| 82% |
With sodium hydrogencarbonate; In tetrahydrofuran; 1,2-dimethoxyethane; water; at 20℃; for 6h; |
Fmoc-val-NHS (1 eq) was added to DME, and L-citrulline (1.05 eq)NaHCO3 (1.05 eq) is dissolved in water.Add THF to dissolve well and stir for 6 hours at room temperature.After completion of the reaction, the organic layer was separated by separatory funnel using EA (1: 1.25) containing citric acid (15%) aqueous solution and 10% isopropanol,Dry with MgSO4. The resulting solid is vacuum dried for 5 hours, then precipitated with ether and filtered. Yield: yellow solid 82%. |
| 81.7% |
With sodium carbonate; In tetrahydrofuran; at 20℃; for 48h;pH 8 - 9; |
The 20 g of compound 31 is dissolved in 200 ml of the solvent in the THF, adding 9.64 g (1.2 eq) L - Citrulline, adding 1 M carbonate to pH 8 - 9, the response [...], stirring at the room temperature reaction 48 h, TLC detection reaction is complete. In ice-bath under stirring, aqueous solution of citric acid for adjusting the pH for the reaction solution 3 - 4, isopropyl alcohol: EA=1:5 (40 ml isopropanol + 200 ml EA) extraction 3 times, the organic phase the merger, anhydrous sodium sulfate drying, filtering turns on lathe does, then adding 200 ml of armor uncle ether stirring, the stirring 2 hours after the filtering, the collection filter cake, and placed in a 45 C and dried in the vacuum drying box 18.6 g white solid product, yield by about 81.7%. |
| 74% |
With sodium carbonate; In water; acetonitrile; at 0 - 35℃; |
Fmoc-Val-OSu (1 eq.) was dissolved in Acetonitrile (5 vol.) at 20C. Separately, sodium carbonate (1.1 eq.) was solubilized in Water (5 vol.) at 20C and L-Citrulline (1.1 eq.) was then added to give a homogeneous clear solution. Water (0.5 vol.) was added to the Fmoc-Val-OSu solution and the reaction mixture was heated to 35C before adding the prepared citrulline solution dropwise over 10 min. The reaction mixture was stirred at 35 C for 3-4 hours until reaction was complete before being cooled to 20C. Acetonitrile (20 vol.) was then added over 2-3 hours at 20C. The resulting suspension was stirred for 1-3 hours before being cooled to 0-5C over 1-4 hours and stirred at that temperature for 2-3 hours. Solids were filtered, washed and dried under vacuum before being re-dissolved in a mixture of N,N-dimethylformamide (3.9 vol.), 35.9 g/L aqueous NaCl solution (3.9 vol.), 10% isopropanol in Ethyl acetate (19.5 vol.) at 20C. Glacial acetic acid (1.3 vol.) was then added and the pH of the solution was adjusted to <2 with concentrated hydrochloric acid (0.78 vol.). After stirring at 20C for 30 minutes, phases were separated and the aqueous layer was re extracted with Ethyl acetate (6.5 vol.). Combined organic layers were washed three times with a mixture of 179.5 g/L aqueous NaCl solution (6.5 vol.) and anhydrous N,N- Dimethylformamide (0.72 vol.). The resulting organic mixture was concentrated to a white paste and diluted with Methanol (19.5 vol.). The resulting suspension is stirred at 20C for 10-14 hours before being concentrated again to a white paste. Methyl tert-butyl ether (19.5 vol.) was then added and the resulting suspension was stirred at 40C for 1-2 hours. After cooling to 20C and stirring followed by cooling to 0-5C and stirring, solids were filtered, washed and dried under vacuum. Solids were re-slurried twice in a mixture of Methanol (1.3 vol.) and Methyl tert-butyl ether (19.5 vol.) and dried under vacuum (74% yield). MS: m/e 497 (MH)+, 519 (M+Na)+. |
| 70% |
|
Fmoc- VaI-NHS (2.5 g, 5.73 mmol, 1 eq) in 15 mL of DME was added to a solution of L- citrulline (1.05 g, 6.01 mmol, 1.05 eq) in 8 mL of THF and NaHCO3 (505 mg, 6.01 mmol, 1.05 eq) in 15 mL of water. The mixture was stirred at room temperature overnight. Aqueous citric acid (75 mL of a 15% solution in water) was added and the mixture was extracted with 10% IP A/EtOAc (2 x 100 mL). The organic layers were washed with water (3 x 100 mL) and the solvent was evaporated under vacuum. The resulting solid was triturated with 100 mL of ethyl ether and filtered to yield the product (1.98 g, 70% yield): 1H NMR (DMSCW0) delta 0.86 (3H, d, J = 6.7 Hz), 0.90 (3H5 d, J = 7.0 Hz), 1.40-1.48 (2H, m), 1.51-1.75 (2H, m), 1.98 (IH, sext, J = 6.8 Hz), 2.95 (2H, q, J = 6.2 Hz), 3.93 (IH, dd, J = 7.3, 8.8 Hz), 4.14-4.29 (4 H, m), 5.40 (2H, brs), 5.96 (IH, t, J = 5.6 Hz), 7.32 (2H, t, J = 7.5 Hz), 7.39-7.44 (3H, m), 7.75 (2H} t, J = 6.3 Hz), 7.89 (2H, d, J = 7.3 Hz), 8.19 (IH, d, J = 7.3 Hz); B C NMR (DMSO-ofc) delta 18.31, 19.25, 26.75, 28.40, 30.59, 46.68, 51.91, 59.81, 64.92, 65.65, 119.98, 125.30, 126.94, 127.52, 140.55, 143.61, 143.76, 155.88, 158.58, 171.12, 173.25. |
| 45% |
With sodium hydrogencarbonate; In tetrahydrofuran; 1,2-dimethoxyethane; water; at 20℃; for 16h; |
Compound [10] (1 .7 g, 3.9 mmol) in dimethoxyethane (10 ml_) is added to a solution of L-citrulline [1 1 ] (700 mg, 4 mmol) dissolved in a mixture of tetrahydrofuran and aqueous sodium bicarbonate (344 mg, 4 mmol in 10 mL of water). The reaction is stirred at room temperature for 16 hours. A solution of citric acid 15% in water (50 mL) is added and the mixture extracted with 10% isopropyl alcohol in ethyl acetate (2x75 mL). The solvent is removed by rotatory evaporation. After addition of diethyl ether and irradiation with ultrasounds, the formation of a solid is obtained. Filtration followed by washing with diethyl ether gave [12] as a white solid, 870 mg (45%). MS: m/z 495 [M-H]-.1H NMR (400 MHz, DMSO) delta 8.19 (bm 3H), 7.87 (t, J = 25.1 Hz, 2H), 7.77 (t, J = 6.8 Hz, 2H), 7.49 - 7.23 (m, 4H), 5.99 (s, 1 H), 5.43 (s, 2H), 4.45 - 4.08 (m, 4H), 3.97 (t, J = 7.5 Hz, 1 H), 2.99 (d, J = 5.1 Hz, 2H), 2.02 (d, J = 6.1 Hz, 1 H), 1 .74 (s, 1 H), 1 .61 (d, J = 7.5 Hz, 1 H), 1 .44 (s, 2H), 0.91 (dd, J = 12.5, 6.3 Hz, 6H).13C NMR (101 MHz, DMSO) delta 173.4, 171 .3, 169.8, 167.8, 158.8, 156.0, 143.8, 140.7, 127.6, 127.0, 65.7, 59.8, 51 .9, 46.7, 30.5, 26.6, 19.18 (2C). |
| 44.3% |
With sodium hydrogencarbonate; In tetrahydrofuran; 1,2-dimethoxyethane; water; at 0 - 20℃; for 24h; |
1.2) Cit (0.4g, 2.3mmol) and NaHCO3 (0.19g, 2.3mmol) were co-dissolved in 50mL distilled water, cooled to 0 C, and a 25mL DME solution of Fmoc-Val-OSu (1g, 2.29mmol) was gradually dropped Add to a mixed solution of Cit and NaHCO3, add another 20mL of tetrahydrofuran to help dissolve, and stir at room temperature for 24h to obtain a reaction solution.1.3) In the reaction solution obtained in step 1.2), saturated potassium carbonate was added dropwise to adjust the pH to 8-9, and then extracted three times with 20 mL of ethyl acetate. The aqueous layer was collected, and the citric acid solution was added to adjust the pH to 3-4. A gelatinous solid precipitated, filtered, and a white gel-like solid was dissolved in a mixed solution of 25 mL of tetrahydrofuran and 10 mL of methanol, and concentrated in a 250 mL round-bottomed flask to 10 mL by rotary evaporation, and 200 mL of methyl tert-butyl ether was added and stirred at 0 C overnight , Filtered and dried under vacuum to obtain the product Fmoc-Val-Cit (0.5 g, yield 44.3%) as a white solid. |
| 4.83 g |
With sodium hydrogencarbonate; In tetrahydrofuran; 1,2-dimethoxyethane; water; at 20℃; for 24h; |
Add Cit 4.0g (1.05 eq) and 20 ml of THFAn aqueous solution of sodium hydrogencarbonate (60 ml (NaHCO3 2 g, 1.05 eq)).Another 22.35 mmol of Fmoc-Val-OSu was dissolved in 60 ml of DME.This was added to the reaction solution.The reaction solution was stirred at room temperature for 24 hours.After the reaction was completed, 110 ml of a 15% aqueous citric acid solution was added to the system.It was then extracted twice with EA. And 100 ml of methyl tert-butyl ether was added to the white solid and stirred.filter,The filter cake was dried under reduced pressure at 40 C for 4 h to obtain 4.83 g of product.The yield was 65%. |
|
With sodium hydrogencarbonate; In tetrahydrofuran; 1,2-dimethoxyethane; water; at 20℃; |
The reaction product of the previous step (16 g, 36.6 mmol) was dissolved in 90 mL of DME, and L-Cit (6.7 g, 38.5 mmol) was dissolved in NaHCO3 (3.2 g, 38.5 mmol) in 90 mL of water to form a salt. In the system,50 mL of THF was solubilized and the reaction was stirred at room temperature overnight until clear.After the reaction is completed,An equal volume of 15% aqueous citric acid solution with THF was added under ice bath.The white solid of the reaction product is completely precipitated.The Buchner funnel was suction filtered until the filtrate was clarified, and the filter cake was drained.Dry in a vacuum oven. After drying, the white solid is ground.Wash with ether,Filtering,A white solid was obtained. |
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