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CAS No. : | 144163-85-9 | MDL No. : | MFCD09833420 |
Formula : | C23H32N2O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | UKFHOTNATOJBKZ-ACRUOGEOSA-N |
M.W : | 384.51 | Pubchem ID : | 11997926 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | 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 |
---|---|---|
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 |
---|---|---|
In dichloromethane; | EXAMPLE 9 The compound (2S,3S,5S)-5-[N-[N-((2-pyridinylmethoxy)carbonyl)anthranilyl]amino]2-[N-((3-S-(tetrahydrofuranyl)oxy)carbonyl)amino]-1,6-diphenyl-3-hydroxy hexane LL-101 was prepared as follows. Compound (2S,3S,5S)-5-[N-(tert-butyloxycarbonyl)amino]-2-[N-((9-fluorenylmethoxy)carbonyl)amino]-1,6-diphenyl-3-hydroxy hexane (LL-87) was first prepared. 9-fluorenylmethyl-N-succinimidyl carbonate (Fmoc-OSu, 1.85 g, 5.5 mmol) was added to a stirred solution of <strong>[144163-85-9](2S,3S,5S)-2-amino-5-[N-(tert-butyloxycarbonyl)amino]-1,6-diphenyl-3-hydroxy hexane</strong> (RS-216, 2 g, 5.2 mmol) in of methylene chloride (120 mL). The reaction mixture was stirred at room temperature for 3 h. The solvent was removed under reduced pressure, residue was taken up in methylene chloride and washed sequentially with aqueous KHSO4, brine, aqueous NaHCO3, and brine. |
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 |
---|---|---|
With palladium on activated charcoal; water; ammonium formate; In ethanol; for 3h;Reflux; | General procedure: A suspension of NaBH4 (300 mg) in ethylene glycol dimethylether (10 mL) was cooled to -5C. Methanesulfonicacid (1.9 g) in ethylene glycol dimethyl ether (1 mL) wasslowly added, while keeping the temperature at -5C. Whenthe addition was complete, a solution of i-PrOH (1.4 mL),compound 5, or 6, or 7 (1.2 g), and ethylene glycol dimethylether (2.7 mL) was slowly added. The mixture was stirredfor 12 h at -5C. Triethanolamine (1.2 mL) was slowly addedwhile maintaining the temperature. After the solution wasstirred at this temperature for 30 min., a solution of NaBH4(250 mg) in dimethylacetamide (1.8 mL) was slowly added.The resulting suspension was stirred for 2 h at 0C, and thenslowly quenched with water (10 mL). The temperature waswarmed to ambient, and methyl tert-butyl ether (8 mL) wasadded. The organics layers were washed successively with 1N NaOH, 18% (w/w) NH4Cl solution, and 7% (w/w) solution(w/w), dried, and purified on silica gel column eludedwith hexanes/i-PrOH/NH4OH (9:1:0.1). The desired compounds9, or 10 or 11 were isolated as the major products inabout 40% yield. After confirming by HPLC and LCMS,compound 9, or 10 or 11 (0.9 mmol) in THF (20 mL) wastreated with di-tert-butyl dicarbonate (1.1 mmol) at roomtemperature for 1 h. The reaction mixture was diluted withethyl acetate (50 mL), washed with 1 N NaOH (50 mL),dried over MgSO4, and concentrated in Vacuo. The residuewas subjected to column chromatography (silica; 15:1 hexanes/EtOAc) to give 12, 13 or 14 in 35% to 50% yield. Afterconfirming by LCMS, the solution of compound 12, or 13,or 14 (0.25 mmol) in ethanol (2.3 mL) was treated with 10% palladium on carbon (24 mg), and NH4CO2H (80.1 mg) inwater (280 muL), heated at reflux for 3 h, cooled to room temperaturefor 12 h, filtered through a pad of Celite, concentratedin vacuo, diluted with EtOAc (20 mL), washed successivelywith water and brine, dried over MgSO4, and concentratedto give 15, or 16 or 17 in 70-80% yield. The productswere confirmed by LCMS. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.6% | With 4-methyl-morpholine; In N,N-dimethyl-formamide; at 25℃; for 48h; | [00259] Example 3. Preparation of tert-butyl (lS,3S,4S)-l-benzyI-3-hydroxy-5-phenyl-4-[(1,3- thiazol-5-ylmethoxy)carbonyl]amino}pentylcarbamate; [00260] A suspension of ter/-butyl (lS^S^SJ-l-benzylO-hydroxy-5-phenyl-4-amino-pentyl carbamate (12 g, 24 mmol, Kempf et al, J. MED. CHEM., 33: 2687-2689 (1990)), carbonic acid 5-methyl thiazole ester 4-nitrophenyl ester hydrochloride (7.93 g, 1.04 equivalents, U.S. Patent No. 5,773,625), and N-methyl morpholine (1 1.82 mL, 4.5 equivalents) in DMF (24 mL) was stirred for 2 days at 25C. The resulting slurry was quenched with saturated sodium bicarbonate (100 mL), extracted with EtOAc (100 mL), washed with 10% citric acid, dried (Na2SO1l), and concentrated in vacuo. Column chromatography on silica (90% EtOAc/hexane) followed by crystallization in hot 50% EtOAc/hexane gave a white solid (9.5 g, 75.6%). IH NMR (300 MHz, DMSO-D6) delta ppm 1.29 (s, 9 H), 1.45 (m, 2 H), 2.55 - 2.62 (m, 2 H), 2.63 - 2.81 (m, 2 H), 3.57 (m, 1 H), 3.87 (m, 2 H), 4.61 (d, J^6.62 Hz, 1 H), 4.97 - 5.28 (m, 2 H), 6.62 (d, ./=9.19 Hz, 1 H), 6.89 (d, J=9.56 Hz, 1 H), 7.05 - 7.36 (m, 10 H), 7.86 (s, 1 H), 9.04 (s, 1 H); MS (-ESI) m/z 560.3 (M+Ciy. |
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; | [00287] Example 17. Preparation of N'-{(lS,2S,4S)-l-benzyl-4-[(tert-butoxycarbonyl)amino]-2- hydroxy-5-phenylpentyl} -3-methyl-N2-[( 1 ,3-thiazol-5-ylmethoxy)carbonyl]-L-valinamide; [002881 A solution of the compound of Example 16 (133 mg, 0.49 mmol), tert-butyl (S,3SAS)-- benzyl-3-hydroxy-5-phenyl-4-amino-pentylcarbamate (198 mg, 1.05 equivalents), l-(3-dimethylamino propyl)-3-ethylcarbodiimide hydrochloride (144.6 mg, 1.5 equivalents), and 1-hydroxybenzotriazole (99.4 mg, 1.5 equivalents) in N,N-dimethylformamide (1 mL) was stirred for 10 minutes at room temperature. To this mixture was added N-methylmorpholine (134 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 (6% MeOH/ CH2Cl2) gave a white solid (240 mg, 76.7%). IH NMR (300 MHz, DMSO-D6) delta ppm 0.82 (s, 9 H), 1.26 (s, 9 H), 1.40 - 1.58 (m, 2 H), 2.53 - 2.79 (m, J=3.31 Hz, 4 H), 3.53 - 3.63 (m, 1 H), 3.71 - 3.83 (m, 1 H), 3.96 (d, 1 H), 4.05 - 4.19 (m, 1 H), 4.78 (d, 1 H), 5.28 (s, 2 H), 6.56 (d, J=9.19 Hz, 1 H), 6.98 - 7.31 (m, 1 1 H), 7.57 (s, 1 H), 7.57 (d, 1 H), 7.94 (s, 1 H), 9.09 (s, 1 H); MS m/z 639.4 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Example 6: Preparation of compound V (l,6-diphenyl-5S-teri-butoxycarbonylamino-3S- hydrox -2S-(5-thiazolemethoxy) carbonylaminohexane). To a magnetically stirred mixture of amino alcohol IV (3.84 g, 10 mmol) in acetonitrile (100 mL) at room temperature, was added ((5-thiazole)methyl)-4-nitrophenyl carbonate (3.08 g, 11 mmol). The reaction mixture was stirred for approximately 20 minutes and then was added diisopropylethylamine (2 mL, 11 mmol). The reaction was allowed to stir at room temperature for 48 hours. At this point, the reaction was analyzed by HPLC and judged to be complete. The reaction mixture was transferred to a round-bottom flask and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and transferred to a separatory funnel. The reaction mixture was washed twice with cold (0 C) 5% sodium bisulfate solution (2 x 75 mL), twice with 1M sodium carbonate solution (2 xlOO mL), brine (100 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford 6 g of crude material. The residue was chromatographed on silica gel (100 mL) using a 20% ethyl acetate/hexane to 60% ethyl acetate/hexane gradient to obtained 4.97 g (94%) of the desired carbamate V as a white solid. Tic assay showed Rf = 0.32 on Si02 using 50% ethyl acetate/hexane as the eluent. 1H NMR (300 MHz, CDC13): delta 8.79 (s, IH), 7.84 (s, IH), 7.35-7.05 (m, 15H), 5.24 (s, 2H), 5.12 (d, IH, J=9.3 Hz), 4.50 (br s, IH), 3.9-3.7 (m, 2H), 3.64 (br s, IH), 2.85 (d, 2H, J=7.5 Hz), 2.73 (d, 2H, J=6.6 Hz), 1.62 (br s, 2H), 1.39 (s, 9H). | |
90% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 50℃; for 5h;Inert atmosphere; | To a stirred solution of compounds 6 (462 mg, 1.2 mmol) and 5 (280 mg, 1 mmol) in dry THF (5 mL) was added DIPEA (258 mg, 2 mmol). The reaction mixture was stirred at 50 oC under N2 for 5 h. After this time, the reaction mixture was diluted with EtOAc (10 mL), washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (hexanes / EtOAc, 1:5) to give 7 (473 mg, 90%) as an off-white solid. 1H NMR (400 MHz, CDCl3), delta (ppm) 1.37 (s, 9H), 1.58 (m, 2H), 2.71 (m, 2H), 2.85 (d, J = 7.6 Hz, 2H), 3.67 (bs, 1H), 3.78-3.88 (m, 3H), 4.63 (d, J = 6.8 Hz, 1H), 5.21 (s, 2H), 5.31 (d, J = 9.2 Hz, 1H), 7.06 (d, J = 7.2 Hz, 2H), 7.17-7.26 (m, 8H), 7.81 (s, 1H), 8.77 (s, 1H). 13C NMR (100 MHz, CDCl3), delta (ppm) 28.5, 38.8, 40.2, 41.6, 50.1, 56.7, 58.3, 69.7, 80.0, 126.5, 126.6, 128.6, 128.6, 129.4, 129.5, 133.6, 137.5, 138.2, 143.4, 154.7, 156.0, 156.1. HRMS (ESI): calcd for C28H35N3O5S, [M+Na]+ 548.2195; found: 548.2207. |
87% | With triethylamine; In tetrahydrofuran; | Synthesis of Intermediate 10:Intermediate 8 (1eqv) and compound 9 (1eqv) were dissolved in THF and triethylamine (2eqv) was added to react overnight.Add water to quench, extract with ethyl acetate, wash with saturated sodium bicarbonate, dry, evaporate to dryness, and column chromatography to obtain Intermediate 4 in 87% yield. |
6.53 g (80%) | In ethyl acetate; N,N-dimethyl-formamide; | Example 20A (2S,3S,5S)-5-(t-Butyloxycarbonylamino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane The product of Example 19D (6.0 g, 15.6 mmoles) was dissolved in 60 mL of DMF under nitrogen atmosphere. To this stirred solution at room temperature was added 5-(p-nitrophenyloxycarbonyloxymethyl)thiazole (4.67 g, 15.6 mmole) and the resulting solution was stirred for 4 h. The solvent was removed under reduced pressure by rotary evaporation and the residue dissolved in 150 mL EtOAc. This solution was washed with 5*75 mL 1N NaOH solution, 100 mL brine, dried over Na2 SO4. The solvent was removed to afford 8.02 g of a slightly yellowish oil. This material was crystallized from 30 mL EtOAc and 40 mL hexane to afford 6.53 g (80%) of the desired product as a white solid. mp 118-120 C. H 1 NMR (CDCl3) delta8.79 (s, 1H), 7.83 (s, 1H), 7.30-715 (m, 8H), 7.08 (m, 2H), 5.23 (s, 2H), 5.14 (d, 1H, J=9 Hz), 4.52 (m, 1H), 3.92-3.72 (m, 3H), 3.65 (m, 1H), 2.85 (d-apparent, 2H, J=7.5 Hz), 2.72 (d-apparent, 2H, J=7 Hz), 1.61 (m, 2H), 1.38 (s, 9H). CIMS m/z (526) (M+H)+, 543 (M+18)+. |
In tetrahydrofuran; | (2S, 3S, 5S) -2- (N- ((5- tiazolyl) methoxycarbonyl) amino)- 5- (t-butyloxycarbonylamine)-1,6-diphenyl-3- hydroxyhexane In a 6.0 L round flask equipped with stirrer system and under N2 atmosphere, add a solution containing (2S, 3S, 5S)- 2-amino- 3- hydroxyl- 5- (t-butyloxycarbonylamine)-1,6- diphenyl hexane (100'g, 0.26 mol) in THF (1.9 L) and a solution containing (N-(5-tiazolyl) methyl)-(4-nitrophenyl) carbonate (76 g, 0.27 mol) in THF (630 mL). Monitor the reaction by thin layer chromatograph, remove the solvent under reduced pressure, dissolve the crude product with ethyl acetate (2.0 L), wash the organic phase using IN sodium hydroxide solution (8x 5.00 mL) and saturated sodium chloride solution, and dry the product with sodium sulfate. Separate the phases, concentrate the crude product and employ it directly in the next step without previous purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; 3-[(diethoxyphosphinyl)oxy]-1,2,3-benzotriazin-4(3H)-one; In tetrahydrofuran; at 25℃; for 16h; | A solution of the product from Example 6A (0.50 g, 1.30 mmol) in THF (13 mL) was treated with the product from Example 5A (0.30 g, 1.59 mmol), DEPBT (0.45 g, 1.50 mmol), and N,N-diisopropylethylamine (1.1 mL, 6.31 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 to give the title compound, used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With N-ethyl-N,N-diisopropylamine; 3-[(diethoxyphosphinyl)oxy]-1,2,3-benzotriazin-4(3H)-one; In tetrahydrofuran; at 25℃; for 16h; | A solution of the product from Example 6A (0.034 g, 0.089 mmol) in THF (0.9 mL) was treated with the product from Example 6H (0.035 g, 0.103 mmol), DEPBT (0.040 g, 0.134 mmol), and N,N-diisopropylethylamine (0.075 mL, 0.431 mmol), stirred at 25 C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography using C18 column, eluting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.047 g, 75% yield). |
75% | With N-ethyl-N,N-diisopropylamine; 3-[(diethoxyphosphinyl)oxy]-1,2,3-benzotriazin-4(3H)-one; In tetrahydrofuran; at 25℃; for 16h; | EXAMPLE 6I tert-butyl(1S,3S,4S)-1-benzyl-3-hydroxy-4-[(2S)-2-(3-[2-(methoxymethyl)-1,3-thiazol-4-yl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenylpentylcarbamate A solution of the product from Example 6A (0.034 g, 0.089 mmol) in THF (0.9 mL) was treated with the product from Example 6H (0.035 g, 0.103 mmol), DEPBT (0.040 g, 0.134 mmol), and N,N-diisopropylethylamine (0.075 mL, 0.431 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 purified by reversed phase chromatography using C18 column, eluding with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.047 g, 75% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 0 - 25℃; for 16h; | A solution of the product from Example 6A (0.046 g, 0.119 mmol) in THF (0.9 mL) was treated with the product from Example 7B (0.050 g, 0.119 mmol), EDAC (0.035 g, 0.183 mmol), HOBT (0.025 g, 0.185 mmol), and NMM (0.040 mL, 0.364 mmol) at 0 C., stirred at 25 C. for 16 hours, and partitioned between ethyl acetate and water. The organic phase phase was washed with 10% citric acid, dilute sodium bicarbonate solution, and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column, eluting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.080 g, 100% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With N-ethyl-N,N-diisopropylamine; 3-[(diethoxyphosphinyl)oxy]-1,2,3-benzotriazin-4(3H)-one; In tetrahydrofuran; at 25℃; for 3h; | A solution of the product from Example 6A (3.0 g, 7.81 mmol) in THF (80 mL) was treated with the product from Example 10D (2.93 g, 8.57 mmol), DEPBT (3.5 g, 11.71 mmol), and N,N-diisopropylethylamine (7 mL, 40.19 mmol) and the mixture was stirred at 25 C for 3 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 product was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In water; ethyl acetate; for 0.5h; | The product from Example 126 (20 g, 39.8 mmol) was partitioned between ethyl acetate and saturated NaHCO3 solution with stirring for 30 minutes. The solid white amine was collected by filtration and the aqueous was extracted twice with portions of ethyl acetate. The solid material collected was dissolved in warm ethyl acetate and this solution was combined with the organic phase extracts, dried over sodium sulfate, filtered and concentrated to give the free amine (14.15 g). | |
With sodium hydrogencarbonate; In ethyl acetate; for 0.5h; | The product from Example 126 (20 g, 39.8 mmol) was partitioned between ethyl acetate and saturated NaHCO3 solution with stirring for 30 minutes. The solid white amine was collected by filtration and the aqueous was extracted twice with portions of ethyl acetate. The solid material collected was dissolved in warm ethyl acetate and this solution was combined with the organic phase extracts, dried over sodium sulfate, filtered and concentrated to give the free amine (14.15 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In chloroform; | (2S, 3S, 5S) -2- [N- [N [[N- methyl- N[(2- isopropyl- 4-tiazolyl) methyl] amino] carbonyl] vanilyl] amino] - 5-(t- butyloxycarbonylamine)-1,6-diphenyl- 3- hydroxyhexane In a 6.0 L round flask equipped with stirrer system and under N2 atmosphere, add (2S, 3S, 5S) -2- amino- 3- hydroxyl- 5- (t-butyloxycarbonylamine)-1,6- diphenyl hexane (100 g, 0.26 mol) and chloroform (1.9 L). After complete dissolution of the solids add a solution of N- [[N- methyl- N-[(2- isopropyl- 4- tiazolyl) methyl] amino] carbonyl] L- vanilyl hydroxysuccinimide ester (107 g, 0.26 mol) in chloroform (630 mL). Monitor the reaction by thin layer chromatograph and at the end of the reaction add a 10% sodium carbonate solution (1.9 L). Separate the phases and use the organic phase without previous purification directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
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72% | EXAMPLE 16 (2S. 3S. 5S)-2-Amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane. To a suspension of 100 mg of 10% palladium hydroxide on charcoal in 10 mL of isopropyl alcohol was added 73 mg of the product of Example 156. The mixture was shaken vigorously under a hydrogen pressure of approx. 60 psi using a Parr hydrogenation apparatus for 18 h. The catalyst was filtered off and washed with 50 mL of isopropyl alcohol. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography (5% to 10% MeOH/CH2 Cl2) to provide 36 mg of desired product (72%). 300 MHz 1 H NMR (CDCl3): d 1.42 (s, 9H), 1.58 (m, 1H), 1.70 (m,1H), 2.20 (br s, 2H), 2.5 (m, 1H), 2.76-2.95 (m, 4H), 3.50 (m, 1H), 3.95 (m, 1H), 4.80 (br d, 1H), 7.15-7.30 (m, 10H). Mass spectrum: (M+H)+=385. | |
F-1. (2S,3S,5S)-2-Amino-3-hydroxy-5-(t-butyloxycarbonylamino)-1,6-diphenylhexane To a stirred solution of [2S,3S,5S]-2-N,N-dibenzylamino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane (12 g, 21.3 mmol) in methanol (350 mL) was charged ammonium formate (8.05 g, 128 mmol, 6.0 eq) and 10% palladium on carbon (2.4 g). The solution was stirred under nitrogen at 60 C. for three hours and then at 75 C. for 12 hours. An additional amount of ammonium formate (6 g) and 10% palladium on carbon (1.5 g) was added as well as 1 mL of glacial acetic acid. The reaction was driven to completion within 2 hours at a reflux temperature. The reaction mixture was then cooled to room temperature and then filtered through a bed of celite. The filter cake was washed with methanol (75 mL) and the combined filtrates were concentrated under reduced pressure. The residue was taken up in 1N NaOH (300 mL) and extracted into methylene chloride (2*200 mL). The combined organic layers were washed with brine (250 mL) and dried over sodium sulfate. Concentration of the solution under reduced pressure provided the desired product as a light colored oil which slowly crystallized upon standing (5 g). | ||
EXAMPLE 8a [ 2S,3S,5S]-2-amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane. To a stirred solution of [2S,3S,5S]-2-N,N-dibenzylamino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane (12 g, 21.3 mmol) in methanol (350 mL) was charged ammonium formate (8.05 g, 128 mmol, 6.0 eq) and 10% palladium on carbon (2.4 g). The solution was stirred under nitrogen at 60 C. for three hours and then at 75 C. for 12 hours. An additional amount of ammonium formate (6 g) and 10% palladium on carbon (1.5 g) was added as well as 1 mL of glacial acetic acid. The reaction was driven to completion within 2 hours at a reflux temperature. The reaction mixture was then cooled to room temperature and then filtered through a bed of celite. The filter cake was washed with methanol (75 mL) and the combined filtrates were concentrated under reduced pressure. The residue was taken up in 1N NaOH (300 mL) and extracted into methylene chloride (2* 200 mL). The combined organic layers were washed with brine (250 mL) and dried over sodium sulfate. Concentration of the solution under reduced pressure provided the desired product as a light colored oil which slowly crystallized upon standing (5 g). |
EXAMPLE 18 Alternative Preparation of (2S,3S,5S)-2-Amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane. A solution of the product from Example 17 (150 gms, 250 mmol) dissolved in absolute EtOH (2 liters) was treated with 10 % Pd/C (18 gms, pre-wetted), followed by addition of ammonium formate (78.6 gms, 1.25 moles) dissolved in H2 O (200ml). The resulting mixture was stirred at reflux for 2.5 hours. The mixture was cooled to room temperature and filtered through a pad of infusorial earth (20 g). The filter cake was washed 3 times with EtOH (70 ml each). The filtrate was concentrated in vacuo. The residue was dissolved into EtOAc (1 L) and washed (1N NaOH, followed by H2 O, followed by brine), dried (Na2 SO4), filtered and concentrated in vacuo to a constant weight of 95 gms. (99.2 % of theory). The light yellow solid (91.5 gms of the 95 gms) was slurried in hot heptane (600 ml) (steam bath) and treated with isopropanol (45 ml), and swirled to effect solution. The solution was allowed to slowly cool to room temperature over 3 hours, kept at room temperature for 2 more hours and filtered. The filter cake was washed 10 times with 9/1 hexane-isopropanol (30 ml each) to give the desired product as an off-white finely crystalline solid which was dried to constant weight of 57.5 gms. | ||
Example 19D (2S,3S,5S)-2-Amino-3-hydroxy-5-(t-butyloxycarbonylamino)-1,6-diphenylhexane A solution of the product from Example 19C (150 gm, 250 mmol) dissolved in absolute EtOH (2 liters) was treated with 10% Pd/C (18 gm, pre-wetted), followed by addition of ammonium formate (78.6 gms, 1.25 moles) dissolved in H2 O (200 ml). The resulting mixture was stirred at reflux for 2.5 hours. The mixture was cooled to room temperature and filtered through a pad of infusorial earth (20 g). The filter cake was washed 3 times with EtOH (70 ml each). The filtrate was concentrated in vacuo. The residue was dissolved into EtOAc (1L) and washed (1N NaOH, followed by H2 O, followed by brine), dried (Na2 SO4), filtered and concentrated in vacuo. to a constant weight of 95 gms. (99.2 % of theory). The light yellow solid (91.5 gm of the 95 gm) was slurried in hot heptane (600 ml) (steam bath) and treated with isopropanol (45 ml), and swirled to effect solution. The solution was allowed to slowly cool to room temperature over 3 hours, kept at room temperature for 2 more hours and filtered. The filter cake was washed 10 times with 9/1 hexane-isopropanol (30 ml each) to give the desired product as an off-white finely crystalline solid which was dried to constant weight of 57.5 gm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
205 mg (99%) | In chloroform; | A. 2-(2,6-Dimethyl-phenoxyacetyl)amino-3-hydroxy-5-(t-butyloxycarbonylamino)-1,6-diphenylhexane To a solution of 162 mg (0.42 mmol) of <strong>[144163-85-9](2S,3S,5S)-2-amino-3-hydroxy-5-(t-butyloxycarbonylamino)-1,6-diphenylhexane</strong> in 3 mL of CHCl3 was added 100 mg (0.64 mmol) of N-(2,6-dimethyl-phenyloxy acetyloxy)succinimide. The resulting solution was refluxed for 4 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography using 30% ethyl acetate:hexanes as an eluent to provide 205 mg (99%) of the desired compound. 1 H NMR (CDCl3) delta 1.58 (s, 9H), 1.68 (m, 2H), 2.17 (s, 6H), 2.78 (m, 2H), 2.97 (d, J=7.5 Hz, 2H), 3.75 (m, 2H), 3.90 (q, J=8.1 Hz, 1H), 4.15 (t, J=7.5 Hz, 1H), 4.19 (s, 2H), 4.60 (m, 1H), 6.98 (m, 3H), 7.13 (d, J=6.6 Hz, 1H), 7.18-7.30 (m, 10H). Mass spectrum: (M+H)+ =547. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.4 g (94%) | With N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide; ethyl acetate; | The compound (2S,3S,5S)-2-[N-[(3-hydroxy-2-methylphenyl)carbonyl]amino]-5-[N-(tert-butyloxycarbonyl)amino]-1,6-diphenyl-3-hydroxy hexane (RS-208) was prepared from RS-216. A solution of <strong>[144163-85-9](2S,3S,5S)-2-amino-5-[N-(tert-butyloxycarbonyl)amino]-1,6-diphenyl-3-hydroxy hexane</strong> (RS-216, 1.1 g, 2.86 mmol), 3-hydroxy-2-methyl-benzoic acid (0.478 g, 3.2 mmol), O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU, 1.02 g, 3.2 mmol), 1-hydroxybenzotriazole hydrate (HOBT, 0.919 g, 6.0 mmol) and diisopropylethylamine (DIPEA, 103 ml, 6.0 mmol) in dimethylformamide (DMF, 30 ml) was stirred at room temperature for 2 h. After addition of aminoethyl morpholine (50 ml) the solvents were removed under vacuum and the residue was diluted with ethyl acetate and washed sequentially with aqueous NaHCO3, aqueous KHSO4, brine, then dried on Na2 SO4, and concentrated in vacuo. Solid was suspended in ethyl acetate, filtered and residue was washed with ethyl acetate. Crystallization from ethyl acetate:methanol:hexane (1:0.2:1.5) provided 1.4 g (94%) of white solid; mp=162-163 C.; TLC ?Rf =0.75 (ethyl acetate:hexane,[7:3)]; HPLC rt=19.5 min; MS m/z 519 (M+H)+; 1 H NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | A solution of the product from Example 1F (7.0 g, 37.0 mmol), EDAC (8.5 g, 44.3 mmol), HOBT (6.0 g, 44.4 mmol), and NMM (8.0 mL, 72.8 mmol) in DMF (30 mL) was stirred at 25 C. for 1 hour, treated with a solution of the product from Example 6A (14.15 g, 36.8 mmol) in DMF (30 mL), stirred at 25 C. for 16 hours, concentrated, and partitioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with saturated NaHCO3 and brine, and concentrated. The solution of the residue in hot methanol (20 mL) and water (10 mL) was allowed to cool and stand for 16 hours. The solids were collected by filtration and rinsed several times with hexanes, followed by drying under vacuum to give the title compound (16.97 g, 77% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In a 2.5 L reactor with stirrer system and under N2 atmosphere, add N-[[N-methyl-N[(2- isopropyl- 4- tiazolyl) methyl] amino] carbonyl] L-valine (98 g, 0.32 mol), 1- hydroxybenzotriazol monohydrate and THF (1.7 L). After complete dissolution of the solids add N,N- dicyclohexylcarbodiimide (76 g, 0.37 mol) in a single portion. Monitor the reaction by TLC, and then filtrate the mixture to remove dicyclohexylurea precipitate. In a 5.0 L reactor, with stirring and under N2 atmosphere, add (2S, 3S, 5S)-2- amino- 3- hydroxy-5- (t-butyloxycarbonylamine) -1, 6- diphenyl hexane (100 g, 0.26 mol), THF (1.9 L) and the solution containing the activate derivative ester HOBt prepared as above mentioned. Monitor the reaction by thin layer chromatography and, at the end of the reaction, concentrate the mixture under reduced pressure, then dilute it with ethyl acetate (1.0 L). Wash it using saturated sodium bicarbonate solution and saturated sodium chloride solution, then concentrate the product under reduced pressure and dilute it with chloroform (1.9 L). Employ this chloroform solution directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With pyridine; In dichloromethane; at 0 - 20℃; | Example 1 : Preparation of compound lb (l,6-diphenyl-5S-iert-butoxycarbonylamino- 3S hydroxy-2S-phenylmethoxy-carbonylaminohexane). Benzyl chloroformate (5.1 mL, 36 mmol) was added by addition funnel over approximately 10 minutes to a mechanically stirred mixture of aminoalcohol IV (11.54 g, 30 mmol) and pyridine (2.94 mL, 36 mmol) in dichloromethane (200 mL) at 0 C. The cooling bath was removed and the reaction was allowed to warm to room temperature and stirred overnight. At the end of this period, HPLC analysis showed the presence of <3 A% of the starting alcohol IV . The reaction mixture was filtered and the white residue (amino alcohol IV) was washed with dichloromethane (100 mL). The filtrate was transferred to a separatory funnel. The organic layer was washed twice with cold (0 C) 5% sodium bisulfate solution (2 x 75 mL), twice with saturated sodium bicarbonate solution (2 x 100 mL), brine (100 mL) and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo afforded a white solid which was triturated with hexane and filtered. The carbamate lb was obtained as white solid weighing 13.22 g (85%). Thin layer chromatography (Tic) assay showed R = 0.19 on Si02 using 25% ethyl acetate/hexane as the eluent or an Rf = 0.75 on Si02 using 50% ethyl acetate/hexane as the eluent. 1H NMR (300 MHz, CDCI3): delta 7.4-7.05 (m, 15H), 5.09 (m, IH), 5.05 (s, 2H), 4.5 (br s, IH), 3.88-3.74 (m, 2H), 3.63 (br s, IH), 2.87-2.85 (d, 2H, J=7.8 Hz), 2.72-2.70 (d, 2H, J=6.3 Hz), 1.63-1.60 (m, 2H), 1.38 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With di-isopropyl azodicarboxylate; triphenylphosphine; In toluene; at 5℃; for 48.17h; | Example 9: Preparation of compound 13 (2R-(2S-t-butoxycarbonylamino-3-phenylpropyl)- 3 S-benzylaziridine) . Diisopropyl diazodicarboxylate (17.3 mL, 88 mmol) was added to a mechanically stirred solution of triphenylphosphine (23.1 g, 88 mmol) in toluene (300 mL) at 5 C. The temperature was not allowed to rise above 10 C during the addition. The solution was cooled back to 5 C and then aminoalcohol IV (30.76 g, 80 mmol) was added portionwise over approximately 10 minutes. The cooling bath was removed and the resulting suspension was allowed to stir for 48 hours. The reaction was filtered, washed with 150 mL of cold (0 C) toluene, and dried afford 35 g of the white solid. The white solid was recrystallized from a mixture of 130 mL of methanol and 88 mL of water to afford 18.7 grams (63%) of 13. The recrystallization mother liquors and the filtrate were added together and concentrated in vacuo to afford 43 g of a yellow semi-solid. The residue was stirred with 400 mL of a 1 :1 mixture of methanol and water overnight to form a white solid (37 g). This material was chromato graphed on C-l 8 reverse-phase silica gel (1200 g) using a 50% methanol/water to 90%> methanol/water gradient. The fractions containing the product were combined and the solvent was removed in vacuo to give 13 as a white solid (2.9 g, 10%). The combined total of the two crops of aziridine 13 was 21.6 g (73%). 1H NMR (300 MHz, CD3OD): delta 7.35-7.15 (m, 10H), 4.0-3.85 (br s, 1H), 2.90-2.6 (m, 4H), 2.35-2.15 (m, 2H), 1.75-1.5 (m, 2H), 1.35 (s, 9H). |
Tags: 144163-85-9 synthesis path| 144163-85-9 SDS| 144163-85-9 COA| 144163-85-9 purity| 144163-85-9 application| 144163-85-9 NMR| 144163-85-9 COA| 144163-85-9 structure
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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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