Structure of Fmoc-Val-OSu
CAS No.: 130878-68-1
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Synonyms: N-Fmoc-L-valine N-succinimidyl ester
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| CAS No. : | 130878-68-1 |
| Formula : | C24H24N2O6 |
| M.W : | 436.46 |
| SMILES Code : | O=C(OCC1C2=C(C3=C1C=CC=C3)C=CC=C2)N[C@H](C(ON4C(CCC4=O)=O)=O)C(C)C |
| Synonyms : |
N-Fmoc-L-valine N-succinimidyl ester
|
| English Name : | Fmoc-Val-OSu |
| MDL No. : | MFCD00153370 |
| InChI Key : | JPJMNCROLRPFHI-QFIPXVFZSA-N |
| Pubchem ID : | 11339559 |
* 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 |
|---|---|---|
| 98% | With sodium hydrogencarbonate In tetrahydrofuran; 1,2-dimethoxyethane; water at 0 - 20℃; for 28h; | 8.a a) Fmoc-Val-Cit-OH (31) To a solution of Fmoc-Val-OSu (1.00 g, 2.29 mmol) and NaHCCh (260 mg, 3.09 mmol) in H2O (7.5 ml.) at 0 °C was added a solution of /.-citrulline (501 mg, 2.87 mmol) in DME (7.5 ml_). THF (4 ml.) was added, the reaction warmed to rt and stirred for 28 h. Upon completion, the reaction was adjusted to pH 10 with saturated aqueous K2CO3 and washed with EtOAc (2 x 50 ml_). The aqueous layer was acidified to pH 4 with 15% aqueous citric acid and the formed gelatinous mixture was filtered. The wet cake was redissolved in THF/MeOH (50 ml_), TBME (100 ml.) was added and the mixture was stirred at rt for 16 h. The mixture was filtered and the filtrate concentrated in vacuo to yield Fmoc-Val-Cit-OH (1.12 g, 2.25 mmol, 98%) as an off-white solid. |
| 87% | With sodium hydrogencarbonate In tetrahydrofuran; water; N,N-dimethyl-formamide at 20℃; | 5 Synthesis of (S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3- rnethylbutanarnido)-5-ureidopentanoic acid 4 Citrulline (420 mg, 2.41 mmol) ws combined with solid NaHCC (200 mg, 2.38 mmol) and dissolved in water (6.0 mL). To this mixture ws added a solution of compound 3 (1.0 g, 2.29 mmol) in DMF (6 mL). The mixture was stirred for 5 minutes and THF (5 mL) was added and the reaction mixture was stirred overnight at room temperature. (1042) [0556] A 15% Citric acid solution (1 1.5 mL) wns added to the reaction mixture with stirring and a precipitate formed. The mixture was extracted with a 9: 1 mixture of EtOAc / i-PrOH (3 x 15 mL). the combined organic layers were washed with brine twice, dried over MgS04, filtered and evaporated to dryness to give a residue. The residue was sonicated with ether and iterated. (1043) A white solid formed, which was collected by filtration and dried under vacuum to give 1 0 g for a 87% yield. MS (ESI): mie 496.56 (MH)+, 497, (M + Na)+, 519. |
| 87.5% | With sodium hydrogencarbonate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water; N,N-dimethyl-formamide at 25℃; for 16h; | 2.2 Step 2: Synthesis of INB INA (35 g, 0.08 mmol) was dissolved in 400 mL of DMF, L-citrulline (30.9 g, 0.177 mol), sodium bicarbonate (18.5 g, 0.221 mol) were added, then 200 mL of water was added, and the reaction was carried out at 25° C. for 16 hours. TLC monitoring showed that DCM/MeOH=10/1, no raw material remained, and the reaction was completed. DMF was removed by rotary evaporation, 500 mL of water and 50 g of citric acid were added, slurry was made for 1 hour, filtered, and the solid was rotated to dryness. It was slurried with 500 mL of dichloromethane for 1 hour, filtered with suction, and the solid was pulled dry with an oil pump to obtain 34.5 g (0.07 mmol, 87.5%) of the target product as a white solid. |
| 83% | With sodium hydrogencarbonate In tetrahydrofuran; 1,2-dimethoxyethane; water at 20℃; | General procedure for the synthesis of 1a and 1b General procedure: A stirred solution of the Fmoc-Val (1 equiv) and HOSu (1.1 equiv) in THF (100 mL) at 0 °C was treated with DCC (1.05 equiv). The mixture was stirred at room temperature overnight until TLC showed completion of reaction. The mixture was filtered off, and the filtrate was evaporated, giving a glassy solid that was carried on without further purification. The glassy solid (1 equiv) was dissolved in dimethoxyethane (DME) (200 mL) and THF (100 mL), then added the NaHCO3 solution of L-Cit-OH or L-Ala-OH (1.05 equiv). The reaction mixture was stirred at room temperature overnight, poured into aqueous citric acid solution (400 mL, 15%), and filtered to give the crude product. The crude product was washed in ethyl acetate and filtered 3 times to give 1a or 1b as a white solid. Fmoc-VC-OH (1a). Yield was 83%, as a white solid. C26H32N4O6, MS (ESI) m/z: 497 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.48 (s, 1H), 8.17 (d, J = 7.4 Hz, 1H), 7.90 (d, J = 7.5 Hz, 2H), 7.76 (t, J = 7.1 Hz, 2H), 7.41 (q, J = 7.7 Hz, 3H), 7.33 (m, 2H), 6.00 (s, 1H), 5.63 (s, 2H), 4.30-4.21 (m, 3H), 4.16 (m, 1H), 3.93 (m, 1H), 2.98-2.89 (m, 2H), 1.99 (m, 1H), 1.77-1.66 (m, 1H), 1.57 (m, 1H), 1.41 (m, 2H), 0.88 (m, 6H). |
| 82% | With sodium hydrogencarbonate In tetrahydrofuran; 1,2-dimethoxyethane at 20℃; for 16h; Inert atmosphere; | Fmoc-Val-Cit 1. To a solution of l-citrulline (0.274 g, 1.56 mmol) and NaHC03 (0.131 g, 1 .56 mmol) in water (4 mL) was added a solution of Fmoc-Val-Osu (0.650 g, 1.49 mmol) in DME (4 mL). THF (2 mL) was added to aid solubility, and the reaction mixture was stirred for 16 h at ambient temperature. HC1 (2 M, 8 mL) was added, and the white solid product began to precipitate but remained in the organic layer. The mixture was extracted with isopropanol/EtOAc ( 1 : 9, 2 χ 20 mL), and the combined organic suspension was washed with water (2 χ 20 mL). The resultant suspension was concentrated under reduced pressure, and then treated with Et20 (20 mL). After sonication and trituration with Et20, the crude product was collected by filtration, and the crude product was purified by flash chromatography using a pre-packed 50 g silica column [solvent A: MeOH; solvent B: CH2C12; gradient: 0%A / 100%B (1 CV), 0%A / 100%B→ 30%A / 70%B (10 CV), 30%A / 70%B (2 CV); flow rate: 40 mL/min; monitored at 254 and 280 nm] to afford Fmoc-protected dipeptide 1 (0.610 g, 1.22 mmol, 82% yield) as a white solid. [000185] NMR (500 MHz, DMSO-d6) δ 8.18 (1 H, d, J = 7.3 Hz), 7.90 (2H, d, J= 7.5 Hz), 7.75 (2H, t, J= 8.0 Hz), 7.41 (3H, q, J = 8.1 Hz), 7.33 (2H, td, J= 6.6, 3.2 Hz), 5.94 (1H, t, J= 5.5 Hz), 5.38 (2H, bs), 4.33 - 4.26 (1 H, m), 4.26 - 4.19 (2H, m), 4.19 - 4.12 (2H, m), 3.93 (1H, dd, J= 9.0, 7.2 Hz), 2.95 (2H, q, J = 6.6 Hz), 2.04 - 1.92 (1H, m), 1.76 - 1.65 (1 H, m), 1.62 - 1.52 (1H, m), 1.46 - 1.34 (2H, m), 0.89 (3H, d, J= 6.8 Hz), 0.87 (3H, d, J= 6.8 Hz). [000186] 1 C NMR (125 MHz, DMSO-d6) δ 173.9, 171.8, 159.2, 156.5, 144.4, 144.2, 141.2, 128.1 , 127.5, 125.9, 120.6, 66.1 , 60.3, 52.4, 47.1 , 31.0, 28.8, 27.2, 19.7, 18.7. |
| 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; | 2.9 9) Compound 32 synthesis of 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%. |
| 77% | With sodium hydrogencarbonate In 1,2-dimethoxyethane; water at 20℃; | |
| 74% | With sodium carbonate In water; acetonitrile at 0 - 35℃; | 2 Example 2. Synthesis of Fmoc-Val-Cit Fmoc-Val-OSu (1 eq.) was dissolved in Acetonitrile (5 vol.) at 20°C. Separately, sodium carbonate (1.1 eq.) was solubilized in Water (5 vol.) at 20°C 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 35°C 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 20°C. Acetonitrile (20 vol.) was then added over 2-3 hours at 20°C. The resulting suspension was stirred for 1-3 hours before being cooled to 0-5°C 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 20°C. 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 20°C 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 20°C 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 40°C for 1-2 hours. After cooling to 20°C and stirring followed by cooling to 0-5°C 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% | Stage #1: Citrulline; 2,5-dioxopyrrolidin-1-yl-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valinate With sodium hydrogencarbonate In tetrahydrofuran; 1,2-dimethoxyethane; water at 20℃; Stage #2: With citric acid In tetrahydrofuran; 1,2-dimethoxyethane; water | 29 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) δ 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) δ 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. |
| 67.64% | With sodium hydrogencarbonate In tetrahydrofuran; 1,2-dimethoxyethane; water at 20℃; for 12h; | 32.2 Step 2: (S)-2-((S)-2-((((9H-fluoren-9-yl) methoxy)carbonyl)amino)-3-methylbutanamido)-5- ureidopentanoic acid (3): Fmoc-Val-NHS (15 g, 34.4 mmol) in 90 mL of DME was added to a solution of L- citrulline (6.32 g, 36.12 mmol) in 50 mL of THF and NaHCO3 (3.03 g, 36.12 mmol) in 90 mL of water. The mixture was stirred at room temperature overnight. The reaction progress was monitored by TLC. TLC system: 10% MeOH in DCM (RF: 0.1, UV visible). Aqueous citric acid (450 mL of a 15% solution in water) was added and the mixture was extracted with 10% IPA/EtOAc (2 x 500 mL). The organic layers were washed with water (3 x 500 mL) and the solvent was evaporated under vacuum. The resulting solid was triturated with 500 mL of ethyl ether and filtered to yield the product. The resulting solid was triturated with 500 mL of diethyl ether and filtered to yield (S)-2-((S)-2-((((9H-fluoren-9-yl) methoxy) carbonyl) amino)-3-methylbutanamido)-5-ureidopentanoic acid (11.5 g, 67.64%) (C3783-023-A2) as a white solid.1H NMR (300 MHz, DMSO-d6) δ ppm 12.33 - 12.64 (m, 1 H) 8.15 (br d, J=7.34 Hz, 1 H) 7.89 (d, J=7.70 Hz, 2 H) 7.60 - 7.80 (m, 2 H) 7.21 - 7.50 (m, 4 H) 5.93 (br t, J=5.69 Hz, 1 H) 5.37 (s, 2 H) 4.07 - 4.41 (m, 4 H) 3.92 (br dd, J=8.80, 6.97 Hz, 1 H) 3.20 - 3.47 (m, 6 H) 2.95 (q, J=6.24 Hz, 2 H) 1.89 - 2.07 (m, 1 H) 1.48 - 1.79 (m, 2 H) 1.30 - 1.47 (m, 2 H) 1.00 - 1.14 (m, 1 H) 0.87 (dd, J=9.35, 6.79 Hz, 6 H); LCMS (C3783-023-A2): 97.37% (497.06, M+H), RT: 1.75 min. |
| 61% | Stage #1: Citrulline With sodium hydrogencarbonate In water at 20℃; Stage #2: 2,5-dioxopyrrolidin-1-yl-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valinate In tetrahydrofuran; 1,2-dimethoxyethane; water at 20℃; for 16h; | |
| 45% | With sodium hydrogencarbonate In tetrahydrofuran; 1,2-dimethoxyethane; water at 20℃; for 16h; | 3 (S)-2-((S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3- methylbutanamido)-5-ureidopentanoic acid [12] 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) δ 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) δ 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; | 1.1.1.2; 1.1.1.3 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. |
| 4.64 g | With sodium hydrogencarbonate In tetrahydrofuran; 1,2-dimethoxyethane; water at 20℃; for 16h; | |
| With sodium hydrogencarbonate In tetrahydrofuran; water | ||
| With sodium hydrogencarbonate In 1,2-dimethoxyethane; water for 2h; | ||
| 4.83 g | With sodium hydrogencarbonate In tetrahydrofuran; 1,2-dimethoxyethane; water at 20℃; for 24h; | 4 Example 4. Synthesis of Fmoc-vc 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℃; | 1.1.2.b Step b: 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. | |
| With sodium hydrogencarbonate In 1,2-dimethoxyethane | 6-7 Example 6: Exemplary Synthesis of Peptide Linked Phosphorothioate Compounds Fmoc-protected valine as succinimide ester A was coupled with citrulline B in dimethoxyethane and sodium bicarbonate led to dipeptide C. This dipeptide was condensed with 4-aminobenzyl alcohol in the presence of EEDQ in DCM:MeOH (2:1) at r. t. for 36 h resulted in intermediate D. | |
| 0.75 g | With sodium hydrogencarbonate In tetrahydrofuran; 1,2-dimethoxyethane; water at 20℃; for 16h; | 3.1 Step 1: (2S)-2-[[ ( 2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methyl - butanoyl ] amino ]-5-ureido-pentanoic acid Fmoc-L-Val-OSu (CAS No. 130878-68-1; 1.59 g; 3.64 mmol; 1.0 eq.) was added at r.t. to a solution of L(+)-citrulline (0.67 g; 3.82 mmol; 1.05 eq.) and sodium bicarbonate (0.32 g; 3.82 mmol; 1.05 eq.) in a mixture of 1,2-dimethoxy ethane (9.5 mL), water (9.5 mL) and THF (4.7 mL). The reaction mixture was stirred at r.t. for 16 hours, then the solvents were removed under vacuum and the residue was acidified with a solution of hydrochloric acid IN until pH 1. The white suspension was filtered, washed with water (3 x 40 mL), diethyl ether (3 x 40 mL) and co-evaporated with acetonitrile (2 x 150 mL). The resulting white solid was purified by flash chromatography over silica gel using (DCM/acetic acid (99/1))/ methanol (10/0 to 7/3) as eluent, then triturated in diethyl ether (2 x 30 mL).The resulting solid was dissolved in a mixture of methanol (50 mL) and water (50 mL), concentrated to dryness, co-evaporated with acetonitrile (100 mL) and dried to afford the title compound (0.75 g; 1.5 mmol) as a white solid. NMK (M80): δ 0.84-0.88 (m, 6H), 1.34-1.41 (m, 2H), 1.51-1.73 (m, 2H), 1.95-2.04 (m, 1H), 2.91-2.96 (m, 2H), 3.88-3.92 (m, 1H), 4.06-4.11 (m, 1H), 4.19-4.31 (m, 3H), 5.36 (s, 2H), 5.91-5.94 (m, 1H), 7.30-7.34 (m, 2H), 7.39-7.45 (m, 3H), 7.75 (t, 2H, J = 7.3 Hz), 7.89 (d, 2H, J = 7.4 Hz), 8.02 (brs, 1H), 12.56 (brs, 1H) |
| 84 % | With sodium hydrogencarbonate In tetrahydrofuran; 1,2-dimethoxyethane; water | |
| 100 % | With sodium hydrogencarbonate In tetrahydrofuran; 1,2-dimethoxyethane; water | 2 19 To a solution of L-citrulline (2.63 g, 15.0 mmol) and NaHCO3(1.26 g, 15 mmol) dissolved in deionised water (28 mL) was added a solution of 18 (4.37 g, 10.0 mmol) in 1 ,2 - di methoxyethane (28 mL). THF (14 mL) was added to increase solubility. The reaction was then left to stir for 2 days. Upon completion of reaction, aqueous citric acid (15%, 50 mL) was added to the reaction mixture and the resulting mixture was extracted with 10% isopropyl alcohol in ethyl acetate (x3). The organic layer was washed with water once and collected. After the organic solvents have been removed, the remaining white solid was dried in vacuo for at least 5h. Diethyl ether was later added to the solid and the mixture was triturated and sonicated for 2 min. The white solid was then collected by filtration. (4.97 g, quantitative).1H NMR (400 MHz, DMSO-d6) 5 8.05 (s, 1 H), 7.89 (d, J = 7.5 Hz, 2H), 7.75 (t, J = 7.7 Hz, 2H), 5.92 (d, J = 5.8 Hz, 1 H), 5.36 (s, 2H), 4.31 - 4.18 (m, 3H), 4.07 (s, 1H), 3.89 (dd, J = 9.2, 6.8 Hz, 1 H), 2.93 (q, J = 7.0 Hz, 3H), 2.05 - 1.92 (m, 1H), 1.76 - 1.47 (m, 2H), 1.37 (t, J = 7.8 Hz, 2H), 0.86 (dd, J = 11.3, 6.7 Hz, 7H).ESI-MScalculated for C26H33N4O6 [M + H]+m/z 497.24, found 497.15 [M + H]+. |
| 61 % | With sodium hydrogencarbonate In tetrahydrofuran; 1,2-dimethoxyethane; water at 0 - 20℃; | 32.1 Step 1: Synthesis of Fmoc-Val-Cit-OH (241) L-citrulline (85 mg, 0.486 mmol) in DME (1.5 mL) was added to a solution of Fmoc-Val-OSu (202 mg, 0.463 mmol) and NaHCO3 (42.8 mg, 0.509 mmol) in H2O (3 mL) and THF (4 mL) at 0 °C. The reaction warmed to rt and stirred for 48 h. Upon completion, the reaction was adjusted to pH 10 with sat. aq. K2CO3 and washed with EtOAc (2 × 20 mL). The aqueous layer was acidified to pH 4 with 10% aq. citric acid and the formed gelatinous mixture was filtered and dried in vacuo to yield Fmoc-Val-Cit-OH 241 (141 mg, 0.284 mmol, 61%) as an off-white solid. 1H NMR (700 MHz, DMSO-d6) δ ppm: 7.89 (d, 2H, J = 7.6 Hz), 7.75 (dd, 2H, J = 11.7, 7.8 Hz), 7.41 (t, 2H, J = 7.4 Hz), 7.34-7.30 (m, 2H), 6.00 (s, 1H), 4.31-4.26 (m, 1H), 4.27-4.19 (m, 2H), 4.17-4.13 (m, 1H), 3.94-3.87 (m, 1H), 2.99-2.92 (m, 2H), 1.98 (app sx, 1H, J = 6.8 Hz), 1.74-1.66 (m, 1H), 1.61-1.53 (m, 1H), 1.46-1.35 (m, 2H), 0.89 (d, 3H, J = 6.8 Hz), 0.86 (d, 3H, J = 6.8 Hz). 13C NMR (176 MHz, DMSO-d6) δ ppm: 173.4, 171.3, 158.8, 156.1, 143.9, 143.9, 140.7, 127.7, 127.1, 125.4, 120.1, 65.7, 59.8, 51.9, 46.7, 38.8, 30.6, 28.4, 26.6, 19.2, 18.2. HRMS (ESI) m/z found [M+H]+ 497.2394, C26H33N4O6+ required 497.2395. |
| 4.97 g | With sodium hydrogencarbonate In tetrahydrofuran; 1,2-dimethoxyethane; water | 2 19 To a solution of L-citrulline (2.63 g, 15.0 mmol) and NaHCO3(1.26 g, 15 mmol) dissolved in deionised water (28 mL) was added a solution of 18 (4.37 g, 10.0 mmol) in 1 ,2 - di methoxyethane (28 mL). THF (14 mL) was added to increase solubility. The reaction was then left to stir for 2 days. Upon completion of reaction, aqueous citric acid (15%, 50 mL) was added to the reaction mixture and the resulting mixture was extracted with 10% isopropyl alcohol in ethyl acetate (x3). The organic layer was washed with water once and collected. After the organic solvents have been removed, the remaining white solid was dried in vacuo for at least 5h. Diethyl ether was later added to the solid and the mixture was triturated and sonicated for 2 min. The white solid was then collected by filtration. (4.97 g, quantitative).1H NMR (400 MHz, DMSO-d6) 5 8.05 (s, 1 H), 7.89 (d, J = 7.5 Hz, 2H), 7.75 (t, J = 7.7 Hz, 2H), 5.92 (d, J = 5.8 Hz, 1 H), 5.36 (s, 2H), 4.31 - 4.18 (m, 3H), 4.07 (s, 1H), 3.89 (dd, J = 9.2, 6.8 Hz, 1 H), 2.93 (q, J = 7.0 Hz, 3H), 2.05 - 1.92 (m, 1H), 1.76 - 1.47 (m, 2H), 1.37 (t, J = 7.8 Hz, 2H), 0.86 (dd, J = 11.3, 6.7 Hz, 7H).ESI-MScalculated for C26H33N4O6 [M + H]+m/z 497.24, found 497.15 [M + H]+. |
| 88 % | With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; Darkness; | |
| 80% | With sodium hydrogencarbonate In tetrahydrofuran; 1,2-dimethoxyethane; water at 0 - 20℃; | |
| 88 % | With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; Darkness; | (S)-2((S)-2((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)- 5-ureidopentanoic acid (33) To a solution of compound 32 (5 g, 11.46 mmol) and L-citrulline (2.1 g, 12 mmol) in dimethoxymethane (50 mL) and THF (25 mL) was added sodium bicarbonate (1 g, 12 mmol) in water (50 mL). The reaction was stirred at r.t and left in the dark. After 5 days, 20% citric acid(aq)was added to the mixture and pH adjusted to approximately 5. The solution was extracted with 10% isopropyl alcohol in EtOAc at equivalent volume three times. The organic layers were combned and washed with water another three times. The organic layer was then collected, dried over MgSO4, and evaporated to dryness in vacuo to give the crude product. Finally, the crude product was spread in ether and sonicated to yield compound 33 (5 g, 88%) as white solids.1H NMR (400 MHz, DMSO-d6) δ 0.85-0.9 (m, 6H), 1.39-1.41 (m, 2H), 1.51- 1.61 (m, 1H), 1.69-1.70 (m, 1H), 1.95-2.00 (m, 1H), 2.94 (m, 2H), 3.92 (t, J = 8.24 Hz, 1H), 4.12-4.17 (m, 1H), 4.21-4.31 (m, 3H), 5.37 (s, 2H), 5.94 (t, J = 4.44 Hz, 1H), 7.30-7.34 (m, 1H), 7.38-7.43 (m, 3H), 7.75 (t, J = 7.12 Hz, 2H), 7.89 (d, J = 7.48 Hz, 2H), 8.17 (d, J = 7.16 Hz, 2H), 12.55 (br, s, 1H) ppm;13C NMR (100 MHz, DMSO-d6) δ 18.2, 19.2, 26.6, 28.4, 30.6, 38.8, 46.7, 51.9, 59.8, 65.7, 120.1, 125.4, 127.1, 127.7, 140.7, 143.8, 143.9, 156.1, 158.7, 171.3, 173.4 ppm. HRMS (ESI TOF-MS) C26H32N4O6 [M+H]+: calc. 497.2395, found: 497.2404. |
| 87.5 % | With sodium hydrogencarbonate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water; N,N-dimethyl-formamide at 25℃; | 2.2 Step 2: Synthesis of INB Dissolve INA (35g, 0.08mmol) in 400mL DMF, add L-citrulline (30.9g, 0.177mol), sodium bicarbonate (18.5g, 0.221mol), then add 200mL water, and react at 25°C for 16 hours. TLC monitoring showed that DCM/MeOH=10/1, no raw materials remained, and the reaction was completed. Remove DMF by rotary evaporation, add 500 mL water and 50 g citric acid, beat for 1 hour, filter, and spin dry the solid. Slurry with 500 mL dichloromethane for 1 hour, filter with suction, and pull the solid to dryness with an oil pump to obtain 34.5 g (0.07 mmol, 87.5%) of the target product as a white solid. |
| 88 % | With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; Darkness; | (S)-2((S)-2((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)- 5-ureidopentanoic acid (33) To a solution of compound 32 (5 g, 11.46 mmol) and L-citrulline (2.1 g, 12 mmol) in dimethoxymethane (50 mL) and THF (25 mL) was added sodium bicarbonate (1 g, 12 mmol) in water (50 mL). The reaction was stirred at r.t and left in the dark. After 5 days, 20% citric acid(aq)was added to the mixture and pH adjusted to approximately 5. The solution was extracted with 10% isopropyl alcohol in EtOAc at equivalent volume three times. The organic layers were combned and washed with water another three times. The organic layer was then collected, dried over MgSO4, and evaporated to dryness in vacuo to give the crude product. Finally, the crude product was spread in ether and sonicated to yield compound 33 (5 g, 88%) as white solids.1H NMR (400 MHz, DMSO-d6) δ 0.85-0.9 (m, 6H), 1.39-1.41 (m, 2H), 1.51- 1.61 (m, 1H), 1.69-1.70 (m, 1H), 1.95-2.00 (m, 1H), 2.94 (m, 2H), 3.92 (t, J = 8.24 Hz, 1H), 4.12-4.17 (m, 1H), 4.21-4.31 (m, 3H), 5.37 (s, 2H), 5.94 (t, J = 4.44 Hz, 1H), 7.30-7.34 (m, 1H), 7.38-7.43 (m, 3H), 7.75 (t, J = 7.12 Hz, 2H), 7.89 (d, J = 7.48 Hz, 2H), 8.17 (d, J = 7.16 Hz, 2H), 12.55 (br, s, 1H) ppm;13C NMR (100 MHz, DMSO-d6) δ 18.2, 19.2, 26.6, 28.4, 30.6, 38.8, 46.7, 51.9, 59.8, 65.7, 120.1, 125.4, 127.1, 127.7, 140.7, 143.8, 143.9, 156.1, 158.7, 171.3, 173.4 ppm. HRMS (ESI TOF-MS) C26H32N4O6 [M+H]+: calc. 497.2395, found: 497.2404. |
| 80.1 % | With sodium hydrogencarbonate In tetrahydrofuran; water; N,N-dimethyl-formamide at 20℃; | |
| 61 % | With sodium hydrogencarbonate In tetrahydrofuran; water; N,N-dimethyl-formamide at 20℃; | 1 Fmoc-Val-Cit (3) : Fmoc-Val-OSu (2) (9.8 g, 22.5 mmol) was dissolved in DME (150 mL) at room temperature. Separately, sodium bicarbonate (2.1 g, 24.7 mmol) was dissolved in water (150 mL) at room temperature followed by the addition of L-citrulline (4.3 g, 24.7 mmol) to give a homogeneous clear solution. The L-citrulline solution prepared was then added to the Fmoc-Val-OSu solution, followed by the addition of THF (75 mL) . The reaction mixture was stirred at room temperature for 16 h. After reaction was completed, the mixture was acidified with 15%citric acid (200 mL) , then concentrated under vacuum. The mixture was suspended in water (500 mL) and the resulting mixture was stirred for 2 h followed by filtration and drying under vacuum. The dried solids were re-suspended in methyl tert-butyl ether (500 mL) and stirred for 12 h. The suspension was filtered and washed. The isolated solids were dried under vacuum to yield Fmoc-Val-Cit (3) (6.8 g, 61%) as white powder. HRMS (ESI) calcd for C 26H 33N 4O 6 [M+H] + 497.2400, found 497.2388. |
| 88 % | With sodium hydrogencarbonate In tetrahydrofuran; 1,2-dimethoxyethane; water at 20℃; Darkness; | (S)-2((S)-2((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)-5-ureidopentanoic acid (33) (S)-2((S)-2((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)-5-ureidopentanoic acid (33) To a solution of compound 32 (5 g, 11.46 mmol) and L-citrulline (2.1 g, 12 mmol) in dimethoxymethane (50 mL) and THF (25 mL) was added sodium bicarbonate (1 g, 12 mmol) in water (50 mL). The reaction was stirred at r.t and left in the dark. After 5 days, 20% citric acid(aq) was added to the mixture and pH adjusted to approximately 5. The solution was extracted with 10% isopropyl alcohol in EtOAc at equivalent volume three times. The organic layers were combined and washed with water another three times. The organic layer was then collected, dried over MgSO4, and evaporated to dryness in vacuo to give the crude product. Finally, the crude product was spread in ether and sonicated to yield compound 33 (5 g, 88%) as white solids. 1H NMR (400 MHz, DMSO-d6) δ 0.85-0.9 (m, 6H), 1.39-1.41 (m, 2H), 1.51-1.61 (m, 1H), 1.69-1.70 (m, 1H), 1.95-2.00 (m, 1H), 2.94 (m, 2H), 3.92 (t, J=8.24 Hz, 1H), 4.12-4.17 (m, 1H), 4.21-4.31 (m, 3H), 5.37 (s, 2H), 5.94 (t, J=4.44 Hz, 1H), 7.30-7.34 (m, 1H), 7.38-7.43 (m, 3H), 7.75 (t, J=7.12 Hz, 2H), 7.89 (d, J=7.48 Hz, 2H), 8.17 (d, J=7.16 Hz, 2H), 12.55 (br, s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 18.2, 19.2, 26.6, 28.4, 30.6, 38.8, 46.7, 51.9, 59.8, 65.7, 120.1, 125.4, 127.1, 127.7, 140.7, 143.8, 143.9, 156.1, 158.7, 171.3, 173.4 ppm. HRMS (ESI TOF-MS) C26H32N4O6 [M+H]+: calc. 497.2395, found: 497.2404. |
| 88 % | With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; | (S)-2((S) -2((((9H-Fu-9-yl)methoxy)carbonyl)amino)-3-Methylbutamido)-5-urea-valeranoic acid(33). .to contain compounds32(5 g, 11.46 mmol), dimethoxymethane (50 mL) containing L-citrulline (2.1 g, 12 mmol) and THF (25 mL) were added to an aqueous solution (50 mL) containing sodium bicarbonate (1 g, 12 mmol). The reactants are stirred at room temperature and placed in the dark. After 5 days, a 20% aqueous solution of citric acid was added to the mixture, and the pH was adjusted to about 5. The solution was extracted three times with the same volume of ethyl acetate containing 10% isopropanol. The organic is laminated and washed three more times with water. The organic layer is then collected, dried by magnesium sulfate, and evaporated in a vacuum until dry to obtain a crude product. Finally, the crude product was dispersed in ether and treated with ultrasonic shock to obtain a white solid compound33(5 g, yield 88%). |
| 61 % | With sodium hydrogencarbonate In 1,2-dimethoxyethane; water at 20℃; | |
| 61 % | With sodium hydrogencarbonate In tetrahydrofuran; 1,2-dimethoxyethane; water at 20℃; | |
| 88 % | With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; | (S)-2((S) -2((((9H-Fu-9-yl)methoxy)carbonyl)amino)-3-Methylbutamido)-5-urea-valeranoic acid(33). .to contain compounds32(5 g, 11.46 mmol), dimethoxymethane (50 mL) containing L-citrulline (2.1 g, 12 mmol) and THF (25 mL) were added to an aqueous solution (50 mL) containing sodium bicarbonate (1 g, 12 mmol). The reactants are stirred at room temperature and placed in the dark. After 5 days, a 20% aqueous solution of citric acid was added to the mixture, and the pH was adjusted to about 5. The solution was extracted three times with the same volume of ethyl acetate containing 10% isopropanol. The organic is laminated and washed three more times with water. The organic layer is then collected, dried by magnesium sulfate, and evaporated in a vacuum until dry to obtain a crude product. Finally, the crude product was dispersed in ether and treated with ultrasonic shock to obtain a white solid compound33(5 g, yield 88%). |
| 88 % | With sodium hydrogencarbonate In tetrahydrofuran; 1,2-dimethoxyethane; water at 20℃; Darkness; | (S)-2((S)-2((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)-5-ureidopentanoic acid (33) (S)-2((S)-2((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)-5-ureidopentanoic acid (33) To a solution of compound 32 (5 g, 11.46 mmol) and L-citrulline (2.1 g, 12 mmol) in dimethoxymethane (50 mL) and THF (25 mL) was added sodium bicarbonate (1 g, 12 mmol) in water (50 mL). The reaction was stirred at r.t and left in the dark. After 5 days, 20% citric acid(aq) was added to the mixture and pH adjusted to approximately 5. The solution was extracted with 10% isopropyl alcohol in EtOAc at equivalent volume three times. The organic layers were combined and washed with water another three times. The organic layer was then collected, dried over MgSO4, and evaporated to dryness in vacuo to give the crude product. Finally, the crude product was spread in ether and sonicated to yield compound 33 (5 g, 88%) as white solids. 1H NMR (400 MHz, DMSO-d6) δ 0.85-0.9 (m, 6H), 1.39-1.41 (m, 2H), 1.51-1.61 (m, 1H), 1.69-1.70 (m, 1H), 1.95-2.00 (m, 1H), 2.94 (m, 2H), 3.92 (t, J=8.24 Hz, 1H), 4.12-4.17 (m, 1H), 4.21-4.31 (m, 3H), 5.37 (s, 2H), 5.94 (t, J=4.44 Hz, 1H), 7.30-7.34 (m, 1H), 7.38-7.43 (m, 3H), 7.75 (t, J=7.12 Hz, 2H), 7.89 (d, J=7.48 Hz, 2H), 8.17 (d, J=7.16 Hz, 2H), 12.55 (br, s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 18.2, 19.2, 26.6, 28.4, 30.6, 38.8, 46.7, 51.9, 59.8, 65.7, 120.1, 125.4, 127.1, 127.7, 140.7, 143.8, 143.9, 156.1, 158.7, 171.3, 173.4 ppm. HRMS (ESI TOF-MS) C26H32N4O6 [M+H]+: calc. 497.2395, found: 497.2404. |
| 4.83 g | With sodium hydrogencarbonate In tetrahydrofuran; 1,2-dimethoxyethane at 20℃; for 24h; | 4 Example 4 Synthesis of Fmoc-vc Add Cit 4.0g (1.05eq) and sodium bicarbonate aqueous solution 60ml (NaHCO3 2g, 1.05eq) to 20ml THF. Take another 22.35mmol Fmoc-Val-OSu and dissolve it in 60ml DME, then add it to the reaction solution. Stir the reaction solution at room temperature for 24 hours. After the reaction is completed, add 110ml of 15% citric acid aqueous solution to the system, then extract twice with EA, combine the organic layers, and concentrate under reduced pressure to obtain a white solid. Add 100ml of methyl tert-butyl ether to the white solid, stir and wash, filter, and dry the filter cake at 40 under reduced pressure for 4h to obtain 4.83g of the product, with a yield of 65%. |
| With sodium hydrogencarbonate In tetrahydrofuran; 1,2-dimethoxyethane; water at 20℃; | 1.2 2. Synthesis of Fmoc-VC The product of step 1 (7g) was dissolved in 90mL DME, i.e., system 1. L-Cit (2.8g) was dissolved in 90mL water containing NaHCO3(1.3g), i.e., system 2. System 2 was added to system 1, and then 50mL THF was added, and the reaction was stirred at room temperature overnight untilclarity. After the reaction was completed, 50mL 15g/100mL citric acid aqueous solution was added to the ice bath, and after the white solid was completely precipitated, it was filtered with a Buchner funnel until the filtrate was clear, and the filter cake was dried and placed in a vacuum drying oven for drying. After drying, the white solid was ground, washed with ether, filtered, and then the solvent was naturally evaporated to obtain a white solid, i.e., the product. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1: sodium hydrogencarbonate / water; acetone / 18 h 2: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / methanol; dichloromethane / 20 °C 3: diethylamine / dichloromethane; acetonitrile / 17 h / 0 - 20 °C | ||
| Multi-step reaction with 3 steps 1: sodium hydrogencarbonate / tetrahydrofuran / 48 h / 20 °C 2: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 24 h / 20 °C 3: diethylamine / N,N-dimethyl-formamide / 2 h / 20 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 6 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran 2: trifluoroacetic acid / dichloromethane 3: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / tetrahydrofuran 4: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 4 h / 20 °C 5: N-ethyl-N,N-diisopropylamine; 1-hydroxy-7-aza-benzotriazole / N,N-dimethyl-formamide / 18 h / 20 °C 6: piperidine / N,N-dimethyl-formamide / 1 h / 20 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 65% | With sodium hydrogencarbonate In tetrahydrofuran; 1,2-dimethoxyethane; water at 20℃; for 24h; | 4 Example 4.Synthesis of Fmoc-vc Add in 20ml THFCit4.0g(1.05 eq) and 60 ml aqueous solution of sodium bicarbonate (NaHCO3 2g,1.05eq).Another 22.35mmol Fmoc-Val-OSu dissolved in 60ml DME,Then add it to the reaction solution.Reaction solution in the roomThe reaction was stirred at the temperature for 24 hours.After the reaction is completed,Add 15% citric acid aqueous solution to the system, 110mlThen use EA extractionTake twice,Combine organic layers,Concentrate under reduced pressure to give a white solid.Add 100 ml methyl tert-butyl ether to white solidwash,filter,The filter cake was dried under reduced pressure at 40°C for 4 hours to obtain 4.83 g of product.Yield 65%. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 65% | With sodium hydrogencarbonate In tetrahydrofuran; 1,2-dimethoxyethane; water at 20℃; for 24h; | 4 Example 4 Synthesis of Fmoc-vc Add Cit 4.0g (1.05 eq) to 20 ml of THFwith an 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 completion of the reaction, 110 ml of a 15% aqueous citric acid solution was added to the mixture, and then extracted twice with EA.And 100 ml of methyl tert-butyl ether was added to the white solid and stirred.After filtration, the cake was dried under reduced pressure at 40 ° C for 4 h to obtain 4.83 g of product, yield 65%. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1.1: N,N-dimethyl-formamide / Inert atmosphere 2.1: diethylamine / N,N-dimethyl-formamide / 2 h / Inert atmosphere 2.2: Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 6 steps 1.1: Sodium hydrogenocarbonate / tetrahydrofuran; 1,2-dimethoxyethane; lithium hydroxide monohydrate / 16 h / 20 °C 2.1: dicyclohexyl-carbodiimide; benzotriazol-1-ol / ethyl acetate / 0.5 h / 0 °C 2.2: 2 h / 0 - 20 °C 3.1: piperidine / N,N-dimethyl-formamide / 1 h / 20 °C 4.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 20 °C 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16 h / 20 °C 6.1: benzotriazol-1-ol; pyridine / dimethyl sulfoxide / 16 h / 20 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 28% | Stage #1: methyl (2S)-2-amino-3-methylbutanoate hydrochloride; (S)-2,5-dioxopyrrolidin-1-yl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanoate With triethylamine In isopropanol at 50℃; for 1h; Stage #2: In isopropanol at 120℃; for 32h; Sealed tube; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 5 steps 1: N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; Sodium hydrogenocarbonate / N,N-dimethyl-formamide; lithium hydroxide monohydrate / 16 h / 25 °C 2: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / methanol; dichloromethane / 16 h / 20 °C 3: dichloromethane / 12 h / 0 - 25 °C / Inert atmosphere; Molecular sieve 4: N-ethylethanamine / N,N-dimethyl-formamide / 2 h / 0 °C / Inert atmosphere 5: 1,1,1,3',3',3'-hexafluoro-propanol / N-ethylethanamine / 2 h / 0 - 45 °C / Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1: sodium hydrogencarbonate / tetrahydrofuran; 1,2-dimethoxyethane; water / 2 d 2: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 2 d / 20 °C / Darkness 3: diethylamine / N,N-dimethyl-formamide / 20 °C | ||
| Multi-step reaction with 4 steps 1.1: sodium hydrogencarbonate / tetrahydrofuran; 1,2-dimethoxyethane; water / 2 d 2.1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 2 d / 20 °C / Darkness 3.1: piperidine / N,N-dimethyl-formamide 4.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 10 min / 20 °C / Inert atmosphere 4.2: 20 °C / Inert atmosphere | ||
| Multi-step reaction with 4 steps 1.1: sodium hydrogencarbonate / tetrahydrofuran; 1,2-dimethoxyethane; water / 2 d 2.1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 2 d / 20 °C / Darkness 3.1: piperidine / N,N-dimethyl-formamide / 1 h 4.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 10 min / 20 °C / Inert atmosphere 4.2: 20 °C / Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 4 steps 1: sodium hydrogencarbonate / tetrahydrofuran; water; 1,2-dimethoxyethane / 48 h / 0 - 20 °C 2: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 22 h / 20 °C / Inert atmosphere 3: diethylamine / N,N-dimethyl-formamide / 19 h / 20 °C / Inert atmosphere 4: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / 20 °C / Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 5 steps 1.1: sodium hydrogencarbonate / tetrahydrofuran; 1,2-dimethoxyethane / 24 h / 20 °C 2.1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 48 h / 20 °C / Darkness 3.1: diethylamine / tetrahydrofuran; 1-methyl-pyrrolidin-2-one / 24 h / 20 °C 4.1: 1-methyl-pyrrolidin-2-one / 24 h / 20 °C 5.1: dmap / dichloromethane / 12 h / 0 °C 5.2: 24 h / 20 °C |