoxy)acetic acid
Similarity: 0.95
[ 13334-49-1 ]
2-(2,4-Dimethylphenoxy)acetic acid
Similarity: 1.00
[ 7356-41-4 ]
2-(2,5-Dimethylphenoxy)acetic acid
Similarity: 0.97
[ 2935-63-9 ]
2-(2,3-Dimethylphenoxy)acetic acid
Similarity: 0.95
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H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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