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CAS No. : | 2900-27-8 | MDL No. : | MFCD00065588 |
Formula : | C13H17NO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HOBFSNNENNQQIU-JTQLQIEISA-N |
M.W : | 251.28 | Pubchem ID : | 11010409 |
Synonyms : |
Boc-Phg-OH
|
Num. heavy atoms : | 18 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.38 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 66.54 |
TPSA : | 75.63 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.26 cm/s |
Log Po/w (iLOGP) : | 2.25 |
Log Po/w (XLOGP3) : | 2.22 |
Log Po/w (WLOGP) : | 2.01 |
Log Po/w (MLOGP) : | 1.7 |
Log Po/w (SILICOS-IT) : | 1.23 |
Consensus Log Po/w : | 1.88 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -2.65 |
Solubility : | 0.566 mg/ml ; 0.00225 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.44 |
Solubility : | 0.0906 mg/ml ; 0.00036 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.78 |
Solubility : | 0.421 mg/ml ; 0.00167 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.53 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
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* 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 |
---|---|---|
95% | With sodium hydroxide In 1,4-dioxane at 0 - 20℃; for 2h; | |
95% | With potassium carbonate In tetrahydrofuran; water at 20℃; for 18h; | 2 Example 2 Preparation of N- -phenylglycinePhenylglycine Example 2 Preparation of N- -phenylglycinePhenylglycine (5.1 g, 33.76 mmol) is suspended in a 1 : 1 mixture of water and THF (50 ml) at room temperature and potassium carbonate (K2CO3, 1 1.66 g, 84,4 mmol) and Boc anhydride (7.36 g, 84.4 mmol) are added. The suspension is stirred at room temperature for 18 hours, controlling by LC-MS. The solids are removed by filtration and THF is evaporated under reduced pressvire. The remaining aqueous phase is acidified with a 2N HC1 aqueous solution and extracted two times with dichloromethane (40 ml each time). The organic phases are combined and dried on sodium sulphate. The suspension is filtered and the solvent is evaporated under reduced pressure. Petroleum ether is added during the evaporation to facilitate the precipitation. A white solid is obtained, which is filtered and dried to give 8.02 g of the title product (31.91 mmol; yield 95%). MS (ESI+): 252.2 ( +H4"), 525.3 (2M+Na) 1HNMR (400 MHz, DMSO): 12.75 (s, 1H, -OH), 7.55 (d, 1Η, -NH-Boc, J=8.4 Hz) 7.41-7.33 (m, 5H, Ph), 5.11 (d, 1H, Ha, J - 8.4 Hz), 1.39 (s, 9H, 3x -CH3). |
94% | With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 21h; |
90% | With sodium hydroxide In 1,4-dioxane for 14h; | |
90% | With potassium carbonate In methanol; water at 10 - 20℃; | 2.1 (1) A mixture of (S)-2-amino-2-phenylacetic acid (100 g, 0.66 mol), potassium carbonate (109 g, 0.79 mol) was dissolved in water (1.0 L) and methanol (0.25 L), cooling to T <10 deg. C, di-tert-butyl dicarbonate (144 g, 0.66 mol) was added dropwise, room temperature reaction overnight, pH 4 to 5 with 1 N HCl, extraction with ethyl acetate (0.5 L * 3), saturated brine (0.5 L * 1) was washed, concentrated to give 150 g of a white solid, yield 90%. |
89% | With sodium hydroxide In 1,4-dioxane | |
88.7% | Stage #1: (S)-2-phenylglycine With sodium hydroxide In 1,4-dioxane; water at 2.5℃; for 0.166667h; Stage #2: di-<i>tert</i>-butyl dicarbonate In 1,4-dioxane; water at 20℃; for 6h; | 1-2 Example 1 In a 250ml four-neck flask, dissolve 4.53g (30mmol) of L-phenylglycine in 60ml of dioxane and 30ml of water, cool to 2.5±2.5, add 30ml of 1N NaOH solution, stir for 10 minutes and add 7.2g of BOC anhydride (33mmol), warm up to room temperature, and continue to stir for 6 hours. After the reaction is over, add 13% potassium hydrogen sulfate dilute solution to adjust the pH of the reaction solution to 2.0, add 50ml ethyl acetate, separate the layers, extract the aqueous phase with 30ml×2 ethyl acetate, combine the organic phases, wash with 50ml purified water, and anhydrous sulfuric acid Sodium is dry. Filter and evaporate the solvent under reduced pressure to dryness to obtain a colorless transparent viscous oil.Weigh, add 0.5% by weight of N-Boc-L-phenylglycine seed crystals (HPLC purity 99.3%) to this oil, let stand at room temperature for 24 hours, the oil is completely solidified and turned into a white solid, add 10 times the volume /Weight ether, beaten at room temperature for 2 hours, and filter. The product was obtained by drying under reduced pressure at 60°C for 15 hours. (Yield 88.7%, HPLC purity 99.1%). |
87% | With sodium hydroxide In 1,4-dioxane; water at 20℃; Cooling with ice; | |
86% | With triethylamine In methanol; water at 25℃; for 8h; | |
86% | With triethylamine In methanol; water at 20℃; for 8h; | |
86% | With triethylamine In methanol; water at 20℃; for 8h; | 1 Synthesis of: Compound (6) (S) -2 - ((t - t-butyl carbonyl) amino) -2-phenylacetic acid The L- phenylglycine (15.1g, 100mmol) placed in a reaction flask was added 200mL of methanol: water (3: 1), room temperatureStirring to dissolve, was added Et3N (15.1mL, 150mmol), the (Boc) 2O (32.7g, 150mmol) was added dropwise to the reaction mixture, followed by stirring at room temperature for 8 hours, the solvent is removed by rotary evaporation, dissolved in 100mL of citric acid, with acetic acid ethyl ester (3 × 50mL) and extracted with anhydrous sodium sulfate, crude did spin with hexane to give product 6 (21.8g, 86% yield). |
82% | With sodium hydroxide In <i>tert</i>-butyl alcohol at 20℃; for 1h; | 24.1 Step 1: (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid To a solution of (S)-2-amino-2-phenylacetic acid (3.0 g, 19.8 mmol) in 1 M sodium hydroxide solution (28 mL) was added a solution of di-tert-butyl dicarbonate (4.75 g, 21.78 mmol) in tert-butyl alcohol (16 mL). The resulting suspension was stirred at roomtemperature for 1 h. The volatile solvent was removed under reduced pressure and the pH of the remaining solution was adjusted with citric acid to 3. The solid was filtered and dried to give (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (4.1 g, 16.3 mmol, 82 % yield). LCMS (2.5 min formic acid): Rt = 1.48 min, [M+H]+= 273.9. |
60% | With triethylamine In methanol; water for 6h; | |
With sodium hydroxide In 1,4-dioxane for 18h; Ambient temperature; | ||
With sodium hydroxide In <i>tert</i>-butyl alcohol | ||
With sodium hydroxide In tetrahydrofuran; water at 20℃; | ||
With sodium hydroxide In 1,4-dioxane at 20℃; | ||
With sodium hydrogencarbonate In tetrahydrofuran at 23℃; for 12h; | ||
With sodium hydroxide In tetrahydrofuran at 20℃; for 18h; | ||
Stage #1: (S)-2-phenylglycine With potassium carbonate In water at 100℃; for 2h; Stage #2: di-<i>tert</i>-butyl dicarbonate In 1,4-dioxane at 20℃; for 24h; Further stages.; | ||
With tert-butylimino-tris(dimethylamino)phosphorane In acetonitrile at 20℃; for 16h; | ||
With triethylamine In tetrahydrofuran; water at 20℃; | ||
With triethylamine In N,N-dimethyl-formamide | General Procedure: Compounds 1-15 were synthesized by standard solution phase peptide synthesis by which sequential elongation and coupling of an amine to a carboxylic acid was performed in DMF with benzotriazol-1-yl-oxytris-(dimethylamino)phosphonium hexafluorophosphate (BOP) or N,N'-carbonyldiimidazole (CDI) as coupling reagent and Et3N as base. Although BOP was favored over CDI for coupling to the P'1 residue, CDI showed higher coupling reactivity with bulky amines. Peptide coupling to the P1 residue was accomplished using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and 1-hydroxybenzotriazole (HOBt) as additive, without a base, to avoid reported side-reactions. Attachment of a Boc protection group to an amino group was achieved with Boc2O and Et3N in DMF, while the removal of the Boc protection group was achieved with 4 N HCl in dioxane. The hydroxyl group in compounds 2 and 9 was acetyl protected with acetic anhydride in pyridine, and eventually removed by a 50% v/v mixture of 4 N NaOH(aq) and MeOH. The N-terminal cap was appended in DMF and Et3N as base by a reaction with methyl chloroformate for compounds 2 and 3, or with benzylbromide for compound 13. The nucleophilic substitution reactions in compounds 11, 12, 14 and 15 was performed with methyl iodide or ethyl iodide, respectively, to afford a mixture of mono- and disubstituted products. After preparative HPLC purification, all target compounds (1-15) were >95% pure by analytical HPLC. The identities of the compounds were confirmed by TOF MS and ESI-Q MS. | |
With sodium hydroxide In methanol | ||
Stage #1: (S)-2-phenylglycine With sodium hydroxide In 1,4-dioxane; water for 0.0833333h; Cooling with ice; Stage #2: di-<i>tert</i>-butyl dicarbonate With sodium hydrogencarbonate In 1,4-dioxane; water at 20℃; for 18h; | ||
With triethylamine In methanol; water | ||
With sodium hydroxide In tetrahydrofuran; water at 20℃; for 4h; | General Procedure for the Synthesis of Compounds 6a-d General procedure: Amino acid derivative (5 mmol) was dissolved in a mixture of tetrahydrofuran (50 mL) and water (20 mL). A 1 N NaOH (6 mL) was added followed by the addition of 1.1 g di-tert-butyl dicarbonate (5mmol) dropwise at room temperature. After stirring for 4 h, the tetrahydrofuran was evaporated under vacuum from the reaction mixture. To the residue was added ethyl acetate (50 mL) and 5% citric acid (30 mL). The organic layer was separated, washed with water (20 mL × 3), dried with anhydrous MgSO4 and rotary evaporated to dryness. The crude residue was used the next reaction without purification. A mixture of the above N-Boc protected amino acids (2.2 mmol), compound 4 (0.98 g, 2 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.42 g,2.2 mmol), 1-hydroxybenzotriazole (0.30 g, 2.2 mmol), triethylamine (0.30 g, 3.0 mmol) and dichloromethane (50 mL) was stirred at room temperature for 36 h. The mixture was washed with saturated aqueous NaHCO3 and water then, evaporated under vacuum and the residue was treated with a mixture of trifluoroacetic acid (TFA, 10 mL) and dichloromethane (10 mL) at room temperature for 30 min. The reaction mixture was quenched with 25% aqueous NaHCO3 (30 mL) and washed with water, dried with anhydrous Na2SO4 overnight and rotary evaporated to dryness. The crude residue thus obtained was purified by silica gel column chromatography (petroleum ether-ethyl acetate 1:2 v/v) to afford the desired compounds. | |
With sodium hydroxide In tetrahydrofuran at 0 - 20℃; for 3h; | 1 Step 1: (S)-2-((terf-butoxycarbonyl)amino)-2-phenylacetic acid At 0°C, to a solution of (S)-2-amino-2-phenylacetic acid (3.0 g, 19.9 mmol) in THF (20 mL) were added 10% NaOH solution (20 mL, 50 mmol) and Boc20 (4.8 g, 22 mmol) and the contents were stirred at ambient temperature. After 3 hr, the reaction mixture was cooled to 0°C and was acidified carefully with 50% citric acid solution (10 mL) until the pH of the solution is 4. The organic contents were extracted with EtOAc (3x25 mL) and the combined organic extracts were washed with brine (1x20 mL), dried over Na2S04, concentrated to afford (S)-2- ((tert-butoxycarbonyl)amino)-2-phenylacetic acid. The residue thus obtained was taken directly for step 2 without further purification. MS ESI calc'd. for Ci3Hi8N04 [M+l]+ 252, found 252.2. | |
With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 1h; | ||
With sodium hydroxide | ||
With sodium hydroxide In water; <i>tert</i>-butyl alcohol | ||
Stage #1: (S)-2-phenylglycine With sodium hydroxide In water; <i>tert</i>-butyl alcohol at 20℃; for 0.25h; Stage #2: di-<i>tert</i>-butyl dicarbonate In water; <i>tert</i>-butyl alcohol | ||
With sodium hydrogencarbonate; sodium hydroxide In 1,4-dioxane; water at 25℃; Cooling with ice; | ||
With triethylamine In methanol at 20℃; for 16h; | ||
With sodium hydroxide In water; <i>tert</i>-butyl alcohol at 20℃; for 1h; | Step 1: (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (115a). A solution of (S)-2-amino-2-phenylacetic acid 114a (1.0 g, 6.6 mmol) in NaOH (1 M aqueous solution, 1.4 mL) was treated with a solution of Boc2O (1.68 mL, 7.34 mmol) in tBuOH (1.4 mL). The resulting suspension was stirred at rt for 1 h. After completion, the solvent was removed under reduced pressure and the pH of the remaining solution was adjusted to 3 with 4 M aq. HCl solution. The resulting suspension was diluted with CHCl3 (2 mL), the layers were separated, and the aqueous solution was extracted with CHCl3 (2 × 1 mL). The combined organic solution was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product (1.56 g, 93%, white powder) was used in the next step without further purification. LCMS (ES+) m/z calculated for C13H17NO4 251.12, found 152 (M+H-Boc)+. | |
With sodium hydroxide In water; <i>tert</i>-butyl alcohol at 20℃; for 1h; | Step 1: (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (115a). A solution of (S)-2-amino-2-phenylacetic acid 114a (1.0 g, 6.6 mmol) in NaOH (1 M aqueous solution, 1.4 mL) was treated with a solution of Boc2O (1.68 mL, 7.34 mmol) in tBuOH (1.4 mL). The resulting suspension was stirred at rt for 1 h. After completion, the solvent was removed under reduced pressure and the pH of the remaining solution was adjusted to 3 with 4 M aq. HCl solution. The resulting suspension was diluted with CHCl3 (2 mL), the layers were separated, and the aqueous solution was extracted with CHCl3 (2 × 1 mL). The combined organic solution was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product (1.56 g, 93%, white powder) was used in the next step without further purification. LCMS (ES+) m/z calculated for C13H17NO4 251.12, found 152 (M+H-Boc)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine In tetrahydrofuran at -20℃; for 0.166667h; | ||
With triethylamine | ||
With N-methylmorpholinepolystyrene In tetrahydrofuran at -20℃; for 2h; |
With triethylamine In dichloromethane at 0℃; for 0.333333h; | ||
With 4-methyl-morpholine In tetrahydrofuran at -15℃; for 0.75h; | ||
With 4-methyl-morpholine In tetrahydrofuran at -15℃; | ||
In dichloromethane at 0℃; Inert atmosphere; | ||
With 4-methyl-morpholine In tetrahydrofuran at -15℃; for 0.75h; Inert atmosphere; | ||
With 4-methyl-morpholine In tetrahydrofuran; dichloromethane at -15℃; for 1h; Inert atmosphere; | Amino acid coupling reaction-general procedure General procedure: A stirred solution of N-α-protected amino acids 1a-f (10.58 mmol) and N-methylmorpholine (11.66 mmol) in anhydrous THF (16 mL) was cooled to -15 °C under nitrogen atmosphere, before the very slow addition of isobutyl chloroformate (11.86 mmol) in anhydrous DCM (5.3 mL). After 1 h of stirring, a solution of N-benzyl-tert-butyl-β-aminoesters 2 (10.58 mmol) and N-methylmorpholine (12.65 mmol) in anhydrous DCM was added slowly. The mixture was stirred for two additional hours at -15 °C and then was allowed to warm to room temperature, and stirring was continued for 18 h. The solvent was removed under vacuum and ethyl acetate (30 mL) was added to the residue. The resulting solution was washed sequentially with water, 1 N HCl, water, saturated solution of NaHCO3, and water. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. In order to have a complete analysis of the physical and spectroscopic properties of the chiral dipeptides it was decided to prepare both enantiomers and also the racemic mixture to serve as chiral HPLC standards. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In tetrahydrofuran at -15℃; for 0.25h; | ||
With 4-methyl-morpholine In tetrahydrofuran at -20 - -5℃; | ||
With 4-methyl-morpholine In tetrahydrofuran at -10℃; for 0.166667h; |
With 4-methyl-morpholine In dichloromethane at 0℃; for 0.166667h; | ||
With triethylamine In tetrahydrofuran at 0℃; for 0.666667h; Inert atmosphere; | 4.3. General procedure for the amide 5 General procedure: To a solution of N-Boc-amino acid 3 (63.5 mmol) in THF (100 mL) at 0 °C were added triethylamine (63.5 mmol) and ethyl chloroformate (63.5 mmol) over a period of ca. 10 min, and the reaction mixture was stired for 30 min. After the addition of the 2-aminobenzamide 4 (95.25 mmol), the mixture was stirred for an additional 1 h at 0 °C. Then, the reaction mixture was warmed to room temperature, and kept stirring overnight. After the solvent was evaporated under reduced pressure, the residue was dissolved in EtOAc (150 mL) and washed with 3 M HCl (2 × 100 mL), and brine (100 mL). The organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure (20 mbar, 20 °C). Crystallization of crude mixture gave the corresponding amide 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine; dicyclohexyl-carbodiimide In chloroform at 0℃; for 1h; Inert atmosphere; | |
With benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide In dichloromethane Yield given; | ||
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In acetonitrile at 0 - 20℃; |
With 1,1'-carbonyldiimidazole In dichloromethane | ||
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 2h; | 2 Step 2: (S)-terf-butyl (2-(methoxy(methyl)amino)-2-oxo-l-phenylethyl)carbamate To a solution of (S)-2-((fert-butoxycarbonyl)amino)-2-phenylacetic acid (1.0 g, 4.0 mmol) in dichloromethane (10 mL) were added Ν,Ο-dimethyl hydroxylamine hydrochloride (0.77 g, 8.0 mmol), EDCI (1.2 g, 6.0 mmol), HOBt (0.05 g, 0.4 mmol), Et3N (0.8 g, 8.0 mmol) and the contents were stirred at ambient temperature. After 2 hr, the reaction was quenched with ice cold H20 (10 mL), and the organic contents were extracted with CH2C12 (2x30 mL). The combined organic extracts were washed with brine (1x20 mL), dried over Na2S04, concentrated and the residue thus obtained was purified by flash column chromatography to afford (S)-tert- butyl (2-(methoxy(methyl)amino)-2-oxo-l-phenylethyl)carbamate. 1H NMR (300MHz , CDC13) δ 7.39-7.29 (m, 5H), 5.77 (bs, 1H), 5.73 (bs, 1H), 3.47 (s, 3H), 3.20 (s, 3H), 1.42 (s, 9H). | |
With triethylamine; dicyclohexyl-carbodiimide In chloroform at 0 - 20℃; for 1h; | ||
2.85 g | Stage #1: (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 0.166667h; Stage #2: N,O-dimethylhydroxylamine*hydrochloride In dichloromethane for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid With ammonium hydroxide; benzotriazol-1-ol In N,N-dimethyl-formamide at 0℃; for 0.166667h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 25℃; for 18h; | 61.A To a solution of (S)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (1.00 g, 3.98 mmol) in DMF (5 mL) and was added ammonium hydroxide (2.0 mL, excess), and HOBt (645 mg, 4.78 mmol) and the resulting solution stirred at 0° C. for 10 minutes. EDCI (916 mg, 4.78 mmol) was added and the reaction stirred at 25° C. for 18 hours. The mixture was concentrated in vacuo, the resulting residue was diluted with ethyl acetate (45 mL), brine (10 mL), and 5% H3PO4 aqueous solution (10 mL), and the layers were separated. The organic layer was washed with 5% H3PO4 aqueous solution (10 mL), twice with saturated aqueous sodium bicarbonate solution (15 mL), water (15 mL), and brine (15 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a light colored solid. The crude material was taken on directly to the next step. (0.990 g, 99% yield) MS (ESI+) m/z=251 (M+H)+ |
Stage #1: (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In N,N-dimethyl-formamide at 0℃; for 0.25h; Stage #2: With ammonium hydroxide In N,N-dimethyl-formamide Further stages.; | ||
Stage #1: (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid With 4-methyl-morpholine; chloroformic acid ethyl ester In tetrahydrofuran at -10℃; for 0.333333h; Stage #2: With ammonia In tetrahydrofuran; water at -10℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 79h; Inert atmosphere; | R.44 (S)-Benzyl 2-[(tert-butoxycarbonyl)amino]-2-phenylacetate To a solution of 2.50 g (9.95 mmol) of (S)-2-[(tert-butoxycarbonyl)amino]-2-phenylacetic acid in 30 ml of DMF, 1.47 g (10.6 mmol) of potassium carbonate was dividedly added with stirring at room temperature in a nitrogen atmosphere, and subsequently, 1.20 ml (10.1 mmol) of benzyl bromide was added dropwise at room temperature, stirred at the same temperature as above for 7 hours, and then left at room temperature for 3 days. After the completion of the reaction, toluene was added to the reaction solution and washed with water twice. All of the obtained organic layers were washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate = 100:0 to 79:21 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 3.24 g of the title compound (yield: 95%) as a white solid. Mass spectrum (CI, m/z): 342 [M+1]+. 1H-NMR spectrum (400 MHz, CDCl3) δ: 7.37 - 7.27 (m, 8H), 7.23 - 7.15 (m, 2H), 5.61 - 5.50 (m, 1H), 5.40 - 5.33 (m, 1H), 5.23 - 5.08 (m, 2H), 1.49 - 1.29 (m, 9H). |
In acetonitrile at 20℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 4-methyl-morpholine; 1,3,5-trichloro-2,4,6-triazine; hydroxylamine hydrochloride In dichloromethane at 0 - 20℃; | |
68% | Stage #1: (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid With dmap; ethyl 2-(tert-butoxycarbonyloxyimino)-2-cyanoacetate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 5℃; for 0.5h; Stage #2: With hydroxylamine hydrochloride In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 2h; | General procedure for the synthesis of hydroxamic acids General procedure: Ethyl 2-(tertbutoxycarbonyloxyimino)-2-cyanoacetate (Boc-Oxyma, I) (1 mmol) wasadded to a stirred solution of carboxylic acid (1 mmol), DIPEA (1 mmol), andDMAP (0.1 mmol) in THF (2 mL) at 0-5 C. Then the reaction mixture wasstirred for 30 min followed by the addition of hydroxylamine hydrochloride inDMF (0.5 mL), DIPEA (1.5 mmol). The progress of the reaction was monitoredby TLC at room temperature. After completion of the reaction, the reactionmixture was concentrated using rotary evaporator and then diluted with15 mL of ethyl acetate and washed with 5% HCl (2 10 mL), 5% NaHCO3(2 10 mL), saturated NaCl solution (2 10 mL), and dried over anhydrousNa2SO4 and the evaporation of the solvent gave a residue that was purified onsilica gel column chromatography using hexane and ethyl acetate. |
61% | With hydroxylamine potassium salt In methanol for 2h; |
10% | With 4-methyl-morpholine; 1,3,5-trichloro-2,4,6-triazine; hydroxylamine hydrochloride In dichloromethane at 20℃; for 14h; | |
Multi-step reaction with 2 steps 1: 3,3-dichloro-1,2-diphenylcyclopropene; N-ethyl-N,N-diisopropylamine / dichloromethane / 0.17 h / -10 - 20 °C 2: hydroxylamine hydrochloride; potassium hydroxide / methanol; dichloromethane / 0.75 h / -10 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid; N,0-dimethylhydroxylamine In toluene at 0℃; for 0.166667h; Stage #2: With phosphorus trichloride In toluene at 20 - 60℃; for 0.5h; | N-Methoxy-N-methylbenzamide (3a);38,39 Typical Procedure General procedure: A solution of NHMe(OMe) (0.360 g, 6.0 mmol) and benzoic acid (0.244 g, 2.0 mmol) was stirred in dry toluene (10 mL) at 0 °C for 10 min. A solution of PCl3 (0.137 g, 1.0 mmol) in dry toluene (2 mL) was then added dropwise to the mixture. The mixture was warmed to r.t. slowly and then stirred at 60 °C for 0.5 h. When the reaction was complete (TLC monitoring), the mixture was cooled to r.t. The mixture was then quenched with sat. NaHCO3 soln (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (anhyd MgSO4). The solvent was removed in vacuo.The product was purified by column chromatography (silica gel, petroleum ether-EtOAc, 3:2) to give pure 3a as a colorless oil; yield: 320 mg (97%). |
90% | With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; | |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 3h; | 54I.3 Step 3 : Synthesis of (^-tert-butyl (2-(methoxymethyl)amino)-2-oxo-l-phenylethyl)carbamate To the solution of (,S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (0.5 g, 1.93 mmol) in dichloromethane (6 mL) was added Ν,Ο-dimethylhydroxylamine (0.233 g, 2.38 mmol). To the resulting mixture was then added HOBT (0.082 g, 0.53 mmol), EDCI.HC1 (0.457 g, 2.38 mmol) and DIPEA (0.87 mL, 4.96 mmol). The reaction mixture was stirred at ambient temperature for 3 h. TLC analysis indicated complete consumption of the starting material. The reaction mixture was bi-phased with dichloromethane (25 mL) and water (15 mL). The aqueous layer was extracted with dichloromethane (2 x 10 mL). The combined organic layers were washed with brine (1 x 10 mL), dried (Na2S04) and concentrated under reduced pressure to afford the title compound. MS calc'd for C15H22N2O4 [M+H]+ 295; Found: 195.2 (M+l-Boc); 1H MR (400 MHz, CDC13) δ 7.41-7.24 (m, 5H), 5.80 (d, 1H, J= 7.6 Hz), 5.72 (d, 1H, J= 7.5 Hz), 3.47 (s, 3H), 3.19 (s, 3H), 1.43 (s, 9H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.3% | With borane-THF In tetrahydrofuran at 0 - 20℃; for 2h; Inert atmosphere; | 1-3 Example 3 Under the protection of nitrogen, 50g (0.199mol) of N-Boc-L-phenylglycine and 100mL of tetrahydrofuran were mixed, and the temperature was lowered to 0C and control the temperature to add (BH3-THF, 1.0M) 600mL dropwise at 0-20C, the dropwise addition is complete, continue to stir for 2 hours, until TLC detectionThe raw material reaction is complete.Cool the reaction solution to about -10C, slowly add methanol dropwise to quench the reaction, and wait until no bubbles overflowWhen the temperature is raised to room temperature, continue to stir for 1 hour, then distill under reduced pressure to generate trimethyl borate and tetrahydrofuran solvent, and distill to noLiquid, add heptane/MTBE (6/1, 185mL) to beat to obtain 45.0g of N-Boc-L-phenylglycinol, HPLC: 97.6%, yield95.3%. |
65% | Stage #1: (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid With triethylamine In tetrahydrofuran Stage #2: With sodium tetrahydroborate In water | |
61% | With borane-THF In tetrahydrofuran at 20℃; for 3.5h; |
Stage #1: (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at -10℃; Stage #2: With sodium tetrahydroborate In tetrahydrofuran | ||
Stage #1: (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid With isobutyl chloroformate In 1-methyl-pyrrolidin-2-one at -10℃; Stage #2: With sodium tetrahydroborate In N,N-dimethyl-formamide at -10℃; | ||
Multi-step reaction with 2 steps 1: 85 percent / K2CO3 / dimethylformamide / 1 h / 0 - 20 °C 2: 89 percent / LiAlH4 / tetrahydrofuran / 1 h / 0 - 20 °C | ||
Multi-step reaction with 2 steps 1: NEt3 / tetrahydrofuran / -10 °C 2: NaBH4 / H2O / 0 °C | ||
Stage #1: (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid With 4-methyl-morpholine; chloroformic acid ethyl ester In tetrahydrofuran at -15℃; for 0.25h; Stage #2: With sodium tetrahydroborate In tetrahydrofuran for 0.5h; Stage #3: With water In tetrahydrofuran for 0.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With 4-methyl-morpholine; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride | |
40% | Stage #1: (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 60℃; for 0.833333h; Inert atmosphere; Stage #2: methanol In N,N-dimethyl-formamide for 12h; | 143.1 To a solution of 1, 1'-carbonyldiimidazole (CDI) (770 mg, 4.8 mmol) in anhydrous DMF (10 mL) was added (S) -2- ( (tert-butoxycarbonyl) amino) -2-phenylacetic acid (1.0 g, 4.0 mmol) at rt.The mixture was stirred at 60 for 50 min, and methanol (10 mL) was added. The resulting mixture was futher stirred for 12 h, and concentrated. The residue was diluted with water (10 mL) , and extracted with EtOAc (10 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with Petroleum ether/EtOAc (v/v) 8/1 to give (S) -methyl 2- ( (tert-butoxycarbonyl) amino) -2-phenylacetate as a a light yellow solid (426 mg, 40) .1H NMR (400 MHz, CDCl3) : δ ppm 7.31-7.36 (m, 5H) , 5.22 (s, 1H) , 5.32 (d, J 7.1 Hz, 1H) , 3.72 (s, 3H) , 1.43 (s, 9H) and MS-ESI: m/z 288.00 [M+Na] +. |
134 mg | In benzene at 20℃; for 2h; Molecular sieve; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 2h; | 26.a a. tert-Butyl ((1S)-2-[(6,7-cis)-7-(1-naphthyl)-5-oxo-1,4-thiazepan-6-yl]amino}-2-oxo-1- phenylethyl) carbamate (26a) To a solution of (6, 7-cis)-6-amino-7-(1-naphthyl)-1, 4-thiazepan-5-one 25e (162 mg, 0.545 mmol) in dichloromethane [(15ML)] at [0°C] under nitrogen was added [(22-[(TERT-] butoxycarbonyl) amino] (phenyl) acetic acid (137 mg, 0.545 mmol) followed by HOBt-hydrate [(190MG,] 1.24mmol), EDAC. HCI (162mg, 0.850mmol) and NMM (93 [1L,] 0. [850MMOL).] The reaction mixture was stirred 1.5 h at [0°C] and for 30 min at RT, concentrated in vacuo and partitioned between [H20] (25ml) and ethyl acetate (25ml). The organic phase was collected and consecutively washed with 0.5 N HCl (2x), H20, brine, dried and the solvent removed in vacuo to give the title compound 29a (272 mg, 95%) as a light pink solid. MS APCI, [M/Z =] 528 (M+Na), [LC/MS] : 2.36 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 2h; | 34.a tert-Butyl ((1S)-2-[(6,7-cis)-4-methyl-5-oxo-7-phenyl-1,4-oxazepan-6-yl]amino}-2-oxo- 1-phenylethyl)carbamate (34a To a suspension of (6, [7-CIS)-6-AMINO-4-METHYL-7-PHENYL-1,] 4-oxazepan-5-one hydrochloride [(30D)] (300mg, 1.17 mmol) in dichloromethane (30ml) at [0°C] under N2 was added [(2S)- [ (TERT-BUTOXYCARBONYL)] amino] (phenyl) acetic acid (293 mg, 1.17 mmol) followed [BY NMM (128, UL,] 1. [17MMOL)] and the mixture stirred 5 min. until solution cleared. To the reaction was added HOBt-hydrate (389mg, 2. [60MMOL),] EDAC. [HC1] (336mg, 1. [76MMOL)] and NMM (193 µL, 1.76 mmol). The reaction mixture was stirred 2 h at [0°C,] concentrated in vacuo and partitioned between water and ethyl acetate. The organic phase was collected and consecutively washed with 0.25 N [HC1] (2x), water, brine, dried and the solvent removed in vacuo to give the title compound [34A] (380 mg, 72%) as a off white solid. MS APCI, [M/Z =] 454 [(M+1)] 476 (M+Na), LC/MS: 2.15 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In DMF (N,N-dimethyl-formamide) at 20℃; | 50.a a. [TERT-BUTYL ( (LS)-2-OXO-2-1 [ (6, 7-CIS)-5-OXO-7-PHENVL-1, 4-THIAZEPAN-6-VLLAMINOL-L-] phenylethyl) carbamate (50a) To a stirred solution of (6, 7-cis)-6-amino-7-phenyl-1, 4-thiazepan-5-one hydrobromide 48a) (150 mg, 0.497 mmol) in DMF (2 mL) under nitrogen was added, (2S)-[(tert- butoxycarbonyl) amino] (phenyl) acetic acid (137 mg, 0.544 mmol), HOBt (100 mg, 0.742 mmol), NMM (75 mg, 0.742 mmol) and EDAC-HC1 (142 mg, 0.742 mmol). The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic solution was separated, extracted in succession with IN aqueous HCl and brine then dried, filtered and evaporated to afford the title compound (221 mg, 97%) as a white solid. [IH] NMR (300 MHz, [CDC13)] [81.] 40 (br s, 9H), 2.74 (m, 1H), 2.98-3. 20 (m, 1H), 3.56-3. 95 (m, 2H), 4.03 (br d, 0.5H), 4. [37] (d, 0.5H, J= 3.9 Hz), 5.12-5. 44 (m, 2H), 5.61 (br d, 0.5H), 5.84 (br d, 0.5H), 6.21 (br 0.5H), 6.58 (br, 0.5H), 6.79 (br d, 1H), 6.96-7. 19 (m, 2H), 7.22-7. 38 (m, 8H). MS APCI, [M/Z=] 456 [(M+1).] LC/MS: 2.63 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | 58.a a. tert-Butyl ((1S)-2-oxo-2-[ (2, [3-CIS)-4-OXO-2-PHENYL-2,] 3,4,5-tetrahydro-1, 5- [BENZOXAZEPIN-3-YLLAMINOL-1-PHENYLETHYL)] carbamate [(58A)] To a stirred solution of (2, 3-cis)-3-amino-2-phenyl-2, [3-DIHYDRO-1,] 5-benzoxazepin- 4 (5H)-one [(] [(98] mg, 0.337 mmol) in dichloromethane (3 mL) was added [(22-[(TERT-] butoxycarbonyl) amino] (phenyl) acetic acid (93 mg, [0.] 370 mmol), HOBt (55 mg, 0.407 mmol), NMM (68 mg, 0.673 mmol) and EDAC-HCl (78 mg, 0.407 mmol). The mixture was stirred at ambient temperature under nitrogen overnight. The reaction mixture was diluted with water and extracted with ethyl acetate three times. The combined organic extracts were washed in succession with saturated aqueous sodium bicarbonate and IN [AQUEOUS HCI.] The organic solution was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 2: 1 [(V/V)] hexane: ethyl acetate to afford the title compound (146 mg, 89%) as a yellow [SOLID. 1H] NMR (300 MHz, CDCl3) [81.] 34 (s, 4.5H), 1.44 (s, 4.5H), 5.17 (m, 1H), 5.55 (m, 1H), 5.73 (d, 0.5H, J= 7.5 Hz), 5.85 (d, 0.5H, J= 7.0 Hz), 6.44-6. 73 (br, 1H), 6.91-7. 12 (m, 3H), 7.14-7. 41 (m, 12H), 7.63 (br s, 0.5H), 8.15 (br, 0.5H). MS APCI, m/z [= 510] (M+Na). [LC/MS] : 2.60 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With 4-methyl-morpholine; isobutyl chloroformate; | tert-butyl [[1- (2-ISOPROPYL-6-METHYLPHENYLCARBAMOYL)-1-PHENYL-METHYL]-] carbamate was isolated as a white solid (216. 1mg, 57%) from BOC- phenylglycine (250. Omg, 0. [99MMOL),] [N-METHYLMORPHOLINE] (0.12mL, 1. 09mmol), isobutylchloroformate (0.14mL, 1. [09MMOL), 2-ISOPROPYL-6-] [METHYLANILINE (0. 19ML,] 1. [19MMOL)] and [N-METHYLMORPHOLINE] (0.13mL, 1. [19MMOL). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With 4-methyl-morpholine; isobutyl chloroformate; | TERT-BUTYL [1- (2-METHYL-1-NAPHTHYLCARBAMOYL)-1-PHENYL-METHYL]-CARBAMATE WAS] isolated as an off-white solid (165.7mg, 43%) from BOC-phenyl glycine (250. Omg, 0. 99mmol), N-methylmorpholine (0.12mL, 1. 09mmol), [ISOBUTYLCHLOROFORMATE] (0.14mL, 1. [09MMOL), 2-METHYL-1-NAPHTHYLAMINE] [(187.] 7mg, 1. 19mmol) and N-methylmorpholine (0. [13ML,] 1. 19mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In dichloromethane at -20℃; for 24h; | |
80% | With tris(2,2,2-trifluoroethyl) borate at 100℃; for 24h; | |
71% | Stage #1: (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In dichloromethane for 0.333333h; Stage #2: benzylamine In dichloromethane at 20℃; for 8h; |
62% | With N-ethyl-N,N-diisopropylamine In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran | 1.e (S)-1-Ethyl-5-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid {2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl} amide: (e) (S)-(Benzylcarbamoyl-phenyl-methyl)-carbamic Acid Tert-Butyl Ester. (S)-tert-Butoxycarbonylamino-phenyl-acetic acid (1.00 g, 4 mmol) was dissolved in DCM (15 mL). Benzylamine (0.428 g, 4 mmol) and DIEA(0.65 g, 5 mmol) were added to the above mixture. The mixture which resulted was stirred at room temperature for a few minutes. PyBroP(2.10 g, 4.5 mmol) was added to the above solution in one portion and the reaction mixture was stirred overnight. The reaction mixture was diluted with DCM (150 mL) and washed with NaHCO3 (50 mL*2, sat.). The organic layer was collected and dried (Na2SO4) and the solvent was removed under reduced pressure. The crude product was purified by chromatography to provide the desired product (0.85 g, 62%). |
62% | Stage #1: (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid; benzylamine With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; Stage #2: With bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate In dichloromethane | 1 Preparation of Intermediate (S) (Benzylcarbamoyl-phenyl-methyl)-carbamic acid tert-butyl ester (I-1c) The (S)-tert-Butoxycarbonylamino-phenyl-acetic acid I-2b (1.00 g, 4 mmol) was dissolved in dichloromethane (DCM) (15 ml).benzylamine (0.428 g, 4 mmol) and diisopropylethylamine (DIEA) (0.65 g, 5 mmol) were added to the above mixture.The mixture was stirred at room temperature for a few minutes. bromo-trispyrrolidino-phosphonium hexafluorophosphate (PyBroP) (2.10 g, 4.5 mmol) was added to the above solution in one portion and the reaction mixture was stirred overnight.The reaction mixture was diluted with dichloromethane (150 ml) and washed with NaHCO3 (50 ML*2, sat.).The organic layer was collected and dried (Na2SO4).The solvent was removed under reduced pressure.The crude product was purified by chromatography to provide the desired product (0.85 g, 62%). |
With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate In dichloromethane at 0 - 20℃; | ||
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; Inert atmosphere; | ||
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 5 - 20℃; for 2h; | Step 2: tert-butyl (S)-(2-(benzylamino)-2-oxo-1-phenylethyl)carbamate (116a). A solution of EDCI (1.1 eq) and HOAt (1.3 eq) in dry DMF (5 mL) was stirred at 5 °C for 10 min, then (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid 115a (0.50 g, 1.99 mmol) was added and stirring was continued for 10 min before the addition of benzylamine (0.23 mL, 2.09 mmol). After complete addition, the cooling bath was removed and stirring was continued at rt for 2 h. After completion, the mixture was diluted with water and the precipitated solid was filtered off, washed with water, and dried. The crude product (566 mg, 83%, off-white solid) was used in the next step without further purification. LCMS (ES+) m/z calculated for C20H24N2O3 340.18, found 241 (M+H-Boc)+. | |
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 5 - 20℃; for 2h; | Step 2: tert-butyl (S)-(2-(benzylamino)-2-oxo-1-phenylethyl)carbamate (116a). A solution of EDCI (1.1 eq) and HOAt (1.3 eq) in dry DMF (5 mL) was stirred at 5 °C for 10 min, then (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid 115a (0.50 g, 1.99 mmol) was added and stirring was continued for 10 min before the addition of benzylamine (0.23 mL, 2.09 mmol). After complete addition, the cooling bath was removed and stirring was continued at rt for 2 h. After completion, the mixture was diluted with water and the precipitated solid was filtered off, washed with water, and dried. The crude product (566 mg, 83%, off-white solid) was used in the next step without further purification. LCMS (ES+) m/z calculated for C20H24N2O3 340.18, found 241 (M+H-Boc)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 1.66667h; | Example 9: Synthesis OF N [5- ( (R)-2- {2- [4- ( (-2-AMINO-2-PHENYL- ethylamino) phenyl] ETHYLAMINO}-L-HYDROXYETHYL)-2-HYDROXYPHENYL]- formamide; a. Preparation of (- { [4- (2-TERT-BUTOXYCARBONYLAMINOETHYL) PHENYLCARBAMOYL] PHENYL- methylcarbamic acid tert-butyl ester; [2- (4-AMINOPHENYL) ethyl] carbamic acid tert-butyl ester (3.95 g, 16.7 mmol) and ( (S)-TERT-BUTOXYCARBONYLAMINO) phenylacetic acid (3.97 g, 15.7 mmol) were dissolved with a 0.5 M solution OF 1-HYDROXY-7-AZABENZOTRIAZOLE IN N, N DIMETHYLFORMAMIDE (31.76 ML) under nitrogen and cooled to 0C. 1- (3-DIMETHYLAMINOPROPYL)-3-ETHYLCARBODIIMIDE hydrochloride (3.57 g, 18.6 mmol) was added and the mixture stirred at 0 C FOR 10 minutes, then at room temperature for 1.5 hours. The mixture was partitioned between water and ethyl acetate, and the organics washed with 1.0 N HC1, saturated sodium hydrogencarbonate, and saturated sodium chloride. The organics were then dried over sodium sulfate and evaporated to dryness. The title intermediate was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate In dichloromethane at 0 - 20℃; | 114.c c) Preparation intermediate of (S)- [(4- Fluorobenzyl)methylcarbamoyl]phenylmethyl}carbamic acid tert-butyl ester; A solution of N-Boc-L-phenylglycine (H, 17.2 g, 68.5 mmol) and (4- fluorobenzyl) methylamine (10.47 g, 75.3 mmol) in CH2C12 (550 mL) was cooled to 0°C. Disopropylethylamine (35.8 mL, 205 mmol) and PyBrOP (38.3 g, 82.1 mmol) were then added sequentially. The cooling bath was removed and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the title compound (24.5 g, 96%) was isolated by chromatography on silica gel eluting with a gradient of 40% to 60% ethyl acetate in hexane. |
81% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 18h; | A mixture containing (5)-2-(ter/-butoxycarbonylamino)-2-phenylacetic acid (4.0 g, 15.9 mmol) and l -(4-fluorophenyl)-N-methylmethanamine (2.4 mL, 17.5 mmol) in CH2Cl2 (50 mL) was cooled in an ice bath under an inert atmosphere of argon. Diisopropylethylamine (DIPEA, 7.9 mL, 47.7 mmol) and PyBOP (8.9 g, 19.1 mmol) were added sequentially. The resulting reaction mixture was wanned to room temperature and stirred for 18 h. It was then concentrated under reduced pressure and the resulting residue was purified by chromatography (gradient elution: EtOAc/petroleum ether=12: l ~8: 1 ) to afford (S)-tert-buty 2-((4-fluorobenzyl)(methyl)amino)-2-oxo-l -phenyl ethylcarbamate as a yellow syrup (4.83 g, yield: 81 %). 1HNMR (400MHz, CDCl3) δ: 7.41-7.32 (5H, m), 7.14 (2H, m), 6.99 (2H, m), 6.05 (IH, d, J= 8. 0 Hz), 5.60 (IH, d, J= 7.6 Hz), 4.61 (2H, m), 2.86 (IH, s), 2.81 (2H, s). |
81% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 18h; | 1 Preparation of (S)-tert-butyl 2-((4-fluorobenzyl)(methyl)amino)-2-oxo-l- phenylethyl carbamate:A mixture containing (S)-2-(7ert-butoxycarbonylamino)-2-phenylacetic acid (4.0 g, 15.9 mmol) and l -(4-fluorophenyl)-N-methylmethanamine (2.4 mL, 17.5 mmol) in CH2Cl2 (50 mL) was cooled in an ice bath under an inert atmosphere of argon. Diisopropylethylamine (DIPEA, 7.9 mL, 47.7 mmol) and PyBOP (8.9 g, 19.1 mmol) were then added sequentially. The resulting reaction mixture was warmed to room temperature and stirred for 18 h. It was then concentrated under reduced pressure and the resulting residue was purified by chromatography (gradient elution: EtO Ac/petroleum ether=12:l ~8:l) to afford (S)-tert-buty 2-((4- fluorobenzyl)(methyl)amino)-2-oxo-l -phenylethyl carbamate as a yellow syrup (4.83 g, yield: 81%). 1HNMR (400MHz, CDCl3) δ: 7.41-7.32 (5H, m), 7.14 (2H, m), 6.99 (2H, m), 6.05 (IH, d, J= 8. 0 Hz), 5.60 (IH, d, J= 7.6 Hz), 4.61 (2H, m), 2.86 (IH, s), 2.81 (2H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 1h; | B. Preparation of (2S) N-[4-(2-rhoyridon-l-yl)rhohenyl]-2-phenyl-2-(4- chlorophenylaminocarbonylamino)-acetamide; [0497] To a solution of (L) N-BOC-phenylglycine (126 mg, 0.500 mmol) and 4-(2- rhoyridon-l-yl)phenylamine (102 mg, 0.548 mmol) in DMF (3 mL), EDC (144 mg, 0.750 mmol) was added. The mixture was stirred at room temperature for 1 h. Water (10 mL) was added to induce precipitation. The precipitate was collected by filtration to give the amide (61 mg). MS 420.2 (M+H).[0498] The amide (61 mg, 0.15 mmol) was dissolved in TFA (4 mL). After being stirred at room temperature for 1 h, TFA was removed in vacuo. The residue was partitioned between EPO <DP n="120"/>EtOAc and aq. 5% NaHCO3. The EtOAc phase was separated, dried over Na2SO4, concentrated in vacuo to give a solid (35 mg).[0499] To a solution of the solid (17 mg, 0.053 mmol) in CH3CN (2 mL), 4- chlorophenylisocyanate (20 mg, 0.13 mmol) was added. After being stirred at room temperature for 30 min, the mixture was purified by HPLC to give the titled compound (10 mg). MS 473.2 and 475.2 (M+H, Cl pattern) | |
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 1h; | B. Preparation of (2S) N-[4-(2-pyridon-l-yl)phenyl]-2-phenyl-2-(4- chlorophenylaminothiocarbonylamino)-acetamide; [0187] To a solution of (L) N-BOC-phenylglycine (126 mg, 0.500 mmol) and 4-(2- rhoyridon-l-yl)phenylamine (102 mg, 0.548 mmol) in DMF (3 mL), EDC (144 mg, 0.750 mmol) was added. The mixture was stirred at room temperature for 1 h. Water (10 mL) was added to induce precipitation. The precipitate was collected by filtration to give the amide (61 mg). MS 420.2 (M+H).[0188] The amide (61 mg, 0.15 mmol) was dissolved in TFA (4 mL). After being stirred at room temperature for 1 h, TFA was removed in vacuo. The residue was partitioned between EtOAc and aq. 5% NaHCO3. The EtOAc phase was separated, dried over Na2SO4, concentrated in vacuo to give a solid (35 mg).[0189] To a solution of the solid (17 mg, 0.053 mmol) in CH3CN (2 mL), 4- chlorophenylisothiocyanate (22 mg, 0.13 mmol) was added. After being stirred at room temperature for 30 min, the mixture was purified by HPLC to give the titled compound (6 mg). MS 489.0 and 491.0 (M+H, Cl pattern). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; In methanol; ethyl acetate; | B. N-BOC-alpha-phenylglycine, methyl ester (1.2 g) is dissolved in methanol (50 ml) containing acetic acid (1 ml). 5% rhodium on aluminum powder (0.60 g) is added and the mixture shaken under 50 psi hydrogen for about 18 hours. The mixture is filtered, evaporated in vacuo, and the residue taken up into ethyl acetate. The organic solution is washed with water, saturated sodium bicarbonate solution, water, brine, dried over magnesium sulfate, filtered, evaporated in vacuo to give N-BOC-alpha-cyclohexylglycine, methyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 72h; | 89.b To a stirred CH2CI2 solution (0.1 M, 7.5 mL) of Λ/-(4-aminobutyl)-2-chloro-4- fluorobenzenesulfonamide (0.25 g, 0.89 mmol) were added EDC hydrogen chloride (0.19 g, 0.98 mmol), HOBt (0.13 g, 0.98 mmol), Λ/-Boc-phenylglycine (0.22 g, 0.89 mmol) and triethylamine (0.3 mL, 2.23 mmol). The resulting solution was stirred at RT for 3 days, after which time 1 N HCI solution was added to the mixture. The layers were separated and the organic portion was washed with 5% aq. NaHCO3 and brine. The organic phase was dried over Na2SO4, filtered and concentrated to a residue, which was purified by flash column chromatography (SiO2, 50% ethyl acetate/hexanes). The title compound was isolated as a white solid in 58% yield (0.27 g); LCMS (m/z): 514 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 3-hydroxy-3,4-dihydrobenzotriazine-4-one In dichloromethane at 20℃; | 60.c To a dichloromethane solution of Λ/-(3-aminopropyl)-4-fluoro-2- (trifluoromethyl)benzenesulfonamide (200mg, 0.594 mmol) was added (2S)-([(1 ,1 - dimethylethyl)oxy]carbonyl}amino)(phenyl)ethanoic acid (179mg, 0.713mmol), HOOBT (1.2 mg, 0.007 mmol), and NMM (0.3ml, 2.97mmol). The mixture was stirred several minutes whereupon EDCHCI (137mg, 0.713 mmol) was added. The reaction mixture was stirred overnight at RT. The solution was washed with 10% citric acid and brine, dried (MgSO4), filtered and concentrated to a solid. Purification by silica gel column chromatography (30%-90% ethyl acetate/hexane) gave the product in 85% yield (269mg): MS (m/z): 533 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In water; N,N-dimethyl-formamide; | Part A. <strong>[13143-47-0]1-(4-Aminophenyl)-1H-pyridin-2-one</strong> (0.59 g, 3.19 mmol) and Boc-DL-PHG-OH (0.80 g, 3.19 mmol) were stirred in dry DMF (8 mL) at RT under N2. HATU (1.33 g, 3.51 mmol, 1.1 eq) was added, followed by the addition of DIEA (1.12 g, 6.38 mmol, 2.0 eq). The resulting mixture was stirred at rt for 3 h. H2O was added, and the mixture was extracted with EtOAc (2*), washed with H2O and brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, CH2Cl2, then CH2Cl2:EtOAc=1:1) to give [4-(2-oxo-2H-pyridin-1-yl)phenylcarbamoyl]phenylmethyl}-carbamic acid tert-butyl ester (1.23 g, yield: 92%). LC/MS-ESI (M+H)+420.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine at 0℃; for 0.333333h; Stage #2: aniline at 20℃; for 8h; | |
85% | With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 16h; Inert atmosphere; | 4.2 General procedure for the preparation of carbamates 2a-e General procedure: To a vigorously stirred solution of the relevant (S)-N-Boc-amino acid 1a-e (15.1 mmol) and aniline (1.93 mL, 21.1 mmol) in CH2Cl2 (25 mL) was added DCC (3.43 g, 16.6 mmol) in small portions. The solution was stirred at room temperature for 16 h, filtered on Celite, and then concentrated under vacuum (40 Torr). The crude product was purified by flash chromatography on silica gel (EtOAc/hexane, 4:1) and then by crystallization from heptane, to afford the relevant compounds 2a-e in good yield. |
Stage #1: (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid With TEA; chloroformic acid ethyl ester In tetrahydrofuran at -15℃; Stage #2: aniline In tetrahydrofuran at 20℃; Further stages.; |
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid With TEA; chloroformic acid ethyl ester In tetrahydrofuran Stage #2: tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate In tetrahydrofuran Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 4h; | 173.3 Step 3: ((S)-{(3,4-Dimethoxy-phenyl)-[2-(4-trifluoromethyl-phenyl)-ethyl]-carbamoyl}-phenyl-methyl)-carbamic acid tert-butyl ester To a 0° C. solution of 3.25 g (10 mmol) (3,4-dimethoxy-phenyl)-[2-(4-trifluoromethyl-phenyl)-ethyl]-amine and 2.8 g (11 mmol) Boc-L-alpha-phenylglycine in 50 ml dichloromethane under argon, was added 2.1 g (11 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The mixture was stirred at 0° C. for 4 hours. The solution was washed once with 50 ml of a sat. NaHCO3 solution and once with 50 ml water. The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was purified with flash column chromatography on silica eluding with a gradient formed from heptane and ethylacetate to provide 5.6 g (100%) of the title compound as a yellow gum. MS (m/e): 558.8 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; Inert atmosphere; | 21.c.3 To a 0° C. solution of 35 mg (0.15 mmol) (3,4-dimethyl-phenyl)-[2-(5-methyl-pyridin-2-yl)-ethyl]-amine and 40.4 mg (0.16 mmol) Boc-L-alpha-phenylglycine in 540 uL dichloromethane under argon, was added 31.4 mg (0.16 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The mixture was stirred at 0° C. for 3 hours then at ambient temperature overnight. The solution was washed once with a sat. NaHCO3 solution (3 mL) and once with water (3 mL). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was purified with flash column chromatography on silica eluting with a gradient formed from heptane and ethylacetate to provide 0.052 g (75%) of the title compound as an oil. MS (m/e): 474.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: methylamine hydrochloride; (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 0℃; for 0.166667h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; N,N-dimethyl-formamide at 25℃; for 18h; | 60.A To a solution of (S)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (1.00 g, 3.98 mmol) in DMF (5 mL) and methylene chloride (5 mL) was added methylamine hydrochloride (403 mg, 5.97 mmol), HOBt (645 mg, 4.78 mmol), and Hunig's Base (1.73 mL, 9.95 mmol) and the resulting solution stirred at 0° C. for 10 minutes. EDCI (916 mg, 4.78 mmol) was added and the reaction stirred at 25° C. for 18 hours. The mixture was concentrated in vacuo, the resulting residue was diluted with ethyl acetate (45 mL), brine (10 mL), and 5% H3PO4 aqueous solution (10 mL), and the layers were separated. The organic layer was washed with 5% H3PO4 aqueous solution (10 mL), twice with saturated aqueous sodium bicarbonate solution (15 mL), water (15 mL), and brine (15 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a light colored solid. The crude material was taken on directly to the next step. (1.04 g, 99% yield) MS (ESI+) m/z=265 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 20℃; for 15h; | To a solution of 2-(tert-butoxycarbonylamino)-2-phenylacetic acid (13)(400 mg, 1.59 mmol) in THF (20 ml), (R)-l-methylpyrrolidin-3-ol (193 mg, 1.91 mmol), N,N'-methanediylidenedicyclohexanamine (394 mg, 1.91 mmol) and lH-benzo[d][ l,2,3]triazol-l-ol (258 mg, 1.91 mmol) were added. The reaction was stirred at RT for 15h then the solvent was evaporated. The residue was taken up with DCM, the insoluble was filtered off and the clear solution was washed twice with aq. Na2CO3 and brine, dried over Na2SO4 and evaporated to obtain (R)-l-methylpyrrolidin-3-yl2-(tert-butoxycarbonylamino)-2-phenylacetate (340 mg; 64% yield). |
64% | With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 20℃; for 15h; | To a solution of 2-(tert-butoxycarbonylamino)-2-phenylacetic acid (I3) (400 mg, 1.59 mmol) in THF (20 ml), were added (R)-1-methylpyrrolidin-3-ol (193 mg, 1.91 mmol), N,N'-methanediylidenedicyclohexanamine (394 mg, 1.91 mmol), and 1H-benzo[d][1,2,3]triazol-1-ol (258 mg, 1.91 mmol). The reaction was stirred at RT for 15, hours, and then the solvent was evaporated. The residue was taken up with DCM, the insoluble was filtered off, and the clear solution was washed twice with aq. Na2CO3 and brine, dried over Na2SO4 and evaporated to obtain (R)-1-methylpyrrolidin-3-yl 2-(tert-butoxycarbonylamino)-2-phenylacetate (340 mg; 64% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 2,4,6-trimethyl-pyridine; benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide at 0℃; for 2h; | 4.11.1 Compound 16a HOBt (104 mg, 0.77 mmol), HBTU (292 mg, 0.77 mmol) and Sym-collidine (169.1 μL, 1.28 mmol) were sequentially added to a stirred solution of commercially available 15a (46.2 mg, 0.32 mmol) and N-Boc-(S)-2-Phenylglycine (200.9 mg, 0.80 mmol) in dry DMF (2 mL) at 0 °C. The reaction mixture was left stirring for 2 h and then, after reaction completion, the mixture was diluted with EtOAc (20 mL) and washed with a saturated solution of ammonium chloride (3 × 20 mL), saturated solution of sodium bicarbonate (3 × 20 mL) and brine (1 × 20 mL. The organic layers were dried over Na2SO4, and then the solvent was removed under reduced pressure. The residue was purified by Biotage flash chromatography, eluant conditions: from 1% of MeOH and 99% of CH2Cl2 to 10% of MeOH and 90% of CH2Cl2. Yield 94% (183 mg, MW 610.80, 0.30 mmol) of pure 16a. Analytical characterization: 1H NMR (400 MHz, CDCl3):δ: 7.38-7.25 (m, 10H), 5.76 (m, 2H), 5.25 (m, 2H), 3.32 (bs, 1H), 3.23 (m, 2H), 3.13 (bs, 1H), 1.57 (s, 4H), 1.42 (m, 18H), 1.21 (d, J = 11.2 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ: 129.0, 128.9, 128.3, 127.2, 39.7, 39.7, 29.2, 28.8, 28.3, 26.4. ESI-MS: m/z 611.4 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 2,4,6-trimethyl-pyridine; benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; In N,N-dimethyl-formamide; at 0℃; for 2h; | HOBt (73 mg, 0.54 mmol), HBTU (204.8 mg, 0.54 mmol) and Sym-collidine (118.9 mL, 0.90 mmol) were sequentially added to a stirred solution of commercially available 15b (50 mg, 0.227 mmol) and N-Boc-(S)-2-Phenylglycine (142 mg, 0.567 mmol) in dry DMF (2 mL) at 0 C. The reaction mixture was left stirring for 2 hours and then, after reaction completion, the mixture was diluted with EtOAc (20 mL) and washed with a saturated solution of ammonium chloride (3 x 20 mL), saturated solution of sodium bicarbonate (3 x 20 mL) and brine (1 x 20 mlL. The organic layers were dried over Na2SO4, and then the solvent was removed under reduced pressure. The residue was purified by BiotageTM flash chromatography, eluant conditions: from 1% of MeOH and 99% of CH2Cl2 to 10% of MeOH and 90% of CH2Cl2. Yield 94 % (146 mg, MW 686.85, 0.212 mmol) of pure 16b. Analytical characterization: 1H-NMR (400 MHz, CDCl3): d: 7.39-7.28 (m, 10H), 6.55 (bs, 2H), 5.94 (bs, 2H), 5.10 (bs, 2H), 3.59-3.31 (m, 16H), 1.70 (t, J = 6.0 Hz, 4H), 1.42 (s, 18H); 13C-NMR (100 MHz, CDCl3): d: 170.3, 138.9, 128.8, 128.1, 127.2, 79.8, 70.4, 70.1, 69.7, 38.1, 28.7, 28.3. ESI-MS: m/z 687.6 [M+H]+, 709.5 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With 2,4,6-trimethyl-pyridine; benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide at 0℃; for 2h; | Compound 16c. HOBt (23 mg, 0.17 mmol), HBTU (64.5 mg, 0.17 mmol) and Sym-collidine (35.7 mL, 0.27 mmol) were sequentially added at 0 °C to a stirred solution of commercially available 3,4-bis-(4-amino-butylamino)-cyclobut-3-ene-1,2-dione (17 mg, 0.068 mmol) and N-Boc-(S)-2-Phenylglycine (43 mg, 0.17 mmol) in dry DMF (0.5 mL). The reaction mixture was left stirring and monitored by LC-MS. After reaction completion, the mixture was diluted with EtOAc and sequentially washed with a saturated aqueous solution of NH4Cl, saturated aqueous solution of sodium bicarbonate, and brine. The organic layer was dried over Na2SO4, and then the solvent removed under reduced pressure. The residue was purified by BiotageTM flash chromatography, eluant conditions: from 1% of MeOH and 99% of CH2Cl2 to 10% of MeOH and 90% of CH2Cl2. Yield 88 % (43 mg, MW 720.87, 0.060 mmol) of pure 16c. Analytical characterization: 1H-NMR (400 MHz, CD3OD): d: 7.41-7.31 (m, 10H), 5.11 (bs, 2H), 3.56 (bs, 4H), 3.30-3.19 (m, 4H), 1.55 (bs, 8H), 1.44 (s, 18H); 13C-NMR (100 MHz, CD3OD): d: 128.3, 127.8, 127.0, 43.4, 38.7, 28.1, 27.3, 25.8. ESI-MS: m/z 721.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With 2,4,6-trimethyl-pyridine; benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide at 0℃; for 2h; | Compound 16d. HOBt (23 mg, 0.17 mmol), HBTU (64.5 mg, 0.17 mmol) and Sym-collidine (35.7 mL, 0.27 mmol) were sequentially added at 0 °C to a stirred solution of commercially available deca-4,6-diynedioic acid bis-[(2-amino-ethyl)-amide] (17 mg, 0.068 mmol) and N-Boc-(S)-2-Phenylglycine (43 mg, 0.17 mmol) in dry DMF (3 mL). The reaction mixture was left stirring and monitored by LC-MS. After reaction completion, the mixture was diluted with EtOAc and sequentially washed with a saturated aqueous solution of NH4Cl, saturated aqueous solution of sodium bicarbonate, and brine. The organic layer was dried over Na2SO4, and then the solvent removed under reduced pressure. The residue was purified by BiotageTM flash chromatography, eluant conditions: from 1% of MeOH and 99% of CH2Cl2 to 10% of MeOH and 90% of CH2Cl2. Yield 83 % (42 mg, MW 744.90, 0.056 mmol) of pure 16d. Analytical characterization: 1H-NMR (400 MHz, CDCl3): d: 7.32-7.19 (m, 10H), 6.81 (bs, 2H), 5.73 (d, J = 6.4 Hz, 2H), 5.08 (bs, 2H), 3.32-3.19 (m, 8H), 2.43 (m, 4H), 2.19 (m, 4H), 1.33 (s, 18H); 13C-NMR (100 MHz, CDCl3): d: 171.3, 129.0, 128.3, 127.2, 80.2, 66.2, 59.0, 41.0, 38.7, 34.8, 28.3, 16.0. ESI-MS: m/z 745.6 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With 2,4,6-trimethyl-pyridine; benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide at 0℃; for 2h; | 4.15.1 Compound 16e HOBt (81 mg, 0.6 mmol), HBTU (227.5 mg, 0.6 mmol) and Sym-collidine (132.1 μL, 1 mmol) were sequentially added to a stirred solution of commercially available 15e (110 mg, 0.503 mmol) and N-Boc-(S)-2-Phenylglycine (158 mg, 0.63 mmol) in dry DMF (3 mL) at 0 °C . The reaction mixture was left stirring and monitored by LC-MS. After reaction completion, the mixture was diluted with EtOAc (20 mL) and sequentially washed with 5% aqueous citric acid (20 mL), saturated aqueous sodium bicarbonate (20 mL) and brine (2 × 20 mL). The organic layer was dried over Na2SO4, and then the solvent was removed under reduced pressure. The residue was purified by Biotage flash chromatography, eluant conditions: from 1% of MeOH and 99% of CH2Cl2 to 10% of MeOH and 90% of CH2Cl2. Yield 74% (167 mg, MW 51.53, 0.37 mmol) of pure 16e. Analytical characterization: 1H NMR (400 MHz, CDCl3): δ: 7.32.7.20 (m, 5H), 6.28 (bs, 1H), 5.77 (bs, 1H), 5.07 (bs, 1H), 3.6-3.28 (m, 16H), 1.35 (s, 9H); 13C NMR (100 MHz, CDCl3): δ: 129.0, 128.3, 127.2, 70.7, 70.6, 70.5, 70.3, 70.0, 69.6, 68.8, 58.5, 50.7, 39.6, 28.3. ESI-MS: m/z 452.5 [M+H]+, 474.5 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In tetrahydrofuran; water at 20℃; for 4h; | General procedure: A suspension of amino acid derivative (5 mmol) was dissolved ina mixture of tetrahydrofuran (50 mL) and water (20 mL). 1 N NaOH(6 mL) was added followed by adding 1.1 g tert-butoxycarbonyl(5 mmol) dropwise at room temperature. After stirring for 4 h,the tetrahydrofuran was evaporated in vacuum from the reaction mixture. The residue was added ethyl acetate (50 mL) and 5% citricacid (30 mL). The organic layer was separated, washed with water(20 mL), dried with anhydrous Na2SO4 and rotary evaporated to dryness. Crude residue was used into next reaction without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 0.5h; Stage #2: methyl (L)-leucinate hydrochloride With N-ethyl-N,N-diisopropylamine In dichloromethane for 7h; | Methyl (pyrazine-2-carbonyl)-L-phenylalaninate (B1) General procedure: At 0 °C, to a solution of pyrazinecarboxylic acid (0.7 g, 5.6 mmol) in anhydrous DCM were added HOBT (0.9 g, 6.8 mmol) and EDCI (1.3 g, 6.8 mmol). After 30 min, L-phenylalanine methyl ester hydrochloride (1.1 g, 5.1 mmol) and DIEA (0.9 g, 7.0 mmol) were added. Stirring was continued for 7 h and then the DCM solution washed with 1 N HCl, saturated NaHCO3 and brine, dried over MgSO4, and evaporated under vacuum. The crude product was purified by flash column chromatography to give desired compound B1 (1.36 g, 80% yield) as the colorless oil. |
Stage #1: (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid; methyl (L)-leucinate hydrochloride With dmap; benzotriazol-1-ol; triethylamine In dichloromethane at 0℃; for 0.25h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 14h; | ||
With ethylene dichloride hydrochloride; C6H5N3O*Cl(1-); N-ethyl-N,N-diisopropylamine In dichloromethane at 21 - 23℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 100% 2: 15.9 g | With sodium hydroxide In water at 20℃; | 4 Example 5 Preparation of levomilnacipran free base ((1S,2R)-cis-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide) Example 5 Preparation of levomilnacipran free base ((1S,2R)-cis-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide) Trimethyl silyl chloride (9.7 ml, 76.7 mmol) is added dropwise to a solution of the compound of Example 4 (15.7 g, 63.9 mmol) in methyl-tert-butyl ether (150 ml) and 2-propanol (25 ml), and the formation of a white solid occurs. The mixture is stirred for 30 minutes, cooled to 20°C and filtered. The filtered solid is washed with 35 ml of cold methyl-tert-butyl ether and dried under vacuum for 20 hours. 17.2 g of levomilnacipran hydrochloride (60.81 mmol, yield 95%) are obtained.2-propanol (44 ml) is added to the obtained product (17.2 g, 60,81 mmol) and it is heated to 75°C until complete dissolution, cooled to RT and the formation of a white solid occurs. It is filtered and washed with cold 2-propanol (6 ml), and 13.5 (g) of the product are obtained.50 ml of methyl-tert-butyl ether are added to the mother liquors and it is stirred at room temperature for 30 minutes, then left to decant, filtered and washed with cold methyl-tert-butyl ether. 2.72 (g) of the product are obtained, that combined with the previous one gives an overall yield of 89.6%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With 2,6-dimethylpyridine; 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate In water at 20℃; for 4h; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; for 0.166667h; Inert atmosphere; Stage #2: (2-aminoethyl)bis(2-pyridylmethyl)amine In dichloromethane; N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere; | N-Boc (S)-PheGly (160 mg, 0.637 mmol, 1.2 eq),TBTU (225 mg, 0.692 mmol, 1.3 eq), HOBt (122 mg, 0.903 mmol, 1.7 eq) and dryDIPEA (0.29 mL, 3 eq) were dissolved under nitrogen atmosphere in dry CH2Cl2 (5 mL) and dry DMF (2 mL). After 10 minutes a solution of compound 14[1](130 mg, 0.531 mmol, 1 eq)in dry CH2Cl2 (5 mL) was added. The reaction mixture was stirred atrt for 24 hours (TLC, hexane/EtOAc 2/8 and CH2Cl2/MeOH 95/5). After 24 hours the solventwas removed under reduced pressure, the crude was diluted with CH2Cl2 (20 mL) and washed with saturated aqueous NH4Cl (2 x 20mL), saturated aqueous NaHCO3 (2 x 20mL) and brine (20mL).The collected organic layers were dried with Na2SO4,filtered and the solvent was removed under reduced pressure. The crude product(298 mg) was purified by flash chromatography on basic alumina (AcOEt/Hexane 7/3),yielding pure compound 15a,b asa white solid (234 mg, 0.477mmol).Yield: 91%[1] Fukuoka, S.; Kida, T.; Nakajima, Y.; Tsumagari,T.; Watanabe, W.; Inaba, Y.; Mori, A.; Matsumura, T.; Nakano, Y.; Takeshita, K.Tetrahedron 2010, 66, 1721. 1H NMR(400 MHz, CDCl3): δ(ppm) 8.59 (d, 2H, J = 4.5 Hz, H8), 8.26 (bs,1H, NH-Boc), 7.61 (t, 2H, J = 7.7 Hz, H6), 7.49 (d, 2H, J = 6.3 Hz, H9),7.36-7.29 (m, 3H, H10, H11), 7.21 (m, 4H, H5, H7), 6.06 (bs, 1H, NH), 5.31 (s, 1H, H1), 3.91(s, 4H, H4), 3.45 (m, 1H, H2), 3.30 (m, 1H, H2), 2.82 (s, 2H, H3), 1.44 (s, 9H,H12).13C NMR (100.6 MHz, CDCl3): 169.9, 158.8, 155.0, 149.0, 139,4, 136.6,128.7, 127.9, 127.1, 123.1, 122.2, 79.6, 59.7, 58.4, 52.2, 37.8, 28.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | General procedure: At first,EDCI (1.22 g, 5.5 mmol) was added into a stirring solution of(tert-butoxycarbonyl)leucine 10 (1.16 g, 5.0 mmol) and DMAP(210 mg, 1.5 mmol) in dry dichloromethane (15 mL). The mixturewas stirred for 15 min and then cooled to 0 C. Triphenylmethanamine11a (1.04 g, 4 mmol) was added to the mixtureand stirred at the same temperature for 30 min. The resulting solutionwas stirred at room temperature until complete consumptionof triphenylmethanamine (monitored by TLC). The reaction wasquenched with water (50 mL) and extracted with dichloromethane(3 50 mL). The combined organic layers were washed with saturatedbrine solution (30 mL), followed by drying over Na2SO4 andevaporation in vacuo. The crude product was purified by columnchromatography to give pure tert-butyl (S)-(4-methyl-1-oxo-1-(tritylamino)pentan-2-yl)carbamate 12a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: cycl-isopropylidene malonate; (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 10℃; Stage #2: With sodium tetrahydroborate; acetic acid at 0 - 10℃; | 2.2 (2) A mixture of (S)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (150g, 0.59mol), 4-dimethylaminopyridine (130g, 1.06mol), Meldrum's acid (102g, 0.71mol), N,N-dicyclohexylcarbodiimide (185g, 0.89mol) was dissolved in methylene chloride (1.5 L), maintaining the temperature of the reaction system was added dropwise at 0-10 deg. C. The filtrate was washed with 1N HCl (0.5 L * 3), washed with water (0.5 L * 1), and washed with saturated brine (0.5 L * 1), and used directly in the next reaction. The organic phase was cooled to 0-10 ° C, acetic acid (214g, 3.56mol) was added, sodium borohydride (67g, 1.78mol) was added in portions and the temperature was maintained between 0 and 10 ° C. The solution was washed with 1N HCl (0.5 L * 3), washed with water (0.5 L * 1), saturated brine (0.5 L * 1), and washed with saturated brine (0.5 L), and concentrated to give 172g of a yellow solid in 79 % yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.96 g | A mixture of 2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (1.0 g, 3.98 mmol), N,N'-dicyclohexylcarbodiimide (1.64 g, 7.97 mmol) and 1- hydroxybenzotriazole hydrate (1.08 g, 7.97 mmol) in THF (25 mL) was stirred at room temperature. After one hour a solution of (l-methyl-4-piperidyl)methanol (0.62 g, 4.78 mmol) was added and the mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo. The residue was taken up into EtOAc (30 mL) and washed with saturated aqueous NaHCC"3 solution (2 x 40 mL), then with brine (40 mL). The organic phase was collected, filtered through a phase separator and the solvent was removed in vacuo to give the title compound as a pink gum (1.96 g, Theoretical yield = 1.44 g).LCMS (Method 1): [MH+] = 363 at 2.54 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 18h; | 4.3 General procedure A General procedure: Boc-Leu-Sta-NH(CH2)2Ph (30). A mixture of HCl.NH2-Sta-NH(CH2)2Ph (50 mg, 0.158 mmol), Boc-Leu-OH (35 mg, 0.151 mmol), HBTU (75 mg, 0.196 mmol) and DIPEA (194 μL, 1.11 mmol) in DMF (2 mL) was allowed to stir for 18 h at 20 °C. The reaction mixture was quenched with 10% citric acid solution (1×10 mL) and the desired product extracted into EtOAc (3×15 mL). The organic layers were combined, washed with saturated NaHCO3 (1×20 mL) and brine (1×20 mL), dried with MgSO4 and concentrated in vacuo to obtain the crude residue. The crude residue was purified using a silica chromatography gradient eluting from 100% DCM to 10% MeOH/DCM to obtain Boc-Leu-NH(CH2)2Ph (30) (46 mg, 59%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 10℃; | N-Boc-D- phenylglycinol 17.5g,DIPEA 11.4g, 80ml of tetrahydrofuran was added to the reaction flask.Cool down to 0 C.Methanesulfonyl chloride was added dropwise to the reactor at 10 C.Additional 26 ml of THF was added.After the completion of the reaction, 0.5 N hydrochloric acid (3.6 g of concentrated hydrochloric acid / 67 ml of water) was added to the reactor, stirred at 10 C, and liquid-separated.The organic layer was added to cyclohexane.A white solid was obtained which was dried to give (S)-Boc-phenylglycanol mesylate in a yield of 91%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate In N,N-dimethyl-formamide at 55℃; | 2.3 Step 3 3-((2R)-amino-2-phenylethyl)-5- [2-fluoro-3-((2H3)-methoxy)phenyl]-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-3H-pyrimidine-2,4-dione 19.7g (S) -Boc- phenylglycinol mesylate,16.6 g of 5-[2-fluoro-3-(D3-methoxy)phenyl]-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2, 4-(1H,3H)-dione,Potassium carbonate 13.4 g, 100 ml DMF was added to the reaction flask.The temperature was raised to 55 ° C, and after the reaction was completed, it was cooled to 20 ° C.150 ml of ethyl acetate was added to separate the layers, and the ester layer was left and washed with water.The organic layer was placed in a reaction flask, 11.2 g of methanesulfonic acid was added, and the reaction mixture was warmed to 60 ° C and stirred for 2 hr.The reaction solution was cooled to room temperature, and an aqueous potassium carbonate solution was added thereto to adjust the pH, and the layers were stood still. The ester layer was spun to near dryness, cyclohexane was added over 1 hr, and the slurry was refluxed.Filtered to a white solid with a yield of 88%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triethylamine In acetonitrile at 0 - 20℃; for 12h; | (8) Cyanomethyl (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetate (1h) To a stirred solution of (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid 22 (5 g, 19.90 mmol) in Acetonitrile (100 mL) cooled to 0 °C TEA (8.32 mL, 59.7 mmol) was added after that chloroacetonitrile (2.52 mL, 39.8 mmol) was added dropwise at 0°C slowly raise the temperature up to room temperature and stirring was continued for another 12h. The reaction mixture was quenched with sodium bicorbonate solution and extracted with Ethyl acetate. Take the Ethyl acetate layer and dried over sodium sulphate and concentrated under reduced pressure to get the crude product the crude product was purified by giving the wash of pet ether (2 x 20 mL). Pet-Ether was decanted out and the remaining was dried under vacuum to produce cyanomethyl (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetate (1h) (4.5 g, 15.51 mmol, 78 % yield). 1H NMR (400 MHz, DMSO-d6): δ 7.39-7.25 (m, 5H), 5.42-5.34 (m, 2H), 4.74-4.70 (m, 2H), 1.43 (s, 9H). MS (ESI): 308.2 as [M+H2O] in +Ve mode. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid With benzotriazol-1-ol; dicyclohexyl-carbodiimide In tetrahydrofuran at 0℃; for 0.25h; Stage #2: 4-(trifluoromethyl)phenylhydrazine In tetrahydrofuran at 0 - 20℃; for 1.5h; | 4.1.1. Synthesis of Hydrazides-General Procedure General procedure: A solution of N-Boc amino acid (0.25 g, 1.43 mmol, 1 equiv.), HOBt (2 equiv.) and DCC (1.2 equiv.)was dissolved in THF (7.5 mL), cooled to 0 C and stirred for 15 min. The solution was treatedwith N-Aryl/Alkyl hydrazine * (1.2 equiv.) before warming to room temperature and stirring fora further 1.5 h. The mixture was then poured into sat. aq. NH4Cl (20 mL) before separating andextracting the aqueous layer with EtOAc (40 mL). The organic layer was further washed with sat.aq. NaHCO3 (20 mL) and then brine (20 mL). The combined organic layers were dried over MgSO4,filtered, concentrated and dried in vacuo. Flash chromatography (DCM/EtOH/NH3 [600:8:1], [400:8:1],[200:8:1]) afforded the desired N-Boc amino acid hydrazides. * When the hydrazine hydrochlorides were used, Et3N (1.2 equiv.) is added to neutralise the salt |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Stage #1: 1,8-dihydroxy-3-(2-hydroxyethoxy)-6-methylanthracene-9,10-dione; (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; Stage #2: With trifluoroacetic acid In dichloromethane for 2h; | General procedure A for preparation of compounds 3a-3z, 4a-4b, and 7a-7l General procedure: To a mixture of compound 2 (1.00mmol) in dry dichloromethane (20mL) were added various N-Boc-amino acids (1.20mmol), dicyclohexyl carbodiimide (DCC) (4.50 mmol) and 4-(N,N-dimethlyamino)pyridine (DMAP) (1.00 mmol) at 0 °C. After stirring about 30 min to 5 h at 0 °C, TLC analysis showedthe complete consumption of compound 2, and then the resulting mixture was added dropwise TFA (5 mL) at the same temperature and kept stirring for anther about 2 h. The insoluble side product was filtered out and the filtrate was evaporated to give the residue, which was purified by reversephase flash chromatography with the following conditions: Column: Spherical C18, 20-40 m, 330 g;Mobile Phase A: Water (plus 5 mM TFA); Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 5%B gradient in 10 min, 25% B-45% B gradient in 25 min; Detector: 254 nm. The fractions containing thedesired product were collected at around 40% B and concentrated under reduced pressure to affordcompounds 3a-3z in 20% to 50% yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.5h; | 1.1.3 1.3 Preparation of compound a1-36 and a1-41 Compound 5 (N-(tert-butoxycarbonyl)-L-2-phenylglycine, 1.26g, 5.0mmol),Benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU, 2.09g, 5.5mmol),Compound 6 (N,N-dimethyl-L-phenylpropionamide, 821mg, 5.0mmol) was added to the reactor,Add 20mL of dichloromethane,Then add N,N-diisopropylethylamine (DIEA, 1.65mL, 10mmol),Stir at room temperature for half an hour to complete the reaction.Add a certain amount of water to quench the reaction,And repeatedly extract the water phase with DCM,The combined organic phase was dried with anhydrous Na2SO4,After filtering and spin-drying,The column was separated to obtain the substrate 1-36a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 24h; | 7: 6 (1.33 g, 5.00 mmol), 1-octanol (0.78 ml, 5.00 mmol), EDC (1.15 g, 6.00 mmol) and DMAP (1.22 g, 10.0 mmol) were dissolved in CH2CI2/DMF (25 ruL:5 mL). The reaction mixture was stirred for 24 h at room temperature. Solvent was removed in vacuo and the crude product was dissolved in CH2CI2 (30 mL), and washed with water (2 x 40 mL) the crude product was purified by flash column chromatography (Hexane:EA = 8: 1, v:v) to give the target compound 7 as a white solid. Yield: 1.70 g, 90%. NMR (400 MHz, CDCL) d 7.31- 7.26 (m, 2H), 7.24 (dd, / = 5.2, 1.9 Hz, 1H), 7.13 (d, / = 6.8 Hz, 2H), 4.98 (d, / = 8.1 Hz, 1H), 4.57 (dd, / = 14.1, 6.1 Hz, 1H), 4.12 - 4.03 (m, 2H), 3.13 - 3.02 (m, 2H), 1.60 - 1.55 (m, 2H), 1.42 (s, 9H), 1.27 (s, 10H), 0.88 (d, 7 = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCL) d 172.03, 155.11, 136.11, 129.37, 128.53, 127.00, 65.58, 54.46, 38.47, 31.81, 29.20, 29.18, 28.49, 28.33, 25.85, 22.68, 14.14. MS-ESI: calculated for [M+Na]+ (C22H3s04NNa): m/z 400.28, found: m/z 400.37. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid; C22H25N3O3 With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: With trifluoroacetic acid | 1 Intermediate 2 (n=l, R13a= phenyl): HATU (13 mg, 0.033 mmol, 1.1 equiv.) was added to a solution of the amino acid compound L (8.5 mg, 0.033 mmol, 1.1 equiv.), compound M (15 mg, 0.03 mmol, 1 equiv.) and DIEA (0.03 mL, 0.18 mmol, 6 equiv.) in DMF (1.0 mL) and the resultant mixture was stirred at room temperature for 30 min. The crude product was purified by HPLC (MeCN/thO 50%-100%, 50 min, 60 mL/min, the product came out when MeCN is 61.3%). TFA was used to remove the Boc group to afford Intermediate 2 (14 mg, 90% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid; C24H31N3O3 With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: With trifluoroacetic acid In dichloromethane | 20 Compound M: HATU (104 mg, 0.27 mmol, 1.1 equiv.) was added to a solution of amino acid compound L (63 mg, 0.25 mmol, 1.0 equiv.), compound K (130 mg, 0.25 mmol, 1.0 equiv.) and DIEA (0.26 mL, 1.5 mmol, 6 equiv.) in DMF (1.5 mL) and the resultant mixture was stirred at room temperature for 30 min. The crude product was purified by HPLC (McCN/HiO 55%-100%, 45 min, 60 mL/min, the product came out when MeCN is 64.6%). TFA/DCM = 1/1 solution was used to remove the Boc group to afford compound M (115 mg, 85% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 4h; | |
82% | Stage #1: (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid With dicyclohexyl-carbodiimide In dichloromethane for 0.25h; Stage #2: 1-(3-Trifluoromethylphenyl)piperazine In dichloromethane at 20℃; for 4h; | 4.1.1. synthetic procedure for Boc-protected compounds (R)-1-(R)-5 and(S)-1 General procedure: To a anhydrous DCM (20 mL) solution of (R) or (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (1.25 g, 5 mmol, 1 eq) was successivelyadded DCC (1.55 g, 7.5 mmol, 1.5 eq) dissolved in 5 mL ofanhydrous DCM. After stirring (15 min), the appropriate phenylpiperazine(5 mmol, 1.0 eq) dissolved in 5 mL of anhydrous DCM wasadded dropwise and the reaction was stirred at room temperature for 4h. The DCM was evaporated in vacuo, and the product purified by columnchromatography using a DCM:MeOH-9:0.5 (v/v) mixture as asolvent system. |
Tags: 2900-27-8 synthesis path| 2900-27-8 SDS| 2900-27-8 COA| 2900-27-8 purity| 2900-27-8 application| 2900-27-8 NMR| 2900-27-8 COA| 2900-27-8 structure
[ 69651-48-5 ]
(S)-2-((tert-Butoxycarbonyl)amino)-2-(4-hydroxyphenyl)acetic acid
Similarity: 0.92
[ 623950-02-7 ]
(S)-2-((tert-Butoxycarbonyl)amino)-3-(4-carbamoyl-2,6-dimethylphenyl)propanoic acid
Similarity: 0.92
[ 114359-37-4 ]
(S)-2-((tert-Butoxycarbonyl)amino)-3-(4-ethylphenyl)propanoic acid
Similarity: 0.91
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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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