| 100% |
With sodium hydroxide In 1,4-dioxane; lithium hydroxide monohydrate Inert atmosphere; |
|
| 100% |
With sodium hydroxide In tetrahydrofuran; 1,4-dioxane; lithium hydroxide monohydrate at 25℃; for 3h; |
|
| 97% |
With triethylamine In 1,4-dioxane; lithium hydroxide monohydrate at 0℃; for 48h; |
|
| 96.7% |
With sodium hydroxide In lithium hydroxide monohydrate; propan-2-one at 20 - 55℃; |
12.1
3-[2-Amino-3-(4-hydroxyphenyl)propanoyl]-3-demethylthiocolchicine was prepared by first tert-butyloxycarbonyl (BOC) protecting L-tyrosine in Stage- 1. L-Tyrosine (10.Og, 0.0552 mol) and 4M sodium hydroxide solution (40.0ml) were charged at RT in a 500 ml three neck round bottomed flask equipped with mechanical stirrer, addition funnel, guard tube, thermo probe and reflux condenser. BOC-anhydride (24.Og, 0.110 mol) dissolved in 30.0ml acetone was added slowly drop wise to the flask at RT. The reaction mass temperature was raised to 50-550C and maintained at this temperature for 6-7 h. The reaction mass was dissolved in demineralized water (250.0ml 25w/v) and cooled to 0-50C. The pH of the reaction mass was adjusted to 2-3 by adding IM potassium hydrogen sulfate and the aqueous layer was extracted with ethyl acetate. The organic layers were washed with demineralized water followed by brine. The resulting organic layer was dried over sodium sulphate and concentrated to 15 g of white solid (96.7% yield). |
| 95% |
With sodium hydroxide In 1,4-dioxane; lithium hydroxide monohydrate at 25℃; for 6h; |
|
| 94% |
With sodium hydroxide In 1,4-dioxane; lithium hydroxide monohydrate at 0 - 20℃; for 72h; Inert atmosphere; |
|
| 94% |
With potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 20℃; |
|
| 94% |
With sodium hydroxide In 1,4-dioxane; lithium hydroxide monohydrate at 0 - 20℃; for 6h; |
|
| 92% |
With triethylamine In 1,4-dioxane; lithium hydroxide monohydrate for 18h; Ambient temperature; |
|
| 92% |
With potassium hydroxide In 1,4-dioxane; lithium hydroxide monohydrate at 20℃; for 6h; |
|
| 92% |
Stage #1: di-<i>tert</i>-butyl dicarbonate; tyrosine With sodium hydroxide In 1,4-dioxane at 20℃; for 14h;
Stage #2: With hydrogenchloride; lithium hydroxide monohydrate In dichloromethane |
|
| 92% |
With triethylamine In 1,4-dioxane; lithium hydroxide monohydrate at 0 - 20℃; for 18.5h; |
|
| 92% |
With triethylamine In 1,4-dioxane; lithium hydroxide monohydrate |
|
| 92% |
With trimethylamine In tetrahydrofuran; lithium hydroxide monohydrate at 0 - 25℃; |
|
| 91% |
With triethylamine In 1,4-dioxane; lithium hydroxide monohydrate at 20℃; |
|
| 90% |
With triethylamine In 1,4-dioxane; lithium hydroxide monohydrate at 0 - 20℃; for 21h; |
|
| 90% |
With sodium hydroxide In 1,4-dioxane; lithium hydroxide monohydrate at 20℃; for 2h; Inert atmosphere; |
4 4.4 .Nα-[tert-butoxycarbonyl]-L-tyrosine (6)
L-Tyrosine (2 g, 11 mmol) was dissolved in a mixture of dioxane/water (50 mL/25 mL), followed by the addition of 25 mL of NaOH (1 M). Di-tert-butyl dicarbonate (2.64 g, 12.1 mmol) was then added and the reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was extracted by EtOAc (3 * 20 mL). The combined extraction was dried over Na2SO4. After removing the solvent by rotary evaporation, the compound 6 was obtained as a white solid (3 g, 10 mmol, 90%). 1H NMR (300 MHz, CDCl3): δ 7.10 (d, J = 8.3 Hz, 2H), 6.71 (d, J = 8.4 Hz, 2H), 5.25 (d, J = 6.9 Hz, 1H), 4.52 (s, 1H, OH), 4.32-4.30 (m, 1H), 3.00-2.96 (m, 2H), 1.38 (s, 9H). |
| 90% |
With sodium hydroxide In 1,4-dioxane; lithium hydroxide monohydrate at 0℃; |
|
| 90% |
With anhydrous sodium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 0 - 25℃; for 16h; |
7.1 Step 1: Synthesis of (S) -2- ( (tert-butoxycarbonyl) amino) -3- (4-hydroxyphenyl) propanoic acid (122)
To a solution of compound 121 (2.0 g, 11.0 mmol) in dioxane/H2O (20/10 mL) was added Na2CO3(3.5 g, 33.0 mmol) and Boc2O (3.5 g, 16.5 mmol) at 0 . The reaction mixture was allowed to warm to 25 and stirred for 16 h and then was removed under vacuum. Water (20 mL) was added to the mixture, and extracted by EA (10 mL) . The water layer was added HCl (4M in water) until pH2-3 and extracted by EA (3×10 mL) . The combined organic layer was washed with aqueous brine (20 mL) , dried over Na2SO4and concentrated in vacuum to give the titled product 122 (2.8 g, 90) as a yellow solid.[0523]MS (ESI) : [M+H+] 281.9. |
| 89% |
With N-ethyl-N,N-diisopropylamine; sodium hydroxide In 1,4-dioxane; lithium hydroxide monohydrate at 20℃; for 3h; |
|
| 86.56% |
With sodium hydroxide In 1,4-dioxane; lithium hydroxide monohydrate at 20℃; for 6h; |
|
| 85% |
Stage #1: di-<i>tert</i>-butyl dicarbonate; tyrosine With sodium hydroxide In 1,4-dioxane; lithium hydroxide monohydrate at 20℃; for 4h;
Stage #2: With sulfuric acid potassium salt In 1,4-dioxane; lithium hydroxide monohydrate; ethyl acetate |
|
| 84% |
Stage #1: tyrosine With sodium hydroxide In 1,4-dioxane; lithium hydroxide monohydrate
Stage #2: di-<i>tert</i>-butyl dicarbonate In 1,4-dioxane; lithium hydroxide monohydrate at 20℃; for 7h; |
4 4.2.4. N-Boc-L-tyrosinol-silane precursor 10
N-Boc-L-tyrosine. The L-tyrosine protection was performed followinga reported procedure62 with some modifications. 10 g (0.06 mol) of l-tyrosine were stirred in 250 ml dioxane and water mixture (1:1) and 75 mL of 1 M sodium hydroxide solution was added until all the solid dissolved. After cooling the solution in an ice bath, 12 g (0.06 mol) of di-tert-butyl dicarbonate was added. After stirring for 7 h in room temperature, the reaction was concentrated by reducing pressure followed by addition of 50 mL of ethyl acetate and a concentrated potassium hydrogen sulphate solution until the pH reached 2. Then the aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried with sodium sulphate. After removing the solvent under reduced pressure a 13 g (84% yield) of pinkish solid were obtained. 1H NMR (400 MHz, DMSO-d6): δ 1.31 (9H, s), 2.67 (1H, dd, J = 9.90, 13.85 Hz), 2.86 (1H, dd, J = 4.95, 13.85 Hz), 3.92-4.02 (1H, m), 6.63 (2H, d, J = 7.73 Hz), 7.01 (2H, d, J = 7.73 Hz), 9.18 (1H, s), 12.5 (1H, br s) ppm. |
| 81% |
Stage #1: di-<i>tert</i>-butyl dicarbonate; tyrosine With sodium hydroxide In tetrahydrofuran; lithium hydroxide monohydrate at 0 - 20℃; for 20.6667h;
Stage #2: With hydrogenchloride In lithium hydroxide monohydrate |
|
| 81% |
In dichloromethane at 20℃; for 20h; |
|
| 80% |
With sodium hydroxide In 1,4-dioxane at 20℃; for 6h; |
|
| 75% |
With sodium hydroxide In lithium hydroxide monohydrate; <i>tert</i>-butyl alcohol at 20℃; |
|
| 75% |
With sodium hydroxide In lithium hydroxide monohydrate; <i>tert</i>-butyl alcohol at 20 - 40℃; for 24h; |
|
| 73% |
With sodium hydroxide In 1,4-dioxane; lithium hydroxide monohydrate at 20℃; for 18h; |
|
| 66% |
With triethylamine In 1,4-dioxane; lithium hydroxide monohydrate at 20℃; |
|
| 61.2% |
With sodium hydroxide In isopropanol Ambient temperature; |
|
| 60% |
With sodium hydroxide In 1,4-dioxane at 25℃; for 1h; |
|
|
With sodium hydroxide In lithium hydroxide monohydrate; <i>tert</i>-butyl alcohol |
|
|
With sodium hydroxide; Sodium hydrogenocarbonate In 1,4-dioxane at 0 - 20℃; |
|
| 9.8 g |
With triethylamine In 1,4-dioxane; lithium hydroxide monohydrate 0 deg C, 30 min; 25 deg C, 24 h; |
|
|
With Sodium hydrogenocarbonate In tetrahydrofuran at 23℃; for 12h; |
|
|
With 1-ethyl-2,2,4,4,4-pentakis(dimethylamino)-2λ5,4λ5-catenadi(phosphazene) In acetonitrile at 20℃; for 16h; |
|
|
With sodium hydroxide In 1,4-dioxane at 20℃; |
|
|
With hydrogenchloride; triethylamine In 1,4-dioxane; lithium hydroxide monohydrate; ethyl acetate |
1 N-t-butoxycarbonyl-L-tyrosine (II)
Example 1 N-t-butoxycarbonyl-L-tyrosine (II) L-Tyrosine (I, 9.06 g, 50 mmol) is suspended in dioxane/water (1/1, 180 ml). Triethylamine (10.45 ml, 75 mmol) is added. The reaction mixture is cooled to -10° and di-tert-butyl dicarbonate (12.0 g, 55 mmol) is added. After 1 hr at -10°, the reaction is warmed to 20-25°e. The suspension is stirred at 20-25° for 18 hr. The resulting mixture is concentrated and then partitioned in ethyl acetate (90 ml) and water (45 ml). The aqueous phase is collected and adjusted to pH 1 using hydrochloric acid (1 M). The aqueous mixture is extracted with ethyl acetate (180 ml). The extract is dried over magnesium sulfate, filtered and concentrated to give the title compound, NMR (DMSO-d6) δ 9.15, 7.01, 6.95, 6.64, 3.98, 2.86, 2.68 and 1.32; CMR (DMSO-d6) δ 174.1, 156.2, 155.8, 130.3, 128.3, 115.3, 78.4, 55.8, 36.0 and 28.5; MS (CI, NH3) m/z (relative intensity) 299, 282, 243, 226, 182 and 124. |
|
With anhydrous sodium carbonate In tetrahydrofuran; lithium hydroxide monohydrate at 0 - 20℃; |
|
|
With triethylamine In 1,4-dioxane; lithium hydroxide monohydrate at 0 - 20℃; |
|
|
With sodium hydroxide In 1,4-dioxane; lithium hydroxide monohydrate at 20℃; for 20h; |
VII.a
To a solution of Tyrosine in 2M NaOH was added a solution of di-t-butyl pyrocarbonate in dioxane and the mixture was stirred at room temperature for about 20 hrs. Dioxane was removed from the reaction mixture. The aqueous solution was acidified with 10% KHSO4 solution and the liberated Boc-Tyr was extracted into ethyl acetate. The ethyl acetate solution was washed with water, dried and concentrated. Precipitation was done using petroleum ether (60-800). |
|
Stage #1: di-<i>tert</i>-butyl dicarbonate; tyrosine With sodium hydroxide In tetrahydrofuran; lithium hydroxide monohydrate at 20℃; for 6h;
Stage #2: With citric acid In lithium hydroxide monohydrate |
5.1.1. (S)-7-(Tert-butoxycarbonyl)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid (2)
General procedure: To a solution of compound 1 (5.72 g, 20.0 mmol) in 44 mL of 1 N NaOH, was added a solution of (Boc)2O (4.80 g, 22.0 mmol) in THF (10 mL). The solution was kept between pH 9-11 by addition of 1 N NaOH. After stirring the mixture at room temperature for 6 h, THF was evaporated in vacuum with the residues being adjusted to pH 4-5 with 1 N aqueous citric acid. Then the mixture was extracted with EtOAc (3 × 25 mL). The extractions were combined, washed with brine (3 × 20 mL), dried over MgSO4 and evaporated to give 5.80 g of crude product compound 2 as a light brown solid. This product was used for the following reaction without further purification. |
| 5.3 g |
Stage #1: di-<i>tert</i>-butyl dicarbonate; tyrosine With sodium hydroxide In tetrahydrofuran at 20℃; for 8h;
Stage #2: With lithium hydroxide monohydrate; citric acid |
5.1.1. (S)-2-((tert-Butoxycarbonyl)amino)-3-(4-hydroxyphenyl)propanoic acid (B)
To a solution of compound A (3.62 g, 20.0 mmol) in 44 mL of 1 N NaOH, was added a solution of (Boc)2O (4.80 g, 22.0 mmol) in THF (10 mL). The solution was kept between pH 9 and 11 by addition of 1 N NaOH. After stirring the mixture at room temperature for 8 h, THF was evaporated in vacuum with the residues being adjusted to pH 4-5 with 1 N aqueous citric acid. Then the mixture was extracted with EtOAc (3 × 25 mL). The extractions were combined, washed with brine (3 × 20 mL), dried over MgSO4 and evaporated to give 5.30 g of crude product compound B as a white solid. This product was used for the following reaction without further purification. ESI-MS m/z: 282.1 [M+H]+. |
|
With sodium hydroxide In methanol |
|
|
With triethylamine In methanol for 3h; Reflux; |
General procedure: To a solution of amino acids 1a-j (20 mmol) in methanol (90 mL) was added di-tert-butyl carbonate (8.73 g, 40 mmol) and triethylamine (11.1 mL, 80 mmol). The reaction mixture was heated to refluxing and stirred for 3 h at the same temperature, and concentrated under reduced pressure. The residue was diluted with water (40 mL), adjusted to pH 2.0-3.0 with 2 N HCl at 0-5 °C, and then extracted with ethyl acetate (50 mL × 3). The combined extracts were washed with saturated brine (30 mL), dried over anhydrous Na2SO4, and then concentrated under reduced pressure to provide 2a-j as white solids [18-23] (64.8%-91.4%). A mixture of IMB-070593 (2.08 g, 4.97 mmol), 2a-j (5.71 mmol), dicyclohexylcarbodiimide (1.18 g, 5.71 mmol) and dry dichloromethane (42 mL) was stirred at room temperature for 1 h and filtered. The filtrate was concentrated under reduced pressure, and the residue was treated with diethyl ether (20 mL), and then filtered. The solid was purified by column chromatography (silica gel) eluted with dichloromethane and methanol (v:v = 55:1) to afford the title compounds 3a-j (36%-79%, from 1a-j) as white or yellow solids. |
|
With triethylamine In 1,4-dioxane at 20℃; |
|
|
With triethylamine In 1,4-dioxane; lithium hydroxide monohydrate at 0 - 20℃; for 25h; |
|
|
With sodium hydroxide In 1,4-dioxane; lithium hydroxide monohydrate at 0℃; for 2h; |
|
|
With sodium hydroxide In 1,4-dioxane; lithium hydroxide monohydrate at 0 - 20℃; |
4.1. General procedures for the synthesis of N-protected phenylalanine and tyrosine amide 1 and dipeptides 3, 5
General procedure: Chloroformate (benzyl chloroformate) or acid anhydride ((Boc)2O) (1.2 equiv.) was added dropwise to a solution of phenylalanine or tyrosine in 0.5 Maq. NaOH:1,4-dioxane = 1:1 at 0 °C. The mixture was stirred overnight at room temperature, and evaporated to remove 1,4-dioxane. The aqueous solution was acidified by the slow addition of 1M HCl until the pH decreased to 3 and then extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was recrystallized by hexane/EtOAc to give the corresponding N-protected phenylalanine and tyrosine (70-80%). |
|
With triethylamine In 1,4-dioxane; lithium hydroxide monohydrate at 20℃; for 10h; |
23.23.1 23.1, (Intermediate 10)
L-Tyrosine (10 g, 55.2 mmol) was dissolved in 300 mL1,4-dioxane and water (v / v 1: 1),Triethylamine (11.2 g, 110.7 mmol) and then were added at room temperatureDi-tert-butyl dicarbonate (13.3 g, 60.9 mmol), stirred at room temperature for 10 hours,TLC monitoring reaction is completed. 1,4-dioxane was distilled off under reduced pressure,And add 500mL dichloromethane,2N aqueous hydrochloric acid was added dropwise to the aqueous layer with stirring at about pH 5,The organic layer was separated and washed once with 200 mL of saturated brine,Dried over anhydrous magnesium sulfate, filtered and the solvent evaporated to dryness under reduced pressure to give the crude product,The yield was 99% and the next reaction was carried out without further purification. |
|
With triethylamine In 1,4-dioxane; lithium hydroxide monohydrate at 20℃; for 10h; |
23.1
L-Tyrosine (10 g, 55.2 mmol) was dissolved in a mixed solution of 300 mL of 1,4-dioxane and water (v / v 1:1) Triethylamine (11.2 g, 110.7 mmol) and di-tert-butyl dicarbonate (13.3 g, 60.9 mmol) were sequentially added at room temperature and the mixture was stirred at room temperature for 10 hours. The reaction was completed by TLC. 1,4-dioxane was evaporated under reduced pressure and 500 mL of methylene chloride was added. 2N aqueous hydrochloric acid was added dropwise to the aqueous layer with stirring at a pH of about 5. The organic layer was separated and washed once with 200 mL of saturated brine, Drying over magnesium sulfate, filtration and evaporation of the solvent under reduced pressure gave a crude product in 99% yield, which was carried on to the next reaction without further purification. |
|
In 1,4-dioxane; lithium hydroxide monohydrate at 20℃; for 18h; Cooling with ice; |
1
3d: L-tyrosine (30.00 g, 0.17 mol), water (300 mL) was added in turn to a 2000 mL round bottom flask.1,4-dioxane (300 mL), triethylamine (35 mL, 248.40 mmol), ice bath,Di-tert-butyl dicarbonate (41.70 mL, 182.40 mmol) was added, stirred for 30 min and allowed to react at room temperature for 18 h.Desolvation, solids were diluted with water, ethyl acetate, pH adjusted to 1 with dilute hydrochloric acid, extracted with ethyl acetate,The organic phase was washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate, and suction-filtered., Desolvation, light yellow transparent oil, plus some Boc anhydride, without further purification directly to the next step.In a 2000 mL round-bottom flask, N-Boc-L-tyrosine generated in the previous step (theory 0.16 mol), N,N-dimethylformamide (890 mL), potassium carbonate (114 g, 0.83 mol), tetrabutylammonium iodide (7.6 g, 0.02 mol),Benzyl bromide (59 mL, 0.49 mol) was reacted at room temperature for 48 h. Water (900 mL) was added and extracted with ethyl acetate (600 mL*3).The organic phases were combined, dried over anhydrous sodium sulfate, suction filtered, desolved, and directly cast to the next step.In a 2000 mL round-bottomed flask, N-Boc-O-benzyl-L-tyrosine benzyl ester (theory 0.16 mol) generated in the previous step was added (500 mL).1,4-dioxane (500 mL) was added sodium hydroxide (22.00 g, 0.55 mol) and stirred at room temperature for 24 h.The 1,4-dioxane was partially removed by dissolving, washed with an appropriate amount of ether, and the aqueous phase was acidified with dilute hydrochloric acid and extracted three times with ethyl acetate.Combine the organic phases, dry over anhydrous sodium sulfate, remove with suction and filter to give a yellow oil, with ethanol,The petroleum ether is recrystallized to give 63.25 g of a white solid, 61.55 g of theory, and some of the solvents are added. The three-step yield is greater than 99%. |
|
With triethylamine In 1,4-dioxane; lithium hydroxide monohydrate at 0 - 80℃; for 96h; Inert atmosphere; |
(S)-2-(tert-butoxycarbonylamino)-3-(4-hydroxyphenyl)propanoic acid (14)
To a mixture of L-tyrosine 13 (0.91 g, 5.03 mmol) and Et3N (1.52 mL, 11.0 mmol) in 50% 1,4-Dioxane/water (100 mL) was added dropwise (Boc)2O (1.52 mL, 11.0 mmol) at 0 °C under N2 atmosphere. After 24 h, the temperature was raised from 0 °C to 80 °C for another 72 h. The mixture was filtered and the concentrated residue was redissolved in EtOAc (100 mL) which was washed with saturated brine (100 mL × 3), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel column chromatography [petroleum ether-EtOAc = (4:1), V/V] to give the corresponding target product as a solid (1.28 g, 91%). HPLC analysis: 92.5%. 1H-NMR (400 MHz, MeOD): 1.29 (s, 9H), 2.71 (dd, J = 13.8, 8.8 Hz, 1H), 2.94 (dd, J = 13.8, 4.9 Hz, 1H), 4.16-4.19 (m, 1H), 6.60 (d, J = 8.2 Hz, 2H), 6.93 (d, J = 8.2 Hz, 2H). 13C-NMR (100 MHz, MeOD): 174.2, 156.4, 155.8, 129.9, 127.8, 114.7, 79.1, 55.1, 36.5, 27.3. ESI-MS m/z: 282.1 (M+H)+. |
|
With sodium hydroxide In 1,4-dioxane; lithium hydroxide monohydrate at 20℃; |
|
|
With sodium hydroxide In 1,4-dioxane; lithium hydroxide monohydrate at 0 - 20℃; for 3h; |
General procedure for the synthesis of N4 amino acid-acylated nucleosides 4a-h
General procedure: Appropriate amino acid 1a-h (6.66 mmol) was dissolved in 24 mL of 1,4-dioxane and water mixture (1:1), 13.3 mL of 1 N NaOH (2 mol. eq.) was slowly added and the mixture was chilled in the freezer for 20 min. Di-tert-butyl dicarbonate (10 mmol) was added and the mixture was stirred for 3 hours at room temperature. The reaction was monitored by TLC analysis. After the reaction was completed, the solvent mixture was concentrated to 2-5 mL using a rotary evaporator and aqueous solution of citric acid (10%) was added until pH reached 2.0. The mixture was extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulphate and evaporated under reduced pressure to recover Boc-protected amino acid 2a-h. The protected amino acid 2a-h was dissolved in 30 mL of ethyl acetate, 7.33 mmol of N-hydroxysuccinimide and 7.33 mmol of N,N'-dicyclohexylcarbodiimide were added and the reaction mixture was stirred for 24 hours at room temperature. The formed white precipitate was filtered, ethyl acetate was removed under reduced pressure to obtain N-Boc protected and NHS-activated amino acid 3a-h. The protected-activated acid was dissolved in dimethylformamide (8-10 mL) and 2'-deoxycytidine (6.66 mmol) was added. The reaction mixture was stirred for 5 days at room temperature. After the reaction was completed, dimethylformamide was removed using a rotary evaporator and the residue was purified by column chromatography (silica gel, chloroform/methanol mixture, 100:0→85:15). The products were obtained in 34-85% yields. Synthesized nucleosides were characterized by NMR spectroscopy and HPLC-MS analysis. |
|
With triethylamine In 1,4-dioxane; lithium hydroxide monohydrate for 12h; Reflux; |
|
|
With sodium hydroxide In 1,4-dioxane; lithium hydroxide monohydrate |
|
|
With sodium hydroxide In 1,4-dioxane at 0 - 20℃; Inert atmosphere; |
2.2.1. (tert-butoxycarbonyl)-L-phenylalanine (c1), (tert-butoxycarbonyl)-D-phenylalanine (c5), (tert-butoxy-carbonyl)-L-tyrosine (c7) and (tert-butoxycarbonyl)-L-tryptophan (c8): General procedure 1
General procedure: Required amino acid (30 mmol, 1 equiv) was taken in 1,4-dioxane (40 mL) as a solvent and stirred at 0°C to get a clear solution. 1M sodium hydroxide (NaOH) solution (20 mL) was added to the reaction mixture, followed by Boc anhydride (36 mmol, 1.2 equiv). After half an hour, the milky white or hazy solution was obtained, which was further stirred overnight. Upon completion of the reaction, the mixture was acidified to pH 4 using dilute HCl (Hydrochloric acid) and extracted by ethyl acetate (50 mL *3). This organic layer was dried over sodium sulfate and distilled under reduced pressure to obtain the product as a semi-solid paste (except for c5, which was obtained as an off-white solid); yield was approximately 90 to 95%. |
|
With sodium hydroxide In 1,4-dioxane at 0 - 20℃; Inert atmosphere; |
2.2.1. (tert-butoxycarbonyl)-L-phenylalanine (c1), (tert-butoxycarbonyl)-D-phenylalanine (c5), (tert-butoxy-carbonyl)-L-tyrosine (c7) and (tert-butoxycarbonyl)-L-tryptophan (c8): General procedure 1
General procedure: Required amino acid (30 mmol, 1 equiv) was taken in 1,4-dioxane (40 mL) as a solvent and stirred at 0°C to get a clear solution. 1M sodium hydroxide (NaOH) solution (20 mL) was added to the reaction mixture, followed by Boc anhydride (36 mmol, 1.2 equiv). After half an hour, the milky white or hazy solution was obtained, which was further stirred overnight. Upon completion of the reaction, the mixture was acidified to pH 4 using dilute HCl (Hydrochloric acid) and extracted by ethyl acetate (50 mL *3). This organic layer was dried over sodium sulfate and distilled under reduced pressure to obtain the product as a semi-solid paste (except for c5, which was obtained as an off-white solid); yield was approximately 90 to 95%. |
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