| 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)+. |
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