| 89% |
With dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 3h; |
Dicyclocarbodiimide (1 .55 g, 7.52 mmol) and N-hydroxysuccinimide (762 mg, 6.63 mmol) are added at room temperature to a stirrer solution of Fmoc-Val-OH [9] (1 .5 g, 4.42 mmol) in anhydrous dichloromethane (25 ml_). The mixture is kept at room temperature for 3 hours. The white solid formed in this reaction is filtrated with dichloromethane to remove the dicyclohexylurea, the organic phase is washed with HCI 0.1 N and water, then dried over anhydrous sodium sulfate and the solvent removed by rotatory evaporation. The residue is subjected to a flash column chromatography in 1 % methanol in dichloromethane to afford product [10] as a white solid, 1 .7 g (89% yield). MS: m/z 459 [M+Na]+.1H NMR (400 MHz, CDCIs) delta 7.80 (d, J = 7.5 Hz, 2H), 7.68 - 7.55 (m, 2H), 7.43 (t, J = 7.4 Hz, 2H), 7.34 (dd, J = 15.9, 8.5 Hz, 2H), 4.70 (d, J = 4.6 Hz, 1 H), 4.56 - 4.40 (m, 3H), 4.28 (t, J = 6.6 Hz, 1 H), 2.85 (s, 4H), 2.37 (dd, J = 12.3, 6.5 Hz, 1 H), 1 .08 (dd, J = 1 1 .0, 6.9 Hz, 6H). |
| 85% |
With dicyclohexyl-carbodiimide; In tetrahydrofuran; at 0 - 20℃; for 15h; |
Taking Fmoc - L - valine (20 g), HoSu (7.46 g, 1.1 eq), for 200 ml of THF after it is dissolved, the reaction bottle is placed in the [...] dropped to 0 C, slowly adding a condensing agent DCC (14.6 g, 1.1 eq), controlling the reaction temperature at 0 - 5 C, 3 hours canada finishes. Out of the ice bath, stirring at the room temperature reaction 12 h. TLC detection Fmoc - L - valine reaction is complete, to stop the reaction. The decompression, and 100 ml of washing the filter cake THF, filtrate turns on lathe does, and then the residue is added in 100 ml of stirring to dissolve in DCM (35 C under stirring to dissolve), a little insoluble organic membrane filter, then is placed on the 35 C pot oil bath, stirring by adding 100 ml of petroleum ether, natural cooling crystallization 1 hour, and then place it in the ice salt bath cooling crystallization 2 hours, filtering, and washing the solid with petroleum ether, the solid is 40 C of drying in the vacuum drying box shall be 21.86 g of white powdery solid, the yield is about 85%. |
| 65% |
With dicyclohexyl-carbodiimide; In 1,2-dimethoxyethane; at 20℃; for 23h;Cooling with ice; Inert atmosphere; |
Fmoc-Valine (1.02 g, 3 mmol) and N-hydroxysuccinimide (0.345 g, 3 mmol) were dissolved in dimethoxy ethane (35 ml) and cooled in an ice bath, then DCC (0.681 g, 3.3 mmol) was added. The resulting mixture was stirred in the ice bath for 3 hours, then at room temperature for 20 hours. The precipitate formed was filtered off and the filtrate concentrated under vacuo. The crude product was further purified by flash chromatography (ethyl acetate/hexane, v:v, 4:6) to afford SI20B as a white solid. Isolated yield: 65%. TLC (EtOAc:Hexane 3:2). Rf=0.57, irradiated by a UV lamp. HPLC: 0.1% TFA (v/v) in water (solvent A):acetonitrile (solvent B); gradient 45-85% in 30 min, flow rate=0.5 mL/min. Retention time (Rt)=15.77 min. 1H NMR (FIG. 26A): (400 MHz, CDCl3) delta 7.76-7.78 (d, J=7.20 Hz, 2H), 7.59-7.60 (d, J=7.20 Hz, 2H), 7.38-7.42 (t, J=7.20 Hz, 2H), 7.30-7.34 (m, 2H), 5.26-5.28 (d, J=9.20 Hz, 1H), 4.67-4.71 (dd, J=4.8, 5.2 Hz, 1H), 4.42-4.46 (dd, J=6.8, 6.4 Hz, 2H), 4.23-4.26 (t, J=6.8 Hz, 1H), 2.84 (s, 4H), 2.04-2.36 (m, 1H), 0.83-088 (m, 6H). 13C NMR (FIG. 26B): (101 MHz, CDCl3) delta 168.7, 141.5, 127.9, 127.3, 127.3, 125.3, 120.2, 120.2, 67.5, 57.7, 47.4, 31.9, 25.8, 18.9, 17.5. |
|
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 15.5h; |
Preparation of PEG-A -2 To a stirred solution of PEG-A-i (30 g, 93 mmol) and EDCI (36.52 g, 138 mmol) at 0C in DCM, HOSu (12.72 g, 111.7 mmol) was added. The mixture wasstirred in ice bath for 30 mills. Then the solution was allowed to warm up to r.t. and stirred for 15 lirs. The mixture was washed with 1120, iN aq. HC1 and sat. NaHCO3, then dried over Na2SO4, the solvent was evaporated to give 36.5 g crude PEG-A-2. |
|
With dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 16.5h; |
For Fmoc-Val-NHS, DCC (227 mg, 1.1 mmol) was added to an ice cold solution of Fmoc-Val-OH (339 mg, 1 mmol) and NHS (127 mg, 1.1 mmol) in DCM (13 ml), stirred for 30 mm, and then at 20 C for 16 h. The solid DCU was filtered off and the solvent was removed in vacuo. |
|
With dicyclohexyl-carbodiimide; In tetrahydrofuran; at 0 - 20℃; for 6h;Inert atmosphere; |
This compound is prepared according to R. A. Firestone et al, US 6,214,345. Fmoc-Val-OH (20.24 g; 59.64 mmol) and N-hydroxysuccinimide (6.86 g = 1.0 eq.) in tetrahydrofuran (200 ml) at 0C were treated with Nu,Nu'- dicyclohexylcarbodiimide (12.30 g; 1.0 eq.). The mixture was stirred at RT under argon atmosphere for 6 h and then the solid dicyclohexyl urea (DCU) by-product was filtered off and washed with THF and the solvent was removed by rotavap. The residue was dissolved in 300 ml dichloromethane, cooled in an ice bath for 1 h and filtered again to remove additional DCU. The dichloromethane was evaporated and the solid foam (26.51 g) was used in the next step without further purification. |
|
With dicyclohexyl-carbodiimide; In tetrahydrofuran; acetonitrile; at 0 - 20℃; for 24h; |
Fmoc-Val 10 g and HOSu 3.4 g were added to 100 ml of THF. Another DCC6g dissolved in 50ml acetonitrile, keepThe internal temperature is about 0C, and it is slowly dropped into the reaction solution. The reaction was stirred at room temperature for 24 hours. Filtration, filter cake with THFWash and concentrate the filtrate under reduced pressure to give a clear oil. The oil was directly transferred to the next reaction without purification |
| 26.51 g |
With dicyclohexyl-carbodiimide; In tetrahydrofuran; at 0 - 20℃; for 6h;Inert atmosphere; |
[00125] This compound is prepared according to R. A. Firestone et al, US 6,214,345. Fmoc-Val-OH (20.24 g; 59.64 mmol) and N-hydroxysuccinimide (6.86 g =1 .0 eq.) in tetrahydrofuran (200 ml) at 000 were treated with N,N?dicyclohexylcarbodiimide (12.30 g; 1.0 eq.). The mixture was stirred at RT under argon atmosphere for 6 h and then the solid dicyclohexyl urea (DCU) by-product was filtered off and washed with THF and the solvent was removed by rotavap. The residue was dissolved in 300 ml dichloromethane, cooled in an ice bath for 1 h and filtered again to remove additional DCU. The dichloromethane was evaporated and the solid foam (26.51 g) was used in the next step without further purification. |
|
With dicyclohexyl-carbodiimide; In tetrahydrofuran; acetonitrile; at 0 - 20℃; for 24h; |
Fmoc-Val 10g and HOSu 3.4g were added to 100 ml of THF.Another DCC6g dissolved in 50ml acetonitrile, keepThe internal temperature was about 0 C, and it was slowly dropped into the reaction liquid. The reaction solution was stirred at room temperature for 24 hours. Filtration, filter cake with THFAfter washing, the filtrate was concentrated under reduced pressure to give a transparent oil.The oil was directly subjected to the next reaction without purification. |
|
With dicyclohexyl-carbodiimide; In tetrahydrofuran; acetonitrile; at 0 - 20℃; for 24h; |
Fmoc-Val 10g and HOSu 3.4g were added to 100 ml of THF. Another DCC 6g was dissolved in 50 ml of acetonitrile. Keep the internal temperature at around 0 C, It was slowly dropped into the reaction liquid. The reaction solution was stirred at room temperature for 24 hours. Filtered, the filter cake was washed with THF. The filtrate was concentrated under reduced pressure to give a transparent oil. The oil was directly subjected to the next reaction without purification. m/z: 437.4 [M+H] +. |
|
With dicyclohexyl-carbodiimide; In tetrahydrofuran; at 0 - 20℃; |
The reaction product Fmoc-L-Val-OH (10 g, 29.3 mmol) and HoSu(3.7 g, 32.3 mmol) was dissolved in 100 mL of THF. DCC (6.6 g, 32.3 mmol) was added to the ice bath.The mixture was stirred at room temperature overnight. After the reaction is completed, the reaction solution is transferred to an ice bath, and after the solid is completely precipitated, it is filtered by suction.The filtrate is spun dry and spun into a foam. The reaction product was pure and did not require further purification. |
|
With dicyclohexyl-carbodiimide; In tetrahydrofuran; at 0℃; for 24h; |
1.1) Fmoc-Val (5g, 14.73mmol), HOSu (1.70g, 14.73mmol) and DCC (3.04g, 14.73mmol) were co-dissolved in tetrahydrofuran (50mL) at 0 C,After stirring for 24 hours, it was filtered and rotary evaporated under reduced pressure to obtain a white solid product.Fmoc-Val-OSu,No further purification was required for the next reaction. |
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