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CAS No. : | 160232-08-6 | MDL No. : | MFCD15144668 |
Formula : | C19H32N2O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NVEPLQDORJSXRO-DLBZAZTESA-N |
M.W : | 336.47 | Pubchem ID : | 9902339 |
Synonyms : |
|
Num. heavy atoms : | 24 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.63 |
Num. rotatable bonds : | 11 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 97.57 |
TPSA : | 70.59 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.06 cm/s |
Log Po/w (iLOGP) : | 3.65 |
Log Po/w (XLOGP3) : | 3.23 |
Log Po/w (WLOGP) : | 2.73 |
Log Po/w (MLOGP) : | 2.46 |
Log Po/w (SILICOS-IT) : | 3.02 |
Consensus Log Po/w : | 3.02 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 1.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.42 |
Solubility : | 0.128 mg/ml ; 0.00038 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.39 |
Solubility : | 0.0139 mg/ml ; 0.0000412 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -4.93 |
Solubility : | 0.00396 mg/ml ; 0.0000118 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.63 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In isopropyl alcohol; at 20℃; | A mixture of tert-butyl(S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (25.0 g) (6.1) and isobutylamine (10.0 eq) in isopropanol (150 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give 6.2 quantitative. The crude product was dried under high vacuum and used as such in the next step. |
100% | In isopropyl alcohol; at 60℃; for 6h; | i-BuNH2 (5.851 g, 80 mmol) was added to a stirred solution of(2S,3S)-1,2-Epoxy-3-(Boc-amino)-4-phenylbutane (8) (1.053 g,4.0 mmol) in i-PrOH (20 mL) and the mixture was warmed at60 C. After 6 h the solvent and the excess of i-BuNH2 wereremoved under reduced pressure and the product (9) was obtainedas white solid in quantitative yield (1.340 g, 4.0 mmol). [a]D20+7.0(c, 1.0, CHCl3); Rf 0.35 (CHCl3/CH3OH 9:1); 1H NMR (500 MHz,CDCl3) dH (ppm) 7.25 (m, 5H), 4.71 (d, J = 8.4 Hz, 1H), 3.80 (m,1H), 3.48 (dd, J1 = 10.8 Hz, J2 = 6.3 Hz, 1H), 3.02 (d, J = 4.7 Hz, 1H),2.99 (d, J = 4.7 Hz, 1H), 2.87 (dd, J1 = 13.7 Hz, J2 = 7.9 Hz, 1H), 2.70(m, 2H), 2.45 (m, 2H), 1.73 (m, 1H), 1.35 (s, 9H), 0.93 (d,J = 6.6 Hz, 6H). 13C NMR (125 MHz, CDCl3): d (ppm) 155.9, 137.9,129.5, 128.4, 126.3, 79.4, 70.6, 57.9, 54.1, 51.4, 36.7, 28.33, 28.27,20.53, 20.51. Anal. Calcd for C19H32N2O3: C, 67.82; H, 9.59; N,8.33; Found C, 67.7; H, 9.7; N, 8.3. |
100% | In isopropyl alcohol; at 60℃;Inert atmosphere; | i-BuNH2 (8.0?mL, 80?mmol) was added to a stirred solution of (2S,3S)-1,2-epoxy-3-(Boc-amino)-4-phenylbutane 15 (1.053?g, 4.0?mmol) in i-PrOH (20?mL). The mixture was warmed at 60?C. After 6?h the solvent and the excess of i-BuNH2 were removed under reduced pressure. The product 16 was obtained as white solid in quantitative yield. 1H and 13C NMR spectra were consistent to literature data.8 |
97.63% | at 65 - 75℃; for 3h; | A mixture of (2S,3S)-1,2-Epoxy-3-(Boc-amino)-4-phenylbutane (II) (100 g) and isobutyl amine (III) (277.9 g) was heated at 65-75C for 3 hours. After completion of the reaction, Isobutyl amine was distilled out completely from reaction mixture at 75-85C. The residue was cooled below 50C and Methanol (200 ml) was added. The mixture was heated at 60-70C to make a clear solution. The solution was cooled at 25-35C and added to water (1000 ml) and stirred for 2 hours. The product was filtered and washed with water (2 X 50 ml) to get wet cake.The wet cake was re-slurried in water (1500 ml), stirred for 2 hours and filtered. The wet cake was washed with water (2 X 50 ml). Solid was dried in air tray dryer for 2 hours at 25-35C and then at 65-75C for 12 hours to give the title product (124.0 g)Yield: 97.63% |
97.87% | at 65 - 70℃; | (0109) Isobutylamine (1 1 1.03 g,1.519 mol) was charged to (2S,3S)-l,2-Epoxy-3-(Boc- (0110) Amino)-4-Phenylbutane (20.0 g, 0.0759 mol) at room temperature. Reaction mass heated to 65-70C and stirred for 3-4 hours for the completion of reaction. Distilled the reaction mass completely under vacuum. Charged methanol (20.0 mi) and charge water (200.0 ml) at 50-55C. Cool the reaction mass to 25-35uC and stir for 2-3 hours. Filtered the solid under vacuum and washed with water (40.0 ml). Dried the wet compound at 5()-55C and obtained the compound tert-Butyl (2S,3R)-3-hydroxy-4- (isobutylamino)- 1 -phenylbutan-2-ylcarbamate. (0111) Yield: 97.87% (0112) Purity: 98.55% (by HPLC) (0113) Purification: tert-Butyl(2S,3R)-3-hydroxy-4-(isobutylamino)- 1 -phenylbutan-2-yl carbamate compound (VI) (5.0 g) was stirred in Diisopropylether (50 ml) at 65-70C for 30-60 minutes. Cooled the reaction mass to room temperature and stirred for 30-45 minutes. Filtered the solid under vacuum and washed with Diisopropyl ether ( 10.0 ml) and dried at 50-55C. (0114) Yield: 78.0 % (0115) Purity: 99.32 %, Dibenzyl impurity (VIII): 0.51 % (by HPLC) |
95.7% | In neat (no solvent); at 50 - 60℃; for 2h;Reflux; | (2S,3S)-1,2-Epoxy-3-(Boc-amino)-4-phenylbutane (40 g, 0.15 moles) was added to isobutyl amine (80 mL, 0.78 moles) in several portions at 50C to 60C. The solution was heated under reflux for 2 hours and isobutyl amine was removed under reduced pressure. Water (200 mL) was added to the residue and the mixture was stirred. The product obtained was filtered, washed with water and dried under vacuum to obtain tert-buiyl [(2S,3R)-3-hydroxy-1-phenyl-4-(propan-2-yl-amino)butan-2-yl]carbamate as white powder. Yield: 49.1 g (95.7%)HPLC Purity: 96% |
85% | In ethanol; at 80℃; for 3h; | To a stirred solution of epoxide 17 (5.00 g,18.98 mmol) in ethanol (140 ml) was added isobutylamine (19.0 ml, 189.9 mmol ) and the reaction mixture was heated to 80 C and stirred for 3 h at that temperature. Upon cooling to rt, the solvents were concentrated off and the residue was triturated with hexanes (3 x 30 mL) to afford amino alcohol 18 (5.43g, 85%) as a white solid: 1H NMR (400 MHz, CDCl3): delta 7.31-7.21 (m, 5H), 4.73-4.70 (m, IH), 3.81 (bs, IH), 3.48-3.46 (m, IH), 3.01-2.96 (m, IH), 2.88-2.86 (m, IH), 2.70-2.68 (m, 2H), 2.42 (m, 2H), 1.75-1.60 (m, 2H), 1.44 (s, 9H), 0.92 (d, J= 5.0 Hz, 2H); MS (ESI) m/z 336 [C19H32N2O3 + H] +. |
83% | In acetonitrile; at 80℃; for 5h; | (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamic acid tert-butyl ester (1) (Belling Technology Co., Ltd.) (20.0 g, 75.94 mmol), acetonitrile 80 mL and Isobutylamine (19.02 mL, 189.46 mmol) was added to a 200 mL eggplant-shaped flask, and the mixture was stirred at 80 C for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. Crude with ethyl acetate /The white target product (21.2 g, 83%) was obtained after recrystallization from n-hexane (1:9), and the white target product was Intermediate 2, |
83% | In acetonitrile; at 80℃; for 5h; | (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamic acid tert-butyl ester(raw material 1,75.94 mmol), acetonitrile 80 mL and isobutylamine (189.46 mmol)It was added to a 200 mL eggplant-shaped flask, and the reaction was stirred at 80 C for 5 hours.After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure.The crude product was recrystallized from a mixture of ethyl acetate and n-hexane (yield: 1:9) to afford white product, Intermediate 2 (21.2 g, 83%). |
83% | In acetonitrile; at 80℃; for 5h; | Tert-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (20.0 g, 75.94 mmol), Acetonitrile 80 mL and isobutylamine (19.02 mL, 189.46 mmol) were placed in a 200 mL eggplant-shaped flask, and the mixture was stirred at 80 C for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was recrystallized from ethyl acetate / n-hexane (1: 9) to give the title compound (21.2 g, 83%) as the desired product as the intermediate b1, LC-MS (ESI, M+H+) m/ z 337.2. |
Heating / reflux; | Example 1 : Preparation of (1-Benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid tert-butyl ester. To 154.4 Kg isobutylamine, (1-Oxiranyl-2 phenyl-ethyl)-carbamic acid tert-butyl ester (53. 3 Kg) was added, and then the solution was heated under reflux. Under reduced pressure, isobutylamine was removed from the reaction mixture, and then replaced by toluene. | |
Description of the chemical reactions for scheme 1; (1 -Benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid tert-butyl ester (2); This compound was synthesized from the commercially available (1-oxiranyl-2-phenyl- ethyl)-carbamic acid tert-butyl ester (1 ), which was reacted with isobutylamine thereby forming the amino alcohol 2. <n="20"/>1 Ng, J. S.; Przybyla, C. A.; Zhang, S. Method of preparing retroviral protease inhibitor intermediates via diasterereomer purification. PCT Int. Appl. 1996, WO 9622275. | ||
In isopropyl alcohol; for 1h;Heating / reflux; | Step 1: To a solution of 1000 mL of isobutylamine and 1000 mL of isopropanol at room temperature was added 500 g of the commercially-available epoxide (9), and the resulting mixture was heated to reflux for 1 hour. After cooling, the mixture was concentrated under vacuum, and the residue was triturated with 1000 mL of heptane. The resulting precipitate was recovered by filtration, washed with heptane, and dried to provide 625 g of the aminoalcohol (10). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With dmap; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 30℃; for 0.5h;Cooling with ice; | Intermediate 2 (5.0 g, 14.86 mmol), tetrahydrofuran (THF) (40 mL) was added to a 250 mL eggplant-shaped flask, and N,N-diisopropylethylamine (DIEA) (3.68 mL, 16.34 mmol) was slowly added to the ice bath. And 4-dimethylaminopyridine (DMAP) (0.18 g, 1.49 mmol), followed by a mixed solution of 4-methoxybenzenesulfonyl chloride (3.38 g, 16.34 mmol) and THF (10 mL). The mixture was stirred for 0.5 hour in an ice bath and moved to room temperature. After completion of the reaction by TLC, THF was evaporated, evaporated, evaporated. Purification of ethyl acetate-n-hexane (1:5) by flash column to give the desired product as a white solid, intermediate 3a(6.14g, 82%), its structural formula is shown in Figure 1. |
82% | With dmap; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 0.5h;Cooling with ice; | Intermediate 2 (14.86 mmol),Tetrahydrofuran (THF, 40 mL) was added to a 250 mL eggplant-shaped bottle.N,N-diisopropylethylamine (DIEA, 3.68 mL, 16.34 mmol) was added slowly under ice bath.And 4-dimethylaminopyridine (DMAP, 1.49 mmol),Then a mixed solution of 4-methoxybenzenesulfonyl chloride (16.34 mmol) and THF (10 mL) was added.The reaction was stirred for 0.5 hours under an ice bath and then transferred to room temperature. After TLC detects the reaction,Concentrated under reduced pressure to remove THF and ethyl acetate (3×30 mL).The organic phase was dried over anhydrous sodium sulfate and concentrated.The crude product was purified by flash column (the eluent used was the mass ratio of ethyl acetate to n-hexane).The mixture of 1:5 gave a white solid, intermediate 3a (6.14 g, 82%). |
82% | With dmap; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 0.5h;Cooling with ice; | Intermediate b1 (5.0 g, 14.86 mmol), tetrahydrofuran (THF) (40 mL) was added to a 250 mL eggplant-shaped flask, and N,N-diisopropylethylamine (DIEA) (3.68 mL, 16.34 mmol) was slowly added to the ice bath. And 4-dimethylaminopyridine (DMAP) (0.18 g, 1.49 mmol), followed by a mixed solution of 4-methoxybenzenesulfonyl chloride (3.38 g, 16.34 mmol) and THF (10 mL). The mixture was stirred for 0.5 hour in an ice bath and moved to room temperature. After completion of the reaction by TLC, THF was evaporated, evaporated, evaporated. The crude product was purified by flash column eluting ethyl acetate-hexanes (1:5) to give the desired product as a white solid, intermediate b2 (6.14 g, 82%), LC-MS (ESI, M+H+) m/z 507.0. |
With sodium carbonate; In dichloromethane; water; at 0 - 20℃; | To an ice-cooled solution of the secondary amine 12 (5 mmol) in CH2Cl2 (20 mL) was added an aqueous solution OfNa2CO3 (8 mmol in 5 mL H2O) followed by the slow addition of sulfonyl chloride (5 mmol) solution in CH2Cl2 (5 mL). After 15 minutes the reaction mixture was warmed to ambient temperature and stirred till no starting material was detected by tic. Reaction mixture was diluted with CH2Cl2 and layers were separated. Organic extract was washed with saturated aqueous NaCl solution, dried (Na2SO4), filtered <n="95"/>and evaporated. Product was purified by flash chromatography on silica gel using mixture of ethyl acetate and hexanes as eluent to afford pure product. | |
With sodium hydrogencarbonate; In dichloromethane; at 23℃; for 12h; | To a stirred solution of amine (1 mmol) in a mixture Of CH2Cl2 (15 mL) and saturated aqueous sodium bicarbonate (15 mL) at 23 0C was added 4-methoxybenzenesufonyl chloride (3 mmol). The resulting mixture was stirred at 23 0C for 12 h. the mixture was then extracted with CH2Cl2 and dried over anhydrous Na2SO4. Removal of solvent under reduced pressure, followed by column chromatography over silica gel provided sulfonamide 3 in 80-95% yield. | |
With triethylamine; In dichloromethane; at 20℃; for 24h;Inert atmosphere; | To a stirred solution of aminoalcohol 16 (0.262?g, 0.78?mmol) in anhydrous CH2Cl2 (40?mL), Et3N (0.28?mL, 2.02?mmol) and 4-methoxybenzenesulfonyl chloride (0.192?g, 0.93?mmol) were added at room temperature and under Ar atmosphere. After 24?h the reaction was quenched with 5% aqueous H2SO4 solution. The organic layer was washed adding saturated aqueous NaHCO3 solution and brine. The organic phases collected were dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified on silica gel (CH2Cl2/EtOAc 98:2) and compound 17 was isolated as white solid. 1H and 13C NMR spectra were consistent to literature data.8 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.5% | With triethylamine; In isopropyl alcohol; at 60 - 65℃; for 1h; | 7.5 g (22.3mmol) of (lS,2R)-(l-benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid tert-butyl ester and 2.7g (26.8mmol, 1.2equiv) of triethylamine are dissolved in lOOg of isopropanol and heated to 60-65C. 5.4 Ig (24.5mmol, 1.1 eq) p-nitrophenyl- sulfonyl chloride are added in several portions within 30 minutes. The reaction mixture <n="13"/>is kept at 60C for another 30 minutes. 1Og of water are added and the suspension is stirred for an additional 30 minutes at 60 0C. The mixture is cooled to 25C within 90 min and the product is filtered off, washed with a mixture of isopropano I/water (1 :1 v/v) and dried under vacuum to yield 11.23g (96.5%) of white (lS,2R)-{l-benzyl- 2-hydroxy-3-[isobutyl-(4-nitro-benzenesulfonyl)-amino]-propyl}-carbamic acid tert-butyl ester. HPLC purity >99.8 %, no single impurity >0.05 %. |
92% | With triethylamine; In isopropyl alcohol; at 40 - 60℃;Large scale; | To 20L 4-neck flask was added successively 9,4 kg, isopropanol, triethylamine (0.18Kg, 1.78mol, 1.20equiv) and the compound C (0.512Kg, 1.52mol, 1equiv. )Was stirred under heating to 40 ~ 60 , p-nitrobenzenesulfonyl chloride was added portionwise (0.388Kg, 1.75mol, 1.15equiv.) .After the addition was complete the mixture was stirred at this temperature for 2 to 3 hours, water was added to the system 1Kg, completion, stirring 0.5 hours, cooled to room temperature, and large amount of solid precipitated.Suction filtered, the filter cake was washed successively with water 1.5L × 3, after washing, washed with 3.6L water 1L of isopropanol / isopropyl alcohol (1/1 by volume), and vacuum dried filter cake, the filter cake washed with 6 volumes of ethanol crystallization 730g compound D (compound D1HNMR spectrum as shown in Figure 3, the measurement process to add all three methoxybenzene as an internal standard, test conditions: 500MHz, ethanol-containing chloroform).Yield 92%, HPLC purity ?99.4%, isomer content of |
80% | With triethylamine; In dichloromethane; at 0 - 20℃; | Triethylamine (2.47 mL, 17.75 mmol) was added to a solution of amine 18 (5.43 g, 16.13 mmol) in CH2Cl2 (25 mL) at 0 0C. To this mixture was added 4-nitrobenzenesulfonylchloride (3.75g, 16.94 mmol) and the reaction was stirred at ambient temperature for 3 h. The reaction mixture was washed with water (2 * 20 mL), dried over Na2SO4, filtered and concentrated. The crude compound was purified by column chromatography (1.5% MeOH in CH2Cl2) to afford sulfonamide 19 (6.73g, 80%) as a pale yellow solid: 1H NMR (400 MHz, DMSO-J6) delta 8.36 (d, J= 8.8 Hz, 2H), 8.05 (d, J= 8.8 Hz, 2H), 7.24-7.13 (m, 5H), 6.68 (d, J= 8.8 Hz, IH), 4.95 (d, J= 6.4 Hz, IH), 4.33 (d, J= 4.4 Hz, IH), 3.78-3.74 (m, IH), 3.49-3.33 (m, 3H), 3.17-3.3.03 (m, 2H), 2.95-2.90 (m, 2H), 1.23 (s, 9H), 0..93-0.90 (m, 6H); MS (ESI) m/z 521 [C25H35N3O7S + H]+. |
76% | With potassium carbonate; In water; ethyl acetate; toluene; at 75℃; for 1h; | BOC protected 2R,3S-N-isobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl)amine (51.1g, 0.152mol) in toluene (12.5eq, 175g) was heated to 750C and aqueous potassium carbonate solution added (2eq, 14.5%w/w, 291 g). With vigourous stirring,, a solution of 4- nitrobenzenesulfonyl chloride (1.3eq, 43.8g) in ethyl acetate (9.7eq, 13Og) was added. The solution was held at 750C for one hour before removing the aqueous phase. The organic phase was washed with hot water at 750C (3 x 20Og). Methanol was charged (205.7g, 42.2eq) and the mixture cooled to 430C over an hour. The mixture was then seeded with BOC-protected 2R,3S-N-isobutyl-N-(2-hydroxy-3-amino-4-phenyibutyl)-p- EPO <DP n="10"/>nitrobenzene-sulfonylamide of Crystal Form Il (0.1 g) and then cooled at a rate of 3.5C/h for 2hrs, then at 5C/hr for 2 hrs and then finally at 10C/hr until 00C was reached. The solid was then isolated by filtration and washed with 10% v/v ethyl acetate/methanol (3 x 144g). The isolated crystals are prismatic (thick needle) and thus are amenabie to easy filtration. Scanning Electron Microscopy (Hitachi S570 Scanning Electron Microscope) shows 'fluted' rod shaped particles that are up to ~ 200.0 micron long. XRD analysis (Siemens D5000 X-Ray Diffractometer, 2Theta, CuKa radiation) shows the crystals to be Crystal Form Il with strong peaks at 5.3 and 8.3, moderate peaks at 6.7, 10.7, 13.4, 18.8, 19.6, 21.3 and 23.8 and weak peaks at 7.9, 17.3, 20.6 and 21.9.The product was dried in a vacuum oven at 500C. Isolated yield = 60.4g (76%). |
With triethylamine; In toluene; at 82 - 88℃;Stirring; | Example 2: Preparation of (1-Benzyl-2-hvdroxy-3-risobutvl-(4-nitro-benzenesulfonvl - amino]-propyl}-carbamic acid tort-butyl ester 26.7 kg triethylamine were added to the prepared solution in Example 1, and the obtained solution was heated to 82-88C. To the solution, a solution of 4-niirobenzene- sulfonyl chloride (53 Kg) in toluene was gradually added and stirred. The obtained reaction mixture was washed with water. The washed solution of (1-Benzyl-2-hydroxy-3- [isobutyl- (4-nitro-benzenesulfonyl)- amino]-propyl)-carbamic acid tert-butyl ester was heated, then toluene and n-hcptanc were added. This solution was cooled and seeded with crystals of (l-Benzyl-2- hydroxy-3-[isobutyl-4-nitro-benzenesulfonyl)-amino]-propyl)-carbamic acid tert-butyl ester. After the deposition of crystals was observed, the solution was kept stirring and then was slowly cooled to 20-30C. The resulting crystals were filtered off and washed with a mixed solution composed of toluene and n-heptane to give the wet crystals of (l-Benzyl-2-hydroxy-3-[isobutyl-(4-nitro-benzenesulfonyl)-amino]-propyl)-carbamic acid tert-butyl ester (yield 87-91%, based on (1-Oxiranyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester). | |
With triethylamine; In dichloromethane; at 0 - 20℃; for 12h; | Step 2: Synthesis of tert-butyl (2S,3R)-3-hydroxy-4-(N-isobutyl-4- nitrophenylsulfonamido -l-phenylbutan-2-ylcarbamate:To a stirred solution of tert-butyl (2S,3R)-3-hydroxy-4-(isobutylamino)-l- phenylbutan-2-ylcarbamate (Step 1 , about 5 g) in DCM (about 75 ml) triethylamine (about 6.2 ml) was added and the reaction was cooled to about 0c then 4- nitrobenzene-l -sulfonyl chloride (about 3.9 g) was added and stirred at room temperature for about 12 hours. Completion of reaction was monitored by TLC, then the reaction mixture was diluted with DCM, the organic layer was washed with saturated NaHC03, brine, dried over Na2S04 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% ethyl acetate in hexane as eluent to furnish the title compound (3 g) as a white solid. 'HNMR (300 MHz in CDC13): 0.86-0.89 (m, 6H); 1 .35 (s, 9H); 1.69-1.73 (m, 1H); 2.97-3.20 (m, 6H); 3. 75-3.80 (m, 2H); 4.69-4.67 (d, j=7.5Htz, 1H); 7.22-7.31 (m, 5H); 7.94-8.30 (m, 4H); MASS (M+l ): 522. | |
A mixture of [N-(t-butoxycarbonyl)L-phenylalanine]chlorohydrine (6, 114 g, 0.38 mol), isobutylamine (28.5, 0.39 mol) and a solution of sodium bicarbonate (33.6 g, 0.4 mol in 100 mL) in methylene chloride (500 mL g) is heated at a gentle reflux for 5 h. Water (1000 g) is added and excess isobutyl amine is removed by distillation under nitrogen at an internal reaction temperature of 70 C. Additional water (500 g) is added and the product is isolated by filtration and dried. Finally, Isobutylamine traces were removed by flushing with methylene dichloride to get compound of formula 7. The resultant compound of formula 7 was dissolved in methylene dichloride (1200 mL), triethylamine (50 g, 0.495 mol) was added and heated to reflux. A solution of p-nitrobenzenesulfonyl chloride (93.0g, 0.42 mol) in methylene chloride (300 mL) was added slowly to the reaction mixture at reflux temperature. After reaction complies by HPLC, water (500 mL) was charged to the reaction mixture. The two layers were separated and methylene dichloride was distilled under atmospheric pressure. Finally, methylene dichloride traces were removed by co-distillation with isopropyl alcohol. Isopropyl alcohol (1000 mL) was added to the mass, heated to reflux and maintained for 60 min. The reaction mass was cooled to 30 - 35C, filtered and washed with isopropyl alcohol. The product obtained was dried at 70-75C to get the compound of formula 3a in 188 g with HPLC purity of 99.3% | ||
With triethylamine; In dichloromethane;Reflux; | A solution of (2S,3S)-1,2-epoxy-3-(butoxycarbonyl)amino-4-phenylbutane (2a, 100 g, 0.380 mol) of) in isobutylamine (150 g, 2.05 mol) of) was heated under and maintained for 3 h. After completion of the reaction, excess of isobutylamine was removed under reduced pressure. Isobutylamine traces were removed by flushing with methylene dichloride. The resultant solid was dissolved in methylene dichloride (1200 mL), triethylamine (50 g, 0.495 mol) was added and heated to reflux. A solution of p-nitrobenzenesulfonyl chloride (93.0 g, 0.42 mol) in methylene chloride (300 mL) was added slowly to the reaction mixture at reflux temperature. After reaction complies by HPLC, water (500 mL) was charged to the reaction mixture. The two layers were separated and methylene dichloride was distilled under atmospheric pressure. Finally, methylene dichloride traces were removed by co-distillation with isopropyl alcohol. Isopropyl alcohol (1000 mL) was added to the mass, heated to reflux and maintained for 60 min. The reaction mass was cooled to 30-35 C., filtered and washed with isopropyl alcohol. The product obtained was dried at 70-75 C. to get the compound of formula 3a in 184 g (yield -92.88%) with HPLC purity of 99.26%. | |
With triethylamine; In dichloromethane;Reflux; | A mixture of [N-(t-butoxycarbonyl)L-phenylalanine]chlorohydrine (6, 114 g, 0.38 mol), isobutylamine (28.5, 0.39 mol) and a solution of sodium bicarbonate (33.6 g, 0.4 mol in 100 mL) in methylene chloride (500 mL g) is heated at a gentle reflux for 5 h. Water (1000 g) is added and excess isobutyl amine is removed by distillation under nitrogen at an internal reaction temperature of 70 C. Additional water (500 g) is added and the product is isolated by filtration and dried. Finally, Isobutylamine traces were removed by flushing with methylene dichloride to get compound of formula 7. The resultant compound of formula 7 was dissolved in methylene dichloride (1200 mL), triethylamine (50 g, 0.495 mol) was added and heated to reflux. A solution of p-nitrobenzenesulfonyl chloride (93.0 g, 0.42 mol) in methylene chloride (300 mL) was added slowly to the reaction mixture at reflux temperature. After reaction complies by HPLC, water (500 mL) was charged to the reaction mixture. The two layers were separated and methylene dichloride was distilled under atmospheric pressure. Finally, methylene dichloride traces were removed by co-distillation with isopropyl alcohol. Isopropyl alcohol (1000 mL) was added to the mass, heated to reflux and maintained for 60 min. The reaction mass was cooled to 30-35 C., filtered and washed with isopropyl alcohol. The product obtained was dried at 70-75 C. to get the compound of formula 3a in 188 g with HPLC purity of 99.3%. | |
145 g | With triethylamine; In dichloromethane; at 40 - 45℃; | Example -3: Preparation of [(1S, 2R)-3-[[(4-nitrophenyl) sulfonyl] (2-methylpropyl) amino]- 2-hydroxy-1-(phenylmethyl) propyl] carbmic acid tert-butylester (3). [(1 S, 2R)-3-[(2-methylpropyl) amino]-2-hydroxy-1 -(phenyl methyl) propyl] carbamic acid tert-butyl ester (4, 100 gm) and triethylamine (39.04 g) was added to methylenedichloride (1200 mL) and the temperature was raised to 40C. p-nitro benzene sulfonyl chloride solution (72.3g of p-NBSC dissolve in 300mL methylenedichloride) was added slowly at 40-45C for 2-3 hrs. The reaction was maintained for 3hours at 40 - 45C. After completion of the reaction, water (500 mL) was added, separated the organic layer and distilled out methylene dichloride at atmospheric pressure. Finally, strip out the methylene dichloride by using isopropyl alcohol (200 mL). Isopropyl alcohol (1000 mL) was added to the distillate and maintained the stirring for 60 minutes at 70- 80C. Cooled the mass to 30 - 35C, filtered and washed with Isopropyl alcohol to get title compound 3 (yield 145 g). |
260 g | With triethylamine; In dichloromethane; at 15 - 30℃; for 1h; | (lS,2R)-[3-(2-Methylpropyl-amino)]-2-hydroxy-l-(phenylmethyl) carbamic acid tert- butyl ester (170 g) was dissolved in methylene chloride (2040 ml) and added triethylamine (56.20 g) at 15-20C. Thereafter, a solution of 4rnitrobenzenesulfonyl chloride (1 17.70 g) in methylene chloride (510 ml) was added to the above solution at 15-30C and stirred at 25-30C for 1 h. After completion of the reaction the reaction mixture was washed sequentially with DM water (340 ml), aqueous sodium bicarbonate solution (2 x 425 ml) and DM water (340 ml) at 25-30C. The organic layer was concentrated under reduced pressure at 30-45C. Toluene (1530 ml) was added to the residue, stirred at 50-55C for 30 min, thereafter cooled to 25-30C and stirred at this temperature for 1 h. The obtained product was filtered, washed with toluene (170 ml) and dried at 50-55C under reduced pressure to obtain title compound. Yield: 260 g |
145 g | With triethylamine; In dichloromethane; at 40 - 45℃; | Example 3 Preparation of [(1S,2R)-3-[[(4-nitrophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]carbmic acid tert-butylester (3) [(1S,2R)-3-[(2-methylpropyl)amino]-2-hydroxy-1-(phenyl methyl)propyl]carbamic acid tert-butyl ester (4, 100 gm) and triethylamine (39.04 g) was added to methylenedichloride (1200 mL) and the temperature was raised to 40 C. p-nitro benzene sulfonyl chloride solution (72.3 g of p-NBSC dissolve in 300 mL methylenedichloride) was added slowly at 40-45 C. for 2-3 hrs. The reaction was maintained for 3 hours at 40-45 C. After completion of the reaction, water (500 mL) was added, separated the organic layer and distilled out methylene dichloride at atmospheric pressure. Finally, strip out the methylene dichloride by using isopropyl alcohol (200 mL). Isopropyl alcohol (1000 mL) was added to the distillate and maintained the stirring for 60 minutes at 70-80 C. Cooled the mass to 30-35 C., filtered and washed with Isopropyl alcohol to get title compound 3 (yield 145 g). |
260 g | With triethylamine; In dichloromethane; at 15 - 30℃; for 1h; | (1S,2R)-[3-(2-Methylpropyl-amino)]-2-hydroxy-1-(phenylmethyl) carbamic acid tert-butyl ester (170 g) was dissolved in methylene chloride (2040 ml) and added triethylamine (56.20 g) at 15-20 C. Thereafter, a solution of 4-nitrobenzenesulfonyl chloride (117.70 g) in methylene chloride (510 ml) was added to the above solution at 15-30 C. and stirred at 25-30 C. for 1 h. After completion of the reaction the reaction mixture was washed sequentially with DM water (340 ml), aqueous sodium bicarbonate solution (2×425 ml) and DM water (340 ml) at 25-30 C. The organic layer was concentrated under reduced pressure at 30-45 C. Toluene (1530 ml) was added to the residue, stirred at 50-55 C. for 30 min, thereafter cooled to 25-30 C. and stirred at this temperature for 1 h. The obtained product was filtered, washed with toluene (170 ml) and dried at 50-55 C. under reduced pressure to obtain title compound. [0099] Yield: 260 g [0100] Chromatographic Purity (by HPLC): 99.95% |
367 g | With triethylamine; In dichloromethane; at 15 - 25℃; | A mixture of isobutyl amine (1000 mL, 9.981 mol), IPA (200 mL, 1.0 volume) and200 g (0.759 mol) of 3 was stirred for 12-14 h at 20-30 C. After completion ofreaction (TLC), volatiles were removed under vacuum. Water (1000 mL) was addedto the residue followed by stirring for 2 h, and subsequent filtration resulted to affordintermediate 6, after drying at 50-60 C in air oven over a period of 10-12 h. Driedsolid was then mixed with DCM (740 mL), TEA (115 mL, 0.835 mol) at 15-25 Cfollowed by slow addition of 4-nitrobenzenesulfonyl chloride solution (168 g,0.759 mol, in 300 mL of DCM) at 15-25 C. Resulted reaction mixture was stirredfor 1-2 h at 15-25 C. After reaction completion (TLC), volatiles were evaporatedunder vacuum completely. Water (1500 mL) and sodium hydroxide solution(200 mL; 0.700 mol) was added to distilled residue followed by stirring for 2 h. Theresulting aqueous slurry was filtered, washed with water and dried in air oven at55-60 C over a period of 10-12 h to yield the intermediate 7. (367 g, 93%): Rf(3-6 = 0.50 and 6-7 = 0.80); 1H NMR (400 MHz, DMSO-d6) delta 0.81-0.85 (m, 6H,-2CH3), 1.24 (s, 9H, -3CH3), 1.94-1.99 (m, 1H, -CH), 2.91-2.96 (m, 2H, -CH2),3.04-3.17 and 3.42-3.50 (m, 5H, -2CH2, -CH(OH)), 4.93 (d, J = 6.4 Hz, 1H, -CH),6.64 (d, J = 8.8 Hz, 1H, -NH), 7.24-7.11 (m, 5H, arom-H), 8.04 (d, J = 8.4 Hz, 2H,arom-H), 8.36 (d, J = 8.4 Hz, 2H, arom-H); 13C NMR (100 MHz, DMSO-d6) delta 19.5, 19.7, 25.7, 28.0, 35.3, 51.1, 55.0, 71.1, 77.4, 124.2, 125.5, 127.7, 128.4, 129.0,139.3, 145.4, 149.3, 155.1; IR (KBr, cm-1) 3562, 3363, 2960, 1697; MS (ES+) m/z:522.23 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With dmap; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 23℃; for 4h; | |
With triethylamine In tetrahydrofuran at 20℃; for 4h; | ||
With triethylamine In tetrahydrofuran at 25℃; for 4h; | 17.B.2 Part 2; (acetyloxy)(4-[{(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl}(isobutyl)amino]sulfonyl}phenyl)methyl Acetate A solution of Example 1 (12.82 g) in tetrahydrofuran (95 mL) was treated with triethylamine (15.9 mL), followed by a solution of the product of Part I of method B (14.0 g) in tetrahydrofuran (95 mL) and stirred at 25° C. for 4 hrs. The mixture was treated with saturated NaHCO3 solution (125 mL), and the solvents were evaporated. The residue was diluted with water and extracted with ethyl acetate (3×), and the combined organic layers were dried over Na2SO4, filtered and concentrated to give the product. |
With dmap; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.67% | In isopropyl alcohol at 20 - 30℃; | Preparation of tert-butyl((1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl[(-4-nitrophenyl)sulfonyl]-amino]propyl]carbamate (7) A mixture of isobutyl amine (1000 mL, 9.981 mol), IPA (200 mL, 1.0 volume) and200 g (0.759 mol) of 3 was stirred for 12-14 h at 20-30 °C. After completion ofreaction (TLC), volatiles were removed under vacuum. Water (1000 mL) was addedto the residue followed by stirring for 2 h, and subsequent filtration resulted to affordintermediate 6, after drying at 50-60 °C in air oven over a period of 10-12 h. Driedsolid was then mixed with DCM (740 mL), TEA (115 mL, 0.835 mol) at 15-25 °Cfollowed by slow addition of 4-nitrobenzenesulfonyl chloride solution (168 g,0.759 mol, in 300 mL of DCM) at 15-25 °C. Resulted reaction mixture was stirredfor 1-2 h at 15-25 °C. After reaction completion (TLC), volatiles were evaporatedunder vacuum completely. Water (1500 mL) and sodium hydroxide solution(200 mL; 0.700 mol) was added to distilled residue followed by stirring for 2 h. Theresulting aqueous slurry was filtered, washed with water and dried in air oven at55-60 °C over a period of 10-12 h to yield the intermediate 7. |
93% | In isopropyl alcohol at 80℃; for 2.5h; | 1 EXAMPLE 1; tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propylcarbamate To a solution of (2R,3S)-3-N-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (10 g) in 2-propanol (100 mL) was added isobutylamine (11.4 mL, 3 equivalents), and the mixture was heated at 80° C. for 2.5 hours. After evaporation of the solvents, 11.86 g (93%) of the amine was produced in pure enough form for use in the next step. 1H NMR (300 MHz, CDCl3) δ ppm 0.90 (d, J=1.47 Hz, 3H), 0.92 (d,J=1.47 Hz, 3H), 1.35 (s, 9H), 1.59 (s, 1H), 1.70 (m, 1H), 2.41 (d, J=6.99 Hz, 2H), 2.68 (d,J=4.78 Hz, 2H), 2.88 (d, J=8.09 Hz, 1H), 2.97 (d,J=4.41 Hz, 1H), 3.01 (d, J=4.78 Hz, 1H), 3.45 (q, J=5.52 Hz, 1H), 3.80 (s, 1H), 4.68 (d, J=8.09 Hz, 1H), 7.21 (m, 3H), 7.29 (m, 2H). |
In isopropyl alcohol at 80℃; for 2.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With N-ethyl-N,N-diisopropylamine;dmap; In tetrahydrofuran; at 20℃; for 4h; | Briefly, to a stirred solution of secondary amine 11 (83 mg, 0.25 mmol), N, N- diisopropylethylamine (65 muL,0.37 mmol) and 4-(N, N-dimethylamino)pyridine (3 mg, 0.03 mmol) in THF (2 mL) at room temperature, sulfonyl chloride 22 (60 mg, 0.27 mmol) in THF (1 mL) was added. The mixture was stirred at room temperature for 4 hours and then concentrated in vacuum and the residue was chromatographed with 25% EtOAc in hexanes to afford sulfonamide 3 (105 mg, 81%) as white amorphous solid. 1HNMR (CDC13, 500 MHz): delta 7.33-7.17 m, 7H), 6.86 (d, IH, J = 8 Hz), 6.06 (s, 2H), 4.67 (d, IH, 8 Hz), 3.78 (d, 2H, J = 24 Hz), 3.08-3.06 (m, 2H), 3.02-2.98 (m, IH), 2.96-2.86 (m, 2H), 2.84-2.80 (m, IH), 1.88-1.82 (m, IH), 1.34 (s, 9H), 0.88 (dd, 6H, J = 6.5 Hz, 15.5 Hz ); 13CNMR (CDC13, 500 MHz): delta 189.4,151.3, 148.1, 137.8, 131.6, 129.4, 128.4, 126.3, 108.2, 107.5, 102.2, 79.6, 72.7, 58.6, 54.6, 53.6, 35.4, 28.1, 27.1, 20.0, 19.8. |
71.2% | With dmap; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; | General procedure: To an ice-cooled solution of the secondary amine 6 (5.00g, 14.9mmol) in anhydrous THF (40mL) was added 3.68mL (2.11g, 16.3mmol) of DIEA and DMAP (0.18g, 1.49mmol) followed by the addition of 4-(trifluoromethoxy)benzenesulfonyl chloride (4.25g, 16.3mmol) solution in anhydrous THF (15mL) slowly. After stirring 0.5h at 0C, the reaction mixture was warmed to room temperature and stirred 3-5h. The solvents were removed under diminished pressure and the residue was added water (30mL) and extracted with three 40mL portions of ethyl acetate. The combined organic extracts were dried over Na2SO4 and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (20×4cm). Elution with 5:1 hexanes-ethyl acetate gave 11 as a colorless solid: yield 7.49g (89.7%), mp 136-138C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.7% | With dmap; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; | To an ice-cooled solution of the secondary amine 6 (5.00g, 14.9mmol) in anhydrous THF (40mL) was added 3.68mL (2.11g, 16.3mmol) of DIEA and DMAP (0.18g, 1.49mmol) followed by the addition of <strong>[94108-56-2]4-(trifluoromethoxy)benzenesulfonyl chloride</strong> (4.25g, 16.3mmol) solution in anhydrous THF (15mL) slowly. After stirring 0.5h at 0C, the reaction mixture was warmed to room temperature and stirred 3-5h. The solvents were removed under diminished pressure and the residue was added water (30mL) and extracted with three 40mL portions of ethyl acetate. The combined organic extracts were dried over Na2SO4 and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (20×4cm). Elution with 5:1 hexanes-ethyl acetate gave 11 as a colorless solid: yield 7.49g (89.7%), mp 136-138C. 1H NMR (400MHz, CDCl3) delta 7.85-7.81 (m, 2H), 7.33 (d, J=8.4Hz, 2H), 7.30-7.28 (m, 2H), 7.25-7.21 (m, 3H), 4.63 (d, J=6.8Hz, 1H), 3.82-3.76 (m, 2H), 3.13-3.11 (m, 2H), 3.03-2.86 (m, 4H), 1.92-1.82 (m, 1H), 1.35 (s, 9H), 0.90 (d, J=6.4Hz, 3H), 0.87 (d, J=6.4Hz, 3H); LC-MS (ESI) [M+H]+ m/z 561.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine; In dichloromethane; at 20℃; for 2.5h; | (l-Benzyl-2-hydroxy-3-isobutylamine-propyl)-carbamic acid tert-butyl ester (SM A, 10.08 g, 30 mmol, 1.0 equiv.) and l-benzofuran-5-sulfonyl chloride (SM B, 9.74 g, 45 mmol, 1.5 equiv.) were dissolved in dichloromethane (100 mL). To the solution was added triethylamine (8.36 mL, 60 mmol, 2.0 equiv.) at room temperature. The mixture was stirred at the same temperature for 2.5 h, after which time the reaction was quenched through the addition of 0.5 N hydrochloric acid aqueous solution (50 mL). The phases were separated and then the organic layer was sequentially washed with 5% sodium bicarbonate (50 mL) and water (50 mL). The final organic solution was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by recrystallization from ethyl <n="43"/>acetate/hexane (30/90, v/v) to afford a white solid, 13.09g, m.p. 121.1 -122.4 0C. The filtrate was concentrated and the residue was purified on silica gel (0-50 % ethyl acetate in hexane) to afford 1.13 g additional target compound. Yield 14.22 g (92%). MS 1055 (2MNa)+, 539 (MNa)+ , 417 (M-BOC)+ and 575 (AcOM)". Purity 97% (HPLC). |
92% | With triethylamine; In dichloromethane; at 20℃; for 2.5h; | (l-Benzyl-2-hydroxy-3-isobutylamine-propyl)-carbamic acid tert-butyl ester (SM A, 10.08 g, 30 mmol, 1.0 equiv.) and l-benzofuran-5-sulfonyl chloride (SM B, 9.74 g, 45 mmol, 1.5 equiv.) were dissolved in dichloromethane (100 mL). To the solution was added triethylamine (8.36 mL, 60 mmol, 2.0 equiv.) at room temperature. The mixture was stirred at the same temperature for 2.5 h, after which time the reaction was quenched through the addition of 0.5 N hydrochloric acid aqueous solution (50 mL). The phases were separated and then the organic layer was sequentially washed with 5% sodium bicarbonate (50 mL) and water (50 mL). The final organic solution was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by recrystallization from ethyl acetate/hexane (30/90, v/v) to afford a white solid, 13.09g, m.p. 121.1 -122.4 C. The filtrate was concentrated and the residue was purified on silica gel (0-50 % ethyl acetate in hexane) to afford 1.13 g additional target compound. Yield 14.22 g (92%). MS 1055 (2MNa)+, 539 (MNa)+ , 417 (M-BOC)+ and 575 (AcOM)'. Purity 97% (HPLC). |
92% | With triethylamine; In dichloromethane; at 20℃; for 2.5h; | 10232] (1 -l3enzyl-2-hydroxy-3-isobutylamine-propyl)-carbamic acid tert-butyl ester (SM A, 10.08 g, 30 mmol, 1.0equiv.) and 1 -benzofuran-5-sulfonyl chloride (SM B, 9.74 g,45 mmol, 1.5 equiv.) were dissolved in dichloromethane (100mE). To the solution was added triethylamine (8.36 mE, 60mmol, 2.0 equiv.) at room temperature. The mixture was stirred at the same temperature for 2.5 h, afier which time the reaction was quenched through the addition of 0.5 N hydrochloric acid aqueous solution (50 mE). The phases were separated and then the organic layer was sequentially washed with 5% sodium bicarbonate (50 mE) and water (50 mE). The final organic solution was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by recrystallization from ethyl acetatehexane (3090, v/v) to afford a white solid, 13.09 g, m.p. 121.1-122.4 C. The filtrate was concentrated and the residue was purified on silica gel (0-50% ethyl acetate in hexane) to afford 1.13 g additional target compound.Yield 14.22 g (92%). MS 1055 (2MNa), 539 (MNa), 417 (M-13OC) and 575 (AcOM)z Purity 97% (HPEC). |
92% | With triethylamine; In dichloromethane; at 20℃; for 2.5h; | (1-Benzyl-2-hydroxy-3-isobutylamine-propyl)-carbamic acid tert-butyl ester (SM A,10.08 g, 30 mmol, 1.0 equiv.) and 1-benzofuran-5-sulfonyl chloride (SM B, 9.74 g, 45 mmol,1.5 equiv.) were dissolved in dichloromethane (100 mL). To the solution was added triethylamine (8.36 mL, 60 mmol, 2.0 equiv.) at room temperature. The mixture was stirredat the same temperature for 2.5 h, after which time the reaction was quenched through the addition of 0.5 N hydrochloric acid aqueous solution (50 mL). The phases were separated and then the organic layer was sequentially washed with 5% sodium bicarbonate (50 mL) and water (50 mL). The final organic solution was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by recrystallization from ethylacetate/hexane (30/90, v/v) to afford a white solid, 13.09g, m.p. 121.1 -122.4 C. The filtratewas concentrated and the residue was purified on silica gel (0-50 % ethyl acetate in hexane)to afford 1.13 g additional target compound. Yield 14.22 g (92%). MS 1055 (2MNa), 539(MNa) , 417 (M-BOC) and 575 (AcOM). Purity 97% (HPLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 18h; Heating / reflux; | 86 [00430] Example 86. Preparation of tert-butyl (lS,2R)-l-benzyI-2-hydroxy-3-{isobutyl[(1,3-thiazol- 5-ylmethoxy)carbonyl]amino}propylcarbamate; [00431] Following the same procedure as in Example 50, using (l-benzyl-2-hydroxy-3-isobutylamino propyl) carbamic acid tert-butyl ester) (46 mg, 0.14 mmol, WO 2005061487), Et3N (23 μL, 0.17 mmol) and carbonic acid 5-methyIthiazole ester 4-nitrophenyl ester hydrochloride (48 mg, 0.15 mmol), gave 39.6 mg, 61% of the title compound. NMR (CDC13) δ ppm 8.81 (s, 1 H) 7.88 (s, 1 H) 7.09 - 7.41 (m, 5H) 5.34 (s, 2 H) 4.13 -4.72 (m, 2 H) 3.77 (s, 2 H) 2.72 - 3.62 (m, 6 H) 1.35 (s, 9 H) 0.80 - 0.82 (d, 6 H);MS (M + H+) = 478. [003581 Example 50. Preparation of 1 ,3-thiazoI-5-ylmethyl benzyl(3-{benzyl[( 1 ,3-thiazol-5- ylmethoxy)carbonyl]amino} -2-hydroxyproρyl)carbamate; [00359] To a solution of the compound of Example 42 (0.93 g, 3.4 mmol) in THF (15 mL) was added diisopropylethylamine (2.4 mL, 13.8 mmol) and carbonic acid 4-nitro-phenyl ester thiazol-5-ylmethyl ester hydrochloride salt (see U.S. Patent No. 5,773,625) (2.2 g, 6.9 mmol) and the resulting solution was refluxed for 18 hours after which time the solution was cooled and diluted with EtOAc (30 mL). This solution was washed with 5% K2CO3 (5 x 30 mL) and brine (1 x 30 mL), dried over Na2SO4, filtered, and the solvent removed from the filtrate in vacuo to give a crude residue that was purified by column chromatography on silica gel (2% CH3OH/CH2CI2) to give the title compound. NMR (d6-DMSO) δ ppm 9.10 (d, 2 H) 7.93 (d, 2 H) 6.99 - 7.50 (m, 10 H) 5.31 (s, 4 H) 4.26 - 4.70 (m, 4 H) 3.80 - 4.10 (m, 1 H) 3.08 - 3.37 (m, 2 H) 2.78 - 3.09 (m, 2 H); MS M + H+ = 554. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 0.88 g / triethylamine / CH2Cl2 / 4 h / 20 °C 2: H2 / Pd(OH)2 on carbon / ethyl acetate / 1 h 3: 0.75 g / trifluoroacetic acid / CH2Cl2 / 20 °C | ||
Multi-step reaction with 3 steps 1: 90 percent / Et3N / CH2Cl2 / 16 h 2: 95 percent / H2 / Pd(OH)2 / ethyl acetate / 4 h 3: 96 percent / TFA / CH2Cl2 / 4 h | ||
Multi-step reaction with 3 steps 1: 96 percent / NaHCO3 / H2O; CH2Cl2 / 12 h / 23 °C 2: 95 percent / H2 / Pd/C / ethyl acetate / 11 h / 23 °C 3: CF3CO2H / CH2Cl2 / 0.67 h / 23 °C |
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / Reflux 2: hydrogen; triethanolamine / palladium 10% on activated carbon / methanol / 2 h / 40 - 45 °C 3: hydrogenchloride; water monomer / 2 h / Reflux | ||
Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 1 h / 0 - 30 °C 2.1: hydrogenchloride; water monomer / ethanol / 10 h / 55 - 65 °C 2.2: 0.5 h / 25 - 30 °C / pH 11.5 - 12.5 | ||
Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / 1 h / 0 - 30 °C 2.1: trifluoroacetic acid / dichloromethane / 5 h / 20 - 25 °C 2.2: pH 9.11 3.1: hydrogenchloride / water monomer; ethanol / 6.5 h / 60 - 65 °C 4.1: anhydrous sodium carbonate / dichloromethane; water monomer / 0.33 h / 20 - 25 °C | ||
Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 40 - 45 °C 2.1: palladium 10% on activated carbon; hydrogen; triethanolamine / isopropanol / 3 h / 40 - 45 °C / 3000.3 - 4500.45 Torr 2.2: Reflux | ||
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 40 - 45 °C 2: palladium 10% on activated carbon; hydrogen; triethanolamine / isopropanol / 3 h / 40 - 45 °C / 3000.3 - 4500.45 Torr 3: water monomer; hydrogenchloride | ||
Multi-step reaction with 3 steps 1: triethylamine / N,N-dimethyl acetamide / 2 h / 25 - 35 °C 2: sulfuric acid / isopropanol; water monomer / 12 h / 25 - 90 °C 3: potassium carbonate / water monomer / 3 h / 50 - 60 °C | ||
Multi-step reaction with 3 steps 1: dmap; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 3 h / 0 - 20 °C / Inert atmosphere 3: palladium 10% on activated carbon; hydrogen / methanol / 2 h / 20 °C / 2585.81 Torr / Inert atmosphere | ||
Multi-step reaction with 3 steps 1: dmap; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 - 20 °C 2: trifluoroacetic acid / dichloromethane / 3 h / 0 - 20 °C 3: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 20 °C / 2585.81 Torr | ||
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 15 - 25 °C 2: hydrogen / methanol / 20 - 25 °C / Autoclave 3: hydrogenchloride / ethyl acetate; water monomer / 20 - 25 °C 4: sodium hydroxide / water monomer / 10 - 20 °C | ||
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; dmap / tetrahydrofuran / 0 - 20 °C 2: trifluoroacetic acid / dichloromethane / 3 h / 0 - 20 °C 3: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 20 °C / 2585.81 Torr | ||
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; dmap / tetrahydrofuran / 0 - 25 °C 2: trifluoroacetic acid / dichloromethane / 3 h 3: palladium 10% on activated carbon; hydrogen / methanol / 2 h / 25 °C / 2585.81 Torr | ||
Multi-step reaction with 3 steps 1: dmap; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 4 h / 0 - 25 °C 2: trifluoroacetic acid / dichloromethane / 2 h / 25 °C 3: palladium 10% on activated carbon; hydrogen / ethyl acetate; methanol / 7 h / 25 °C / 2585.81 Torr | ||
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; dmap / tetrahydrofuran / 4 h / 20 °C 2: trifluoroacetic acid / dichloromethane / 2 h / 25 °C 3: palladium 10% on activated carbon; hydrogen / methanol / 2 h / 20 °C / 2585.81 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 96 percent / NaHCO3 / H2O; CH2Cl2 / 12 h / 23 °C 2: 95 percent / H2 / Pd/C / ethyl acetate / 11 h / 23 °C 3: CF3CO2H / CH2Cl2 / 0.67 h / 23 °C 4: 75 mg / Et3N / CH2Cl2 / 3 h / 23 °C | ||
Multi-step reaction with 3 steps 1.1: triethylamine / dichloromethane / Reflux 1.2: Reflux 2.1: hydrogen; triethanolamine / palladium 10% on activated carbon / methanol / 2 h / 40 - 45 °C 2.2: 2 h / Reflux 2.3: 10 h / 20 °C / pH 9 - 10 3.1: 1-methyl-pyrrolidin-2-one / 10 h / -4 - 30 °C | ||
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / Reflux 2: hydrogen; triethanolamine / 10% Pd/C / methanol / 2 h / 40 - 45 °C 3: hydrogenchloride; water / 2 h / Reflux |
Multi-step reaction with 5 steps 1.1: triethylamine / dichloromethane / Reflux 2.1: hydrogen; triethanolamine / 10% Pd/C / methanol / 2 h / 40 - 45 °C 3.1: hydrogenchloride; water / 2 h / Reflux 4.1: 1-methyl-pyrrolidin-2-one / 10 h / -4 - 30 °C 4.2: 1 h / 45 - 50 °C 5.1: dichloromethane / 2 h / 36 - 40 °C / 580 Torr | ||
Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / 1 h / 15 - 30 °C 2.1: hydrogenchloride / ethanol; water / 1 h / 75 - 80 °C 3.1: hydrogen / methanol / 10 h / 25 - 30 °C / 3000.3 - 4500.45 Torr 4.1: sodium hydroxide / dichloromethane; water / 20 - 30 °C / pH 10 4.2: 3 h / 5 - 30 °C | ||
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 40 - 45 °C 2: 10% Pd/C; hydrogen; triethanolamine / isopropyl alcohol / 3 h / 40 - 45 °C / 3000.3 - 4500.45 Torr 3: water; hydrogenchloride 4: 1-methyl-pyrrolidin-2-one / -5 - 30 °C / Inert atmosphere | ||
Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / 1 h / 15 - 30 °C 2.1: hydrogenchloride / dichloromethane; ethanol; water / 2 h / 5 - 80 °C 3.1: hydrogen / methanol / 10 h / 25 - 30 °C / 3000.3 - 4500.45 Torr 4.1: sodium hydroxide / dichloromethane; water / 20 - 30 °C / pH 10 4.2: 3 h / 5 - 30 °C | ||
Multi-step reaction with 4 steps 1: sodium hydrogencarbonate / dichloromethane; water / 21 h / 20 °C 2: trifluoroacetic acid / dichloromethane / 3 h / 0 - 20 °C 3: triethylamine / dichloromethane / 24 h / 20 °C / Inert atmosphere 4: 10% Pd/C; hydrogen / methanol / 24 h / 20 °C | ||
Multi-step reaction with 4 steps 1: triethylamine / N,N-dimethyl acetamide / 2 h / 25 - 35 °C 2: sulfuric acid / isopropyl alcohol; water / 12 h / 25 - 90 °C 3: potassium carbonate / water / 3 h / 50 - 60 °C 4: potassium carbonate / water; Isopropyl acetate / 4 h / 15 - 35 °C | ||
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 25 - 30 °C 2: triethylamine / water; ethyl acetate / 25 - 35 °C 3: methylamine / water / 12 h / 10 - 15 °C | ||
Multi-step reaction with 5 steps 1: triethylamine / dichloromethane / 15 - 25 °C 2: hydrogen / methanol / 20 - 25 °C / Autoclave 3: hydrogenchloride / ethyl acetate; water / 20 - 25 °C 4: sodium hydroxide / water / 10 - 20 °C 5: dimethyl sulfoxide / 15 - 30 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: 88 percent / Et3N / CH2Cl2 / 12 h / 20 °C 2.1: HCl(g) / CH2Cl2 / 1.5 h 2.2: 85 percent / Et3N / CH2Cl2 / 4 h / 20 °C 3.1: 90 percent / SnCl2*2H2O / ethyl acetate / 1 h / 70 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.56% | With triethylamine; In N,N-dimethyl acetamide; at 25 - 35℃; for 2h; | N-Acetyl Sulphanilyl chloride (72.9 g) (V) was added at 05-15C to pre-cooled mix of (1S,2R)-(1-Benzyl-2-hydroxy-3-(isobutyl-amino)propyl)carbamic acid tert-butylester (IV) (100 g) in N,N-Dimethylacetamide (500 ml). Triethyl amine (36.1 g) was added to the reaction mixture below 30C and stirred for 2 hours at 25-35C. Water (100 ml) was added to the reaction mixture at 25-35C. This mixture was added to water (2000 ml) at 25-35C under stirring and stirred for 2 hours. The reaction mixture was filtered and solid was washed with water (2 X 100 ml). The wet cake is reslurried in to water (1500 ml) and stirred for 2 hours. The solid was filtered and washed with water (2 X 100 ml). Solid was dried in air tray dryer for 2 hours at 25- 35C and then at 65-75C for 12 hours to give the title product (144.0 g)Yield: 90.56%1H NMR (DMSO-d6) oeppm: 0.78-0.85 (6H, dd), 1.11-1.25 (9H, m), 1.93-2.00 (1H, m), 2.08(3H, s), 2.48-2.54 (1H, m), 2.74-2.84 (2H, m), 2.96-3.03 (2H, m), 3.31-3.35 (1H, m), 3.46-3.51(1H, m), 3.56-3.60 (1H, m), 4.96-4.97 (1H, d), 6.68-6.70 (1H, d) , 7.12-7.25 (SH, m), 7.69-7.78(4H, m), 10.32 (1H, s)Mass: 534.2 (M+H)Purity: 96.78% |
86.8% | With triethylamine; In dichloromethane; at 0 - 30℃; for 1h; | Triethylamine (26.48 g, 0.26 moles) was added to a solution of tert-butyl [(2S,3R)-3-hydroxy-1-phenyl-4-(propan-2-yl-amino)butan-2-yl]carbamate (40 g, 0.12 moles) in dichloromethane (400 mL) at 0C to 5C. 4-Acetyl sulfanilyl chloride (29.2 g, 0.13 moles) was added to the solution lot-wise at 0C to 5C. The solution was stirred for 1 hour at 25C to 30C and water (200 mL) was added. The layers were separated. The organic layer was poured over hexanes and the resulting crystals of tert-butyl {(2S,3R)-4-[[4-(acetylamino)phenyl]sulfonyl}(propan-2-yl)amino]-3-hydroxy-1-phenylbutan-2-yl]carbamate were filtered. The wet crystals obtained were washed with hexanes and dried under vacuum to obtain white powder.Yield: 55 g (86.8%)HPLC Purity: 98.2% |
In dichloromethane; water; at 10 - 30℃; for 1h; | 3 L round bottom flask fitted with a mechanical stirrer, thermometer socket, addition funnel was charged (1-benzyl-2-hydroxy-3-isobutylaminopropyl) carbamic acid tertiary butyl ester of Formula IV (100 gms) and MDC (2000 ml). The reaction temperature was stirred for 10 minutes at 20 C. to 30 C. and N-(Acetylamino)benzene sulfonyl chloride (79.8 gms) was charged. The reaction mixture was allowed to cool to 10 C. and aqueous sodium bicarbonate solution (1000 ml) was added. The reaction temperature was raised to 25 C. to 30 C. and maintained for about 1 hour. The layers were separated and organic layer was washed with ammonia solution (100 ml) and then with DM water (500 ml). The layers were separated and the MDC was distilled off completely to obtain residue. To the residue, methanol (800 ml) and CP. HCl (125 ml) was charged and the reaction temperature was raised to 60 C. to 65 C. and maintained for 4 hours. Methanol was distilled completely under vacuum at below 60 C. and the obtained residue was charged water (2200 ml) and ethyl acetate (2200 ml). The reaction mass pH was adjusted to about 9 with aqueous sodium hydroxide solution and layers were separated. The organic layer was washed with water and the ethyl acetate was distilled under vacuum below 40 C. up to minimum volume remains in the flask. The reaction solution was allowed to cool to 20 C. to 30 C. and stirred for about 60 minutes and further allowed to cool to 0 C. to 5 C. Precipitated solid was filtered and washed with ethyl acetate (100 ml). The wet product was dried at about 50 C. to about 55 C. under reduced pressure to provide the title compound. Yield: 102 gms.HPLC purity: 99% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In dichloromethane; at -1.5 - 20℃; for 48h; | (S-te/t-Butoxycarbonylamino^-hydroxy^-phenyl-butylJ-isobutyl-carbamic acid benzyl ester (3); (1-Benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid terf-butyl ester (2) (24.50 g, 72.80 mmol, 1 equiv) and triethylamine (7.37 g, 72.80 mmol, 1 equiv) were dissolved in dichloromethane (500 ml_). The solution was cooled to -1.5C, followed by the dropwise addition of benzylchloroformate (12.40 g, 72.80 mmol, 1 equiv). The solution was stirred at 0C for 24 h. Due to the incompleteness of the reaction, benzylchloroformate (2.40 g, 14.07 mmol) and triethylamine (1.44 g, 14.23 mmol) were added to the solution. The solution was stirred at room temperature for 24 h. The solution was diluted with 2% Na2CU3 solution (300 ml.) and the mixture was stirred for 10 min. The organic layer was separated, washed with water (2x) and saturated sodium chloride solution (1x). The organic layer was dried on MgSO4, filtered, and evaporated to dryness to obtain the desired product as a yellow colored oil (34.30 g, 72.80 mmol, quantitative). LRMS(ES+): m/z 471 [M+H]+. |
100% | (1-Benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid tert-butyl ester (2) (24.50 g, 72.80 mmol, 1 equiv) and triethylamine (7.37 g, 72.80 mmol, 1 equiv) were dissolved in dichloromethane (500 ml_). The solution was cooled to -1.5C, followed by the dropwise addition of benzylchloroformate (12.40 g, 72.80 mmol, 1 equiv). The solution was stirred at 0C for 24 h. Due to the incompleteness of the reaction, benzylchloroformate (2.40 g, 14.07 mmol) and triethylamine (1.44 g, 14.23 mmol) were added to the solution. The solution was stirred at room temperature for 24 h. The solution was diluted with 2% Na2CO3 solution (300 ml.) and the mixture was stirred for 10 min. The organic layer was separated, washed with water (2x) and saturated sodium chloride solution (1x). The organic layer was dried on MgSO4, filtered, and evaporated to dryness to obtain the desired product as a yellow colored oil (34.30 g, 72.80 mmol, quantitative). LRMS(ES+): m/z 471 [M+H]+. | |
77% | With sodium carbonate; In tetrahydrofuran; at 5 - 10℃; for 3h; | To (1-Benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid tert-butyl ester2 15 (94 g, 0.279 mol) in 600 ml THF was added a solution of Na2CO3 (32.5 g, 0.307 mol) in 200 ml H2O. Cbz-chloride (52.4 g, 0.307 mol, 1.1 eq) dissolved in THF (100 mL) was added dropwise to the above mixture at 5-10 C. (ice bath) over the course of 1 h, after which time the mixture was stirred for additional 2 h at 10 C. Ethyl acetate (1000 ml) was then added to the reaction mixture, the organic layer was separated, washed sequentially by aqueous NaHCO3, KHSO4 and brine, dried over Na2SO4, filtered and concentrated in vacuo. The oily residue crystallized from EtOAc/hexane to give 3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-isobutyl-carbamic acid benzyl ester 16 (101 g, 77%) as a white solid, m.p. 79-81 C. 2. Ghosh, et al. J. Org. Chem. 63; 18; 6146-6152 (1998). |
77% | 3-tert-Butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-isobutyl-carbamic acid benzyl ester 16 To (1-Benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid tert-butyl ester2 15 (94 g, 0.279 mol) in 600 ml THF was added a solution of Na2CO3 (32.5 g, 0.307 mol) in 200 ml H2O. Cbz-chloride (52.4 g, 0.307 mol, 1.1 eq) dissolved in THF (100 mL) was added dropwise to the above mixture at 5-10 C. (ice bath) over the course of 1 h, after which time the mixture was stirred for additional 2 h at 10 C. Ethyl acetate (1000 ml) was then added to the reaction mixture, the organic layer was separated, washed sequentially by aqueous NaHCO3, KHSO4 and brine, dried over Na2SO4, filtered and concentrated in vacuo. The oily residue crystallized from EtOAc/hexane to give 3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-isobutyl-carbamic acid benzyl ester 16 (101 g, 77%) as a white solid, m.p. 79-81 C. Elem. anal. calc: C, 68.91%, H, 8.14%, N, 5.95%; found: C, 68.91%, H, 8.27%, N, 5.85%. NMR spectrum is consistent with the structure. | |
77% | With sodium carbonate; In tetrahydrofuran; water; at 5 - 10℃; for 3h; | To [(1S,2R)-2-hydroxy-3-[(2-methylpropyl)amino]-1-(phenylmethyl)propyl]- carbamic acid, 1,1-dimethylethyl ester 1 (CAS 160232-08-6)i,ii,iii (94 g, 0.279 mol) in 600 ml THF was added a solution of Na2CO3 (32.5 g, 0.307 mol) in 200 ml H2O. Cbz-chloride (52.4 g, 0.307 mol, 1.1 eq) dissolved in THF (100 ml) was added dropwise to the above mixture at 5-10 0C (ice bath) over the course of 1 h, after which time the mixture was stirred for additional 2 h at 10 0C. EtOAc (1000 ml) was then added to the reaction mixture, the organic layer was separated, washed sequentially by aqueous NaHCO3, KHSO4 and brine, dried over Na2SO4, filtered and concentrated in vacuo. The oily residue crystallized from EtOAc/hexane to give [(2R,3S)-3- [[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl](2-methylpropyl)-carbamic acid, phenylmethyl ester 2 (101 g, 77%) as a white solid, mp 79 - 81 0C. Anal. calcd: C 68.91%, H 8.14%, N 5.95%; found: C 68.91%, H 8.27%, N 5.85%. 1H NMR (CDCl3) 7.25 (m, 10H), 5.14 (s, 2H), 4.72 (br s, 1H), 4.12 (br s, 1H), 3.78 (br s, 2H), 3.11 (d, J = 7.2, 2H), 2.65 - 3.55 (m, 4H), 1.87 (m, 1H), 1.34 (s, 9H), 0.83 (d, J = 6.4, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
156 mg | With sodium hydrogencarbonate In dichloromethane; water at 20℃; for 60h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.3% | With potassium hydroxide; In ethanol; at 15 - 20℃;Large scale; | To 20L 4-neck flask followed by the addition of ethanol 6.5Kg, 1Kg water and compound B (1Kg, 3.36mol), stirring solution of the system isobutylamine (2.46Kg, 33.6mol, 10equiv.) ,And then slowly into the system solution containing KOH (0.207 Kg, 2.69mol, 1equiv )in water (1Kg) was added.After the dropwise addition was stirred at a temperature of 15 ~ 20 15 ~ 20 hours.Then the ethanol is distilled off under reduced pressure, added to the system 4Kg water, and crystallization in an ice water bath.Filtered, the filter cake was washed with water 1L × 3, after the filter cake was dried under vacuum to afford 1.1Kg Compound C (Compound C1HNMR spectrum as shown in Figure 2, the measurement process trimethoxybenzene were added the internal standard, the test conditions are: compound C 50.8mg, mesitylene methoxybenzene 28.9 × 97% mg, 400MHz, chloroform).Yield 97.3%, HPLC purity 96%. |
105 g | With sodium carbonate; In water; at 60 - 65℃; for 3h; | Example -2: Preparation of [(1 S, 2R)-3-[(2-methylpropyl) amino]-2-hydroxy-1- (phenylmethyl) propyl] carbamic acid tert-butyl ester (4). The mixture of [(1S, 2S)-3-chloro-2-hydroxy-1-(phenylmethyl) propyl] carbamic acid tert-butyl ester (5,100 g), isobutyl amine (294 g), sodium carbonate (31.3 g) and water was heated to 60 - 65C and maintained for 3hours. After completion of reaction water (200 mL) was added and distilled out excess isobutyl amine under vacuum at below 75C. Water (800 mL) was added to the distillate, cooled to 25-35C and stirred for 2 hours. The obtained solid was filtered and washed with water to get title compound 4 (yield 105 g). |
105 g | With sodium carbonate; In water; at 60 - 65℃; for 3h; | Example 2 Preparation of [(1S,2R)-3-[(2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid tert-butyl ester (4) The mixture of [(1S, 2S)-3-chloro-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid tert-butyl ester (5, 100 g), isobutyl amine (294 g), sodium carbonate (31.3 g) and water was heated to 60-65 C. and maintained for 3hours. After completion of reaction water (200 mL) was added and distilled out excess isobutyl amine under vacuum at below 75 C. Water (800 mL) was added to the distillate, cooled to 25-35 C. and stirred for 2 hours. The obtained solid was filtered and washed with water to get title compound 4 (yield 105 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In toluene at 20 - 30℃; | Preparation of tert-butyl((1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl[(-4-nitrophenyl)sulfonyl]-amino]propyl]carbamate (7) A mixture of isobutyl amine (1000 mL, 9.981 mol), IPA (200 mL, 1.0 volume) and200 g (0.759 mol) of 3 was stirred for 12-14 h at 20-30 °C. After completion ofreaction (TLC), volatiles were removed under vacuum. Water (1000 mL) was addedto the residue followed by stirring for 2 h, and subsequent filtration resulted to affordintermediate 6, after drying at 50-60 °C in air oven over a period of 10-12 h. Driedsolid was then mixed with DCM (740 mL), TEA (115 mL, 0.835 mol) at 15-25 °Cfollowed by slow addition of 4-nitrobenzenesulfonyl chloride solution (168 g,0.759 mol, in 300 mL of DCM) at 15-25 °C. Resulted reaction mixture was stirredfor 1-2 h at 15-25 °C. After reaction completion (TLC), volatiles were evaporatedunder vacuum completely. Water (1500 mL) and sodium hydroxide solution(200 mL; 0.700 mol) was added to distilled residue followed by stirring for 2 h. Theresulting aqueous slurry was filtered, washed with water and dried in air oven at55-60 °C over a period of 10-12 h to yield the intermediate 7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With dmap; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 25℃; | 4.1.5. Tert-butyl ((2S, 3R)-3-hydroxy-4-((N-isobutyl-4-methoxyphenyl)sulfonamido)-1-phenylbutan-2-yl)carbamate (14) General procedure: To a stirred solution of 6 (5.0 g, 14.86 mmol) in tetrahydrofuran(40 mL) at 0 °C was added DIEA (3.68 mL, 16.34 mmol) and DMAP(0.18 g, 1.49 mmol) in batches, followed by a mixture of 4-methoxybenzenesulfonyl chloride (10, 3.37 g, 16.34 mmol) andtetrahydrofuran (15 mL). The resulting mixture was stirred at 0 °Cfor 0.5 h and at 25 °C for another 3-5 h. The mixture was thenconcentrated under reduced pressure and extracted with ethylacetate and dried over anhydrous Na2SO4. Removal of solvent,followed by column chromatography over silica gel (20% EtOAc inn-hexane as the eluent), yielded compound 14 (6.14 g, 82%) aswhite amorphous solid |
Tags: 160232-08-6 synthesis path| 160232-08-6 SDS| 160232-08-6 COA| 160232-08-6 purity| 160232-08-6 application| 160232-08-6 NMR| 160232-08-6 COA| 160232-08-6 structure
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P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
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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